WO2019149228A1 - 取代咪唑甲酸酯类衍生物及其用途 - Google Patents

取代咪唑甲酸酯类衍生物及其用途 Download PDF

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WO2019149228A1
WO2019149228A1 PCT/CN2019/074002 CN2019074002W WO2019149228A1 WO 2019149228 A1 WO2019149228 A1 WO 2019149228A1 CN 2019074002 W CN2019074002 W CN 2019074002W WO 2019149228 A1 WO2019149228 A1 WO 2019149228A1
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PCT/CN2019/074002
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马海军
王昌华
解振彪
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成都安诺晨创医药科技有限公司
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Priority to EP19747964.5A priority Critical patent/EP3747869A4/en
Priority to JP2020542264A priority patent/JP7215758B2/ja
Priority to US16/966,380 priority patent/US11434205B2/en
Publication of WO2019149228A1 publication Critical patent/WO2019149228A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00Anaesthetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4151,2-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/08Antiepileptics; Anticonvulsants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/20Hypnotics; Sedatives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a novel substituted imidazole formate derivative, and the application of the compound in preparing a medicament having sedative, hypnotic and/or anesthetic effects and preparing a medicament capable of controlling epilepticus. .
  • An imidazole derivative etomidate is a hypnotic intravenous general anesthetic It has a wide range of safety and was once one of the commonly used drugs for induction of anesthesia.
  • the imidazole derivative has been used clinically for 30 years (Br J Anaesth. 1976; 48(3): 213-6. PubMed: 1259887; Arch Int Pharmacodyn Ther. 1975; 214(1): 92-132. PubMed : 1156027; Acad Emerg Med. 2006; 13(4): 378-83. PubMed: 16531603).
  • Etomidate is a non-barbital intravenous sedative with a strength of 4 times that of barbital sodium and 12 times that of thiopental, and the induction of general anesthesia is fast, and the recovery and recovery after administration are fast. After the patient wakes up, there is no more lethargy, dizziness and other adverse reactions, and there is a certain anti-vomiting effect, so it has been widely used. Its structural formula is shown in the figure below, the molecular formula C14H16N2O2, molecular weight 244.29. The imidazole derivative is insoluble in water and unstable in a neutral solution.
  • the treatment window is relatively large and the inhibition of the circulatory system is relatively small, and this feature is especially suitable for the elderly, coronary heart disease, hypertensive patients, and critically ill patients. It was once a standard drug for anesthesia induction and was also used as a drug for total intravenous anesthesia.
  • etomidate the main product of etomidate metabolism, etomidate, was found to have little effect of inhibiting 11-beta hydroxylase compared to etomidate (Anesthesiology. 2016; 125(5): 943-951. PubMed: 27541316) . If the modification of the structure of etomidate reduces or eliminates the inhibition of adrenal function by the compound itself and does not affect the adrenal function of the compound, it can reduce or eliminate the inhibitory effect of the drug on adrenal function. . Subsequent studies based on the structure of etomidate focused on how to reduce or not inhibit the function of the adrenal cortex, in addition to the advantages of retaining the clinical application of etomidate.
  • WO 2009/146024 A1 discloses an etomidate analog having improved pharmacokinetic properties and pharmacodynamic properties and its use as an anesthetic, and discloses that the compound may be MOC-(R)-etomidate.
  • WO 2011/005969 A2 discloses an etomidate analog having improved pharmacokinetic properties and pharmacodynamic properties and its use as an anesthetic, and discloses that the compound may be MOC-carbon etomidate.
  • CN201380014062 discloses an analog of metoprolol and etomidate which has improved pharmacokinetic and pharmacodynamic properties, and discloses that the compound may be cyclopropyl MOC-menitolimidate.
  • DMMM dimethylmethoxycarbonyl metomidate
  • CPMM cyclopropyl methoxycarbonyl metomidate
  • the present invention provides a novel substituted imidazole formate derivative.
  • the present invention also provides the central nervous system inhibitory effect of the substituted imidazole formate derivative, and provides the use of the substituted imidazole formate derivative in the preparation of a medicament having sedative, hypnotic and/or anesthetic effects, and The use in the preparation of a medicament capable of controlling the status of epileptic seizures.
  • the present invention provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a deuterated derivative thereof :
  • X is selected from O, S or NR 30 , wherein R 30 is selected from hydrogen, deuterium or C 1-8 alkyl;
  • Y is N
  • R 1 is each independently selected from the group consisting of hydrazine, halogen, -CN, -NO 2 , -OR 32 , -C(O)R 32 , -CO 2 R 32 , -CON(R 32 ) 2 , -N(R 32 ) 2 , -OC(O)R 32 , -SO 2 R 32 , substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted C 1-8 alkyl group, substituted or unsubstituted C 2-8 Alkenyl, substituted or unsubstituted C 2-8 alkynyl;
  • R 32 are each independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 alkynyl, substituted Or an unsubstituted C 3-8 cycloalkyl group, a substituted or unsubstituted 3-8 membered heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group; the substituent is hydrazine or cyanide a base, a hydroxyl group, a carboxyl group, a halogen, a C 3-8 cycloalkyl group or a halogenated or halogenated product thereof, a 3 to 8 membered heterocyclic group or a halogenated or halogenated product thereof, an aryl group or a halogenated or halogenated product thereof, or a hetero
  • n is an integer from 0 to 5;
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-8 alkyl or halogen or deuterated thereof, C 1-8 alkoxy or halogenated or halogenated thereof, C 2-8 alkenyl or halogenated or a progeny, a C 2-8 alkynyl group or a halogenated or halogenated product thereof, a 3 to 8 membered heterocyclic group or a halogenated or halogenated product thereof;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-8 alkyl; the substituent is deuterium, halogen, C 1-8 alkyl or halogen or deuterated thereof, a C 1-8 alkoxy group or a halogenated or halogenated product thereof, a C 3-8 cycloalkyl group or a halogenated or halogenated product thereof, a 3 to 8 membered heterocyclic group or a halogenated or halogenated product thereof, an aryl group or a halogen thereof Substituted or progeny, heteroaryl or its halogenated or halogenated;
  • L 1 and L 2 are each independently selected from a C 1-8 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a cyano group, a hydroxyl group, a carboxyl group, a halogen, a C 1-8 alkyl group or a halogen thereof a substituted or deuterated compound, a C 1-8 alkoxy group or a halogenated or halogenated product thereof, a C 3-8 cycloalkyl group or a halogenated or halogenated product thereof, a 3-8 membered heterocyclic group or a halogenated or halogenated thereof, An aryl group or a halogenated or halogenated product thereof, a heteroaryl group or a halogenated or halogenated product thereof;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, cyano, allenyl, isocyano, isothiocyanato, Substituted or unsubstituted C 1-8 alkyl, -OR 33 , -SR 33 , -OC(O)R 33 , C 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, aryl group, heteroaryl a group, -N(R 33 ) 2 ; or, R 5 is selected from -C(O)R 33 , -C(S)R 33 , -S(O)R 33 , -CON(R 33 ) 2 , -SO 2 R 33 ; or R 5 is selected from a substituted or unsubstituted C 2-8 alkenyl group, a substituted or unsubstituted C 2-8 alkynyl group;
  • R 33 is each independently selected from hydrogen, hydrazine, methylsulfonyl, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2 - 8 alkynyl, -L 31 -COO-L 32 , substituted or unsubstituted C 3-8 membered cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group, substituted or unsubstituted aryl group, substituted or Unsubstituted heteroaryl, -SC 1-8 alkyl;
  • L 31 is selected from substituted or unsubstituted C 1-8 alkylene;
  • L 32 is selected from substituted or unsubstituted C 1-8 alkyl;
  • R 5 and R 33 are an anthracene, a cyano group, a hydroxyl group, a carboxyl group, a halogen, a C 1-4 alkyl group or a halogenated or halogenated product thereof, a C 1-4 alkoxy group or a halogenated group thereof.
  • the ring A is not, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring substituted by 0 to 4 R 34 , a 3 to 6-membered unsaturated carbocyclic ring, a 3 to 6-membered saturated heterocyclic ring or 3 to 6 yuan.
  • Saturated heterocycle
  • L 33 is selected from C 1-4 alkylene
  • R 36 is selected from the group consisting of cyano, nitro, -OC(O)R 35 , -C(O)R 35 , -S(O)R 35 , -C(O)N(R 35 ) 2 ;
  • R 35 are each independently selected from C 1-4 alkyl or a halo or deuterated thereof;
  • R 37 is selected from the group consisting of O, S, N(R 38 ), C(R 38 ) 2 ;
  • R 38 is selected from H or C 1-4 alkyl;
  • L 1 and L 2 are each independently selected from a C 1-8 alkylene group which is unsubstituted, substituted or unsubstituted, which is a C 1-8 alkyl group or a halogen;
  • R 5 is C (O) R 41 or S(O)R;
  • R 41 is a C 1-3 alkyl group or a halogenated or halogenated product thereof;
  • R 5 is not hydrogen or ethoxy; if L 1 is absent, L 2 is methylene. , R 5 is not a methoxy group; if L 1 is a methylene group and L 2 is a no or methylene group, then R 5 is not a methoxy group;
  • ring A is a 4- to 6-membered saturated heterocyclic ring substituted by 0 R 34 , if L 2 is absent, R 5 is not H; if R 5 is H, then L 2 is not absent;
  • R 2 is methyl
  • Y is N
  • R 3 and R 4 are hydrogen
  • X is O
  • L 1 is methylene
  • a ring is none
  • L 2 is absent
  • R 5 is not ethylene.
  • Base ethynyl or propenyl.
  • Y is N
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-8 alkyl; the substituent is deuterium, halogen, C 1-8 alkyl or halogen or deuterated thereof, a C 1-8 alkoxy group or a halogenated or halogenated product thereof, a C 3-8 cycloalkyl group or a halogenated or halogenated product thereof, a 3 to 8 membered heterocyclic group or a halogenated or halogenated product thereof, an aryl group or a halogen thereof Substituted or progeny, heteroaryl or its halogenated or halogenated;
  • X is selected from O or S;
  • R 1 are each independently selected from the group consisting of hydrazine, halogen, -CN, -NO 2 , -OR 32 , -C(O)R 32 , -CO 2 R 32 , -CON(R 32 ) 2 , -N(R 32 ) 2 , -OC(O)R 32 , C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl;
  • R 32 are each independently selected from the group consisting of hydrogen, deuterium, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl;
  • n is an integer from 0 to 2;
  • R 2 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl or a halogenated or halogenated product thereof.
  • Y is N
  • X is selected from O or S
  • R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, cyano, allenyl, isocyano, isothiocyanato, Substituted or unsubstituted C 1-8 alkyl, -OR 33 , -SR 33 , -OC(O)R 33 , C 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, aryl group, heteroaryl a group, -N(R 33 ) 2 ; or, R 5 is selected from -C(O)R 33 , -C(S)R 33 , -S(O)R 33 , -CON(R 33 ) 2 , -SO 2 R 33 ; or R 5 is selected from a substituted or unsubstituted C 2-8 alkenyl group, a substituted or unsubstituted C 2-8 alkynyl group; wherein R 33 is each independently selected from the group consisting of hydrogen, hydrazine
  • R 5 and R 33 are an anthracene, a cyano group, a hydroxyl group, a carboxyl group, a halogen, a C 1-4 alkyl group or a halogenated or halogenated product thereof, a C 1-4 alkoxy group or a halogenated group thereof.
  • the ring A is not, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring substituted with 0 to 4 R 34 , a 3 to 6-membered unsaturated carbocyclic ring, a 3 to 6-membered saturated heterocyclic ring or 3 to 6 yuan.
  • Saturated heterocycle
  • L 33 is selected from C 1-4 alkylene
  • R 36 is selected from the group consisting of cyano, nitro, -OC(O)R 35 , -C(O)R 35 , -S(O)R 35 , -C(O)N(R 35 ) 2 ;
  • R 35 are each independently selected from C 1-4 alkyl or a halo or deuterated thereof;
  • R 37 is selected from O, S, N(R 38 ); and R 38 is selected from H or C 1-4 alkyl.
  • Y is N
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-4 alkyl; the substituent is deuterium, halogen, C 1-4 alkyl or halogenated or halogenated thereof a C 1-4 alkoxy group or a halogenated or halogenated product thereof, a C 3-6 cycloalkyl group or a halogenated or halogenated product thereof, a 3 to 6 membered heterocyclic group or a halogenated or halogenated product thereof;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, allenyl, cyano, isocyano, isothiocyanato, Substituted or unsubstituted C 1-8 alkyl, -OR 33 , -SR 33 , -OC(O)R 33 , C 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, aryl group, heteroaryl a group, -N(R 33 ) 2 ; or, R 5 is selected from -C(O)R 33 , -C(S)R 33 , -S(O)R 33 , -CON(R 33 ) 2 , -SO 2 R 33 ; or R 5 is selected from a substituted or unsubstituted C 2-8 alkenyl group, a substituted or unsubstituted C 2-8 alkynyl group;
  • R 33 is each independently selected from hydrogen, hydrazine, methylsulfonyl, substituted or unsubstituted C 1-4 alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2 - 4 alkynyl group, C 3-8 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, heteroaryl;
  • R 5 and R 33 are an anthracene, a cyano group, a hydroxyl group, a carboxyl group, a halogen, a C 1-4 alkyl group or a halogenated or halogenated product thereof, a C 1-4 alkoxy group or a halogenated group thereof.
  • Deuterated compound, C 3-6 membered cycloalkyl, 3 to 6 membered heterocyclic group, aryl, heteroaryl, -SC 1-4 alkyl, R 39 , substituted or unsubstituted C 2-4 alkenyl Or a C 2-4 alkynyl group; wherein R 39 is selected from O, S, NR 40 or C(R 40 ) 2 , and R 40 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl or halo or hydrazine thereof a substitute, the substituent on the C 2-4 alkenyl or C 2-4 alkynyl group is selected from the group consisting of hydrazine, cyano, hydroxy, carboxy, halogen, C 1-4 alkyl; or, L 1 and L 2 are each independently Is selected from a C 1-4 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene
  • ring A is none, or ring A is selected from a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered unsaturated carbocyclic ring, a 3- to 6-membered saturated carbon ring, or a 3 to 6-membered saturated carbon ring substituted by 0 to 4 R 34 .
  • R 37 is selected from O or S.
  • Y is N
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, substituted or unsubstituted C 1-2 alkyl; the substituent is deuterium, halogen, C 1-2 alkyl or halogenated or halogenated thereof , C 1-2 alkoxy or a halogenated or halogenated product thereof;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, allenyl, cyano, isocyano, isothiocyanato, Substituted or unsubstituted C 1-8 alkyl, -OR 33 , -SR 33 , -OC(O)R 33 , C 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, aryl group, heteroaryl a group, -N(R 33 ) 2 ; or, R 5 is selected from -C(O)R 33 , -C(S)R 33 , -S(O)R 33 , -CON(R 33 ) 2 , -SO 2 R 33 ; or R 5 is selected from a substituted or unsubstituted C 2-8 alkenyl group, a substituted or unsubstituted C 2-8 alkynyl group;
  • R 33 is each independently selected from the group consisting of hydrogen, deuterium, methylsulfonyl, substituted or unsubstituted C 1-2 alkyl, C 3-6 membered cycloalkyl, 3 to 6 membered heterocyclic, aryl, Heteroaryl
  • R 5 and R 33 are an anthracene, a halogen, a cyano group, a hydroxyl group, a C 1-3 alkyl group or a halogenated or halogenated product thereof, a C 1-3 alkoxy group or a halogenated or halogenated substance thereof.
  • C 3-6 membered cycloalkyl, 3 to 6 membered heterocyclic group, aryl, heteroaryl, -SC 1-2 alkyl, R 39 , substituted or unsubstituted C 2-4 alkenyl or C a 2-4 alkynyl group; wherein R 39 is selected from O, S, NR 40 or C(R 40 ) 2 , and R 40 is selected from the group consisting of hydrogen, deuterium, halogen, C 1-3 alkyl or a halogenated or halogenated thereof,
  • the substituent on the C 2-4 alkenyl group or the C 2-4 alkynyl group is selected from the group consisting of an anthracene, a cyano group, a hydroxyl group, a carboxyl group, a halogen, and a C 1-3 alkyl group;
  • L 1 and L 2 are each independently selected from a C 1-3 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a halogen, a C 1-3 alkyl group or a halogenated or halogenated thereof, a C 1-3 alkoxy group or a halogenated or halogenated product thereof;
  • the ring A is none, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered unsaturated heterocyclic ring or a 3- to 6-membered saturated heterocyclic ring substituted with 0 to 3 R 34 ;
  • R 37 is selected from O or S.
  • Y is N
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, halogenated or unhalogenated methyl;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, halogen, allenyl, cyano, isocyano, isothiocyanato, Substituted or unsubstituted C 1-8 alkyl, -OR 33 , -SR 33 , -OC(O)R 33 , C 3-8 membered cycloalkyl, 3-8 membered heterocyclic group, aryl group, heteroaryl a group, -N(R 33 ) 2 ; or, R 5 is selected from -C(O)R 33 , -C(S)R 33 , -S(O)R 33 , -CON(R 33 ) 2 , -SO 2 R 33 ; or R 5 is selected from a substituted or unsubstituted C 2-6 alkenyl group, a substituted or unsubstituted C 2-6 alkynyl group;
  • R 33 is selected from the group consisting of hydrogen, hydrazine, methylsulfonyl, acetyl, C 1-2 alkyl;
  • the alkyl group, the substituent on the C 2-4 alkenyl group or the C 2-4 alkynyl group is selected from the group consisting of an anthracene, a cyano group, a hydroxyl group, a carboxyl group, a halogen, and a C 1-2 alkyl group;
  • L 1 and L 2 are each independently selected from a C 1-2 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a halogen, a C 1-2 alkyl group;
  • the ring A is none, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered unsaturated heterocyclic ring or a 3- to 6-membered saturated heterocyclic ring substituted with 0 to 2 R 34 ;
  • R 37 is selected from O or S.
  • Y is selected from N;
  • R 3 and R 4 are each independently selected from hydrogen or hydrazine
  • L 1 and L 2 are each independently selected from no or methylene
  • R 33 is selected from the group consisting of hydrogen, hydrazine, C 1-2 alkyl, -L 31 -COO-L 32 , 6-membered heterocyclic group; L 31 is selected from methylene; and L 32 is selected from methyl;
  • Ring A is selected from a 3 to 4 member saturated carbon ring
  • Y is selected from N;
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from hydrogen or hydrazine
  • L 1 and L 2 are each independently selected from a C 1-2 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is fluorene, F, methyl;
  • R 5 is selected from the group consisting of hydrogen, deuterium, halogen, substituted or unsubstituted methyl, -OC(O)R 33 , 3-membered heterocyclic;
  • R 33 is selected from a methyl group; and the substituent is fluorene, fluorine, C 1-2 alkyl, or a 3-membered heterocyclic group;
  • X is selected from O or S
  • L 1 and L 2 are each independently selected from no or methylene
  • R 33 is selected from C 1-2 alkyl, -S-CH 3 ;
  • Ring A is selected from a 3 to 4 member saturated carbon ring
  • Y is selected from N;
  • R 3 and R 4 are each independently selected from hydrogen or hydrazine
  • L 1 and L 2 are each independently selected from no or methylene
  • R 33 is selected from the group consisting of hydrogen, hydrazine, C 1-2 alkyl, -L 31 -COO-L 32 , 6-membered heterocyclic group; L 31 is selected from methylene; and L 32 is selected from methyl;
  • Ring A is selected from a 3 to 4 member saturated carbon ring
  • L 1 and L 2 are each independently selected from a methylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a methyl group;
  • R 33 is selected from the group consisting of hydrogen, hydrazine, methylsulfonyl, acetyl, methyl;
  • Ring A is selected from a 4-membered saturated heterocyclic ring
  • Y is selected from N;
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from hydrogen or hydrazine
  • L 1 and L 2 are each independently selected from a C 1-2 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is fluorene, F, Cl, C 1-2 alkyl;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, F, Cl, substituted or unsubstituted C 1-2 alkyl, 3 membered heterocyclic;
  • the substituent is ⁇ , F, Cl, C 1-2 alkyl, 3-membered heterocyclic group, -S-CH 3 ;
  • the A ring is selected from a 3- to 4-membered saturated heterocyclic ring substituted with 0 to 2 R 34 ; wherein R 34 is each independently selected from hydrazine or methyl;
  • L 1 is selected from the group consisting of no or methylene
  • X is selected from O or S
  • Y is N
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and hydrazine
  • L 1 and L 2 are each independently selected from a C 1-2 alkylene group which is unsubstituted, substituted or unsubstituted; the substituted substituent is a hydrazine, a methyl group;
  • R 33 is selected from the group consisting of hydrogen, hydrazine, and C 1-2 alkyl;
  • the ring A is not, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring or a 4-membered saturated heterocyclic ring;
  • L 1 and L 2 are each independently selected from the group consisting of C 1-2 alkylene;
  • R 33 is selected from a methyl group
  • a ring is none
  • X is selected from O or S
  • Y is N
  • L 1 and L 2 are each independently selected from the group consisting of C 1-2 alkylene;
  • R 33 is selected from a methyl group
  • a ring is none
  • X is O or S
  • L 1 and L 2 are each independently selected from a C 1-4 alkylene group which is unsubstituted, substituted or unsubstituted; the substituent is a C 1-4 alkyl group or a C 1-4 alkoxy group;
  • a ring is none
  • R 5 is H
  • Y is selected from N;
  • L 1 and L 2 are each independently selected from a C 1-2 alkylene group which is unsubstituted, substituted or unsubstituted; the substituted substituent is an anthracene, a C 1-2 alkyl group;
  • R, R' are each independently selected from the group consisting of hydrogen, hydrazine, C 1-2 alkyl, C 1-2 alkoxy, substituted or unsubstituted C 2-4 alkenyl or C 2-4 alkynyl, said substitution
  • the group is selected from a hydroxyl group, a C 1-2 alkyl group;
  • the ring A is not, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring;
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and hydrazine
  • L 1 and L 2 are each independently selected from a methylene group which is unsubstituted, substituted or unsubstituted; the substituted substituent is an anthracene, a C 1-2 alkyl group;
  • R" is selected from the group consisting of hydrogen, hydrazine, C 1-2 alkyl, C 1-2 alkoxy, substituted or unsubstituted C 2-4 alkenyl or C 2-4 alkynyl, said substituent being selected from hydroxy, C 1-2 alkyl;
  • the ring A is not, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring;
  • X is selected from O or S
  • R 3 and R 4 are each independently selected from the group consisting of hydrogen and hydrazine
  • L 1 and L 2 are each independently selected from a methylene group which is unsubstituted, substituted or unsubstituted; the substituted substituent is an anthracene, a C 1-2 alkyl group;
  • R 5 ' is selected from S or CH 2 ;
  • the ring A is not, or the ring A is selected from a 3- to 6-membered saturated carbocyclic ring or a 4- to 6-membered saturated heterocyclic ring;
  • Y is selected from N;
  • X is selected from O or S
  • the A ring is selected from a 3- to 6-membered saturated carbocyclic ring substituted with 0 to 2 R 34 ;
  • R 34 is each independently selected from the group consisting of hydrazine, halogen, cyano, and isothiocyana;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, halogenated or unhalogenated methyl, and R 3 and R 4 are not simultaneously hydrogen or deuterium;
  • L 1 and L 2 are each independently selected from a methylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a C 1-4 alkyl group;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, cyano, isocyano, isothiocyanato, C 1-2 alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 alkynyl, -OR 33 , -C(O)R 33 ;
  • the compound is as shown in formula IIEA, and Y is selected from N;
  • X is selected from O or S
  • the A ring is selected from a 3- to 6-membered saturated heterocyclic ring substituted with 0 to 2 R 34 ;
  • R 34 is each independently selected from the group consisting of hydrazine, halogen, cyano, and isothiocyana;
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, halogenated or unhalogenated methyl, and R 3 and R 4 are not simultaneously hydrogen or deuterium;
  • L 1 and L 2 are each independently selected from a methylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a C 1-4 alkyl group;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, cyano, isocyano, isothiocyanato, C 1-2 alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 alkynyl, -OR 33 , -C(O)R 33 ;
  • the compound is as shown in formula IIEA, and Y is selected from N;
  • X is selected from O or S
  • a ring is none
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, halogen, halogenated or unhalogenated methyl, and R 3 and R 4 are not simultaneously hydrogen or deuterium;
  • L 1 and L 2 are each independently selected from a methylene group which is unsubstituted, substituted or unsubstituted; the substituent is an anthracene, a C 1-4 alkyl group;
  • R 5 is selected from the group consisting of hydrogen, hydrazine, cyano, isocyano, isothiocyanato, C 1-2 alkyl, substituted or unsubstituted C 2-4 alkenyl, substituted or unsubstituted C 2-4 alkynyl, -OR 33 , -C(O)R 33 ;
  • the compound is:
  • the compound is:
  • the present invention also provides a medicament, which is a compound according to any one of the above, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or A preparation prepared by the metabolite thereof, or a deuterated derivative thereof, or a combination thereof, together with a pharmaceutically acceptable adjuvant.
  • the present invention also provides the above compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or a derivative thereof, or A composition thereof for use in the manufacture of a medicament having sedative, hypnotic, and/or anesthetic effects, and/or useful for controlling epilepticus.
  • the "sedative drug” as used in the present invention means a drug which is effective for helping sleep and effectively improving sleep. That is to avoid serious harm to the human body caused by insomnia, treatment of insomnia, improve sleep quality.
  • hypothalamic drug refers to a drug capable of inducing drowsiness and promoting sleep. That is, it has an inhibitory effect on the central nervous system, a small dose causes sedation, and an excess causes general anesthesia.
  • the "drug with anesthesia” as used in the present invention refers to a reversible functional inhibition of a central nervous system and/or a peripheral nervous system produced by a drug, which is mainly characterized by a feeling of loss of pain, particularly pain.
  • the anesthesia is general anesthesia.
  • general anesthesia refers to general anesthesia, which refers to temporary inhibition of the central nervous system after the anesthetic enters the body, and the clinical manifestations are disappearance of consciousness, loss of systemic pain, forgetting, reflex inhibition, and skeletal muscle relaxation.
  • the "sustained state of epilepsy" means that the consciousness is not completely recovered between the episodes of epileptic seizures and is frequently re-issued, or does not stop spontaneously for more than 30 minutes.
  • Long-term seizures, if not treated in time, may cause irreversible brain damage due to high fever, circulatory failure or neurotoxic excitotoxicity, and the disability rate and mortality rate are high, so epilepsy is a common emergency in internal medicine.
  • the present invention provides a medicament which is a compound of the foregoing, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, or A preparation prepared from a deuterated derivative, together with a pharmaceutically acceptable excipient.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the structures of the compounds described in the present invention all refer to structures which are stably present.
  • refers to the isotope of hydrogen (H), also known as heavy hydrogen, and the elemental symbol is generally D or 2H.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b" carbon atoms.
  • C 1 -C 8 alkyl means an alkyl group containing from 1 to 8 carbon atoms.
  • the C 1 -C 8 alkyl group means a straight or branched hydrocarbon chain having one to eight carbon atoms.
  • alkyl group is a hydrocarbon group in which one hydrogen atom is removed from an alkane molecule, such as methyl-CH 3 , ethyl-CH 3 CH 2 or the like.
  • alkylene group means a hydrocarbon group in which two hydrogen atoms are absent from an alkane molecule, such as methylene-CH 2 -, ethylene-CH 2 CH 2 - or the like.
  • C 1-8 alkylene means a straight or branched hydrocarbon chain containing from one to eight carbon atoms.
  • the "substituted or unsubstituted C 1-8 alkyl group” means that the C 1-8 alkyl group may be substituted or unsubstituted.
  • the "3- to 6-membered saturated carbocyclic ring" in the "A ring is a 3- to 6-membered saturated carbocyclic ring” in the present invention means a carbocyclic ring composed of 3 to 6 carbon atoms, wherein the carbocyclic ring has no double bond.
  • the "3- to 6-membered unsaturated carbocyclic ring" in the "A ring is a 3- to 6-membered unsaturated carbocyclic ring” in the present invention means a carbocyclic ring composed of 3 to 6 carbon atoms, wherein the carbon ring contains a double key.
  • the "3- to 6-membered saturated heterocyclic ring" in the "A ring is a 3- to 6-membered saturated heterocyclic ring” in the present invention means a saturated heterocyclic ring having no double bond, wherein the heterocyclic ring carries at least one member selected from O, S or a substituted nitrogen atom, the remaining ring atoms are carbon.
  • the heterocyclic ring carries at least one member selected from O, S or a substituted nitrogen atom, the remaining ring atoms are carbon.
  • the "3- to 6-membered unsaturated carbocyclic ring" in the "A ring is a 3- to 6-membered unsaturated heterocyclic ring” in the present invention means a saturated heterocyclic ring containing a double bond, wherein the heterocyclic ring carries at least one selected from the group consisting of O, S or a substituted nitrogen atom, the remaining ring atoms are carbon.
  • the heterocyclic ring carries at least one selected from the group consisting of O, S or a substituted nitrogen atom, the remaining ring atoms are carbon.
  • Alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group can be straight or branched.
  • the alkynyl group has a carbon number limitation (e.g., a C 2-8 alkynyl group), for example, the term "C 2-8 alkynyl group” means a straight or branched alkynyl group having 2 to 8 carbon atoms.
  • Alkenyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon double bond.
  • the alkenyl group may be straight or branched.
  • the alkenyl group has a carbon number limitation (e.g., C 2-8 alkenyl group), for example, the term “C 2-8 alkenyl group” means a straight or branched alkenyl group having 2 to 8 carbon atoms.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Aryl means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a conjugated ⁇ -electron system, such as phenyl and naphthyl.
  • the aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings), but may not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be in a conjugated pi-electron system.
  • the aryl group can be substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic group containing one to more heteroatoms.
  • the heteroatoms referred to herein include oxygen, sulfur, and nitrogen.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring.
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic.
  • C 3-8 cycloalkyl means a cycloalkyl group having 3 to 8 carbon atoms.
  • 3- to 8-membered heterocyclic group means a saturated or unsaturated cyclic hydrocarbon substituent; the cyclic hydrocarbon may be monocyclic or polycyclic, and carries at least one ring selected from O, S or substituted nitrogen atoms. Alkyl groups, the remaining ring atoms are carbon.
  • the A ring is a 3- to 6-membered saturated carbocyclic ring, a 3- to 6-membered unsaturated carbocyclic ring, a 3- to 6-membered saturated heterocyclic ring or a 3- to 6-membered unsaturated heterocyclic ring which is not substituted by "0 to 4 R 34 ";
  • the carbon atom to which the "substituent R 34 " is attached is not a carbon atom directly bonded to L 1 or L 2 .
  • C 1-4 alkyl group or a halogenated or halogenated product thereof means a C 1-4 alkyl group, a C 1-4 alkyl group substituted by halogen or hydrazine. Others have a similar definition of "or its halogenated or progeny”.
  • each chiral carbon atom may optionally be in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention with a pharmaceutically acceptable inorganic and organic acid, suitable for contact with the tissues of a subject (eg, human) without the appearance of unpleasant side effects.
  • preferred inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid;
  • preferred organic acids include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, naphthalene Disulfonic acid (1,5), asiamic acid, oxalic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, valeric acid, diethyl acetic acid, malonic acid, succinic acid, fumaric acid, pimelic acid, hexane Acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascor
  • pharmaceutically acceptable solvate means that the compound of the present invention forms a solvate with a pharmaceutically acceptable solvent, wherein the pharmaceutically acceptable solvent includes, but is not limited to, water, ethanol, methanol , isopropanol, propylene glycol, tetrahydrofuran, dichloromethane.
  • pharmaceutically acceptable stereoisomer means that the chiral carbon atom to which the compound of the invention relates may be in the R configuration, in the S configuration, or a combination thereof.
  • the compound of the present invention and various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient can be used for sedation, hypnosis and/or whole body anesthesia.
  • the compounds of the invention may also be used to control status epilepticus and the like.
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • the use of the compounds or pharmaceutical compositions of the invention includes, but is not limited to, intragastric, enteral, parenteral (intravenous, intramuscular or subcutaneous), oral and various topical administrations.
  • compositions for parenteral (intravenous, intramuscular, subcutaneous) injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and for reconstitution into sterile injectables A sterile powder of the solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a safe and effective dosage which is pharmaceutically considered to be pharmaceutically acceptable.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kilogram body weight person,
  • the daily dose is usually from 1 to 2000 mg, preferably from 5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the "room temperature" described in the present invention is 25 ⁇ 5 °C.
  • the "overnight” as described herein is 12 ⁇ 1 hour.
  • the "1N HCl" of the present invention is 1 mol/L of HCl.
  • the present invention provides a compound of formula I which is a novel substituted imidazole formate derivative which has a good inhibitory effect on the central nervous system and which can be used for the preparation of sedative, hypnotic and/or Anesthetic drugs, as well as drugs used to prepare for the control of status epilepticus, provide a new option for clinical screening and/or preparation of drugs with sedative, hypnotic and/or anesthetic effects and control of status epilepticus.
  • MAP mean arterial pressure
  • FIGS 2, 6, 10, 14, and 18 show the effect of the compounds of the invention on mean arterial pressure (MAP) (rate of change).
  • FIGs 3, 7, 11, 15, and 19 are the effects of the compounds of the present invention on heart rate (HR) (measured values).
  • FIGs 4, 8, 12, 16, and 20 are the effects of the compounds of the invention on heart rate (HR) (rate of change).
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400) nuclear magnetic apparatus, and the solvent was determined to be deuterated dimethyl sulfoxide (d 6 -DMSO) or deuterated chloroform (CDCl 3 ), and the internal standard was tetramethylsilane (TMS).
  • the LCMS was measured (Agilent LCMS 1260-6110) (ESI), column: Waters X-Bridge C18 (50 mm x 4.6 mm x 3.5 ⁇ m). Column temperature: 40 ° C; flow rate: 2.0 mL / min; mobile phase: gradient from 95% [water + 0.05% TFA] and 5% [CH 3 CN + 0.05% TFA] to 0% in 3 minutes [water+ 0.05% TFA] and 100% [CH 3 CN + 0.05% TFA], maintained under this condition for 1 minute, and then gradient to 95% [water + 0.05% TFA] and 5% [CH 3 CN + 0.05 in 0.05 minutes %TFA], then maintain this condition for 0.7 minutes.
  • the thin layer chromatography silica gel plate was made of Yantai Xinnuo Chemical Co., Ltd. HSGF254 silica gel plate with a thickness of 1 mm.
  • Thin layer chromatography uses the product of Yantai Jiangyou Silicone Development Co., Ltd., and its specification is 0.2 ⁇ 0.03mm.
  • Rotary vane vacuum pump (Linhai Yongzhen Vacuum Equipment Co., Ltd.);
  • UV high pressure mercury lamp Beijing Tianmai Henghui Light Source Electric Co., Ltd.
  • the methanesulfonate (1 eq) was dissolved in dry DMF under ice-water bath, and NaHS (1.5 eq) was added to the system in portions at a rate of 0.5 mmol/min, and the reaction temperature was controlled below 0 ° C. The temperature was continued to stir for 1 hour. After the reaction was completed by TLC, the saturated aqueous solution was added to the reaction mixture, and ethyl acetate (3 ⁇ 10 mL) was evaporated. Concentration gave the crude thiol, which was used in the next step without purification.
  • tert-Butyldiphenylchlorosilane (29.1 g, 0.106 mol) was added dropwise to ethyl glycolate (1-1) (10.0 g, 96.1 mmol), triethylamine (29.1) in an ice water bath at 0 °C. g, 0.288 mol) and a solution of DMAP (1.17 g, 9.61 mmol) in dichloromethane (100 mL) were added over 30 minutes, then warmed naturally, and the reaction was stirred at room temperature for 4 hours. After the reaction mixture was washed with water, the organic layer was separated, washed with EtOAc EtOAc.
  • Tetraisopropyl titanate (1.17 g, 4.12 mmol) was slowly added to a solution of 1-2 (6.50 g, 19.0 mmol) in THF (100 mL) with a syringe at -10 ° C, and then added over 5 minutes, then Ethyl magnesium bromide (45 mL, 1 mol/L in THF, 45 mmol) was added dropwise to the system at a rate of 1 mL/min, and the temperature was controlled below 5 ° C. After the reaction was stirred at room temperature for four hours, the reaction was completely monitored by TLC. The mixture was extracted with hexane (3 ⁇ 50 mL). EtOAc (EtOAc m.
  • the preparation of the compound 1-4 was carried out by using the compound 1b-2 (910 mg, 4.21 mmol) and 1-3 (1.30 g, 3.98 mmol) as a starting material.
  • the compound 1-4 (1.50 g, yield 72% yield) was obtained as colorless oil.
  • ESI[M+H] + 525.3
  • the compound A3 was prepared by the procedure of the general procedure B using the compound A1 (181 mg, 0.63 mmol) and methyl bromoacetate (115 mg, 0.75 mmol).
  • ESI[M+H] + 359.2
  • LiAlH 4 (3.72 g, 98.0 mmol) was added to 10 mmol per 1 min in an ice salt bath at -10 ° C, and added to a solution of 2-1 (5.00 g, 49.0 mmol) in THF (50 mL) in 10 portions. The reaction was continued for 2 hours after completion. After the reaction was completely monitored by TLC, Na 2 SO 4 .10H 2 O (10 g) was added to 1 g per 1 min in an ice salt bath, and the mixture was added to the reaction system in 10 portions, and the filtrate was spin-dried by column filtration.
  • ESI[M+H] + 359.3
  • LAH (2.28 g, 0.06 mol) was added to 10 mmol per 1 min in an ice water bath at 0 ° C, and added to 1,1-cyclobutyldicarboxylic acid (10-1) (4.32 g, 0.03 mol) in 6 portions. It was stirred at room temperature overnight in THF (80 mL). Add 5 g of Na 2 SO 4 .10H 2 O (20 g) per 1 min at 0 ° C, and add the reaction system to the reaction system in 4 portions, suction filtration, and the filter cake was washed with THF (150 mL).
  • Compound A10 (340 mg, yield 54%).
  • ESI[M+H] + 315.3
  • ESI[M+H] + 329.2
  • the compound A14 was prepared by the procedure of the general procedure B using the compound A10 (157 mg, 0.50 mmol) and ethyl iodide (94 mg, 0.60 mmol).
  • the crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v/v)
  • ESI[M+H] + 343.3
  • ESI[M+H] + 271.3.
  • ESI[M+H] + 271.3
  • the compound A19 was prepared by the procedure of the general procedure A using the compound 1b-2 (127 mg, 0.59 mmol) and 19-3 (80 mg, 0.59 mmol).
  • ESI[M+H] + 335.3
  • the compound A20 was prepared by the procedure of the general procedure A using the compound 1b-2 (216 mg, 1.0 mmol) and the crude material of the previous step 20-2.
  • the crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v/v)
  • ESI[M+H] + 313.3
  • Compound 21-1 was prepared in a similar manner to 20-2 to give a crude material.
  • the compound A23 was prepared by the procedure of the general procedure B using the compound 23-1 (150 mg, 0.50 mmol) and methyl iodide (85 mg, 0.60 mmol).
  • ESI[M+H] + 315.2
  • ESI[M+H] + 313.3
  • ESI[M+H] + 301.1
  • the compound A28 was prepared by the procedure of the general procedure A using the compound 1b-2 (100 mg, 0.46 mmol) and 28-3 (156 mg, 1.07 mmol).
  • ESI[M+H] + 345.2
  • ESI[M+H] + 287.0
  • ESI[M+H] + 271.1
  • ESI[M+H] + 285.1
  • ESI[M+H] + 299.1
  • ESI[M+H] + 299.1
  • ESI[M+H] + 285.1
  • the compound A40 was prepared by the procedure of the general procedure A using the compound 1b-2 (216 mg, 1.0 mmol) and 40-3 (146 mg, 1.0 mmol).
  • ESI[M+H] + 345.3
  • the compound A42 was prepared by the procedure of the general procedure A using the compound 1b-2 (216 mg, 1.0 mmol) and 42-3 (192 mg, 1.2 mmol).
  • ESI[M+H] + 359.3
  • ESI[M+H] + 317.3
  • the compound A45 was prepared by the procedure of the general procedure A using the compound 1b-2 (216 mg, 1.0 mmol) and 45-2 (166 mg, 1.2 mmol).
  • ESI[M+H] + 313.2
  • the compound 46-4 was prepared by using the compound 46-3 (yield: 438 mg, 3.0 mmol) as a starting material to give compound 46-4 (yield: 35%).
  • ESI[M+H]+ 163.1
  • the compound B3 was prepared by the compound 1b (234 mg, 1.0 mmol) and (S)-3-hydroxy- ⁇ -butyrolactone (102 mg, 1.0 mmol).
  • ESI[M+H] + 301.2
  • the compound B8 was prepared by the procedure of the general procedure A using the compound 1b-2 (324 mg, 1.50 mmol) and 8-2 (306 mg, 2.59 mmol).
  • ESI[M+H] + 317.2
  • Valentaldehyde (10-1) (8.0 g, 0.093 mol) was slowly added dropwise to acetonitrile (470 mg, 2.57 mmol), paraformaldehyde (470 mg, 2.57 mmol) and NaOH (470 mg) at a rate of 1 mL/min. In a mixed system of 2.57 mmol), the reaction was carried out at 80 ° C for 1 hour after the dropwise addition.
  • the compound B12 was prepared by the procedure of the general procedure B using the compound B11 (70.0 mg, 0.22 mmol) and iodomethane (565 mg, 3.98 mmol).
  • ESI[M+H] + 331.3
  • the compound 17-2 was prepared by the procedure of the general procedure B using the compound 17-1 (200 mg, 0.54 mmol) and methyl iodide (77 mg, 0.54 mmol).
  • the compound B17 was prepared by the procedure of the general procedure A using the compound 1b-2 (59 mg, 0.27 mmol) and 17-3 (40 mg, 0.27 mmol).
  • ESI[M+H] + 345.3
  • ESI[M+H] + 315.4
  • ESI[M+H] + 287.1
  • the compound B22 was prepared by the procedure of the general procedure A using the compound 1b-2 (216 mg, 1.0 mmol) and the crude product 22-2 of the previous step.
  • the crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v/v)
  • the compound of Rf 0.3 to 0.4 was collected to obtain a colorless oily compound B22 (66 mg, yield 20%).
  • ESI[M+H] + 329.2
  • the preparation of the compound B25 was carried out by using the compound 1b (108 mg, 0.5 mmol) and 2-(3,3-dimethyloxiran-2-yl)propan-2-ol (65 mg, 0.5 mmol).
  • ESI[M+H] + 329.2
  • the compound B28 was prepared by the procedure of the general procedure A using the compound 1b-2 (200 mg, 0.92 mmol) and 28-1 (132 mg, 1.5 mmol).
  • ESI[M+H] + 287.2
  • the compound 30-2 was prepared by using the compound 30-1 (306 mg, 3.0 mmol) as a starting material to give the compound (30% (yield: 40%).
  • ESI[M+H]+ 119.1
  • the title compound B30 was prepared by using the compound 1b-2 (216 mg, 1.0 mmol) and 30-2 (142 mg, 1.2 mmol) as the starting material.
