CN112574269A - Purine nucleoside compound and application thereof - Google Patents

Purine nucleoside compound and application thereof Download PDF

Info

Publication number
CN112574269A
CN112574269A CN201910922150.0A CN201910922150A CN112574269A CN 112574269 A CN112574269 A CN 112574269A CN 201910922150 A CN201910922150 A CN 201910922150A CN 112574269 A CN112574269 A CN 112574269A
Authority
CN
China
Prior art keywords
group
radical
alkyl
hydrogen
added
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201910922150.0A
Other languages
Chinese (zh)
Inventor
谢元超
沈敬山
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Materia Medica of CAS
Original Assignee
Shanghai Institute of Materia Medica of CAS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Institute of Materia Medica of CAS filed Critical Shanghai Institute of Materia Medica of CAS
Priority to CN201910922150.0A priority Critical patent/CN112574269A/en
Publication of CN112574269A publication Critical patent/CN112574269A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate

Abstract

The present disclosure provides a purine of formula (I)Nucleoside compounds or pharmaceutically acceptable salts, crystalline hydrates or solvates thereof, pharmaceutical compositions containing the compounds and the use thereof in the preparation of antiviral medicaments. The therapeutically effective amount of the compound of formula (I), or pharmaceutically acceptable salts, crystalline hydrates and solvates thereof or pharmaceutical compositions provided by the invention can be used alone or in combination with one or more other antiviral drugs for the reduction or treatment of viral infections. The antiviral nucleoside provided by the invention has obvious anti-HBV activity and novel structure, and is expected to be developed into a novel nucleoside hepatitis B treatment drug.

Description

Purine nucleoside compound and application thereof
Technical Field
The present disclosure relates to a pharmaceutical compound. Specifically, the disclosure relates to a purine nucleoside compound and application thereof.
Background
Viruses are the smallest and most widespread pathogenic microorganisms that depend on the metabolic system of the host cell for propagation. Currently, hundreds of viruses have been discovered that can infect humans, many of which pose serious threats to human life and health, such as Human Immunodeficiency Virus (HIV), influenza virus (inflenza virus), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), dengue virus, Ebola virus (Ebola virus), Respiratory Syncytial Virus (RSV), middle east respiratory syndrome virus, SARS virus, zika virus, and the like.
Viruses have extremely strong replication capacity and extremely high mutation rate, and many viral infections are difficult to prevent by means of vaccination, so in many cases, antiviral drugs are the most important means for preventing and treating viral infections.
Replication of viral genetic material requires the use of nucleoside or deoxynucleoside triphosphates as substrates. Nucleoside drugs can be converted into the corresponding triphosphate form in organisms, and the triphosphate can be disguised as a substrate to be incorporated into a DNA or RNA chain of a virus in the virus replication stage, so that the replication of genetic materials is inhibited, and the antiviral effect is achieved. Nucleoside drugs have long played an important role in clinical treatment of antiviral infections, but clinically specific drugs are lacking for some high-lethality viruses, such as Ebola virus, Marburg virus, coronavirus (MERS), Respiratory Syncytial Virus (RSV), and the like. Meanwhile, in the treatment of HBV, HIV and HCV with a wide range of influence, the emergence of drug-resistant viruses and the continuous rise of the drug-resistant rate of the viruses make the demand of patients for new-generation drugs more urgent.
According to WHO statistics, more than 2.5 hundred million HBV infected people all over the world still have hepatitis B as one of the most serious epidemic diseases. The nucleoside drugs are used as main treatment means for resisting HBV, and can achieve the purpose of functional cure of part of hepatitis B patients by being used alone or in combination with interferon. Aids is another extremely threatening infectious disease whose pathogen is HIV that specifically destroys the human immune system. In the world, the number of AIDS patients exceeds three thousand five million, and the number of newly-increased infected patients is continuously increased, and the prevention and control situation of AIDS is not optimistic.
Although many of the nucleoside drugs are available on the market, most of them are old drugs, and some problems have occurred clinically, such as large toxic and side effects of the drugs, drug resistance of viruses and the like. So far, no new therapy capable of completely eliminating viruses in patients with hepatitis B or AIDS is found in the clinical research stage, so that in recent years, the anti-HBV and anti-HIV nucleoside medicaments with strong effect, low toxicity and high drug resistance barrier still have wide application prospects.
The nucleoside analogue has high polarity and low oral bioavailability, and needs to be converted into nucleoside triphosphate form in vivo to exert bioactivity, so the medicinal dosage is often higher, and the toxic and side effects of the medicament are obvious after long-term use. In recent years, the application of phosphate prodrug strategies has broken through the bottleneck of nucleoside drug development. The phosphoramidate prodrug (ProTide) can improve the lipid solubility of nucleoside drugs, can bypass the rate-limiting step of monophosphorylation in vivo, and can be efficiently converted into the active form of nucleoside triphosphate, thereby not only improving the drug effect, but also obviously reducing the toxic and side effects.
Disclosure of Invention
An object of the present invention is to provide purine nucleosides represented by general formula (I), pharmaceutically acceptable salts, crystalline hydrates and solvates thereof.
The invention also aims to provide application of the compound with the general formula (I), and pharmaceutically acceptable salts, crystal hydrates and solvates thereof in preparing antiviral drugs.
It is a further object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable inorganic or organic salt, crystalline hydrate and solvate thereof.
The technical scheme of the invention is as follows:
according to one aspect of the present invention, there is provided a compound represented by the following general formula (I), pharmaceutically acceptable salts, crystalline hydrates and solvates thereof:
Figure BDA0002217910480000021
wherein:
a is O, -C ═ CH2Or CX1X2，
When A is O, R1Is selected from C1-6Alkyl, halo C1-6Alkyl, azido C1-6Alkyl, cyano C1-6Alkyl, hydroxy C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl, halo C2-6Alkenyl radical, C2-6Alkynyl, halo C2-6Alkynyl, C3-6Cycloalkyl radical C2-6Alkynyl, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C1-3Alkyl radical C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl, azido, cyano, halogen, -CHR4CH(CH2CH2)；
R2Selected from hydroxyl, fluorine;
R3selected from hydrogen, amino, halogen, R5OCONH-；
Y1Selected from hydrogen,
Figure BDA0002217910480000031
Y2Selected from hydrogen,
Figure BDA0002217910480000032
Figure BDA0002217910480000033
Or Y1And Y2Are connected with each other to form
Figure BDA0002217910480000034
R4Selected from hydroxy, halogen, cyano, azide;
R5is selected from C1-18Alkyl radical, C3-6Cycloalkyl, aryl, heteroaryl;
R6is selected from C1-18Alkyl radical, C3-6A cycloalkyl group;
R7is selected from C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-20Aryl radical, C5-20A heteroaryl group;
R8is selected from C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-20Aryl radical, C5-20A heteroaryl group;
R9is selected from C1-18Alkyl radical, C3-6Cycloalkyl radical, C6-20Aryl radical, C5-20A heteroaryl group;
when A is-C ═ CH2When R is1Selected from hydrogen, hydroxy, amino, C1-6Alkylamino radical, C1-6Alkylamide group, C3-6Cycloalkyl amide group, C6-20Aryl amide group, C1-6Alkyl, halo C1-6Alkyl, azido C1-6Alkyl, cyano C1-6Alkyl, hydroxy C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl, halo C2-6Alkenyl radical, C2-6Alkynyl, halo C2-6Alkynyl, C3-6Cycloalkyl radical C2-6Alkynyl, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C1-3Alkyl radical C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl, azido, cyano, halogen, -CHR4CH(CH2CH2)；
R2Selected from hydrogen, hydroxy, fluorine;
R3、Y1、Y2、R4、R5、R6、R7、R8、R9the definition is the same as that when A is O;
when A is CX1X2When, X1And X2Each independently selected from hydrogen, hydroxy, halogen, azido, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkylcarboxamide radical, C2-6Cycloalkyl carboxamido radical, C6-20Aryl carboxamido radical, C5-20Heteroaryl carboxamido, azido C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, and X1And X2Not being simultaneously hydrogen, or X1And X2Are linked to each other to form- (CH)2)n-, or halogen substituted- (CH)2)n-, wherein n is an integer of 2 to 5, thereby comprising a 5-membered ring of A and X1And X2Together form a spiro ring;
R1selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, azido C1-6Alkyl, cyano C1-6Alkyl, hydroxy C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl, halo C2-6Alkenyl radical, C2-6Alkynyl, halo C2-6Alkynyl, C3-6Cycloalkyl radical C2-6Alkynyl, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C1-3Alkyl radical C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl, azido, cyano, halogen, -CHR4CH(CH2CH2)；
R2Selected from hydrogen, hydroxy, fluorine;
R3、Y1、Y2、R4、R5、R6、R7、R8、R9the definition is the same as that when A is O.
