WO2022242558A1 - 一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用 - Google Patents

一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用 Download PDF

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WO2022242558A1
WO2022242558A1 PCT/CN2022/092681 CN2022092681W WO2022242558A1 WO 2022242558 A1 WO2022242558 A1 WO 2022242558A1 CN 2022092681 W CN2022092681 W CN 2022092681W WO 2022242558 A1 WO2022242558 A1 WO 2022242558A1
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compound
substituted
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pyrimidodiazepanone
chiral
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邱立勤
蒋晓丁
钱旭
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Sun Yat Sen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
    • B01J31/22—Organic complexes
    • B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
    • B01J31/2208—Oxygen, e.g. acetylacetonates
    • B01J31/2221—At least one oxygen and one phosphorous atom present as complexing atoms in an at least bidentate or bridging ligand
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
    • B01J2531/80—Complexes comprising metals of Group VIII as the central metal
    • B01J2531/82—Metals of the platinum group
    • B01J2531/827—Iridium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the technical field of chiral compound synthesis, and in particular relates to a chiral or racemic pyrimidodiazepanone compound and a preparation method and application thereof.
  • the benzodiazepine skeleton is an important structural unit in drug molecules, and its derivatives usually have a wide range of pharmacological activities. Using this as the key core to develop a series of promising drug candidates for different pathological characteristics molecular.
  • structural analogues pyrimidodiazepanones have attracted extensive attention from synthetic chemists because of their potential pharmacological activities, and their preparation methods play an extremely important role in the development of new drugs.
  • Santilli's research group prepared pyrimidodiazepanones for the first time. Preliminary activity screening experiments showed that it has a certain degree of sedative activity and also exhibits antispasmodic effects [Kim, DH; Santilli, AAJMed. Chem.
  • VGCC voltage-gated calcium channel
  • NET phenylephrine transporter
  • Depression is a chronic disease faced by modern medicine, and there is still a lack of effective treatment methods and drugs. Depression induces neurological dysfunction, disrupting the functional and structural connectivity of neural circuits that regulate emotion. Glucocorticoids (GCs) and their receptors (GR) are important signaling molecules that regulate mood in response. Chronic stress and HPA dysregulation promote neuroinflammation, resulting in elevated pro-inflammatory cytokines and chemokines, such as NF- ⁇ B. Depression-induced inflammation and HPA axis dysfunction further induce synaptic plasticity. The process of neuroplasticity is controlled by regulatory proteins, and cofilin-1 is one of the key regulators. Therefore, GR, NF- ⁇ B and cofilin-1 are considered to be key targets for the treatment of depression.
  • pyrimidodiazepines have structural similarity to benzodiazepines, and have a wide range of biological activities, which have potential research value. Although some progress has been made in its synthesis, the method of constructing such compounds by asymmetric catalysis has not been reported yet. Therefore, the development of effective asymmetric synthesis methods is of great significance for enriching the structures of such compounds and drug development.
  • the primary purpose of the present invention is to provide a chiral or racemic pyrimidodiazepanone compound or a pharmaceutically acceptable salt thereof.
  • the pyrimidodiazepine compound of the present invention is a L-body, a D-body or a racemate.
  • the levorotatory isomer is a pure levorotatory product, or a mixture of enantiomers with excess levorotatory.
  • the dextrorotatory isomer is a dextrorotatory pure product, or a dextrorotatory enantiomeric mixture in excess.
  • the racemate is a mixture of enantiomers and has an ee value of zero.
  • Another object of the present invention is to provide a preparation method of the above-mentioned chiral or racemic pyrimidodiazepine compounds.
  • the preparation method of the present invention is that pyrimidine allyl compounds are used as substrates through intramolecular allyl catalyzed amination reaction to effectively synthesize pyrimidodiazepanone compounds and enantiomers or racemates thereof.
  • the method of the invention can realize high-efficiency and high-enantioselectivity synthesis of optically active center-chiral pyrimidodiazepanone compounds.
  • Another object of the present invention is to provide the above-mentioned chiral or racemic pyrimidodiazepanone compounds or their pharmaceutically acceptable salts in the preparation of drugs for preventing or treating depression or their lead compounds.
  • C1-C20 amido group C2-C20 ketocarbonyl group, C1-C20 sulfonyl group, C1-C9 alkylsilyl group, phenylsilyl group, amino group, C1-C20 N-alkyl substituted amino group, C1 -C20 N,N-dialkyl substituted amino group, substituted or unsubstituted C3-C20 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S, substituted or unsubstituted Substituted aryl, substituted or unsubstituted aryl methylene;
  • substituted substituents are independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, C1-C20 alkyl, C1-C20 fluoroalkyl, C1-C20 alkoxy, amino, C1 -One or more combinations of C20 N-alkyl substituted amino groups or C1-C20 N,N-dialkyl substituted amino groups;
  • C1-C20 straight chain or branched chain alkyl, C1-C20 fluoroalkyl, C2-C20 alkenyl, C2-C20 alkynyl, C1-C20 alkoxy, C3-C20 cycloalkane C1-C20 amide group, C2-C20 ketocarbonyl group, C1-C20 sulfonyl group, C1-C9 alkylsilyl group, phenylsilyl group, amino group, C1-C20 N-alkyl substituted amino group , C1-C20 N,N-dialkyl substituted one or more hydrogen atoms in the amine group can be replaced by fluorine atom, chlorine atom, bromine atom, oxygen atom, alkenyl, alkynyl, aryl, hydroxyl, amino, Carbonyl, carboxyl, ester, cyano, methyl, ethyl, methoxy, nitro substitution.
  • the above-mentioned aryl groups are independently C6-C20 aryl groups.
  • R 3 and R 4 are independently selected from hydrogen, C1-C20 linear or branched chain alkyl, C3-C20 cycloalkyl, C3-C20 cycloalkylmethylene, C3-C20 allyl, C3-C20 propargyl group, C1-C20 acyl group, C1-C20 sulfonyl group, substituted or unsubstituted C3-C20 heterocyclic group or heterocyclic group containing one or more of N, O and S Cycloaryl, substituted or unsubstituted heterocyclyl methylene or heterocyclic aryl methylene, substituted or unsubstituted C1-C20 alkoxycarbonyl, substituted or unsubstituted aryl acyl, substituted arylsulfonyl Acyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl methylene;
  • substituted substituents are independently selected from hydrogen, C1-C20 alkyl, C1-C20 fluoroalkyl, halogen, nitro, C1-C20 alkoxy, hydroxyl, cyano, C1-C20
  • One or more combinations of N-alkyl substituted amine groups or C1-C20 N,N-dialkyl substituted amine groups are independently selected from hydrogen, C1-C20 alkyl, C1-C20 fluoroalkyl, halogen, nitro, C1-C20 alkoxy, hydroxyl, cyano, C1-C20
  • N-alkyl substituted amine groups or C1-C20 N,N-dialkyl substituted amine groups are independently selected from hydrogen, C1-C20 alkyl, C1-C20 fluoroalkyl, halogen, nitro, C1-C20 alkoxy, hydroxyl, cyano, C1-C20
  • N,N-dialkyl substituted amine groups are independently
  • C1-C20 straight chain or branched chain alkyl, C3-C20 cycloalkyl, C3-C20 cycloalkylmethylene, C3-C20 allyl, C3-C20 propargyl, C1- One or more hydrogen atoms in C20 acyl group and C1-C20 sulfonyl group can be replaced by fluorine atom, chlorine atom, bromine atom, oxygen atom, alkenyl, alkynyl, aryl, hydroxyl, amino, carbonyl, carboxyl, ester Substituted by group, cyano group, methyl group, ethyl group, methoxy group, nitro group.
  • the above-mentioned aryl groups are independently C6-C20 aryl groups.
  • the structural formula of the chiral or racemic pyrimidodiazepane compound is formula (I) with a pyrimidodiazepane skeleton structure; wherein, R 1 and R 2 are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoro Methyl, benzyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, C1-C20 amides group, trimethylsilyl group, triethylsilyl group, triphenylsilyl group, C3-C20 heterocyclic group or heterocyclic aryl group containing one or more of N, O and S,
  • the structural formula of the chiral or racemic pyrimidodiazepanone compound is formula (I) with a pyrimidodiazepane skeleton structure; wherein, R 1 and R 2 are respectively independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, trifluoromethyl, methoxy, ethoxy radical, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, hydroxyl, carboxyl, cyano, cyclopentyl, cyclohexyl, amino, methylamino, ethylamino , diethylamino, diisopropylamino, trimethylsilyl, triethylsilyl, triphenylsilyl, acetamido, acety
  • the structural formula of the chiral or racemic pyrimidodiazepanone compound is formula (I) with a pyrimidodiazepane skeleton structure; wherein, R 3 and R 4 are respectively independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclohexyl, cyclopentylmethyl, allyl, propargyl, carbonyl, ethoxycarbonyl, tert-butoxycarbonyl, trichloroethyl Oxyformyl, benzoyl, 4-bromobenzoyl, 9-fluorenylidenemethoxyformyl, 3-fluoro-4-(allylamido)phenyl, sulfonyl, tosyl, phenyl , 4-methoxyphenyl, 4-(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, benzyl, p-fluorobenzyl
  • the present invention also provides a preparation method of the above-mentioned chiral or racemic pyrimidodiazepanone compounds, specifically, the pyrimidine allyl compound intermediate is used as the raw material, and the iridium compound and the phosphoramidite ligand The iridium complex formed by the action is used as a catalyst, and under the action of a base, the chiral or racemic pyrimidodiazepanone compound is obtained through the reaction.
  • the halogen in the halogen-substituted C1-C20 alkyl is fluorine, chlorine, bromine or iodine.
  • the halogen-substituted C1-C20 alkyl group is trichloromethyl.
  • the substituent of the substituted aryl group is one or more combinations of C1-C20 alkyl, halogen or C1-C20 alkoxy.
  • the aryl group is a C6-C20 aryl group.
  • the C1-C20 alkyl groups are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tertiary butyl.
  • the C1-C20 alkoxy groups are independently selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or benzyloxy.
  • the substituents can be one or more, and when there are multiple substituents, the substituents can be the same or different.
  • the pyrimidine allyl compound intermediate (S) can be prepared by a method comprising the following steps: 2,4-dichloro-6-substituted-pyrimidine-5-carboxylic acid methyl ester compound and amine compound
  • the reaction generates 2-chloro-4-substituted amino-6-substituted-pyrimidine-5-carboxylic acid methyl ester compounds, and the group R 1 is introduced by conventional nucleophilic substitution reaction or coupling reaction such as Suzuki, and then hydrolyzed to generate carboxyl compounds, and then The reaction gives the compound of formula S.
  • Compound S was further catalyzed as a substrate to obtain product I.
  • the reaction equation is as follows:
  • the 2,4-dichloro-6-substituted-pyrimidine-5-carboxylic acid methyl ester compound can be 2,4-dichloro-pyrimidine-5-carboxylic acid methyl ester, 2,4-dichloro-6- Hydroxy-pyrimidine-5-carboxylic acid methyl ester, 2,4-dichloro-6-cyano-pyrimidine-5-carboxylic acid methyl ester, 2,4-dichloro-6-phenyl-pyrimidine-5-carboxylic acid Methyl 2,4-dichloro-6-benzoyl-pyrimidine-5-carboxylate methyl 2,4-dichloro-6-benzyl-pyrimidine-5-carboxylate methyl 2,4- Dichloro-6-amino-pyrimidine-5-carboxylic acid methyl ester, 2,4-dichloro-6-ethyl-pyrimidine-5-carboxylic acid methyl ester, 2,4-dichloro-6-methylsul
  • the base can be an organic base or an inorganic base, such as triethylamine, 4-dimethylaminopyridine, 1,8-diazabicyclo[5,4,0] Undec-7-ene, 1,5-diazabicyclo[4,3,0]non-5-ene, triethylenediamine, N,O-bis(trimethylsilyl)acetamide, Cesium carbonate, potassium carbonate, lithium carbonate, potassium fluoride, sodium hydride, cesium fluoride, potassium phosphate, potassium acetate, sodium phosphate, sodium acetate, lithium acetate, n-butyl lithium, sodium bis(trimethylsilyl)amide , lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, proton sponge, lithium tert-butoxide, potassium tert-butoxide, tert-butanol sodium or diis
  • the base and silver trifluorosulfonate, lithium chloride or molecular sieve additives are combined into the reaction system.
  • the molar ratio of the pyrimidine allyl compound intermediate, the iridium atom of the iridium compound, the phosphoramidite ligand, and the base is 1: (0.005-0.1): (0.005-0.2): (0.05- 3).
  • the reaction can be carried out at 0-120°C.
  • the reaction time can be 20min-24h.
  • the iridium compound can be [Ir(COD)Cl] 2 , [Ir(dncot)Cl] 2 , [Ir(OMe)(COD)] 2 , [Ir(COD) 2 ]BArF 4 , Ir(COD) 2 BF 4 , [Ir(OH)(COD)] 2 , Ir(ppy) 3 , [Ir(COD) 2 ]SbF 6 and the like.
  • the phosphoramidite ligand described refers to the phosphoramidite ligand in CN109336887A, see paragraph [0076] of the description for details.
  • the product after the reaction can be purified through a silica gel short column to obtain chiral pyrimidodiazepanone compounds and their enantiomers or racemates.
  • the reaction is carried out in an organic solvent system.
  • the organic solvent can be a polar solvent or a non-polar solvent.
  • the organic solvent can be an aromatic solvent or a substituted aromatic solvent, a halogenated hydrocarbon solvent, an ether solvent, an amide solvent, an alkane solvent, a cycloalkane solvent, a nitrile solvent, dimethyl sulfoxide and one or more combinations of alcoholic solvents.
  • the aromatic solvent or substituted aromatic solvent is preferably at least one of toluene, xylene, ethylbenzene, cumene, chlorobenzene and nitrobenzene;
  • the halogenated hydrocarbon solvent is preferably At least one of dichloromethane, 1,2-dichloroethane and chloroform;
  • the ether solvent is preferably tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, methyl tert-butyl ether, 1, At least one of 4-dioxane;
  • the amide solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpropionamide, At least one of ⁇ -pyrrolidone and N-methylpyrrolidone;
  • the alkane solvent is preferably at least one of n-hexane, n-pentane and n-heptane;
  • the preparation method of the present invention may comprise the following specific steps:
  • step (1) the molar ratio of compound 1 and compound 2 can be 1:1-1:1.2; the reaction temperature can be 50°C-100°C, and the reaction time can be 1-6h.