  • ESI[M+H] + 317.2
  • ESI[M+H] + 347.2
  • Vinyl ether (2-1) (3.60 g, 50.0 mmol) was dissolved in anhydrous THF (20 mL). The reaction system was replaced with nitrogen and cooled to -78 ° C with dry ice acetone under nitrogen atmosphere. Lithium (20 mL, 1.0 mol/L in pentane, 20 mmol) was slowly added to the system at a rate of 1 mL/min, maintaining the temperature below -70 °C during the addition.
  • ESI[M+H] + 313.3
  • the compound C5 was prepared by the procedure of the general procedure A using the compound 1b-2 (130 mg, 0.6 mmol) and 5-4 (80 mg).
  • ESI[M+H] + 329.2
  • ESI[M+H] + 273.4
  • ESI[M+H] + 287.4
  • ESI[M+H] + 301.3
  • the compound C14 was prepared by using the compound 1b-2 (216 mg, 1.0 mmol) and 3,3-dimethyl-4-hydroxy-2-butanone (116 mg, 1.0 mmol) as a starting material.
  • ESI[M+H] + 313.2
  • ESI[M+H] + 313.3
  • ESI[M+H] + 287.3
  • the compound C20 was prepared by the procedure of the general procedure A using the compound 1b-2 (100 mg, 0.46 mmol) and 4-heptanol (64 mg, 0.55 mmol).
  • ESI[M+H] + 315.1
  • ESI[M+H] + 319.0
  • the compound 22-2 was prepared by the procedure of the general procedure C, using Compound 22-1 (306 mg, 3.0 mmol) as the starting material to afford compound 22-2 (124 mg, yield: 35%).
  • ESI[M+H] + 119.1
  • ESI[M+H] + 317.2
  • ESI[M+H] + 303.2
  • ESI[M+H] + 343.1

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Abstract

本发明公开了式(Ⅰ)所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,该化合物是一种结构新颖的取代咪唑甲酸酯类衍生物,属于药物化学领域。本发明还公开了该取代咪唑甲酸酯类衍生物在制备具有镇静、催眠和/或麻醉作用的药物中的应用,以及在制备能够控制癫痫持续状态的药物中的应用,该化合物对中枢神经系统具有较好的抑制作用,为临床上筛选和/或制备具有镇静、催眠和/或麻醉作用及控制癫痫持续状态的药物提供了一种新的选择。

Description

取代咪唑甲酸酯类衍生物及其用途 技术领域
本发明属于药物化学领域,具体涉及一种结构新颖的取代咪唑甲酸酯类衍生物,以及该化合物在制备具有镇静、催眠和/或麻醉作用的药物和制备能够控制癫痫持续状态的药物中的应用。
背景技术
一种咪唑类衍生物依托咪酯,化学名称为R-(+)-1-(1-苯乙基)-1-氢-咪唑-5-甲酸乙酯,是一种催眠性静脉全身麻醉药,安全性范围大,曾是麻醉诱导常用的药物之一。该咪唑类衍生物临床应用已有30年的历史(Br J Anaesth.1976;48(3):213-6.PubMed:1259887;Arch Int Pharmacodyn Ther.1975;214(1):92-132.PubMed:1156027;Acad Emerg Med.2006;13(4):378-83.PubMed:16531603)。依托咪酯为非巴比妥类静脉镇静药,其作用强度分别为巴比妥钠的4倍和硫喷妥钠的12倍,且全麻诱导快,给药后的苏醒、恢复也快,病人苏醒后不再出现嗜睡、眩晕及其他不良反应,并有一定的抗呕吐的作用,因此得到了广泛的应用。其结构式如下图所示,分子式C14H16N2O2,分子量244.29。该咪唑类衍生物不溶于水,中性溶液中不稳定。
Figure PCTCN2019074002-appb-000001
杨森制药最早于上世纪70年代开始将依托咪酯推入临床。作为最主要研发人员,Janssen PA等在1965年发表的一篇研究报道中记录了合成依托咪酯的主要过程,且描述了如何将依托咪酯从42个类似化合物中筛选而出的经过。在明确有麻醉作用的11种化合物之中,依托咪酯在大鼠体内表现出了最好的安全性(即最高的治疗指数TI)。此外,科研人员还发现了依托咪酯的镇静催眠作用是具有立体选择性的,R构型药物的药效比S构型药物的药效高十倍(J Med Chem.1965;8:220-3.PubMed:14332665;Anesthesiology.1998;88(3):708-17.PubMed:9523815)。该咪唑类衍生物的优点十分突出,比如在现有全身麻醉药中治疗窗比较大、对循环系统的抑制比较小,这种特点尤其适用于老年人、冠心病和高血压病人、危重病人。曾经是麻醉诱导的标准药物、也被用于作为全凭静脉麻醉的药物。
但是,自上世纪八十年代以来,随着临床上的长期使用,依托咪酯的一些缺点(如苏醒质量比另一种全身麻醉药物丙泊酚略差)尤其是对肾上腺皮质功能产生抑制这一不良反应逐渐被人们所发现。有文献报道由于依托咪酯具有抑制肾上腺皮质激素的合成,从而降低危重症病人的存活率(Lancet.1983;1(8339):1434.PubMed:6134189;Crit Care.2007;11(3):145.PubMed:17610749;Anesthesiology.2011;114(3):695-707.PubMed:21263301)。甚至一些研究表明单次快速顺序诱导中使用依托咪酯会增加住院病人的死亡率(Crit Care Med.2012;40(11):2945-53.PubMed:22971586;Anesth Analg.2013;117(6):1329-37.PubMed:24257383);许多研究者推测这种高死亡率的发生和依托咪酯抑制肾上腺皮质激素合成有关(Cochrane Database Syst Rev.2015;1:CD010225.PubMed:25568981)。同时,另一种目前临床上常用的静脉全身麻醉药丙泊酚,除了治疗窗比较小之外,麻醉诱导过程中有明显降低血压的不良反应(Crit Care.2015;19:45.PubMed:25887642),常常会增加心血管不良事件的发生。因此,设计一种新的化合物,使其既可以保留依托咪酯循环稳定性的优良特点,又可以不抑制肾上腺皮质激素的合成则具有非常重要的临床意义和广阔的应用前景。
文献提示,依托咪酯抑制肾上腺皮质激素的合成位点主要有11-β羟化酶和胆固醇侧链裂解酶,这些酶是肾上腺皮质合成皮质酮、皮质醇等途径中的关键酶。(N Engl J Med.1984;310(22):1415-21.PubMed:6325910)。Atucha等(Bioorg Med Chem Lett.2009;19(15):4284-7.PubMed:19497738)发现依托咪酯的酯质侧链不仅可以影响GABA受体(依托咪酯起麻醉效应的主要位点)还可以影响肾上腺皮质激素的合成。此外,依托咪酯代谢主要产物依托咪酯酸相较于依托咪酯几乎没有发现其有抑制11-β羟化酶的效应(Anesthesiology.2016;125(5):943-951.PubMed:27541316)。如果通过对依托咪酯的结构进行修饰减少或消除化合物本身对肾上腺皮质功能的抑制并且使化合物的代谢产物也没有对肾上腺皮质功能的影响,那么就可以减少或消除药物对肾上腺皮质功能的抑制作用。后续基于依托咪酯结构的研究,则主要集中在保留依托咪酯临床应用上的优点之外,如何降低或没有对肾上腺皮质功能的抑制上。
WO 2009/146024A1公开了一种具有提高的药物动力学性能和药效学性能的依托咪酯类似物及其作为麻醉剂的用途,并公开了该化合物可以为MOC-(R)-依托咪酯。
WO 2011/005969A2公开了一种具有提高的药物动力学性能和药效学性能的依托咪酯类似物及其作为麻醉剂的用途,并公开了该化合物可以为MOC-碳依托咪酯。
CN201380014062公开了一种能提高的药代动力学和药效学性质的美托咪酯和依托咪酯的类似物,并公开了该化合物可以为环丙基MOC-美托咪酯。
虽然科学家们后续基于依托咪酯结构的研究,主要集中在保留依托咪酯临床应用上的优 点之外,如何降低或没有对肾上腺皮质功能的抑制上。且陆续发现了诸如dimethylmethoxycarbonyl metomidate(DMMM)和cyclopropyl methoxycarbonyl metomidate(CPMM)等的依托咪酯类似物,但仍然还没有寻找到既保留了依托咪酯独特优点(如高效,安全),又消除了其对肾上腺皮质功能的抑制效应的化合物。
因此,设计一种新的化合物,使其既可以保留依托咪酯循环稳定性的优良特点,又可以不抑制肾上腺皮质激素的合成则具有非常重要的临床意义和广阔的应用前景。
同时,临床上也亟需更安全的咪唑类衍生物用于制备具有镇静、催眠和/或麻醉作用的药物以及控制癫痫持续状态的药物。
发明内容
为了解决上述问题,本发明提供了一种结构新颖的取代咪唑甲酸酯类衍生物。
本发明还提供了该取代咪唑甲酸酯类衍生物具有中枢神经系统抑制作用,并提供了该取代咪唑甲酸酯类衍生物在制备具有镇静、催眠和/或麻醉作用的药物中的应用,以及在制备能够控制癫痫持续状态的药物中的应用。
本发明提供了式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物:
Figure PCTCN2019074002-appb-000002
X选自O、S或NR 30,其中,R 30选自氢、氘或C 1-8烷基;
Y为N;
R 1各自独立地选自氘、卤素、-CN、-NO 2、-OR 32、-C(O)R 32、-CO 2R 32、-CON(R 32) 2、-N(R 32) 2、-OC(O)R 32、-SO 2R 32、取代或未取代的3~8元杂环基、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
其中,R 32各自独立地选自氢、氘、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-8环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代基为氘、氰基、羟基、 羧基、卤素、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
n为0~5的整数;
R 2选自氢、氘、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物;
R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代C 1-8烷基;所述取代基为氘、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
L 1和L 2各自独立地选自无、取代或未取代的C 1-8亚烷基;所述取代基为氘、氰基、羟基、羧基、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
R 5选自氢、氘、卤素、氰基、丙二烯基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000003
取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、-L 31-COO-L 32、取代或未取代的C 3-8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-S-C 1-8烷基;L 31选自取代或未取代的C 1-8亚烷基;L 32选自取代或未取代的C 1-8烷基;
上述R 5、R 33中所述的取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-8元环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物、-S-C 1-4烷基、=R 39、取代或未取代的C 2-8烯基或C 2-8炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-4烷基或其卤代或氘代物,所述C 2-8烯基或C 2-8炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-4烷基;
A环为无,或者,A环选自被0~4个R 34取代的3~6元饱和碳环、3~6元不饱和碳环、3~6 元饱和杂环或3~6元不饱和杂环;
其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、硝基、C 1-8烷基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2、-L 33-R 36或=R 37
L 33选自C 1-4亚烷基;
R 36选自氰基、硝基、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2
R 35各自独立地选自C 1-4烷基或其卤代或氘代物;
R 37选自O、S、N(R 38)、C(R 38) 2;R 38选自H或C 1-4烷基;
其中,当R 5为H、L 2为无时,A环不为3~6元饱和杂环;
当A环为无时,L 1和L 2各自独立地选自无、取代或未取代的C 1-8亚烷基,所述取代基为C 1-8烷基或卤素;R 5为C(O)R 41或S(O)R;R 41为C 1-3烷基或其卤代或氘代物;
当A环为被0个R 34取代的3元饱和碳环时,若L 1和L 2为无,则R 5不为氢、乙氧基;若L 1为无,L 2为亚甲基,则R 5不为甲氧基;若L 1为亚甲基,L 2为无或亚甲基,则R 5不为甲氧基;
当A环为被0个R 34取代的4~6元饱和杂环时,若L 2为无,则R 5不为H;若R 5为H,则L 2不为无;
当n为0,R 2为甲基,Y为N,R 3、R 4为氢,X为O,L 1为亚甲基,A环为无,L 2为无时,R 5不为乙烯基、乙炔基或丙烯基。
进一步地,
Y为N;
R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代C 1-8烷基;所述取代基为氘、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
或,X选自O或S;
或,R 1各自独立地选自氘、卤素、-CN、-NO 2、-OR 32、-C(O)R 32、-CO 2R 32、-CON(R 32) 2、-N(R 32) 2、-OC(O)R 32、C 1-3烷基、C 2-3烯基、C 2-3炔基;
其中,R 32各自独立地选自氢、氘、C 1-3烷基、C 2-3烯基、C 2-3炔基;
或,n为0~2的整数;
或,R 2选自氢、氘、卤素、C 1-3烷基或其卤代或氘代物。
进一步地,
所述化合物如式Ⅱ所示:
Figure PCTCN2019074002-appb-000004
Y为N;
X选自O或S;
R 5选自氢、氘、卤素、氰基、丙二烯基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000005
取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
上述R 5、R 33中所述的取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-8元环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物、-S-C 1-4烷基、=R 39、取代或未取代的C 2-6烯基或C 2-6炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-4烷基或其卤代或氘代物,所述C 2-6烯基或C 2-6炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-4烷基;
A环为无,或者,A环选自被0~4个R 34取代的3~6元饱和碳环、3~6元不饱和碳环、3~6元饱和杂环或3~6元不饱和杂环;
其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、硝基、C 1-8烷基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、-OC(O)R 35、 -C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2、-L 33-R 36或=R 37
L 33选自C 1-4亚烷基;
R 36选自氰基、硝基、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2
R 35各自独立地选自C 1-4烷基或其卤代或氘代物;
R 37选自O、S、N(R 38);R 38选自H或C 1-4烷基。
进一步地,
Y为N;
X选自O或S;
R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代的C 1-4烷基;所述取代基为氘、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-6环烷基或其卤代或氘代物、3~6元杂环基或其卤代或氘代物;
或,R 5选自氢、氘、卤素、丙二烯基、氰基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000006
取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-4烷基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基;
上述R 5、R 33中所述的取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-6元环烷基、3~6元杂环基、芳基、杂芳基、-S-C 1-4烷基、=R 39、取代或未取代的C 2-4烯基或C 2-4炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-4烷基或其卤代或氘代物,所述C 2-4烯基或C 2-4炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-4烷基;或,L 1和L 2各自独立地选自无、取代或未取代的C 1-4亚烷基;所述取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-5环烷基或其卤代或氘代物、3~5元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
或,A环为无,或者,A环选自被0~4个R 34取代的3~6元饱和碳环、3~6元不饱和碳环、3~6元饱和杂环或3~6元不饱和杂环;
其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、C 1-4烷基或其卤代或 氘代物、C 2-4烯基或其卤代或氘代物、C 2-4炔基或其卤代或氘代物、=R 37
R 37选自O或S。
进一步地,
Y为N;
X选自O或S;
R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代的C 1-2烷基;所述取代基为氘、卤素、C 1-2烷基或其卤代或氘代物、C 1-2烷氧基或其卤代或氘代物;
或,R 5选自氢、氘、卤素、丙二烯基、氰基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000007
取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-2烷基、C 3-6元环烷基、3~6元杂环基、芳基、杂芳基;
上述R 5、R 33中所述的取代基为氘、卤素、氰基、羟基、C 1-3烷基或其卤代或氘代物、C 1-3烷氧基或其卤代或氘代物、C 3-6元环烷基、3~6元杂环基、芳基、杂芳基、-S-C 1-2烷基、=R 39、取代或未取代的C 2-4烯基或C 2-4炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-3烷基或其卤代或氘代物,所述C 2-4烯基或C 2-4炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-3烷基;
或,L 1和L 2各自独立地选自无、取代或未取代的C 1-3亚烷基;所述取代基为氘、卤素、C 1-3烷基或其卤代或氘代物、C 1-3烷氧基或其卤代或氘代物;
或,A环为无,或者,A环选自被0~3个R 34取代的3~6元饱和碳环、3~6元不饱和杂环或3~6元饱和杂环;
其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、=R 37
R 37选自O或S。
进一步地,
Y为N;
X选自O或S;
R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基;
或,R 5选自氢、氘、卤素、丙二烯基、氰基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000008
取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基;
其中,R 33选自氢、氘、甲基磺酰基、乙酰基、C 1-2烷基;
上述R 5、R 33中所述的取代基为氘、卤素、羟基、氰基、C 1-2烷基、3~5元杂环基、-S-CH 3、=R 39、取代或未取代的C 2-4烯基或C 2-4炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-3烷基,所述C 2-4烯基或C 2-4炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-2烷基;
或,L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代基为氘、卤素、C 1-2烷基;
或,A环为无,或者,A环选自被0~2个R 34取代的3~6元饱和碳环、3~6元不饱和杂环或3~6元饱和杂环;
其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、C 2-3烯基、C 2-3炔基、C 1-2烷基、=R 37
R 37选自O或S。
进一步地,
所述化合物如式ⅡAA所示:
Figure PCTCN2019074002-appb-000009
其中,Y选自N;
R 3和R 4各自独立地选自氢或氘;
L 1和L 2各自独立地选自无或亚甲基;
R 33选自氢、氘、C 1-2烷基、-L 31-COO-L 32、6元杂环基;L 31选自亚甲基;L 32选自甲基;
A环选自3~4元饱和碳环;
或,
所述化合物如式ⅡAB所示:
Figure PCTCN2019074002-appb-000010
其中,Y选自N;
X选自O或S;
R 3和R 4各自独立地选自氢或氘;
L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代基为氘、F、甲基;
R 5选自氢、氘、卤素、取代或未取代的甲基、-OC(O)R 33、3元杂环基;
其中,R 33选自甲基;所述取代基为氘、氟、C 1-2烷基、3元杂环基;
A环选自被0~2个R 34取代的3~6元饱和碳环;其中,R 34各自独立地选自氘、氟或=R 37;R 37选自O;
或,
所述化合物如式ⅡAC所示:
Figure PCTCN2019074002-appb-000011
其中,X选自O或S;
L 1和L 2各自独立地选自无或亚甲基;
R 33选自C 1-2烷基、-S-CH 3
A环选自3~4元饱和碳环;
或,
所述化合物如式ⅡAD所示:
Figure PCTCN2019074002-appb-000012
其中,Y选自N;
R 3和R 4各自独立地选自氢或氘;
L 1和L 2各自独立地选自无或亚甲基;
R 33选自氢、氘、C 1-2烷基、-L 31-COO-L 32、6元杂环基;L 31选自亚甲基;L 32选自甲基;
A环选自3~4元饱和碳环;
或,
所述化合物如式ⅡBA所示:
Figure PCTCN2019074002-appb-000013
L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘、甲基;
R 33选自氢、氘、甲基磺酰基、乙酰基、甲基;
A环选自4元饱和杂环;
或,
所述化合物如式ⅡBB所示:
Figure PCTCN2019074002-appb-000014
Y选自N;
X选自O或S;
R 3和R 4各自独立地选自氢或氘;
L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代基为氘、F、Cl、C 1-2烷基;
R 5选自氢、氘、F、Cl、取代或未取代的C 1-2烷基、3元杂环基;
所述取代基为氘、F、Cl、C 1-2烷基、3元杂环基、-S-CH 3
A环选自被0~2个R 34取代的3~4元饱和杂环;其中,R 34各自独立地选自氘或甲基;
或,
所述化合物如式ⅡBC所示:
Figure PCTCN2019074002-appb-000015
L 1选自无或亚甲基;
A环选自被1个R 34取代的4~5元饱和杂环或5元不饱和杂环;其中,R 34选自=R 37;R 37选自O;
或,
所述化合物如式ⅡCA所示:
Figure PCTCN2019074002-appb-000016
式中,
X选自O或S;
Y为N;
R 3和R 4各自独立地选自氢、氘;
L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代的取代基为氘、甲基;
R 33选自氢、氘、C 1-2烷基;
A环为无,或者,A环选自3~6元饱和碳环或4元饱和杂环;
或,
所述化合物如式ⅡCB所示:
Figure PCTCN2019074002-appb-000017
式中,
L 1和L 2各自独立地选自无、C 1-2亚烷基;
R 33选自甲基;
A环为无;
或,
所述化合物如式ⅡCC所示:
Figure PCTCN2019074002-appb-000018
式中,
X选自O或S;
Y为N;
L 1和L 2各自独立地选自无、C 1-2亚烷基;
R 33选自甲基;
A环为无;
或,
所述化合物如式ⅡCD所示:
Figure PCTCN2019074002-appb-000019
式中,
X为O或S;
L 1和L 2各自独立地选自无、取代或未取代的C 1-4亚烷基;所述取代基为C 1-4烷基或C 1-4烷氧基;
A环为无;
R 5为H;
或,
所述化合物如式ⅡDA所示:
Figure PCTCN2019074002-appb-000020
Y选自N;
L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代的取代基为氘、C 1-2烷基;
R、R’各自独立地选自氢、氘、C 1-2烷基、C 1-2烷氧基、取代或未取代的C 2-4烯基或 C 2-4炔基,所述取代基选自羟基、C 1-2烷基;
A环为无,或者,A环选自3~6元饱和碳环或4~6元饱和杂环;
或,
所述化合物如式ⅡDB所示:
Figure PCTCN2019074002-appb-000021
X选自O或S;
R 3和R 4各自独立地选自氢、氘;
L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代的取代基为氘、C 1-2烷基;
R”选自氢、氘、C 1-2烷基、C 1-2烷氧基、取代或未取代的C 2-4烯基或C 2-4炔基,所述取代基选自羟基、C 1-2烷基;
A环为无,或者,A环选自3~6元饱和碳环或4~6元饱和杂环;
或,
所述化合物如式ⅡDC所示:
Figure PCTCN2019074002-appb-000022
X选自O或S;
R 3和R 4各自独立地选自氢、氘;
L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代的取代基为氘、C 1-2烷基;
R 5’选自S或CH 2
A环为无,或者,A环选自3~6元饱和碳环或4~6元饱和杂环;
或,
所述化合物如式ⅡEA所示:
Figure PCTCN2019074002-appb-000023
Y选自N;
X选自O或S;
A环选自被0~2个R 34取代的3~6元饱和碳环;
其中,R 34各自独立地选自氘、卤素、氰基、异硫氰基;
R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基,并且R 3和R 4不同时为氢或氘;
L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘,C 1-4烷基;
R 5选自氢、氘、氰基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000024
C 1-2烷基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、-OR 33、-C(O)R 33
其中,R 33各自独立地选自C 1-2烷基;R 5中所述取代基选自=R 39、C 2-4烯基或C 2-4炔基,R 39选自S、CH 2
或,
所述化合物如式ⅡEA所示,Y选自N;
X选自O或S;
A环选自被0~2个R 34取代的3~6元饱和杂环;
其中,R 34各自独立地选自氘、卤素、氰基、异硫氰基;
R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基,并且R 3和R 4不同时为氢或氘;
L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘,C 1-4烷基;
R 5选自氢、氘、氰基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000025
C 1-2烷基、取代或未取代的C 2-4 烯基、取代或未取代的C 2-4炔基、-OR 33、-C(O)R 33
其中,R 33各自独立地选自C 1-2烷基;R 5中所述取代基选自=R 39、C 2-4烯基或C 2-4炔基,R 39选自S、CH 2
或,
所述化合物如式ⅡEA所示,Y选自N;
X选自O或S;
A环为无;
R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基,并且R 3和R 4不同时为氢或氘;
L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘,C 1-4烷基;
R 5选自氢、氘、氰基、异氰基、异硫氰基、
Figure PCTCN2019074002-appb-000026
C 1-2烷基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、-OR 33、-C(O)R 33
其中,R 33各自独立地选自C 1-2烷基;R 5中所述取代基选自=R 39、C 2-4烯基或C 2-4炔基,R 39选自S、CH 2
进一步地,
所述化合物为:
所述化合物为:
Figure PCTCN2019074002-appb-000027
Figure PCTCN2019074002-appb-000028
Figure PCTCN2019074002-appb-000029
Figure PCTCN2019074002-appb-000030
Figure PCTCN2019074002-appb-000031
Figure PCTCN2019074002-appb-000032
Figure PCTCN2019074002-appb-000033
Figure PCTCN2019074002-appb-000034
Figure PCTCN2019074002-appb-000035
Figure PCTCN2019074002-appb-000036
Figure PCTCN2019074002-appb-000037
Figure PCTCN2019074002-appb-000038
Figure PCTCN2019074002-appb-000039
Figure PCTCN2019074002-appb-000040
Figure PCTCN2019074002-appb-000041
Figure PCTCN2019074002-appb-000042
Figure PCTCN2019074002-appb-000043
Figure PCTCN2019074002-appb-000044
Figure PCTCN2019074002-appb-000045
Figure PCTCN2019074002-appb-000046
Figure PCTCN2019074002-appb-000047
本发明还提供了一种药物,它是以上述任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物、或其组合物,加上药学上可接受的辅料制备而成的制剂。
本发明还提供了上述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物、或其组合物,在制备具有镇静、催眠、和/或麻醉作用、和/或可用于控制癫痫持续状态的药物中的用途。
前述化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备具有镇静、催眠和/或麻醉作用的药物中的用途。
本发明所述“具有镇静的药物”是指一种有效帮助睡眠和有效改善睡眠的药物。即能避免失眠对人体的严重危害,治疗失眠病,提高睡眠质量。
本发明所述“具有催眠的药物”是指一种能诱导睡意、促使睡眠的药物。即对中枢神经系统有抑制作用,小剂量引起镇静,过量导致全身麻醉。
本发明所述“具有麻醉的药物”是指由药物产生的一种中枢神经和(或)周围神经系统的可逆性功能抑制,这种抑制的特点主要是感觉特别是痛觉的丧失。
优选地,所述麻醉为全身麻醉。
本发明所述“全身麻醉”简称全麻,是指麻醉药进入体内后对中枢神经系统产生的暂时抑制,临床表现为神志消失、全身痛觉消失、遗忘、反射抑制和骨骼肌松弛。
前述化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备能够控制癫痫持续状态的药物中的应用。
本发明所述的“癫痫持续状态”是指癫痫连续发作之间意识未完全恢复又频繁再发,或发 作持续30分钟以上不自行停止。长时间癫痫发作,若不及时治疗,可因高热、循环衰竭或神经元兴奋毒性损伤导致不可逆的脑损伤,致残率和病死率很高,因而癫痫状态是内科常见的急症。
本发明提供了一种药物,它是以前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,加上药学上可接受的辅料制备而成的制剂。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
本发明中所述化合物的结构均是指能够稳定存在的结构。
“氘”是指氢(H)的同位素,也被称为重氢,元素符号一般为D或2H。
本发明中取代基“-C(O)R 32”的结构式为:
Figure PCTCN2019074002-appb-000048
本发明中取代基“-CO 2R 32”的结构式为:
Figure PCTCN2019074002-appb-000049
本发明中取代基“-CON(R 32) 2”的结构式为:
Figure PCTCN2019074002-appb-000050
本发明中取代基“-N(R 32) 2”的结构式为:
Figure PCTCN2019074002-appb-000051
本发明中取代基“-OC(O)R 32”的结构式为:
Figure PCTCN2019074002-appb-000052
本发明中取代基“-SO 2R 32”的结构式为:
Figure PCTCN2019074002-appb-000053
本发明中取代基“-C(S)R 33”的结构式为:
Figure PCTCN2019074002-appb-000054
本发明中取代基“-S(O)R 33”的结构式为:
Figure PCTCN2019074002-appb-000055
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(C a~C b)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C 1~C 8烷基是指包含1~8个碳原子的烷基。C 1~C 8烷基是指含有一个至八个碳原子的直链或支链的烃链。
“烷基”是烷烃分子中少掉一个氢原子而成的烃基,例如甲基-CH 3,乙基-CH 3CH 2等。
“亚烷基”是指烷烃分子中少掉两个氢原子而成的烃基,例如亚甲基-CH 2-,亚乙基-CH 2CH 2-等。“C 1-8亚烷基”是指含有一个至八个碳原子的直链或支链的烃链。
“取代或未取代的C 1-8烷基”是指C 1-8烷基可以是被取代的,也可以没有取代基的。
本发明所述“A环为3~6元饱和碳环”中的“3~6元饱和碳环”是指由3~6个碳原子组成的碳环,其中该碳环中无双键。例如:
Figure PCTCN2019074002-appb-000056
本发明所述“A环为3~6元不饱和碳环”中的“3~6元不饱和碳环”是指由3~6个碳原子组成的碳环,其中该碳环中含有双键。例如:
Figure PCTCN2019074002-appb-000057
Figure PCTCN2019074002-appb-000058
等。
本发明所述“A环为3~6元饱和杂环”中的“3~6元饱和杂环”是指没有双键的饱和的杂环,其中该杂环中携带至少一个选自O、S或取代的氮原子,其余环原子为碳。例如:
Figure PCTCN2019074002-appb-000059
Figure PCTCN2019074002-appb-000060
等。
本发明所述“A环为3~6元不饱和杂环”中的“3~6元不饱和碳环”是指含有双键的饱和的杂环,其中该杂环中携带至少一个选自O、S或取代的氮原子,其余环原子为碳。例如:
Figure PCTCN2019074002-appb-000061
Figure PCTCN2019074002-appb-000062
等。
“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的。当炔基前具有碳原子数限定(如C 2-8炔基)时,例如,术语“C 2-8炔基”指具有2-8个碳原子的直链或支链炔基。
“烯基”是指具有至少一个碳-碳双键的脂肪族碳氢基团。所述的烯基可以是直链或支链的。当烯基前具有碳原子数限定(如C 2-8烯基)时,例如,术语“C 2-8烯基”指具有2-8个碳原子的直链或支链烯基。
卤素为氟、氯、溴或碘。
“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环),但不能含有杂原子如氮,氧,或硫,同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。
“杂芳基”指包含一个到多个杂原子的杂芳族基团。这里所指的杂原子包括氧、硫和氮。例如呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。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。杂芳基可以是任选取代的或未取代的。
“环烷基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环。例如,“C 3-8环烷基”指碳原子数为3~8的环烷基。
“3~8元杂环基”指饱和或不饱和的环状烃取代基;环状烃可以是单环也可以是多环,且携带至少一个选自O、S或取代的氮原子的环烷基,其余环原子为碳。
本发明化合物中的“A环”上的一个碳原子是与L 1和L 2直接相连的。例如:
Figure PCTCN2019074002-appb-000063
Figure PCTCN2019074002-appb-000064
等。
A环为无或被“0~4个R 34取代”的3~6元饱和碳环、3~6元不饱和碳环、3~6元饱和杂环或3~6元不饱和杂环;其中,R 34选自氘、卤素、氰基、硝基、C 1-8烷基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2、-L 33-R 36或=R 37
此处,与“取代基R 34”相连的碳原子不是与L 1或L 2直接相连的碳原子。例如:
Figure PCTCN2019074002-appb-000065
等。
“C 1-4烷基或其卤代或氘代物”是指C 1-4烷基、被卤素或氘取代的C 1-4烷基。其它关于“或其卤代或氘代物”具有类似的定义。
本发明的所有化合物之中,各手性碳原子(手性中心)可以任选地为R构型或S构型,或R构型和S构型的混合物。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2019074002-appb-000066
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无 热原水等。
术语“药学上可接受的盐”指本发明化合物与药学上可接受的无机酸和有机酸所形成的盐,适合与对象(例如,人)的组织接触,而不会产生不适度的副作用的盐。其中,优选的无机酸包括(但并不限于):盐酸、氢溴酸、磷酸、硝酸、硫酸;优选的有机酸包括(但并不限于):甲酸、乙酸、丙酸、丁二酸、萘二磺酸(1,5)、亚细亚酸、草酸、酒石酸、乳酸、水杨酸、苯甲酸、戊酸、二乙基乙酸、丙二酸、琥珀酸、富马酸、庚二酸、己二酸、马来酸、苹果酸、氨基磺酸、苯丙酸、葡糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸、对甲苯磺酸、柠檬酸,以及氨基酸。
术语“药学上可接受的溶剂合物”指本发明化合物与药学上可接受的溶剂形成溶剂合物,其中,所述药学上可接受的溶剂包括(但并不限于):水、乙醇、甲醇、异丙醇、丙二醇、四氢呋喃、二氯甲烷。
如本文所用,术语“药学上可接受的立体异构体”指本发明化合物所涉及手性碳原子可以为R构型,也可以为S构型,或其组合。
本发明化合物或其组合物及使用方法:
本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于实施镇静、催眠和/或全身麻醉。本发明化合物也可用于控制癫痫持续状态等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。
本发明化合物或药物组合物的使用方式包括(但并不限于):胃内、肠内、肠胃外(静脉内、肌肉内或皮下)、口服和各种局部给药。
用于肠胃外(静脉内、肌肉内、皮下)注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例 如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的安全和有效给药剂量。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60公斤体重的人而言,日给药剂量通常为1~2000毫克,优选5~500毫克。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明所述“室温”为25±5℃。
本发明所述“过夜”为12±1小时。
本发明所述“1N的HCl”为1mol/L的HCl。
本发明提供了式Ⅰ所示的化合物,该化合物是一种结构新颖的取代咪唑甲酸酯类衍生物,该化合物对中枢神经系统具有较好的抑制作用,可用于制备具有镇静、催眠和/或麻醉作用的 药物,以及用于制备能够控制癫痫持续状态的药物,为临床上筛选和/或制备具有镇静、催眠和/或麻醉作用及控制癫痫持续状态等的药物提供了一种新的选择。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1、5、9、13、17为本发明化合物对平均动脉压(MAP)的影响(实测值)。
备注:
1.所有试验动物均在给药结束后1min内翻正反射消失;
2.图中横坐标的0min代表给药结束;
3.各化合物或药物翻正反射恢复的时间分别是PRO:645s(10.75min);ETO:440s(7.33min);化合物A7:110s(1.83min);化合物A8:129s(2.15min);化合物A11:225s(3.75min);化合物A12:254s(4.23min);化合物A15:193s(3.22min);化合物A16:167s(2.78min);化合物A17:327s(5.45min);化合物A18:273s(4.55min);化合物A27:126s(2.10min);化合物A28:435s(7.25min);化合物A29:255s(4.25min);化合物A45:200s(3.33min);B5:255s(4.25min);化合物B9:109s(1.82min);化合物B10:81s(1.35min);化合物B18:279s(4.65min);化合物B19:125s(2.08min);化合物B20:161s(2.68min);化合物B29:112s(1.87min);化合物C1:130s(2.17min);化合物C2:182s(3.03min);化合物C3:75s(1.25min);化合物C6:120s(2.0min);化合物C7:112s(1.87min);化合物C8:170s(2.83min);化合物C18:115s(1.92min);化合物C20:243s(4.05min);化合物C22:93s(1.55min);化合物C23:206s(3.43min);化合物C24:135s(2.25min);化合物C25:125s(2.08min);化合物C26:137s(2.28min);化合物C27:186s(3.1min);化合物D1:785s(13.08min);化合物D2:355s(5.92min)化合物D3:76s(1.27min);化合物D7:410s(6.83min);化合物D10:605s(10.08min);化合物D13:109s(1.82min);化合物D14:210s(3.5min);化合物D15:225s(3.75min);化合物D18:317s(5.28min);化合物D21:360s(6.0min);化合物D22:50s(0.83min);化合物D34:170s(2.83min);化合物D35:200s(3.33min);化合物D36:143s(2.38min);化合物D37:165s(2.75min);化合物D38:193s(3.22min);化合物D39:375s(6.25min);化合物D40:441s(7.35min);化合物D41:355s(5.92min);化合物D42:323s(5.38min);化合物D43:117s(1.95min);化合物E2:129s(2.15min);化合物E6:174s(2.90min);化合物E8:120s(2.00min);化合物E9:77s(1.28min);化合物E10:162s(2.70min);化合物E11:93s(1.55min);化合物E12: 214s(3.57min);化合物E15:72s(1.20min);化合物E16:200s(3.33min);化合物E17:196s(3.27min);化合物E18:158s(2.63min);化合物E19:56s(0.93min);化合物E20:51s(0.85min);化合物E21:155s(2.58min);化合物E22:66s(1.10min);化合物E23:92s(1.53min);化合物E24:75s(1.25min);化合物E25:134s(2.23min);化合物E26:94s(1.57min);化合物E27:246s(4.10min);化合物E28:150s(2.5min);化合物E29:165s(2.75min);化合物E30:80s(1.33min);化合物E31:105s(1.75min);化合物E32:219s(3.65min);化合物E33:247s(4.12min);化合物E35:151s(2.52min);化合物E37:100s(1.67min);化合物E38:122s(2.03min);化合物E64:149s(2.48min);化合物E90:85s(1.42min);化合物E100:110s(1.83min);化合物E102:288s(4.80min);化合物E116:92s(1.53min);化合物E121:184s(3.07min);化合物E129:52s(0.87min);化合物E133:138s(2.30min);化合物E146:201s(3.35min);化合物E148:58s(0.97min);化合物E157:182s(3.03min);化合物E160:65s(1.08min);化合物E161:140s(2.33min);化合物E163:95s(1.58min);化合物E164:77s(1.28min)。
图2、6、10、14、18为本发明化合物对平均动脉压(MAP)的影响(变化率)。
备注:
1.所有试验动物均在给药结束后1min内翻正反射消失;
2.图中横坐标的0min代表给药结束;
3.各化合物或药物翻正反射恢复的时间分别是PRO:645s(10.75min);ETO:440s(7.33min);化合物A7:110s(1.83min);化合物A8:129s(2.15min);化合物A11:225s(3.75min);化合物A12:254s(4.23min);化合物A15:193s(3.22min);化合物A16:167s(2.78min);化合物A17:327s(5.45min);化合物A18:273s(4.55min);化合物A27:126s(2.10min);化合物A28:435s(7.25min);化合物A29:255s(4.25min);化合物A45:200s(3.33min);化合物B5:255s(4.25min);化合物B9:109s(1.82min);化合物B10:81s(1.35min);化合物B18:279s(4.65min);化合物B19:125s(2.08min);化合物B20:161s(2.68min);化合物B29:112s(1.87min);化合物C1:130s(2.17min);化合物C2:182s(3.03min);化合物C3:75s(1.25min);化合物C6:120s(2.0min);化合物C7:112s(1.87min);化合物C8:170s(2.83min);化合物C18:115s(1.92min);化合物C20:243s(4.05min);化合物C22:93s(1.55min);化合物C23:206s(3.43min);化合物C24:135s(2.25min);化合物C25:125s(2.08min);化合物C26:137s(2.28min);化合物C27:186s(3.1min);化合物D1:785s(13.08min);化合物D2:355s(5.92min)化合物D3:76s(1.27min);化合物D7:410s(6.83min);化合物D10:605s(10.08min);化合物D13:109s(1.82min);化合物D14:210s(3.5min);化合物D15:225s(3.75min);化合物D18:317s(5.28min);化合物D21:360s(6.0min);化合物D22:50s(0.83min);化合物D34:170s(2.83min);化合物D35: 200s(3.33min);化合物D36:143s(2.38min);化合物D37:165s(2.75min);化合物D38:193s(3.22min);化合物D39:375s(6.25min);化合物D40:441s(7.35min);化合物D41:355s(5.92min);化合物D42:323s(5.38min);化合物D43:117s(1.95min);化合物E2:129s(2.15min);化合物E6:174s(2.90min);化合物E8:120s(2.00min);化合物E9:77s(1.28min);化合物E10:162s(2.70min);化合物E11:93s(1.55min);化合物E12:214s(3.57min);化合物E15:72s(1.20min);化合物E16:200s(3.33min);化合物E17:196s(3.27min);化合物E18:158s(2.63min);化合物E19:56s(0.93min);化合物E20:51s(0.85min);化合物E21:155s(2.58min);化合物E22:66s(1.10min);化合物E23:92s(1.53min);化合物E24:75s(1.25min);化合物E25:134s(2.23min);化合物E26:94s(1.57min);化合物E27:246s(4.10min);化合物E28:150s(2.5min);化合物E29:165s(2.75min);化合物E30:80s(1.33min);化合物E31:105s(1.75min);化合物E32:219s(3.65min);化合物E33:247s(4.12min);化合物E35:151s(2.52min);化合物E37:100s(1.67min);化合物E38:122s(2.03min);化合物E64:149s(2.48min);化合物E90:85s(1.42min);化合物E100:110s(1.83min);化合物E102:288s(4.80min);化合物E116:92s(1.53min);化合物E121:184s(3.07min);化合物E129:52s(0.87min);化合物E133:138s(2.30min);化合物E146:201s(3.35min);化合物E148:58s(0.97min);化合物E157:182s(3.03min);化合物E160:65s(1.08min);化合物E161:140s(2.33min);化合物E163:95s(1.58min);化合物E164:77s(1.28min)。
图3、7、11、15、19为本发明化合物对心率(HR)的影响(实测值)。
备注:
1.所有试验动物均在给药结束后1min内翻正反射消失;
2.图中横坐标的0min代表给药结束;
3.各化合物或药物翻正反射恢复的时间分别是PRO:645s(10.75min);ETO:440s(7.33min);化合物A7:110s(1.83min);化合物A8:129s(2.15min);化合物A11:225s(3.75min);化合物A12:254s(4.23min);化合物A15:193s(3.22min);化合物A16:167s(2.78min);化合物A17:327s(5.45min);化合物A18:273s(4.55min);化合物A27:126s(2.10min);化合物A28:435s(7.25min);化合物A29:255s(4.25min);化合物A45:200s(3.33min);化合物B5:255s(4.25min);化合物B9:109s(1.82min);化合物B10:81s(1.35min);化合物B18:279s(4.65min);化合物B19:125s(2.08min);化合物B20:161s(2.68min);化合物B29:112s(1.87min);化合物C1:130s(2.17min);化合物C2:182s(3.03min);化合物C3:75s(1.25min);化合物C6:120s(2.0min);化合物C7:112s(1.87min);化合物C8:170s(2.83min);化合物C18:115s(1.92min);化合物C20:243s(4.05min);化合物C22:93s(1.55min);化合物C23:206s(3.43min);化合物C24:135s(2.25min);化合物C25: 125s(2.08min);化合物C26:137s(2.28min);化合物C27:186s(3.1min);化合物D1:785s(13.08min);化合物D2:355s(5.92min)化合物D3:76s(1.27min);化合物D7:410s(6.83min);化合物D10:605s(10.08min);化合物D13:109s(1.82min);化合物D14:210s(3.5min);化合物D15:225s(3.75min);化合物D18:317s(5.28min);化合物D21:360s(6.0min);化合物D22:50s(0.83min);化合物D34:170s(2.83min);化合物D35:200s(3.33min);化合物D36:143s(2.38min);化合物D37:165s(2.75min);化合物D38:193s(3.22min);化合物D39:375s(6.25min);化合物D40:441s(7.35min);化合物D41:355s(5.92min);化合物D42:323s(5.38min);化合物D43:117s(1.95min);化合物E2:129s(2.15min);化合物E6:174s(2.90min);化合物E8:120s(2.00min);化合物E9:77s(1.28min);化合物E10:162s(2.70min);化合物E11:93s(1.55min);化合物E12:214s(3.57min);化合物E15:72s(1.20min);化合物E16:200s(3.33min);化合物E17:196s(3.27min);化合物E18:158s(2.63min);化合物E19:56s(0.93min);化合物E20:51s(0.85min);化合物E21:155s(2.58min);化合物E22:66s(1.10min);化合物E23:92s(1.53min);化合物E24:75s(1.25min);化合物E25:134s(2.23min);化合物E26:94s(1.57min);化合物E27:246s(4.10min);化合物E28:150s(2.5min);化合物E29:165s(2.75min);化合物E30:80s(1.33min);化合物E31:105s(1.75min);化合物E32:219s(3.65min);化合物E33:247s(4.12min);化合物E35:151s(2.52min);化合物E37:100s(1.67min);化合物E38:122s(2.03min);化合物E64:149s(2.48min);化合物E90:85s(1.42min);化合物E100:110s(1.83min);化合物E102:288s(4.80min);化合物E116:92s(1.53min);化合物E121:184s(3.07min);化合物E129:52s(0.87min);化合物E133:138s(2.30min);化合物E146:201s(3.35min);化合物E148:58s(0.97min);化合物E157:182s(3.03min);化合物E160:65s(1.08min);化合物E161:140s(2.33min);化合物E163:95s(1.58min);化合物E164:77s(1.28min)。
图4、8、12、16、20为本发明化合物对心率(HR)的影响(变化率)。
备注:
1.所有试验动物均在给药结束后1min内翻正反射消失。;
2.图中横坐标的0min代表给药结束;
3.各化合物或药物翻正反射恢复的时间分别是PRO:645s(10.75min);ETO:440s(7.33min);化合物A7:110s(1.83min);化合物A8:129s(2.15min);化合物A11:225s(3.75min);化合物A12:254s(4.23min);化合物A15:193s(3.22min);化合物A16:167s(2.78min);化合物A17:327s(5.45min);化合物A18:273s(4.55min);化合物A27:126s(2.10min);化合物A28:435s(7.25min);化合物A29:255s(4.25min);化合物A45:200s(3.33min);化合物B5:255s(4.25min);化合物B9:109s(1.82min);化合物B10:81s(1.35min);化合 物B18:279s(4.65min);化合物B19:125s(2.08min);化合物B20:161s(2.68min);化合物B29:112s(1.87min);化合物C1:130s(2.17min);化合物C2:182s(3.03min);化合物C3:75s(1.25min);化合物C6:120s(2.0min);化合物C7:112s(1.87min);化合物C8:170s(2.83min);化合物C18:115s(1.92min);化合物C20:243s(4.05min);化合物C22:93s(1.55min);化合物C23:206s(3.43min);化合物C24:135s(2.25min);化合物C25:125s(2.08min);化合物C26:137s(2.28min);化合物C27:186s(3.1min);化合物D1:785s(13.08min);化合物D2:355s(5.92min)化合物D3:76s(1.27min);化合物D7:410s(6.83min);化合物D10:605s(10.08min);化合物D13:109s(1.82min);化合物D14:210s(3.5min);化合物D15:225s(3.75min);化合物D18:317s(5.28min);化合物D21:360s(6.0min);化合物D22:50s(0.83min);化合物D34:170s(2.83min);化合物D35:200s(3.33min);化合物D36:143s(2.38min);化合物D37:165s(2.75min);化合物D38:193s(3.22min);化合物D39:375s(6.25min);化合物D40:441s(7.35min);化合物D41:355s(5.92min);化合物D42:323s(5.38min);化合物D43:117s(1.95min);化合物E2:129s(2.15min);化合物E6:174s(2.90min);化合物E8:120s(2.00min);化合物E9:77s(1.28min);化合物E10:162s(2.70min);化合物E11:93s(1.55min);化合物E12:214s(3.57min);化合物E15:72s(1.20min);化合物E16:200s(3.33min);化合物E17:196s(3.27min);化合物E18:158s(2.63min);化合物E19:56s(0.93min);化合物E20:51s(0.85min);化合物E21:155s(2.58min);化合物E22:66s(1.10min);化合物E23:92s(1.53min);化合物E24:75s(1.25min);化合物E25:134s(2.23min);化合物E26:94s(1.57min);化合物E27:246s(4.10min);化合物E28:150s(2.5min);化合物E29:165s(2.75min);化合物E30:80s(1.33min);化合物E31:105s(1.75min);化合物E32:219s(3.65min);化合物E33:247s(4.12min);化合物E35:151s(2.52min);化合物E37:100s(1.67min);化合物E38:122s(2.03min);化合物E64:149s(2.48min);化合物E90:85s(1.42min);化合物E100:110s(1.83min);化合物E102:288s(4.80min);化合物E116:92s(1.53min);化合物E121:184s(3.07min);化合物E129:52s(0.87min);化合物E133:138s(2.30min);化合物E146:201s(3.35min);化合物E148:58s(0.97min);化合物E157:182s(3.03min);化合物E160:65s(1.08min);化合物E161:140s(2.33min);化合物E163:95s(1.58min);化合物E164:77s(1.28min)。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm) 的单位给出。NMR的测定是用(Bruker Avance III 400)核磁仪,测定溶剂为氘代二甲基亚砜(d 6-DMSO)或者氘代氯仿(CDCl 3),内标为四甲基硅烷(TMS)。
LCMS的测定用(Agilent LCMS 1260-6110)(ESI),柱子:Waters X-Bridge C18(50mm x 4.6mm x 3.5μm)。柱温:40℃;流速:2.0mL/min;流动相:在3分钟时间内从95%[water+0.05%TFA]和5%[CH 3CN+0.05%TFA]梯度到0%[water+0.05%TFA]和100%[CH 3CN+0.05%TFA],在此条件下保持1分钟,再在0.05分钟内梯度到95%[water+0.05%TFA]和5%[CH 3CN+0.05%TFA],再保持此条件0.7分钟。
1)药材与试剂
薄层层析硅胶板使用烟台新诺化工有限公司HSGF254硅胶板,厚度为1mm。
薄层色谱法(TLC)使用烟台江友硅胶开发有限公司的产品,其规格为0.2±0.03mm。
柱层层析一般采用乳山市太阳干燥剂有限公司(山东威海)100~200目或者200~300目硅胶为载体。
2)主要仪器
JA2003N电子天平(上海佑科仪器仪表有限公司);
98-2磁力搅拌器(上海司乐仪器有限公司);
接触式调压器(浙江天正电器股份有限公司);
温控仪(上海禄霖电器有限公司);
ZF-2三用紫外仪(上海安亭电子仪器厂);
R-201旋转蒸发器(上海市申顺生物科技有限公司);
W201D恒温水浴锅(上海市申顺生物科技有限公司);
SHB-III循环水式真空泵(郑州汇成科工贸有限公司);
SHB-B95移动水泵(郑州汇成科工贸有限公司);
低温冷却循环泵(巩义市予华仪器有限公司);
旋片式真空泵(临海市永昊真空设备有限公司);
紫外线高压汞灯(北京天脉恒辉光源电器有限公司)。
通用操作A:
在室温下,将R-1-(1-苯乙基)-1H-咪唑-5羧酸相关衍生物羧酸(1eq),DCC(1.5eq)和DMAP(1.5eq)溶解在二氯甲烷中,室温搅拌5分钟,再用注射器将醇或硫醇(1eq)缓慢加至反应体系,室温搅拌过夜。经TLC监测体系反应完全,经过减压浓缩将溶剂移除,加入甲基叔丁基醚搅拌,抽滤,滤饼用甲基叔丁基醚洗涤,将滤液减压浓缩得到粗产品,用制备TLC或者硅胶柱层析纯化得到纯的产品。
通用操作B:
在冰水浴0℃下,将NaH(60%in mineral oil,1.2eq)缓慢分批加至依托咪酯相关醇衍生物的THF溶液中,加完后在0℃继续搅拌30分钟。用注射器将碘甲烷(1.2eq),碘乙烷(1.2eq)或者溴乙酸甲酯(1.2eq)的四氢呋喃溶液缓慢加至体系,在0℃反应直到经TLC监测反应完全,将反应体系用饱和氯化铵溶液(20mL)终止,用乙酸乙酯萃取,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品,用制备TLC或者硅胶柱层析纯化得到目标化合物。
通用操作C:
在冰水浴下,将醇(1eq),三乙胺(1.5eq)溶解在二氯甲烷中,再用注射器将甲烷磺酰氯(1.5eq)以0.5mmol/min的速度滴加至体系,并控制温度在0℃以下,在此温度继续搅拌1小时。经TLC监测体系反应完全,用1NHCl终止反应并将PH调至5~6,分离有机相,依次用饱和NaHCO 3和饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品甲烷磺酸酯,粗品未经纯化直接用于下一步反应。
在冰水浴下,将甲烷磺酸酯(1eq)溶解在干燥DMF中,再将NaHS(1.5eq)以0.5mmol/min的速度分批加至体系,并控制反应温度在0℃以下,在此温度继续搅拌1小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品硫醇,粗品未经纯化直接用于下一步反应。
实施例A1本发明化合物A1和化合物A3的制备
Figure PCTCN2019074002-appb-000067
1、1-1(Ethyl 2-((tert-butyldiphenylsilyl)oxy)acetate)(1-2)的制备
Figure PCTCN2019074002-appb-000068
在冰水浴0℃下,将叔丁基二苯基氯硅烷(29.1g,0.106mol)逐滴滴加到乙醇酸乙酯(1-1)(10.0g,96.1mmol),三乙胺(29.1g,0.288mol)和DMAP(1.17g,9.61mmol)的二氯甲烷(100mL)溶液中,30分钟加完,然后自然升温,在室温下搅拌反应4小时。反应液加水破坏后,分离有机相,依次用1N HCl,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,经过硅胶柱层析分离,以乙酸乙酯:石油醚(v/v)在1/100~1/50范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/10)检测,收集Rf=0.6~0.7部分,得到无色油状化合物1-2(34.0g,收率100%)。ESI[M+H] +=365.2
2、1-(((Tert-butyldiphenylsilyl)oxy)methyl)cyclopropan-1-ol(1-3)的制备
Figure PCTCN2019074002-appb-000069
在-10℃下,将钛酸四异丙酯(1.17g,4.12mmol)用注射器缓慢加入到1-2(6.50g,19.0mmol)的THF(100mL)溶液中,5分钟加完,然后将乙基溴化镁(45mL,1mol/L in THF,45mmol)以1mL/min的速度滴加至体系,并控制温度在5℃以下,反应体系室温搅拌反应四小时后,经TLC监测反应完全,加水破坏,用正己烷(3×50mL)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/3~1/1.5范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.4~0.5部分,得到无色油状化合物1-3(1.34g,收率22%)。ESI[M+Na] +=349.3
3、1-(((Tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl(R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate(1-4)的制备
Figure PCTCN2019074002-appb-000070
化合物1-4的制备是用化合物1b-2(910mg,4.21mmol)和1-3(1.30g,3.98mmol)为原料按 照通用操作A方法合成,粗产品经过硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例),TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.5~0.6部分,得到无色油状化合物1-4(1.50g,收率72%yield)。ESI[M+H] +=525.3
4、目标化合物A1的制备
Figure PCTCN2019074002-appb-000071
在室温下,将TBAF(2.86mL,1mol/L in THF,2.86mmol)一次性加入到1-4(1.5g,2.86mmol)的THF中,室温反应2小时。经TLC监测反应完全,将反应体系减压浓缩后经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)在1/3~1/1范围内的任一比例),TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状化合物A1(778mg,收率95%)。ESI[M+H] +=287.2
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.84(s,1H),7.40–7.27(m,3H),7.21–7.16(m,2H),6.35(q,J=7.1Hz,1H),4.31(dd,J=35.4,12.0Hz,2H),1.88(d,J=7.1Hz,3H),0.89(t,J=5.8Hz,2H),0.70–0.63(m,2H).