According to an aspect of the present invention, in the compound represented by the general formula (I),
when A is O, R1Selected from the group consisting of methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxymethyl, methoxyethyl, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, vinyl, 2-fluorovinyl, 2, 2-difluorovinyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-fluoroethynyl, 2-methylethynyl, 2-cyclopropylethynyl, vinylmethyl, 3-fluorovinylmethyl, 3-difluorovinylmethyl, trifluoromethyl, and mixtures thereof, Ethynylmethyl, cyclopropyl, 2-difluorocyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, 1-cyclopropyl-1-hydroxymethyl, 1-cyclopropyl-1-fluoromethyl, azido, fluoro, cyano; r2Selected from hydroxyl, fluorine;
R3selected from hydrogen, amino, halogen;
Y1selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure BDA0002217910480000041
Y2Selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure BDA0002217910480000042
Figure BDA0002217910480000043
Or Y1And Y2Are connected with each other to form
Figure BDA0002217910480000051
R7Is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R8is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R9is selected from C2-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl radical, C5-10A heteroaryl group;
when A is-C ═ CH2When R is1Selected from the group consisting of hydrogen, hydroxy, fluoro, azido, amino, methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxymethyl, methoxyethyl, methylamino, acetylamino, cyclopropylamino, benzamido, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, vinyl, 2-fluorovinyl, 2, 2-difluorovinyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-fluoroethynyl, 2-methylethynyl, 2-cyclopropylethynyl, methyl, fluoromethylethynyl, methyl, trifluoromethyl, methyl, 2-azido, 2-methyl, 2-cyanoethyl, vinylmethyl, 3-fluorovinylmethyl, 3-difluorovinylmethyl, ethynylmethyl, cyclopropyl, 2-difluorocyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, 1-cyclopropyl-1-hydroxymethyl, 1-cyclopropyl-1-fluoromethyl, azido, fluoro, cyano;
R2selected from hydrogen, hydroxy, fluorine;
R3selected from hydrogen, amino, halogen;
Y1selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure BDA0002217910480000052
Y2Selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure BDA0002217910480000053
Figure BDA0002217910480000054
Or Y1And Y2Are connected with each other to form
Figure BDA0002217910480000055
R7Is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R8is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R9is selected from C2-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl radical, C5-10A heteroaryl group;
when A is CX1X2When, X1And X2Each independently selected from hydrogen, hydroxy, fluoro, azido, amino, methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxy, ethoxy, methylamino, acetylamino, cyclopropylamino, benzamido, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, methoxymethyl, methoxyethyl, vinyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-methylethynyl, but not both simultaneously hydrogen, or X1And X2Are linked to each other to form-CH2CH2-，-CF2CH2-or-CH2CH2CH2-, thereby containing the 5-membered ring of A and X1And X2Together form a spiro ring;
R1selected from the group consisting of hydrogen, hydroxy, fluoro, azido, amino, methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxymethyl, methoxyethyl, methylamino, acetylamino, cyclopropylamino, benzamido, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, vinyl, vinylmethyl, 3-fluorovinylmethyl, 3-difluorovinylmethyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-fluoroethynyl, 2-methylacetylenyl, methyl, ethyl, trifluoromethyl, methyl-ethyl, 3, 2-cyclopropylethynyl, vinylmethyl, 3-fluorovinylmethyl, 3-difluorovinylmethyl, alkynylmethA group selected from the group consisting of cyclopropyl, 2-difluorocyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, 1-cyclopropyl-1-hydroxymethyl, 1-cyclopropyl-1-fluoromethyl, azido, fluoro, cyano;
R2selected from hydrogen, hydroxy, fluorine;
R3selected from hydrogen, amino, halogen;
Y1selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure BDA0002217910480000061
Y2Selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure BDA0002217910480000062
Figure BDA0002217910480000063
Or Y1And Y2Are connected with each other to form
Figure BDA0002217910480000064
R7Is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R8is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R9is selected from C2-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl radical, C5-10A heteroaryl group.
According to another aspect of the invention, in the compounds of formula I,
a is O.
According to another aspect of the invention, in the compounds of formula I,
a is-C ═ CH2。
According to another aspect of the invention, in the compounds of formula I,
a is-CX1X2。
Further preferably, the compound in formula I has the following structure:
Figure BDA0002217910480000071
Figure BDA0002217910480000081
Figure BDA0002217910480000091
Figure BDA0002217910480000101
Figure BDA0002217910480000111
Figure BDA0002217910480000121
Figure BDA0002217910480000131
Figure BDA0002217910480000141
Figure BDA0002217910480000151
Figure BDA0002217910480000161
Figure BDA0002217910480000171
in the present invention, each term is defined as follows:
halogen substituted C1-6Alkyl means that the hydrogen atoms of a straight-chain or branched saturated hydrocarbon radical having from 1 to 6 carbon atoms are replaced by 1 or more identical or different halogen atoms, e.g. -CH2F、-CHF2、-CF3、-CH2Cl、-CH2CH2F、-CHFCH3、-CH2Br、-CH2CH2Cl、-CH2CF3；
Azido C1-6Alkyl means that the azido group is bound to one carbon atom of a straight-chain or branched-chain alkyl group containing 1 to 6 carbon atoms, e.g. -CH2N3、-CH3CH2N3、-CH(CH3)N3Etc.;
cyano group C1-6Alkyl means that the cyano group is attached to one carbon atom of a straight-chain or branched alkyl group containing 1 to 6 carbon atoms, e.g. -CH2CN、-CH3CH2CN、-CH(CH3) CN and the like;
hydroxy radical C1-6Alkyl means that the hydroxy group is bound to one carbon atom of a straight-chain or branched alkyl group containing 1 to 6 carbon atoms, e.g. -CH2OH、-CH3CH2OH、-CH(CH3) OH and the like;
methoxy group C1-6The alkyl group being a methoxy group bound to one carbon atom of a straight-chain or branched alkyl group containing 1 to 6 carbon atoms, e.g. -CH2OCH3、-CH3CH2OCH3、-CH(CH3)OCH3Etc.;
C2-6alkenyl means straight-chain or branched alkenyl having 2 to 6 carbon atoms and a double bond, e.g. -CH ═ CH2、-CH2-CH＝CH2、-CH＝CHCH3、-C(CH3)＝CH2、-CH＝CHCH(CH3)2、-CH2CH2CH＝C(CH3)2Etc.;
C2-6alkynyl means a straight-chain or branched alkynyl group containing 2 to 6 carbon atoms and a triple bond, such as-C.ident.CH, -CH2-C≡CH、-C≡CCH3、-C≡CCH(CH3)2、-CH2CH2-C≡CCH3Etc.;
halogen substituted C2-6Alkenyl means straight-chain or branched alkenyl having 2 to 6 carbon atoms in which the hydrogen atom is replaced by 1 or more identical or different halogen atoms, e.g. -CH ═ CHF, -CF2-CH＝CH2、-CH＝CF2、-CH＝CHCH2Cl、-CH＝CHCF3、-CH2-CH＝CHF、-CH2-CH＝CF2Etc.;
halogen substituted C2-6Alkynyl means that the hydrogen atoms of a straight-chain or branched alkynyl group containing 2 to 6 carbon atoms are replaced by 1 or more identical or different halogen atoms, such as-C.ident.CF, -CF2-C≡CH、-C≡CCH2Cl、-C≡CCF3、-CH2CH2-C ≡ CF etc.;
C3-6cycloalkyl radical C2-6Alkynyl means a straight or branched chain alkynyl group containing 2 to 6 carbon atoms, having 1 hydrogen atom substituted by 1C3-6Cycloalkyl substituents, e.g. -C.ident.CCH (CH)2CH2)、-C≡CCH2CH(CH2CH2) Etc.;
halogen substituted C3-6Cycloalkyl means that the hydrogen atoms of a cyclic saturated hydrocarbon radical containing from 3 to 6 carbon atoms are replaced by 1 or more identical or different halogen atoms, such as-CH (CH)2CF2)、-CH(CH2CHF)、-CH(CH2CCl2) Etc.;
C1-3alkyl radical C3-6Cycloalkyl means a cycloalkyl group containing 3 to 6 carbon atoms, wherein 1 hydrogen atom is replaced by 1C1-3Alkyl substitution, e.g. -C (CH)3)(CH2CH2)、-C(CH2CH3)(CH2CH2)、-CH(CH2CH(CH3) Etc.);
C3-6cycloalkyl radical C1-3Alkyl means a straight or branched chain alkyl group containing 1 to 3 carbon atoms, having 1 hydrogen atom substituted by 1C3-6CycloalkanesRadicals substituted, e.g. by-CH2CH(CH2CH2)、-CH2CH2CH(CH2CH2)、-CH(CH3)CH(CH2CH2) And the like.