  • step (2) the molar ratio of compound 3 and boric acid compound, amine compound or sodium alkoxide compound, alkali can be 1:(1-2):(1-2):(1-3);
  • Reaction temperature can be The temperature is 20°C-130°C, and the reaction time can be 30min-4h.
  • step (3) the molar ratio of compound 4 to the base can be 1:1-1:3; the reaction temperature can be 20°C-100°C, and the reaction time can be 10min-2h; the base can be sodium hydroxide , potassium hydroxide or lithium hydroxide, etc.
  • step (4) the molar ratio of compound 5, compound 6, HOBt, and EDCI can be 1:1:(1-2):(1-2); the reaction temperature can be 0-80°C; the reaction time can be 1 -10 h; the reaction is carried out in a solvent such as dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.
  • a solvent such as dichloromethane, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or dimethyl sulfoxide.
  • the molar ratio of substrate S, iridium, ligand, and base can be 1:(0.005-0.1):(0.005-0.2):(0.05--3); the reaction temperature can be 0-70°C ; The reaction time can be 3min-24h.
  • the preparation method of the present invention uses the iridium-phosphoramidite ligand complex as the catalyst, especially when the iridium-chiral bridged phosphoramidite ligand complex is used as the catalyst, through the careful design of the pyrimidine allyl carbonate substrate , Synthesis, a method for synthesizing pyrimidodiazepanone compounds with high efficiency and high enantioselectivity through intramolecular allyl amination reaction; its enantiomer is prepared from a ligand of opposite configuration to a corresponding catalyst , to be obtained by similar intramolecular allyl amination catalytic reaction; its racemate is obtained by preparing the corresponding catalyst from the racemic ligand, and performing similar intramolecular allyl amination catalytic reaction.
  • the present invention also provides the use of the above-mentioned chiral or racemic pyrimidodiazepanone compound or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating depression or its lead compound.
  • the present invention has the following advantages and beneficial effects:
  • the invention provides an effective iridium-phosphoramidite ligand complex as a catalyst, and the carefully designed and synthesized pyrimidine allyl substrate undergoes an intramolecular allyl catalyzed amination reaction, with high efficiency and high regioselectivity
  • the strategies and methods for synthesizing novel chiral pyrimidodiazepanones with high enantioselectivity can prepare a variety of chiral pyrimidodiazepanes.
  • the present invention also conducts preliminary in vitro antidepressant activity evaluation on the constructed chiral or racemic pyrimidodiazepanone compounds.
  • the results show that the compound of the present invention has a good inhibitory effect on GR, cofilin-1 and NF- ⁇ B proteins, and can reverse the apoptosis of PC12 cells caused by corticosterone in a depressed state, indicating that the pyrimidodiazepine ring of the present invention Heptanone compounds have good antidepressant activity.
  • the preparation method of the present invention is applicable to many different types of pyrimidine allyl compounds, and has high catalytic activity, mild reaction conditions, wide application range of substrates, simple and convenient operation, and good reaction yield ( up to 99%) with high enantioselectivity (up to 99% ee).
  • This method of using catalytic asymmetric intramolecular allyl amination reaction to efficiently construct chiral pyrimidodiazepanone compounds and the corresponding compounds synthesized therefrom have not been reported in the literature at home and abroad.
  • the invention not only enriches the application of bridged phosphoramidite ligands and other types of phosphoramidite ligands, but also broadens the scope of application of allylation reaction substrates, and provides novel chiral heterocyclic molecules for the development of new drugs Structure and efficient construction of new methods.
  • Figure 1 is a single crystal structure diagram of compound I-9 prepared in Example 3.
  • Fig. 2 is a graph showing the relationship between the concentration and time of the antidepressant effect of the compounds of the present invention.
  • concentration used in B is 0.625uM
  • concentration used in C and D is 1.0uM.
  • Fig. 3 is the inhibitory effect of the compounds of the present invention on the overexpression of GR, cofilin-1 and NF- ⁇ B proteins.
  • concentration used in A and B is 0.625uM
  • concentration used in C and D is 1.0uM.
  • Figure 4 shows the antidepressant effects of compounds with different chiral configurations. Among them, the concentration used in A is 1.0uM, and the concentration used in B, C, and D is 0.625uM.
  • Fig. 5 is an experiment of the compound of the present invention on the mouse depression model induced by reserpine.
  • A is the tail suspension test of mice;
  • B is the forced swimming test of mice;
  • C is the sugar water preference test of mice;
  • D is the open field test of mice;
  • E is the tail suspension test of mice with single administration; Single-dose forced-swim test in mice.
  • Embodiment 1 the preparation of pyrimidine allyl compound (S)
  • N,N-diisopropylethylamine (2.0 equivalent) was Alkali, acetonitrile is a solvent, stir reaction at 80 °C, obtain compound 3 through nucleophilic substitution reaction;
  • compound 4 can be obtained by conventional coupling reaction such as Suzuki or nucleophilic substitution reaction; compound 4 is hydrolyzed in the presence of sodium hydroxide (1.0mol/L) in methanol solvent to obtain Compound 5;
  • Compound 5 was dissolved in DMF, and then 1-hydroxybenzotriazole (HOBt, 1.1 equivalents) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride were added (EDCI, 1.1 equivalents), stirred and reacted at room temperature for 30 minutes, then added compound 6 (1.1 equivalents) to the reaction solution
  • the reaction solution was poured into ice water, and then extracted with ethyl acetate , the organic phase was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the pyrimidine allyl intermediate S.
  • the pyrimidine allyl intermediate (S) is used as a substrate under the catalysis of an iridium-phosphoramidite complex to undergo an intramolecular allyl amination reaction to prepare chiral pyrimidodiazepanone compounds, and the specific steps can be as follows:
  • Figure 1 is a single crystal structure diagram of compound I-9 prepared in Example 3.
  • the molar ratio in Table 1 refers to the molar ratio of substrate S: iridium: ligand: base.
  • LG is a leaving group
  • Bn is benzyl
  • DIPEA is diisopropylethylamine
  • DMAP is 4-dimethylaminopyridine
  • DABCO is triethylenediamine
  • DBU is 1,8-diazepine Bicycloundec-7-ene
  • BSA is N,O-bistrimethylsilylacetamide
  • DBN is 1,5-diazabicyclo[4.3.0]non-5-ene
  • Ac stands for acetyl
  • Boc Re represents tert-butoxycarbonyl
  • Piv represents 2,2-dimethylpropionyl
  • Bz represents benzoyl
  • Troc represents 2,2,2-trichloroethoxycarbonyl
  • DME represents ethylene glycol dimethyl ether
  • MTBE represents methyl Base tert-butyl ether.
  • Example 4 According to the aforementioned substrate synthesis method, Example 3 and the reaction conditions for the synthesis of compound I-1, specific compounds I-19 to compound I-38 were prepared, and the results are shown in Table 2:
  • PC12 cells were purchased from Procell Life Science & Technology Co., Ltd. (Wuhan, China). All cell culture reagents were purchased from Life Technologies (Grand Island, Iowa, USA). Cells were cultured in Dulbecco's modified Eagle's medium (Gibco, USA) containing 10% fetal bovine serum (Gibco, USA) at 37°C in an incubator containing 5% CO 2 .
  • Corticosterone (CORT)-induced PC12 cells are commonly used to establish depression models in vitro.
  • PC12 cells were treated with 600 ⁇ M corticosterone for 24 hours, at this concentration of corticosterone, the cell viability was reduced to 60%, and thus could be used for subsequent in vitro experiments.
  • CORT Corticosterone
  • Cell viability was determined using MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]. Specific steps: inoculate 1 ⁇ 105 cells into each well of a 96-well plate, culture for 24 hours to stabilize, add 600 ⁇ M corticosterone for 24 hours, pour out the medium containing corticosterone, and add The culture medium containing different concentrations of drugs (compound of the present invention/fluoxetine) was treated for 12, 24 and 48 hours respectively, and MTT was added to incubate at 37°C for 4 hours, measured in a microplate reader (BIO-RAD, USA) Absorbance at 570nm, the results are shown in Figure 2 and Table 3. Table 3 shows the cell viability results when the drug concentration is 0.625uM and cultured for 24h.
  • PC12 cells were lysed on ice in RIPA lysate containing 1% phenylmethylsulfonyl fluoride (PMSF) for 30 minutes, and the supernatant solution was collected and centrifuged, and BCA assay kit (Beyotime, Beyotime , Shanghai) to measure the protein concentration of the supernatant. Protein samples were loaded on 10% SDS-polyacrylamide gel electrophoresis, and then further transferred to PVDF membrane (Millipore, MA, USA). Membranes were blocked with 5% skim milk and then incubated overnight at 4°C with primary antibodies alone. After washing with Tris-buffered saline-tween 20 (TBST), PVDF membranes were incubated with secondary antibodies at room temperature.
  • TST Tris-buffered saline-tween 20
  • Hoechst and PI staining were used to detect the apoptosis of PC12 cells.
  • Hoechst can bind to the nucleus of living cells
  • PI sodium iodide
  • They were plated in 12-well plates, and after 48 hours of drug treatment, the cells were stained with the nuclear dye Hoechst. In short, the cells were washed twice with PBS, and incubated with 10 mg/L Hoechst for 20 minutes in the incubator.
  • PI staining incubate at 4°C for 10 minutes at room temperature with a working solution containing PI (final concentration 1 ⁇ g/mL). The cells were observed and photographed using a fluorescence microscope (Zeiss, Germany), and the results are shown in Figure 2 and Figure 3 . Blue fluorescence (white background) represents live cells, and red fluorescence (black background) represents dead cells.
  • a adopts a concentration of 0.625uM, and the value is the average value of three independent experiments; b is corticosterone; c is a positive control drug.
  • the present invention uses the MTT method to measure the cell viability at different drug concentrations (20uM, 10uM, 5uM, 2.5uM, 1.25uM and 0.625uM) at different times (12h, 24h and 48h), and the results are shown in Figure 2.
  • normal cells were used as blank control (Control)
  • corticosterone treated group (CORT) was used as control group
  • DMSO+control was used as solvent control group.
  • Figure 2A is the result of different concentrations of drugs after 12 hours of culture;
  • Figure 2B is the result of different culture times when the drug concentration is 0.625uM.
  • corticosterone causes the survival rate of PC12 cells to be reduced to about 60%
  • adding the compound (S)-I-11 of the present invention and the positive drug fluoxetine can effectively reduce the cell death rate caused by CORT, and the compound of the present invention Compared with the positive drug fluoxetine, the effect is more significant and tends to normal cells.
  • Fig. 2B it can be seen from Fig. 2B that the positive drug fluoxetine needs 48 hours to exert its effect, while the compound (S)-I-11 of the present invention shows excellent effect within 12 hours (Fig. 2A and Fig. 2B).
  • Depression pathogenesis is associated with HPA axis hyperactivity, synaptic remodeling, and inflammation. Among them, GR, cofilin-1 and NF- ⁇ B play a key role in the pathogenesis of depression.
  • the results show that the compounds (S)-I-17 and (R)-I-9 in the examples exhibit the same effect as fluoxetine, can promote the expression of GR during depression, and inhibit the expression of cofilin-1 and NF- ⁇ B proteins Overexpression ( Figure 3A and Figure 3B); and compounds (S)-I-17 and (R)-I-9 can reverse the massive apoptosis of PC12 cells induced by corticosterone ( Figure 3C and Figure 3D). These results further prove that compounds (S)-I-17 and (R)-I-9 have good antidepressant activity in vitro.
  • pyrimidodiazepanone compound of the present invention has better antidepressant effect, even part compound antidepressant activity is better than the effect of positive control drug fluoxetine; And introduce in the present invention The antidepressant activity of compounds with allyl moieties was significantly better than that of compounds without allyl moieties.
  • Embodiment 6 Mouse depression model experiment of pyrimidodiazepanones
  • the chronic depression model was induced by intraperitoneal injection of 0.4 mg/kg reserpine into mice for 14 days.
  • Tail suspension test (TST), forced swim test (FST), sucrose preference test (SWP) and open field test (OFT) were used as evaluation criteria for depression.
  • fluoxetine Fluooxetine
  • SWP sucrose preference test
  • OFT open field test
  • Tail Suspension Test Tape was used to fix the end of the tail of the mouse at about 1 cm, and hang it. A video camera was used to record the activity of the mice within 6 minutes, and the immobility time of the mice within 4 minutes after statistical analysis.
  • FST Forced swimming test
  • Open field test The experiment is carried out in a quiet environment. Put the animals into the center of the bottom surface of the 40 ⁇ 40cm box, and observe and record the activity of the tested mice in the open field test box for 15 minutes by the video behavior analysis system.
  • Fig. 5 is an experiment of the compound of the present invention on the mouse depression model induced by reserpine.
  • A is the tail suspension test of mice;
  • B is the forced swimming test of mice;
  • C is the sugar water preference test of mice;
  • D is the open field test of mice;
  • E is the tail suspension test of mice with single administration; Single-dose forced-swim test in mice.
  • mice without depression were used as blank contrast (control), and mice without drug administration for depression were used as control groups (expressed as "-" in Figure 5A- Figure 5D; expressed as "depression” in Figure 5E and Figure 5F ).
  • the pyrimidodiazepanone compounds of the present invention can significantly reduce the immobility time of the tail suspension (Fig. 5A) and the immobility time of forced swimming (Fig. ), and restore the mouse's preference for sugar (Fig. 5C), and increase the moving distance of the mouse in the central area (Fig. 5D), which tends to normal mice, which is consistent with the effect of the positive drug fluoxetine, and the effect is higher than that of The positive drug fluoxetine is more significant, indicating that the compound of the present invention has more excellent antidepressant effect than the positive drug fluoxetine.
  • the pyrimidodiazepanone compound of the present invention has an excellent, fast-acting antidepressant effect and a long-lasting drug effect.