5、目标化合物A3的制备
Figure PCTCN2019074002-appb-000072
化合物A3的制备是用化合物A1(181mg,0.63mmol)和溴乙酸甲酯(115mg,0.75mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A3(80mg,收率35%)。ESI[M+H] +=359.2
1H NMR(400MHz,CDCl 3)δ7.92(s,1H),7.86(s,1H),7.41–7.28(m,3H),7.24–7.16(m,2H),6.39(q,J=6.9Hz,1H),4.39(q,J=12.5Hz,2H),4.22(s,2H),3.69(s,3H),1.89(d,J=7.1Hz,3H),1.12–0.96(m,2H),0.82–0.62(m,2H).
实施例A2本发明化合物A2,化合物A4和化合物A6的制备
Figure PCTCN2019074002-appb-000073
1、1-(Hydroxymethyl)cyclopropanol(2-2)的制备
Figure PCTCN2019074002-appb-000074
在冰盐浴-10℃下,将LiAlH 4(3.72g,98.0mmol)以每1min加入10mmol,共分10次加入到2-1(5.00g,49.0mmol)的THF(50mL)溶液中,加完后继续反应2小时。经TLC监测反应完全后,在冰盐浴下,将Na 2SO 4.10H 2O(10g)以每1min加入1g,共分10次加至反应体系,经抽滤,滤液旋干,柱层析分离(甲醇/二氯甲烷(v/v)在1/50~1/10范围内的任一比例),TLC(甲醇/二氯甲烷(v/v)=1/20)检测,收集Rf=0.2~0.3部分,得到无色油状物2-2(1g,收率23%)。
2、(R)-1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid(1b-2)的制备
Figure PCTCN2019074002-appb-000075
在室温下,将LiOH(980mg,41.0mmol)一次性加至1b-1(5.00g,20.5mmol)的 MeOH/THF/H 2O(60mL,1/1/1)溶液,室温搅拌过夜。反应液浓缩后倒入水(50mL)中,用1N的盐酸调pH到4-5后,用二氯甲烷(3×15mL)萃取,合并有机相用无水硫酸钠干燥,抽滤,减压浓缩得到白色固体1b-2(4.10g,收率31%)
3、(R)-1-(1-Phenylethyl)-1H-imidazole-5-carbonyl chloride(1b)的制备
Figure PCTCN2019074002-appb-000076
在冰水浴0℃下,用注射器将(COCl) 2(2mL)以1mL/min的速度缓慢加至1b-2(3.00g,13.9mmol)的二氯甲烷(30mL)溶液,室温反应1小时。反应液经过减压浓缩得到白色固体1b(3.10g,粗品)。
4、目标化合物A2的制备
Figure PCTCN2019074002-appb-000077
在冰水浴0℃下,将1b(3.10g,粗品)加入2-2(1.22g,13.9mmol)和三乙胺(2.81g,27.8mmol)的二氯甲烷(30mL)溶液里,加完后继续反应1小时。将反应液减压浓缩得到粗品,经过硅胶柱层析分离(乙酸乙酯/石油醚(v/v)在1/8~1/1范围内的任一比例),TLC(乙酸乙酯/石油醚(v/v)=1/1)监测,收集Rf=0.3~0.4部分,得到无色油状化合物A2(1.80g,两步反应收率45%)。ESI[M+H] +=287.2
1H NMR(400MHz,d 6-DMSO)δ8.31(d,J=0.7Hz,1H),7.76(d,J=1.0Hz,1H),7.37–7.29(m,2H),7.27–7.25(m,1H),7.22–7.10(m,2H),6.26(t,J=7.2Hz,1H),5.60(s,1H),4.15(s,2H),1.85(d,J=7.2Hz,3H),0.72–0.58(m,2H),0.60–0.50(m,2H).
5、目标化合物A4的制备
Figure PCTCN2019074002-appb-000078
化合物A4的制备是用化合物2(1.10g,3.84mmol)和溴乙酸甲酯(609mg,3.98mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A4(190mg,收率14%)。ESI[M+H] +=359.3
1H NMR(400MHz,d 6-DMSO)δ8.33(s,1H),7.69(d,J=0.4Hz,1H),7.34–7.31(m,2H),7.28–7.26(m,1H),7.20–7.18(m,2H),6.25–6.24(m,1H),4.30–4.29(m,2H),4.19(s,2H),3.52(s,3H),1.85(d,J=7.2Hz,3H),0.88–0.87(m,2H),0.69–0.64(m,2H).
6、目标化合物A6的制备
Figure PCTCN2019074002-appb-000079
在室温下,用注射器将乙酰氯(151mg,1.92mmol)以1mmol/min的速度加入到化合物A2(550mg,1.92mmol)和三乙胺(388mg,3.84mmol)的二氯甲烷(20mL)溶液中,室温下反应30分钟。反应液经减压浓缩后,粗品通过硅胶柱层析分离(乙酸乙酯/石油醚(v/v)在1/8~1/1范围内的任一比例),TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.4~0.5部分,得到无色油状化合物A6(250mg,收率40%)。ESI[M+H] +=329.2
1H NMR(400MHz,d 6-DMSO)δ8.91(s,1H),8.06(s,1H),7.37–7.34(m,2H),7.31–7.27(m,1H),7.24–7.22(m,2H),6.30–6.26(m,1H),4.52(d,J=12.4Hz,1H),4.39(d,J=12.4Hz,1H),1.96–1.87(m,3H),1.86(s,3H),0.92–0.86(m,4H).
实施例A3本发明化合物A5的制备
Figure PCTCN2019074002-appb-000080
1、1-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropanol(5-1)的制备
Figure PCTCN2019074002-appb-000081
在室温下,将3,4-二氢-2H-吡喃(478mg,5.68mmol),2-2(500mg,5.68mmol)和对甲基苯磺酸吡啶(70.4mg,0.28mmol)加至二氯甲烷(10mL)溶液中,室温反应2小时。TLC监测反应完全后,将反应体系减压浓缩,经胶柱层析分离(乙酸乙酯/石油醚(v/v)在1/10~1/1范围内 的任一比例),TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状化合物5-1(510mg,收率52%)。
2、目标化合物A5的制备
Figure PCTCN2019074002-appb-000082
在室温下,将5-1(510mg,2.96mmol),1b-2(640mg,2.96mmol),EDCI(567mg,2.96mmol),HOBT(400mg,2.96mmol)和DIEA(765mg,5.92mmol)溶解在DMF(5mL)中,室温搅拌过夜。经TLC监测反应完全后,将反应液用水破坏,乙酸乙酯(3×15mL)萃取。合并有机相用食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状化合物A5(50mg,收率5%)。ESI[M+H] +=371.2
1H NMR(400MHz,d 6-DMSO)δ8.33-8.30(m,1H),7.69-7.64(m,1H),7.34-7.31(m,2H),7.28-7.26(m,1H),7.19-7.17(m,2H),6.27-6.25(m,1H),4.80-4.13(m,2H),3.78-3.51(m,2H),2.52-2.51(m,1H),1.86-1.82(m,3H),1.70-1.32(m,6H),0.85-0.66(m,4H).
实施例A4本发明化合物A7的制备
Figure PCTCN2019074002-appb-000083
化合物A7的制备是用化合物1b-2(200mg,0.92mmol)和1,1-环丙烷二甲醇(94mg,0.92mmol)为原料经由酰氯1b按照制备化合物2的操作方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.2~0.3的部分,得到无色油状化合物A7(223mg,两步反应收率81%)。ESI[M+H] +=301.3
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.79(s,1H),7.36–7.29(m,3H),7.18–7.17(m,2H),6.35(q,J=7.1Hz,1H),4.20(s,2H),3.45–3.33(m,2H),1.87(d,J=7.1Hz,3H),0.64–0.51(m,4H).
实施例A5本发明化合物A8的制备
Figure PCTCN2019074002-appb-000084
化合物A8的合成是用化合物1b-2(324mg,1.50mmol)和环丁甲醇(80.0mg,0.93mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A8(136mg,收率52%)。ESI[M+H] +=285.3
1H NMR(400MHz,d 6-DMSO)δ8.31(s,1H),7.68(d,J=0.8Hz,1H),7.33(t,J=7.3Hz,2H),7.26(t,J=7.3Hz,1H),7.16(d,J=7.2Hz,2H),6.23(q,J=7.2Hz,1H),4.23–3.99(m,2H),2.58-2.51(m,1H),2.03–1.89(m,2H),1.89-1.76(m,5H),1.76-1.69(m,2H).
实施例A6本发明化合物A9的制备
Figure PCTCN2019074002-appb-000085
化合物A9的制备是用化合物1b-2(216mg,1.0mmol)和(1-ethylcyclopropyl)methanol(100.0mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A9(56mg,收率19%)。ESI[M+H] +=299.3
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.79(s,1H),7.40-7.25(m,3H),7.21-7.14(m,2H),6.30(q,J=7.1Hz,1H),4.20(s,2H),1.87(d,J=7.1Hz,3H),1.56–1.50(m,2H),1.10–0.96(m,3H),0.64-0.51(m,4H).
实施例A7本发明化合物A10和化合物A11的制备
Figure PCTCN2019074002-appb-000086
1、Cyclobutane-1,1-diyldimethanol(10-2)的制备
Figure PCTCN2019074002-appb-000087
在冰水浴0℃下,将LAH(2.28g,0.06mol)以每1min加入10mmol,共分6次加入到 1,1-环丁基二甲酸(10-1)(4.32g,0.03mol)的THF(80mL)中,室温搅拌过夜。在0℃下,将Na 2SO 4.10H 2O(20g)每1min加入5g,共分4次加入反应体系,抽滤,滤饼用THF(150mL)洗涤,滤液经减压浓缩,硅胶柱层析分离纯化(乙酸乙酯/石油醚(v/v)=1/1),TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.2~0.3部分,得到无色油状化合物10-2(3.02g,收率87%)。ESI[M+H] +=116.1
2、目标化合物A10的制备
Figure PCTCN2019074002-appb-000088
化合物A10的制备是用化合物1b-2(432mg,2.00mmol)和10-2(648mg,5.58mmol)为原料按照通用操作A方法合成,粗产品经过柱层析纯化(甲醇/二氯甲烷(v/v)在1/100~1/10范围内的任一比例),TLC(甲醇/二氯甲烷(v/v)=1/50)检测,收集Rf=0.5~0.6部分,得到无色油状化合物A10(340mg,收率54%)。ESI[M+H] +=315.3
1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.82(s,1H),7.39-7.28(m,3H),7.21-7.16(m,2H),6.36(q,J=7.0Hz,1H),4.37-4.27(m,2H),3.52(q,J=11.4Hz,2H),2.02-1.91(m,2H),1.88(d,J=7.1Hz,3H),1.87-1.79(m,4H).
3、目标化合物A11的制备
Figure PCTCN2019074002-appb-000089
化合物A11的制备是用化合物A10(157mg,0.50mmol)和碘甲烷(85mg,0.60mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A11(15mg,收率9%)。ESI[M+H] +=329.2
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.79(s,1H),7.41-7.27(m,3H),7.24-7.18(m,2H),6.41(q,J=7.1Hz,1H),4.27(q,J=10.9Hz,2H),3.37(s,2H),3.33(s,3H),1.97-1.80(m,6H),1.90(d,J=7.1Hz,3H).
实施例A8本发明化合物A12的制备
Figure PCTCN2019074002-appb-000090
化合物A12的制备是用化合物1b-2(177mg,0.82mmol)和(3,3-二氟环丁基)甲醇(100mg,0.82mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物12(142mg,收率54%)。ESI[M+H] +=321.2.
1H NMR(400MHz,d 6-DMSO)δ8.32(s,1H),7.71(s,1H),7.33(t,J=7.3Hz,2H),7.26(t,J=7.3Hz,1H),7.16(d,J=7.2Hz,2H),6.21(q,J=7.1Hz,1H),4.30–3.93(m,2H),2.66–2.60(m,2H),2.42–2.24(m,3H),1.84(d,J=7.2Hz,3H).
实施例A9本发明化合物A13的制备
Figure PCTCN2019074002-appb-000091
1、1-((Tetrahydro-2H-pyran-2-yl)oxy)cyclopropanecarboxylic acid(13-2)的制备
Figure PCTCN2019074002-appb-000092
在室温下,将3,4-二氢-2H-吡喃(823mg,9.79mmol),13-1(1.00g,9.79mmol)和对甲基苯磺酸吡啶(123mg,0.49mmol)溶解在二氯甲烷(10mL)溶液中,室温搅拌2小时。将反应液浓缩后经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)=1/10),TLC(乙酸乙酯/石油醚(v/v)=1/5)检测,收集Rf=0.3~0.4部分,得到白色固体13-2(1.20g,收率66%)。
2、N-Methoxy-N-methyl-1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropanecarboxamide(13-3)的制备
Figure PCTCN2019074002-appb-000093
在室温下,将N,O-二甲羟胺盐酸盐(628mg,6.44mmol),13-2(1.20g,6.44mmol),HATU(2.45g,6.44mmol)和DIEA(1.67g,12.9mmol)溶解在DMF(10mL)溶液中,室温搅拌过夜。经TLC监测反应完全后,用水终止,乙酸乙酯(3×10mL)萃取。合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,经硅胶柱层析分离(乙酸乙酯/石油醚(v/v)=1/10),TLC(乙酸乙酯/石油醚(v/v)=1/5)检测,收集Rf=0.5~0.6部分,得白色固体13-3(1.20g,收率81%)。
3、2-Hydroxy-2-methylcyclobutan-1-one(13-4)的制备
Figure PCTCN2019074002-appb-000094
在室温下,将甲基溴化镁(1M的THF溶液,6.54mL,6.54mmol)用注射器以1mL/min的速度加至13-3(750mg,3.27mmol)的THF(10mL)溶液中,室温反应30分钟。经TLC监测反应完全后,用水终止,乙酸乙酯(3×15mL)萃取。合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,经硅胶柱层析分离(乙酸乙酯/石油醚(v/v)=1/10),TLC(乙酸乙酯/石油醚(v/v)=1/7)监测,收集Rf=0.5~0.6部分,得到无色油状化合物13-4(80mg,收率24%)。
4、目标化合物A13的制备
Figure PCTCN2019074002-appb-000095
在室温下,将盐酸二氧六环溶液(4M,0.15mL)一次性加到13-4(150mg,0.81mmol)的二氯甲烷(10mL)溶液中,室温下反应5分钟后,加入1b(190mg,0.81mmol),继续反应2小时。将反应体系减压浓缩得到粗产品,经过制备TLC纯化(甲醇/二氯甲烷(v/v)=1/10),收集Rf=0.3~0.4的部分得到无色油状化合物A13(35mg,收率14%)。ESI[M+H] +=299.1
1H NMR(400MHz,d 6-DMSO)δ8.35(d,J=6.3Hz,1H),7.74(s,1H),7.38–7.30(m,2H),7.29–7.27(m,1H),7.20–7.10(m,2H),6.15–6.11(m,1H),3.05–2.97(m,2H),2.31–2.28(m,1H),2.05–1.94(m,1H),1.84(dd,J=7.2,2.3Hz,3H),1.45(d,J=5.8Hz,3H).
实施例A10本发明化合物A14的制备
Figure PCTCN2019074002-appb-000096
化合物A14的制备是用化合物A10(157mg,0.50mmol)和碘乙烷(94mg,0.60mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物14(35mg,收率20%)。ESI[M+H] +=343.3
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.81(s,1H),7.39-7.25(m,3H),7.25-7.19(m,2H),6.39(q,J=7.1Hz,1H),4.29–4.25(m,2H),3.39(s,2H),3.47-3.45(m,2H),1.96-1.79(m,6H),1.90(d,J=7.1Hz,3H),1.01–1.10(m,3H)
实施例A11本发明化合物A15的制备
Figure PCTCN2019074002-appb-000097
化合物A15的制备是用化合物1b-2(100mg,0.46mmol)和羟甲基环丙烷(33mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.5~0.6的部分,得到无色油状化合物A15(83mg,收率66%)。ESI[M+H] +=271.3.
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.77(s,1H),7.40–7.27(m,3H),7.23–7.15(m,2H),6.38(q,J=7.2Hz,1H),4.05(qd,J=11.4,7.3Hz,2H),1.87(d,J=7.1Hz,3H),1.17–1.14(m,1H),0.66–0.43(m,2H),0.42–0.18(m,2H).
实施例A12本发明化合物A16的制备
Figure PCTCN2019074002-appb-000098
化合物A16的制备是用化合物1b-2(100mg,0.46mmol)和1-环丙基乙醇(39.6mg,0.46 mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物A16(96mg,收率73%)。ESI[M+H] +=285.3
1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.74(s,1H),7.38–7.28(m,3H),7.22–7.14(m,2H),6.43–6.29(m,1H),4.57–4.41(m,1H),1.87(d,J=7.1Hz,3H),1.34(t,J=6.2Hz,3H),1.12–0.95(m,1H),0.64–0.18(m,4H).
实施例A13本发明化合物A17的制备
Figure PCTCN2019074002-appb-000099
化合物A17的制备是用化合物1b-2(100mg,0.46mmol)和环丁醇(33.2mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到白色固体化合物A17(66mg,收率53%)。ESI[M+H] +=271.3
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.79(s,1H),7.39–7.27(m,3H),7.22–7.16(m,2H),6.36(q,J=7.1Hz,1H),5.19–5.02(m,1H),2.50–2.28(m,2H),2.21–2.07(m,2H),1.86(d,J=7.1Hz,3H),1.85–1.77(m,1H),1.73–1.56(m,1H).
实施例A14本发明化合物A18的制备
Figure PCTCN2019074002-appb-000100
1、2-Cyclobutylethanol(18-2)的制备
Figure PCTCN2019074002-appb-000101
在室温下,将LiAlH 4(133mg,3.50mmol)每1min加入1mmol,共分4次加入到环丁基乙酸(18-1)(200mg,1.75mmol)的THF(10mL)中,室温下反应2小时。反应体系用Na 2SO 4.10H 2O终止,抽滤,滤液浓缩得到无色油状化合物18-2(120mg,收率68%)。ESI[M+H] +=100.1.
2、目标化合物A18的制备
Figure PCTCN2019074002-appb-000102
化合物A18的制备是用化合物1b-2(100mg,0.46mmol)和2-环丁基乙醇(18-2)(46.1mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A18(84mg,收率61%)。ESI[M+H] +=299.3.
1H NMR(400MHz,CDCl 3)δ7.76(s,2H),7.36–7.32(m,3H),7.21–7.18(m,2H),6.37(q,J=7.1Hz,1H),4.26–3.88(m,2H),2.37–2.31(m,1H),2.06–2.00(m,2H),1.90–1.71(m,7H),1.68–1.64(m,2H).
实施例A15本发明化合物A19的制备
Figure PCTCN2019074002-appb-000103
1、(1-(Difluoromethyl)cyclobutyl)methanol(19-3)的制备
Figure PCTCN2019074002-appb-000104
在室温下,用注射器将DAST(484mg,3.0mmol)加入到19-1(705mg,2.0mmol)的CH 2Cl 2(10mL)溶液中,每1min加入1mmol,在3分钟内加完,室温搅拌5小时。经TLC监测反应完全后,用水终止,乙酸乙酯(3×15mL)萃取。合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗产品19-2。将粗产品溶解在THF(10mL)中,一次性加入TBAF(6.0mL,1mol/L in THF,6mmol),室温反应2小时。反应液减压浓缩后经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)在1/3~1/1范围内的任一比例),TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状化合物19-3(83mg,收率30%)。ESI[M+H] +=137.2
2、目标化合物A19的制备
Figure PCTCN2019074002-appb-000105
化合物A19的制备是用化合物1b-2(127mg,0.59mmol)和19-3(80mg,0.59mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.4的部分,得到无色油状化合物A19(35mg,收率18%)。ESI[M+H] +=335.3
1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.71(s,1H),7.40–7.27(m,3H),7.21–7.15(m,2H),6.40(q,J=7.2Hz,1H),4.91(q,J=57.6Hz,1H),4.25(m,2H),2.00-1.81(m,6H),1.86(d,J=7.1Hz,3H).
实施例A16本发明化合物A20的制备
Figure PCTCN2019074002-appb-000106
1、1-(Oxiran-2-yl)cyclobutan-1-ol(20-2)的制备
Figure PCTCN2019074002-appb-000107
在室温下,将m-CPBA(777mg,4.5mmol)分批加入到20-1(294mg,3.0mmol)的CH 2Cl 2(10mL)溶液中,每1min加入1mmol,在3分钟内加完,然后在室温搅拌48小时。经TLC监测反应完全后,用水终止,CH 2Cl 2(3×15mL)萃取。合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗产品20-2。粗产品未经进一步纯化直接用于下一步反应。
2、目标化合物A20的制备
Figure PCTCN2019074002-appb-000108
化合物A20的制备是用化合物1b-2(216mg,1.0mmol)和上一步的粗品20-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A20(78mg,收率25%)。ESI[M+H] +=313.3
实施例A17本发明化合物A21的制备
Figure PCTCN2019074002-appb-000109
化合物21-1按照20-2类似的方法制备得到粗品。
化合物A21的制备是用化合物1b-2(216mg,1.0mmol)和粗品21-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A21(56mg,收率17%)。ESI[M+H] +=327.3
实施例A18本发明化合物A22的制备
Figure PCTCN2019074002-appb-000110
1、1-(Oxiran-2-ylmethyl)cyclobutan-1-ol(22-2)的制备
Figure PCTCN2019074002-appb-000111
在冰浴下,将化合物环丁酮(500mg,7.13mmol)溶解在THF(15mL)中,用注射器将烯丙基溴化镁(28.5mL,14.27mmol,0.5mol/L)以2mL/min的速度滴加至体系,并控制温度在0℃以下,在此温度继续搅拌30分钟。经TLC监测体系反应完全,用饱和氯化铵终止反应,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品22-1(486mg,61%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=113.1
在冰浴下,将粗品化合物22-1(486mg,4.33mmol)溶解在二氯甲烷(10mL)中,分批加入间氯过氧苯甲酸(1.12g,6.49mmol),在5分钟加完。缓慢升至室温,继续搅拌2小时。经TLC监测体系反应完全,用饱和碳酸氢钠终止反应,用二氯甲烷(3×10mL)萃取, 合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品22-2(80mg,14%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=129.1
2、目标化合物A22的制备
Figure PCTCN2019074002-appb-000112
化合物A22的制备是用化合物1b-2(43mg,0.20mmol)和粗品22-2(80mg,0.62mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A22(10mg,收率15%)。ESI[M+H] +=327.1
1H NMR(400MHz,CDCl 3)δ7.87–7.60(m,2H),7.38–7.28(m,3H),7.22–7.12(m,2H),6.31(q,J=7.0Hz,1H),2.97–2.87(m,1H),2.65–2.57(m,1H),2.49–2.09(m,7H),2.05–1.92(m,2H),1.86(d,J=7.1Hz,3H),1.80–1.66(m,1H).
实施例A19本发明化合物A23的制备
Figure PCTCN2019074002-appb-000113
1、(1-Hydroxycyclobutyl)methyl(R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate(23-1)的制备
Figure PCTCN2019074002-appb-000114
化合物23-1的制备是用化合物1b-2(432mg,2.0mmol)和1-(羟甲基)环丁烷-1-醇(204mg,2.0mmol)为原料按照通用操作A方法合成,粗产品经过柱层析纯化(甲醇/二氯甲烷(v/v)在1/100~1/10范围内的任一比例),TLC(甲醇/二氯甲烷(v/v)=1/50)检测,收集Rf=0.4~0.5部分,得到无色油状化合物23-1(281mg,收率47%)。ESI[M+H] +=301.3
2、目标化合物A23的制备
Figure PCTCN2019074002-appb-000115
化合物A23的制备是用化合物23-1(150mg,0.50mmol)和碘甲烷(85mg,0.60mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A23(35mg,收率22%)。ESI[M+H] +=315.2
实施例A20本发明化合物A24的制备
Figure PCTCN2019074002-appb-000116
1、1-(Hydroxymethyl)cyclobutyl(R)-1-(1-phenylethyl)-1H-imidazole-5-carboxylate(24-1)的制备
Figure PCTCN2019074002-appb-000117
化合物24-1的制备是用化合物1b-2(632mg,3.0mmol)和1-(羟甲基)环丁烷-1-醇(306mg,3.0mmol)为原料按照通用操作A方法合成,粗产品经过柱层析纯化(甲醇/二氯甲烷(v/v)在1/100~1/10范围内的任一比例),TLC(甲醇/二氯甲烷(v/v)=1/50)检测,收集Rf=0.4~0.5部分,得到无色油状化合物24-1(147mg,收率16%)。ESI[M+H] +=301.3
2、目标化合物A24的制备
Figure PCTCN2019074002-appb-000118
化合物A24的制备是用化合物24-1(102mg,0.34mmol)和碘甲烷(48mg,0.34mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A24(15mg,收率14%)。ESI[M+H] +=315.2
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.79(s,1H),7.43-7.27(m,3H),7.26-7.18(m,2H),6.41(q,J=7.1Hz,1H),3.37(s,2H),3.25(s,3H),2.10-1.85(m,6H),1.90(d,J=7.1Hz,3H).
实施例A21本发明化合物A25的制备
Figure PCTCN2019074002-appb-000119
化合物A25的制备是用化合物1b-2(216mg,1.0mmol)和1-乙基环丁烷甲醇(114mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A25(189mg,收率60%)。ESI[M+H] +=313.3
实施例A22本发明化合物A26的制备
Figure PCTCN2019074002-appb-000120
化合物A26的制备是用化合物1b-2(216mg,1.0mmol)和3-(羟甲基)-环丁酮(100mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A26(102mg,收率34%)。ESI[M+H] +=299.3.
实施例A23本发明化合物A27的制备
Figure PCTCN2019074002-appb-000121
1、Cyclobutylmethanethiol(27-3)的制备
Figure PCTCN2019074002-appb-000122
化合物27-3的制备是用化合物27-1(200mg,2.32mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品27-3(130mg)。ESI[M+H] +=103.1
2、目标化合物A27的制备
Figure PCTCN2019074002-appb-000123
化合物A27的制备是用化合物1b-2(100mg,0.46mmol)和27-3(130mg,1.27mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A27(22mg,收率16%)。ESI[M+H] +=301.1
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.78(s,1H),7.38–7.28(m,3H),7.18(d,J=7.0Hz,2H),6.28(q,J=7.1Hz,1H),3.27–2.97(m,2H),2.51(dt,J=15.6,7.8Hz,1H),2.08(ddd,J=19.7,9.8,5.7Hz,2H),1.91–1.78(m,5H),1.70(dd,J=20.2,8.8Hz,2H).
实施例A24本发明化合物A28的制备
Figure PCTCN2019074002-appb-000124
1、(1-(Methoxymethyl)cyclobutyl)methanethiol(28-3)的制备
Figure PCTCN2019074002-appb-000125
化合物28-3的制备是用化合物28-1(200mg,1.54mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品28-3(156mg)。ESI[M+H] +=147.1
2、目标化合物A28的制备
Figure PCTCN2019074002-appb-000126
化合物A28的制备是用化合物1b-2(100mg,0.46mmol)和28-3(156mg,1.07mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A28(44mg,收率13%)。ESI[M+H] +=345.2
1H NMR(400MHz,CDCl 3)δ7.95(s,1H),7.81(s,1H),7.39–7.28(m,3H),7.18(d,J=7.0Hz, 2H),6.30(d,J=7.0Hz,1H),3.33(s,3H),3.30(s,2H),3.27(s,2H),1.94–1.73(m,9H).
实施例A25本发明化合物A29的制备
Figure PCTCN2019074002-appb-000127
1、(1-(Methoxymethyl)cyclobutyl)methanethiol(29-3)的制备
Figure PCTCN2019074002-appb-000128
化合物29-3的制备是用化合物29-1(200mg,2.77mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品29-3(94mg)。ESI[M+H] +=89.1
2、目标化合物A29的制备
Figure PCTCN2019074002-appb-000129
化合物A29的制备是用化合物1b-2(100mg,0.46mmol)和29-3(94mg,1.07mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A29(24mg,收率18%)。ESI[M+H] +=287.0
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.76(s,1H),7.39–7.27(m,3H),7.22–7.15(m,2H),6.28(q,J=6.9Hz,1H),5.87–5.71(m,1H),5.16–5.00(m,2H),3.16–2.89(m,2H),2.37(q,J=7.1Hz,2H),1.85(d,J=7.1Hz,3H).
实施例A26本发明化合物A30的制备
Figure PCTCN2019074002-appb-000130
化合物A30的制备是用化合物1b-2(100mg,0.46mmol)和1-甲基环丙醇(50mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A30(93mg,收率75%)。ESI[M+H] +=271.1
1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.79(s,1H),7.39–7.25(m,3H),7.21–7.14(m,2H), 6.27(q,J=7.0Hz,1H),1.83(d,J=7.1Hz,3H),1.55(s,3H),1.00–0.82(m,2H),0.76–0.60(m,2H).
实施例A27本发明化合物A31的制备
Figure PCTCN2019074002-appb-000131
化合物A31的制备是用化合物1b-2(100mg,0.46mmol)和1-甲基环丁醇(59mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A31(101mg,收率77%)。ESI[M+H] +=285.1
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.78(s,1H),7.34–7.26(m,3H),7.25–7.10(m,2H),6.38(q,J=7.1Hz,1H),2.45–2.00(m,4H),1.86(d,J=7.1Hz,3H),1.80–1.45(m,2H),1.49(s,3H).
实施例A28本发明化合物A32的制备
Figure PCTCN2019074002-appb-000132
化合物A32的制备是用化合物1b-2(100mg,0.46mmol)和1-乙基环丁醇(69mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物32(113mg,收率82%)。ESI[M+H] +=299.1
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.79(s,1H),7.35–7.28(m,3H),7.26–7.13(m,2H),6.39(q,J=7.1Hz,1H),2.50–2.28(m,2H),2.21–2.07(m,2H),1.87(d,J=7.1Hz,3H),1.80–1.45(m,4H),0.96(t,J=7.2Hz,3H).
实施例A29本发明化合物A33的制备
Figure PCTCN2019074002-appb-000133
化合物A33的制备是用化合物1b-2(100mg,0.46mmol)和(1-甲基环丁基)甲醇(69mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1) 并收集Rf=0.5~0.6的部分,得到无色油状化合物A33(108mg,收率79%)。ESI[M+H] +=299.1
1H NMR(400MHz,d 6-DMSO)δ8.29(s,1H),7.67(s,1H),7.37–7.30(m,2H),7.29–7.25(m,1H),7.17-7.15(m,2H),6.27(q,J=7.2Hz,1H),4.20–3.85(m,2H),1.90–1.75(m,2H),1.80–1.54(m,5H),1.65–1.40(m,2H).
实施例A30本发明化合物A34的制备
Figure PCTCN2019074002-appb-000134
化合物A34的制备是用化合物1b-2(100mg,0.46mmol)和1-环丁基-1-乙醇(69mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A34(99mg,收率72%)。ESI[M+H] +=299.1
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.78(s,1H),7.42–7.26(m,3H),7.25–7.14(m,2H),6.39(q,J=7.2Hz,1H),4.58–4.40(m,1H),2.59-2.50(m,1H),1.86(d,J=7.1Hz,3H),1.86-1.54(m,6H),1.34(t,J=6.2Hz,3H).
实施例A31本发明化合物A35的制备
Figure PCTCN2019074002-appb-000135
化合物A35的制备是用化合物1b-2(100mg,0.46mmol)和环戊醇(59mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A35(113mg,收率86%)。ESI[M+H] +=285.1
1H NMR(400MHz,CDCl 3)δ7.92(s,1H),7.78(s,1H),7.40–7.24(m,3H),7.20–7.12(m,2H),6.26(q,J=7.0Hz,1H),5.25–5.01(m,1H),1.98-2.02(m,2H),1.84(d,J=7.1Hz,3H),,1.95-1.61(m,6H).