According to still another aspect of the present invention, the present invention also provides the use of the compound represented by the general formula (I) according to the present invention, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof for the preparation of antiviral drugs. Preferably, the virus is hepatitis B virus, human immunodeficiency virus, influenza virus; more preferably, the virus is hepatitis B virus, human immunodeficiency virus.
According to a further aspect of the present invention, there is also provided a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of formula (I), a pharmaceutically acceptable inorganic or organic salt, a crystalline hydrate and a solvate thereof, which composition may optionally comprise a pharmaceutically acceptable carrier or excipient.
Advantageous effects
The therapeutically effective amount of the compound of formula (I), or pharmaceutically acceptable salts, crystalline hydrates and solvates thereof or pharmaceutical compositions provided by the invention can be used alone or in combination with one or more other antiviral drugs for the reduction or treatment of viral infections. The antiviral nucleoside provided by the invention has obvious anti-HBV activity and novel structure, and is expected to be developed into a novel nucleoside hepatitis B treatment drug.
Detailed Description
The present invention will be further described with reference to the following examples, but is not limited thereto.
Example 1
Figure BDA0002217910480000191
Intermediate 1-1 synthesis: the literature references report methods (Nucleotides, Nucleotides Nucleic Acids 2001,20(8): 1583-1598; Nucleotides, Nucleotides&nucleic acids2009,28 (5):657-677) synthesized this intermediate. Product obtained 1H NMR (400MHz, CDCl)3)δ8.09-8.16(m,4H),7.64(t,J＝7.8Hz,1H),7.57(t,J＝7.8Hz,1H),7.51(t,J＝7.8Hz,2H),7.44(t,J＝7.8Hz,2H),5.95(dd,J＝17.2,7.4Hz,1H),5.27(ddd,J＝52.6,7.4,4.5Hz,1H),5.06(d,J＝4.5Hz,1H),4.60(d,J＝11.5Hz,1H),4.50(d,J＝11.5Hz,1H),3.46(s,3H),1.37(s,3H).
Synthesis of intermediates 1-2: intermediate 1-1(500mg, 1.3mmol) was dissolved in dichloromethane (10mL), acetic acid (618mg, 10.2 mmol) and acetic anhydride (783mg, 7.7mmol) were added, stirred under ice bath, concentrated sulfuric acid (256mg,2.6mmol) was added, and after 10min, the mixture was returned to room temperature and stirred. After the reaction, dichloromethane and water were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous layer was extracted once with dichloromethane, and the dichloromethane layers were combined. The extract was washed with saturated sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated to be used in the next step.
Synthesis of intermediates 1 to 3: the product from the previous step was dissolved in dichloromethane (10mL), iced, HBr/AcOH solution (1.3mL, 33%) was added and stirred overnight at 25 deg.C, the next day TLC showed the starting material was essentially complete. To the reaction solution were added dichloromethane and water, the organic layer was separated, the aqueous layer was extracted once with dichloromethane, the organic phases were combined, and the organic phase was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give a pale yellow oil (445 mg).
Synthesis of intermediates 1 to 4: potassium tert-butoxide (400mg, 3.5mmol) was added to a mixed solution of tert-butanol and acetonitrile (15mL, 1:1), followed by addition of 6-chloro-2-aminopurine (340mg, 2.0mmol), and after stirring for 30min, intermediate 1-3(436mg, 1.0mmol) was added and reacted at 60 ℃ until the reaction was complete. The reaction mixture was added with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain a product (273 mg). The resulting product ESI-MS M/z 526.2[ M + H ]]+。
Synthesis of intermediates 1-5 2-4(210mg, 0.4mmol) was dissolved in methanolic ammonia (15mL) and stirred at room temperature for 1h, TLC indicated complete reaction of starting material. Acetic acid was added to make the reaction solution neutral, the solvent was distilled off, and column chromatography was performed to obtain a white solid (100 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝1.7Hz,1H),7.04(s,2H),6.27(dd,J＝10.7,5.2Hz,1H),5.96(d,J＝5.1Hz,1H),5.33(dt,J＝53.2,5.2Hz,1H),5.25(t,J＝5.6Hz,1H),4.50(dt,J＝20.0,5.2Hz,1H),3.53–3.42(m,2H),1.15(s,3H)。ESI-MS m/z:318.3[M+H]+。
Synthesis of Compound 1: intermediate 1-5(30mg, 0.09mmol) was dissolved in methanol (10mL), 10% palladium on carbon (8mg) and triethylamine (27mg, 0.27mmol) were added, and hydrogen was introduced and the reaction was allowed to proceed overnight. The reaction solution was filtered, the filtrate was concentrated, and preparative plate separation gave a white solid (16 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.25(s,1H),6.63(s,2H),6.31(dd,J＝11.4,5.2Hz,1H),5.97(d,J＝5.0Hz,1H),5.45-5.13(m,2H),4.51(dt,J＝20.1,5.2Hz,1H),3.13–2.95(m,3H),1.15(s,3H)。ESI-MS m/z:284.2[M+H]+。
Example 2
Figure BDA0002217910480000201
Intermediate 2-3 synthesis: 17g, 24.6mmol of intermediate 2-1 (synthesized in reference US20150366888A 1) was dissolved in acetonitrile (50mL), IBX (8.2g, 29.3mmol) was added, heated to reflux, monitored by TLC, and the starting material disappeared after 4 h. Insoluble matter is filtered off, filter residue is washed by acetonitrile, filtrate is combined and concentrated to obtain yellow foamy solid. The solid was added to 1, 4-dioxane (50mL) without purification, followed by addition of formaldehyde solution (37%, 9.8mL) and dropwise addition of aqueous NaOH (2N, 18mL) in ice. After the addition, the temperature was slowly raised to room temperature, after 6 hours, ethanol (15mL) was added to the reaction solution, and NaBH was added under ice bath4(3.2g, 84.6 mmol). The reaction was monitored by TLC and after no more product was added, stirring was stopped. Adding saturated NH to the reaction solution4Aqueous Cl solution, ethyl acetate extraction, organic phase drying, concentration, column chromatography, to obtain 5.2g of foamy solid with 29% yield. The resulting product ESI-MS M/z was 720.3[ M + H ]]+。
Intermediate 2-4 synthesis: dissolving intermediate 2-3(5.2g, 6.0mmol) in dichloromethane (20mL), adding pyridine (0.87mL, 10.8mmol) under nitrogen protection, reacting at-60 deg.C,p-chlorobenzoyl chloride (1.38g, 7.92mmol) was added dropwise, monitored by TLC, and a small amount of starting material remained after 2 h. Adding saturated NaHCO into the reaction solution3The aqueous solution was extracted with dichloromethane, the organic layer was separated, and the extract was washed with dilute hydrochloric acid and saturated brine in this order, dried, concentrated, and separated by column chromatography to give 3.4g of an oily substance in 66% yield. The resulting product ESI-MS M/z 858.4[ M + H ]]+。
Intermediate 2-5 synthesis: intermediate 2-4(3.4g, 3.97mmol) was dissolved in DMF (20mL), imidazole (1.3g, 19.1mmol) was added, and TBDPSCl (2.1g, 7.6mmol) was added dropwise over an ice bath and reacted at room temperature overnight. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried, concentrated, and separated by column chromatography to give 3.1g of an oily substance with a yield of 71%. The resulting product ESI-MS M/z 1096.5[ M + H ]]+。
Synthesis of intermediates 2 to 6: intermediate 2-5(3.1g, 2.83mmol) was dissolved in methanol (20mL) and catalytic amount of K was added2CO3(100mg, 0.72mmol), monitored by TLC, and after 4h the reaction was complete. Adding saturated ammonium chloride aqueous solution into the reaction solution, evaporating most of the solvent, extracting with ethyl acetate, drying and concentrating the organic phase, and separating by column chromatography to obtain 2g of white foamy solid with the yield of 74%. The resulting product ESI-MS M/z 958.4[ M + H ]]+。
Synthesis of intermediates 2 to 8: intermediate 2-6(100mg, 0.1mmol) was dissolved in dichloromethane (5mL) under nitrogen, pyridine (60. mu.L, 0.7mmol) was added, and Tf was added dropwise under ice salt bath2O (42mg, 0.15mmol) in dichloromethane (3mL) was monitored by TLC until the starting material reaction was complete. The reaction mixture was added with ice water, extracted with dichloromethane, washed with dilute hydrochloric acid and saturated brine in succession, dried and concentrated to give an oil. This oil was dissolved in DMF (5mL), LiCl (22.7mg, 0.5mmol) was added, and the reaction was allowed to proceed overnight at 30 ℃. TLC showed disappearance of the starting material, water and ethyl acetate were added to the reaction solution, the organic phase was separated, dried and concentrated, and purified by column chromatography to give 80mg of a foamy solid in 80% yield. The resulting product ESI-MS M/z 976.7[ M + H ]]+。
Synthesis of intermediates 2 to 9: intermediate 2-8(150mg, 0.15mmol) was dissolved in THF (2mL) and TBAF in tetrahydrofuran (0.15mL, 0.1) was added5mmol, 1M), reaction at room temperature, monitored by TLC until the starting material disappeared. Water was added to the reaction mixture, extracted with ethyl acetate, the organic phase was dried and concentrated, and the resulting oil was dissolved in THF (1mL) and 80% aqueous acetic acid (2mL) was added to the solution and reacted at room temperature overnight. The solvent was evaporated to dryness and column chromatography separated to give 30mg of a white solid in 57% yield. The resulting product ESI-MS M/z 352.1[ M + H ]]+。
Synthesis of Compound 2: intermediate 2-9(15mg, 0.042mmol) was dissolved in methanol (2mL), 10% palladium on carbon (5mg) and triethylamine (13mg,0.13mmol) were added, hydrogen was bubbled through, and the reaction was allowed to proceed overnight. The reaction solution was filtered, concentrated, and then separated on a preparative plate to obtain a white solid (8 mg). The resulting product ESI-MS M/z 318.2[ M + H ]]+。
Example 3
Figure BDA0002217910480000221
Intermediate 3-1 synthesis: the literature references report methods (Nucleotides, Nucleotides Nucleic Acids 2001,20(8): 1583-1598; Nucleotides, Nucleotides&nucleic acids2009,28(5): 657-; journal of medical chemistry 2015,58(4):1862-1878) to synthesize 3-1. The product obtained1H NMR(400MHz,CDCl3)δ8.15–7.96(m,4H),7.62(t,J＝7.4Hz,1H),7.54(t,J＝7.4Hz,1H),7.48(t,J＝7.7Hz,2H),7.38(t,J＝7.8Hz,2H),6.09(dd,J＝17.4,7.9Hz,1H),5.40(dd,J＝7.7,4.6Hz,0.5H),5.26(dd,J＝7.4,5.1Hz,0.5H),5.11(d,J＝4.6Hz,1H),4.67–4.46(m,4H),3.50(s,3H).