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Abstract

本发明属于手性化合物合成技术领域，特别涉及一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用。本发明的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，结构式如式(I)所示。本发明还提供上述嘧啶并二氮杂环庚酮类化合物的制备方法，具体为以嘧啶类烯丙基化合物中间体为原料，以铱化合物与亚膦酰胺配体作用生成的铱配合物作为催化剂，在碱的作用下，反应得到。本发明的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐对GR、cofilin-1和NF-κB蛋白具有较好的抑制作用，且可逆转抑郁状态下皮质酮导致的PC12细胞的凋亡，可应用于制备预防或治疗抑郁症的药物或其先导化合物中。

Description

一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用 技术领域
本发明属于手性化合物合成技术领域，特别涉及一种手性或消旋的嘧啶并二氮杂环庚酮类化合物及其制备方法和应用。
背景技术
苯并二氮杂环庚酮类骨架是药物分子中重要的结构单元，其衍生物通常具有广泛的药理活性，以此为关键母核针对不同的病理特征开发了一系列有前景的候选药物小分子。作为结构类似物，嘧啶并二氮杂环庚酮类化合物因其潜在的药理学活性受到合成化学家们的广泛关注，其制备方法研究在新药研发中占据着极其重要的地位。1969年，Santilli课题组首次制备了嘧啶并二氮杂环庚酮类化合物，初步的活性筛选实验表明，其具有一定程度的镇静活性同时也表现出抗痉挛作用[Kim,D.H.；Santilli,A.A.J.Med.Chem.1969,12,1121–1122.]。随后科学研究者合成了多种不同结构的嘧啶并二氮杂环庚酮类化合物，并发现具有不同的生物活性。如，2005年Seto课题组提供的化合物，对神经激肽受体NK1有较强的抑制作用(K B＝0.480nM)，可增加天竺鼠的有效膀胱容量，在治疗尿失禁方面表现出良好的前景[Seto,S.；Tanioka,A.；Ikeda,M.；Izawa,S.Bioorg.Med.Chem.2005,13,5717–5732.]。2008年，Schulz课题组研究报道了一类嘧啶并二氮杂环庚酮类化合物可有效抑制PDK1激酶，其中一些化合物对PDK1激酶的抑制作用尤为突出，IC 50值可达皮摩尔级别[Schulz,M.；Burgdorf,L.T.；Finsinger,D.；Blaukat,A.；Greiner,H.；Esdar,C.；Kreysch,H.-G.；Henzler,T.PCT Int.Appl.2008,US20080318934A1,20081225.]。2012年，丁克课题组设计、合成了一系列嘧啶并二氮杂环庚酮类衍生物，发现此类化合物对EGFR蛋白及其临床相关突变体具有很好的体外抑制作用，其中一些化合物对EGFR L858R/T790M的抑制活性达纳摩尔级别(IC 50＝14nM)；同时，此类化合物也能抑制非小细胞肺癌细胞H1975和HCC827的增值[Xu,S.；Zhang,L.,Chang,S.；Luo,J；Lu,X.；Tu,Z.；Liu,Y.；Zhang,Z.；Xu,Y.；Rena,X.；Ding,K.Med.Chem.Commun.2012,3,1155–1159.]。Cuevas-Cordobes和Almansa-Rosales等于2017年设计、合成的嘧啶并二氮杂环庚酮类化合物与电压门控钙离子通道(VGCC)亚结构α2δ有很强的亲和力，特别是对α2δ-1表现很强的抑制作用；此外，这类化合物也能有效抑制去氧肾上腺素转运体(NET)；双重抑制作用使此类化合物在治疗脑损伤及其相关疾病方面具有很好的应用前景[Cuevas-Cordobes,F.；Almansa-Rosales,C.PCT Int.Appl.2017,WO 2017191304 A1,20171109.]。
抑郁症是现代医学面临的顽症，目前还缺少有效的治疗手段和药物。抑郁症诱发神经系统功能障碍，使得调节情绪的神经回路功能和结构连接中断。糖皮质激素(GCs)及其受体(GR)是响应调节情绪重要的信号分子。慢性应激和HPA失调促进了神经炎症发生，导致促炎性细胞因子和趋化因子，如NF-κB升高。抑郁症引起的炎症和HPA轴功能障碍进一步诱导神经突触可塑性。神经可塑性发生的过程由调节蛋白控制，cofilin-1是关键调节剂之一，因此，GR、NF-κB和cofilin-1被认为是抑郁症治疗的关键靶标。
综上所述，嘧啶并二氮杂环庚酮类化合物与苯并二氮杂卓具有结构类似性，生物学活性广泛，具有潜在的研究价值。虽然目前其合成已取得一些进展，但是不对称催化构建此类化 合物的方法还未见报道。因此，开发有效的不对称合成方法对于丰富此类化合物的结构及药物研发具有重要的意义。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供一种手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐。本发明的嘧啶并二氮杂环庚酮类化合物为左旋体、右旋体或消旋体。所述左旋体为左旋纯品，或左旋过量的对映体混合物。所述右旋体为右旋纯品，或右旋过量的对映体混合物。所述消旋体为对映体混合物，且其ee值为0。
本发明的另一目的在于提供一种上述手性或消旋的嘧啶并二氮杂环庚酮类化合物的制备方法。本发明制备方法为由嘧啶烯丙基类化合物为底物经分子内烯丙基催化胺化反应，有效合成得到嘧啶并二氮杂环庚酮类化合物及其对映体或消旋体。本发明方法可实现高效率、高对映选择性地合成光学活性的含中心手性的嘧啶并二氮杂环庚酮类化合物。
本发明的再一目的在于提供上述手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐在制备预防或治疗抑郁症的药物或其先导化合物中的应用。
本发明的目的通过下述方案实现：
Figure PCTCN2022092681-appb-000001
C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的芳基、取代或未取代的芳基亚甲基；
其中，上述取代的取代基分别独立选自氢、卤素、羟基、氰基、硝基、C1-C20的烷基、C1-C20的氟代烷基、C1-C20的烃氧基、氨基、C1-C20的N-烷基取代胺基或C1-C20的N,N-二烷基取代胺基中的一种或一种以上的组合；
上述C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基中的一个或一个以上氢原子可被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
优选地，上述的芳基分别独立为C6-C20的芳基。
R 3、R 4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的杂环基亚甲基或杂环芳基亚甲基、取代或未取代C1-C20的烃氧羰基、取代或未取代的芳基酰基、取代的芳基磺酰基、取代或未取代的芳基、取代或未取代芳基亚甲基；
其中，上述取代的取代基分别独立选自氢、C1-C20的烷基、C1-C20的氟代烷基、卤素、 硝基、C1-C20的烃氧基、羟基、氰基、C1-C20的N-烷基取代胺基或C1-C20的N,N-二烷基取代胺基中的一种或一种以上的组合；
上述C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基中的一个或一个以上氢原子可被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
优选地，上述的芳基分别独立为C6-C20的芳基。
进一步的，所述手性或消旋的嘧啶并二氮杂环庚酮类化合物的结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；其中，R 1、R 2分别独立选自氢、氟、氯、溴、碘、羟基、羧基、氰基、硝基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、苄基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、苄氧基、氨基、C1-C20的酰胺基、三甲基硅基、三乙基硅基、三苯基硅基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、C2-C20的酮羰基、C1-C20的磺酰基、取代或未取代的芳基；所述取代的芳基中的取代基为C1-C20的烷基、卤素或C1-C20的烃氧基中的一种或一种以上的组合；R 3、R 4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、杂环基亚甲基或杂环芳基亚甲基、烯丙基、炔丙基、乙酰基、苯甲酰基、C1-C20的磺酰基、叔丁氧羰基、芴甲氧羰基、2,2,2-三氯乙氧羰基、取代或未取代的芳基、取代或未取代的芳基亚甲基、取代或未取代的苯磺酰基；其中，上述取代的取代基分别独立选自氢、C1-C20的烷基、C1-C20的氟代烷基、卤素、硝基或C1-C20的烃氧基中的一种或一种以上的组合。
更进一步的，所述手性或消旋的嘧啶并二氮杂环庚酮类化合物的结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；其中，R 1、R 2分别独立选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、羟基、羧基、氰基、环戊基、环己基、氨基、甲胺基、乙胺基、二乙基胺基、二异丙基胺基、三甲基硅基、三乙基硅基、三苯基硅基、乙酰胺基、乙酰基、三氟乙酰基、苯基、苯胺基、苯甲酰基、3,4,5-三甲氧基苯基、苄基、4-二甲氨基苄基、苄氧基、甲磺酰基、苯磺酰基、萘基、吗啉基、吡咯基、四氢吡咯基、1-哌嗪基、1-甲基哌嗪基、吡啶基、4-甲基吡啶基、甲氧基吡啶基、呋喃基、哌啶基、4-羟甲基-3,5-二甲基哌啶基、噻吩基、噁唑基。
更进一步的，所述手性或消旋的嘧啶并二氮杂环庚酮类化合物的结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；其中，R 3、R 4分别独立选自氢、甲基、乙基、正丙基、异丙基、环己基、环戊基甲基、烯丙基、炔丙基、羰基、乙氧羰基、叔丁氧羰基、三氯乙氧甲酰基、苯甲酰基、4-溴苯甲酰基、9-亚芴基甲氧甲酰基、3-氟-4-(烯丙基酰胺基)苯基、磺酰基、甲苯磺酰基、苯基、4-甲氧基苯基、4-(三氟甲基)苯基、3,5-双(三氟甲基)苯基、苄基、对氟苄基、4-二甲氨基苄基、4-甲氧基苄基、2-四氢吡喃基、4-(三氟甲基)苄基、3,5-双(三氟甲基)苄基、嘧啶基、4-氟嘧啶基甲基、4-氯嘧啶基甲基、吡咯并嘧啶基、吗啉基、吡啶基、3-甲基吡啶基、吡啶基甲基、吡嗪基、4-三氟甲基吡嗪基、哌嗪基、3-甲基哌嗪基、哌啶基、哌啶基甲基。
本发明还提供一种上述手性或消旋的嘧啶并二氮杂环庚酮类化合物的制备方法，具体为 以嘧啶类烯丙基化合物中间体为原料，以铱化合物与亚膦酰胺配体作用生成的铱配合物作为催化剂，在碱的作用下，反应得到所述手性或消旋的嘧啶并二氮杂环庚酮类化合物。
Figure PCTCN2022092681-appb-000002
本发明方法中，所述嘧啶类烯丙基化合物中间体的结构式如式(S)所示，其中，LG是
Figure PCTCN2022092681-appb-000003
优选的，式(S)的R 5中，卤素取代的C1-C20的烷基中的卤素为氟、氯、溴或碘。进一步的，卤素取代的C1-C20的烷基为三氯甲基。
优选的，式(S)的R 6中，取代的芳基的取代基为C1-C20的烷基、卤素或C1-C20的烃氧基中一种或一种以上的组合。所述的芳基为C6-C20的芳基。
优选的，式(S)的R 5和R 6中，所述C1-C20的烷基分别独立选自甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。所述C1-C20的烃氧基分别独立选自甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基或苄氧基。
所述的取代基可以为一个或多个，当取代基为多个时，所述的取代基可以相同或不同。
进一步的，所述嘧啶类烯丙基化合物中间体(S)，可由包括以下步骤方法制备得到：2,4-二氯-6-取代-嘧啶-5-羧酸甲酯类化合物和胺类化合物反应生成2-氯-4-取代胺基-6-取代-嘧啶-5-羧酸甲酯类化合物，通过常规的亲核取代反应或Suzuki等偶联反应引入基团R 1，然后水解生成羧基类化合物，进而与
Figure PCTCN2022092681-appb-000004
反应得到式S化合物。化合物S作为底物进一步进行催化反应，得到产物I。反应方程式如下所示：
Figure PCTCN2022092681-appb-000005
反应式(二)
所述2,4-二氯-6-取代-嘧啶-5-羧酸甲酯类化合物可为2,4-二氯-嘧啶-5-羧酸甲酯、2,4-二氯-6-羟基-嘧啶-5-羧酸甲酯、2,4-二氯-6-氰基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苯基-嘧啶-5-羧酸甲 酯、2,4-二氯-6-苯甲酰基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苄基-嘧啶-5-羧酸甲酯、2,4-二氯-6-氨基-嘧啶-5-羧酸甲酯、2,4-二氯-6-乙基-嘧啶-5-羧酸甲酯、2,4-二氯-6-甲磺酰基-嘧啶-5-羧酸甲酯、2,4-二氯-6-苯甲氧基-嘧啶-5-羧酸甲酯、2,4-二氯-6-三苯基硅基-嘧啶-5-羧酸甲酯、2,4-二氯-6-二乙氨基-嘧啶-5-羧酸甲酯、2,4-二氯-6-羧基-嘧啶-5-羧酸甲酯、2,4-二氯-6-N-甲基哌嗪-嘧啶-5-羧酸甲酯等；基团R 2可由市售品直接带入或由2,4,6-三氯-嘧啶-5-羧酸甲酯经常规的亲核取代反应、Suzuki等偶联反应或Grignard反应等引入，得到化合物1。
本发明方法中，所述的碱可以是有机碱，也可以是无机碱，如可为三乙胺、4-二甲氨基吡啶、1,8-二氮杂二环[5,4,0]十一碳-7-烯、1,5-二氮杂二环[4,3,0]壬-5-烯、三乙烯二胺、N,O-双(三甲基硅基)乙酰胺、碳酸铯、碳酸钾、碳酸锂、氟化钾、氢化钠、氟化铯、磷酸钾、醋酸钾、磷酸钠、醋酸钠、醋酸锂、正丁基锂、二(三甲基硅基)氨基钠、二(三甲基硅基)氨基锂、二(三甲基硅基)氨基钾、甲醇钠、乙醇钠、异丙醇钠、质子海绵、叔丁醇锂、叔丁醇钾、叔丁醇钠或者二异丙基乙基胺。
进一步的，所述的碱和三氟磺酸银、氯化锂或分子筛添加剂组合加入反应体系中。
本发明方法中，所述嘧啶类烯丙基化合物中间体、铱化合物的铱原子、亚膦酰胺配体、碱的摩尔比为1：(0.005-0.1)：(0.005-0.2)：(0.05-3)。
本发明方法中，所述反应可在0-120℃下进行。所述反应的时间可为20min-24h。
本发明方法中，所述的铱化合物可为[Ir(COD)Cl] 2、[Ir(dncot)Cl] 2、[Ir(OMe)(COD)] 2、[Ir(COD) 2]BArF 4、Ir(COD) 2BF 4、[Ir(OH)(COD)] 2、Ir(ppy) 3、[Ir(COD) 2]SbF 6等中的至少一种。
本发明中，所述的亚膦酰胺配体参照CN109336887A中的亚膦酰胺配体，详见说明书【0076】段。
本发明方法中，所述反应后产物可通过硅胶短柱纯化得到手性嘧啶并二氮杂环庚酮类化合物及其对映体或消旋体。