实施例A32本发明化合物A36的制备
Figure PCTCN2019074002-appb-000136
化合物A36的制备使用化合物1b(108mg,0.5mmol)和1-(环氧乙烷-2-基)环戊烷-1-醇(64mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A36(75mg,收率46%)。ESI[M+H] +=327.3
实施例A33本发明化合物A37的制备
Figure PCTCN2019074002-appb-000137
化合物A37的制备使用化合物1b(108mg,0.5mmol)和1-(环氧乙烷-2-基)环己-1-醇(71mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A37(78mg,收率46%)。ESI[M+H] +=341.2
1H NMR(400MHz,CDCl 3)δ8.11(s,1H),7.87(s,1H),7.45–7.33(m,4H),7.29–7.26(m,1H),6.50–6.39(m,1H),3.37–3.31(m,1H),2.83–2.71(m,2H),2.29–2.11(m,2H),1.87(d,J=7.1Hz,3H),1.64–1.32(m,8H).
实施例A34本发明化合物A38的制备
Figure PCTCN2019074002-appb-000138
化合物A38的制备使用化合物1b(108mg,0.5mmol)和1-(环氧乙烷-2-基甲基)环戊烷-1-醇(71mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A38(89mg,收率52%)。ESI[M+H] +=341.2
实施例A35本发明化合物A39的制备
Figure PCTCN2019074002-appb-000139
化合物A39的制备使用化合物1b(108mg,0.5mmol)和1-(环氧乙烷-2-基甲基)环己-1-醇(78mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物A39(76mg,收率43%)。ESI[M+H] +=355.2
实施例A36本发明化合物A40的制备
Figure PCTCN2019074002-appb-000140
1、(1-((Methylthio)methyl)cyclobutyl)methanol(40-3)的制备
Figure PCTCN2019074002-appb-000141
40-3的制备是以40-1(1.0g,3.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物40-2(631mg)。ESI[M+H] +=385.3
在室温下,将粗品化合物40-2(631mg,1.5mmol)溶解在THF(10mL)中,一次性加入TBAF(6.0mL,1mol/L in THF,6.0mmol),室温反应2小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品40-3(221mg,三步收率50%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=147.1
2、目标化合物A40的制备
Figure PCTCN2019074002-appb-000142
化合物A40的制备是用化合物1b-2(216mg,1.0mmol)和40-3(146mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A40(75mg,收率22%)。ESI[M+H] +=345.3
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.80(s,1H),7.42–7.28(m,3H),7.25–7.16(m,2H),6.40(q,J=7.2Hz,1H),4.43–4.14(m,2H),2.75(s,2H),2.10(s,3H),1.97–1.90(m,6H),1.88(d, J=7.1Hz,3H).
实施例A37本发明化合物A41的制备
Figure PCTCN2019074002-appb-000143
1、(1-((Methyldisulfanyl)methyl)cyclobutyl)methanol(41-3)的制备
Figure PCTCN2019074002-appb-000144
41-2的制备是以41-1(1.0g,3.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物41-2(631mg)。ESI[M+H] +=417.3
在室温下,将粗品化合物41-2(631mg,1.5mmol)溶解在THF(10mL)中,一次性加入TBAF(6.0mL,1mol/L in THF,6.0mmol),室温反应2小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品41-3(221mg,三步收率41%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=179.1
2、(1-((Methyldisulfanyl)methyl)cyclobutyl)methanethiol(41-4)的制备
Figure PCTCN2019074002-appb-000145
41-4的制备是以41-3(221mg,1.2mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物41-4(95mg,收率40%)。ESI[M+H] +=195.0
3、目标化合物A41的制备
Figure PCTCN2019074002-appb-000146
化合物A41的制备是用化合物1b-2(100mg,0.46mmol)和41-4(95mg,0.49mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物A41(104mg,收率58%)。ESI[M+H] +=393.2
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.79(s,1H),7.42–7.28(m,3H),7.23–7.12(m,2H),6.36(q,J=7.1Hz,1H),4.45–3.98(m,4H),2.95(s,3H),2.09–1.90(m,6H),1.88(d,J=7.1Hz,3H).
实施例A38本发明化合物A42的制备
Figure PCTCN2019074002-appb-000147
1、(1-((Ethylthio)methyl)cyclobutyl)methanol(42-3)的制备
Figure PCTCN2019074002-appb-000148
化合物42-2的制备是用化合物42-1(1.4g,4.0mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品42-2(758mg)。ESI[M+H] +=399.3
在室温下,将粗品化合物42-2(758mg,1.9mmol)溶解在THF(10mL)中,一次性加入TBAF(7.6mL,1mol/L in THF,7.6mmol),室温反应2小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品42-3(214mg,三步反应收率33%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=161.2
2、目标化合物A42的制备
Figure PCTCN2019074002-appb-000149
化合物A42的制备是用化合物1b-2(216mg,1.0mmol)和42-3(192mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收 集Rf=0.5~0.6的部分,得到无色油状化合物A42(88mg,收率25%)。ESI[M+H] +=359.3
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.81(s,1H),7.41–7.25(m,3H),7.22–7.15(m,2H),6.37(q,J=7.2Hz,1H),4.41–4.12(m,2H),2.77–2.68(m,4H),1.95–1.88(m,6H),1.85(d,J=7.1Hz,3H),1.30(t,J=7.1Hz,3H).
实施例A39本发明化合物A43的制备
Figure PCTCN2019074002-appb-000150
1、(1-(Methylthio)cyclopropyl)methanol(43-3)的制备
Figure PCTCN2019074002-appb-000151
43-2的制备是以43-1(689mg,4.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物43-2(402mg)。ESI[M+H] +=203.3
在室温下,将粗品化合物43-2(402mg,1.99mmol)溶解在CH 2Cl 2(5mL)中,一次性加入HCl/Dioxane(0.5mL,4mol/L in THF,2mmol),室温反应5分钟。经TLC监测体系反应完全,反应体系未经任何处理直接用于下一步反应。ESI[M+H] +=119.1
2、目标化合物A43的制备
Figure PCTCN2019074002-appb-000152
化合物A43的制备是用化合物1b-2(216mg,1.0mmol)和上一步的反应体系43-3为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物A43(47mg,收率15%)。ESI[M+H] +=317.3
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.80(s,1H),7.43–7.28(m,3H),7.25–7.18(m,2H), 6.39(q,J=7.1Hz,1H),4.35–4.24(m,2H),2.15(s,3H),1.88(d,J=7.1Hz,3H),0.68–0.52(m,4H).
实施例A40本发明化合物A44的制备
Figure PCTCN2019074002-appb-000153
1、(1-((Methylthio)methyl)cyclopropyl)methanol(44-3)的制备
Figure PCTCN2019074002-appb-000154
44-2的制备是以44-1(1.70g,5.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物44-2(871mg)。ESI[M+H] +=371.3
在室温下,将粗品化合物44-2(871mg,2.35mmol)溶解在THF(10mL)中,一次性加入TBAF(9.4mL,1mol/L in THF,9.4mmol),室温反应2小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品44-3(165mg,三步收率25%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=133.2
2、目标化合物A44的制备
Figure PCTCN2019074002-appb-000155
化合物A44的制备是用化合物1b-2(216mg,1.0mmol)和44-3(160mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物A44(247mg,收率82%)。ESI[M+H] +=331.3
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.82(s,1H),7.41–7.28(m,3H),7.23–7.16(m,2H),6.37(q,J=7.1Hz,1H),4.31–4.21(m,2H),2.60(d,J=1.5Hz,2H),2.11(s,3H),1.87(d,J=7.1Hz,3H),0.66–0.52(m,4H).
实施例A41本发明化合物A45的制备
Figure PCTCN2019074002-appb-000156
45的制备是以45-1(244mg,2.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物45-2(171mg,两步反应收率621%)。ESI[M+H] +=139.1
化合物A45的制备是用化合物1b-2(216mg,1.0mmol)和45-2(166mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物A45(45mg,收率14%)。ESI[M+H] +=313.2
1H NMR(400MHz,CDCl 3)δ7.91(d,J=0.6Hz,1H),7.76(s,1H),7.39–7.27(m,3H),7.21–7.07(m,2H),6.22(q,J=7.1Hz,1H),3.12(d,J=7.3Hz,2H),2.75–2.55(m,2H),2.44–2.31(m,1H),2.30–2.13(m,2H),1.85(d,J=7.1Hz,3H).
实施例A42本发明化合物A46的制备
Figure PCTCN2019074002-appb-000157
1、(1-((Methylthio)methyl)cyclobutyl)methanol(46-3)的制备
Figure PCTCN2019074002-appb-000158
化合物46-2的制备是用化合物46-1(1.77g,5.0mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品46-2(1.3g)。ESI[M+H] +=385.3
在室温下,将粗品化合物46-2(1.3g,3.4mmol)溶解在THF(10mL)中,一次性加入TBAF(13.6mL,1mol/L in THF,13.6mmol),室温反应2小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品46-3(438mg,三步反应收率60%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=147.2
2、目标化合物A46的制备
Figure PCTCN2019074002-appb-000159
化合物46-4的制备是用化合物46-3(438mg,3.0mmol)为初始原料按照通用操作C方法合成,得到无色油状化合物46-4(197mg,两步反应收率35%)。ESI[M+H]+=163.1
化合物A46的制备是用化合物1b-2(216mg,1.0mmol)和46-2(194mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物A46(120mg,收率33%)。ESI[M+H] +=361.1
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.75(s,1H),7.40–7.28(m,3H),7.21–7.15(m,2H),6.18(q,J=7.2Hz,1H),2.77–2.66(m,4H),2.11(s,3H),1.90–1.85(m,6H),1.89(d,J=7.1Hz,3H).
实施例B1本发明化合物B1的制备
Figure PCTCN2019074002-appb-000160
1、(R)-1-(1-Phenylethyl)-1H-imidazole-5-carbonyl chloride(1b)的制备
Figure PCTCN2019074002-appb-000161
在冰水浴0℃下,用注射器将(COCl) 2(2mL)以1mL/min的速度缓慢加至1b-2(200mg,0.92mmol)的二氯甲烷(20mL)溶液,室温反应1小时。反应液经过减压浓缩得到白色固体1b(220mg,粗品)。
2、目标化合物B1的制备
Figure PCTCN2019074002-appb-000162
在冰水浴0℃下,将上一步制备的1b加入(S)-5-羟甲基二氢呋喃-2-酮(107mg,0.92mmol) 和三乙胺(2.81g,27.8mmol)的二氯甲烷(30mL)溶液里,加完后继续反应1小时。将反应液减压浓缩得到粗品,经过硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状化合物B1(75mg,总收率26%)。ESI[M+H] +=315.3
1H NMR(400MHz,d 6-DMSO)δ8.35(s,1H),7.71(d,J=0.8Hz,1H),7.35-7.32(m,2H),7.28–7.26(m,1H),7.19–7.17(m,2H),6.23–6.21(m,1H),4.80–4.78(m,1H),4.40(dd,J=12.0,2.8Hz,1H),4.27–4.22(m,1H),2.49-2.47(m,2H),2.26–2.25(m,1H),1.96-1.91(m,1H),1.85(d,J=7.2Hz,3H).
实施例B2本发明化合物B2的制备
Figure PCTCN2019074002-appb-000163
在冰水浴0℃下,将步骤1制得的1b加入(S)-(-)-4-羟甲基-2(5H)-呋喃酮(65mg,0.56mmol)和三乙胺(113mg,1.12mmol)的二氯甲烷(5mL)溶液里,加完后继续反应1小时。将反应液减压浓缩得到粗品,经过硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.4~0.5部分,得到无色油状化合物B2(20mg,两步反应收率12%)。ESI[M+H] +=313.2
1H NMR(400MHz,d 6-DMSO)δ8.34(s,1H),7.73–7.71(d,J=0.8Hz,1H),7.59(s,1H),7.36–7.32(m,2H),7.29–7.27(m,1H),7.17–7.15(m,2H),6.24–6.22(m,1H),6.18–6.16(m,1H),5.47(d,J=1.6Hz,1H),4.57(dd,J=12.0,3.2Hz,1H),4.37(dd,J=12.0,4.4Hz,1H),1.83(d,J=7.6Hz,3H).
实施例B3本发明化合物B3的制备
Figure PCTCN2019074002-appb-000164
化合物B3的制备是用化合物1b(234mg,1.0mmol)和(S)-3-羟基-γ-丁内酯(102mg,1.0mmol)为原料,按照实施例B1的方法合成化合物B3。ESI[M+H] +=301.2
实施例B4本发明化合物B4的制备
Figure PCTCN2019074002-appb-000165
化合物B4的制备是用化合物1b(234mg,1.0mmol)和(R)-4-hydroxyoxetan-2-one(88mg,1.0mmol)为原料,按照实施例B1的方法制得化合物B4。ESI[M+H] +=287.2
实施例B5本发明化合物B5的制备
Figure PCTCN2019074002-appb-000166
在冰水浴0℃下,将1b加入3-羟甲基-3-甲基-1-氧杂环丁烷(102mg,1.00mmol)和吡啶(79.1mg,1.00mmol)的二氯甲烷(10mL)溶液里,加完后继续反应1小时。将反应液减压浓缩得到粗品,经过硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得无色油状化合物B5(170mg,两步反应收率57%)。ESI[M+H] +=301.3
1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.85(s,1H),7.44–7.29(m,3H),7.24–7.16(m,2H),6.39(q,J=7.0Hz,1H),4.51(dd,J=6.1,2.0Hz,2H),4.42(dd,J=6.1,1.5Hz,2H),4.39–4.30(m,2H),1.90(d,J=7.1Hz,3H),1.35(s,3H).
实施例B6本发明化合物B6的制备
Figure PCTCN2019074002-appb-000167
化合物B6的制备是用化合物1b(234mg,1.0mmol)和(3-methoxyoxetan-3-yl)methanol(118mg,1.0mmol)为原料,按照实施例B1的方法制得化合物B6。ESI[M+H] +=317.2
1H NMR(400MHz,d 6-DMSO)δ8.29(s,1H),7.65(s,1H),7.32(t,J=7.3Hz,2H),7.25(t,J=7.3 Hz,1H),7.17(d,J=7.2Hz,2H),6.24–6.22(m,1H),4.39–4.22(m,6H),3.75(s,3H),1.88(d,J=7.2Hz,3H).
实施例B7本发明化合物B7的制备
Figure PCTCN2019074002-appb-000168
化合物B7的合成是用化合物1b(234mg,1.0mmol)和(3-fluorooxetan-3-yl)methanol(106mg,1.0mmol)为原料,按照实施例B1的方法制得化合物B7。ESI[M+H] +=305.2
1H NMR(400MHz,d 6-DMSO)δ8.33(s,1H),7.74(s,1H),7.35(t,J=7.3Hz,2H),7.25–7.17(m,3H),6.24–6.22(m,1H),4.70–4.51(m,6H),1.91(d,J=7.2Hz,3H).
实施例B8本发明化合物B8的制备
Figure PCTCN2019074002-appb-000169
1、(3-Methylthietan-3-yl)methanol(8-2)的制备
Figure PCTCN2019074002-appb-000170
Na(2.4mg,0.104mmol)加入到2-(羟甲基)-2-甲基-1,3-丙二醇(8-1)(3.6g,0.03mol)和碳酸二乙酯(3.54g,0.03mol)的混合溶液中,120℃下反应1小时后,减压浓缩后加入预先干燥的KSCN(3.54g,0.03mol),180℃继续反应一小时。将反应体系用饱和氯化铵溶液(10mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品。粗品经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/30~1/5范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/5)检测,收集Rf=0.3~0.4部分,得到无色油状混合物8-2(1.3g,收率37%)。
2、目标化合物B8的制备
Figure PCTCN2019074002-appb-000171
化合物B8的制备是用化合物1b-2(324mg,1.50mmol)和8-2(306mg,2.59mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分得到无色油状化合物B8(300mg,收率63%)。ESI[M+H] +=317.2
1H NMR(400MHz,CDCl 3)δ7.85(s,2H),7.41–7.28(m,3H),7.23–7.17(m,2H),6.38(q,J=7.0Hz,1H),4.24(q,J=10.9Hz,2H),3.08(d,J=9.4Hz,2H),2.92(dd,J=9.4,1.1Hz,2H),1.89(d,J=7.1Hz,3H),1.33(s,3H).
实施例B9本发明化合物B9的制备
Figure PCTCN2019074002-appb-000172
化合物B9的制备是用化合物1b-2(200mg,0.93mmol)和3-乙基-3-氧杂环丁烷甲醇(107mg,0.93mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),并收集Rf=0.3~0.4的部分得到无色油状化合物B9(210mg,收率72%)。ESI[M+H] +=315.3
1H NMR(400MHz,d 6-DMSO)δ8.33(s,1H),7.71(d,J=0.8Hz,1H),7.33(t,J=7.3Hz,2H),7.26(dd,J=8.5,6.0Hz,1H),7.16(d,J=7.2Hz,2H),6.23(q,J=7.2Hz,1H),4.34–4.18(m,6H),1.85(d,J=7.2Hz,3H),1.63(q,J=7.5Hz,2H),0.85–0.81(m,3H).
实施例B10本发明化合物B10的制备
Figure PCTCN2019074002-appb-000173
1、2-(Hydroxymethyl)-2-propylpropane-1,3-diol(10-2)的制备
Figure PCTCN2019074002-appb-000174
在室温下,将戊醛(10-1)(8.0g,0.093mol)以1mL/min的速度缓慢滴加到乙腈(470mg,2.57mmol),多聚甲醛(470mg,2.57mmol)和NaOH(470mg,2.57mmol)的混合体系中,滴加完后在80℃下反应1小时。经TLC监测反应完全,用饱和氯化铵溶液(20mL)终止反应,经二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥后,抽滤,减压浓缩得到粗品,经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/1~10/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯)检测,收集Rf=0.2~0.3部分,得到无色油状化合物10-2(7.2g,收率52%)。
2、(3-Propyloxetan-3-yl)methanol(10-3)的制备
Figure PCTCN2019074002-appb-000175
将10-2(1.0g,6.75mmol),碳酸二乙酯(797mg,6.75mmol)和K 2CO 3(7.7mg,0.056mmol)的混合体系在125℃下反应3小时。经TLC监测反应完全,反应用饱和氯化铵溶液(20mL)终止,经二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥后,抽滤,减压浓缩得到粗品,经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分, 得到无色油状化合物10-3(338mg,收率38%)。
3、目标化合物B10的制备
Figure PCTCN2019074002-appb-000176
化合物B10的制备是用化合物1b-2(324mg,1.50mmol)和10-3(338mg,2.60mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分得到无色油状化合物B10(130mg,收率26%)。ESI[M+H] +=329.4
1H NMR(400MHz,CDCl 3)δ7.87(s,1H),7.81(s,1H),7.42–7.29(m,3H),7.23–7.16(m,2H),6.38(q,J=7.0Hz,1H),4.51–4.34(m,6H),1.89(d,J=7.1Hz,3H),1.75–1.67(m,2H),1.39–1.22(m,3H),0.94(t,J=7.3Hz,3H).
实施例B11本发明化合物B11,B12,B13,B14,B15的制备
Figure PCTCN2019074002-appb-000177
1、目标化合物B11的制备
Figure PCTCN2019074002-appb-000178
化合物B11的制备是用化合物1b-2(200mg,0.93mmol)和3,3-双羟甲基-1-氧杂环丁烷(161mg,1.36mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.4的部分得到无色油状化合物B11(170mg,收率41%)。ESI[M+H] +=317.2
1H NMR(400MHz,d 6-DMSO)δ8.31(s,1H),7.71(s,1H),7.34(t,J=7.3Hz,2H),7.26(t,J=7.3Hz,1H),7.18(d,J=7.2Hz,2H),6.25–6.23(m,1H),4.98(t,J=5.4Hz,1H),4.39–4.22(m,6H),3.60(d,J=5.4Hz,2H),1.85(d,J=7.2Hz,3H).
2、目标化合物B12的制备
Figure PCTCN2019074002-appb-000179
化合物B12的制备是用化合物B11(70.0mg,0.22mmol)和碘甲烷(565mg,3.98mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到无色油状化合物B12(8.0mg,收率11%)。ESI[M+H] +=331.3
1H NMR(400MHz,d 6-DMSO)δ8.20(d,J=2.0Hz,1H),7.90(s,1H),7.40–7.40(m,3H),7.26–7.25(m,2H),6.47(brs,1H),6.54–6.47(m,6H),3.63(s,2H),3.36(s,3H),1.94–1.93(m,3H).
3、目标化合物B13的制备
Figure PCTCN2019074002-appb-000180
在室温下,用注射器将乙酰氯(17.3mg,0.22mmol)以1mL/min的速度缓慢加入到化合物B11(70.0mg,0.22mmol)和三乙胺(45mg,0.44mmol)的二氯甲烷(5mL)溶液中,室温下反应30分钟。反应液经减压浓缩后,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/3)并收集 Rf=0.4~0.6的部分得到无色油状化合物B13(39.0mg,收率49%)。ESI[M+H] +=359.2
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.80(s,1H),7.38–7.31(m,3H),7.20–7.18(m,2H),6.34–6.32(m,1H),4.53–4.43(m,6H),4.33(s,2H),2.07(s,3H),1.88(d,J=7.2Hz,3H).
4、目标化合物B14的制备
Figure PCTCN2019074002-appb-000181
将化合物B11(316mg,1.0mmol)溶于二氯亚砜(10mL)中,60℃下反应1小时。反应液经减压浓缩后,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分得到无色油状化合物B14(39.0mg,收率12%)。ESI[M+H] +=335.2
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.81(s,1H),7.37–7.30(m,3H),7.21–7.19(m,2H),6.34–6.32(m,1H),4.53–4.43(m,6H),3.95(s,2H),1.89(d,J=7.2Hz,3H).
5、目标化合物B15的制备
Figure PCTCN2019074002-appb-000182
在冰水浴0℃下,将甲烷磺酰氯(25.2mg,0.22mmol)加入到化合物B11(70.0mg,0.22mmol)和Et 3N(44.4mg,0.44mmol)的二氯甲烷(20mL)溶液中,在室温下反应过夜。反应液浓缩,粗品经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,得到无色油状化合物B15(54.0mg,收率62%)。ESI[M+H] +=395.2
1H NMR(400MHz,d 6-DMSO)δ8.33(s,1H),7.79(d,J=0.8Hz,1H),7.34(t,J=7.3Hz,2H),7.27(t,J=7.3Hz,1H),7.18(d,J=7.2Hz,2H),6.26–6.17(m,1H),4.52–4.33(m,8H),3.22(s,3H),1.85(d,J=7.2Hz,3H).
实施例B12本发明化合物B16的制备
Figure PCTCN2019074002-appb-000183
1、(R)-(3-Formyloxetan-3-yl)methyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate(16-1)的制备
Figure PCTCN2019074002-appb-000184
在冰水浴0℃下,将Dess-Martin(848mg,2.0mmol)每10min加入0.2mmol,共分10次加至B11(316mg,1.0mmol)的二氯甲烷(30mL)溶液,反应体系在室温反应2小时。反应液浓缩,粗品经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,得到无色油状化合物16-1(151mg,收率48%)。ESI[M+H] +=315.2
2、目标化合物B16的制备
Figure PCTCN2019074002-appb-000185
将DAST(77mg,0.48mmol)加入到16-1(151mg,0.48mmol)的二氯甲烷(20mL)溶液,反应体系在室温反应过夜。经TLC监测反应完全后,反应液减压浓缩,粗品经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状化合物B16(32mg,收率20%)。ESI[M+H] +=337.2
1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.85(s,1H),7.40–7.27(m,3H),7.21–7.15(m,2H),6.30(q,J=7.2Hz,1H),4.90(q,J=57.6Hz,1H),4.45–4.22(m,6H),1.86(d,J=7.1Hz,3H).
实施例B13本发明化合物B17的制备
Figure PCTCN2019074002-appb-000186
1、Tert-butyl((3-(1-methoxyethyl)oxetan-3-yl)methoxy)diphenylsilane(17-2)的制备
Figure PCTCN2019074002-appb-000187
化合物17-2的制备是用化合物17-1(200mg,0.54mmol)和碘甲烷(77mg,0.54mmol)为原料按照通用操作B方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/5)并收集Rf=0.3~0.4的部分得到无色油状化合物17-2(180mg,收率87%)。
2、(3-(1-Methoxyethyl)oxetan-3-yl)methanol(17-3)的制备
Figure PCTCN2019074002-appb-000188
TBAF(1M,2.34mL,2.34mmol)加入到17-2(180mg,0.47mmol)的THF溶液中,室温反应30分钟。反应液浓缩,残留物经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,得到无色油状化合物17-3(40mg,收率58%)。
3、目标化合物B17的制备
Figure PCTCN2019074002-appb-000189
化合物B17的制备是用化合物1b-2(59mg,0.27mmol)和17-3(40mg,0.27mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分得到无色油状化合物B17(61mg,收率65%)。ESI[M+H] +=345.3
1H NMR(400MHz,CDCl 3)δ7.80(s,2H),7.40–7.28(m,3H),7.19(d,J=7.1Hz,2H),6.38–6.36(m,1H),4.62–4.34(m,6H),3.67–3.58(m,1H),3.34(d,J=6.9Hz,3H),1.88(d,J=7.1Hz,3H),1.19(t,J=6.2Hz,3H).
实施例B14本发明化合物B18的制备
Figure PCTCN2019074002-appb-000190
1、3-Ethyloxetan-3-ol(18-1)的制备
Figure PCTCN2019074002-appb-000191
在冰浴下,将化合物3-氧杂环丁酮(360mg,5mmol)溶解在THF(5mL)中,用注射器将乙基溴化镁(6.0mL,6mmol,1.0mol/L)以1mL/min的速度滴加至体系,并控制温度在0℃以下,在此温度继续搅拌30分钟。经TLC监测体系反应完全,用饱和氯化铵终止反应,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品18-1(455mg,89%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=103.1
2、目标化合物B18的制备
Figure PCTCN2019074002-appb-000192
化合物B18的制备是用化合物1b-2(200mg,0.92mmol)和18-1(153mg,1.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物B18(143mg,收率52%)。ESI[M+H] +=301.3
1H NMR(400MHz,CDCl 3)δ7.99(s,1H),7.85(s,1H),7.48–7.29(m,3H),7.26–7.08(m,2H),6.31(d,J=6.8Hz,1H),4.78(dd,J=24.8,7.5Hz,2H),4.64–4.50(m,2H),2.24–2.05(m,2H),1.90(d,J=7.0Hz,3H),0.91(t,J=7.5Hz,3H).
实施例B15本发明化合物B19的制备
Figure PCTCN2019074002-appb-000193
1、3-Ethyloxetan-3-ol(19-1)的制备
Figure PCTCN2019074002-appb-000194
在冰浴下,将化合物3-氧杂环丁酮(360mg,5mmol)溶解在THF(5mL)中,用注射器将丙基溴化镁(6.0mL,6mmol,1.0mol/L)以1mL/min的速度滴加至体系,并控制温度在0℃以下,在此温度继续搅拌30分钟。经TLC监测体系反应完全,用饱和氯化铵终止反应,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品19-1(486mg,84%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=117.1
2、目标化合物B19的制备
Figure PCTCN2019074002-appb-000195
化合物B19的制备是用化合物1b-2(200mg,0.92mmol)和19-1(174mg,1.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物B19(120mg,收率41%)。ESI[M+H] +=315.4
1H NMR(400MHz,CDCl 3)δ7.79(s,2H),7.41–7.27(m,3H),7.19–7.11(m,2H),6.26(d,J=7.1Hz,1H),4.80(d,J=7.3Hz,1H),4.74(d,J=7.3Hz,1H),4.57(t,J=7.2Hz,2H),2.10(td,J=7.1,3.0Hz,2H),1.87(d,J=7.1Hz,3H),1.35–1.26(m,2H),0.89(t,J=7.4Hz,3H).
实施例B16本发明化合物B20的制备
Figure PCTCN2019074002-appb-000196
1、1-(Oxiran-2-yl)ethan-1-ol(20-1)的制备
Figure PCTCN2019074002-appb-000197
在冰浴0℃下,将化合物间氯过氧苯甲酸(518mg,3mmol)分批加至3-丁烯-2-醇(144mg,2mmol)的二氯甲烷(10mL)溶液中,在2分钟内加完,室温搅拌4小时。经TLC监测体系反应完全,用饱和碳酸钠终止反应,用二氯甲烷(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品20-1(98mg,56%),粗品未经纯化直接用于下一步反应。
2、目标化合物B20的制备
Figure PCTCN2019074002-appb-000198
化合物B20的制备是用化合物1b-2(43mg,0.20mmol)和20-1(35mg,0.40mmol)为原 料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物B20(20mg,收率35%)。ESI[M+H] +=287.1
1H NMR(400MHz,CDCl 3)δ8.10(s,1H),7.93(s,1H),7.45–7.31(m,3H),7.25–7.17(m,2H),6.29–6.23(m,1H),5.18–4.96(m,1H),3.21–3.12(m,1H),2.83–2.69(m,2H),1.91(d,J=7.0Hz,3H),1.42–1.39(m,3H)
实施例B17本发明化合物B21的制备
Figure PCTCN2019074002-appb-000199
在室温下,将m-CPBA(117mg,0.68mmol)加入到21-1(100mg,0.34mmol)的二氯甲烷(10mL)中,每1min加入0.2mmol,在4分钟内加完,然后在室温搅拌48小时。经TLC监测反应完全后,反应液减压浓缩,粗品经硅胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚=1/1)检测,收集Rf=0.4~0.5部分,得到无色油状化合物B21(20mg,收率19%)。ESI[M+H] +=315.2
实施例B18本发明化合物B22的制备
Figure PCTCN2019074002-appb-000200
1、3-(Oxiran-2-ylmethyl)oxetan-3-ol(22-2)的制备
Figure PCTCN2019074002-appb-000201
在室温下,将m-CPBA(777mg,4.5mmol)分批加入到22-1(342mg,3.0mmol)的CH 2Cl 2(10mL)溶液中,每1min加入1mmol,在3分钟内加完,然后在室温搅拌48小时。经TLC监测反应完全后,用水终止,CH 2Cl 2(3×15mL)萃取。合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗产品22-2。粗产品未经进一步纯化直接用于下一步 反应。
2、目标化合物B22的制备
Figure PCTCN2019074002-appb-000202
化合物B22的制备是用化合物1b-2(216mg,1.0mmol)和上一步的粗品22-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.4的部分,得到无色油状化合物B22(66mg,收率20%)。ESI[M+H] +=329.2
实施例B19本发明化合物B23的制备
Figure PCTCN2019074002-appb-000203
化合物B23的合成使用化合物1b-2(216mg,1.0mmol)和thietan-3-ylmethanol(104mg,1.0mmol)为原料按照通用操作A方法合成,粗产品制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到无色油状化合物B23(180mg,收率60%)。ESI[M+H] +=303.2
实施例B20本发明化合物B24的制备
Figure PCTCN2019074002-appb-000204
化合物B24的合成使用化合物1b-2(216mg,1.0mmol)和(3-(methoxymethyl)thietan-3-yl)methanol(148mg,1.0mmol)为原料按照通用操作A方法合成,粗产品制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到无色油状化合物B24(150mg,收率43%)。ESI[M+H] +=347.2
1H NMR(400MHz,CDCl 3)δ7.90(s,1H),7.62(s,1H),7.42–7.27(m,3H),7.21–7.15(m,2H),6.20–6.15(m,1H),4.24–4.08(m,4H),3.69(s,3H),3.08–2.93(m,4H),1.88(d,J=7.1Hz,3H).
实施例B21本发明化合物B25的制备
Figure PCTCN2019074002-appb-000205
化合物B25的制备使用化合物1b(108mg,0.5mmol)和2-(3,3-dimethyloxiran-2-yl)propan-2-ol(65mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物B25(62mg,收率38%)。ESI[M+H] +=329.2
实施例B22本发明化合物B26的制备
Figure PCTCN2019074002-appb-000206
化合物B26的制备使用化合物1b(108mg,0.5mmol)和3-(oxiran-2-yl)pentan-3-ol(65mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物B26(63mg,收率38%)。ESI[M+H] +=329.3
实施例B23本发明化合物B27的制备
Figure PCTCN2019074002-appb-000207
化合物B27的制备使用化合物1b(108mg,0.5mmol)和2-methyl-1-(oxiran-2-yl)propan-2-ol(58mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物B27(89mg,收率57%)。ESI[M+H] +=315.2
实施例B24本发明化合物B28的制备
Figure PCTCN2019074002-appb-000208
1、3-Methyloxetan-3-ol(28-1)的制备
Figure PCTCN2019074002-appb-000209
在冰浴下,将化合物3-氧杂环丁酮(360mg,5mmol)溶解在THF(5mL)中,用注射器将甲基溴化镁(6.0mL,6mmol,1.0mol/L)以1mL/min的速度滴加至体系,并控制温度在0℃以下,在此温度继续搅拌30分钟。经TLC监测体系反应完全,用饱和氯化铵终止反应,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品28-1(352mg,80%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=89.1
2、目标化合物B28的制备
Figure PCTCN2019074002-appb-000210
化合物B28的制备是用化合物1b-2(200mg,0.92mmol)和28-1(132mg,1.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物B28(150mg,收率57%)。ESI[M+H] +=287.2
1H NMR(400MHz,CDCl 3)δ7.79(s,2H),7.39–7.28(m,3H),7.20–7.10(m,2H),6.27(q,J=7.1Hz,1H),4.80(dd,J=26.3,7.2Hz,2H),4.60–4.48(m,2H),1.87(d,J=7.1Hz,3H),1.73(s,3H).
实施例B25本发明化合物B29的制备
Figure PCTCN2019074002-appb-000211
化合物29-2的制备是用化合物29-1(264mg,3.0mmol)为初始原料按照通用操作C方法 合成,得到无色油状粗品6-1-1-2(134mg,两步反应收率43%)。ESI[M+H] +=105.1
目标化合物B29的制备是用化合物1b-2(216mg,1.0mmol)和29-2(134mg,1.3mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物B29(109mg,收率36%)。ESI[M+H] +=303.3
1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.90(s,1H),7.52–7.31(m,3H),7.19–7.17(m,2H),6.25(q,J=6.8Hz,1H),4.82–4.75(m,2H),4.41–4.35(m,2H),3.31(d,J=7.2Hz,2H),3.24–3.14(m,1H),1.87(d,J=7.2Hz,3H).
实施例B26本发明化合物B30的制备
Figure PCTCN2019074002-appb-000212
化合物30-2的制备是用化合物30-1(306mg,3.0mmol)为初始原料按照通用操作C方法合成,得到无色油状化合物30-2(142mg,两步反应收率40%)。ESI[M+H]+=119.1
目标化合物B30的制备是用化合物1b-2(216mg,1.0mmol)和30-2(142mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物B30(291mg,收率92%)。ESI[M+H] +=317.2
1H NMR(400MHz,CDCl 3)δ7.96(s,1H),7.86(s,1H),7.37–7.30(m,3H),7.17–7.16(m,2H),6.25(q,J=7.2Hz,1H),4.41–4.38(m,2H),4.36–4.33(m,2H),3.33(s,2H),1.86(d,J=6.8Hz,3H),1.32(s,3H).
实施例B27本发明化合物B31的制备
Figure PCTCN2019074002-appb-000213
1、(3-((Methylthio)methyl)oxetan-3-yl)methanol(31-3)的制备
Figure PCTCN2019074002-appb-000214
化合物31-2的制备是用化合物31-1(1.1g,3.1mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品31-2(540mg)。ESI[M+H] +=387.3
在室温下,将粗品化合物31-2(540mg,1.4mmol)溶解在THF(10mL)中,一次性加入TBAF(5.6mL,1mol/L in THF,5.6mmol),室温反应2小时。经TLC监测体系反应完全,将饱和食盐水加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品31-3(165mg,三步反应收率36%),粗品未经纯化直接用于下一步反应。ESI[M+H] +=149.2
2、目标化合物B31的制备
Figure PCTCN2019074002-appb-000215
化合物B31的制备是用化合物1b-2(216mg,1.0mmol)和31-3(148mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物B31(125mg,收率36%)。ESI[M+H] +=347.2
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.75(s,1H),7.39–7.29(m,3H),7.15(d,J=6.9Hz,2H),6.22(d,J=7.1Hz,1H),4.81(d,J=6.7Hz,2H),4.68(q,J=11.5Hz,2H),4.59–4.51(m,2H),2.71–2.68(m,2H),2.10(s,3H),1.88(d,J=7.1Hz,3H).
实施例C1本发明化合物C1的制备
Figure PCTCN2019074002-appb-000216
在室温下,将盐酸二氧六环溶液(4M,0.15mL)以1ml/min的速度滴加到1-1(150mg,0.81mmol)的二氯甲烷(10mL)中,常温下反应5分钟后,加入1b(190mg,0.81mmol),继续在室温反应2小时。将反应体系减压浓缩,经制备TLC纯化(甲醇/二氯甲烷(v/v)=1/10)并收集Rf =0.4~0.6的部分得到无色油状化合物C1(15mg,收率6%)。ESI[M+H] +=299.2
1H NMR(400MHz,d 6-DMSO)δ8.38(s,1H),7.77(s,1H),7.33(t,J=7.3Hz,2H),7.28-7.26(m,1H),7.16(d,J=7.2Hz,2H),6.15(q,J=7.2Hz,1H),1.89(s,3H),1.85(d,J=7.2Hz,3H),1.59–1.44(m,2H),1.35–1.10(m,2H).
实施例C2本发明化合物C2的制备
Figure PCTCN2019074002-appb-000217
1、1-(1-Ethoxyvinyl)cyclobutan-1-ol(2-2)的制备
Figure PCTCN2019074002-appb-000218
将乙烯基乙醚(2-1)(3.60g,50.0mmol)溶于无水THF(20mL),反应体系用氮气置换,并在氮气保护下用干冰丙酮降温至-78℃,用注射器将叔丁基锂(20mL,1.0mol/L in pentane,20mmol)以1mL/min的速度缓慢加至体系,在加料过程中维持温度在-70℃以下。加完叔丁基锂后继续维持在-78℃反应15分钟,然后用冰水浴替换干冰丙酮浴,继续反应15分钟,再用干冰丙酮浴将温度降至-78℃,将环丁酮(700.9mg,10.0mmol)的无水THF(20mL)溶液以1mL/min的速度缓慢加至反应体系。反应体系自然升温至室温,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(30mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品。粗品经硅胶柱层析分离(乙酸乙酯/石油醚(v/v)=1/100),TLC(乙酸乙酯/石油醚(v/v)=1/10)检测,收集Rf=0.6~0.7部分,得到无色油状混合物2-2(1.98g,含有很多二氯甲烷,由于产品容易被减压蒸馏掉,所以产品没有旋干)。
2、1-(1-Hydroxycyclobutyl)ethan-1-one(2-3)的制备
Figure PCTCN2019074002-appb-000219
在室温下,将HCl(0.1mol/L)(45mL)一次性加至2-2(288mg,2mmol)的THF/H 2O(45mL,4/1)溶液。将反应体系室温搅拌15分钟。经TLC监测反应完全,反应体系用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状混合物2-3,产品没有进一步纯化直接用于下一步反应。
3、目标化合物C2的制备
Figure PCTCN2019074002-appb-000220
化合物C2的制备是用化合物1b-2(324mg,1.50mmol)和2-3为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分得到无色油状化合物C2(115mg,收率25%)。ESI[M+H] +=313.3
1H NMR(400MHz,CDCl 3)δ7.90(s,1H),7.85(s,1H),7.36–7.27(m,3H),7.15–7.08(m,2H),6.25(q,J=7.1Hz,1H),2.74–2.64(m,1H),2.58–2.49(m,1H),2.35–2.20(m,2H),2.00–1.90(m,1H),1.88(s,3H),1.86(d,J=7.2Hz,3H),1.90–1.83(m,1H).
实施例C3本发明化合物C3的制备
Figure PCTCN2019074002-appb-000221
1、1-(3-Hydroxyoxetan-3-yl)ethan-1-one(3-2)的制备
Figure PCTCN2019074002-appb-000222
在室温下,将HCl(0.1mol/L)(45mL)一次性加至3-1(288mg,2mmol)的THF/H 2O(45mL,4/1)溶液。反应体系在室温搅拌15分钟,经TLC监测反应完全,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状混合物3-2,产品没有进一步纯化直接用于下一步反应
2、目标化合物C3的制备
Figure PCTCN2019074002-appb-000223
化合物C3的制备是用化合物1b-2(324mg,1.50mmol)和3-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到白色固体状化合物C3(26mg,收率5.5%)。ESI[M+H] +=315.3
1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.91(s,1H),7.39–7.27(m,3H),7.16–7.07(m,2H),6.19(q,J=7.0Hz,1H),4.98(d,J=7.6Hz,1H),4.91(d,J=7.7Hz,1H),4.79(d,J=7.6Hz,1H),4.74(d,J=7.6Hz,1H),2.17(s,3H),1.87(d,J=7.1Hz,3H).
实施例C4本发明化合物C4的制备
Figure PCTCN2019074002-appb-000224
化合物C4的制备使用化合物1b-2(216mg,1.0mmol)和1-(1-(羟基甲基)环丙基)乙酮(114mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物C4(98mg,收率31%)。ESI[M+H] +=313.2
1H NMR(400MHz,d 6-DMSO)δ8.35(s,1H),7.74(s,1H),7.32(t,J=7.3Hz,2H),7.27-7.25(m,1H),7.17(d,J=7.2Hz,2H),6.11(q,J=7.2Hz,1H),4.31–4.21(m,2H),1.88(s,3H),1.82(d,J=7.2Hz,3H),1.50–1.40(m,2H),1.30–1.11(m,2H).
实施例C5本发明化合物C5的制备
Figure PCTCN2019074002-appb-000225
1、1-(3-(((Tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)ethan-1-ol(5-2)的制备
Figure PCTCN2019074002-appb-000226
在室温下,将5-1(500mg,1.41mmol)溶于无水THF(20mL)中,将反应体系用氮气置换,并在氮气保护下用干冰丙酮浴降温至-78℃,用注射器将甲基溴化镁(1M的THF溶液,6.54mL,6.54mmol)以1mL/min的速度缓慢加至体系,在此温度下反应30分钟。经TLC监测反应完全后,用饱和氯化铵溶液(10mL)终止反应。反应体系用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,滤液经减压浓缩得到粗品,经制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.5~0.6的部分得到无色油状化合物5-2(345mg,收率24%)。
2、1-(3-(((Tert-butyldiphenylsilyl)oxy)methyl)oxetan-3-yl)ethan-1-one(5-3)的制备
Figure PCTCN2019074002-appb-000227
在冰水浴0℃下,将Dess-Martin(339mg,0.8mmol)分批加至5-2(145mg,0.4mmol)的二氯甲烷(30mL)溶液,每1min加入0.1mmol,共分8次加完,然后在室温反应2小时。经TLC监测反应完全后,将反应体系抽滤,用二氯甲烷(50mL)洗滤饼,将滤液用饱和碳酸氢钠碱化,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品5-3(200mg)。
3、1-(3-(Hydroxymethyl)oxetan-3-yl)ethan-1-one(5-4)的制备
Figure PCTCN2019074002-appb-000228
在室温下,将TBAF(1.0mL,1mol/L in THF,1.0mmol)一次性加至5-3(200mg,0.54mmol)的THF(10mL)溶液中,反应体系在室温下搅拌20分钟,经TLC监测反应完全后,将反应体系减压浓缩得到粗产品,经过硅胶柱层析分离(乙酸乙酯/石油醚(v/v)=1/10)为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状粗品5-4(80mg)。
4、目标化合物C5的制备
Figure PCTCN2019074002-appb-000229
化合物C5的制备是用化合物1b-2(130mg,0.6mmol)和5-4(80mg)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1.5)并收集Rf=0.3~0.4的部分得到无色油状化合物C5(40mg,收率20%)。ESI[M+H] +=329.2
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.76(s,1H),7.40–7.29(m,3H),7.17(d,J=6.9Hz,2H),6.30(d,J=7.1Hz,1H),4.86(d,J=6.7Hz,2H),4.69(q,J=11.5Hz,2H),4.60–4.50(m,2H),2.30(s,4H),1.88(d,J=7.1Hz,3H).