Intermediate 3-2 synthesis: 3-1(40mg, 0.1mmol) was dissolved in dichloromethane (2mL), acetic acid (48mg, 0.8mmol) and acetic anhydride (66mg, 0.6mmol) were added sequentially, stirred in ice bath, concentrated sulfuric acid (20mg,0.2mmol) was added, stirred for 10min, and then returned to room temperature for reaction. After about 2h, TLC showed disappearance of the starting material, methylene chloride and water were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous layer was extracted once with methylene chloride, the methylene chloride layers were combined, and the extract was washed with saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated to be used directly in the next step.
Intermediate 3-3 synthesis: the product from the previous step was dissolved in dichloromethane (5mL), iced, HBr/AcOH solution (0.18mL, 33%) was added and stirred overnight at 25 deg.C, the next day TLC showed the starting material was essentially complete. Dichloromethane and water were added to the reaction solution, the organic layer was separated, the aqueous layer was extracted once with dichloromethane, the organic phases were combined, the organic phase was washed successively with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and subjected to column chromatography to obtain an oil (23 mg).
Synthesis of intermediates 3 to 4: potassium tert-butoxide (16mg, 0.15mmol) was added to a mixed solution of tert-butanol and acetonitrile (4mL, 1:1), followed by addition of 6-chloro-2-aminopurine (30mg, 0.15mmol), and after stirring for 30min, intermediate 3-3(23mg, 0.05mmol) was added. After 10min, the temperature is raised to 60 ℃ for about 1h, and TLC shows that the raw materials are basically completely reacted. To the reaction solution was added a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain a white solid (18 mg). The product obtained1H NMR(400MHz,CDCl3)δ8.06–7.94(m,5H),7.67(t,J＝7.5Hz,1H),7.56-7.48(m,3H),7.37(t,J＝7.8Hz,2H),6.60(dd,J＝19.4,4.0Hz,1H),6.54(dd,J＝12.1,4.8Hz,1H),5.68-5.62(m,0.5H),5.54-5.50(m,0.5H),5.42-5.33(m,2H),5.05(dd,J＝11.7,2.3Hz,1H),4.97(d,J＝10.1Hz,0.5H),4.84(dd,J＝10.0,7.2Hz,1H),4.72(d,J＝10.1Hz,0.5H),4.64(d,J＝11.8Hz,1H)。
Synthesis of intermediates 3 to 5: dissolving 3-4(15mg, 0.03mmol) in ammonia methanol solution (8mL), stirring at room temperature for 1h, TLC to show that the raw materials are basically reacted completely, adding acetic acid to make the pH of the reaction solution neutral, evaporating the solvent, and performing column chromatography separation to obtain a white solid (7 mg). The resulting product 1H NMR (400MHz, DMSO) δ 8.25(d, J ═ 1.9Hz,1H),7.06(s,2H),6.37(dd, J ═ 11.8,5.2Hz,1H),6.25(d, J ═ 5.1Hz,1H), 5.38-5.15 (m,2H), 4.77-4.39 (m,3H),3.65(dd, J ═ 11.5,5.2Hz,1H),3.56(dd, J ═ 11.5,5.4Hz, 1H).
Synthesis of Compound 3: intermediate 3-5(10mg, 0.03mmol) was dissolved in methanol (8mL), 10% palladium on carbon (3mg) and triethylamine (9mg, 0.09mmol) were added, hydrogen was bubbled through, and the reaction was allowed to proceed overnight. The reaction solution was filtered, concentrated, and then separated by preparative plate to obtain a white solid (5 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.18(d,J＝2.2Hz,1H),6.63(s,2H),6.42(dd,J＝12.4,5.2Hz,1H),6.22(d,J＝5.1Hz,1H),5.36-5.32(m,0.5H),5.29(t,J＝5.7Hz,1H),5.24–5.18(m,0.5H),4.76–4.65(m,1.5H),4.64–4.56(m,1H),4.51–4.44(m,0.5H),3.69–3.62(m,1H),3.61–3.53(m,1H)，ESI-MS m/z:302.3[M+H]+。
Example 4
Figure BDA0002217910480000231
Intermediate 4-2 synthesis: intermediate 2-3(720mg, 1.0mmol) was dissolved in tetrahydrofuran (20mL), and TBAF in tetrahydrofuran (1.5mL, 1.5mmol, 1M) was added dropwise at room temperature, after 5h the reaction was complete. Evaporating to remove solvent, adding ethyl acetate and water, separating out organic phase, drying, and evaporating to dryness to obtain colorless foamy solid. The obtained solid was added to 80% aqueous acetic acid (10mL), and the reaction was completed in about 10 hours with stirring at room temperature. The solvent was evaporated under reduced pressure and separated by column chromatography to give 273mg of a white solid in 82% yield. The product obtained1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.03(s,2H),6.44(t,J＝6.2Hz,1H),5.94(d,J＝5.2Hz,1H),5.46(dt,J＝56.8,6.1Hz,1H),5.18(t,J＝5.4Hz,1H),5.00(t,J＝5.4Hz,1H),4.60(dt,J＝26.3,5.8Hz,1H),3.63(dd,J＝11.4,5.6Hz,1H),3.51(d,J＝5.3Hz,2H),3.38(dd,J＝11.6,5.1Hz,1H)。ESI-MS m/z:334.2[M+H]+。
Synthesis of Compound 4: intermediate 4-2(40mg, 0.12mmol), palladium hydroxide (10mg) and triethylamine (36mg, 0.36mmol) were added to methanol (6mL), and hydrogen gas was introduced and the mixture was stirred at room temperature. The reaction was completed for about 10h, the solvent was evaporated after filtration, and the plate preparation was separated to give 20mg of a white solid with a yield of 56%. The product obtained1H NMR(400MHz,DMSO-d6)δ8.61(s,1H),8.24(d,J＝1.1Hz,1H),6.60(s,2H),6.48(t,J＝6.5Hz,1H),5.92(d,J＝5.3Hz,1H),5.45(dt,J＝56.8,6.1Hz,1H),5.16(t,J＝5.6Hz,1H),4.98(t,J＝5.4Hz,1H),4.62(dt,J＝26.1,5.8Hz,1H),3.64(dd,J＝11.5,5.6Hz,1H),3.50(d,J＝5.4Hz,2H),3.39(dd,J＝11.5,3.9Hz,1H)。ESI-MS m/z:300.3[M+H]+。
Example 5
Figure BDA0002217910480000241
Intermediate 5-2 synthesis: compounds 2-6(0.15g, 0.15mmol) were added to acetonitrile (10mL), IBX (0.06g, 0.22mmol) was added, the reaction was refluxed at 80 ℃ for 3-4h, and the reaction was monitored by TLC for completion. The temperature was reduced to room temperature, the white insoluble material was removed by filtration, and the filtrate was evaporated to dryness to give an oil which was dissolved in THF (5mL) for further use. Methyltriphenylphosphonium bromide (0.16g, 0.45mmol) was added to THF (5mL) at-78 deg.C, a solution of n-butyllithium in n-hexane (0.2mL, 0.5mmol, 2.5M) was added dropwise and the temperature was raised to 0 deg.C after dropping. The aldehyde THF solution obtained in the previous step was added in one portion, stirred at 0 ℃ for 2-3h, monitored by TLC until the reaction was complete. Saturated ammonium chloride was added to the reaction solution, extraction was performed with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness to give a yellow oil, and column chromatography was performed to give a foamy solid (0.04 g). The resulting product ESI-MS M/z 954.6[ M + H ]]+。