本发明方法中，所述反应在有机溶剂体系中进行。所述有机溶剂可以为极性溶剂或非极性溶剂。优选的，所述的有机溶剂可为芳烃类溶剂或取代芳烃类溶剂、卤代烃类溶剂、醚类溶剂、酰胺类溶剂、烷烃类溶剂、环烷烃类溶剂、腈类溶剂、二甲亚砜和醇类溶剂中的一种或一种以上的组合。进一步的，所述的芳烃类溶剂或取代芳烃类溶剂优选为甲苯、二甲苯、乙苯、异丙苯、氯苯和硝基苯中的至少一种；所述的卤代烃类溶剂优选为二氯甲烷、1,2-二氯乙烷和三氯甲烷中的至少一种；所述的醚类溶剂优选为四氢呋喃、乙醚、乙二醇二甲醚、甲基叔丁基醚、1,4-二氧六环中的至少一种；所述的酰胺类溶剂优选为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N,N-二甲基丙酰胺、α-吡咯烷酮、N-甲基吡咯烷酮中的至少一种；所述的烷烃类溶剂优选为正己烷、正戊烷和正庚烷中的至少一种；所述的环烷烃类溶剂优选为环戊烷、环己烷和环庚烷中的至少一种；所述的腈类溶剂优选为乙腈；所述的醇类溶剂优选为甲醇、乙醇、异丙醇、正丙醇和叔丁醇中的至少一种。
本发明制备方法可包括如下具体步骤：
(1)以2,4-二氯-5-嘧啶甲酸乙酯类化合物1和胺类化合物2为起始原料，N,N-二异丙基乙胺为碱，经亲核取代反应得到化合物3；
(2)化合物3与硼酸化合物、胺类化合物或醇钠类化合物，在无水溶剂中和碱存在条件下，经常规的Suzuki等偶联反应或亲核取代反应，得到多种不同取代的化合物4；
(3)化合物4在水中，在碱存在下，发生水解反应得到化合物5；
(4)化合物5在1-羟基苯并三唑(HOBt)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸 盐(EDCI)作用下，与化合物6缩合，得到嘧啶类烯丙基化合物中间体(S)，作为下一步烯丙基胺化催化反应的底物；
(5)在有机碱或无机碱存在的条件下、铱化合物和亚磷酰胺配体形成的金属铱配合物，在有机溶剂中催化底物S发生分子内的烯丙基胺化反应得到式(I)所示的化合物。
步骤(1)中，化合物1和化合物2的摩尔比可为1:1-1:1.2；反应温度可为50℃–100℃，反应时间可为1-6h。
步骤(2)中，化合物3与硼酸化合物、胺类化合物或醇钠类化合物、碱的摩尔比可为1:(1-2):(1-2):(1-3)；反应温度可为20℃-130℃，反应时间可为30min-4h。
步骤(3)中，化合物4与碱的摩尔比可为1:1-1:3；反应温度可为20℃-100℃，反应时间可为10min–2h；所述的碱可为氢氧化钠、氢氧化钾或氢氧化锂等。
步骤(4)中，化合物5、化合物6、HOBt、EDCI的摩尔比可为1:1:(1-2):(1-2)；反应温度可为0-80℃；反应时间可为1-10h；所述反应在溶剂中进行，如二氯甲烷、四氢呋喃、二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜。
步骤(5)中，底物S、铱、配体、碱的摩尔比可为1:(0.005-0.1):(0.005-0.2):(0.05--3)；反应温度可为0-70℃；反应时间可为3min-24h。
本发明制备方法以铱-亚磷酰胺配体配合物为催化剂，尤其是以铱-手性桥连亚膦酰胺配体配合物为催化剂时，通过嘧啶类烯丙基碳酸酯底物的精心设计、合成，经分子内烯丙基胺化反应高效率、高对映选择性地合成嘧啶并二氮杂环庚酮类化合物的方法；其对映体由相反构型的配体制备相应的催化剂，进行类似的分子内烯丙基胺化催化反应得到；其消旋体则由消旋的配体制备相应的催化剂，进行类似的分子内烯丙基胺化催化反应得到。
本发明还提供上述手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐在制备预防或治疗抑郁症的药物或其先导化合物中的应用。
本发明相对于现有技术，具有如下的优点及有益效果：
本发明提供了一种有效的以铱-亚磷酰胺配体配合物作为催化剂，由精心设计合成的嘧啶类烯丙基底物经分子内烯丙基催化胺化反应，高效率、高区域选择性和高对映选择性地合成新型手性嘧啶并二氮杂环庚酮类化合物的策略和方法，可制备得到多种手性嘧啶并二氮杂环庚酮类化合物。
同时，本发明还对构建的手性或消旋的嘧啶并二氮杂环庚酮类化合物进行了初步体外抗抑郁活性评价。结果显示：本发明化合物对GR、cofilin-1和NF-κB蛋白具有较好的抑制作用，且可逆转抑郁状态下皮质酮导致的PC12细胞的凋亡，表明本发明的嘧啶并二氮杂环庚酮化合物具有较好的抗抑郁活性。
与现有方法相比，本发明制备方法可适用于多种不同类型的嘧啶类烯丙基化合物，其催化活性高、反应条件温和、底物适用范围广、操作简便，且反应产率好(高达99％)，对映选择性高(高达99％ee)。这种运用催化不对称分子内烯丙基胺化反应、高效构建手性嘧啶并二氮杂环庚酮类化合物的方法和由此合成得到的相应的此类化合物目前国内外尚无文献报道。
本发明既丰富了桥连亚磷酰胺配体及其它类型亚膦酰胺配体的应用，同时也拓宽了烯丙基化反应底物的适用范围，为新药研发提供了新颖的手性杂环分子结构和高效构建新方法。
附图说明
图1为实施例3中制备的化合物I-9的单晶结构图。
图2为本发明化合物抗抑郁作用浓度和时间的关系图。其中，B中采用的浓度为0.625uM， C、D中采用的浓度为1.0uM。
图3为本发明化合物对GR、cofilin-1和NF-κB蛋白过度表达的抑制作用。其中，A、B中采用的浓度为0.625uM，C、D中采用的浓度为1.0uM。
图4为不同手性构型化合物抗抑郁作用的效果。其中，A中采用的浓度为1.0uM，B、C、D中采用的浓度为0.625uM。
图5为本发明化合物对利血平诱导的小鼠抑郁模型实验。其中，A为小鼠悬尾实验；B为小鼠强迫游泳实验；C为小鼠糖水偏好实验；D为小鼠开放旷场实验；E为单次给药的小鼠悬尾实验；F为单次给药的小鼠强迫游泳实验。
具体实施方式
下面结合实施例对本发明作进一步详细的描述，但本发明的实施方式不限于此。下列实施例中涉及的物料若无特殊说明均可从商业渠道获得。所述方法若无特别说明均为常规方法。各组分用量以摩尔体积份计，mol、L。
实施例1：嘧啶类烯丙基化合物(S)的制备
Figure PCTCN2022092681-appb-000006
以2,4-二氯-5-嘧啶甲酸乙酯类化合物1(1.0当量)和胺类化合物2(1.05当量)为起始原料，N,N-二异丙基乙胺(2.0当量)为碱，乙腈为溶剂，于80℃搅拌反应，经亲核取代反应得到化合物3；化合物3与硼酸化合物(2.0当量)、胺类化合物(1.2当量)或醇钠类化合物(3.0当量)，在无水溶剂中和碱存在条件下，经常规的Suzuki等偶联反应或亲核取代反应，得到化合物4；化合物4在甲醇溶剂中，氢氧化钠(1.0mol/L)存在下，发生水解反应得到化合物5；用DMF将化合物5溶解，然后分别加入1-羟基苯并三唑(HOBt，1.1当量)和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐(EDCI，1.1当量)，于室温搅拌反应30min，再将化合物6(1.1当量)加入反应液中，继续室温搅拌反应，原料反应完全后，将反应液倒入冰水中，然后用乙酸乙酯萃取，有机相减压浓缩，粗品经柱层析纯化得到嘧啶类烯丙基中间体S。
产物嘧啶类烯丙基中间体S：
Figure PCTCN2022092681-appb-000007
Figure PCTCN2022092681-appb-000008
S1：(E)-4-(N-苄基-2-吗啉基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，0.93g，产率90％。 1H NMR(400MHz,CDCl 3)δ9.55(s,1H),8.15(s,1H),7.67–7.54(m,2H),7.40–7.28(m,5H),7.28–7.23(m,1H),7.12–7.04(m,1H),5.92–5.82(m,1H),5.78–5.68(m,1H),4.71(s,2H),4.65(dd,J＝5.8,1.2Hz,2H),4.04(d,J＝5.6Hz,2H),3.86–3.77(m,7H),3.76–3.70(m,4H). 13C NMR(100MHz,CDCl 3)δ170.51,160.79,159.61,156.55,155.53,138.76,136.42,129.76,128.95,128.95,128.69,128.69,128.69,127.69,127.40,127.37,123.31,121.23,121.23,100.02,67.34,66.80,66.80,54.91,50.58,48.65,44.30,44.30.HRMS(ESI)calcd for C 28H 31N 5O 5[M+H] +:518.2398,found:518.2393.
S2：(E)-4-(N-苄基-2-吗啉基-4-(4-三氟甲基苯胺基)嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，1.08g，产率93％。 1H NMR(400MHz,CDCl 3)δ9.89(s,1H),8.19(s,1H),7.72(d,J＝8.1Hz,2H),7.59(d,J＝8.5Hz,2H),7.41–7.34(m,2H),7.33–7.23(m,3H),5.93–5.82(m,1H),5.80–5.64(m,1H),4.71(s,2H),4.65(dd,J＝5.8,1.2Hz,2H),4.05(d,J＝5.5Hz,2H),3.85–3.80(m,4H),3.79(s,3H),3.78–3.71(m,4H). 13C NMR(100MHz,CDCl 3)δ169.25,159.63,158.46,155.81,154.47,140.99,135.26,128.49,127.91,127.91,126.67,126.49, 126.31,126.31,124.87,124.87,123.48(q,J＝32.8Hz),121.99,119.36,119.36,99.18,66.21,65.64,65.64,53.78,49.55,47.68,43.29,43.29. 19F NMR(376MHz,CDCl 3)δ-61.74.HRMS(ESI)calcd for C 29H 30F 3N 5O 5[M+H] +:586.2272,found:586.2265.
S3：(E)-4-(N-苄基-4-(4-甲氧基苯胺基)-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，0.93g，产率85％。 1H NMR(400MHz,CDCl 3)δ9.37(s,1H),8.12(s,1H),7.50–7.44(m,2H),7.39–7.33(m,2H),7.33–7.28(m,1H),7.28–7.23(m,2H),7.05–6.82(m,2H),5.94–5.82(m,1H),5.78–5.68(m,1H),4.70(s,2H),4.68–4.63(m,2H),4.04(d,J＝5.6Hz,2H),3.82(s,3H),3.79(s,3H),3.79–3.74(m,4H),3.74–3.68(m,4H). 13C NMR(101MHz,CDCl 3)δ170.58,160.79,159.70,156.41,155.86,155.52,136.47,131.79,129.82,129.82,128.92,128.92,127.65,127.39,127.31,123.09,123.09,113.85,113.85,99.71,67.34,66.79,66.79,55.48,54.89,50.63,48.65,44.23,44.23.HRMS(ESI)calcd for C 29H 33N 5O 6[M+H] +:548.2504,found:548.2508.
S4：(E)-4-(N-苄基-4-(3,5-二三氟甲基苯胺基)-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，1.04g，产率80％. 1H NMR(400MHz,CDCl 3)δ10.14(s,1H),8.25(s,1H),8.18(s,2H),7.55(s,1H),7.43–7.36(m,2H),7.35–7.24(m,3H),5.98–5.85(m,1H),5.84–5.69(m,1H),4.74(s,2H),4.68(dd,J＝5.8,1.3Hz,2H),4.08(d,J＝5.6Hz,2H),3.87–3.81(m,4H),3.80(s,3H),3.79–3.71(m,4H). 13C NMR(101MHz,CDCl 3)δ169.95,160.36,159.37,157.15,155.45,140.36,136.25,131.62(q,J＝33.1Hz),129.31,128.85,127.65,127.29,124.75,122.04,120.61(q,J＝4.2Hz),119.33,115.75,115.71,115.68,115.64,115.60,100.09,67.10,67.10,66.48,54.62,50.10,48.70,44.31,44.31. 19F NMR(376MHz,CDCl 3)δ-63.09.HRMS(ESI)calcd for C 30H 29F 6N 5O 5[M+H] +:654.2146,found:654.2130.
S5：(E)-4-(N-苄基-2-吗啉基-4-丙胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.79g，产率82％. 1H NMR(400MHz,CDCl 3)δ8.00(s,1H),7.39–7.32(m,2H),7.32–7.20(m,4H),5.90–5.79(m,1H),5.76–5.64(m,1H),4.74–4.60(m,4H),4.01(d,J＝5.3Hz,2H),3.86–3.78(m,7H),3.76–3.70(m,4H),3.46–3.34(m,2H),1.71–1.59(m,2H),0.99(t,J＝7.4Hz,3H). 13C NMR(101MHz,CDCl 3)δ170.51,161.59,160.85,155.50,155.40,136.73,129.98,128.71,128.71,127.41,127.31,127.31,126.97,99.56,67.24,66.69,66.69,54.68,50.81,48.41,44.06,44.06,42.15,22.44,11.60.HRMS(ESI)calcd for C 25H 33N 5O 5[M+H] +:484.2554,found:484.2546.
S6：(E)-4-(N-苄基-4-异丙胺基-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.82g，产率85％. 1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.99(s,1H),7.40–7.30(m,2H),7.26–7.16(m,2H),7.03(d,J＝7.2Hz,1H),5.83(dt,J＝16.0,5.6Hz,1H),5.69(dt,J＝15.9,6.1Hz,1H),4.69–4.55(m,4H),4.24(h,J＝6.6Hz,1H),3.99(d,J＝5.7Hz,2H),3.83–3.68(m,11H),1.24(d,J＝6.5Hz,6H). 13C NMR(101MHz,CDCl 3)δ170.59,160.90,160.71,155.61,155.47,136.68,130.06,128.79,128.79,127.50,127.34,127.34,127.02,99.58,67.32,66.78,66.78,54.81,54.76,50.44,48.46,44.11,44.11,42.03,22.53.HRMS(ESI)calcd for C 25H 33N 5O 5[M+H] +:484.2554,found:484.2559.