实施例C6本发明化合物C6的制备
Figure PCTCN2019074002-appb-000230
化合物C6的制备是用化合物1b-2(230mg,1.06mmol)和1-羟基-2-丙酮(78.8mg,1.06mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到无色油状化合物C6(95mg,收率33%)。ESI[M+H] +=273.4
1H NMR(400MHz,d 6-DMSO)δ8.37(s,1H),7.77(d,J=0.8Hz,1H),7.33(t,J=7.3Hz,2H),7.29–7.22(m,1H),7.21–7.14(m,2H),6.20(q,J=7.1Hz,1H),4.94–4.83(m,2H),2.08(s,3H),1.85(d,J=7.2Hz,3H).
实施例C7本发明化合物C7的制备
Figure PCTCN2019074002-appb-000231
化合物C7的制备是用化合物1b-2(230mg,1.06mmol)和4-羟基-2-丁酮(93.4mg,1.06mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分得到无色油状化合物C7(28mg,收率9%)。ESI[M+H] +=287.4
1H NMR(400MHz,d 6-DMSO)δ8.30(s,1H),7.63(s,1H),7.33(t,J=7.3Hz,2H),7.26(t,J=7.2Hz,1H),7.17(d,J=7.3Hz,2H),6.21(q,J=7.1Hz,1H),4.35–4.27(m,2H),2.82(t,J=6.2Hz,2H),2.11(s,3H),1.83(d,J=7.2Hz,3H).
实施例C8本发明化合物C8的制备
Figure PCTCN2019074002-appb-000232
化合物C8的制备是用化合物1b-2(324mg,1.50mmol)和3-羟基-3-甲基-2-丁酮(153mg,1.50mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分得到无色油状化合物C8(25mg,收率8%)。ESI[M+H] +=301.3
1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.87(s,1H),7.40–7.28(m,3H),7.18–7.12(m,2H),6.29(q,J=7.0Hz,1H),1.95(s,3H),1.88(d,J=7.1Hz,3H),1.54(s,3H),1.49(s,3H).
实施例C9本发明化合物C9的制备
Figure PCTCN2019074002-appb-000233
在室温下,将NaIO 4(90mg,0.50mmol)一次加至4-12-8A(90mg,0.33mmol)的MeOH/H 2O(20mL,v/v=1/1)溶液中,室温搅拌过夜。经TLC监测反应完全,反应用饱和氯化铵溶液(20mL)终止,二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,经过制备TLC纯化(甲醇/二氯甲烷(v/v)=1/20)并收集Rf=0.5~0.6的部分得到白色固体化合物C9(83mg,收率86%)。ESI[M+H] +=293.2
1H NMR(400MHz,CDCl 3)δ8.07(d,J=14.1Hz,1H),8.00(d,J=3.1Hz,1H),7.45–7.31(m,3H),7.21(t,J=6.3Hz,2H),6.32(q,J=7.1Hz,1H),5.40–5.17(m,1H),5.07(dd,J=49.9,10.5Hz,1H),2.62(d,J=11.8Hz,3H),1.91(d,J=7.1Hz,3H).
实施例C10本发明化合物C10的制备
Figure PCTCN2019074002-appb-000234
在室温下,将NaIO 4(199mg,0.93mmol)一次加至化合物C27(180mg,0.62mmol)的MeOH/H 2O(20mL,v/v=1/1)溶液中,室温搅拌过夜。经TLC监测反应完全,反应用饱和氯化铵溶液(20mL)终止,二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,经过制备TLC纯化(甲醇/二氯甲烷(v/v)=1/20)并收集Rf=0.5~0.6的部分得到白色固体化合物C10(149mg,收率78%)。ESI[M+H] +=307.3
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.81(s,1H),7.40–7.28(m,3H),7.20–7.16(m,2H),6.32(d,J=7.1Hz,1H),4.85–4.48(m,2H),3.26–2.84(m,2H),2.64(d,J=2.5Hz,3H),1.87(d,J=7.1Hz,3H).
实施例C11本发明化合物C11的制备
Figure PCTCN2019074002-appb-000235
化合物C11的制备是用化合物1b-2(216mg,1.0mmol)和1-(1-(羟甲基)环丁基)乙酮(128mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分得到无色油状化合物C11(108mg,收率33%)。ESI[M+H] +=327.1
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.73(s,1H),7.40–7.27(m,3H),7.22–7.10(m,2H),6.30(q,J=7.1Hz,1H),4.50(dd,J=27.4,11.3Hz,2H),2.46–2.35(m,2H),2.16(s,3H),2.05–1.88(m,4H),1.86(d,J=7.1Hz,3H).
实施例C12本发明化合物C12的制备
Figure PCTCN2019074002-appb-000236
在冰水浴0℃下,将Dess-Martin(848mg,2.0mmol)以0.5mmol/min加至12-1(316mg,1.0mmol)的二氯甲烷(30mL)溶液,四分钟加完,然后室温搅拌2小时。经TLC监测反应完全后,将反应体系抽滤,用二氯甲烷(50mL)洗滤饼,将滤液用饱和NaHCO 3碱化,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗产品,经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到无色油状化合物C12(75mg,收率24%)。ESI[M+H] +=315.2
实施例C13本发明化合物C13的制备
Figure PCTCN2019074002-appb-000237
化合物C13的制备是用化合物1b-2(216mg,1.0mmol)和4-甲基-4-羟基-2-戊酮(116mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分得到无色油状化合物C13(115mg,收率37%)。ESI[M+H] +=315.3
实施例C14本发明化合物C14的制备
Figure PCTCN2019074002-appb-000238
化合物C14的制备是用化合物1b-2(216mg,1.0mmol)和3,3-二甲基-4-羟基-2-丁酮(116 mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到无色油状化合物C14(180mg,收率57%)。ESI[M+H] +=315.3
实施例C15本发明化合物C15的制备
Figure PCTCN2019074002-appb-000239
化合物C15的制备是用化合物1b-2(216mg,1.0mmol)和2-羟基-2-甲基戊-3-酮(116mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.4的部分得到无色油状化合物C15(110mg,收率35%)。ESI[M+H] +=315.3
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.84(s,1H),7.35–7.22(m,3H),7.19–7.10(m,2H),6.11(q,J=7.0Hz,1H),2.83(q,J=7.2Hz,2H),1.88(d,J=7.1Hz,3H),1.51(s,3H),1.45(s,3H),1.40(t,J=7.2Hz,3H).
实施例C16本发明化合物C16的制备
Figure PCTCN2019074002-appb-000240
化合物C16的制备是用化合物1b-2(216mg,1.0mmol)和1-(1-羟基环丙基)丙-1-酮(114mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.5的部分得到无色油状化合物C16(46mg,收率15%)。ESI[M+H] +=313.2
1H NMR(400MHz,CDCl 3)δ7.92(s,1H),7.85(s,1H),7.41–7.22(m,3H),7.17–7.10(m,2H),6.11(q,J=7.0Hz,1H),2.82(q,J=7.2Hz,2H),1.89(d,J=7.1Hz,3H),1.51–1.41(m,5H),1.30–1.11(m,2H).
实施例C17本发明化合物C17的制备
Figure PCTCN2019074002-appb-000241
1、1-(Hydroxymethyl)cyclobutane-1-carbaldehyde(17-2)的制备
Figure PCTCN2019074002-appb-000242
在室温下,将TBAF(3.0mL,1mol/L in THF,3.0mmol)一次性加至粗品17-1(460mg,1.3mmol)的THF(15mL)溶液中,然后在室温下搅拌2小时,经TLC监测反应完全后,将反应体系减压浓缩得到粗产品,经过硅胶柱层析分离(乙酸乙酯/石油醚(v/v)=1/20~1/5)为洗脱剂,TLC(乙酸乙酯/石油醚=1/10)监测,收集Rf=0.3~0.4部分,得到无色油状化合物17-2(92mg,收率62%)。
2、目标化合物C17的制备
Figure PCTCN2019074002-appb-000243
化合物C17的制备是用化合物1b-2(216mg,1.0mmol)和17-2(92mg,0.81mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1.5)并收集Rf=0.5~0.6的部分得到白色固体化合物C17(97mg,收率31%)。ESI[M+H] +=313.3
1H NMR(400MHz,CDCl 3)δ9.71(s,1H),7.84(s,1H),7.75(s,1H),7.40–7.28(m,3H),7.23–7.15(m,2H),6.32(q,J=7.1Hz,1H),4.52(dd,J=29.6,11.4Hz,2H),2.43–2.31(m,2H),2.13–2.04(m,1H),2.04–1.93(m,3H),1.87(d,J=7.1Hz,3H).
实施例C18本发明化合物C18的制备
Figure PCTCN2019074002-appb-000244
化合物C18的制备是用化合物1b-2(216mg,1.0mmol)和叔丁醇(82mg,1.1mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf= 0.5~0.6的部分,得到无色油状化合物C18(220mg,收率81%)。ESI[M+H] +=273.3
1H NMR(400MHz,CDCl 3)δ7.71(s,1H),7.69(s,1H),7.41–7.27(m,3H),7.23–7.14(m,2H),6.37(q,J=7.1Hz,1H),1.86(d,J=7.1Hz,3H),1.51(s,9H).
实施例C19本发明化合物C19的制备
Figure PCTCN2019074002-appb-000245
化合物C19的制备是用化合物1b-2(100mg,0.46mmol)和2-甲基-2-丁醇(61mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物C19(143mg,收率52%)。ESI[M+H] +=287.3
1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.83(s,1H),7.38–7.25(m,3H),7.24–7.08(m,2H),6.38(d,J=7.1Hz,1H),2.00–1.75(m,5H),1.48(s,3H),1.46(s,3H),0.89(t,J=7.4Hz,3H).
实施例C20本发明化合物C20的制备
Figure PCTCN2019074002-appb-000246
化合物C20的制备是用化合物1b-2(100mg,0.46mmol)和4-庚醇(64mg,0.55mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C20(133.1mg,收率92%)。ESI[M+H] +=315.1
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.79(s,1H),7.38–7.28(m,3H),7.22–7.16(m,2H),6.39(q,J=7.0Hz,1H),5.05–4.91(m,1H),1.88(d,J=7.1Hz,3H),1.69–1.52(m,4H),1.38–1.17(m,4H),0.94–0.81(m,6H).
实施例C21本发明化合物C21的制备
Figure PCTCN2019074002-appb-000247
1、1,3-二甲氧基-2-丙醇(21-1)的制备
Figure PCTCN2019074002-appb-000248
在室温下,将1,3-二氯丙醇(645mg,5.0mmol)和甲醇钠(810mg,15.0mmol)溶解在甲醇(20mL)中,室温下搅拌过夜。经TLC监测体系反应完全,抽滤,母液旋干得到无色油状粗品21-1(200.6mg,粗品未经纯化直接用于下一步反应。ESI[M+H] +=121.1
2、目标化合物C21的制备
Figure PCTCN2019074002-appb-000249
化合物C21的制备是用化合物1b-2(216mg,1.0mmol)和21-1(180mg,1.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物C21(269mg,收率84%)。ESI[M+H] +=319.0
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.77(s,1H),7.39–7.28(m,3H),7.24–7.16(m,2H),6.36(q,J=7.0Hz,1H),5.29(p,J=5.1Hz,1H),3.63–3.55(m,4H),3.37(s,3H),3.33(s,3H),1.87(d,J=7.1Hz,3H).
实施例C22本发明化合物C22的制备
Figure PCTCN2019074002-appb-000250
化合物22-2的制备是用化合物22-1(306mg,3.0mmol)为初始原料按照通用操作C方法合成,得到无色油状化合物22-2(124mg,两步反应收率35%)。ESI[M+H] +=119.1
化合物C22的制备是用化合物1b-2(216mg,1.0mmol)和22-2(124mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C22(169mg,收率53%)。ESI[M+H] +=317.2
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.80(s,1H),7.37–7.27(m,3H),7.15–7.05(m,2H),6.17(q,J=7.1Hz,1H),2.12(s,3H),1.82(d,J=7.1Hz,3H),1.55(s,3H),1.47(s,3H).
实施例C23本发明化合物C23的制备
Figure PCTCN2019074002-appb-000251
23-2的制备是以23-1(264mg,3.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物23-2(165mg,两步反应收率53%)。ESI[M+H] +=105.1
化合物C23的制备是用化合物1b-2(216mg,1.0mmol)和23-2(125mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物C23(247mg,收率82%)。ESI[M+H] +=303.2
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.78(s,1H),7.41–7.27(m,3H),7.22–7.13(m,2H),6.25(q,J=7.1Hz,1H),3.20–3.12(m,2H),2.79(t,J=6.7Hz,2H),2.15(s,3H),1.85(d,J=7.1Hz,3H).
实施例C24本发明化合物C24的制备
Figure PCTCN2019074002-appb-000252
化合物C24的制备是用化合物1b-2(108mg,0.50mmol)和3-戊醇(53mg,0.60mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C24(98mg,收率68%)。ESI[M+H] +=287.1
1H NMR(400MHz,CDCl 3)δ7.77(d,J=0.6Hz,1H),7.72(s,1H),7.38–7.27(m,3H),7.22–7.14(m,2H),6.37(q,J=7.1Hz,1H),4.93–4.84(m,1H),1.87(d,J=7.1Hz,3H),1.70–1.52(m,4H),0.89(t,J=7.4Hz,3H),0.84(t,J=7.5Hz,3H).
实施例C25本发明化合物C25的制备
Figure PCTCN2019074002-appb-000253
化合物C25的制备是用化合物1b-2(108mg,0.50mmol)和5-壬醇(87mg,0.60mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集 Rf=0.5~0.6的部分,得到白色粉状化合物C25(132mg,收率77%)。ESI[M+H] +=343.1
1H NMR(400MHz,CDCl 3)δ7.77(s,2H),7.38–7.27(m,3H),7.22–7.12(m,2H),6.38(q,J=7.1Hz,1H),5.07–4.95(m,1H),1.87(d,J=7.1Hz,3H),1.65–1.49(m,4H),1.38–1.13(m,8H),0.95–0.77(m,6H).
实施例C26本发明化合物C26的制备
Figure PCTCN2019074002-appb-000254
1、(Methylthio)methanol(26-2)的制备
Figure PCTCN2019074002-appb-000255
在室温下,将26-1(721mg,6.0mmol)溶解在H 2O(10mL)中,加热回流10分钟。经TLC监测体系反应完全,将温度降至室温,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品26-2(454mg,粗品未经纯化直接用于下一步反应。
2、目标化合物C26的制备
化合物C26的制备是用化合物1b-2(216mg,1.0mmol)和26-2(78.0mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C26(152mg,收率55%)。ESI[M+H] +=277.3
1H NMR(400MHz,CDCl 3)δ7.86(s,2H),7.39–7.30(m,3H),7.22–7.20(m,2H),6.37(q,J=7.2Hz,1H),5.35(d,J=11.6Hz,1H),5.26(d,J=11.6Hz,1H),2.25(s,3H),1.89(d,J=7.2Hz,3H).
实施例C27本发明化合物C27的制备
Figure PCTCN2019074002-appb-000256
化合物C27的制备是用化合物1b-2(216mg,1.0mmol)和2-甲硫基乙醇(92.0mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)= 1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C27(100mg,收率34%)。ESI[M+H] +=291.2
1H NMR(400MHz,d 6-DMSO)δ8.32(s,1H),7.69(s,1H),7.33(t,J=7.3Hz,2H),7.26(t,J=7.3Hz,1H),7.17(d,J=7.2Hz,2H),6.24(d,J=7.2Hz,1H),4.30(qd,J=11.2,4.6Hz,2H),2.73(t,J=6.6Hz,2H),2.08(s,3H),1.84(d,J=7.2Hz,3H).
实施例C28本发明化合物C28的制备
Figure PCTCN2019074002-appb-000257
1、1-(1-Hydroxycyclohexyl)ethan-1-one(28-2)的制备
Figure PCTCN2019074002-appb-000258
在室温下,将28-1(300mg,2.42mmol)和硫酸汞/硫酸/硅胶(1g)溶解在二氯甲烷(10mL)中,室温下搅拌过夜。经TLC监测体系反应完全,用饱和碳酸氢钠中和反应体系,用二氯甲烷(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品28-2(123mg,粗品未经纯化直接用于下一步反应。ESI[M+H] +=143.1
2、目标化合物C28的制备
Figure PCTCN2019074002-appb-000259
化合物C28的制备是用化合物1b-2(43mg,0.20mmol)和28-2(123mg,1.1mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物C28(22mg,收率32%)。ESI[M+H] +=341.2
1H NMR(400MHz,CDCl 3)δ7.95(s,1H),7.90(s,1H),7.40–7.26(m,3H),7.18–7.07(m,2H),6.28(q,J=7.1Hz,1H),2.17–1.95(m,2H),1.89(s,3H),1.87(d,J=7.2Hz,3H),1.80–1.41(m,7H),1.39–1.18(m,1H).
实施例C29本发明化合物C29的制备
Figure PCTCN2019074002-appb-000260
1、(Methylthio)methanol(29-2)的制备
Figure PCTCN2019074002-appb-000261
在室温下,将29-1(721mg,6.0mmol)溶解在H 2O(10mL)中,加热回流10分钟。经TLC监测体系反应完全,将温度降至室温,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品29-2(454mg,粗品未经纯化直接用于下一步反应。
2、(Methylthio)methanethiol(29-3)的制备
Figure PCTCN2019074002-appb-000262
化合物29-3的合成是用化合物29-2(454mg,5.8mmol)为初始原料按照通用操作C方法合成,得到无色油状粗品29-3(214mg,三步反应收率39%),粗品未经纯化直接用于下一步反应。
3、目标化合物C29的制备
Figure PCTCN2019074002-appb-000263
化合物C29的合成是用化合物1b-2(216mg,1.0mmol)和29-3(79mg,1.2mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C29(76mg,收率26%)。ESI[M+H] +=293.2
1H NMR(400MHz,CDCl 3)δ7.80(s,2H),7.44–7.32(m,3H),7.33–7.27(m,2H),6.07(q,J=7.4Hz,1H),4.35–4.16(m,1H),4.06–3.84(m,1H),1.93(d,J=7.1Hz,6H).
实施例C30本发明化合物C30的制备
Figure PCTCN2019074002-appb-000264
化合物30-2的制备是用化合物30-1(276mg,3.0mmol)为初始原料按照通用操作C方法合成,得到无色油状化合物30-2(123mg,两步反应收率38%)。ESI[M+H] +=109.1
化合物C30的制备是用化合物1b-2(216mg,1.0mmol)和30-2(123mg,1.1mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.5~0.6的部分,得到无色油状化合物C30(89mg,收率29%)。ESI[M+H] +=307.1
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.74(s,1H),7.40–7.26(m,3H),7.21–7.14(m,2H),6.26(q,J=7.1Hz,1H),3.37–2.95(m,2H),2.76–2.59(m,2H),2.18(s,3H),1.85(d,J=7.1Hz,3H).
实施例D1本发明化合物D1的制备
Figure PCTCN2019074002-appb-000265
1、1-乙炔基环丁醇(1-2)的制备
Figure PCTCN2019074002-appb-000266
将环丁酮(1-1)(700.6mg,10.0mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至0℃。在0℃下,用注射器将炔丙基溴化镁(26mL,1.3mol/L in THF,13mmol)以在25分钟时间内缓慢加至体系,室温反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(30mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品1-2,产品未经进一步纯化直接用于下一步反应。
2、目标化合物D1的制备
Figure PCTCN2019074002-appb-000267
化合物D1的制备是用化合物1b-2(432mg,2.0mmol)和1-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分得到白色粉状固体化合物D1(519mg,收率88%)。ESI[M+H] +=295.3
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.69(s,1H),7.39–7.27(m,3H),7.24–7.17(m,2H),6.36(q,=7.2Hz,1H),2.68–2.62(m,2H),2.61(s,1H),2.57–2.35(m,2H),2.11–1.89(m,2H),1.86(d,J=7.1Hz,3H).
实施例D2本发明化合物D2的制备
Figure PCTCN2019074002-appb-000268
1、3-(1-Ethoxyvinyl)oxetan-3-ol(2-2)的制备
Figure PCTCN2019074002-appb-000269
将乙烯基乙醚(2-1)(3.60g,50.0mmol)溶于无水THF(20mL),反应体系用氮气置换,并在氮气保护下用干冰丙酮降温至-78℃,用注射器将叔丁基锂(20mL,1.0mol/L in pentane,20mmol)以在5分钟时间内缓慢加至体系,在加料过程中维持温度在-70℃以下。加完叔丁基锂后继续维持在-78℃反应15分钟,然后用冰水浴替换干冰丙酮浴,继续反应15分钟,再用干冰丙酮浴将温度降至-78℃,将3-氧杂环丁酮(720.6mg,10.0mmol)的无水THF(20mL)溶液在10分钟时间内缓慢加至反应体系。反应体系自然升温至室温,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(30mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品。粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/5~1/3范围内的任一比例为洗脱剂,TLC(乙酸乙 酯/石油醚(v/v)=1/3)检测,收集Rf=0.5~0.6部分,得到无色油状混合物2-2(545mg,收率8%)。
2、目标化合物D2的制备
Figure PCTCN2019074002-appb-000270
化合物D2的制备是用化合物1b-2(324mg,1.50mmol)和2-2(545mg)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.3~0.4部分得到白色固体化合物D2(98mg,收率19%),ESI[M+H] +=343.3。
1H NMR(400MHz,CDCl 3)δ7.90(d,J=0.7Hz,1H),7.79(s,1H),7.38–7.27(m,3H),7.20–7.11(m,2H),6.27(q,J=7.1Hz,1H),4.96(dd,J=12.1,7.5Hz,2H),4.83(d,J=7.2Hz,1H),4.74(d,J=7.4Hz,1H),4.14(d,J=3.2Hz,1H),4.08(d,J=3.2Hz,1H),3.81(q,J=7.0Hz,2H),1.86(d,J=7.1Hz,3H),1.32(t,J=7.0Hz,3H).
实施例D3本发明化合物D3的制备
Figure PCTCN2019074002-appb-000271
1、3-Ethynyloxetan-3-ol(3-2)的制备
Figure PCTCN2019074002-appb-000272
将乙烯基乙醚(3-1)(3.60g,50.0mmol)溶于无水THF(20mL),反应体系用氮气置换,并在氮气保护下用干冰丙酮降温至-78℃,用注射器将叔丁基锂(20mL,1.0mol/L in pentane,20mmol)以在5分钟时间内缓慢加至体系,在加料过程中维持温度在-70℃以下。加完叔丁基锂后继续维持在-78℃反应15分钟,然后用冰水浴替换干冰丙酮浴,继续反应15分钟,再用干冰丙酮浴将温度降至-78℃,将3-氧杂环丁酮(720.6mg,10.0mmol)的无水THF(20mL)溶液在 10分钟时间内缓慢加至反应体系。反应体系自然升温至室温,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(30mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品。粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/5~1/3范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/3)检测,收集Rf=0.5~0.6部分,得到无色油状混合物3-2(365mg,收率8%)。
2、目标化合物D3的制备
Figure PCTCN2019074002-appb-000273
化合物D3的制备是用化合物1b-2(324mg,1.50mmol)和3-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.3~0.4得到白色固体化合物D3(27mg,收率8.3%),ESI[M+H] +=297.3。
1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.93(s,1H),7.42–7.35(m,3H),7.25–7.21(m,2H),6.35(q,J=7.0Hz,1H),4.96(dd,J=7.5,3.9Hz,2H),4.88(d,J=7.5Hz,1H),4.77(d,J=7.6Hz,1H),2.82(s,1H),1.91(d,J=7.1Hz,3H).
实施例D4本发明化合物D4的制备
Figure PCTCN2019074002-appb-000274
化合物D4的制备是用化合物1b-2(216mg,1.0mmol)和1-乙基环丙烷-1-醇(82mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5得到白色固体化合物D4(87mg,收率31%),ESI[M+H] +=281.2。
实施例D5本发明化合物D5的制备
Figure PCTCN2019074002-appb-000275
1、1-(1-Ethoxyvinyl)cyclobutan-1-ol(5-2)的制备
Figure PCTCN2019074002-appb-000276
化合物5-2的制备是用环丁酮(700.9mg,10.0mmol)为原料按照2-2类似的方法制备出来的。粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/5~1/3范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/3)检测,收集Rf=0.5~0.6部分,得到无色油状化合物5-2(415mg,收率29%)。
2、目标化合物D5的制备
Figure PCTCN2019074002-appb-000277
化合物D5的制备是用化合物1b-2(216mg,1.0mmol)和5-2(142mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.3~0.4部分得到无色油状化合物D5(18mg,收率5%),ESI[M+H] +=341.3。
实施例D6本发明化合物D6的制备
Figure PCTCN2019074002-appb-000278
1、3-乙烯基-3-羟基-1-环丁烷(6-2)的制备
Figure PCTCN2019074002-appb-000279
将环丁酮(6-1)(140mg,2.0mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至0℃。维持反应温度在0℃,用注射器将乙烯基溴化镁(2.0mL,1.3mol/L in THF,2.6mmol)在5分钟时间内缓慢加至体系,室温搅拌两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品6-2,产品未经进一步纯化直接用于下一步反应。
2、目标化合物D6的制备
Figure PCTCN2019074002-appb-000280
化合物D6的制备是用化合物1b-2(216mg,1.0mmol)和6-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D6(54mg,两步反应收率18%)。ESI[M+H] +=297.1
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.73(s,1H),7.38–7.27(m,3H),7.22–7.16(m,2H),6.34(q,J=7.1Hz,1H),6.16(dd,J=17.4,10.8Hz,1H),5.27–5.13(m,2H),2.49–2.35(m,4H),1.94–1.86(m,1H),1.85(d,J=7.1Hz,3H),1.79–1.68(m,1H).
实施例D7本发明化合物D7的制备
Figure PCTCN2019074002-appb-000281
1、3-乙烯基-3-羟基-1-氧杂环丁烷(7-2)的制备
Figure PCTCN2019074002-appb-000282
将3-氧杂环丁酮(7-1)(144mg,2.0mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至0℃。维持反应温度在0℃,用注射器将乙烯基溴化镁(2.0mL,1.3 mol/L in THF,2.6mmol)在15分钟时间内缓慢加至体系,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品7-2,产品未经进一步纯化直接用于下一步反应。
2、目标化合物D7的制备
Figure PCTCN2019074002-appb-000283
化合物D7的制备是用化合物1b-2(216mg,1.0mmol)和7-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D7(61mg,两步反应收率20%)。ESI[M+H] +=299.2
1H NMR(400MHz,d 6-DMSO)δ8.36–8.32(m,1H),7.81(d,J=0.7Hz,1H),7.35–7.31(m,2H),7.28–7.25(m,1H),7.14–7.13(m,2H),6.28–5.98(m,2H),5.18(t,J=14.5Hz,2H),4.78(d,J=7.5Hz,1H),4.66–4.63(m,3H),1.84(d,J=7.2Hz,3H).
实施例D8本发明化合物D8的制备
Figure PCTCN2019074002-appb-000284
1、Tert-butyl((3-ethynyloxetan-3-yl)methoxy)diphenylsilane(8-2)的制备
Figure PCTCN2019074002-appb-000285
在冰水浴0℃下,将8-1(300mg,0.85mmol),(1-重氮基-2-氧代丙基)膦酸二甲酯(211mg,1.1mmol)和K 2CO 3(470mg,3.4mmol)溶于MeOH(30mL),反应体系在室温搅拌20分钟。经TLC监测反应完全后,将反应体系抽滤,用乙酸乙酯(20mL)洗滤饼,将滤液减压浓缩得到粗品,粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/20~1/10范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/10)检测,收集Rf=0.5~0.6部分,纯化后得到无色油状化合物8-2(280mg,收率94.0%)。
2、(3-Ethynyloxetan-3-yl)methanol(8-3)的制备
Figure PCTCN2019074002-appb-000286
在室温下,将TBAF(1.60mL,1mol/L in THF,1.60mmool)一次性加至8-2(280mg,0.80mmol)的THF(10mL)溶液中,反应体系在室温下搅拌20分钟,经TLC监测反应完全后,将反应体系减压浓缩得到粗产品8-3(350mg),粗产品未经进一步纯化直接用于下一步反应。
3、目标化合物D8的制备
Figure PCTCN2019074002-appb-000287
化合物D8的制备是用化合物1b-2(324mg,1.5mmol)和8-3为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.5~0.6部分得到无色油状化合物D8(153mg,收率33%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.79(s,1H),7.42–7.28(m,3H),7.18(d,J=7.1Hz,2H),6.34(q,J=7.1Hz,1H),4.81(dd,J=5.9,3.5Hz,2H),4.54–4.51(m,4H),2.39(s,1H),1.88 (d,J=7.1Hz,3H).
实施例D9本发明化合物D9的制备
Figure PCTCN2019074002-appb-000288
将化合物D8(93mg,0.3mmol)和林德拉催化剂(9mg)溶解在甲醇(10mL)中,用氢气置换反应体系三次,将反应体系置于氢气球环境中室温搅拌1小时。经TLC监测反应完全后,减压浓缩得到粗品,经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D9(63mg,收率67%)。ESI[M+H] +=313.2
实施例D10本发明化合物D10的制备
Figure PCTCN2019074002-appb-000289
1、1-(((Tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbaldehyde(10-2)的制备
Figure PCTCN2019074002-appb-000290
在冰水浴0℃下,将Dess-Martin(12.72g,30.0mmol)每1min加入5mmol,共分6次加至10-1(5.31g,15.0mmol)的二氯甲烷(30mL)溶液,反应体系在0℃反应1小时。经TLC监测反应完全后,将反应体系抽滤,用二氯甲烷(50mL)洗滤饼,将滤液用饱和NaHCO 3碱化,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,粗品经硅胶柱层析 纯化,以乙酸乙酯/石油醚(v/v)在1/20~1/10范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/10)检测,收集Rf=0.4~0.5部分得到无色油状化合物10-2(4.58g,收率87%)。
2、Tert-butyl((1-ethynylcyclobutyl)methoxy)diphenylsilane(10-3)的制备
Figure PCTCN2019074002-appb-000291
在冰水浴0℃下,将10-2(528mg,1.5mmol),(1-重氮基-2-氧代丙基)膦酸二甲酯(384mg,2.0mmol)和K 2CO 3(829mg,6.0mmol)溶于MeOH(50mL),反应体系在室温搅拌20分钟。经TLC监测反应完全后,将反应体系抽滤,用乙酸乙酯(30mL)洗滤饼,将滤液减压浓缩得到粗品10-3,粗品未经进一步纯化直接用于下一步反应。
3、(1-Ethynylcyclobutyl)methanol(10-4)的制备
Figure PCTCN2019074002-appb-000292
在室温下,将TBAF(3.0mL,1mol/L in THF,3.0mmool)加至粗品10-3的THF(15mL)溶液中,反应体系在室温下搅拌2小时,经TLC监测反应完全后,将反应体系减压浓缩得到粗产品,粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/5~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.5~0.6部分,纯化得到无色油状化合物10-4(85mg,两步反应收率51%)。
4、目标化合物D10的制备
Figure PCTCN2019074002-appb-000293
化合物D10的制备是用化合物1b-2(216mg,1.0mmol)和10-4(85mg,0.77mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收 集Rf=0.5~0.6部分得到无色油状化合物D10(183mg,收率59%)。ESI[M+H] +=309.3
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.77(s,1H),7.40–7.27(m,3H),7.23–7.15(m,2H),6.37(q,J=7.1Hz,1H),4.43–4.14(m,2H),2.37–2.26(m,2H),2.25(s,1H),2.20–2.02(m,3H),2.02–1.90(m,1H),1.87(d,J=7.1Hz,3H).
实施例D11本发明化合物D11的制备
Figure PCTCN2019074002-appb-000294
将化合物D10(93mg,0.3mmol)和林德拉催化剂(9mg)溶解在甲醇(10mL)中,用氢气置换反应体系三次,将反应体系置于氢气球环境中室温搅拌1小时。经TLC监测反应完全后,减压浓缩得到粗品,经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D11(48mg,收率52%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.79(s,1H),7.42–7.28(m,3H),7.18(d,J=7.1Hz,2H),6.34(q,J=7.1Hz,1H),5.86(dd,J=10.5Hz,1H),5.18(dd,J=1.5Hz,J=1.3Hz,1H),5.11(dd,J=1.3Hz,1H),4.17(s,2H),2.05-1.82(m,6H),1.87(d,J=7.1Hz,3H).
实施例D12本发明化合物D12的制备
Figure PCTCN2019074002-appb-000295
化合物12-2的制备是用环丁酮(12-1)(210.3mg,3.0mmol)和烯丙基氯化镁为原料按照6-2类似的方法制备出来的。
化合物D12的制备是用化合物1b-2(216mg,1.0mmol)和12-2(112mg,0.77mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.5~0.6部分得到无色油状化合物D12(183mg,收率59%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.76(s,1H),7.43–7.28(m,3H),7.24–7.16(m,2H),6.39(q,J=7.1Hz,1H),5.95-5.84(m,1H),5.23-5.21(m,1H),5.21-5.15(m,1H),2.40–2.38(m,2H),2.13–2.02(m,4H),1.87(d,J=7.1Hz,3H),1.83-1.69(m,1H),1.65-1.46(m,1H).
实施例D13本发明化合物D13的制备
Figure PCTCN2019074002-appb-000296
化合物13-2的制备方法与制备化合物21-2的方法相同,使用环丁酮为初始原料。
化合物D13的制备是用化合物1b-2(50mg,0.23mmol)和13-2(39mg,0.35mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到无色油状化合物D13(18mg,收率25%)。ESI[M+H] +=309.3
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.73(s,1H),7.40–7.27(m,3H),7.23–7.13(m,2H),6.35(q,J=7.0Hz,1H),5.61(t,J=6.6Hz,1H),4.99–4.82(m,2H),2.53–2.34(m,4H),1.89–1.78(m,1H),1.85(d,J=7.1Hz,3H),1.77–1.60(m,1H).
实施例D14本发明化合物D14的制备
Figure PCTCN2019074002-appb-000297
化合物D14的制备是用化合物1b-2(108mg,0.50mmol)和3-丁炔-2-醇(35mg,0.50mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到白色粉状化合物D14(71mg,收率53%)。ESI[M+H] +=269.2
1H NMR(400MHz,CDCl 3)δ7.89–7.78(m,2H),7.43–7.28(m,3H),7.26–7.11(m,2H),6.43–6.31(m,1H),5.64–5.47(m,1H),2.49(dd,J=8.8,2.1Hz,1H),1.88(d,J=7.1Hz,3H),1.57(dd,J=6.7,3.8Hz,3H).
实施例D15本发明化合物D15的制备
Figure PCTCN2019074002-appb-000298
化合物D15的制备是用化合物1b-2(100mg,0.46mmol)和3-甲基-1-丁炔-3-醇(39mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到白色粉状化合物D15(95mg,收率73%)。ESI[M+ H] +=283.3
1H NMR(400MHz,CDCl 3)δ7.73(s,1H),7.70(s,1H),7.38–7.27(m,3H),7.25–7.17(m,2H),6.38(q,J=7.1Hz,1H),2.58(s,1H),1.86(d,J=7.1Hz,3H),1.74(s,3H),1.72(s,3H).
实施例D16本发明化合物D16的制备
Figure PCTCN2019074002-appb-000299
1、2-((2-Methylbut-3-yn-2-yl)oxy)tetrahydro-2H-pyran(16-2)的制备
Figure PCTCN2019074002-appb-000300
在室温下,将3,4-二氢-2H-吡喃(420.6mg,5.0mmol),16-1(420.6mg,5.0mmol)和对甲基苯磺酸吡啶(63mg,0.25mmol)加至二氯甲烷(20mL)溶液中,室温反应2小时。TLC监测反应完全后,将反应体系减压浓缩,经胶柱层析分离,乙酸乙酯/石油醚(v/v)在1/15~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,得到无色油状化合物16-2(546mg,收率65%)。
2、2-((2-Methylbut-3-yn-2-yl)oxy)tetrahydro-2H-pyran(16-3)的制备
Figure PCTCN2019074002-appb-000301
将16-2(532mg,3.2mmol)溶于无水THF(10mL),反应体系用氮气置换,并在氮气保护下用干冰丙酮降温至-78℃,用注射器将叔丁基锂(5.8mL,1.0mol/L in pentane,5.8mmol)在5分钟时间内缓慢加至体系,在加料过程中维持温度在-70℃以下。加完叔丁基锂后继续维持 在-78℃下搅拌2小时。然后用D 2O(2mL)终止反应,反应体系用乙醚萃取(3×10mL),合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品16-3。粗品没有纯化直接用于下一步反应。
3、2-Methylbut-3-yn-4-d-2-ol(16-4)的制备
Figure PCTCN2019074002-appb-000302
在室温下,将16-3(3.2mmol)和对甲基苯磺酸吡啶(402mg,1.6mmol)溶解在乙醇(20mL)中,室温反应12小时。TLC监测反应完全后,将反应体系减压浓缩,经胶柱层析分离,以乙酸乙酯/石油醚(v/v)在1/10~1/1范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/1)检测,收集Rf=0.3~0.4部分,得到无色油状化合物16-4(143mg,两步反应收率52%)。
4、目标化合物D16的制备
Figure PCTCN2019074002-appb-000303
化合物D16的制备是用化合物1b-2(216mg,1.0mmol)和16-4(126mg,1.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.5~0.6部分得到无色油状化合物D16(53mg,收率19%)。ESI[M+H] +=284.3
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.69(s,1H),7.40–7.28(m,3H),7.26–7.16(m,2H),6.39(q,J=7.1Hz,1H),1.85(d,J=7.1Hz,3H),1.75(s,3H),1.71(s,3H).
实施例D17本发明化合物D17的制备
Figure PCTCN2019074002-appb-000304
化合物D17的制备是用化合物1b-2(100mg,0.46mmol)和3-乙基-1-戊炔-3-醇(52mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到无色油状化合物D17(53mg,收率37%)。ESI[M+ H] +=311.3
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.76(s,1H),7.43–7.28(m,3H),7.25–7.14(m,2H),6.40(q,J=6.9Hz,1H),2.63(s,1H),2.21–2.03(m,2H),2.03–1.92(m,2H),1.87(d,J=7.1Hz,3H),1.02(t,J=7.4Hz,3H),0.96(t,J=7.4Hz,3H).
实施例D18本发明化合物D18的制备
Figure PCTCN2019074002-appb-000305
化合物D18的制备是用化合物1b-2(100mg,0.46mmol)和2-丁炔-1-醇(32mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到无色油状化合物D18(95mg,收率73%)。ESI[M+H] +=269.2
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.75(s,1H),7.40–7.27(m,3H),7.23–7.14(m,2H),6.34(q,J=7.1Hz,1H),4.78(qq,J=15.2,2.3Hz,2H),1.87(d,J=1.3Hz,3H),1.86(d,J=3.2Hz,3H).
实施例D19本发明化合物D19的制备
Figure PCTCN2019074002-appb-000306
化合物D19的制备是用化合物1b-2(100mg,0.46mmol)和1-乙炔环己醇(57mg,0.46mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.4~0.5部分得到无色油状化合物D19(86mg,收率58%)。ESI[M+H] +=323.2
1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.74(s,1H),7.39–7.28(m,3H),7.25–7.20(m,2H),6.40(q,J=7.1Hz,1H),2.65(s,1H),2.23–2.09(m,2H),2.04–1.90(m,2H),1.87(d,J=7.1Hz,3H),1.72–1.57(m,4H),1.57–1.47(m,1H),1.43–1.32(m,1H).
实施例D20本发明化合物D20的制备
Figure PCTCN2019074002-appb-000307
化合物D20的制备是用化合物1b-2(216mg,1.0mmol)和(E)-1-(丙-1-烯-1-基)环丁烷-1-醇(112.2mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物D20(105mg,收率34%)。ESI[M+H] +=311.3
实施例D21本发明化合物D21的制备
Figure PCTCN2019074002-appb-000308
1、3-Ethynyloxetan-3-ol(21-1)的制备
Figure PCTCN2019074002-appb-000309
将3-氧杂环丁酮(300mg,4.16mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至-10℃。维持反应温度在-10℃,用注射器将乙炔基溴化镁(8.32mL,0.5mol/L in THF,4.16mmol)在15分钟时间内缓慢加至体系,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品,粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/10~1/5范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,纯化后得到无色油状化合物21-1(498mg,收率73.2%)。
2、3-(Propa-1,2-dien-1-yl)oxetan-3-ol(21-2)的制备
Figure PCTCN2019074002-appb-000310
将21-1(498mg,5.08mmol),二环己胺(1.66g,9.14mmol),CuI(483mg,2.54mmol)和(HCHO)n(381mg,12.7mmol)溶于二氧六环(10mL)溶液,加完所有的原料后,反应液在90℃下搅拌两个小时。经TLC监测反应完全后,将反应体系冷却后抽滤,将滤液用水稀释,用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品21-2,粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/10~1/5范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,纯化后得到无色油状化合物21-2(120mg,收率21%)。
3、目标化合物D21的制备
Figure PCTCN2019074002-appb-000311
化合物D21的制备是用化合物1b-2(216mg,1.0mmol)和21-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D21(30.0mg,收率10%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.76(s,1H),7.39–7.28(m,3H),7.15(d,J=7.0Hz,2H),6.32–6.20(m,1H),5.63(t,J=6.6Hz,1H),5.00–4.95(m,1H),4.92–4.88(m,2H),4.82–4.80(m,1H),4.78–4.74(m,2H),1.86(d,J=7.1Hz,3H).
实施例D22本发明化合物D22的制备
Figure PCTCN2019074002-appb-000312
1、Penta-3,4-dien-2-ol(22-1)的制备
Figure PCTCN2019074002-appb-000313
将3-丁炔-2-醇(350mg,4.99mmol),二异丙胺(909mg,8.98mmol),CuI(476mg,2.50mmol)和(HCHO)n(375mg,12.5mmol)溶于二氧六环(10mL)溶液,加完所有的原料后,反应液在90℃下搅拌两个小时。经TLC监测反应完全后,将反应体系冷却后抽滤,将滤液用水稀释,用乙酸乙酯萃取(3×10mL),合并有机相用盐酸(50mL,6N)洗涤,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品21-2。粗品没有纯化直接用于下一步反应。
2、目标化合物D22的制备
Figure PCTCN2019074002-appb-000314
化合物D22的制备是用化合物1b-2(216mg,1.0mmol)和22-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D22(80.0mg,收率28%)。ESI[M+H] +=283.2
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.74(d,J=1.6Hz,1H),7.39–7.28(m,3H),7.23–7.15(m,2H),6.36(dd,J=7.1,3.5Hz,1H),5.51–5.48(m,1H),5.34–5.26(m,1H),4.90–4.87(m,1H),4.85–4.79(m,1H),1.86(d,J=7.1Hz,3H),1.39(dd,J=6.4,4.1Hz,3H).