Intermediate 5-3 synthesis: intermediate 5-2(0.04g, 0.04mmol) was added to ethanol (5ml), followed by 10% palladium on carbon (0.01g) and triethylamine (0.04g, 0.4mmol), hydrogen was added, and the mixture was stirred overnight at room temperature, and TLC indicated completion of the reaction. The reaction solution was filtered and evaporated to dryness to obtain 32mg of a white solid. The resulting product ESI-MS M/z 922.7[ M + H ]]+。
Synthesis of Compound 5: 5-3(32mg, 0.035mmol) was added to THF (5mL), a THF solution of TBAF (0.2mL, 0.2mmol, 1M) was added, the reaction was monitored by TLC for completion after stirring at room temperature for 1-2h, the solvent was evaporated to dryness, followed by addition of 80% acetic acid solution (5mL) and stirring at room temperature overnight. TLC monitored the reaction complete, evaporated to dryness and purified on prep plates to give a white solid (3 mg). The product obtained1H NMR(400MHz,CD3OD)δ8.60(s,1H),8.35(s,1H),6.48(dd,J＝12.8,4.9Hz,1H),5.25(dt,J＝53.4,4.7Hz,1H),4.72(dd,J＝20.3,4.5Hz,1H),3.75(dd,J＝11.8,1.8Hz,1H),3.66(d,J＝11.8Hz,1H),1.86–1.64(m,2H),1.03(t,J＝7.5Hz,3H)。ESI-MS m/z:298.30[M+H]+。
Example 6
Figure BDA0002217910480000251
Intermediate 6-1 synthesis: reference is made to the literature for the synthesis of 6-1 (Nucleotides, Nucleotides Nucleic Acids 2001,20(8): 1583-1598; Nucleotides, Nucleotides&nucleic acids2009,28(5) 657-677; WO2013095275a 1). The product obtained1H NMR(400MHz,DMSO-d6)δ8.02(dd,J＝18.3,8.0Hz,4H),7.69(dt,J＝24.9,7.0Hz,2H),7.58(t,J＝7.6Hz,2H),7.50(t,J＝7.5Hz,2H),5.92(dd,J＝18.0,7.9Hz,1H),5.55–5.24(m,1H),5.04(d,J＝4.3Hz,1H),4.48(d,J＝11.5Hz,1H),4.35(d,J＝11.5Hz,1H),3.29(s,3H),0.96(d,J＝8.4Hz,1H),0.59–0.31(m,4H)。
Intermediate 6-2 synthesis: 6-1(170mg,0.41mmol) was dissolved in dichloromethane (5mL), acetic anhydride (251mg, 2.46mmol) and acetic acid (197mg, 3.28mmol) were added sequentially, stirring was performed in an ice bath, concentrated sulfuric acid (82mg, 0.82mmol) was added, stirring was maintained at this temperature for 10min, the reaction was returned to room temperature, and TLC showed completion after about 1 h. Adding ice water into the reaction solution, extracting with ethyl acetate for 2 times, combining ethyl acetate layers, washing with saturated sodium bicarbonate and saturated sodium chloride water in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain oily matter.
Intermediate 6-3 synthesis: the oil from the previous step was dissolved in dichloromethane (5mL) and after addition of HBr/AcOH (0.82mL, 33%) under ice, the reaction was returned to room temperature and after about 4 hours TLC indicated substantial completion of the starting material. Adding ice water into the reaction solution, extracting with ethyl acetate for 2 times, combining ethyl acetate layers, washing with saturated sodium bicarbonate and saturated sodium chloride water in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain oily matter.
Synthesis of intermediate 6-4 by adding potassium tert-butoxide (138mg, 1.23mmol) and 6-chloro-2-aminopurine (237mg, 1.25mmol) to a mixed solution of acetonitrile and tert-butanol (10mL,1:1), stirring for 10min, adding the oily substance obtained in the above step, heating to 60 ℃ after completion of the addition, reacting for 1h, and TLC showing completion of the reaction. Concentrating the reaction solution, adding water and ethyl acetate, separating layers, washing the water layer with ethyl acetateWashing for 1 time, combining organic layers, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and performing column chromatography to obtain a white solid (35 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.20(s,1H),8.09(d,J＝7.9Hz,2H),7.98(d,J＝7.9Hz,2H),7.76(t,J＝7.5Hz,1H),7.69–7.58(m,3H),7.48(t,J＝7.7Hz,2H),7.08(s,2H),6.45(dd,J＝15.7,4.3Hz,1H),6.29(dd,J＝16.9,3.0Hz,1H),5.80(d,J＝50.6Hz,1H),4.77(d,J＝11.8Hz,1H),4.60(d,J＝11.4Hz,1H),1.26(d,J＝8.2Hz,1H),0.72–0.41(m,4H)。ESI-MS m/z:552.3[M+H]+。
Intermediate 6-5 synthesis: adding the intermediate 6-4(40mg,0.07mmol) into ammonia methanol solution (15mL), stirring overnight at room temperature, TLC the next day to show that the raw materials are basically reacted completely, concentrating the reaction solution, and performing column chromatography to obtain 18mg of the product. The product obtained1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.03(s,2H),6.24–6.20(m,1H),6.05(d,J＝5.2Hz,1H),5.50–5.45(m,.0.5H),5.41(t,J＝5.2Hz,1H),5.36–5.31(m,0.5H),4.82–4.72(m,1H),3.55–3.46(m,2H),1.06–1.01(m,1H),0.47–0.24(m,4H)。ESI-MS m/z:344.1[M+H]+。
Synthesis of Compounds 6-6: intermediate 7-5(51mg, 0.15mmol) was dissolved in ethanol (5mL), hydrazine hydrate (45mg, 0.76mmol, 85%) was added, and the reaction was allowed to react at 40 ℃ for about 12h, TLC showed completion. The reaction solution was cooled and filtered, and the filter cake was washed with ethanol to give a white solid (40 mg).
Synthesis of Compound 6: the product of the above step was dissolved in NaOMe (1.0mmol) in methanol (8mL) and heated at reflux for about 6h, and TLC showed complete reaction and the reaction solution was dark purple. Adding acetic acid into the reaction solution under ice bath condition, and adjusting the pH of the reaction solution to 7-8. The reaction mixture was concentrated and subjected to column chromatography to give a white solid (18 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.59(s,1H),8.33(s,1H),6.57(s,2H),6.30–6.21(m,1H),6.00(d,J＝4.93Hz,1H),5.49–5.27(m,2H),4.78(dt,J＝21.37,6.41Hz,1H),3.60–3.43(m,2H),1.11-0.98(m,1H),0.50-0.17(m,4H)。ESI-MS m/z:310.3[M+H]+。
Example 7
Figure BDA0002217910480000261
Intermediate 7-1 synthesis: intermediate 2-6(200mg, 0.21mmol) was dissolved in dichloromethane (15mL) and Dess-Martin (400mg, 0.94mmol) was added at room temperature and after 4h the reaction was complete. Dichloromethane (20mL), saturated aqueous sodium bicarbonate (10mL) and sodium thiosulfate solution (5mL, 10%) were added to the reaction mixture, and after stirring for 10min, the dichloromethane layer was separated, dried, and evaporated to dryness to give a foamy solid, which was dissolved in anhydrous tetrahydrofuran (5mL) for further use. Bromomethyl triphenyl phosphonium bromide (180mg, 0.41mmol) is added to anhydrous tetrahydrofuran (10mL), potassium tert-butoxide (70mg, 0.60mmol) is added at-78 deg.C, and after stirring for 5min, the solution of the aldehyde from the previous step in tetrahydrofuran is added. The reaction was run at this temperature and checked by TLC until the reaction was complete. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution to separate an organic layer, which was dried, concentrated, and purified by column chromatography to obtain 150mg of a foamy solid with a yield of 69%.