S7：(E)-4-(N-苄基-4-环己胺基-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.90g，产率86％. 1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.38–7.27(m,3H),7.24–7.19(m,2H),7.11(d,J＝7.5Hz,1H),5.88–5.78(m,1H),5.74–5.62(m,1H),4.71–4.56(m,4H),3.98(d,J＝5.6Hz,2H),3.96–3.88(m,1H),3.80(s,3H),3.79–3.75(m,4H),3.75–3.69(m,4H),2.09–1.89(m,2H),1.80–1.68(m,2H),1.66–1.55(m,1H),1.47–1.16 (m,5H). 13C NMR(101MHz,CDCl 3)δ170.42,160.83,160.58,155.60,155.31,136.80,129.95,128.60,128.60,127.30,127.27,127.27,126.93,99.48,67.13,66.58,66.58,54.51,50.27,48.66,48.42,44.00,44.00,32.41,32.41,25.69,25.49,24.59.HRMS(ESI)calcd for C 28H 37N 5O 5[M+H] +:524.2867,found:524.2853.
S8：(E)-4-(N-苄基-4-苄基-2-吗啉基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.93g，产率88％. 1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.63(t,J＝5.7Hz,1H),7.38–7.28(m,5H),7.26–7.17(m,5H),5.90–5.78(m,1H),5.74–5.62(m,1H),4.69–4.54(m,4H),3.99(d,J＝5.6Hz,3H),3.80(s,2H),3.78–3.72(m,4H),3.69(q,J＝4.7Hz,4H). 13C NMR(101MHz,CDCl 3)δ170.29,161.52,160.82,155.77,155.42,139.45,136.90,129.98,128.73,128.43,128.43,127.42,127.39,127.35,127.35,127.33,127.33,127.05,126.94,99.84,67.23,66.57,66.57,54.62,50.33,48.47,44.24,44.11,44.11.HRMS(ESI)calcd for C 29H 33N 5O 5[M+H] +:532.2554,found:532.2544.
S9：(E)-4-(N-苄基-2-甲氧基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.87g，产率94％. 1H NMR(400MHz,CDCl 3)δ9.42(s,1H),8.24(s,1H),7.70–7.60(m,2H),7.40–7.32(m,5H),7.30–7.22(m,2H),7.12(ddt,J＝8.5,7.0,1.2Hz,1H),5.92–5.81(m,1H),5.80–5.69(m,1H),4.71(s,2H),4.68–4.60(m,2H),4.06(d,J＝5.5Hz,2H),3.97(s,3H),3.79(s,3H). 13C NMR(101MHz,CDCl 3)δ169.49,165.46,160.80,157.09,155.51,138.09,135.99,129.20,129.05,129.05,128.87,128.87,128.41,127.89,127.74,123.99,121.33,121.33,104.39,67.20,63.88,54.99,54.94,50.46,48.85.HRMS(ESI)calcd for C 25H 26N 4O 5[M+H]+:463.1976,found:463.1964.
S10：(E)-4-(N-苄基-2-甲基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.84g，产率95％. 1H NMR(400MHz,CDCl 3)δ8.99(s,1H),8.29(s,1H),7.68(d,J＝8.0Hz,2H),7.42–7.30(m,4H),7.28–7.20(m,2H),7.11(t,J＝7.4Hz,1H),5.85(dt,J＝15.9,5.5Hz,1H),5.74(dt,J＝15.6,5.7Hz,1H),4.71(s,2H),4.64(d,J＝5.4Hz,2H),4.05(d,J＝5.4Hz,2H),3.79(s,3H),2.57(s,3H). 13C NMR(101MHz,CDCl 3)δ168.71,168.56,162.24,158.12,155.26,153.97,138.52,136.12,128.94,128.76,128.76,128.61,128.61,127.62,127.62,123.41,120.92,120.92,108.01,66.94,54.57,35.97,31.00,26.02.HRMS(ESI)calcd for C 25H 26N 4O 4[M+H] +:447.2027,found:447.2031.
S11：(E)-4-(N-苄基-2-(4-甲基-1-哌嗪基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，1.02g，产率96％. 1H NMR(400MHz,CDCl 3)δ9.56(s,1H),8.14(s,1H),7.63–7.56(m,2H),7.40–7.30(m,5H),7.30–7.23(m,2H),7.11–7.04(m,1H),5.93–5.82(m,1H),5.79–5.65(m,1H),4.70(s,2H),4.65(dd,J＝5.8,1.3Hz,2H),4.04(d,J＝5.6Hz,2H),3.87(t,J＝5.1Hz,4H),3.79(s,3H),2.48(t,J＝5.0Hz,4H),2.35(s,3H). 13C NMR(101MHz,CDCl 3)δ170.59,160.64,159.58,156.63,155.50,138.89,136.48,129.81,128.91,128.91,128.65,128.65,127.64,127.40,127.40,127.32,127.32,123.15,121.12,121.12,99.68,67.31,54.89,54.86,50.57,48.67,46.15,43.77,43.77.HRMS(ESI)calcd for C 29H 34N 6O 4[M+H] +:531.2714,found:531.2710.
S12：(E)-4-(N-苄基-4-苯胺基-2-四氢吡咯基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
白色油状物，0.95g，产率95％. 1H NMR(400MHz,CDCl 3)δ9.57(s,1H),8.08(s,1H),7.76–7.62(m,2H),7.32–7.12(m,7H),6.99–6.91(m,1H),5.88–5.73(m,1H),5.71–5.55(m,1H),4.62(s,2H),4.56(dd,J＝5.9,1.3Hz,2H),3.95(d,J＝5.6Hz,2H),3.69(s,3H),3.60–3.46(m,4H),1.93–1.83(m,4H). 13C NMR(101MHz,CDCl 3)δ170.93,159.32,159.23,156.45,155.52,139.30,136.50,129.88,128.91,128.91,128.62,128.62,127.62,127.42,127.42,127.27, 122.78,120.65,120.65,99.05,67.38,54.88,50.58,48.68,47.07,46.52,25.58,25.30.HRMS(ESI)calcd for C 28H 31N 5O 4[M+H] +:502.2449,found:502.2447.
S13：(E)-4-(N-苄基-2-苯基-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.93g，产率92％. 1H NMR(400MHz,CDCl 3)δ9.13(s,1H),8.48(s,1H),8.42–8.34(m,2H),7.79–7.71(m,2H),7.47(dd,J＝5.8,1.7Hz,3H),7.45–7.39(m,3H),7.39–7.34(m,2H),7.34–7.26(m,3H),7.18–7.12(m,1H),5.88(dt,J＝15.7,5.5Hz,1H),5.77(dt,J＝15.6,5.7Hz,1H),4.76(s,2H),4.66(dd,J＝5.7,1.2Hz,2H),4.16–4.02(m,2H),3.79(s,3H). 13C NMR(101MHz,CDCl 3)δ169.06,164.65,158.74,155.52,154.66,138.56,137.44,136.08,131.19,129.12,129.05,129.05,128.92,128.65,128.56,127.91,127.83,123.82,121.32,121.32,108.45,77.80,77.48,77.16,67.20,67.20,60.38,54.90,54.90,53.69.HRMS(ESI)calcd for C 30H 28N 4O 4[M+H] +:509.2183,found:509.2171.
S14：(E)-4-(N-苄基-2-(1-萘基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.98g，产率88％. 1H NMR(400MHz,CDCl 3)δ9.18(s,1H),8.86–8.79(m,1H),8.58(s,1H),8.13(dd,J＝7.2,1.3Hz,1H),7.96(d,J＝8.1Hz,1H),7.92–7.87(m,1H),7.77–7.71(m,2H),7.59–7.53(m,1H),7.52–7.46(m,2H),7.42–7.36(m,2H),7.36–7.28(m,5H),7.13–7.06(m,1H),5.98–5.85(m,1H),5.85–5.76(m,1H),4.80(s,2H),4.68(dd,J＝5.6,1.3Hz,2H),4.15(d,J＝5.3Hz,2H),3.80(s,3H). 13C NMR(101MHz,CDCl 3)δ169.14,167.21,158.66,155.54,154.22,138.44,135.57,134.12,131.05,130.92,129.59,129.12,129.12,129.04,128.94,128.94,128.70,128.44,128.00,127.96,127.53,126.67,126.36,125.87,125.12,124.19,123.85,121.23,121.23,107.94,67.19,62.54,54.97.HRMS(ESI)calcd for C 34H 30N 4O 4[M+H] +:559.2340,found:559.2337.
S15：(E)-4-(N-苄基-4-苯胺基-2-(3,4,5-三甲氧基苯基)嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡棕色油状物，1.08g，产率90％. 1H NMR(400MHz,CDCl 3)δ9.10(s,1H),8.46(s,1H),8.01(s,2H),7.79–7.66(m,3H),7.38(m,3H),7.35–7.28(m,2H),7.17–7.10(m,1H),5.89(dt,J＝15.9,5.5Hz,1H),5.77(dt,J＝15.6,5.7Hz,1H),4.76(s,2H),4.69–4.62(m,2H),4.14–4.08(m,2H),3.94(s,6H),3.91(s,3H),3.80(s,3H). 13C NMR(101MHz,CDCl 3)δ168.91,163.78,163.76,162.48,158.44,155.41,154.53,153.03,153.03,140.69,138.37,135.94,132.50,129.03,128.95,128.95,128.50,128.50,127.82,127.77,123.85,121.58,121.58,108.13,105.53,105.53,67.10,60.79,55.91,55.91,54.81,36.35,31.29.HRMS(ESI)calcd for C 33H 34N 4O 7[M+H] +:599.2500,found:599.2485.
S16：(E)-4-(N-苄基-2-(2-呋喃基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡棕色油状物，0.94g，产率95％. 1H NMR(400MHz,CDCl 3)δ9.21(s,1H),8.43(s,1H),8.01(s,1H),7.75(m,2H),7.61(d,J＝1.8Hz,1H),7.44–7.31(m,4H),7.30–7.20(m,3H),7.14(t,J＝7.4Hz,1H),6.55(dd,J＝3.5,1.7Hz,1H),5.97–5.82(m,1H),5.81–5.66(m,1H),4.73(s,2H),4.65(d,J＝5.5Hz,2H),4.09(d,J＝5.4Hz,2H),3.79(s,3H). 13C NMR(101MHz,CDCl 3)δ162.50,158.47,157.29,155.46,154.58,151.98,145.45,138.36,135.85,129.03,129.03,128.94,128.83,128.83,127.89,127.84,127.33,123.80,121.01,121.01,114.59,112.27,112.27,107.87,67.11,54.88,50.48,48.60.HRMS(ESI)calcd for C 28H 26N 4O 5[M+H] +:499.1976,found:499.1965.
S17：(E)-4-(N-苄基-2-(4-甲氧基-3-吡啶基)-4-苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
透明油状物，1.02g，产率95％. 1H NMR(400MHz,CDCl 3)δ9.18(d,J＝2.3Hz,1H),9.14(s,1H),8.50(dd,J＝8.7,2.4Hz,1H),8.43(s,1H),7.74–7.66(m,2H),7.46–7.35(m,4H),7.35–7.27(m,3H),7.19–7.10(m,1H),6.80(d,J＝8.8Hz,1H),5.93–5.84(m,1H),5.77(dt,J＝15.6,5.7Hz,1H),4.75(s,2H),4.71–4.62(m,2H),4.10(dd,J＝6.5,2.9Hz,2H),4.01(s,3H), 3.80(s,3H). 13C NMR(101MHz,CDCl 3)δ169.08,165.93,163.20,158.66,155.51,154.55,148.59,138.65,138.26,135.91,134.55,129.08,129.08,128.94,128.94,127.96,127.88,127.88,127.47,126.69,123.94,121.34,121.34,110.61,108.10,67.17,62.46,60.41,54.95,53.85.HRMS(ESI)calcd for C 30H 29N 5O 5[M+H] +:540.2241,found:540.2233.
S18：(E)-4-(N-苄基-2,4-二苯胺基嘧啶-5-甲酰胺基)-2-丁烯碳酸甲酯
淡黄色油状物，0.94g，产率90％. 1H NMR(400MHz,CDCl 3)δ9.50(s,1H),8.18(s,1H),7.67–7.57(m,2H),7.56–7.50(m,2H),7.40–7.20(m,9H),7.18–7.10(m,1H),7.08–7.00(m,1H),5.95–5.82(m,1H),5.82–5.64(m,1H),4.72(s,2H),4.64(dd,J＝5.9,1.2Hz,2H),4.06(d,J＝5.6Hz,2H),3.78(s,3H). 13C NMR(101MHz,CDCl 3)δ170.10,160.05,159.69,156.27,155.59,139.26,138.50,136.44,129.61,129.01,129.01,128.78,128.78,128.76,128.76,127.80,127.59,127.52,123.98,123.15,122.27,122.27,120.81,120.81,120.81,101.89,67.33,54.92,50.62,48.86.HRMS(ESI)calcd for C 30H 29N 5O 4[M+H] +:524.2292,found:524.2281.
实施例2
Figure PCTCN2022092681-appb-000009
Lett.2019,21,608.