实施例D23本发明化合物D23的制备
Figure PCTCN2019074002-appb-000315
1、4-Ethynyltetrahydro-2H-pyran-4-ol(23-2)的制备
Figure PCTCN2019074002-appb-000316
将四氢吡喃-4-酮(600mg,5.99mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至-10℃。维持反应温度在-10℃,用注射器将乙炔基溴化镁(12.0mL,0.5mol/L in THF,5.99mmol)在15分钟时间内缓慢加至体系,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用二氯甲烷萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品21-1,粗品经硅胶柱层析纯化,以乙酸乙酯/石油醚(v/v)在1/10~1/5范围内的任一比例为洗脱剂,TLC(乙酸乙酯/石油醚(v/v)=1/2)检测,收集Rf=0.3~0.4部分,纯化后得到无色油状化合物21-1(313mg,收率41%)。
2、目标化合物D23的制备
Figure PCTCN2019074002-appb-000317
化合物D23的制备是用化合物1b-2(216mg,1.0mmol)和23-2为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.5部分得到无色油状化合物D23(194mg,收率60%)。ESI[M+H] +=325.2
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.79(s,1H),7.40–7.28(m,3H),7.24–7.16(m,2H),6.37(q,J=6.9Hz,1H),3.99–3.65(m,4H),2.34–2.19(m,2H),2.15–2.00(m,2H),1.88(d,J=7.1Hz,3H).
实施例D24本发明化合物D24的制备
Figure PCTCN2019074002-appb-000318
化合物D24的制备是用化合物1b-2(216mg,1.0mmol)和3-ethylpent-1-en-3-ol(114mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)= 1/2),收集Rf=0.5~0.6部分得到无色油状化合物D24(110mg,收率35%)。ESI[M+H] +=313.3
实施例D25本发明化合物D25的制备
Figure PCTCN2019074002-appb-000319
化合物D25的制备是用化合物1b-2(216mg,1.0mmol)和3-乙基-5-甲基己-5-烯-3-醇(142mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.3~0.5部分得到无色油状化合物D25(88mg,收率26%)。ESI[M+H] +=341.3
实施例D26本发明化合物D26的制备
Figure PCTCN2019074002-appb-000320
化合物D26的制备是用化合物1b-2(216mg,1.0mmol)和1-(2-甲基烯丙基)环丁醇(126mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到无色油状化合物D26(35mg,收率11%)。ESI[M+H] +=325.3
实施例D27本发明化合物D27的制备
Figure PCTCN2019074002-appb-000321
3-Ethynylthietan-3-ol的制备是用化合物3-硫杂环丁酮和乙炔基溴化镁反应制得。
化合物D27的制备是用化合物1b-2(216mg,1.0mmol)和3-ethynylthietan-3-ol(114mg,1.0 mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.3~0.4部分得到无色油状化合物D27(78mg,收率25%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.91(s,1H),7.43–7.35(m,3H),7.27–7.21(m,2H),6.31(q,J=7.0Hz,1H),4.11–3.87(m,4H),2.81(s,1H),1.90(d,J=7.1Hz,3H).
实施例D28本发明化合物D28的制备
Figure PCTCN2019074002-appb-000322
化合物28-2的制备方法与制备化合物21-2的方法相同,使用3-硫杂环丁酮为初始原料。
化合物D28的制备是用化合物1b-2(216mg,1.0mmol)和3-(propa-1,2-dien-1-yl)thietan-3-ol(1286mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.3~0.5部分得到无色油状化合物D28(42mg,收率13%)。ESI[M+H] +=326.1
1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.73(s,1H),7.40–7.28(m,3H),7.25–7.14(m,2H),6.39(q,J=7.0Hz,1H),5.75(t,J=6.8Hz,1H),5.15–4.91(m,2H),3.887–3.61(m,2H),3.46–3.31(m,2H),1.85(d,J=7.1Hz,3H).
实施例D29本发明化合物D29的制备
Figure PCTCN2019074002-appb-000323
化合物D29的制备是用化合物1b-2(216mg,1.0mmol)和3-(prop-1-ynyl)thietan-3-ol(128mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.3~0.5部分得到无色油状化合物D29(21mg,收率6.4%)。ESI[M+H] +=327.2
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.77(s,1H),7.40–7.20(m,3H),7.17–7.10(m,2H),6.31(q,J=7.2Hz,1H),4.82–4.77(m,2H),4.10–3.87(m,4H),2.81(s,1H),1.88(d,J=7.2Hz,3H).
实施例D30本发明化合物D30的制备
Figure PCTCN2019074002-appb-000324
化合物D30的制备是用化合物1b-2(216mg,1.0mmol)和3-(丙-1-炔基)四氢噻吩-3-醇(140mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1),收集Rf=0.4~0.6部分得到无色油状化合物D30(79mg,收率24%)。ESI[M+H] +=341.1
实施例D31本发明化合物D31的制备
Figure PCTCN2019074002-appb-000325
化合物D31的制备是用化合物1b-2(216mg,1.0mmol)和2-methylpent-3-yn-2-ol(98mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D31(35mg,收率12%)。ESI[M+H] +=297.3
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.77(s,1H),7.41–7.28(m,3H),7.24–7.14(m,2H),6.31(q,J=7.1Hz,1H),1.87(d,J=7.1Hz,3H),1.84(s,3H),1.70(s,3H),1.70(s,3H).
实施例D32本发明化合物D32的制备
Figure PCTCN2019074002-appb-000326
化合物D32的制备是用化合物1b-2(216mg,1.0mmol)和pent-3-yn-2-ol(84mg,1.0mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.5部分得到无色油状化合物D32(45mg,收率16%)。ESI[M+H] +=283.3
1H NMR(400MHz,CDCl 3)δ7.81(d,J=3.2Hz,1H),7.72(d,J=23.7Hz,1H),7.40–7.26(m,3H),7.23–7.12(m,2H),6.47–6.25(m,1H),5.64–5.32(m,1H),1.94–1.74(m,6H),1.55–1.43(m,3H).
实施例D33本发明化合物D33的制备
Figure PCTCN2019074002-appb-000327
33-2的制备是以33-1(294mg,3.0mmol)为初始原料按照通用操作C的方法合成,得到无色油状化合物33-2(140mg,两步反应收率41%)。ESI[M+H] +=115.1
化合物33-3的制备方法与制备化合物21-2的方法相同,用化合物33-2为原料。
化合物D33的制备是用化合物1b-2(100mg,0.46mmol)和33-3(88mg,10.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2)并收集Rf=0.4~0.5的部分,得到无色油状化合物D33(45mg,收率30%)。ESI[M+H] +=327.2
1H NMR(400MHz,CDCl 3)δ8.05(s,1H),7.91(s,1H),7.45–7.30(m,3H),7.25–7.19(m,2H),6.38(q,J=7.0Hz,1H),6.35–6.25(m,1H),5.68(t,J=6.6Hz,1H),5.50–4.84(m,6H),1.87(d,J=7.1Hz,3H).
实施例D34本发明化合物D34的制备
Figure PCTCN2019074002-appb-000328
1、4-(Propa-1,2-dien-1-yl)tetrahydro-2H-pyran-4-ol(34-1)的制备
Figure PCTCN2019074002-appb-000329
将化合物23-2(213mg,1.69mmol),二环己胺(551mg,3.04mmol),CuI(162mg,0.85mmol)和(HCHO)n(127mg,4.23mmol)溶于二氧六环(10mL)溶液,加完所有的原料后,反应液在90℃下搅拌两个小时。经TLC监测反应完全后,将反应体系冷却后抽滤,将滤液用水稀释,用乙酸乙酯萃取(3×10mL),合并有机相用盐酸(50mL,6N)洗涤,饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品34-1。粗品没有纯化直接用于下一步反应。
2、目标化合物D34的制备
Figure PCTCN2019074002-appb-000330
化合物D34的制备是用化合物1b-2(216mg,1.0mmol)和34-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.3~0.4部分得到无色油状化合物D34(59.0mg,收率18%)。ESI[M+H] +=339.3
1H NMR(400MHz,CDCl 3)δ8.24(s,1H),7.88(s,1H),7.42(d,J=6.3Hz,3H),6.45(d,J=6.6Hz,1H),5.65(t,J=6.7Hz,1H),5.03–4.87(m,2H),3.70(dd,J=22.4,4.7Hz,4H),2.18(d,J=12.3Hz,2H),2.13–2.01(m,2H),1.93(d,J=6.7Hz,3H).
实施例D35本发明化合物D35的制备
Figure PCTCN2019074002-appb-000331
1、1-Vinylcyclohexan-1-ol(35-1)的制备
Figure PCTCN2019074002-appb-000332
将1-乙炔基环己醇(1.0g,8.05mmol)溶于四氢呋喃(20mL)中,加入林德拉催化剂(100mg)。加完所有的原料后,反应液氢化反应两个小时。经TLC监测反应完全后,将反应体系冷却后抽滤,将滤液减压浓缩得到无色油状粗品35-1。粗品没有纯化直接用于下一步反应。
2、目标化合物D35的制备
Figure PCTCN2019074002-appb-000333
化合物D35的制备是用化合物1b-2(216mg,1.0mmol)和35-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D35(59.0mg,收率18%)。ESI[M+H] +=325.3
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.70(s,1H),7.39–7.28(m,3H),7.18(d,J=6.7Hz,2H),6.36(q,J=7.1Hz,1H),6.10(dd,J=17.6,11.0Hz,1H),5.14(d,J=8.3Hz,1H),5.10(d,J=0.8Hz,1H),2.25–2.22(m,2H),1.84(d,J=7.1Hz,3H),1.68–1.40(m,7H),1.30–1.25(m,1H).
实施例D36本发明化合物D36的制备
Figure PCTCN2019074002-appb-000334
化合物D36的制备是用化合物1b-2(108mg,0.5mmol)和3-己炔-2-醇(49.1mg,0.5mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D36(105mg,收率53%)。ESI[M+H] +=297.3
1H NMR(400MHz,CDCl 3)δ7.90–7.79(m,2H),7.40–7.27(m,3H),7.24–7.14(m,2H),6.45–6.32(m,1H),5.62–5.48(m,1H),2.27–2.14(m,2H),1.92–1.81(m,3H),1.55–1.45(m,3H),1.17–1.03(m,3H).
实施例D37本发明化合物D37和化合物D38的制备
Figure PCTCN2019074002-appb-000335
1、2-Methylhex-5-en-3-yn-2-ol(37-1)和2,7-Dimethylocta-3,5-diyne-2,7-diol(37-2)的制备
Figure PCTCN2019074002-appb-000336
在室温下,将2-甲基-3-丁炔-2-醇(253mg,3.0mmol),碘化亚酮(229mg,1.2mmol),二三苯基膦二氯化钯(421mg,0.6mmol)和二异丙胺(607mg,6mmol)溶于无水THF(10mL)中,用氮气置换反应体系,用注射器将溴乙烯(15mL,1M in THF,15mmol)一次性加入体系,室温搅拌过夜。将反应体系倒入水(30mL)中,用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品。粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/8)得到无色油状化合物37-1(139mg,收率42%)和37-2(98mg,收率20%).
2、目标化合物D37的制备
Figure PCTCN2019074002-appb-000337
化合物D37的制备是用化合物1b-2(100mg,0.46mmol)和37-1(76mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D37(101mg,收率71%)。ESI[M+H] +=309.3
1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.73(s,1H),7.40–7.28(m,3H),7.25–7.14(m,2H),6.39(q,J=7.0Hz,1H),5.88–5.73(m,1H),5.61(dd,J=17.6,2.2Hz,1H),5.48(dd,J=11.1,2.2Hz,1H),1.87(d,J=7.1Hz,3H),1.75(s,3H),1.73(s,3H).
3、目标化合物D38的制备
Figure PCTCN2019074002-appb-000338
化合物D38的制备是用化合物1b-2(100mg,0.46mmol)和37-2(95mg,0.57mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D38(83mg,收率50%)。ESI[M+H] +=365.3
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.74(s,1H),7.40–7.30(m,3H),7.25–7.21(m,2H),6.39(q,J=7.0Hz,1H),1.88(d,J=7.1Hz,3H),1.74(s,3H),1.70(s,3H),1.53(s,6H).
实施例D38本发明化合物D39的制备
Figure PCTCN2019074002-appb-000339
1、3-(Prop-1-yn-1-yl)oxetan-3-ol(39-1)的制备
Figure PCTCN2019074002-appb-000340
将氧杂环丁酮(181mg,2.51mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至-10℃。维持反应温度在-10℃,用注射器将丙炔基溴化镁(5.0mL,0.5 mol/L in THF,2.51mmol)在15分钟时间内缓慢加至体系,继续反应两小时。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品39-1。粗品没有纯化直接用于下一步反应。
2、目标化合物D39的制备
Figure PCTCN2019074002-appb-000341
化合物D39的制备是用化合物1b-2(216mg,1.0mmol)和39-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D39(220mg,收率68%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.83(s,1H),7.43–7.27(m,3H),7.23–7.16(m,2H),6.31(q,J=7.0Hz,1H),4.99–4.82(m,3H),4.74(d,J=7.3Hz,1H),1.89(s,3H),1.88(d,J=7.2Hz,3H).
实施例D39本发明化合物D40的制备
Figure PCTCN2019074002-appb-000342
1、1-(Prop-1-yn-1-yl)cyclohexan-1-ol(40-1)的制备
Figure PCTCN2019074002-appb-000343
将环己酮(181mg,1.85mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至-10℃。维持反应温度在-10℃,用注射器将丙炔基溴化镁(3.69mL,0.5mol/L in THF,1.85mmol)在15分钟时间内缓慢加至体系,继续反应两小时。经TLC监测反应完全, 将反应体系用饱和氯化铵溶液(10mL)终止,用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品40-1。粗品没有纯化直接用于下一步反应。
2、目标化合物D40的制备
Figure PCTCN2019074002-appb-000344
化合物D40的制备是用化合物1b-2(216mg,1.0mmol)和40-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D40(225mg,收率67%)。ESI[M+H] +=337.3
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.74(s,1H),7.40–7.28(m,3H),7.26–7.20(m,2H),6.42(q,J=7.1Hz,1H),2.17–2.02(m,2H),2.01–1.90(m,2H),1.87(d,J=7.0Hz,3H),1.87(s,3H),1.69–1.54(m,4H),1.54–1.29(m,2H).
实施例D40本发明化合物D41的制备
Figure PCTCN2019074002-appb-000345
1、3-Allyloxetan-3-ol(41-1)的制备
Figure PCTCN2019074002-appb-000346
将3-氧杂环丁酮(360mg,4.99mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至0℃。维持反应温度在0℃,用注射器将烯丙基氯化镁(4.99mL,1.0mol/L in THF,4.99mmol)在15分钟时间内缓慢加至体系,继续反应30分钟。经TLC监测反 应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品41-1。粗品没有纯化直接用于下一步反应。
2、目标化合物D41的制备
Figure PCTCN2019074002-appb-000347
化合物D41的制备是用化合物1b-2(216mg,1.0mmol)和41-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D41(80mg,收率26%)。ESI[M+H] +=313.2
1H NMR(400MHz,CDCl 3)δ7.79(s,2H),7.38–7.28(m,3H),7.18–7.13(m,2H),6.25(q,J=7.1Hz,1H),5.72(ddt,J=17.3,10.3,7.1Hz,1H),5.15–5.06(m,2H),4.80(d,J=7.4Hz,1H),4.74(d,J=7.4Hz,1H),4.64–4.56(m,2H),2.86(d,J=7.0Hz,2H),1.87(d,J=7.1Hz,3H).
实施例D41本发明化合物D42的制备
Figure PCTCN2019074002-appb-000348
1、(E)-3-(Prop-1-en-1-yl)oxetan-3-ol(42-1)的制备
Figure PCTCN2019074002-appb-000349
将3-氧杂环丁酮(360mg,4.99mmol)溶于无水THF(10mL)溶液,用氮气置换反应体系,并用冰水浴将温度降至0℃。维持反应温度在0℃,用注射器将1-丙烯基氯化镁(4.99mL,1.0mol/L in THF,4.99mmol)在15分钟时间内缓慢加至体系,继续反应30分钟。经TLC监测反应完全,将反应体系用饱和氯化铵溶液(10mL)终止,用乙酸乙酯萃取(3×10mL),合并有 机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品42-1。粗品没有纯化直接用于下一步反应。
2、目标化合物D42的制备
Figure PCTCN2019074002-appb-000350
化合物D42的制备是用化合物1b-2(216mg,1.0mmol)和42-1为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D42(80mg,收率26%)。ESI[M+H] +=313.2
1H NMR(400MHz,CDCl 3)δ7.90–7.80(m,2H),7.43–7.30(m,3H),7.18(dd,J=9.8,3.9Hz,2H),6.29(dd,J=7.1,3.8Hz,1H),5.95(ddd,J=17.1,13.3,1.5Hz,1H),5.80–5.64(m,1H),5.02–4.77(m,3H),4.72(d,J=8.0Hz,1H),1.87(dd,J=7.1,2.9Hz,3H),1.73(dd,J=6.3,1.4Hz,1.34H),1.60(dd,J=7.2,1.7Hz,1.67H).
实施例D42本发明化合物D43的制备
Figure PCTCN2019074002-appb-000351
化合物43-2的制备方法与制备化合物21-2的方法相同,使用环己酮为初始原料。
化合物D43的制备是用化合物1b-2(100mg,0.46mmol)和43-2(95mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/2),收集Rf=0.5~0.6部分得到无色油状化合物D43(124mg,收率80%)。ESI[M+H] +=337.3
1H NMR(400MHz,CDCl 3)δ8.20(s,1H),7.98(s,1H),7.45–7.35(m,3H),7.33–7.26(m,2H),6.50–6.40(m,1H),5.60(s,1H),4.99–4.90(m,2H),2.36–2.25(m,2H),2.13(t,J=5.8Hz,2H),1.93(d,J=7.0Hz,3H),1.63–1.50(m,6H).
实施例D43本发明化合物D44的制备
Figure PCTCN2019074002-appb-000352
在室温氮气保下,将1b-2(216mg,1.0mmol),醋酸银(13mg,1.0mmol),三苯基膦氯化金(25mg,0.05mmol),2-戊炔(82mg,1.2mmol)溶解在水(3.0mL)中,反应体系在封管60℃下搅拌过夜。经TLC监测反应未完全,将反应体系用饱和氯化铵溶液(10mL)终止,用乙酸乙酯萃取(3×10mL),合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6部分得到无色油状化合物D44(15mg,收率5%)。ESI[M+H] +=285.2
1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.80(s,1H),7.40–7.26(m,3H),7.24–7.10(m,2H),6.35(q,J=7.1Hz,1H),5.09(t,J=7.1Hz,1H),1.86(d,J=7.1Hz,3H),1.90–1.74(m,2H),0.85(t,J=7.5Hz,3H).
实施例D44本发明化合物D45的制备
Figure PCTCN2019074002-appb-000353
化合物D45的制备同化合物D44,用化合物1b-2(216mg,1.0mmol)和3-庚炔(99mg,1.2mmol)为原料,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5部分得到无色油状化合物D45(7mg,收率2%)。ESI[M+H] +=299.0
1H NMR(400MHz,CDCl 3)δ7.88(s,1H),7.81(s,1H),7.39–7.27(m,3H),7.22–7.11(m,2H),6.31(q,J=7.0Hz,1H),5.05(t,J=7.2Hz,1H),2.23–2.14(m,2H),1.88(d,J=7.1Hz,3H),1.86–1.75(m,2H),1.01(t,J=7.5Hz,3H),0.87(t,J=7.5Hz,3H).
实施例D45本发明化合物D46的制备
Figure PCTCN2019074002-appb-000354
化合物D46的制备是用化合物1b-2(100mg,0.46mmol)和1-烯丙基环丙醇(68mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物D46(45mg,收率14%)。ESI[M+H] +=297.2
1H NMR(400MHz,CDCl 3)δ8.04(s,1H),7.96(s,1H),7.41–7.33(m,3H),7.25–7.20(m,2H),6.36(q,J=7.1Hz,1H),5.75–5.36(m,1H),5.10–4.98(m,2H),2.69–2.54(m,2H),1.86(d,J=7.1Hz,3H),0.86–0.61(m,4H).
实施例D46本发明化合物D47的制备
Figure PCTCN2019074002-appb-000355
化合物47-1的制备是用3-氧杂环丁酮和乙炔基溴化镁反应制得,化合物47-2是用化合物47-1与正丁基锂反应后再与硫粉反应得到。
化合物D47的制备是用化合物1b-2(100mg,0.46mmol)和47-2(90mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物D47(18mg,收率12%)。ESI[M+H] +=329.1
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.78(s,1H),7.40–7.28(m,3H),7.20–7.15(m,2H),6.35–6.27(m,1H),5.63–4.89(m,5H),1.87(d,J=7.1Hz,3H).
实施例D47本发明化合物D48的制备
Figure PCTCN2019074002-appb-000356
化合物D48的制备是用化合物1b-2(100mg,0.46mmol)和1-丙炔基环丙醇(66mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.5的部分,得到无色油状化合物D48(56mg,收率41%)。ESI[M+H] +=295.2
1H NMR(400MHz,CDCl 3)δ8.00(s,1H),7.86(s,1H),7.45–7.35(m,3H),7.27–7.22(m,2H),6.35(q,J=7.1Hz,1H),1.87(d,J=7.1Hz,3H),1.85(s,3H),0.85–0.61(m,4H).
实施例D48本发明化合物D49的制备
Figure PCTCN2019074002-appb-000357
化合物D49的制备是用化合物1b-2(100mg,0.46mmol)和1-(propa-1,2-dien-1-yl)cyclopropan-1-ol(66mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D49(26mg,收率19%)。ESI[M+H] +=295.1
1H NMR(400MHz,CDCl 3)δ8.00(s,1H),7.88(s,1H),7.44–7.29(m,3H),7.25–7.20(m,2H),6.30(q,J=7.0Hz,1H),5.65–5.60(m,1H),5.04–4.85(m,2H),1.83(d,J=7.1Hz,3H),0.86–0.60(m,4H).
实施例D49本发明化合物D50的制备
Figure PCTCN2019074002-appb-000358
化合物D50的制备是用化合物1b-2(100mg,0.46mmol)和1-allylcyclopentan-1-ol(87mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D50(96mg,收率64%)。ESI[M+H] +=325.2
1H NMR(400MHz,CDCl 3)δ8.01(s,1H),7.90(s,1H),7.40–7.30(m,3H),7.25–7.21(m,2H),6.29(q,J=7.1Hz,1H),5.75–5.67(m,1H),5.15–5.06(m,2H),2.87(d,J=7.0Hz,2H),2.08–1.91(m,2H),1.85(d,J=7.1Hz,3H),1.81–1.30(m,6H).
实施例D50本发明化合物D51的制备
Figure PCTCN2019074002-appb-000359
化合物D51的制备是用化合物1b-2(100mg,0.46mmol)和1-乙炔基环戊醇(76mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D51(116mg,收率82%)。ESI[M+H] +=309.1
1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.91(s,1H),7.45–7.30(m,3H),7.25–7.21(m,2H),6.37(q,J=7.0Hz,1H),2.63(s,1H),2.04–1.90(m,2H),1.85(d,J=7.1Hz,3H),1.83–1.34(m,6H).
实施例D51本发明化合物D52的制备
Figure PCTCN2019074002-appb-000360
化合物D52的制备是用化合物1b-2(100mg,0.46mmol)和1-丙炔基环戊醇(86mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D52(80mg,收率54%)。ESI[M+H] +=323.2
1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.89(s,1H),7.42–7.30(m,3H),7.25–7.21(m,2H),6.38(q,J=7.0Hz,1H),2.01–1.90(m,2H),1.87(d,J=7.1Hz,3H),1.86(s,3H),1.83–1.34(m,6H).
实施例D52本发明化合物D53的制备
Figure PCTCN2019074002-appb-000361
化合物53-1的制备方法与制备化合物21-2的方法相同,使用1-乙炔基环戊醇为原料。
化合物D53的制备是用化合物1b-2(100mg,0.46mmol)和53-1(86mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D53(43mg,收率29%)。ESI[M+H] +=323.2
1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.73(s,1H),7.41–7.29(m,3H),7.25–7.21(m,2H),6.38(q,J=7.1Hz,1H),5.67–5.61(m,1H),5.05–4.87(m,2H),2.08–1.92(m,2H),1.87(d,J=7.1Hz,3H),1.85–1.34(m,6H).
实施例D53本发明化合物D54的制备
Figure PCTCN2019074002-appb-000362
化合物54-1的制备方法与制备化合物21-2的方法相同,使用3-甲基丁炔醇为原料。
化合物D54的制备是用化合物1b-2(100mg,0.46mmol)和54-1(68mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D54(28mg,收率21%)。ESI[M+H] +=297.2
1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.89(s,1H),7.44–7.30(m,3H),7.24–7.21(m,2H),6.38(q,J=7.0Hz,1H),6.17–5.55(m,1H),5.45–4.69(m,2H),2.06–1.85(m,6H),1.82–1.59(m,3H).
实施例D54本发明化合物D55的制备
Figure PCTCN2019074002-appb-000363
化合物55-1的制备方法与制备化合物21-2的方法相同,使用丙炔醇为原料。
化合物D55的制备是用化合物1b-2(100mg,0.46mmol)和55-1(48mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D55(79mg,收率64%)。ESI[M+H] +=269.1
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.79(s,1H),7.42–7.27(m,3H),7.25–7.19(m,2H),6.39–6.25(m,1H),5.50–5.25(m,3H),4.89–4.73(m,2H),1.83(d,J=7.1Hz,3H).
实施例D55本发明化合物D56的制备
Figure PCTCN2019074002-appb-000364
化合物56-1的制备方法与制备化合物21-2的方法相同,使用1-戊炔-3-醇为原料。
化合物D56的制备是用化合物1b-2(100mg,0.46mmol)和56-1(48mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D56(98mg,收率72%)。ESI[M+H] +=297.2
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.79(s,1H),7.35–7.27(m,3H),7.24–7.21(m,2H),6.35–6.21(m,1H),5.26–5.18(m,2H),4.92–4.74(m,2H),1.82(d,J=7.1Hz,3H),1.70–1.68(m,2H),0.93(t,J=7.4Hz,3H).
实施例D56本发明化合物D57的制备
Figure PCTCN2019074002-appb-000365
化合物D57的制备是用化合物1b-2(100mg,0.46mmol)和hept-4-yn-3-ol(78mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D57(113mg,收率79%)。ESI[M+H] +=311.2
1H NMR(400MHz,CDCl 3)δ7.92–7.75(m,2H),7.41–7.28(m,3H),7.25–7.11(m,2H),6.44–6.31(m,1H),5.65–5.41(m,1H),2.30–2.11(m,4H),1.95–1.80(m,3H),1.16–1.02(m,3H),0.95–0.79(m,3H).
实施例D57本发明化合物D58的制备
Figure PCTCN2019074002-appb-000366
化合物D58的制备是用化合物1b-2(100mg,0.46mmol)和4-己炔-3-醇(68mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D58(100mg,收率73%)。ESI[M+H] +=297.2
1H NMR(400MHz,CDCl 3)δ7.80(d,J=3.2Hz,1H),7.72(m,1H),7.39–7.25(m,3H),7.25–7.10(m,2H),6.49–6.25(m,1H),5.60–5.35(m,1H),1.94–1.74(m,5H),1.55–1.43(m,3H),0.98–0.85(m,3H).
实施例D58本发明化合物D59的制备
Figure PCTCN2019074002-appb-000367
化合物59-1的制备方法与制备化合物37-1的方法相同,使用3-丁炔-2-醇和溴乙烯为原料。
化合物D59的制备是用化合物1b-2(100mg,0.46mmol)和59-1(66mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D59(98mg,收率72%)。ESI[M+H] +=295.2
1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.85(s,1H),7.39–7.27(m,3H),7.25–7.11(m,2H),6.38(q,J=7.1Hz,1H),5.85–5.72(m,1H),5.63–5.48(m,3H),1.85(d,J=7.1Hz,3H),1.75(s,3H).
实施例D59本发明化合物D60的制备
Figure PCTCN2019074002-appb-000368
化合物60-1的制备方法与制备化合物37-1的方法相同,使用1-戊炔-3-醇和溴乙烯为原料。
化合物D60的制备是用化合物1b-2(100mg,0.46mmol)和60-1(76mg,0.69mmol)为原料按照通用操作A方法合成,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分,得到无色油状化合物D60(76mg,收率54%)。ESI[M+H] +=309.2
1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.71(s,1H),7.38–7.26(m,3H),7.25–7.12(m,2H),6.38(q,J=7.1Hz,1H),5.84–5.77(m,1H),5.64–5.59(m,2H),5.50–5.46(m,1H),2.03–1.92(m,2H),1.87(d,J=7.1Hz,3H),0.95(t,J=7.3Hz,3H).
实施例E1本发明化合物E1的制备
Figure PCTCN2019074002-appb-000369
1、Ethyl 4-amino-1H-imidazole-5-carboxylate(1-1)的制备
Figure PCTCN2019074002-appb-000370
在室温下,将5-氨基-1H-咪唑-4-甲酰胺(3.0g,23.8mmol),乙醇(30mL)和甲烷磺酸(6mL)依次加入到200mL的封管中,120℃反应10小时。反应液浓缩后用饱和NaHCO 3的水溶液调pH=8,经乙酸乙酯(3×150mL)萃取,饱和食盐水洗(100mL),干燥,抽滤,滤液浓缩得白色固体1-1(3.0g,收率81%)。
2、4-氟-1H-咪唑-5-甲酸乙酯(1-2)的制备
Figure PCTCN2019074002-appb-000371
在冰盐浴-10℃下,将1-1(250mg,1.61mmol)溶于40%的HBF 4中,加入NaNO 2(117mg,1.69mmol)的水溶液(0.15mL),在汞灯(254nm)照射下反应2小时。反应完全后,冰水浴下用1N的NaOH的水溶液调pH=7,水层用乙酸乙酯(3×10mL)萃取,合并有机相,经饱和食盐水洗涤后,干燥,抽滤,减压浓缩得到粗产品,经过柱层析分离(乙酸乙酯/石油醚(v/v)=1/1),TLC(乙酸乙酯/石油醚(v/v)=1/1)监测,收集Rf=0.4~0.5部分,得到无色油状化合物1-2(100mg,收率39%)。
3、4-氟-1H-咪唑-5-甲酸(1-3)的制备
Figure PCTCN2019074002-appb-000372
在室温下,将NaOH(50mg,1.26mmol)加入到1-2(100mg,0.63mmol)的乙醇/水(5mL,v/v=1/1)溶液中,室温反应5小时。反应完全后,浓缩,降温,用1N HCl调pH为5,乙酸乙酯萃取(3×5mL),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得到灰色固体化合物1-3(74mg,总收率90%)。ESI[M+H] +=131.0
4、(3-Methyloxetan-3-yl)methyl 4-fluoro-1H-imidazole-5-carboxylate(1-4)的制备
Figure PCTCN2019074002-appb-000373
在室温下,将1-3(74mg,0.57mmol),DCC(173mg,0.84mmol)和DMAP(103mg,0.84mmol)溶解在二氯甲烷(5mL)中,室温搅拌5分钟,再用注射器将(3-methyloxetan-3-yl)methanol(86mg,0.84mmol)缓慢加至反应体系,室温搅拌过夜。经TLC监测体系反应完全,经过减压 浓缩将溶剂移除,加入甲基叔丁基醚搅拌,抽滤,滤饼用甲基叔丁基醚洗涤,将滤液减压浓缩得到粗品,粗品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)=1/3),TLC(乙酸乙酯/石油醚(v/v)=1/1)监测,收集Rf=0.5~0.6部分,得到无色油状化合物1-4(109mg,收率89%)。ESI[M+H] +=215.1
5、目标化合物E1的制备
Figure PCTCN2019074002-appb-000374
在冰水浴0℃下,将1-4(109mg,0.51mmol),S-苯乙醇(94mg,0.77mmol)和PPh 3(202mg,0.77mmol)溶解在THF(10mL)溶液中,然后用注射器将DEAD(230mg,1.32mmol)缓慢滴加至上述反应体系中,滴加完后缓慢升至室温搅拌5小时。经TLC监测反应完全后,将饱和食盐水(10mL)加至反应体系,用乙酸乙酯(3×10mL)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到粗品,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/1)并收集Rf=0.4~0.6的部分得到无色油状化合物E1(102mg,收率63%)。ESI[M+H] +=319.2
1H NMR(400MHz,CDCl 3)δ7.42–7.28(m,4H),7.24–7.17(m,2H),6.26(q,J=7.0Hz,1H),4.52(dd,J=6.0,2.8Hz,2H),4.40(dd,J=6.1,1.5Hz,2H),4.33(q,J=11.0Hz,2H),1.85(d,J=7.1Hz,3H),1.36(s,3H).
以下所列化合物制备方法类同化合物E1,使用2-氟-1H-咪唑-5-甲酸(4-氟-1H-咪唑-5-甲酸或者2,4-二氟-1H-咪唑-5-甲酸)与相应的醇制备得到相应的咪唑-5-甲酸酯中间体,再与S-苯乙醇按照实施例E1化合物E1的方法制备得到相应的目标化合物。
化合物E2:50mg,ESI[M+H] +=347.2
1H NMR(400MHz,CDCl 3)δ7.41–7.28(m,4H),7.25–7.18(m,2H),6.30(q,J=7.1Hz,1H),4.25(dd,J=25.0,10.8Hz,2H),3.40(s,2H),3.33(s,3H),1.98–1.86(m,6H),1.85(d,J=7.1Hz,3H).
化合物E3:50mg,ESI[M+H] +=339.2
1H NMR(400MHz,CDCl 3)δ7.71(s,1H),7.47–7.21(m,5H),6.26(q,J=7.0Hz,1H),4.29–4.14(m,2H),2.77–2.60(m,2H),2.59–2.30(m,3H),1.81(d,J=7.1Hz,3H).
化合物E4:51mg,ESI[M+H] +=315.4
1H NMR(400MHz,CDCl 3)δ7.41–7.29(m,4H),7.21(d,J=6.8Hz,2H),6.20(d,J=7.1Hz,1H),4.93(t,J=6.5Hz,2H),4.87(d,J=7.4Hz,1H),4.75(d,J=8.0Hz,1H),2.78(s,1H),1.85(d,J=7.1Hz,3H).
化合物E5:40mg,ESI[M+H] +=305.2
1H NMR(400MHz,CDCl 3)δ7.71(s,1H),7.35–7.19(m,5H),6.13(q,J=7.0Hz,1H),4.51–4.35(m,2H),2.77(td,J=6.3,2.2Hz,2H),2.20(s,3H),1.91(d,J=7.1Hz,3H).
化合物E6:32mg,ESI[M+H] +=305.2
1H NMR(400MHz,CDCl 3)δ7.42(s,1H),7.33(dd,J=13.7,6.2Hz,3H),7.14(d,J=6.9Hz,2H),6.17(q,J=7.0Hz,1H),1.91(s,3H),1.84(d,J=7.1Hz,3H),1.52(s,3H),1.47(s,3H).
化合物E7:50mg,ESI[M+H]+=303.2
1H NMR(400MHz,CDCl 3)δ7.70(s,1H),7.45–7.19(m,5H),6.25(q,J=7.0Hz,1H),4.24–4.07(m,2H),2.75–2.56(m,1H),2.16–1.98(m,2H),1.97–1.71(m,4H),1.79(d,J=7.1Hz,3H).
化合物E8:83mg,ESI[M+H] +=289.0
1H NMR(400MHz,CDCl 3)δ7.40–7.28(m,4H),7.23–7.16(m,2H),6.28(q,J=7.0Hz,1H),4.19–3.92(m,2H),1.85(d,J=7.1Hz,3H),1.24–1.11(m,1H),0.65–0.49(m,2H),0.39–0.20(m,2H).
化合物E9:63mg,ESI[M+H] +=289.0
1H NMR(400MHz,CDCl 3)δ7.42–7.28(m,4H),7.23–7.14(m,2H),6.26(q,J=6.8Hz,1H),5.31–4.92(m,1H),2.49–2.29(m,2H),2.25–2.06(m,2H),1.83(d,J=7.1Hz,3H),1.90–1.76(m,1H),1.72–1.59(m,1H).
化合物E10:93mg,ESI[M+H] +=291.0
1H NMR(400MHz,CDCl 3)δ7.45–7.28(m,4H),7.22–7.13(m,2H),6.18(q,J=7.0Hz,1H),5.56(p,J=5.9Hz,1H),5.00–4.78(m,2H),4.76–4.57(m,2H),1.85(d,J=7.1Hz,3H).
化合物E11:33mg,ESI[M+H] +=307.0
1H NMR(400MHz,CDCl 3)δ7.46–7.28(m,4H),7.22–7.08(m,2H),6.19(q,J=7.1Hz,1H),5.75(p,J=8.0Hz,1H),3.64–3.43(m,2H),3.42–3.16(m,2H),1.84(d,J=7.1Hz,3H).
化合物E12:63mg,ESI[M+H] +=291.1
1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,4H),7.24–7.17(m,2H),6.27(q,J=6.6Hz,1H),1.84(d,J=7.1Hz,3H),1.51(s,9H).
化合物E13:29mg,ESI[M+H] +=333.0
1H NMR(400MHz,CDCl 3)δ7.47(s,1H),7.41–7.28(m,3H),7.22–7.03(m,2H),6.21–5.97(m, 1H),5.10–4.57(m,4H),2.13(s,3H),1.85(d,J=7.1Hz,3H).
化合物E14:63mg,ESI[M+H] +=317.0
1H NMR(400MHz,CDCl 3)δ7.48(s,1H),7.42–7.25(m,3H),7.24–7.01(m,2H),6.20–5.96(m,1H),2.17(s,3H),1.86(d,J=7.1Hz,3H),1.21–0.85(m,4H).
化合物E15:104mg,ESI[M+H] +=329.0
1H NMR(400MHz,CDCl 3)δ7.46–7.29(m,4H),7.24–7.15(m,2H),6.21(q,J=7.1Hz,1H),4.95–4.79(m,3H),4.73(d,J=7.3Hz,1H),1.89(s,3H),1.85(d,J=7.1Hz,3H).
化合物E16:88mg,ESI[M+H] +=301.0
1H NMR(400MHz,CDCl 3)δ7.41–7.28(m,4H),7.24–7.16(m,2H),6.37–6.17(m,1H),5.61–5.37(m,1H),1.91–1.77(m,6H),1.51(d,J=6.6Hz,3H).
化合物E17:56mg,ESI[M+H] +=315.1
1H NMR(400MHz,CDCl 3)δ7.41–7.27(m,4H),7.26–7.18(m,2H),6.30(q,J=7.0Hz,1H),1.84(d,J=5.4Hz,6H),1.70(s,3H),1.67(s,3H).
化合物E18:36mg,ESI[M+H] +=301.0
1H NMR(400MHz,CDCl 3)δ7.47–7.29(m,4H),7.24–7.15(m,2H),6.34–6.22(m,1H),5.58–5.44(m,1H),5.37–5.23(m,1H),4.95–4.73(m,2H),1.85(d,J=7.0Hz,3H),1.47–1.31(m,3H).
化合物E19:39mg,ESI[M+H] +=315.0
1H NMR(400MHz,CDCl 3)δ7.44–7.27(m,4H),7.24–7.17(m,2H),6.37–6.17(m,1H),6.00–5.59(m,1H),5.46–4.71(m,2H),2.01–1.65(m,6H),1.59(d,J=5.1Hz,3H).
化合物E20:94mg,ESI[M+H] +=313.0
1H NMR(400MHz,CDCl 3)δ7.45–7.28(m,4H),7.25–7.09(m,2H),6.38–6.16(m,1H),5.90–5.73(m,1H),5.73–5.58(m,2H),5.56–5.37(m,1H),1.85(d,J=7.1Hz,3H),1.56(d,J=6.7Hz,3H).
化合物E21:88mg,ESI[M+H] +=327.1
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,4H),7.25–7.19(m,2H),6.30(q,J=7.0Hz,1H),5.88–5.74(m,1H),5.67–5.57(m,1H),5.50–5.41(m,1H),1.84(d,J=7.1Hz,3H),1.75(s,3H),1.71(s,3H).
化合物E22:87mg,ESI[M+H] +=305.1
1H NMR(400MHz,CDCl 3)δ7.40–7.28(m,4H),7.23–7.15(m,2H),6.28(q,J=5.9Hz,1H),4.90(p,J=6.3Hz,1H),1.85(d,J=7.0Hz,3H),1.69–1.54(m,4H),0.90(t,J=7.4Hz,3H),0.83(t,J=7.4Hz,3H).
化合物E23:36mg,ESI[M+H] +=373.1
1H NMR(400MHz,CDCl 3)7.44–7.15(m,6H),6.27(q,J=7.1Hz,1H),5.86(s,1H),2.49–2.08(m,4H),1.89(d,J=7.1Hz,3H),1.68–1.44(m,6H).
化合物E24:62mg,ESI[M+H] +=277.0
1H NMR(400MHz,CDCl 3)δ7.49–7.28(m,4H),7.24–7.12(m,2H),6.35–6.19(m,1H),5.28–5.03(m,1H),1.85(d,J=6.7Hz,3H),1.34–1.26(m,6H).
化合物E25:48mg,ESI[M+H] +=301.0
1H NMR(400MHz,CDCl 3)δ7.41–7.18(m,6H),6.30(q,J=6.3Hz,1H),2.59(s,1H),1.84(d,J=6.9Hz,3H),1.74(s,3H),1.72(s,3H).
化合物E26:73mg,ESI[M+H] +=305.1
1H NMR(400MHz,CDCl 3)δ7.44–7.28(m,4H),7.25–7.17(m,2H),6.30(q,J=6.6Hz,1H),3.91(dd,J=31.2,10.4Hz,2H),1.85(d,J=7.0Hz,3H),0.98(s,9H).
化合物E27:48mg,ESI[M+H] +=303.1
1H NMR(400MHz,CDCl 3)δ7.44–7.28(m,4H),7.24–7.16(m,2H),6.33–6.18(m,1H),2.44–2.29(m,2H),2.25–2.10(m,2H),1.84(d,J=6.7Hz,3H),1.74–1.66(m,2H),1.56(s,3H).
化合物E28:27mg ESI[M+H] +=305.1
1H NMR(400MHz,CDCl 3)δ7.41–7.28(m,4H),7.24–7.17(m,2H),6.27(q,J=6.9Hz,1H),1.90–1.74(m,5H),1.49(s,1H),1.47(s,3H),0.88(t,J=7.5Hz,3H).
化合物E29:28mg,ESI[M+H] +=319.0
1H NMR(400MHz,CDCl 3)δ7.41–7.27(m,4H),7.24–7.12(m,2H),6.27(q,J=6.4Hz,1H),1.83(d,J=6.9Hz,3H),1.80–1.74(m,2H),1.48(s,3H),1.48(s,3H),1.41–1.20(m,2H),0.88(t,J=7.3Hz,3H).