Intermediate 7-2 synthesis: intermediate 7-1(420mg, 0.41mmol) was dissolved in anhydrous tetrahydrofuran (10mL), potassium tert-butoxide (182mg, 1.62mmol) was added at-78 deg.C, the temperature was slowly raised to room temperature, and the reaction was complete after 30 min. Saturated aqueous ammonium chloride and ethyl acetate were added to the reaction solution to separate the organic layer, which was dried, concentrated, and purified by column chromatography to obtain 180mg of a foamy solid with a yield of 46%.
Intermediate 7-3: intermediate 7-2(160mg, 0.17mmol) was dissolved in tetrahydrofuran (6mL), a solution of TBAF in tetrahydrofuran (0.42mL, 0.42mmol, 1M) was added, the mixture was stirred at room temperature, and after 5h the reaction was complete. The solvent was distilled off, and column chromatography separation was performed to obtain 70mg of a white solid in a yield of 69%.
Intermediate 7-4 synthesis: the product 7-2 from the above step (70mg, 0.12mmol) was added to 80% acetic acid solution (5mL) and stirred overnight. The solvent was evaporated under reduced pressure and isolated on preparative plates to give 32mg of a white solid in 84% yield. The product obtained1H NMR(400MHz,CD3OD):δ8.28(d,J＝1.8Hz,1H),6.53(dd,J＝9.5,5.7Hz,1H),5.35(dt,J＝53.9,5.7Hz,1H),4.78(dd,J＝22.5,5.7Hz,1H),3.89(dd,J＝12.4,1.7Hz,1H),3.80(d,J＝12.4Hz,1H),3.24(s,1H)。ESI-MS m/z:328.2[M+H]+。
Intermediate 7-5 synthesis: intermediate 7-4(98mg, 0.3mmol) was dissolved in ethanol (5mL), hydrazine hydrate (90mg, 1.5mmol, 85%) was added, and the reaction was allowed to proceed at 40 ℃ for about 12h, TLC showed complete reaction of the starting material. The reaction solution was cooled and filtered, and the filter cake was washed with ethanol to give a white solid (110 mg).
Synthesis of Compound 7: the product of the above step was dissolved in NaOMe (2.1mmol) in methanol (10mL) and heated at reflux for about 6h, and TLC showed complete reaction and the reaction solution was dark purple. Adding acetic acid into the reaction solution under ice bath condition, and adjusting the pH of the reaction solution to 7-8. The reaction solution was concentrated and subjected to column chromatography to obtain a pale yellow solid (30 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.15(d,J＝3.4Hz,1H),6.73(s,2H),5.91(dd,J＝24.7,2.4Hz,1H),5.32(dd,J＝49.2,2.5Hz,1H),5.22-5.12(m,2H),5.00(d,J＝13.0Hz,1H),3.78(dd,J＝11.8,5.6Hz,1H),3.69(dd,J＝11.8,7.2Hz,1H),3.17(d,J＝5.2Hz,1H)。ESI-MS m/z:294.2[M+H]+。
Example 8
Figure BDA0002217910480000281
Intermediate 8-2 synthesis: compound 8-1 reference synthesis (Nucleotides, Nucleic Acids 2001,20(8): 1583-. 8-1(80mg, 0.19mmol) was dissolved in dichloromethane (5mL), acetic anhydride (122mg, 1.2mmol) and acetic acid (96mg,1.6mmol) were added sequentially, stirred in an ice bath, concentrated sulfuric acid (0.4mmol) was added, the temperature was maintained after addition and stirred for 10min, then returned to room temperature, and TLC after about 3h indicated complete reaction of the starting material. Dichloromethane and water were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous layer was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give an oil (87mg) which was used in the next reaction.
Intermediate 8-3 synthesis: the product from the previous step was dissolved in dichloromethane (3mL) and returned to room temperature upon completion of the addition of HBr/AcOH solution (0.4mL, 33%) in an ice bath, after about 3 hours TLC indicated complete reaction of the starting materials. Dichloromethane and water were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous layer was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give an oil which was used directly in the next reaction.
Intermediate 8-4 synthesis: potassium tert-butoxide (64mg, 0.57mmol) and 6-chloro-2-aminopurine (112mg, 0.59mmol) were added to a mixed solution of acetonitrile and tert-butanol (4mL, 1:1), and after stirring for 10min, the product from the previous step was added, and after completion of addition, the reaction was carried out at 85 ℃ for 3h, and TLC showed completion of the reaction. The reaction solution was concentrated, water and ethyl acetate were added, extraction was carried out for separation, the aqueous layer was washed with ethyl acetate 1 time, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to give a white solid (15 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝3.1Hz,1H),8.12–8.06(m,2H),8.01–7.94(m,2H),7.76(t,J＝7.4Hz,1H),7.65(dt,J＝15.4,7.5Hz,3H),7.50(t,J＝7.8Hz,2H),7.13(s,2H),6.52(dd,J＝17.4,4.4Hz,1H),6.11(dd,J＝20.4,3.0Hz,1H),5.97–5.92(m,0.5H),5.84–5.80(m,0.5H),4.82(d,J＝11.6Hz,1H),4.70(d,J＝11.5Hz,1H),1.81(s,3H)。ESI-MS m/z:550.2[M+1]。
Intermediate 8-5 synthesis: 8-4(15mg) was dissolved in methanolic ammonia (5mL), stirred at room temperature overnight, and TLC the next day showed complete reaction of starting materials, concentrated and separated by column chromatography to give a white solid (8 mg). The product obtained1H NMR(400MHz,CD3OD):δ8.27(d,J＝1.8Hz,1H),6.49(dd,J＝9.3,5.7Hz,1H),5.33(dt,J＝54.2Hz,5.8Hz,1H),4.72(dd,J＝22.9,5.8Hz,1H),3.84(dd,J＝12.4,1.7Hz,1H),3.75(d,J＝12.3Hz,1H),1.94(s,3H)。ESI-MS m/z:342.3[M+H]+。
Synthesis of Compound 8: reference to the synthesis of compound 7 gave a white solid. The resulting product ESI-MS M/z was 308.3[ M +1 ]]+。
Example 9
Figure BDA0002217910480000291
Intermediate 9-1 synthesis: intermediate 2 to 6(100mg, 0.11mmol), palladium hydroxide (10mg) and triethylamine (32mg, 3eq) were added to methanol (6mL), and hydrogen gas was introduced and the mixture was stirred at room temperature. The reaction was complete after about 10h, the solvent was evaporated after filtration and plate separation was carried out to obtain a white solid (85mg) with 88% yield.
Intermediate 9-3 synthesis: the product of the above step (85mg, 0.092mmol) and pyridine (60mg, 0.76mmol) were dissolved in dichloromethane (10mL), and a solution of triflic anhydride (78mg, 0.28mmol) in dichloromethane (1mL) was slowly added dropwise under ice bath, after addition, by TLC until the reaction was complete. Dichloromethane and water were added to separate the organic phase, which was washed successively with saturated aqueous sodium bicarbonate and 10% aqueous citric acid, dried and evaporated to dryness, and the resulting oil was dissolved in DMF (5mL), followed by addition of sodium azide (18mg, 0.37mmol) and reaction at 45 ℃. And (3) completely reacting for about 4 hours, adding ethyl acetate and water into the reaction solution, separating an organic phase, drying the organic phase, and evaporating to dryness to obtain an oily substance.
Synthesis of Compound 9: the product 9-3 from the previous step was dissolved in tetrahydrofuran (5mL), TBAF (0.2mL, 0.2mmol, 1M) was added, and the reaction was stirred at room temperature for 4h to completion. The reaction solution was evaporated to dryness, separated on a preparative plate to give a foamy solid. The solid was added to 80% acetic acid solution (5mL), stirred overnight at room temperature, the solvent was evaporated to dryness, and the preparative plate separation gave 8mg of white solid in 27% yield from the three steps. The product obtained1H NMR(400MHz,CD3OD)δ8.59(s,1H),8.29(s,1H),6.60(dd,J＝11.9,5.1Hz,1H),5.38(dt,J＝53.7,4.8Hz,1H),4.79(dd,J＝20.7,4.5Hz,1H),3.80–3.66(m,3H),3.50(d,J＝12.8Hz,1H)。ESI-MS m/z:325.3[M+H]+。
Example 10
Figure BDA0002217910480000301
Intermediate 10-2 synthesis: 10-1 (Nucleotides, Nucleic Acids 2001,20(8): 1583-. 10-1(826mg, 2.0mmol) was dissolved in dichloromethane (10mL), acetic anhydride (1.22g, 12.0mmol) and acetic acid (960mg, 16.0mmol) were added sequentially, concentrated sulfuric acid (400mg, 4.0mmol) was added under ice bath, after addition, the temperature was maintained and stirred for 10min, then the reaction was returned to room temperature, after about 1h TLC showed complete reaction of the starting materials. Adding ice water into the reaction solution, extracting with ethyl acetate for 2 times, combining organic phases, washing the organic phases with saturated sodium bicarbonate and saturated sodium chloride water successively, drying with anhydrous sodium sulfate, and concentrating to obtain oily matter which is directly used for the next reaction without purification.