实施例3
嘧啶类烯丙基中间体(S)作为底物在铱-亚磷酰胺络合物催化下发生分子内烯丙基胺化反应制备手性嘧啶并二氮杂环庚酮类化合物，具体步骤可如下：
在氮气保护下，依次加入铱化合物(0.004摩尔份)、亚磷酰胺配体L1-L9、正丙胺(0.5体积份)和四氢呋喃(1体积份)，50℃条件下搅拌30min，然后冷却至室温，减压除去溶剂，再依次加入底物S(0.2摩尔份)、碱(0.22摩尔份)、有机溶剂(2.0体积份)，于25-80℃下搅拌反应，反应产物经柱层析纯化得到烯丙基胺化产物I。
Figure PCTCN2022092681-appb-000010
Figure PCTCN2022092681-appb-000011
化合物I-1至化合物I-18的制备方法如上，具体反应条件参见表1。图1为实施例3中制备的化合物I-9的单晶结构图。表1中的摩尔比是指底物S:铱:配体:碱的摩尔比。
表1化合物I-1至化合物I-18的反应条件
Figure PCTCN2022092681-appb-000012
Figure PCTCN2022092681-appb-000013
其中，LG是离去基团，Bn是苄基，DIPEA是二异丙基乙基胺，DMAP是4-二甲胺基 吡啶，DABCO是三乙烯二胺，DBU是1,8-二氮杂二环十一碳-7-烯，BSA是N,O-双三甲硅基乙酰胺，DBN是1,5-二氮杂双环[4.3.0]壬-5-烯，Ac代表乙酰基，Boc代表叔丁氧羰基，Piv代表2,2-二甲基丙酰基，Bz代表苯甲酰基，Troc代表2,2,2-三氯乙氧羰基，DME代表乙二醇二甲醚，MTBE代表甲基叔丁基醚。
化合物I-1：(R)-6-苄基-2-吗啉基-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，84mg，产率95％；M.P.：125.4-125.5℃；98％ee；Ee值通过手性色谱柱检测(Daicel Chiralcel IA-3，流动相，n-hexane/2-propanol＝80/20，流速：1mL/min，检测温度：30℃，检测波长：254nm，保留时间：11.084min，14.645min)，[α] D 20＝-27.4°(c＝0.15,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.95(s,1H),7.39–7.27(m,7H),7.26–7.20(m,1H),7.14–7.06(m,2H),5.76(ddd,J＝16.9,10.4,6.4Hz,1H),5.44(d,J＝14.8Hz,1H),5.29–5.08(m,2H),4.56–4.45(m,1H),4.10(d,J＝14.9Hz,1H),3.93(d,J＝15.2Hz,1H),3.69–3.45(m,9H). 13C NMR(101MHz,CDCl 3)δ167.68,164.36,160.75,158.37,145.52,137.21,132.95,129.00,129.00,128.69,128.69,128.33,128.33,127.86,127.86,127.59,126.53,118.84,102.64,66.70,66.70,66.63,52.70,50.20,43.95,43.95.HRMS(ESI)calcd for C 26H 27N 5O 2[M+H] +:442.2238,found:442.2241.
化合物I-2：(S)-6-苄基-2-吗啉基-9-(4-三氟甲基苯基)-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，91mg，产率90％；M.P.：153.0-153.4℃；92％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：11.660min，20.165min)，[α] D 20＝+27.3°(c＝0.15,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.97(s,1H),7.62(d,J＝8.5Hz,2H),7.40–7.26(m,5H),7.28–7.21(m,2H),5.77(ddd,J＝16.9,10.4,6.4Hz,1H),5.41(d,J＝14.8Hz,1H),5.29–5.15(m,2H),4.51(ddt,J＝6.4,5.0,1.4Hz,1H),4.17(d,J＝14.9Hz,1H),3.92(d,J＝15.2Hz,1H),3.62(dd,J＝15.2,6.1Hz,9H). 13C NMR(101MHz,CDCl 3)δ167.39,164.33,160.87,158.36,148.65,137.03,132.84,132.84,128.73,128.73,128.33,128.33,127.69,127.54,127.54,126.02(q,J＝3.8Hz),125.34,122.64,119.18,103.65,66.63,66.63,66.34,52.47,50.11,43.99,43.99. 19F NMR(376MHz,CDCl 3)δ-62.25.HRMS(ESI)calcd for C 27H 26F 3N 5O 2[M+H] +:510.2111,found:510.2103.
化合物I-3：(R)-6-苄基-9-(4-甲氧基苯基)-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，67mg，产率72％；M.P.：189.6-190.4℃；83％ee；Ee值通过手性色谱柱检测(Daicel Chiralcel IF-3，流动相，n-hexane/2-propanol＝75/25，流速：1mL/min，检测温度：30℃，检测波长：254nm，保留时间：31.325min，33.575min)，[α] D 20＝-18.5°(c＝0.10,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.96(s,1H),7.41–7.24(m,5H),7.08–6.98(m,2H),6.93–6.79(m,2H),5.78(ddd,J＝17.0,10.3,6.5Hz,1H),5.46(d,J＝14.8Hz,1H),5.34–5.09(m,2H),4.45(t,J＝5.9Hz,1H),4.11(d,J＝14.9Hz,1H),3.94(d,J＝15.2Hz,1H),3.83(s,3H),3.68–3.41(m,9H). 13C NMR(101MHz,CDCl 3)δ167.73,164.32,160.83,158.53,157.82,138.39,137.24,133.04,132.05,131.93,128.90,128.67,128.67,128.45,128.32,127.57,118.76,114.12,102.56,67.04,66.72,66.72,55.44,52.68,50.16,43.98,43.98.HRMS(ESI)calcd for C 27H 29N 5O 3[M+H] +:472.2343,found:472.2347.
化合物I-4：(R)-6-苄基-9-(3,5-二三氟甲基苯基)-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，95mg，产率82％；M.P.：153.3-153.4℃；89％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：5.540min，10.430min)，[α] D 20 ＝-31.2°(c＝0.20,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.98(s,1H),7.69(s,1H),7.61(d,J＝1.6Hz,2H),7.37–7.27(m,5H),5.73(ddd,J＝16.8,10.4,6.2Hz,1H),5.38–5.14(m,3H),4.56–4.47(m,1H),4.23(d,J＝14.8Hz,1H),3.88(d,J＝15.1Hz,1H),3.71–3.44(m,9H). 13C NMR(101MHz,CDCl 3)δ167.04,164.68,160.68,157.88,146.54,136.89,132.64,132.06(q,J＝33.4Hz),128.77,128.77,128.42,128.42,127.80,127.80,127.30,124.39,121.68,119.54,119.54,119.14,103.87,66.57,66.11,66.11,52.41,50.08,44.00,44.00. 19F NMR(376MHz,CDCl 3)δ-62.93.HRMS(ESI)calcd for C 28H 25F 6N 5O 2[M+H] +:578.1985,found:578.1971.
化合物I-5：(S)-6-苄基-2-吗啉基-9-丙基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，63mg，产率78％。86％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：12.215min，14.187min)，[α] D 20＝+20.5°(c＝0.10,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.85(s,1H),7.50–6.93(m,5H),5.64(ddd,J＝17.1,10.3,5.8Hz,1H),5.36(d,J＝14.9Hz,1H),5.22(d,J＝10.3Hz,1H),5.13(d,J＝17.0Hz,2H),4.12(t,J＝5.4Hz,1H),4.05(d,J＝14.9Hz,1H),3.91–3.77(m,4H),3.81–3.69(m,4H),3.65(d,J＝15.3Hz,1H),3.48(dd,J＝15.3,5.9Hz,1H),3.05(ddd,J＝13.6,9.8,5.6Hz,1H),1.78–1.38(m,2H),0.88(t,J＝7.4Hz,3H). 13C NMR(101MHz,CDCl 3)δ167.98,163.74,161.31,157.48,137.25,132.78,128.63,128.63,128.26,128.26,127.51,118.18,102.73,66.86,66.86,64.08,52.47,51.63,49.53,44.30,44.30,20.23,11.56.HRMS(ESI)calcd for C 23H 29N 5O 2[M+H] +:408.2402,found:408.2401.
化合物I-6：(R)-6-苄基-9-异丙基-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，46mg，产率56％。80％ee；(流动相，n-hexane/2-propanol＝85/15，其他参数同化合物I-1，保留时间：12.218min，19.029min)，[α] D 20＝-13.4°(c＝0.12,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.92(s,1H),7.52–6.94(m,5H),5.73–5.60(m,1H),4.88–4.35(m,4H),3.89–3.68(m,4H),3.62–3.53(m,4H),3.32–3.24(m,1H),3.10–3.03(m,1H),2.02–1.94(m,2H),1.36(d,J＝6.7Hz,6H). 13C NMR(101MHz,CDCl 3)δ169.30,160.04,159.13,156.68,136.77,128.75,128.75,128.60,128.51,127.48,127.32,127.32,99.70,67.08,66.84,66.84,53.88,53.83,48.92,44.08,44.08,22.50,22.50.HRMS(ESI)calcd for C 23H 29N 5O 2[M+H] +:408.2394,found:408.2387.
化合物I-7：(S)-6-苄基-9-环己基-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，74mg，产率83％。84％ee；(其他参数同化合物I-1，保留时间：13.320min，16.457min)，[α] D 20＝-12.6°(c＝0.10,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ7.99(s,1H),7.43–6.87(m,5H),5.87–5.56(m,1H),4.93–4.47(m,4H),4.02–3.86(m,3H),3.81–3.59(m,8H),3.21–3.06(m,1H),2.07–1.96(m,2H),1.83–1.48(m,3H),1.46–1.14(m,5H). 13C NMR(101MHz,CDCl 3)δ170.64,161.00,160.68,155.69,136.80,128.79,128.79,128.63,128.55,127.50,127.45,127.45,99.74,66.87,66.87,66.87,64.25,48.95,44.14,44.14,42.80,32.64,32.64,25.81,24.81,24.81.HRMS(ESI)calcd for C 26H 33N 5O 2[M+H] +:448.2716,found:448.2714.
化合物I-8：(R)-6,9-二苄基-2-吗啉基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：淡黄色油状物，90mg，产率88％。90％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-3，保留时间：15.127min，22.066min)，[α] D 20＝-21.2°(c＝0.12,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ8.89(s,1H),7.39–7.14(m,10H),5.77–5.62(m,2H),5.40(d,J＝14.9Hz, 1H),5.29(d,J＝10.2Hz,1H),5.18(d,J＝17.1Hz,1H),4.09–4.03(m,1H),4.02(d,J＝4.2Hz,1H),3.98(d,J＝4.9Hz,1H),3.80–3.69(m,4H),3.68–3.58(m,5H),3.41(dd,J＝15.4,5.8Hz,1H). 13C NMR(101MHz,CDCl 3)δ167.79,163.68,161.08,157.97,137.76,137.14,132.39,128.65,128.65,128.65,128.64,128.64,128.30,128.30,127.56,127.26,127.26,118.73,102.66,66.74,66.74,62.82,52.43,51.35,49.34,44.36,44.36.HRMS(ESI)calcd for C 27H 29N 5O 2[M+H] +:456.2394,found:456.2394.
化合物I-9：(R)-6-苄基-2-甲氧基-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，71mg，产率92％；M.P.：136.7-136.9℃.96％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝75/25，检测温度：25℃，其他参数同化合物I-1，保留时间：10.080min，12.555min)，[α] D 20＝-22.1°(c＝0.12,CHCl 3)。 1H NMR(400MHz,CDCl 3)δ9.08(s,1H),7.44–7.34(m,4H),7.34–7.27(m,4H),7.17–7.11(m,2H),5.77(ddd,J＝16.9,10.3,6.4Hz,1H),5.46(d,J＝14.8Hz,1H),5.31–5.12(m,2H),4.60–4.53(m,1H),4.14(d,J＝14.8Hz,1H),3.96(d,J＝15.4Hz,1H),3.65(dd,J＝15.4,6.0Hz,1H),3.57(s,3H). 13C NMR(101MHz,CDCl 3)δ166.99,166.05,165.45,159.25,144.81,136.81,132.23,129.31,129.31,128.77,128.77,128.40,128.40,127.77,127.71,127.71,127.07,119.26,106.48,67.06,54.40,52.88,49.97.HRMS(ESI)calcd for C 23H 22N 4O 2[M+H] +:387.1816,found:387.1805.
化合物I-10：(S)-6-苄基-2-甲基-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，58mg，产率78％。M.P.：152.8-153.0℃。84％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：11.343min，15.262min)，[α] D 20＝+18.4°(c＝0.12,CHCl 3). 1H NMR(400MHz,CDCl 3)δ9.08(s,1H),7.42–7.23(m,8H),7.13–7.06(m,2H),5.72(ddd,J＝16.8,10.4,6.2Hz,1H),5.43(d,J＝14.8Hz,1H),5.28–5.09(m,2H),4.62–4.56(m,1H),4.13(d,J＝14.8Hz,1H),3.91(d,J＝15.4Hz,1H),3.62(dd,J＝15.4,6.1Hz,1H),2.35(s,3H). 13C NMR(101MHz,CDCl 3)δ169.05,167.27,162.40,157.62,145.00,136.67,132.34,129.25,129.25,128.79,128.79,128.42,128.42,127.83,127.44,127.44,126.68,119.20,109.72,67.05,52.89,49.91,25.94.HRMS(ESI)calcd for C 23H 22N 4O[M+H] +:371.1866,found:371.1861.
化合物I-11：(S)-6-苄基-2-(4-甲基-1-哌嗪基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，71mg，产率78％；M.P.：187.3-188.1℃。79％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝70/30，检测温度：25℃，其他参数同化合物I-1，保留时间：10.481min，14.420min)，[α] D 20＝+21.2°(c＝0.12,CHCl 3). 1H NMR(400MHz,CDCl 3)δ8.94(s,1H),7.38–7.27(m,7H),7.25–7.20(m,1H),7.13–7.07(m,2H),5.76(ddd,J＝16.9,10.4,6.4Hz,1H),5.44(d,J＝14.9Hz,1H),5.25–5.11(m,2H),4.55–4.46(m,1H),4.10(d,J＝14.9Hz,1H),3.93(d,J＝15.2Hz,1H),3.80–3.15(m,5H),2.35–2.10(s,7H). 13C NMR(101MHz,CDCl 3)δ167.75,164.36,160.62,158.38,145.60,137.26,133.04,128.95,128.95,128.67,128.67,128.31,128.31,127.86,127.86,127.56,126.41,118.78,102.32,66.57,54.81,54.81,52.65,50.21,46.17,43.38,43.38.HRMS(ESI)calcd for C 27H 30N 6O[M+H] +:455.2554,found:455.2562.
化合物I-12：(S)-6-苄基-9-苯基-2-(1-四氢吡咯基)-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，70mg，产率82％；M.P.：153.8-154.3℃。90％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-1，保留时间：11.038min，15.181min)，[α] D 20 ＝-20.4°(c＝0.16,CHCl 3). 1H NMR(400MHz,CDCl 3)δ8.98(s,1H),7.40–7.29(m,7H),7.27–7.22(m,1H),7.15–7.09(m,2H),5.78(ddd,J＝16.9,10.3,6.4Hz,1H),5.46(d,J＝14.8Hz,1H),5.27–5.14(m,2H),4.56–4.47(m,1H),4.13(d,J＝14.9Hz,1H),3.96(d,J＝15.2Hz,1H),3.69–3.36(m,9H). 13C NMR(101MHz,CDCl 3)δ166.57,163.19,159.59,157.29,144.45,136.15,131.86,127.94,127.94,127.61,127.61,127.25,127.25,126.77,126.52,125.48,117.73,101.58,65.59,65.53,51.64,49.14,42.89,42.89,28.62,28.62.HRMS(ESI)calcd for C 26H 27N 5O[M+H] +:426.2288,found:426.2272.