化合物E30:16mg,ESI[M+H] +=319.0
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,4H),7.23–7.14(m,2H),6.27(q,J=7.0Hz,1H),1.98–1.86(m,2H),1.83(d,J=7.1Hz,3H),1.82–1.71(m,2H),1.44(s,3H),0.84(td,J=7.5,5.0Hz,6H).
化合物E31:14mg,ESI[M+H] +=343.0
1H NMR(400MHz,CDCl 3)δ7.50–7.42(m,1H),7.41–7.27(m,5H),7.22–7.15(m,1H),6.24–6.13(m,1H),2.82–2.52(m,3H),2.40–2.27(m,2H),2.22(s,1H),2.03–1.74(m,6H).
化合物E32:40mg,ESI[M+H] +=303.1
1H NMR(400MHz,CDCl 3)δ7.42–7.28(m,4H),7.23–7.16(m,2H),6.27(q,J=7.0Hz,1H),6.08(dd,J=17.5,10.9Hz,1H),5.15(dd,J=48.6,14.2Hz,2H),1.82(d,J=7.0Hz,3H),1.57(s,6H).
化合物E33:36mg,ESI[M+H] +=303.1
1H NMR(400MHz,CDCl 3)δ7.40–7.28(m,4H),7.24–7.16(m,2H),6.40–6.04(m,1H),1.84(d,J=6.4Hz,3H),1.59(s,3H),1.37–1.24(m,2H),0.99–0.82(m,1H),0.74–0.61(m,1H).
化合物E34:70mg,ESI[M+H] +=275.0
1H NMR(400MHz,CDCl 3)δ7.41–7.29(m,4H),7.24–7.16(m,2H),6.26(q,J=7.0Hz,1H),4.28–4.14(m,1H),1.84(d,J=7.1Hz,3H),0.86–0.60(m,4H).
化合物E35:72mg,ESI[M+H] +=287.0
1H NMR(400MHz,CDCl 3)δ7.42–7.28(m,4H),7.24–7.17(m,2H),6.26(q,J=7.1Hz,1H),4.89–4.68(m,2H),1.94–1.79(m,6H).
化合物E36:48mg ESI[M+H] +=355.1
1H NMR(400MHz,CDCl 3)7.40–7.29(m,4H),7.22–7.15(m,2H),6.28(q,J=7.1Hz,1H),5.61–5.51(m,1H),5.00–4.95(m,2H),2.46–2.08(m,4H),1.90(d,J=7.0Hz,3H),1.65–1.49(m,6H).
化合物E37:680mg,ESI[M+H] +=329.0
1H NMR(400MHz,CDCl 3)δ7.40–7.29(m,4H),7.22–7.15(m,2H),6.18(q,J=7.1Hz,1H),5.62(t,J=6.6Hz,1H),5.03–4.86(m,3H),4.84–4.71(m,3H),1.84(d,J=7.1Hz,3H).
化合物E38:55mg,ESI[M+H] +=305.0
1H NMR(400MHz,CDCl 3)δ7.42–7.29(m,4H),7.21–7.16(m,2H),6.17(q,J=7.0Hz,1H),4.80(dd,J=28.1,7.2Hz,2H),4.55–4.48(m,2H),1.84(d,J=7.1Hz,H),1.73(s,3H).
化合物E39:58mg,ESI[M+H] +=317.2
1H NMR(400MHz,CDCl 3)δ7.40–7.21(m,4H),7.18–7.09(m,2H),6.16(q,J=7.0Hz,1H),2.50–2.28(m,2H),2.21–2.07(m,2H),1.79(d,J=7.1Hz,3H),1.85–1.56(m,4H),0.94(t,J=7.3Hz,3H).
化合物E40:52mg,ESI[M+H] +=331.2
1H NMR(400MHz,CDCl 3)δ7.40–7.20(m,4H),7.15–7.10(m,2H),6.20(q,J=7.0Hz,1H),2.50–2.28(m,2H),2.21–2.07(m,2H),1.80(d,J=7.1Hz,3H),1.85–1.56(m,4H),1.41–1.20(m,2H),0.88(t,J=7.3Hz,3H).
化合物E41:44mg,ESI[M+H] +=303.1
1H NMR(400MHz,CDCl 3)δ7.45–7.22(m,4H),7.20–7.16(m,2H),6.25(q,J=7.0Hz,1H),4.50–4.31(m,1H),1.84(d,J=7.1Hz,3H),1.56-1.40(m,3H),1.24–1.11(m,1H),0.65–0.49(m,2H),0.39–0.20(m,2H).
化合物E43:56mg,ESI[M+H] +=319.2
1H NMR(400MHz,CDCl 3)δ7.45–7.25(m,4H),7.22–7.15(m,2H),6.27(q,J=7.0Hz,1H), 4.87-4.72(m,2H),4.64–4.50(m,2H),2.24–2.05(m,2H),1.85(d,J=7.1Hz,3H),0.91(t,J=7.5Hz,3H).
化合物E44:24mg,ESI[M+H] +=333.2
1H NMR(400MHz,CDCl 3)δ7.48–7.15(m,6H),6.26(q,J=7.0Hz,1H),4.85–4.70(m,4H),2.10(td,J=7.1,3.0Hz,2H),1.87(d,J=7.1Hz,3H),1.38–1.21(m,2H),0.94(t,J=7.3Hz,3H).
化合物E45:32mg,ESI[M+H]+=321.2
1H NMR(400MHz,CDCl 3)δ7.49–7.28(m,4H),7.23–7.10(m,2H),6.25(q,J=7.1Hz,1H),5.00–4.78(m,2H),4.76–4.57(m,2H),1.80(d,J=7.1Hz,3H),1.73(s,3H).
化合物E46:39mg,ESI[M+H] +=333.1
1H NMR(400MHz,CDCl 3)δ7.40–7.28(m,4H),7.26–7.17(m,2H),6.25(q,J=7.0Hz,1H),2.90–2.75(m,2H),1.88(d,J=7.1Hz,3H),1.52(s,3H),1.44(s,3H),1.38(t,J=7.2Hz,3H).
化合物E47:46mg,ESI[M+H] +=347.0
1H NMR(400MHz,CDCl 3)δ7.43(s,1H),7.42–7.27(m,3H),7.25–7.03(m,2H),6.21–5.97(m,1H),5.10–4.57(m,4H),2.70–2.55(m,2H),1.86(d,J=7.1Hz,3H),1.38(t,J=7.2Hz,3H).
化合物E48:54mg,ESI[M+H] +=361.1
1H NMR(400MHz,CDCl 3)δ7.48–7.20(m,4H),7.19–7.15(m,2H),6.23(q,J=7.0Hz,1H),3.80–3.66(m,4H),2.19–1.90(m,7H),1.84(d,J=7.1Hz,3H).
化合物E49:39mg,ESI[M+H] +=331.1
1H NMR(400MHz,CDCl 3)δ7.47–7.21(m,4H),7.20–7.15(m,2H),6.24(q,J=7.1Hz,1H),2.61–2.40(m,4H),2.20(s,3H),1.84(d,J=7.1Hz,3H),1.80–1.74(m,2H).
化合物E50:54mg,ESI[M+H] +=345.2
1H NMR(400MHz,CDCl 3)δ7.47–7.21(m,4H),7.20–7.15(m,2H),6.24(q,J=7.0Hz,1H),2.75–2.49(m,4H),2.25(s,3H),1.89–1.53(m,7H).
化合物E51:50mg,ESI[M+H] +=359.2
1H NMR(400MHz,CDCl 3)δ7.45–7.20(m,4H),7.19–7.15(m,2H),6.22(q,J=7.0Hz,1H),2.75–2.49(m,4H),2.27(s,3H),1.89–1.53(m,9H).
化合物E54:42mg,ESI[M+H] +=343.2
1H NMR(400MHz,CDCl 3)δ7.47–7.24(m,4H),7.19–7.13(m,2H),6.23(q,J=7.1Hz,1H),3.98–3.65(m,4H),2.72(s,1H),2.33–2.19(m,2H),2.16–2.00(m,2H),1.88(d,J=7.1Hz,3H).
化合物E55:59mg,ESI[M+H] +=341.2
1H NMR(400MHz,CDCl 3)δ7.48–7.20(m,4H),7.19–7.15(m,2H),6.23(q,J=7.1Hz,1H),2.66(s,1H),2.25–1.90(m,4H),1.86(d,J=7.1Hz,3H),1.72–1.32(m,6H).
化合物E56:38mg,ESI[M+H] +=327.2
1H NMR(400MHz,CDCl 3)δ7.47–7.15(m,6H),6.27(q,J=7.1Hz,1H),2.66(s,1H),2.36–1.90(m,4H),1.89(d,J=7.1Hz,3H),1.85–1.55(m,4H).
化合物E57:36mg,ESI[M+H] +=313.1
1H NMR(400MHz,CDCl 3)δ7.48–7.22(m,4H),7.19–7.14(m,2H),6.24(q,J=7.1Hz,1H),2.70–2.62(m,2H),2.61(s,1H),2.56–2.36(m,2H),2.08–1.88(m,2H),1.86(d,J=7.1Hz,3H).
化合物E58:24mg,ESI[M+H] +=357.2
1H NMR(400MHz,CDCl 3)δ7.45–7.22(m,4H),7.20–7.14(m,2H),6.20(q,J=7.1Hz,1H),3.96–3.65(m,4H),2.34–2.19(m,2H),2.17–2.00(m,2H),1.90(d,J=7.1Hz,3H),1.88(s,3H).
化合物E59:40mg,ESI[M+H] +=355.3
1H NMR(400MHz,CDCl 3)δ7.48–7.20(m,4H),7.19–7.15(m,2H),6.26(q,J=7.0Hz,1H),2.15–1.90(m,4H),1.88(d,J=7.1Hz,3H),1.86(s,3H),1.69–1.29(m,6H).
化合物E60:47mg,ESI[M+H] +=341.2
1H NMR(400MHz,CDCl 3)δ7.49–7.21(m,4H),7.20–7.14(m,2H),6.22(q,J=7.0Hz,1H),2.50–2.10(m,4H),1.86(d,J=7.1Hz,3H),1.80–1.63(m,4H),1.61(s,3H)..
化合物E61:27mg,ESI[M+H] +=327.1
1H NMR(400MHz,CDCl 3)δ7.47–7.22(m,4H),7.20–7.14(m,2H),6.23(q,J=7.0Hz,1H),2.46–2.10(m,4H),1.87(d,J=7.1Hz,3H),1.78–1.65(m,2H),1.60(s,3H).
化合物E62:34mg,ESI[M+H] +=357.2
1H NMR(400MHz,CDCl 3)δ7.47–7.22(m,4H),7.20–7.14(m,2H),6.23(q,J=7.0Hz,1H),5.68–5.63(m,1H),5.03–4.87(m,2H),3.75–3.65(m,4H),2.22–2.01(m,4H),1.93(d,J=7.0Hz,3H).
化合物E63:46mg,ESI[M+H] +=341.2
1H NMR(400MHz,CDCl 3)δ7.44–7.20(m,4H),7.19–7.15(m,2H),6.24(q,J=7.0Hz,1H),5.67–5.64(m,1H),5.04–4.86(m,2H),2.74–2.00(m,4H),1.89–1.55(m,7H).
化合物E64:24mg,ESI[M+H] +=327.1
1H NMR(400MHz,CDCl 3)δ7.43–7.28(m,4H),7.24–7.15(m,2H),6.25(q,J=6.9Hz,1H),5.59(t,J=6.6Hz,1H),5.01–4.80(m,2H),2.51–2.33(m,4H),1.83(d,J=7.1Hz,3H),1.79–1.66(m,2H).
化合物E65:41mg,ESI[M+H] +=343.1
1H NMR(400MHz,CDCl 3)δ7.48–7.14(m,6H),6.23(q,J=7.1Hz,1H),4.99–4.74(m,4H),2.45–2.25(m,2H),1.88(d,J=7.1Hz,3H),1.38(t,J=7.1Hz,3H).
化合物E66:45mg,ESI[M+H] +=315.2
1H NMR(400MHz,CDCl 3)δ7.47–7.22(m,4H),7.20–7.14(m,2H),6.27(q,J=7.1Hz,1H),5.64–5.32(m,1H),2.45–1.25(m,2H),1.94–1.74(m,6H),1.36–1.14(m,3H).
化合物E67:52mg,ESI[M+H] +=329.2
1H NMR(400MHz,CDCl 3)δ7.42–7.15(m,6H),6.30(q,J=7.1Hz,1H),2.38–2.25(m,2H),1.84(d,J=7.0Hz,3H),1.71(s,3H),1.68(s,3H),1.36–1.14(m,3H).
化合物E68:43mg,ESI[M+H] +=329.2
1H NMR(400MHz,CDCl 3)δ7.41–7.26(m,4H),7.23–7.16(m,2H),6.38–6.17(m,1H),5.61–5.37(m,1H),2.38–2.25(m,4H),1.36–1.14(m,6H).
化合物E69:25mg,ESI[M+H] +=327.1
1H NMR(400MHz,CDCl 3)δ7.45–7.28(m,4H),7.25–7.09(m,2H),6.38–6.16(m,1H),5.90–5.73(m,1H),5.73–5.58(m,2H),5.56–5.37(m,1H),2.12–2.03(m,2H),1.85(d,J=7.1Hz,3H),1.36–1.14(m,3H).
化合物E70:48mg,ESI[M+H] +=315.2
1H NMR(400MHz,CDCl 3)δ7.42–7.16(m,6H),6.35–6.17(m,1H),5.61–5.37(m,1H),2.37–2.25(m,2H),1.92–1.80(m,6H),1.37–1.14(m,3H).
化合物E71:33mg,ESI[M+H] +=363.1
1H NMR(400MHz,CDCl 3)δ7.42–7.29(m,4H),7.22–7.15(m,2H),6.55(s,1H),6.19(q,J=7.1Hz,1H),5.08–4.92(m,2H),3.91–3.75(m,2H),3.65–3.39(m,2H),1.84(d,J=7.1Hz,3H).
化合物E72:41mg,ESI[M+H] +=345.1
1H NMR(400MHz,CDCl 3)δ7.46–7.15(m,6H),6.55(s,1H),6.27(q,J=6.5Hz,1H),2.65–2.43(m,4H),1.83(d,J=7.1Hz,3H),1.84–1.71(m,2H).
化合物E73:45mg,ESI[M+H] +=359.1
1H NMR(400MHz,CDCl 3)δ7.43–7.15(m,6H),6.54(s,1H),6.28(q,J=7.1Hz,1H),2.84–1.55(m,11H).
化合物E74:18mg,ESI[M+H] +=375.1
1H NMR(400MHz,CDCl 3)δ7.45–7.21(m,4H),7.20–7.15(m,2H),6.53(s,1H),6.21(q,J=7.1Hz,1H),3.79–3.61(m,4H),2.25–2.00(m,4H),1.93(d,J=6.7Hz,3H).
化合物E75:28mg,ESI[M+H] +=333.1
1H NMR(400MHz,CDCl 3)δ7.43–7.26(m,4H),7.23–7.16(m,2H),6.58(s,1H),6.38–6.16(m,1H),2.06–1.65(m,6H),1.60(d,J=5.2Hz,3H).
化合物E76:20mg,ESI[M+H] +=319.1
1H NMR(400MHz,CDCl 3)δ7.46–7.28(m,4H),7.24–7.16(m,2H),6.57(s,1H),6.33–6.19(m,1H),5.37–5.23(m,1H),1.87(d,J=7.1Hz,3H),1.49–1.29(m,3H).
化合物E77:32mg,ESI[M+H] +=315.2
1H NMR(400MHz,CDCl 3)δ7.47–7.29(m,4H),7.24–7.15(m,2H),6.34–6.22(m,1H),5.58–5.44(m,1H),5.37–5.23(m,1H),4.95–4.73(m,2H),1.97–1.81(m,5H),1.17–0.97(m,3H).
化合物E78:24mg,ESI[M+H] +=348.1
1H NMR(400MHz,CDCl 3)δ7.45–7.28(m,4H),7.23–7.15(m,2H),6.20(q,J=7.1Hz,1H),5.33–5.00(m,4H),1.85(d,J=7.1Hz,3H).
化合物E79:21mg,ESI[M+H] +=346.1
1H NMR(400MHz,CDCl 3)δ7.44–7.29(m,4H),7.24–7.15(m,2H),6.20(q,J=7.1Hz,1H),6.64(s,1H),5.23–4.71(m,4H),1.87(d,J=7.1Hz,3H).
化合物E80:19mg,ESI[M+H] +=329.0
1H NMR(400MHz,CDCl 3)δ7.45–7.15(m,6H),6.20(q,J=7.1Hz,1H),5.69(t,J=6.8Hz,1H),5.53–4.70(m,6H),1.85(d,J=7.1Hz,3H).
化合物E81:33mg,ESI[M+H] +=371.0
1H NMR(400MHz,CDCl 3)7.45–7.15(m,6H),6.30(q,J=7.1Hz,1H),5.90–5.75(m,1H),5.25–5.00(m,2H),2.76–2.28(m,4H),1.91(d,J=7.0Hz,3H),1.68–1.41(m,6H).
化合物E82:30mg,ESI[M+H] +=373.2
1H NMR(400MHz,CDCl 3)δ7.48–7.14(m,6H),6.21(q,J=7.1Hz,1H),5.70–5.63(m,1H),5.23–4.96(m,2H),3.85–3.65(m,4H),2.42–2.16(m,2H),2.33–2.00(m,2H),1.89(d,J=7.1Hz,3H).
化合物E83:ESI[M+H] +=2357.2
1H NMR(400MHz,CDCl 3)δ7.45–7.15(m,6H),6.28(q,J=7.1Hz,1H),5.75–5.68(m,1H),5.24–4.98(m,2H),2.84–1.55(m,11H).
化合物E84:23mg,ESI[M+H] +=289.0
1H NMR(400MHz,CDCl 3)δ7.45–7.15(m,6H),6.23(q,J=7.0Hz,1H),5.78(t,J=6.6Hz,1H),5.61–4.85(m,2H),2.65–2.32(m,4H),1.80(d,J=7.1Hz,3H),1.85–1.64(m,2H).
化合物E85:34mg,ESI[M+H] +=345.1
1H NMR(400MHz,CDCl 3)δ7.47–7.29(m,4H),7.25–7.14(m,2H),6.24(q,J=7.1Hz,1H),5.30–4.64(m,4H),1.91(s,3H),1.88(d,J=7.1Hz,3H).
化合物E86:38mg,ESI[M+H] +=303.0
1H NMR(400MHz,CDCl 3)δ7.45–7.29(m,4H),7.25–7.16(m,2H),6.31(q,J=7.1Hz,1H),4.95–4.70(m,2H),2.05–1.75(m,6H).
化合物E87:47mg,ESI[M+H] +=331.1
1H NMR(400MHz,CDCl 3)δ7.45–7.16(m,6H),6.30(q,J=7.0Hz,1H),6.08(dd,J=17.5,10.9 Hz,1H),4.47–4.14(m,1H),2.18–2.01(m,2H),1.39(d,J=7Hz,3H),1.15(t,J=8Hz,3H)
化合物E88:51mg,ESI[M+H] +=331.1
1H NMR(400MHz,CDCl 3)δ7.45–7.28(m,4H),7.26–7.16(m,2H),6.28(q,J=7.0Hz,1H),1.95(s,3H),1.83(s,3H),1.79(s,3H),1.68(s,3H).
化合物E89:56mg,ESI[M+H] +=319.2
1H NMR(400MHz,CDCl 3)δ7.42–7.16(m,6H),6.29(q,J=7.1Hz,1H),6.08–5.15(m,3H),1.85(d,J=7.1Hz,3H),1.65(s,6H).
化合物E90:16mg,ESI[M+H] +=329.0
1H NMR(400MHz,CDCl 3)δ7.40–7.30(m,4H),7.21–7.15(m,2H),6.18(q,J=6.9Hz,1H),5.74(t,J=6.7Hz,1H),5.08–4.92(m,2H),3.78(dd,J=23.0,10.3Hz,2H),3.41–3.34(m,2H),1.83(d,J=7.1Hz,3H).
化合物E91:25mg,ESI[M+H] +=345.1
1H NMR(400MHz,CDCl 3)δ7.45–7.25(m,4H),7.25–7.08(m,2H),6.28(q,J=7.0Hz,1H),5.05–4.74(m,4H),1.88(s,3H),1.88(d,J=7.1Hz,3H).
化合物E92:19mg,ESI[M+H] +=346.1
1H NMR(400MHz,CDCl 3)δ7.47–7.15(m,6H),6.28(q,J=7.1Hz,1H),3.02–2.62(m,4H),1.85(d,J=7.1Hz,3H),1.95–1.67(m,2H).
化合物E93:34mg,ESI[M+H] +=373.1
1H NMR(400MHz,CDCl 3)7.42–7.15(m,6H),6.24(q,J=7.1Hz,1H),5.71–5.62(m,1H),5.14–5.00(m,2H),1.89(d,J=7.1Hz,3H),1.85–1.34(m,10H).
化合物E94:39mg,ESI[M+H] +=287.1
1H NMR(400MHz,CDCl 3)δ7.49–7.08(m,6H),6.18(q,J=7.1Hz,1H),4.95–4.55(m,2H),1.98–1.73(m,6H).
化合物E95:18mg,ESI[M+H] +=329.2
1H NMR(400MHz,CDCl 3)δ7.48–7.09(m,6H),6.20(q,J=7.1Hz,1H),5.69(t,J=6.7Hz,1H),5.08(d,J=6.6Hz,2H),4.84–4.70(m,4H),1.89(d,J=7.1Hz,3H).
化合物E96:21mg,ESI[M+H] +=348.1
1H NMR(400MHz,CDCl 3)δ7.48–7.06(m,6H),6.19(q,J=7.1Hz,1H),5.30–4.96(m,4H),1.87(d,J=7.1Hz,3H).
化合物E97:56mg,ESI[M+H] +=316.1
1H NMR(400MHz,CDCl 3)δ7.45–7.01(m,6H),6.21(q,J=7.1Hz,1H),5.52–5.01(m,4H),1.87(d,J=7.1Hz,3H).
化合物E98:56mg,ESI[M+H] +=305.1
1H NMR(400MHz,CDCl 3)δ7.42–7.10(m,5H),6.28(q,J=7.1Hz,1H),4.90–4.65(m,2H),1.95–1.75(m,6H).
化合物E99:31mg,ESI[M+H] +=347.1
1H NMR(400MHz,CDCl 3)δ7.45–7.10(m,5H),6.62(q,J=7.1Hz,1H),5.70(t,J=6.6Hz,1H),5.10(d,J=6.6Hz,2H),4.89–4.72(m,4H),1.90(d,J=7.1Hz,3H).
实施例E2本发明化合物E100,化合物E128和化合物E129的制备
Figure PCTCN2019074002-appb-000375
将1H-咪唑-5-甲酸乙酯(1eq)和NCS(2eq)溶于乙腈(10mL/mmol)溶液,回流搅拌3小时。经TLC监测反应完全,将反应体系降至室温,加入水(100mL),用乙酸乙酯(3×20mL)萃取,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无 色油状粗品,经过柱层析分离(乙酸乙酯/石油醚(v/v)=1/100),TLC(乙酸乙酯/石油醚(v/v)=1/30)监测,收集到得到中间体100-1。化合物100-1,化合物128-1和化合物129-1分别与S-苯乙醇按照制备化合物E1的方法分别制备得到目标化合物E100,化合物E128和化合物E129
化合物E100,1.56g,无色油状液体,收率39%,ESI[M+H] +=279.0
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.38–7.27(m,3H),7.21–7.14(m,2H),6.73(q,J=7.1Hz,1H),4.29(q,J=7.1Hz,2H),1.98(d,J=7.2Hz,3H),1.34(t,J=7.1Hz,3H).
化合物E128,1.54g,无色油状液体,收率39%,ESI[M+H] +=279.0
1H NMR(400MHz,CDCl 3)δ7.59(s,1H),7.42–7.28(m,3H),7.22–7.13(m,2H),6.33(q,J=7.1Hz,1H),4.41–4.22(m,2H),1.85(d,J=7.1Hz,3H),1.34(t,J=7.1Hz,3H).
化合物E129,1.10g,无色油状液体,收率39%,ESI[M+H–104] +=209.0
1H NMR(400MHz,CDCl 3)δ7.41–7.28(m,3H),7.22–7.14(m,2H),6.65(q,J=6.9Hz,1H),4.39–4.24(m,2H),1.97(d,J=7.2Hz,3H),1.35(t,J=7.1Hz,3H).
实施例E3本发明化合物E116和化合物E125的制备
Figure PCTCN2019074002-appb-000376
在室温下,将LiOH.H 2O(2eq)加入到化合物100-1(1eq)的甲醇/四氢呋喃/水(10mL/mmol,V/V/V=1/1/1.5)溶液中,室温反应3小时。反应完全后,浓缩,降温,用1N HCl调pH为5,乙酸乙酯(3×20mL)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得到白色固体化合物100-2。100-2与醇通过缩合反应得到羧酸酯中间体116-1,再与S-苯乙醇按照制备化合物E1的方法制备化合物E116,经过TLC纯化(乙酸乙酯/石油醚(v/v)=1/3)并收集Rf=0.4~0.5的部分,得到无色油状化合物E116(52mg)。ESI[M+H] +=317.0
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.41–7.27(m,3H),7.24–7.11(m,2H),6.79–6.62(m,1H),5.61–5.45(m,1H),2.04–1.94(m,3H),1.90–1.78(m,3H),1.53(t,J=6.2Hz,3H).
化合物E125制备方法类同化合物E116,使用4-氯-1H-咪唑-5-羧酸与相应的醇制备得到4-氯-1H-咪唑-5-羧酸酯中间体,再与S-苯乙醇反应得到目标化合物E125(53mg),ESI[M+H] +=379.1
1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.41–7.10(m,5H),6.84(s,1H),6.57(q,J=7.1Hz,1H),4.89–4.40(m,4H),1.99(d,J=7.2Hz,3H).
以下化合物的制备方法类同实施例E3的化合物E116.
化合物E52:55mg,ESI[M+H] +=363.0
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.40–7.11(m,5H),6.58(q,J=7.1Hz,1H),4.99–4.64(m,4H),2.73(q,J=7.2Hz,2H),1.88(d,J=7.1Hz,3H),1.41(t,J=7.2Hz,3H).
化合物E101:28mg,ESI[M+H] +=335.2
1H NMR(400MHz,CDCl 3)δ7.60(s,1H),7.42–7.28(m,3H),7.19(d,J=7.0Hz,2H),6.36–6.34(m,1H),4.55(dd,J=6.0,1.3Hz,2H),4.45–4.33(m,4H),1.86(d,J=7.1Hz,3H),1.40(s,3H).
化合物E102:150mg,ESI[M+H] +=363.3
1H NMR(400MHz,CDCl 3)δ7.57(s,1H),7.34(dt,J=13.5,6.9Hz,3H),7.21(d,J=7.0Hz,2H),6.39(d,J=7.1Hz,1H),4.28(q,J=10.9Hz,2H),3.44(s,2H),3.34(s,3H),1.96–1.81(m,9H).
化合物E103:112mg,ESI[M+H] +=355.1
1H NMR(400MHz,CDCl 3)δ7.57(s,1H),7.40–7.25(m,3H),7.18(d,J=7.0Hz,2H),6.39(d,J=7.1Hz,1H),4.23–4.19(m,2H),2.66–2.35(m,5H),1.86(d,J=7.1Hz,3H).
化合物E104:38mg,ESI[M+H] +=331.2.
1H NMR(400MHz,CDCl 3)δ7.61(s,1H),7.34(dq,J=14.2,7.0Hz,3H),7.18(d,J=6.9Hz,2H),6.26(q,J=7.1Hz,1H),4.94(t,J=8.0Hz,2H),4.88(d,J=7.9Hz,1H),4.74(d,J=7.6Hz,1H),2.78(s,1H),1.86(d,J=7.1Hz,3H).
化合物E105:64mg,ESI[M+H] +=321.2
1H NMR(400MHz,CDCl 3)δ7.58(s,1H),7.40–7.25(m,3H),7.18(d,J=7.0Hz,2H),6.31–6.28(m,1H),4.53–4.34(m,2H),2.81–2.77(m,2H),2.18(s,3H),1.86(d,J=7.1Hz,3H).
化合物E106:28mg,ESI[M+H] +=335.1
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.39–7.28(m,3H),7.11(d,J=7.5Hz,2H),6.23(d,J=6.4Hz,1H),1.90(s,3H),1.85(d,J=6.9Hz,3H),1.54(s,3H),1.48(s,3H).
化合物E107:83mg,ESI[M+H] +=319.2
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.38–7.13(m,5H),6.65(q,J=7.1Hz,1H),4.25– 4.00(m,2H),2.60-2.50(m,1H),2.48–1.98(m,4H),1.88(d,J=7.2Hz,3H),1.80-1.69(m,2H).
化合物E108:108mg,ESI[M+H] +=305.0
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.39–7.27(m,3H),7.23–7.13(m,2H),6.74(q,J=7.1Hz,1H),4.10–4.04(m,2H),1.99(d,J=7.2Hz,3H),1.24–1.11(m,1H),0.69–0.54(m,2H),0.40–0.24(m,2H).
化合物E109:76mg,ESI[M+H] +=305.0
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.41–7.27(m,3H),7.21–7.09(m,2H),6.73(q,J=7.0Hz,1H),5.25–5.04(m,1H),2.52–2.32(m,2H),2.25–2.08(m,2H),1.98(d,J=7.2Hz,3H),1.91–1.78(m,1H),1.75–1.56(m,1H).
化合物E110:89mg,ESI[M+H] +=307.0
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.39–7.27(m,3H),7.19–7.10(m,2H),6.61(q,J=6.7Hz,1H),5.56(p,J=6.0Hz,1H),4.92(q,J=6.8Hz,2H),4.79–4.61(m,2H),1.98(d,J=7.2Hz,3H).
化合物E111:79mg,ESI[M+H] +=323.0,ESI[M+H–104] +=219.0
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.47–7.20(m,3H),7.21–7.08(m,2H),6.80–6.51(m,1H),5.95–5.60(m,1H),3.73–3.45(m,2H),3.42–3.16(m,2H),1.99(d,J=7.1Hz,3H).
化合物E112:91mg,ESI[M+H] +=307.0
1H NMR(400MHz,CDCl 3)δ7.62(s,1H),7.39–7.27(m,3H),7.21–7.12(m,2H),6.74(q,J=7.0Hz,1H),1.98(d,J=7.2Hz,3H),1.52(s,9H).
化合物E113:43mg,ESI[M+Na] +=370.9
1H NMR(400MHz,CDCl 3)δ7.89(s,1H),7.39–7.27(m,3H),7.18–7.07(m,2H),6.52–6.42(m,1H),5.02–4.68(m,4H),2.25(s,3H),1.99(d,J=7.0Hz,3H).
化合物E114:46mg,ESI[M+H] +=333.0
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.40–7.25(m,3H),7.17–7.07(m,2H),6.54–6.44(m,1H),2.21(s,3H),1.99(d,J=7.0Hz,3H),1.19–0.80(m,4H).
化合物E115:101mg,ESI[M+H] +=345.0
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.41–7.28(m,3H),7.22–7.09(m,2H),6.70–6.53(m,1H),5.09–4.48(m,4H),2.04–1.97(m,3H),1.90(d,J=3.3Hz,3H).
化合物E117:48mg,ESI[M+H] +=331.0
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),7.42–7.28(m,3H),7.22–7.12(m,2H),6.84–6.70(m,1H),2.01(d,J=7.0Hz,3H),1.84(s,3H),1.72(s,3H),1.69(s,3H).
化合物E118:70mg,ESI[M+H] +=317.0
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.41–7.28(m,3H),7.21–7.12(m,2H),6.81–6.70(m,1H),5.58–5.45(m,1H),5.42–5.26(m,1H),4.99–4.84(m,2H),2.00(d,J=7.1Hz,3H),1.43(t,J=5.9Hz,3H).
化合物E119:71mg,ESI[M+H] +=331.0
1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.41–7.15(m,5H),6.58(q,J=7.1Hz,1H),5.85–4.69(m,3H),2.01–1.58(m,9H).
化合物E120:219mg,ESI[M+H] +=317.0
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.40–7.27(m,3H),7.21–7.11(m,2H),6.74(q,J=6.8Hz,1H),2.60(s,1H),2.00(d,J=7.2Hz,3H),1.76(s,3H),1.73(s,3H).
化合物E121:100mg,ESI[M+H] +=329.0
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.40–7.28(m,3H),7.22–7.13(m,2H),6.79–6.65(m,1H),5.87–5.77(m,1H),5.74–5.64(m,2H),5.57–5.51(m,1H),2.00(d,J=6.8Hz,3H),1.62–1.56(m,3H).
化合物E122:79mg,ESI[M+H] +=343.0
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.40–7.28(m,3H),7.22–7.15(m,2H),6.85–6.72(m,1H),5.87–5.76(m,1H),5.68–5.59(m,1H),5.53–5.44(m,1H),2.01(d,J=7.0Hz,3H),1.77(s,3H),1.75(s,3H).
化合物E123:6mg,ESI[M+H] +=359.0
1H NMR(400MHz,CDCl 3)δ7.95–7.78(m,1H),7.41–7.24(m,4H),7.21–7.13(m,1H),6.70–6.49(m,1H),2.82–2.69(m,2H),2.66–2.58(m,1H),2.39–2.28(m,1H),2.25(s,1H),2.11–1.86(m,7H).
化合物E124:90mg,ESI[M+H] +=321.0
1H NMR(400MHz,CDCl 3)δ7.73(s,1H),7.40–7.28(m,3H),7.21–7.13(m,2H),6.82–6.69(m,1H),4.96–4.85(m,1H),2.00(d,J=7.0Hz,3H),1.74–1.56(m,4H),0.93(t,J=7.4Hz,3H),0.88(t,J=7.3Hz,3H).
化合物E126:110mg,ESI[M+H] +=303.0
1H NMR(400MHz,CDCl 3)δ7.78(s,1H),7.40–7.27(m,3H),7.23–7.12(m,2H),6.78–6.61(m,1H),4.79(d,J=1.7Hz,2H),1.99(d,J=6.7Hz,3H),1.88(s,3H).
化合物E127:119mg,ESI[M+H] +=345.0
1H NMR(400MHz,CDCl 3)δ7.75(s,1H),7.39–7.27(m,3H),7.19–7.10(m,2H),6.58(q,J=6.9 Hz,1H),5.63(t,J=6.6Hz,1H),5.02(d,J=6.6Hz,2H),4.89(d,J=7.4Hz,1H),4.84–4.70(m,3H),1.99(d,J=7.2Hz,3H).
实施例E4本发明化合物E132的制备
Figure PCTCN2019074002-appb-000377
在室温下,将LiOH.H 2O(2eq)加入到化合物129-1(1eq)的甲醇/四氢呋喃/水(10mL/mmol,V/V/V=1/1/1.5)溶液中,室温反应3小时。反应完全后,浓缩,降温,用1N HCl调pH为5,乙酸乙酯(3×20mL)萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,抽滤,浓缩得到白色固体化合物129-2。129-2与3-氧杂环丁醇通过缩合反应得到化合物132-1,再与S-苯乙醇按照实施例E1制备化合物E1的方法制备化合物E132,粗品经过TLC纯化(乙酸乙酯/石油醚(v/v)=1/3)并收集Rf=0.4~0.5的部分,得到无色油状化合物E132,51mg,ESI[M+H] +=341.0
1H NMR(400MHz,CDCl 3)δ7.42–7.28(m,3H),7.20–7.10(m,2H),6.56(q,J=7.2Hz,1H),5.66–5.45(m,1H),4.98–4.57(m,4H),1.98(d,J=7.2Hz,3H).
下列化合物制备方法类同化合物E132,使用2,4-二氯-1H-咪唑-5-甲酸与相应的醇制备得到2,4-二氯-1H-咪唑-5-羧酸酯中间体,再与S-苯乙醇按照制备化合物E1的方法制备得到目标化合物
化合物E130:145mg,ESI[M+Na] +=360.9
1H NMR(400MHz,CDCl 3)δ7.41–7.28(m,3H),7.22–7.14(m,2H),6.64(q,J=7.1Hz,1H),4.19–4.02(m,2H),1.98(d,J=7.2Hz,3H),1.28–1.12(m,1H),0.66–0.53(m,2H),0.40–0.26(m,2H).
化合物E131:98mg,ESI[M+H–104] +=235.0
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,3H),7.22–7.12(m,2H),6.63(q,J=7.0Hz,1H),5.42–4.84(m,1H),2.54–2.31(m,2H),2.27–2.07(m,2H),1.97(d,J=7.2Hz,3H),1.92–1.78 (m,1H),1.75–1.63(m,1H).
化合物E133:29mg,ESI[M+H] +=356.9
1H NMR(400MHz,CDCl 3)δ7.41–7.28(m,3H),7.22–7.11(m,2H),6.57(q,J=7.1Hz,1H),5.75(p,J=8.0Hz,1H),3.64–3.44(m,2H),3.41–3.19(m,2H),1.97(d,J=7.2Hz,3H).
化合物E134:44mg,ESI[M+H–104] +=290.9
1H NMR(400MHz,CDCl 3)δ7.41–7.29(m,3H),7.24–7.11(m,2H),6.55(q,J=6.9Hz,1H),5.33(p,J=5.2Hz,1H),3.90–3.70(m,4H),1.99(d,J=7.2Hz,3H).
化合物E135:44mg,ESI[M+H–160] +=181.0
1H NMR(400MHz,CDCl 3)δ7.38–7.27(m,3H),7.21–7.14(m,2H),6.59(q,J=7.0Hz,1H),1.98(d,J=7.2Hz,3H),1.53(s,9H).
化合物E136:18mg,ESI[M+Na] +=404.9
1H NMR(400MHz,CDCl 3)δ7.41–7.27(m,3H),7.20–7.09(m,2H),6.42(q,J=6.9Hz,1H),5.08–4.58(m,4H),2.25(s,3H),1.98(d,J=7.2Hz,3H).
化合物E137:24mg,ESI[M+H] +=367.0
1H NMR(400MHz,CDCl 3)δ7.39–7.25(m,3H),7.20–7.12(m,2H),6.60(q,J=7.1Hz,1H),1.99(d,J=7.1Hz,3H),1.15–0.79(m,4H).
化合物E138:117mg,ESI[M+H] +=379.0
1H NMR(400MHz,CDCl 3)δ7.39–7.28(m,3H),7.21–7.13(m,2H),6.56(q,J=6.8Hz,1H),4.92–4.82(m,3H),4.69(d,J=7.3Hz,1H),2.00(d,J=7.2Hz,3H),1.90(s,3H).
化合物E139:121mg,ESI[M+Na] +=373.0
1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,3H),7.23–7.11(m,2H),6.76–6.50(m,1H),5.60–5.46(m,1H),1.98(dd,J=7.2,2.3Hz,2H),1.89–1.81(m,3H),1.54(d,J=6.7Hz,3H).
化合物E140:89mg,ESI[M+Na] +=386.9
1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,3H),7.24–7.10(m,2H),6.64(q,J=6.9Hz,1H),1.99(d,J=7.2Hz,3H),1.84(s,3H),1.73(s,1H),1.69(s,3H).
化合物E141:45mg,ESI[M+Na–104] +=247.0
1H NMR(400MHz,CDCl 3)δ7.38–7.28(m,3H),7.21–7.15(m,2H),6.62(q,J=6.9Hz,1H),5.60–5.46(m,1H),5.38–5.24(m,1H),4.97–4.78(m,2H),1.98(d,J=7.2Hz,3H),1.43(t,J=6.8Hz,3H).
化合物E142:35mg,ESI[M+H] +=265.0
1H NMR(400MHz,CDCl 3)δ7.41–7.29(m,3H),7.25–7.15(m,2H),6.59(q,J=7.1Hz,1H),6.05–5.58(m,1H),5.47–4.69(m,2H),2.01–1.58(m,9H).
化合物E143:130mg,ESI[M+Na] +=372.9
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,3H),7.22–7.13(m,2H),6.63(q,J=7.1Hz,1H),2.60(s,1H),1.99(d,J=7.2Hz,3H),1.77(s,3H),1.73(s,3H).
化合物E144:125mg,ESI[M+Na] +=384.9
1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,3H),7.25–7.11(m,2H),6.69–6.54(m,1H),5.89–5.74(m,1H),5.72–5.61(m,2H),5.58–5.42(m,1H),2.02–1.94(m,3H),1.62–1.55(m,3H).
化合物E145:83mg,ESI[M+Na] +=398.9
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,3H),7.23–7.10(m,2H),6.64(q,J=7.0Hz,1H),5.89–5.74(m,1H),5.69–5.56(m,1H),5.54–5.40(m,1H),1.99(d,J=7.2Hz,3H),1.77(s,3H),1.74(s,3H).
化合物E146:6mg,ESI[M+Na] +=414.9
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,4H),7.22–7.15(m,1H),6.67–6.51(m,1H),2.77–2.71(m,1H),2.69–2.61(m,1H),2.35–2.29(m,1H),2.24(s,1H),2.07–1.88(m,8H).
化合物E147:166mg,ESI[M+Na] +=377.0
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,3H),7.22–7.15(m,2H),6.64(q,J=7.0Hz,1H),4.94(p,J=6.1Hz,1H),1.99(d,J=7.2Hz,3H),1.73–1.59(m,4H),0.95(t,J=7.4Hz,3H),0.88(t,J=7.4Hz,3H).
化合物E148:198mg,ESI[M+H] +=365.0
1H NMR(400MHz,CDCl 3)δ7.42–7.27(m,3H),7.23–7.09(m,2H),6.54(q,J=7.0Hz,1H),4.99–4.83(m,3H),4.69(d,J=7.4Hz,1H),2.80(s,1H),2.00(d,J=7.2Hz,3H).
实施例E5本发明化合物E149,化合物E152和化合物E153的制备
Figure PCTCN2019074002-appb-000378
化合物E149,化合物E152和化合物E153的制备方法同实施例E2,使用1H-咪唑-5-甲酸乙酯和NBS反应得到无色油状粗品,经过柱层析分离(乙酸乙酯/石油醚(v/v)=1/100),TLC(乙酸乙酯/石油醚(v/v)=1/30)监测,收集到得到目标化合物。
化合物E149,3.81g,无色油状液体,收率53%,ESI[M+H] +=323.0
1H NMR(400MHz,CDCl 3)δ7.77(s,1H),7.39–7.28(m,3H),7.20–7.10(m,2H),6.78–6.58(m,1H),4.35–4.16(m,2H),2.01(d,J=7.2Hz,3H),1.31(t,J=7.1Hz,3H).
化合物E152,570mg,ESI[M+H] +=323.0
1H NMR(400MHz,CDCl 3)δ7.64(s,1H),7.42–7.28(m,3H),7.22–7.11(m,2H),6.35(q,J=7.0Hz,1H),4.39–4.20(m,2H),1.85(d,J=7.1Hz,3H),1.36(t,J=7.1Hz,3H).
化合物E153,15mg,ESI[M+H–104] +=296.9
1H NMR(400MHz,CDCl 3)δ7.39–7.27(m,3H),7.19–7.09(m,2H),6.54(q,J=6.8Hz,1H),4.40–4.14(m,2H),2.00(d,J=7.1Hz,3H),1.32(t,J=7.1Hz,3H).