Intermediate 10-3 synthesis: the product from the previous step was dissolved in dichloromethane (10mL), HBr/AcOH solution (4.0mL, 33%) was added under ice bath and after addition was returned to room temperature and TLC after about 4h indicated complete reaction. Adding ice water into the reaction solution, extracting with ethyl acetate for 2 times, combining organic phases, washing the organic phases with saturated sodium bicarbonate and saturated sodium chloride water successively, drying with anhydrous sodium sulfate, and concentrating to obtain oily matter.
Intermediate 10-4 synthesis: potassium tert-butoxide (673mg, 6.0mmol) and 6-chloro-2-aminopurine (1.18g, 6.2mmol) were added to a mixed solution of acetonitrile and tert-butanol (20mL, 1:1), after stirring for 10min, the product from the previous step was added, followed by reaction at 60 ℃ and after 1h TLC showed complete reaction of the starting materials. The reaction mixture was concentrated, water and ethyl acetate were added, the organic layer was separated, the aqueous layer was extracted with ethyl acetate 1 time, the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain a white solid (300 mg).
Intermediate 10-5 synthesis: the intermediate (310mg, 0.56mmol) was added to methanolic ammonia (15mL), stirred at room temperature overnight, TLC the next day showed complete reaction of starting material, the reaction was concentrated, and column chromatography gave a white solid (104 mg). The product obtained1H NMR (500MHz, DMSO) δ 8.42(s,1H),7.06(s,2H),6.06(dd, J ═ 14.2,5.6Hz,1H),6.02(d, J ═ 5.4Hz,1H),5.68(dt, J ═ 55.1,5.9Hz,1H),4.98(s,1H),4.52(dt, J ═ 20.9,5.8Hz,1H),3.68(d, J ═ 11.6Hz,1H), 3.48-3.41 (m,2H), 3.38-3.29 (m, 4H). Obtained byProduct ESI-MS M/z 348.3[ M + H ]]+。
Synthesis of Compound 10: intermediate 10-5(20mg, 0.058mmol), 10% palladium on carbon (5mg), and triethylamine (18mg, 0.18mmol) were added to methanol (6mL), and hydrogen was introduced and the mixture was stirred at room temperature. The reaction was completed for about 10h, the solvent was evaporated after filtration, and the plate preparation was separated to give 12mg of a white solid with a yield of 66%. The resulting product ESI-MS M/z was 314.3[ M + H ]]+。
Example 11
Figure BDA0002217910480000311
Intermediate 11-1 synthesis: synthesis of starting materials 11-1 reference methods (Nucleotides, Nucleic Acids 2001,20(8): 1583-1598; Nucleotides, Nucleotides&nucleic acids2009,28(5): 657-; WO2014209979A1) which is a pair of non-corresponding isomers 11-2a (less polar) and 11-2b (more polar), intermediate 11-2a1H NMR(400MHz,CDCl3) δ 8.08-7.97 (m,4H), 7.66-7.58 (m,1H), 7.56-7.43 (m,3H), 7.38-7.29 (m,2H),6.23(dd, J ═ 18.6,8.2Hz,1H),5.40(ddd, J ═ 54.3,8.2,4.6Hz,1H),5.22(q, J ═ 6.5Hz,1H),5.13(dd, J ═ 4.6,1.5Hz,1H),4.57(d, J ═ 11.6Hz,1H),4.51(d, J ═ 11.6Hz,1H),3.49(s,3H),2.05(s,3H),1.38(d, J ═ 6.5, 3H). Intermediate 11-2b1H NMR(400MHz,CDCl3):δ8.13–8.03(m,4H),7.70–7.61(m,1H),7.60–7.46(m,3H),7.41(t,J＝7.8Hz,2H),6.32(dd,J＝17.7,8.0Hz,1H),5.36(dd,J＝8.0,4.6Hz,0.5H),5.29–5.17(m,1.5H),5.11(dd,J＝4.6,1.1Hz,1H),4.72-4.63(m,2H),3.47(s,3H),1.75(s,3H),1.43(d,J＝6.5Hz,3H)。
Intermediate 11-2 synthesis: intermediate 11-1(250mg, 0.54mmol) was dissolved in dichloromethane (15mL), acetic anhydride (331mg, 3.24mmol) and acetic acid (261mg, 4.34mmol) were added sequentially, concentrated sulfuric acid (108mg, 1.08mmol) was added under ice bath, after addition, the temperature was maintained and stirred for 10min, then returned to room temperature and after about 1h TLC indicated complete reaction of starting materials. Adding dichloromethane and water into the reaction solution, standing for layering, separating an organic phase, drying by using anhydrous sodium sulfate, and concentrating to obtain an oily substance, wherein the oily substance is directly used for the next reaction without purification.
Intermediate 11-3 synthesis: the product from the previous step was dissolved in dichloromethane (5mL) and the reaction was allowed to return to room temperature after the addition of HBr/AcOH (0.8mL, 33%) in the ice bath. After 5h, dichloromethane and water were added to the reaction solution, the mixture was allowed to stand for separation, the aqueous layer was extracted with dichloromethane, and the organic phases were combined. The organic phase was washed with saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated to give an oil which was used directly in the next reaction.
Intermediate 11-4 synthesis: potassium tert-butoxide (105.0mg, 0.94mmol) and 6-chloro-2-aminopurine (127mg, 0.75mmol) were added to a mixed solution of acetonitrile and tert-butanol (4mL, 1:1), stirred for 10min, and after addition of the product from the previous step, the reaction was followed at 85 ℃ with TLC monitoring until the reaction was complete. The reaction solution was concentrated, water and ethyl acetate were added, extraction was carried out for separation, the aqueous layer was washed with ethyl acetate 1 time, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give two white solids, 60mg and 40mg, respectively. First product1H NMR(400MHz,DMSO-d6) δ 8.25(d, J ═ 2.2Hz,1H), 8.07-8.00 (m,2H), 7.96-7.87 (m,2H),7.76(t, J ═ 7.5Hz,1H),7.63(dt, J ═ 15.3,7.5Hz,3H),7.46(t, J ═ 7.7Hz,2H),7.07(s,2H),6.68(dd, J ═ 14.7,5.0Hz,1H),6.48(dd, J ═ 18.9,3.8Hz,1H),5.94(dt, J ═ 51.3,4.4Hz,1H),5.39(q, J ═ 6.5Hz,1H),4.91(d, J ═ 11.8, 1H),4.81 (J ═ 11.81, 7.85 Hz,1H), 7.6.7.7H, 1H, 11.85H, 6.6H, 1H, 6H, 11H, 11.8H, 6H, 3H, 1H, 6H, and the like1H NMR(400MHz,DMSO-d6)δ8.37(d,J＝1.9Hz,1H),7.93(d,J＝7.0Hz,2H),7.80–7.65(m,3H),7.62–7.50(m,3H),7.19(t,J＝7.9Hz,2H),7.10(s,2H),6.76(t,J＝7.0Hz,1H),6.69(dd,J＝24.9,5.6Hz,1H),5.95(dt,J＝54.1,6.1Hz,1H),5.41(q,J＝6.3Hz,1H),5.01(d,J＝11.1Hz,1H),4.48(d,J＝11.0Hz,1H),2.27(s,3H),1.31(d,J＝6.4Hz,3H)。
Intermediate 11-5 synthesis: the two diastereoisomers obtained in the above step were dissolved in methanolic ammonia (10mL) and stirred overnight at room temperature, and TLC was performed the next day to show complete reaction of the starting materials, followed by concentration and column chromatography to obtain white solids, 25mg and 18mg, respectively. First product1H NMR(400MHz,DMSO-d6)δ8.31(d, J ═ 1.6Hz,1H),7.02(s,2H),6.44(dd, J ═ 7.6,6.0Hz,1H),5.97(d, J ═ 5.5Hz,1H),5.50(dt, J ═ 56.3,6.0Hz,1H),5.14(t, J ═ 5.5Hz,1H),4.95(d, J ═ 5.6Hz,1H),4.69(dt, J ═ 26.1,5.8Hz,1H), 3.93-3.83 (m,1H), 3.71-3.60 (m,2H),1.24(d, J ═ 6.6Hz, 3H). A second product1H NMR(400MHz,CD3OD):δ8.39(d,J＝1.4Hz,1H),6.60(t,J＝6.4Hz,1H),5.57(dt,J＝57.2,6.0Hz,1H),4.97(dd,J＝28.1,5.9Hz,1H),4.07(q,J＝6.5Hz,2H),3.69(dd,J＝11.9,1.7Hz,2H),3.54(d,J＝11.9Hz,1H),1.20(d,J＝6.5Hz,3H)。