化合物I-13：(R)-6-苄基-2,9-二苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，53mg，产率62％；M.P.：212.7-213.6℃。76％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-6，保留时间：25.880min，28.153min)，[α] D 20＝-25.4°(c＝0.12,CHCl 3). 1H NMR(400MHz,CDCl 3)δ9.29(s,1H),8.10–7.96(m,2H),7.50–7.43(m,2H),7.43–7.30(m,9H),7.25–7.18(m,2H),5.80(ddd,J＝16.8,10.4,6.2Hz,1H),5.49(d,J＝14.8Hz,1H),5.35–5.20(m,2H),4.68(td,J＝6.1,1.2Hz,1H),4.20(d,J＝14.9Hz,1H),4.02(d,J＝15.4Hz,1H),3.70(dd,J＝15.5,6.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ167.19,164.35,163.03,157.71,145.05,137.08,136.70,132.42,130.90,129.35,129.35,128.83,128.83,128.47,128.47,128.47,128.29,128.29,127.86,127.74,127.74,126.93,119.25,119.25,110.05,66.96,52.98,49.99.HRMS(ESI)calcd for C 28H 24N 4O[M+H] +:433.2023,found:433.2022.
化合物I-14：(S)-6-苄基-2-(1-萘基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，84mg，产率88％；M.P.：227.2-227.4℃。86％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-3，保留时间：21.740min，25.554min)，[α] D 20＝+24.4°(c＝0.15,CHCl 3). 1H NMR(400MHz,CDCl 3)δ9.35(s,1H),8.56–8.46(m,1H),8.23(dd,J＝7.4,1.3Hz,1H),7.85(d,J＝8.1Hz,1H),7.76(d,J＝8.3,1H),7.50–7.40(m,3H),7.40–7.27(m,7H),7.24–7.19(m,2H),7.18–7.10(m,1H),5.81(ddd,J＝16.9,10.3,6.5Hz,1H),5.51(d,J＝14.7Hz,1H),5.33–5.17(m,2H),4.70–4.51(m,1H),4.17(d,J＝14.8Hz,1H),4.04(d,J＝15.4Hz,1H),3.67(dd,J＝15.4,5.8Hz,1H). 13C NMR(101MHz,CDCl 3)δ167.24,166.78,162.59,157.94,145.21,136.69,134.11,134.03,132.44,131.37,131.18,130.47,129.67,129.67,128.86,128.86,128.47,128.47,128.22,128.12,128.12,127.89,127.18,126.42,126.31,125.45,125.00,119.42,109.66,67.42,52.97,49.94.HRMS(ESI)calcd for C 32H 26N 4O[M+H] +:483.2179,found:483.2174.
化合物I-15：(S)-6-苄基-9-苯基-2-(3,4,5-三甲氧基苯基)-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，85mg，产率82％；M.P.:115.0–115.4℃。87％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝65/35，其他参数同化合物I-3，保留时间：14.863min，17.718min)，[α] D 20＝+31.3°(c＝0.20,CHCl 3). 1H NMR(400MHz,CDCl 3)δ9.24(s,1H),7.43(m,2H),7.39–7.28(m,8H),7.24–7.17(m,2H),5.79(ddd,J＝16.8,10.3,6.3Hz,1H),5.47(d,J＝14.7Hz,1H),5.34–5.15(m,2H),4.65(t,J＝5.9Hz,1H),4.17(d,J＝14.8Hz,1H),4.01(d,J＝15.4Hz,1H),3.84(s,3H),3.73(s,6H),3.71–3.64(m,1H). 13C NMR(101MHz,CDCl 3)δ167.14,163.54,163.03,157.53,152.91,152.91,145.31,140.49,136.67,132.42,132.22,129.31,129.31,128.82,128.82,128.47,128.47,128.23,128.23,127.86,126.71,119.30,109.46,105.32,105.32,66.86,60.85,55.93,55.93,53.00,49.99.HRMS(ESI)calcd for C 31H 30N 4O 4[M+H] +:523.2340,found:523.2326.
化合物I-16：(R)-6-苄基-2-(2-呋喃基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，71mg，产率84％；M.P.：178.5-178.6℃。92％ee；Ee值通过手性色谱柱检测(其他参数同化合物I-8，保留时间：26.611min，29.809min)，[α] D 20＝-42.3°(c＝0.20,CHCl 3). 1H NMR(400MHz,CDCl 3)δ9.25(s,1H),7.53(m,1H),7.44(m,2H),7.41–7.31(m,6H),7.22–7.15(m,2H),6.71(dd,J＝3.4,0.9Hz,1H),6.41(dd,J＝3.5,1.7Hz,1H),5.78(ddd,J＝16.8,10.4,6.2Hz,1H),5.46(d,J＝14.8Hz,1H),5.31–5.17(m,2H),4.70–4.61(m,1H),4.19(d,J＝14.8Hz,1H),4.00(d,J＝15.4Hz,1H),3.69(dd,J＝15.4,5.9Hz,1H). 13C NMR(101MHz,CDCl 3)δ166.90,163.10,157.71,157.34,151.87,145.20,144.80,136.63,132.34,129.25,129.25,128.82,128.82,128.49,128.49,127.87,127.64,127.64,126.91,119.31,114.34,112.04,109.95,66.96,52.99,49.91.HRMS(ESI)calcd for C 26H 22N 4O 2[M+H] +:423.1816,found:423.1814.
化合物I-17：(S)-6-苄基-2-(4-甲氧基-3-吡啶基)-9-苯基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，74mg，产率80％；M.P.：158.5-159.3℃。85％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝80/20，其他参数同化合物I-3，保留时间：10.868min，13.600min)，[α] D 20＝+23.4°(c＝0.12,CHCl 3). 1H NMR(400MHz,CDCl 3)δ9.22(s,1H),8.74(d,J＝2.3Hz,1H),8.18(dd,J＝8.7,2.4Hz,1H),7.43(t,J＝7.7Hz,2H),7.38–7.27(m,6H),7.21–7.10(m,2H),6.66(d,J＝8.7Hz,1H),5.77(ddd,J＝16.8,10.4,6.3Hz,1H),5.46(d,J＝14.8Hz,1H),5.36–5.12(m,2H),4.73–4.56(m,1H),4.16(d,J＝14.8Hz,1H),3.99(d,J＝15.4Hz,1H),3.93(s,3H),3.67(dd,J＝15.4,6.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ167.12,165.77,162.98,157.63,148.50,144.91,138.59,136.65,132.33,129.45,129.45,128.82,128.82,128.45,128.45,127.86,127.65,127.65,127.13,126.46,119.32,110.32,109.90,67.07,53.75,52.96,49.95,29.72.HRMS(ESI)calcd for C 28H 25N 5O 2[M+H] +:464.2081,found:464.2072.
化合物I-18：(R)-6-苄基-9-苯基-2-苯胺基-8-乙烯基-6,7,8,9-四氢-5H-嘧啶并[4,5-e][1,4]二氮杂卓-5-酮：白色固体，76mg，产率86％；M.P.：232.1-232.3℃。88％ee；Ee值通过手性色谱柱检测(流动相，n-hexane/2-propanol＝70/30，其他参数同化合物I-1，保留时间：7.127min，12.460min)，[α] D 20＝-36.4°(c＝0.10,CHCl 3). 1H NMR(400MHz,CDCl3)δ8.99(s,1H),7.52–7.46(m,2H),7.44–7.38(m,1H),7.38–7.28(m,5H),7.22–7.10(m,3H),7.01–6.89(m,4H),6.86–6.79(m,1H),5.81(ddd,J＝17.0,10.3,6.6Hz,1H),5.48(d,J＝14.8Hz,1H),5.30–5.07(m,2H),4.53(t,J＝6.2Hz,1H),4.10(d,J＝14.8Hz,1H),4.00(d,J＝15.3Hz,1H),3.63(dd,J＝15.3,5.8Hz,1H). 13C NMR(101MHz,CDCl 3)δ167.38,164.09,159.04,159.01,145.72,139.26,137.09,132.56,129.85,129.85,128.75,128.75,128.50,128.50,128.46,128.46,128.39,128.39,127.69,127.05,121.86,119.18,118.26,118.26,103.79,67.13,52.86,50.09.HRMS(ESI)calcd for C 28H 25N 5O[M+H] +:448.2132,found:448.2120.
实施例4：根据前述底物合成方法、实施例3及合成化合物I-1的反应条件，制备具体化合物I-19至化合物I-38，结果如表2所示：
表2化合物I-19至化合物I-38的收率及对映体过量值
Figure PCTCN2022092681-appb-000014
Figure PCTCN2022092681-appb-000015
实施例5：嘧啶并二氮杂环庚酮类化合物的抗抑郁活性评价
(1)细胞培养及抑郁模型的建立
PC12细胞购于Procell Life Science&Technology Co.，Ltd.(武汉，中国)。所有细胞培养试剂均购于Life Technologies(Grand Island，Nebraska,USA)。细胞在含有10％胎牛血清(Gibco，USA)的Dulbecco’s modified Eagle’s medium(Gibco，USA)中，并在37℃，含有5％CO 2培养箱中培养。
皮质酮(corticosterone，CORT)诱导PC12细胞通常用于在体外建立抑郁模型。PC12细胞用600μM皮质酮处理24小时，在此皮质酮浓度下，细胞活力降低至60％，进而可用于随后的体外实验。
(2)细胞活力(Cell Viability)测定
使用MTT[3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-溴化四唑]测定细胞活力。具体步骤：将1×10 5个细胞接种到96孔板的每个孔中，培养24小时以稳定化后，加入600μM皮质酮处理24小时，再将含皮质酮的培养基倒掉，分别加入含不同浓度药物(本发明化合物/氟西汀)的培养基，分别处理12、24和48小时，再加入MTT在37℃下孵育4小时，在酶标仪(BIO-RAD，USA)中测量570nm处的吸光度，结果见图2和表3。表3为药物浓度为0.625uM时培养24h的细胞活力结果。
(3)蛋白质印迹法
将PC12细胞在含有1％苯基甲基磺酰氟(PMSF)的RIPA裂解液中，在冰上裂解30分钟后后，收取上清溶液后离心，并使用BCA测定试剂盒(Beyotime，碧云天，上海)测定上清液蛋白质浓度。将蛋白质样品上样至10％SDS-聚丙烯酰胺凝胶电泳，然后进一步转移至PVDF膜上(Millipore,MA,USA)。将膜用5％脱脂奶封闭，然后与单独的一抗在4℃下孵育过夜。用Tris-buffered saline-tween 20(TBST)洗涤后，在室温下将PVDF膜与二抗孵育。用ECL试剂(Beyotime，上海)并使用BIO-RAD ChemiDoc XRS系统进行了分析。利用好Image J软件(The National Institutes of Health,Bethesda,MD,USA)进行光密度分析。结果见图3。
(4)Hoechst和PI染色
Hoechst和PI染色法检测PC12细胞凋亡。Hoechst可与活细胞的细胞核结合，而PI(碘化丙啶)可以与死细胞的细胞核结合。将它们铺在12孔板中，药物处理48小时后，用核染料Hoechst对细胞进行染色。简而言之，将细胞用PBS洗2遍后，并继续在培养箱中与10mg/L的Hoechst孵育20分钟。对PI染色，在4℃下与含有PI(终浓度1μg/mL)工作溶液在室温下孵育10分钟。使用荧光显微镜(Zeiss,Germany)观察细胞并拍照，结果见图2和图3。蓝色荧光(白底)表示为活细胞，红色荧光(黑底)表述为死细胞。
(5)结果分析：
表3嘧啶并二氮杂环庚酮类化合物抗抑郁活性的测定结果
Figure PCTCN2022092681-appb-000016
Figure PCTCN2022092681-appb-000017
备注：a采用浓度为0.625uM，数值为三次独立实验的平均值；b为皮质酮；c为阳性对照药。
本发明采用MTT法测定了不同药物浓度(20uM、10uM、5uM、2.5uM、1.25uM和0.625uM)在不同时间(12h、24h和48h)时的细胞存活率，结果见图2。其中，正常细胞作为空白对照(Control)，皮质酮处理组(CORT)为对照组，DMSO+control为溶剂对照组。图2A为培养12h后不同浓度药物作用的结果；图2B为药物浓度为0.625uM时不同培养时间下作用的结果。由图可见，皮质酮导致PC12细胞存活率降低至60％左右，而添加本发明化合物(S)-I-11和阳性药物氟西汀均可有效降低CORT导致细胞的死亡率，且本发明化合物作用效果相对于阳性药物氟西汀更显著，趋向于正常细胞。此外，由图2B可见，阳性药物氟西汀需要48h才发挥其作用，而本发明化合物(S)-I-11在12h就显示了优异的作用效果(图2A和图2B)。
Hoechst和PI法结果表明，皮质酮导致PC12细胞死亡，从而表现为蓝色荧光数减少和红色荧光数增加，而化合物(S)-I-11与氟西汀作用相似可减少细胞的死亡，表现为可使蓝色荧光数增加并且使红色荧光数减少(图2C和图2D，采用的浓度为1.0uM)。
抑郁症发病机制与HPA轴亢进、突触重塑和炎症有关。其中，GR、cofilin-1和NF-κB在抑郁症发病中起着关键作用。结果表明，实施例中化合物(S)-I-17和(R)-I-9表现出与氟西汀相同的作用，可促进抑郁时GR的表达，抑制cofilin-1和NF-κB蛋白的过度表达(图3A和图3B)；而且化合物(S)-I-17和(R)-I-9可逆转皮质酮导致的PC12细胞的大量凋亡(图3C和图3D)。这些结果进一步证明了化合物(S)-I-17和(R)-I-9在体外具有良好的抗抑郁活性。
此外由图4可见，化合物(S)-I-10结构蓝色荧光数量高于(R)-I-9，红色荧光数量低于(R)-I-9(图4A)；并且与(R)-I-9相比，(S)-I-9可更好地增加PC12存活率(图4B)。(S)-I-14和(S)-I-13与其对应的消旋体比可更好地增加存活率(图4C和图4D)。这些结果表明，(S)-构型化合物嘧啶并氮杂酮类化合物比(R)-构型及其对应的外消旋体可能具有更好的抗抑郁作用。