化合物149-1水解得到4-溴-1H-咪唑-5-甲酸,与相应的醇缩合得到咪唑羧酸酯中间体,再与S-苯乙醇反应得到以下化合物。
化合物E150:158mg,ESI[M+H] +=347.0
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.38–7.27(m,3H),7.21–7.08(m,2H),6.72–6.52(m,1H),4.78–4.71(m,2H),2.02(d,J=7.1Hz,3H),1.87(t,J=2.1Hz,3H).
化合物E151:130mg,ESI[M+H] +=388.9
1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.38–7.28(m,3H),7.18–7.06(m,2H),6.59–6.45(m,1H),5.59(t,J=6.6Hz,1H),5.00(d,J=6.7Hz,2H),4.86(d,J=7.4Hz,1H),4.77–4.67(m,3H),2.01(d,J=7.1Hz,4H).
实施例E6本发明化合物E154的制备
Figure PCTCN2019074002-appb-000379
1、Ethyl 4-iodo-1H-imidazole-5-carboxylate(154-1)的制备
Figure PCTCN2019074002-appb-000380
在冰浴0℃下,将ethyl 4-amino-1H-imidazole-5-carboxylate(5.43g,35.0mmol)溶于HCl(6M,65mL)中,滴加NaNO 2(6.04g,87.5mmol)的水溶液(10mL),在10分钟内加完,滴完之后,在0℃下搅拌一小时。然后,分批加入KI(46.5g,280mmol),加完后在0℃下继续搅拌两小时。反应完全后,水层用乙酸乙酯(3×30mL)萃取,合并有机相,经饱和食盐水洗涤后,干燥,抽滤,减压浓缩得到粗产品,经过柱层析分离(乙酸乙酯/石油醚(v/v)=1/1),TLC(乙酸乙酯/石油醚(v/v)=1/1)监测,收集Rf=0.3~0.4部分,得到灰色固体化合物154-1(6.78g,收率73%)。ESI[M+H] +=267.0
2、目标化合物E154的制备
Figure PCTCN2019074002-appb-000381
在冰水浴0℃下,将S-苯乙醇(4.05g,33.1mmol)加到154-1(6.78g,25.5mmol)和PPh 3(10.0g,38.1mmol)的THF(100mL)溶液中,然后滴加DEAD(6.66g,38.2mmol)的THF(5mL)溶液,以0.5mmol/min的速率滴加至体系,滴加完后缓慢升至室温搅拌5小时。反应液浓缩,粗品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)=1/10),TLC(乙酸乙酯/石油醚(v/v)=1/3)监测,收集Rf=0.5~0.6部分,得到无色油状化合物E154(7.0g,收率68%)。ESI[M+H] +=370.9
1H NMR(400MHz,CDCl 3)δ7.65(s,1H),7.42–7.28(m,3),7.22–7.11(m,2H),6.37(q,J=6.0Hz,1H),4.44–4.18(m,2H),1.84(d,J=6.9Hz,3H),1.38(t,J=7.1Hz,3H).
实施例E7本发明化合物E155和化合物E156的制备
Figure PCTCN2019074002-appb-000382
化合物E155和化合物E156的制备方法类同实施例E3,用4-碘-1H-咪唑-5-甲酸乙酯水解,缩合再与S-苯乙醇反应得到。
化合物E155:110mg,ESI[M+H] +=394.9
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.42–7.28(m,3H),7.23–7.12(m,2H),6.34(q,J=7.0Hz,1H),4.81(q,J=2.4Hz,2H),1.87(t,J=2.4Hz,3H),1.85(d,J=7.1Hz,3H).
化合物E156:73.0mg,ESI[M+H] +=436.9
1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.42–7.28(m,3H),7.20–7.10(m,2H),6.29(q,J=6.5Hz,1H),5.60(t,J=6.6Hz,1H),5.07–4.91(m,3H),4.88(d,J=7.6Hz,1H),4.78(t,J=7.0Hz,2H),1.85(d,J=6.9Hz,3H).
实施例E8本发明化合物E157和化合物E164的制备
Figure PCTCN2019074002-appb-000383
1、Ethyl 4-(trifluoromethyl)-1H-imidazole-5-carboxylate(164-1)的制备
Figure PCTCN2019074002-appb-000384
在室温下,将2-氯-4,4,4-三氟乙酰乙酸乙酯(4.89g,22.4mmol),水(0.8mL)和甲酰胺(10.1g,224mmol)依次加入到100mL的封管中,150℃反应2小时。反应完全后,反应液用稀冷NaHCO 3的水溶液调pH=8,经乙酸乙酯萃取(3×150mL),饱和食盐水洗(100mL),干燥,抽滤,滤液浓缩得白色固体164-1(1.9g,收率41%)。ESI[M+H] +=209-1
2、目标化合物E164的制备
Figure PCTCN2019074002-appb-000385
在冰水浴0℃下,将S-苯乙醇(1.66g,13.6mmol)加到164-1(1.9g,9.1mmol)和PPh 3(3.57g,13.6mmol)的THF(50mL)溶液中,然后滴加DEAD(2.37g,13.6mmol)的THF(5mL)溶液,以0.5mmol/min的速率滴加至体系,滴加完后缓慢升至室温搅拌1小时。反应液浓缩,粗品经硅胶柱层析纯化(乙酸乙酯/石油醚(v/v)=1/10),TLC(乙酸乙酯/石油醚(v/v)=1/10)监测,收集Rf=0.3~0.4部分,得到无色油状化合物E164(2.2g,收率77%)。ESI[M+H] +=313.1 1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.41–7.30(m,3H),7.23–7.16(m,2H),6.34(q,J=7.0Hz,1H),4.40–4.24(m,2H),1.89(d,J=7.1Hz,3H),1.32(t,J=7.1Hz,3H).
以下化合物的制备方法类同实施例E8化合物E157。
化合物E42:37mg,ESI[M+H] +=383.1
1H NMR(400MHz,CDCl 3)δ7.70(s,1H),7.45–7.30(m,3H),7.24–7.13(m,2H),6.28(q,J=7.1Hz,1H),4.81(d,J=7.3Hz,1H),4.75(d,J=7.3Hz,1H),4.57(t,J=7.2Hz,2H),2.10(td,J=7.1,3.0Hz,2H),1.86(d,J=7.1Hz,3H),1.34–1.25(m,2H),0.95(t,J=7.3Hz,3H).
化合物E53:53mg,ESI[M+H]+=383.3
1H NMR(400MHz,CDCl 3)δ7.66(s,1H),7.45–7.29(m,3H),7.24–7.14(m,2H),6.30(q,J=7.1Hz,1H),2.84(q,J=7.2Hz,2H),1.89(d,J=7.1Hz,3H),1.54(s,3H),1.48(s,3H),1.45(t,J=7.2Hz,3H).
化合物E157:51.4mg,ESI[M+H] +=397.0
1H NMR(400MHz,CDCl3)δ7.68(s,1H),7.41–7.29(m,3H),7.23–7.15(m,2H),6.38(q,J=5.8Hz,1H),4.36–4.23(m,2H),3.45–3.34(m,2H),3.32(s,3H),1.97–1.77(m,9H).
化合物E158:35mg,ESI[M+H] +=299.0
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.41–7.29(m,3H),7.22–7.15(m,2H),6.32(q,J=7.0Hz,1H),3.86(s,3H),1.89(d,J=7.1Hz,3H).
化合物E159:81.4mg,ESI[M+H] +=355.0
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.42–7.30(m,3H),7.20–7.11(m,2H),6.22(q,J=7.0Hz,1H),4.75(dd,J=38.4,7.2Hz,2H),4.51(dd,J=10.6,7.2Hz,2H),1.90(d,J=7.1Hz,3H),1.70(s,3H).
化合物E160:35.8mg,ESI[M+H] +=369.0
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.39–7.27(m,3H),7.16–7.07(m,2H),6.26(q,J=6.9Hz,1H),1.89(s,3H),1.88(d,J=5.6Hz,3H),1.53(s,3H),1.44(s,3H).
化合物E161:70.8mg,ESI[M+H] +=337.0
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),7.42–7.29(m,3H),7.24–7.16(m,2H),6.30(q,J=7.1Hz,1H),4.91–4.69(m,2H),1.89(d,J=7.1Hz,3H),1.86(t,J=2.4Hz,3H).
化合物E162:43mg,ESI[M+H] +=405.1
1H NMR(400MHz,CDCl 3)δ7.73(s,0.38H),7.62(s,0.61H),7.41–7.28(m,3H),7.22–7.12(m,2H),6.38–6.23(m,1H),5.59–5.46(m,1H),4.93–4.79(m,2H),2.40–2.14(m,1H),2.14–1.99(m,2H),1.93–1.85(m,3H),1.85–1.76(m,1H),1.46–1.36(m,2H).
化合物E163:74mg,ESI[M+H] +=379.0
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.40–7.29(m,3H),7.22–7.10(m,2H),6.30–6.16(m,1H),5.55(t,J=6.6Hz,1H),4.99(qd,J=11.8,6.7Hz,2H),4.85(d,J=7.5Hz,1H),4.76(d,J=7.6Hz,1H),4.74(s,2H),1.90(d,J=6.9Hz,3H).
化合物E165:61mg,ESI[M+H] +=337.0
1H NMR(400MHz,CDCl 3)δ7.65–7.29(m,4H),7.25–7.13(m,2H),6.34(q,J=7.1Hz,1H),4.90–4.65(m,2H),1.85(d,J=7.1Hz,3H),1.84(t,J=2.4Hz,3H).
化合物E166:31mg,ESI[M+H] +=379.1
1H NMR(400MHz,CDCl 3)δ7.66–7.29(m,4H),7.26–7.13(m,2H),6.35(q,J=7.1Hz,1H),5.57(t,J=6.6Hz,1H),4.99-4.76(m,6H),1.89(d,J=7.0Hz,3H).
实施例E9本发明化合物E167的制备
Figure PCTCN2019074002-appb-000386
1、Ethyl(Z)-2-((E)-4-ethoxy-4-oxobut-2-en-2-yl)diazene-1-carboxylate(167-2)的制备
Figure PCTCN2019074002-appb-000387
在室温下,将2-氯乙酰乙酸乙酯(1.5g,9.1mmol)和肼基甲酸乙酯(947mg,9.1mmol)溶解在乙醚(10mL)中,室温搅拌3小时。反应完全后,向反应体系中加入饱和碳酸氢钠(10mL),室温搅拌30分钟,用乙醚(3×10mL)萃取,合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,抽滤,减压浓缩得到无色油状粗品167-2(770mg,收率39%),产品未经纯化直接用于下一步反应。
2、目标化合物E167的制备
Figure PCTCN2019074002-appb-000388
将化合物167-2(100mg,0.47mmol),R(+)-а-甲基苄胺(57mg,0.47mmol)和多聚甲醛(28mg,0.94mmol)溶解在乙腈(10mL)中,反应体系在封管130℃反应1小时,冷却反应体系,减压浓缩得到粗品,粗产品经过制备TLC纯化(乙酸乙酯/石油醚(v/v)=1/3)并收集Rf=0.4~0.6的部分得到无色油状化合物E167(51mg,收率42%)。ESI[M+H] +=259.3
1H NMR(400MHz,CDCl 3)δ7.62(s,1H),7.39–7.27(m,3H),7.19–7.11(m,2H),6.32(q,J= 7.1Hz,1H),4.35–4.18(m,2H),2.50(s,3H),1.83(d,J=7.1Hz,3H),1.32(t,J=7.1Hz,3H).
以下用实验例的方式说明本发明的有益效果:
实验例1以大鼠翻正反射消失作为判定指标评价本发明化合物的全身麻醉作用
选择体重范围在250~300克的成年雄性SD大鼠进行试验。将上述实施例中化合物和对照药物依托咪酯、CPMM溶解于二甲基亚砜(DMSO),空白对照组给予等体积DMSO。采用序贯法(Up-and-down method)测定本发明化合物的以翻正反射消失作为判定指标的全身麻醉作用的ED 50。试验时经大鼠尾静脉给药,每只大鼠给药体积为0.6ml、给药速度为0.1ml/秒。以大鼠翻正反射消失(LORR)持续30秒作为产生全身麻醉效应的指标。结果如表A1-E1所示。结果显示:本发明化合物和对照依托咪酯、CPMM一样可以产生确切的、一过性的全身麻醉作用。并且本发明化合物表现出与依托咪酯、CPMM一样或更好的效价。
表A1本发明化合物以大鼠翻正反射消失作为判定指标的全身麻醉作用的ED 50
化合物/药物 ED 50(mg/kg) 最小致死量(mg/kg) 近似治疗指数
依托咪酯 0.75(0.72-0.77)* 12.75 17
CPMM 0.78(0.74-0.82)* >7.8 >10
DMSO / / /
化合物A8 B >2 >10
化合物A9 B >5 >13
化合物A11 A >1 >12
化合物A12 C >10 >16
化合物A13 B >4 >10
化合物A16 B >10 >33
化合物A17 C >6 >11
化合物A18 B >5 >22
化合物A19 B >5 >10
化合物A20 A >3 >22
化合物A21 B >5 >16
表B1本发明化合物以大鼠翻正反射消失作为判定指标的全身麻醉作用的ED 50
化合物/药物 ED 50(mg/kg) 最小致死量(mg/kg) 近似治疗指数
依托咪酯 0.75(0.72-0.77)* 12.75 17
CPMM 0.78(0.74-0.82)* >7.8 >10
DMSO / / /
化合物B5 B >10 >11
化合物B8 C >10 >10
化合物B9 C >18 >12
化合物B19 C >20 >11
化合物B20 C >17 >10
化合物B22 C >17 >10
化合物B28 B >10 >13
表C1本发明化合物以大鼠翻正反射消失作为判定指标的全身麻醉作用的ED 50
化合物/药物 ED 50(mg/kg) 最小致死量(mg/kg) 近似治疗指数
依托咪酯 0.75(0.72-0.77)* 12.75 17
CPMM 0.78(0.74-0.82)* >7.8 >10
DMSO / / /
化合物C1 A >20 >90
化合物C3 C >10 >14
化合物C7 B >4 >10
化合物C16 C >10 >14
化合物C18 B >5 >14
化合物C19 B >5 >20
化合物C20 B >7 >16
化合物C24 A >1 >11
化合物C25 B >4 >10
化合物C26 C >6 >11
化合物C27 C >9 >11
化合物C30 C >11 >11
表D1本发明化合物以大鼠翻正反射消失作为判定指标的全身麻醉作用的ED 50
化合物/药物 ED 50(mg/kg) 最小致死量(mg/kg) 近似治疗指数
依托咪酯 0.75(0.72-0.77)* 12.75 17
CPMM 0.78(0.74-0.82)* >7.8 >10
DMSO / / /
化合物D1 B >6 >14
化合物D3 C >8 >10
化合物D7 C >6 >10
化合物D10 C >6 >12
化合物D12 C >10 >14
化合物D13 A >6 >12
化合物D14 B >3 >13
化合物D15 B >4 >10
化合物D16 C >6 >12
化合物D18 B >3 >12
化合物D21 A >1 >16
化合物D22 B >2 >11
化合物D24 C >7 >13
化合物D26 B >4 >10
化合物D27 C >10 >10
化合物D28 A >10 >16
化合物D29 C >10 >13
化合物D30 C >5 >11
化合物D31 C >9 >13
化合物D32 B >5 >16
化合物D33 C >8 >10
化合物D34 C >8 >13
化合物D36 B >4 >15
化合物D37 C >10 >13
化合物D39 C >9 >15
化合物D40 B >4 >16
化合物D42 C >9 >12
化合物D43 A >1 >13
化合物D59 B >13 >11
表E1本发明化合物以大鼠翻正反射消失作为判定指标的全身麻醉作用的ED 50
化合物/药物 ED 50(mg/kg) 最小致死量(mg/kg) 近似治疗指数
依托咪酯 0.75(0.72-0.77)* 12.75 17
CPMM 0.78(0.74-0.82)* >7.8 >10
DMSO / / /
化合物E2 B >5 >25
化合物E4 B >10 >20
化合物E6 C >10 >24
化合物E8 B >4 >22
化合物E9 B >6 >48
化合物E10 C >10 >14
化合物E11 A >4 >60
化合物E15 B >5 >32
化合物E16 B >4 >20
化合物E17 B >9 >32
化合物E18 A >1 >20
化合物E19 A >4 >40
化合物E20 A >5 >80
化合物E21 C >9 >12
化合物E22 B >4 >30
化合物E24 A >4 >45
化合物E25 B >6 >24
化合物E26 A >4 >50
化合物E27 B >6 >24
化合物E28 B >6 >16
化合物E29 B >6 >15
化合物E30 B >6 >42
化合物E32 B >4 >30
化合物E33 B >4 >30
化合物E34 B >2 >12
化合物E35 B >4 >17
化合物E36 C >5 >26
化合物E37 A >0.6 >30
化合物E38 B >7 >20
化合物E64 A >1.5 >40
化合物E77 C >10 >12
化合物E79 B >14 >10
化合物E90 A >1.5 >30
化合物E91 C >20 >6
化合物E100 B >12 >30
化合物E116 C >10 >16
化合物E125 C >24 >5
化合物E129 B >9 >30
化合物E132 C >10 >14
化合物E133 C >10 >12
化合物E148 C >10 >12
备注:
*括号内数字表示95%可信限(mg/kg);
A表示测得的ED 50在0.01-0.10mg/kg范围(包括0.01和0.10mg/kg);
B表示测得的ED 50在0.10-0.50mg/kg范围(不包括0.10mg/kg、包括0.50mg/kg);
C表示测得的ED 50在0.50-1.00mg/kg范围(不包括0.50mg/kg、包括1.00mg/kg)。
实验例2以致大鼠翻正反射消失的2ED 50剂量比较本发明化合物的药理效应
选择体重范围在250~300克的成年雄性SD大鼠进行试验(n=8)。将上述实施例中化合物和对照药物依托咪酯、CPMM溶解于二甲基亚砜(DMSO),空白对照组给予等体积DMSO。采用致大鼠翻正反射消失的2ED 50剂量进行试验。试验时经大鼠尾静脉给药,每只大鼠给药体积为0.6ml、给药速度为0.1ml/s。以翻正反射消失(LORR)的时间记作开始产生麻醉效应的时间。结果如表A2-E2所示。结果显示:本发明化合物和对照依托咪酯、CPMM一样都表现出起效迅速、并能快速恢复的特点。药理作用的持续时间均能满足全身麻醉快速诱导时 的时间需要和诊断性检查、短小创伤性检查或操作的时间需要。实验中,本发明化合物的不良反应的种类及发生率均少于对照依托咪酯和CPMM。
表A2以大鼠致翻正反射消失2ED 50剂量比较本发明化合物的药理效应
Figure PCTCN2019074002-appb-000389
表B2以大鼠致翻正反射消失2ED 50剂量比较本发明化合物的药理效应
Figure PCTCN2019074002-appb-000390
Figure PCTCN2019074002-appb-000391
表C2以大鼠致翻正反射消失2ED 50剂量比较本发明化合物的药理效应
Figure PCTCN2019074002-appb-000392
表D2以大鼠致翻正反射消失2ED 50剂量比较本发明化合物的药理效应
Figure PCTCN2019074002-appb-000393
Figure PCTCN2019074002-appb-000394
表E2以大鼠致翻正反射消失2ED 50剂量比较本发明化合物的药理效应
Figure PCTCN2019074002-appb-000395
Figure PCTCN2019074002-appb-000396
备注:
A表示测得的ED 50在0.01-0.10mg/kg范围(包括0.01和0.10mg/kg);
B表示测得的ED 50在0.10-0.50mg/kg范围(不包括0.10mg/kg、包括0.50mg/kg);
C表示测得的ED 50在0.50-1.00mg/kg范围(不包括0.50mg/kg、包括1.00mg/kg)。
实验例3体外细胞试验测定本发明化合物对肾上腺皮质功能的影响
选择H295R细胞株进行细胞培养,对培养的细胞给予溶媒DMSO、依托咪酯、CPMM、依托咪酯的代谢产物依托咪酯酸、及本发明化合物进行孵育,然后在培养细胞的上清液中利用HPLC-MS/MS法测定细胞分泌的皮质醇和皮质酮以判断本发明化合物是否存在对肾上腺皮质功能的抑制。
结果显示:本发明化合物达到了设计要求(见表A3-E3),试验中均没有对肾上腺皮质功能的抑制。
表A3细胞试验测试本发明化合物对肾上腺皮质功能的影响
Figure PCTCN2019074002-appb-000397
表B3细胞试验测试本发明化合物对肾上腺皮质功能的影响
Figure PCTCN2019074002-appb-000398
Figure PCTCN2019074002-appb-000399
表C3细胞试验测试本发明化合物对肾上腺皮质功能的影响
Figure PCTCN2019074002-appb-000400
Figure PCTCN2019074002-appb-000401
表D3细胞试验测试本发明化合物对肾上腺皮质功能的影响
Figure PCTCN2019074002-appb-000402
表E3细胞试验测试本发明化合物对肾上腺皮质功能的影响
Figure PCTCN2019074002-appb-000403
实验例4利用小动物植入式生理信号遥测系统测定本发明化合物对大鼠循环功能的影响
根据序贯法(Up-and-down method)的测定本发明化合物的以大鼠翻正反射消失为麻醉指标的ED 50,给予2ED 50剂量(n=6),利用DSI(Data Science International,Inc.)小动物植入式生理信号遥测系统观察给药过程中和给药后30分钟内大鼠心率、血压的变化,以平均动脉压(MAP)和心率(HR)为代表性指标判断本发明化合物对大鼠循环功能的影响。
主要测试仪器设备如下:
DSI(Data Science International,Inc.)小动物植入式生理信号遥测系统包括植入子(型号HD‐S21,DSI公司,美国)、接收板(型号RPC‐1,DSI公司,美国)、信号转换器(型号DEM,DSI公司,美国)、灌注胶(型号,DSI公司,美国)、纤维蛋白膜(DSI公司,美国)等。
小动物呼吸机(型号:HX‐101E,生产厂家:成都泰盟科技有限责任公司);电子天平(型号:ME215S,生产厂家:德国Sartorius公司)。
首先进行动物模型的建立,置入左心室导管、腹主动脉导管和进行心电导线的置放。术后至少稳定一周后可采集信号开始试验。
给药过程:将大鼠装入固定器中,露出尾静脉,将20G留置针置入大鼠尾静脉,给0.2mL的肝素,再接上预抽好药物的延长管,粘上胶布以固定延长管于尾静脉上,将大鼠取出固定器放回饲养笼中再一起放在信号接收器上。待数据采集开始,大鼠安静适应30分钟后按计算好的2ED 50剂量给药,匀速给药,给完药后观察并记录大鼠的药理效应、不良反应及行为表现等。
数据采集:完成软件设置采集数据的参数后,打开植入子的电源,即可开始采集数据。本实验设定实验数据记录频率为15秒一次。数据采集在大鼠给药前后均持续记录30分钟。数据采集结束,停止试验。
结果显示:本发明化合物和对照依托咪酯、CPMM一样几乎没有对循环功能的抑制效应,而对照丙泊酚则表现出对循环系统功能的明显抑制(见图1-图20)。
实验例5本发明化合物对大鼠持续输注的药理效应
选择体重范围在250~300克的成年雄性SD大鼠进行持续输注试验。将本发明化合物和对照药物依托咪酯、CPMM试验前制备成脂肪乳剂,以2倍MIR(最小输注速度)进行经大鼠尾静脉持续输注,自致其翻正反射消失开始维持翻正反射消失持续1小时,记录停止输注后实验动物的苏醒时间和完全恢复时间。结果见表A4-E4。结果显示:本发明化合物2倍MIR条件下持续输注1小时后,其恢复时间与单次静脉注射2ED 50剂量后相比,没有明显延长,并在恢复时间上明显短于依托咪酯。其不良反应的种类和发生率也明显优于依托咪酯和CPMM。
表A4大鼠持续输注本发明化合物的药理效应
Figure PCTCN2019074002-appb-000404
Figure PCTCN2019074002-appb-000405
表B4大鼠持续输注本发明化合物的药理效应
Figure PCTCN2019074002-appb-000406
表C4大鼠持续输注本发明化合物的药理效应
Figure PCTCN2019074002-appb-000407
Figure PCTCN2019074002-appb-000408
表D4大鼠持续输注本发明化合物的药理效应
Figure PCTCN2019074002-appb-000409
表E4大鼠持续输注本发明化合物的药理效应
Figure PCTCN2019074002-appb-000410
Figure PCTCN2019074002-appb-000411
综上,本发明公开了一种结构新颖的依托咪酯衍生物,该依托咪酯衍生物具有较好的中枢神经系统的抑制效应,可以产生镇静、催眠和/或全身麻醉的作用以及控制癫痫持续状态,为临床上筛选和/或制备具有镇静、催眠和/或全身麻醉作用的药物以及控制癫痫持续状态的药物提供了一种新的选择。

Claims (10)

  1. 式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物:
    Figure PCTCN2019074002-appb-100001
    X选自O、S或NR 30,其中,R 30选自氢、氘或C 1-8烷基;
    Y为N;
    R 1各自独立地选自氘、卤素、-CN、-NO 2、-OR 32、-C(O)R 32、-CO 2R 32、-CON(R 32) 2、-N(R 32) 2、-OC(O)R 32、-SO 2R 32、取代或未取代的3~8元杂环基、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
    其中,R 32各自独立地选自氢、氘、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-8环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基;所述取代基为氘、氰基、羟基、羧基、卤素、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
    n为0~5的整数;
    R 2选自氢、氘、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物;
    R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代C 1-8烷基;所述取代基为氘、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
    L 1和L 2各自独立地选自无、取代或未取代的C 1-8亚烷基;所述取代基为氘、氰基、羟基、羧基、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 3-8环 烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
    R 5选自氢、氘、卤素、氰基、丙二烯基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100002
    取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
    其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、-L 31-COO-L 32、取代或未取代的C 3-8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-S-C 1-8烷基;L 31选自取代或未取代的C 1-8亚烷基;L 32选自取代或未取代的C 1-8烷基;
    上述R 5、R 33中所述的取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-8元环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物、-S-C 1-4烷基、=R 39、取代或未取代的C 2-8烯基或C 2-8炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-4烷基或其卤代或氘代物,所述C 2-8烯基或C 2-8炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-4烷基;
    A环为无,或者,A环选自被0~4个R 34取代的3~6元饱和碳环、3~6元不饱和碳环、3~6元饱和杂环或3~6元不饱和杂环;
    其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、硝基、C 1-8烷基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2、-L 33-R 36或=R 37
    L 33选自C 1-4亚烷基;
    R 36选自氰基、硝基、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2
    R 35各自独立地选自C 1-4烷基或其卤代或氘代物;
    R 37选自O、S、N(R 38)、C(R 38) 2;R 38选自H或C 1-4烷基;
    其中,当R 5为H、L 2为无时,A环不为3~6元饱和杂环;
    当A环为无时,L 1和L 2各自独立地选自无、取代或未取代的C 1-8亚烷基,所述取代基为C 1-8烷基或卤素;R 5为C(O)R 41或S(O)R;R 41为C 1-3烷基或其卤代或氘代物;
    当A环为被0个R 34取代的3元饱和碳环时,若L 1和L 2为无,则R 5不为氢、乙氧基; 若L 1为无,L 2为亚甲基,则R 5不为甲氧基;若L 1为亚甲基,L 2为无或亚甲基,则R 5不为甲氧基;
    当A环为被0个R 34取代的4~6元饱和杂环时,若L 2为无,则R 5不为H;若R 5为H,则L 2不为无;
    当n为0,R 2为甲基,Y为N,R 3、R 4为氢,X为O,L 1为亚甲基,A环为无,L 2为无时,R 5不为乙烯基、乙炔基或丙烯基。
  2. 根据权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:
    Y为N;
    R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代C 1-8烷基;所述取代基为氘、卤素、C 1-8烷基或其卤代或氘代物、C 1-8烷氧基或其卤代或氘代物、C 3-8环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
    或,X选自O或S;
    或,R 1各自独立地选自氘、卤素、-CN、-NO 2、-OR 32、-C(O)R 32、-CO 2R 32、-CON(R 32) 2、-N(R 32) 2、-OC(O)R 32、C 1-3烷基、C 2-3烯基、C 2-3炔基;
    其中,R 32各自独立地选自氢、氘、C 1-3烷基、C 2-3烯基、C 2-3炔基;
    或,n为0~2的整数;
    或,R 2选自氢、氘、卤素、C 1-3烷基或其卤代或氘代物。
  3. 根据权利要求1~2任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:所述化合物如式Ⅱ所示:
    Figure PCTCN2019074002-appb-100003
    Y为N;
    X选自O或S;
    R 5选自氢、氘、卤素、氰基、丙二烯基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100004
    取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-8烷基、取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基、取代或未取代的C 3-8元环烷基、取代或未取代的3~8元杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
    上述R 5、R 33中所述的取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-8元环烷基或其卤代或氘代物、3~8元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物、-S-C 1-4烷基、=R 39、取代或未取代的C 2-6烯基或C 2-6炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-4烷基或其卤代或氘代物,所述C 2-6烯基或C 2-6炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-4烷基;
    A环为无,或者,A环选自被0~4个R 34取代的3~6元饱和碳环、3~6元不饱和碳环、3~6元饱和杂环或3~6元不饱和杂环;
    其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、硝基、C 1-8烷基或其卤代或氘代物、C 2-8烯基或其卤代或氘代物、C 2-8炔基或其卤代或氘代物、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2、-L 33-R 36或=R 37
    L 33选自C 1-4亚烷基;
    R 36选自氰基、硝基、-OC(O)R 35、-C(O)R 35、-S(O)R 35、-C(O)N(R 35) 2
    R 35各自独立地选自C 1-4烷基或其卤代或氘代物;
    R 37选自O、S、N(R 38);R 38选自H或C 1-4烷基。
  4. 根据权利要求1~3任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:
    Y为N;
    X选自O或S;
    R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代的C 1-4烷基;所述取代基为 氘、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-6环烷基或其卤代或氘代物、3~6元杂环基或其卤代或氘代物;
    或,R 5选自氢、氘、卤素、丙二烯基、氰基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100005
    取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
    其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-4烷基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基;
    上述R 5、R 33中所述的取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-S-C 1-4烷基、=R 39、取代或未取代的C 2-4烯基或C 2-4炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-4烷基或其卤代或氘代物,所述C 2-4烯基或C 2-4炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-4烷基;
    或,L 1和L 2各自独立地选自无、取代或未取代的C 1-4亚烷基;所述取代基为氘、氰基、羟基、羧基、卤素、C 1-4烷基或其卤代或氘代物、C 1-4烷氧基或其卤代或氘代物、C 3-5环烷基或其卤代或氘代物、3~5元杂环基或其卤代或氘代物、芳基或其卤代或氘代物、杂芳基或其卤代或氘代物;
    或,A环为无,或者,A环选自被0~4个R 34取代的3~6元饱和碳环、3~6元不饱和碳环、3~6元饱和杂环或3~6元不饱和杂环;
    其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、C 1-4烷基或其卤代或氘代物、C 2-4烯基或其卤代或氘代物、C 2-4炔基或其卤代或氘代物、=R 37
    R 37选自O或S。
  5. 根据权利要求4所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:
    Y为N;
    X选自O或S;
    R 3和R 4各自独立地选自氢、氘、卤素、取代或未取代的C 1-2烷基;所述取代基为氘、卤素、C 1-2烷基或其卤代或氘代物、C 1-2烷氧基或其卤代或氘代物;
    或,R 5选自氢、氘、卤素、丙二烯基、氰基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100006
    取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-8烯基、取代或未取代的C 2-8炔基;
    其中,R 33各自独立地选自氢、氘、甲基磺酰基、取代或未取代的C 1-2烷基、C 3-6元环烷基、3~6元杂环基、芳基、杂芳基;
    上述R 5、R 33中所述的取代基为氘、卤素、氰基、羟基、C 1-3烷基或其卤代或氘代物、C 1-3烷氧基或其卤代或氘代物、C 3-6元环烷基、3~6元杂环基、芳基、杂芳基、-S-C 1-2烷基、=R 39、取代或未取代的C 2-4烯基或C 2-4炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-3烷基或其卤代或氘代物,所述C 2-4烯基或C 2-4炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-3烷基;
    或,L 1和L 2各自独立地选自无、取代或未取代的C 1-3亚烷基;所述取代基为氘、卤素、C 1-3烷基或其卤代或氘代物、C 1-3烷氧基或其卤代或氘代物;
    或,A环为无,或者,A环选自被0~3个R 34取代的3~6元饱和碳环、3~6元不饱和杂环或3~6元饱和杂环;
    其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、C 1-3烷基、C 2-3烯基、C 2-3炔基、=R 37
    R 37选自O或S。
  6. 根据权利要求5所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:
    Y为N;
    X选自O或S;
    R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基;
    或,R 5选自氢、氘、卤素、丙二烯基、氰基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100007
    取代或未取代的C 1-8烷基、-OR 33、-SR 33、-OC(O)R 33、C 3-8元环烷基、3~8元杂环基、芳基、杂芳基、-N(R 33) 2;或者,R 5选自-C(O)R 33、-C(S)R 33、-S(O)R 33、-CON(R 33) 2、-SO 2R 33;或者,R 5选自取代或未取代的C 2-6烯基、取代或未取代的C 2-6炔基;
    其中,R 33选自氢、氘、甲基磺酰基、乙酰基、C 1-2烷基;
    上述R 5、R 33中所述的取代基为氘、卤素、羟基、氰基、C 1-2烷基、3~5元杂环基、 -S-CH 3、=R 39、取代或未取代的C 2-4烯基或C 2-4炔基;其中,R 39选自O、S、NR 40或C(R 40) 2,R 40选自氢、氘、卤素、C 1-3烷基,所述C 2-4烯基或C 2-4炔基上的取代基选自氘、氰基、羟基、羧基、卤素、C 1-2烷基;
    或,L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代基为氘、卤素、C 1-2烷基;
    或,A环为无,或者,A环选自被0~2个R 34取代的3~6元饱和碳环、3~6元不饱和杂环或3~6元饱和杂环;
    其中,R 34各自独立地选自氘、卤素、氰基、异氰基、异硫氰基、C 2-3烯基、C 2-3炔基、C 1-2烷基、=R 37
    R 37选自O或S。
  7. 根据权利要求1~6任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:
    所述化合物如式ⅡAA所示:
    Figure PCTCN2019074002-appb-100008
    其中,Y选自N;
    R 3和R 4各自独立地选自氢或氘;
    L 1和L 2各自独立地选自无或亚甲基;
    R 33选自氢、氘、C 1-2烷基、-L 31-COO-L 32、6元杂环基;L 31选自亚甲基;L 32选自甲基;
    A环选自3~4元饱和碳环;
    或,
    所述化合物如式ⅡAB所示:
    Figure PCTCN2019074002-appb-100009
    其中,Y选自N;
    X选自O或S;
    R 3和R 4各自独立地选自氢或氘;
    L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代基为氘、F、甲基;
    R 5选自氢、氘、卤素、取代或未取代的甲基、-OC(O)R 33、3元杂环基;
    其中,R 33选自甲基;所述取代基为氘、氟、C 1-2烷基、3元杂环基;
    A环选自被0~2个R 34取代的3~6元饱和碳环;其中,R 34各自独立地选自氘、氟或=R 37;R 37选自O;
    或,
    所述化合物如式ⅡAC所示:
    Figure PCTCN2019074002-appb-100010
    其中,X选自O或S;
    L 1和L 2各自独立地选自无或亚甲基;
    R 33选自C 1-2烷基、-S-CH 3
    A环选自3~4元饱和碳环;
    或,
    所述化合物如式ⅡAD所示:
    Figure PCTCN2019074002-appb-100011
    其中,Y选自N;
    R 3和R 4各自独立地选自氢或氘;
    L 1和L 2各自独立地选自无或亚甲基;
    R 33选自氢、氘、C 1-2烷基、-L 31-COO-L 32、6元杂环基;L 31选自亚甲基;L 32选自甲基;
    A环选自3~4元饱和碳环;
    或,
    所述化合物如式ⅡBA所示:
    Figure PCTCN2019074002-appb-100012
    L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘、甲基;
    R 33选自氢、氘、甲基磺酰基、乙酰基、甲基;
    A环选自4元饱和杂环;
    或,
    所述化合物如式ⅡBB所示:
    Figure PCTCN2019074002-appb-100013
    Y选自N;
    X选自O或S;
    R 3和R 4各自独立地选自氢或氘;
    L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代基为氘、F、Cl、C 1-2烷基;
    R 5选自氢、氘、F、Cl、取代或未取代的C 1-2烷基、3元杂环基;
    所述取代基为氘、F、Cl、C 1-2烷基、3元杂环基、-S-CH 3
    A环选自被0~2个R 34取代的3~4元饱和杂环;其中,R 34各自独立地选自氘或甲基;
    或,
    所述化合物如式ⅡBC所示:
    Figure PCTCN2019074002-appb-100014
    L 1选自无或亚甲基;
    A环选自被1个R 34取代的4~5元饱和杂环或5元不饱和杂环;其中,R 34选自=R 37;R 37选自O;
    或,
    所述化合物如式ⅡCA所示:
    Figure PCTCN2019074002-appb-100015
    式中,
    X选自O或S;
    Y为N;
    R 3和R 4各自独立地选自氢、氘;
    L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代的取代基为氘、甲基;
    R 33选自氢、氘、C 1-2烷基;
    A环为无,或者,A环选自3~6元饱和碳环或4元饱和杂环;
    或,
    所述化合物如式ⅡCB所示:
    Figure PCTCN2019074002-appb-100016
    式中,
    L 1和L 2各自独立地选自无、C 1-2亚烷基;
    R 33选自甲基;
    A环为无;
    或,
    所述化合物如式ⅡCC所示:
    Figure PCTCN2019074002-appb-100017
    式中,
    X选自O或S;
    Y为N;
    L 1和L 2各自独立地选自无、C 1-2亚烷基;
    R 33选自甲基;
    A环为无;
    或,
    所述化合物如式ⅡCD所示:
    Figure PCTCN2019074002-appb-100018
    式中,
    X为O或S;
    L 1和L 2各自独立地选自无、取代或未取代的C 1-4亚烷基;所述取代基为C 1-4烷基或C 1-4烷氧基;
    A环为无;
    R 5为H;
    或,
    所述化合物如式ⅡDA所示:
    Figure PCTCN2019074002-appb-100019
    Y选自N;
    L 1和L 2各自独立地选自无、取代或未取代的C 1-2亚烷基;所述取代的取代基为氘、C 1-2烷基;
    R、R’各自独立地选自氢、氘、C 1-2烷基、C 1-2烷氧基、取代或未取代的C 2-4烯基或 C 2-4炔基,所述取代基选自羟基、C 1-2烷基;
    A环为无,或者,A环选自3~6元饱和碳环或4~6元饱和杂环;
    或,
    所述化合物如式ⅡDB所示:
    Figure PCTCN2019074002-appb-100020
    X选自O或S;
    R 3和R 4各自独立地选自氢、氘;
    L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代的取代基为氘、C 1-2烷基;
    R”选自氢、氘、C 1-2烷基、C 1-2烷氧基、取代或未取代的C 2-4烯基或C 2-4炔基,所述取代基选自羟基、C 1-2烷基;
    A环为无,或者,A环选自3~6元饱和碳环或4~6元饱和杂环;
    或,
    所述化合物如式ⅡDC所示:
    Figure PCTCN2019074002-appb-100021
    X选自O或S;
    R 3和R 4各自独立地选自氢、氘;
    L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代的取代基为氘、C 1-2烷基;
    R 5’选自S或CH 2
    A环为无,或者,A环选自3~6元饱和碳环或4~6元饱和杂环;
    或,
    所述化合物如式Ⅱ EA所示:
    Figure PCTCN2019074002-appb-100022
    Y选自N;
    X选自O或S;
    A环选自被0~2个R 34取代的3~6元饱和碳环;
    其中,R 34各自独立地选自氘、卤素、氰基、异硫氰基;
    R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基,并且R 3和R 4不同时为氢或氘;
    L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘,C 1-4烷基;
    R 5选自氢、氘、氰基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100023
    C 1-2烷基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、-OR 33、-C(O)R 33
    其中,R 33各自独立地选自C 1-2烷基;R 5中所述取代基选自=R 39、C 2-4烯基或C 2-4炔基,R 39选自S、CH 2
    或,
    所述化合物如式Ⅱ EA所示,Y选自N;
    X选自O或S;
    A环选自被0~2个R 34取代的3~6元饱和杂环;
    其中,R 34各自独立地选自氘、卤素、氰基、异硫氰基;
    R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基,并且R 3和R 4不同时为氢或氘;
    L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘,C 1-4烷基;
    R 5选自氢、氘、氰基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100024
    C 1-2烷基、取代或未取代的C 2-4 烯基、取代或未取代的C 2-4炔基、-OR 33、-C(O)R 33
    其中,R 33各自独立地选自C 1-2烷基;R 5中所述取代基选自=R 39、C 2-4烯基或C 2-4炔基,R 39选自S、CH 2
    或,
    所述化合物如式Ⅱ EA所示,Y选自N;
    X选自O或S;
    A环为无;
    R 3和R 4各自独立地选自氢、氘、卤素、卤代或未卤代的甲基,并且R 3和R 4不同时为氢或氘;
    L 1和L 2各自独立地选自无、取代或未取代的亚甲基;所述取代基为氘,C 1-4烷基;
    R 5选自氢、氘、氰基、异氰基、异硫氰基、
    Figure PCTCN2019074002-appb-100025
    C 1-2烷基、取代或未取代的C 2-4烯基、取代或未取代的C 2-4炔基、-OR 33、-C(O)R 33
    其中,R 33各自独立地选自C 1-2烷基;R 5中所述取代基选自=R 39、C 2-4烯基或C 2-4炔基,R 39选自S、CH 2
  8. 根据权利要求1~7任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物,其特征在于:所述化合物为:
    Figure PCTCN2019074002-appb-100026
    Figure PCTCN2019074002-appb-100027
    Figure PCTCN2019074002-appb-100028
    Figure PCTCN2019074002-appb-100029
    Figure PCTCN2019074002-appb-100030
    Figure PCTCN2019074002-appb-100031
    Figure PCTCN2019074002-appb-100032
    Figure PCTCN2019074002-appb-100033
    Figure PCTCN2019074002-appb-100034
    Figure PCTCN2019074002-appb-100035
    Figure PCTCN2019074002-appb-100036
    Figure PCTCN2019074002-appb-100037
    Figure PCTCN2019074002-appb-100038
    Figure PCTCN2019074002-appb-100039
    Figure PCTCN2019074002-appb-100040
    Figure PCTCN2019074002-appb-100041
    Figure PCTCN2019074002-appb-100042
    Figure PCTCN2019074002-appb-100043
    Figure PCTCN2019074002-appb-100044
    Figure PCTCN2019074002-appb-100045
    Figure PCTCN2019074002-appb-100046
  9. 一种药物,其特征在于:它是以权利要求1~8任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物、或其组合物,加上药学上可接受的辅料制备而成的制剂。
  10. 权利要求1~8任意一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物、或其氘代衍生物、或其组合物,在制备具有镇静、催眠、和/或麻醉作用、和/或可用于控制癫痫持续状态的药物中的用途。
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