结合表3及附图表明，本发明的嘧啶并二氮杂环庚酮化合物具有较好的抗抑郁作用，甚至部分化合物抗抑郁活性优于阳性对照药氟西汀的效果；并且本发明中引入烯丙基片段 的化合物抗抑郁活性明显优于不含烯丙基片段的化合物。
实施例6：嘧啶并二氮杂环庚酮类化合物的小鼠抑郁模型实验
采用利血平0.4mg/kg腹腔注射小鼠14天诱导慢性抑郁模型。采用悬尾实验(TST)、强迫游泳实验(FST)、糖水偏好实验(SWP)和开放旷场实验(OFT)来作为抑郁程度的评判标准。慢性抑郁模型建立后，以氟西汀(Fluoxetine)为阳性对照药，采用本发明的化合物治疗14天，确定本发明化合物的抗抑郁效果；采用单次给药探究化合物的起效时间。
实验步骤
悬尾实验(TST)：用胶带固定小鼠尾部末端约1cm处，将其悬挂。用摄像机记录小鼠6min内的活动情况，统计分析后4min内小鼠不动时间。
强迫游泳实验(FST)；将小鼠单独置于水深15cm的玻璃缸内(高20cm，直径14cm)，水温(25±1)℃，游泳6min，观察记录后4min内小鼠在水中累计不动时间。
糖水偏好实验(SWP)：啮齿类动物天生对甜食有强烈的喜好，给小鼠提供可自由选择蔗糖溶液和普通水的两个饮水装置时，计算24h糖水消耗。糖水偏好指数％＝糖水消耗量/(糖水消耗量+纯水消耗量)×100％。
开放旷场实验(OFT)：实验在安静的环境下进行。将动物放入40×40cm的箱内底面中心，视频行为分析系统观察和记录受试小鼠在旷场试验箱内15min活动情况。
图5为本发明化合物对利血平诱导的小鼠抑郁模型实验。其中，A为小鼠悬尾实验；B为小鼠强迫游泳实验；C为小鼠糖水偏好实验；D为小鼠开放旷场实验；E为单次给药的小鼠悬尾实验；F为单次给药的小鼠强迫游泳实验。
其中，以正常无抑郁症小鼠为空白对比(control)，抑郁症无给药小鼠为对照组(图5A-图5D中表述为“-”；图5E和图5F中表述为“depression”)。
结果表明：相比于患病对照组，本发明的嘧啶并二氮杂环庚酮类化合物可显著降低抑郁小鼠悬尾的不动时间(图5A)和强迫游泳的不动时间(图5B)，并恢复小鼠对糖的喜好(图5C)，增加小鼠在中央区的移动距离(图5D)，从而趋向于正常小鼠，与阳性药物氟西汀的影响趋势一致，且效果比阳性药物氟西汀的更显著，表明本发明化合物较阳性药物氟西汀具有更优异的抗抑郁效果。
再，由图5E和图5F可见，本发明的嘧啶并二氮杂环庚酮类化合物在给药24h后即可产生明显的抗抑郁作用，使小鼠行为趋向于正常小鼠(图5E)，明显优于氟西汀的起效时间；且效果可持续144h(图5F)，表明本发明化合物的抗抑郁作用药效迅速且持久。
综合以上结果表明：本发明的嘧啶并二氮杂环庚酮类化合物具有优异、快速起效的抗抑郁作用且药效持久。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 一种手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式如式(I)所示，其中，用*标注的碳原子为手性碳原子，其构型为R、S或R/S，所述嘧啶并二氮杂环庚酮类化合物为左旋体、右旋体或消旋体；
    Figure PCTCN2022092681-appb-100001
    其中，R 1、R 2分别独立选自氢、卤素原子、羟基、羧基、氰基、硝基、C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的芳基亚甲基、取代或未取代的芳基；
    R 3、R 4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基、取代或未取代的C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、取代或未取代的杂环基亚甲基或杂环芳基亚甲基、取代或未取代C1-C20的烃氧羰基、取代或未取代的芳基酰基、取代的芳基磺酰基、取代或未取代的芳基、取代或未取代芳基亚甲基。
  2. 根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于：R 1、R 2中，所述C1-C20的直链或支链烷基、C1-C20的氟代烷基、C2-C20的烯基、C2-C20的炔基、C1-C20的烃氧基、C3-C20的环烷基、C1-C20的酰胺基、C2-C20的酮羰基、C1-C20的磺酰基、C1-C9的烷基硅基、苯基硅基、氨基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基中的一个或一个以上氢原子被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代；
    R 3、R 4中，所述C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的烯丙基、C3-C20的炔丙基、C1-C20的酰基、C1-C20的磺酰基中的一个或一个以上氢原子被氟原子、氯原子、溴原子、氧原子、烯基、炔基、芳基、羟基、氨基、羰基、羧基、酯基、氰基、甲基、乙基、甲氧基、硝基取代。
  3. 根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)；
    其中，R 1、R 2分别独立选自氢、氟、氯、溴、碘、羟基、羧基、氰基、硝基、甲基、 乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、苄基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、苄氧基、氨基、C1-C20的酰胺基、三甲基硅基、三乙基硅基、三苯基硅基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、C1-C20的N-烷基取代胺基、C1-C20的N,N-二烷基取代胺基、C2-C20的酮羰基、C1-C20的磺酰基、取代或未取代的芳基；所述取代的芳基中的取代基为C1-C20的烷基、卤素或C1-C20的烃氧基中的一种或一种以上的组合；
    R 3、R 4分别独立选自氢、C1-C20的直链或支链烷基、C3-C20的环烷基、C3-C20的环烷基亚甲基、C3-C20的含N、O和S中的一种或一种以上的杂环基或杂环芳基、杂环基亚甲基或杂环芳基亚甲基、烯丙基、炔丙基、乙酰基、苯甲酰基、C1-C20的磺酰基、叔丁氧羰基、芴甲氧羰基、2,2,2-三氯乙氧羰基、取代或未取代的芳基、取代或未取代的芳基亚甲基、取代或未取代的苯磺酰基；其中，上述取代的取代基分别独立选自氢、C1-C20的烷基、C1-C20的氟代烷基、卤素、硝基或C1-C20的烃氧基中的一种或一种以上的组合。
  4. 根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)：
    其中，R 1、R 2分别独立选自氢、氟、氯、溴、碘、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、羟基、羧基、氰基、环戊基、环己基、氨基、甲胺基、乙胺基、二乙基胺基、二异丙基胺基、三甲基硅基、三乙基硅基、三苯基硅基、乙酰胺基、乙酰基、三氟乙酰基、苯基、苯胺基、苯甲酰基、3,4,5-三甲氧基苯基、苄基、4-二甲氨基苄基、苄氧基、甲磺酰基、苯磺酰基、萘基、吗啉基、吡咯基、四氢吡咯基、1-哌嗪基、1-甲基哌嗪基、吡啶基、4-甲基吡啶基、甲氧基吡啶基、呋喃基、哌啶基、4-羟甲基-3,5-二甲基哌啶基、噻吩基、噁唑基。
  5. 根据权利要求1所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐，其特征在于结构式为具有嘧啶并二氮杂环庚酮骨架结构的式(I)：
    其中，R 3、R 4分别独立选自氢、甲基、乙基、正丙基、异丙基、环己基、环戊基甲基、烯丙基、炔丙基、羰基、乙氧羰基、叔丁氧羰基、三氯乙氧甲酰基、苯甲酰基、4-溴苯甲酰基、9-亚芴基甲氧甲酰基、3-氟-4-(烯丙基酰胺基)苯基、磺酰基、甲苯磺酰基、苯基、4-甲氧基苯基、4-(三氟甲基)苯基、3,5-双(三氟甲基)苯基、苄基、对氟苄基、4-二甲氨基苄基、4-甲氧基苄基、2-四氢吡喃基、4-(三氟甲基)苄基、3,5-双(三氟甲基)苄基、嘧啶基、4-氟嘧啶基甲基、4-氯嘧啶基甲基、吡咯并嘧啶基、吗啉基、吡啶基、3-甲基吡啶基、吡啶基甲基、吡嗪基、4-三氟甲基吡嗪基、哌嗪基、3-甲基哌嗪基、哌啶基、哌啶基甲基。
  6. 一种权利要求1-5任一项所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物的制备方法，其特征在于具体为以嘧啶类烯丙基化合物中间体为原料，以铱化合物与亚膦酰胺配体作用生成的铱配合物作为催化剂，在碱的作用下，反应得到所述手性或消旋的嘧啶并二氮杂环庚酮类化合物。
  7. 根据权利要求6所述的制备方法，其特征在于：所述嘧啶类烯丙基化合物中间体的结构式如式(S)所示，
    Figure PCTCN2022092681-appb-100002
    其中，LG是离去基团，为羟基、氯、溴、
    Figure PCTCN2022092681-appb-100003
    M为NH或O；R 5为卤素取代或未取代的C1-C20的烷基、卤素取代或未取代的C1-C20的烃氧基；R 6为C1-C20的烷基、取代或未取代的芳基。
  8. 根据权利要求7所述的制备方法，其特征在于：所述嘧啶类烯丙基化合物中间体，由包括以下步骤方法制备得到：2,4-二氯-6-取代-嘧啶-5-羧酸甲酯类化合物和胺类化合物反应生成2-氯-4-取代胺基-6-取代-嘧啶-5-羧酸甲酯类化合物，通过常规的亲核取代反应或偶联反应引入基团R 1，然后水解生成羧基类化合物，进而与
    Figure PCTCN2022092681-appb-100004
    反应得到式S化合物。
  9. 根据权利要求5所述的制备方法，其特征在于具体包括以下步骤：
    (1)以2,4-二氯-5-嘧啶甲酸乙酯类化合物1和胺类化合物2为起始原料，N,N-二异丙基乙胺为碱，经亲核取代反应得到化合物3；
    (2)化合物3与硼酸化合物、胺类化合物或醇钠类化合物，在无水溶剂中和碱存在条件下，经常规的偶联反应或亲核取代反应，得到多种不同取代的化合物4；
    (3)化合物4在水中，在碱存在下，发生水解反应得到化合物5；
    (4)化合物5在1-羟基苯并三唑和1-乙基-(3-二甲基胺基丙基)碳二亚胺盐酸盐作用下，与化合物6缩合，得到嘧啶类烯丙基化合物中间体，作为下一步烯丙基胺化催化反应的底物；
    (5)在有机碱或无机碱存在的条件下、铱化合物和亚磷酰胺配体形成的金属铱配合物，在有机溶剂中催化底物发生分子内的烯丙基胺化反应得到式(I)所示的化合物。
  10. 权利要求1-5任一项所述的手性或消旋的嘧啶并二氮杂环庚酮类化合物或其药学上可接受的盐在制备预防或治疗抑郁症的药物或其先导化合物中的应用。
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001798A1 (fr) * 1984-09-07 1986-03-27 Mitsui Petrochemical Industries, Ltd. Derives de 2-piperazinopyrimidine et leur procede de preparation
WO2003080619A1 (en) * 2002-03-26 2003-10-02 Kyorin Pharmaceutical Co., Ltd. Fused bicyclic pyrimidine derivatives
WO2005085210A1 (ja) * 2004-03-10 2005-09-15 Ono Pharmaceutical Co., Ltd. ニトリル化合物およびその化合物を有効成分として含有する医薬組成物
WO2010106249A1 (fr) * 2009-03-20 2010-09-23 Les Laboratoires Servier Derives de benzothiadiazepines en tant que modulateures des recepteurs ampa et nmda
WO2010132015A1 (en) * 2009-05-12 2010-11-18 Astrazeneca Ab New compounds modulating gamma-secretase and their use in the treatment of alpha beta related pathologies, such as alzheimer's disease
CN108358893A (zh) * 2018-02-10 2018-08-03 安徽唯诗杨信息科技有限公司 一种一锅法合成四氢化苯并-[1,4]-二氮杂环庚烷衍生物的方法
WO2020089478A1 (en) * 2018-11-02 2020-05-07 Esteve Pharmaceuticals, S.A. New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105968137B (zh) * 2016-05-15 2018-04-06 中山大学 一类含萘并呋喃结构的联芳基单膦配体及其制备方法和应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001798A1 (fr) * 1984-09-07 1986-03-27 Mitsui Petrochemical Industries, Ltd. Derives de 2-piperazinopyrimidine et leur procede de preparation
WO2003080619A1 (en) * 2002-03-26 2003-10-02 Kyorin Pharmaceutical Co., Ltd. Fused bicyclic pyrimidine derivatives
CN1656098A (zh) * 2002-03-26 2005-08-17 杏林制药株式会社 稠合双环嘧啶衍生物
WO2005085210A1 (ja) * 2004-03-10 2005-09-15 Ono Pharmaceutical Co., Ltd. ニトリル化合物およびその化合物を有効成分として含有する医薬組成物
WO2010106249A1 (fr) * 2009-03-20 2010-09-23 Les Laboratoires Servier Derives de benzothiadiazepines en tant que modulateures des recepteurs ampa et nmda
WO2010132015A1 (en) * 2009-05-12 2010-11-18 Astrazeneca Ab New compounds modulating gamma-secretase and their use in the treatment of alpha beta related pathologies, such as alzheimer's disease
CN108358893A (zh) * 2018-02-10 2018-08-03 安徽唯诗杨信息科技有限公司 一种一锅法合成四氢化苯并-[1,4]-二氮杂环庚烷衍生物的方法
WO2020089478A1 (en) * 2018-11-02 2020-05-07 Esteve Pharmaceuticals, S.A. New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIANG XIAODING, BENDU PAN, XU QIAN, HAO LIANG, YAQI ZHANG, BIN CHEN, XIAOBO HE, HOI SHAN CHAN, ALBERT S. C. CHAN, LIQIN QIU: "Enantioselective Construction of Pyrimidine-Fused Diazepinone Derivatives Bearing a Tertiary Stereogenic Center Enabled by Iridium-Catalysed Intramolecular Allylic Substitution", ADVANCED SYNTHESIS AND CATALYSIS, vol. 363, no. 13, 21 May 2021 (2021-05-21), pages 3227 - 3232, XP093005709, DOI: 10.1002/adsc.202100444 *

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