Synthesis of Compound 11: intermediate 11-5(15mg, 0.043mmol), palladium hydroxide (5mg) and triethylamine (13.1mg, 0.13mmol) were added to methanol (6mL), and hydrogen gas was introduced and the mixture was stirred at room temperature. The reaction is completed in about 6h, the solvent is evaporated after filtration, and the white solid is obtained after separation by a preparation plate. First product1H NMR(400MHz,DMSO-d6):δ8.60(s,1H),8.24(d,J＝1.7Hz,1H),6.61(s,2H),6.47(dd,J＝8.1,5.9Hz,1H),5.99(d,J＝5.6Hz,1H),5.49(dt,J＝56.3,5.9Hz,1H),5.15(t,J＝5.5Hz,1H),4.96(d,J＝5.7Hz,1H),4.70(dt,J＝26.0,5.7Hz,1H),3.91–3.83(m,1H),3.69–3.60(m,2H),1.25(d,J＝6.5Hz,3H)。ESI-MS m/z:314.3[M+1]+. A second product1H NMR(400MHz,CD3OD):δ8.58(s,1H),8.37(s,1H),6.63(t,J＝6.5Hz,1H),5.57(dt,J＝57.2,6.0Hz,1H),4.99(dd,J＝28.1,5.8Hz,1H),4.08(q,J＝6.5Hz,1H),3.70(dd,J＝11.9,1.8Hz,1H),3.55(d,J＝11.9Hz,1H),1.20(d,J＝6.5Hz,3H)。ESI-MS m/z:314.3[M+1]+。
Example 12
Figure BDA0002217910480000331
Synthesis of intermediate 12-2: the intermediate 12-1 reference reports the synthesis (Nucleotides, Nucleic Acids 2001,20(8): 1583-1598; Nucleotides, Nucleotides & Nucleic Acids2009,28(5): 657-677; Organic & Biomolecular Chemistry,2012,10(28), 5452-5455). Intermediate 12-1(713mg, 1.37mmol) was dissolved in dichloromethane (10mL), acetic acid (658mg, 10.96mmol) and acetic anhydride (838mg, 8.22mmol) were added sequentially, and concentrated sulfuric acid (274mg, 2.74mmol) in dichloromethane (0.5mL) was added under ice bath. After stirring for 10min, the temperature was raised to room temperature and stirring was continued for 3h, TLC showed the starting material was completely reacted. Dichloromethane and water were added to the reaction solution, the organic phase was separated, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, and concentrated to be used in the next step.
Synthesis of intermediate 12-3: the product from the previous step was dissolved in dichloromethane (10mL), iced, and a solution of HBr/HOAc (2.74mL, 33%) was added, which was allowed to return to room temperature after the addition. After 3h, TLC showed the starting material had reacted to completion. Adding dichloromethane and water into the reaction solution, separating an organic phase, washing the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, drying with anhydrous sodium sulfate, and concentrating to be directly used for the next reaction.
Synthesis of intermediate 12-4: potassium tert-butoxide (461mg, 4.11mmol), 6-chloro-2-aminopurine (806mg, 4.25mmol) and the product from the previous step were added to a mixed solution of tert-butanol/acetonitrile (10mL,1:1), after addition the temperature was raised to 60 ℃ for reaction, after 1h TLC showed that the starting material had reacted completely. The reaction mixture was concentrated, ethyl acetate was added, and the mixture was washed successively with saturated ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and subjected to column chromatography to give a white solid (361 mg). The product obtained1H NMR(400MHz,DMSO)δ8.25(d,J＝2.6Hz,1H),8.12–8.04(m,2H),7.92–7.80(m,4H),7.75(t,J＝7.4Hz,1H),7.66–7.52(m,4H),7.44–7.31(m,4H),7.06(s,2H),6.60(dd,J＝16.6,4.5Hz,1H),6.21(dd,J＝18.4,3.3Hz,1H),5.84(dt,J＝51.1,3.5Hz,1H),4.83(d,J＝11.8Hz,1H),4.69(d,J＝11.4Hz,1H),4.64–4.57(m,1H),4.56–4.46(m,1H),2.61–2.53(m,1H),2.47–2.40(m,1H)。ESI-MS m/z:660.3[M+H]+。
Synthesis of intermediate 12-5: adding the product obtained in the previous step into ammonia/methanol solution (20mL), stirring overnight at room temperature, TLC (thin layer chromatography) shows that the raw materials completely react, evaporating to remove the solvent, and performing column chromatography separation to obtain a white solid. The product obtained1H NMR(400MHz,DMSO)δ8.30(d,J＝1.7Hz,1H),7.03(s,2H),6.29(dd,J＝11.8,5.0Hz,1H),5.96(d,J＝5.2Hz,1H),5.36(t,J＝5.0Hz,0.5H),5.26–5.18(m,1.5H),4.65–4.50(m,2H),3.63–3.52(m,3H),3.47(dd,J＝11.7,5.8Hz,1H),1.87–1.68(m,7.4Hz,2H)。ESI-MS m/z:348.2[M+H]+。
Synthesis of Compound 12: intermediate 13-5(50mg, 0.14mmol), 10% palladium on carbon (20mg), and triethylamine (101mg, 1.0mmol) were added to methanol (10mL), and the mixture was stirred at room temperature overnight with hydrogen gas. TLC showed complete reaction of the starting material, the reaction solution was filtered, the filtrate was evaporated to dryness and separated by column chromatography to give a white solid (20 mg). The product obtained1H NMR(400MHz,DMSO)δ8.60(s,1H),8.21(d,J＝1.9Hz,1H),6.62(s,2H),6.31(dd,J＝12.5,5.0Hz,1H),5.95(d,J＝5.2Hz,1H),5.33(t,J＝4.9Hz,0.5H),5.23–5.16(m,1.5H),4.62(t,J＝4.9Hz,1H),4.56(dt,J＝20.2,4.9Hz,1H),3.63–3.51(m,3H),3.45(dd,J＝11.8,5.6Hz,1H),1.88–1.67(m,2H)。ESI-MS m/z:314.3[M+H]+。
Example 13
Figure BDA0002217910480000351
Synthesis of intermediate 13-1: reference methods for the synthesis of such intermediates (Nucleotides, Nucleotides Nucleic Acids 2001,20(8): 1583-1598; Nucleotides, Nucleotides&nucleic acids 2009,28(5):657-677；Organic&Biomolecular Chemistry,2012,10(28), 5452-5455; tetrahedron Lett 2015,56(29):4345-4348) to obtain the product1H NMR(400MHz,DMSO):δ8.05(d,J＝7.3Hz,2H),7.97(d,J＝7.4Hz,2H),7.74(t,J＝7.4Hz,1H),7.66(t,J＝7.4Hz,1H),7.60(t,J＝7.7Hz,2H),7.48(t,J＝7.7Hz,2H),5.96(dd,J＝17.4,7.8Hz,1H),5.53(ddd,J＝52.1,7.7,4.5Hz,1H),5.14(d,J＝4.5Hz,1H),4.81–4.73(m,1H),4.69–4.61(m,1H),4.49(d,J＝11.7Hz,1H),4.33(d,J＝11.6Hz,1H),3.32(s,3H),2.25–2.08(m,1H)。
Synthesis of intermediate 13-2: 13-1(202mg, 0.5mmol) was dissolved in dichloromethane (6mL), acetic acid (240mg, 4.0mmol) and acetic anhydride (306mg, 3.0mmol) were added sequentially, and concentrated sulfuric acid (100mg, 1.0mmol) in dichloromethane (0.5mL) was added under ice bath. After stirring for 10min, the temperature was raised to room temperature and stirring was continued for 3h, TLC showed the starting material was completely reacted. Dichloromethane and water were added to the reaction solution, the organic phase was separated, and the organic phase was washed with saturated sodium bicarbonate solution and saturated brine, respectively, dried over anhydrous sodium sulfate, and concentrated to be used in the next step.
Synthesis of intermediate 13-3: the product from the previous step was dissolved in dichloromethane (5mL), iced, and a solution of HBr/HOAc (1mL, 33%) was added, which was allowed to return to room temperature after the addition. After 3h, TLC showed the starting material was completely reacted. Adding dichloromethane and water into the reaction solution, separating an organic phase, washing the organic phase with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively, drying with anhydrous sodium sulfate, and concentrating to be directly used for the next reaction.
Synthesis of intermediate 13-4: potassium tert-butoxide (168mg, 1.50mmol), 6-chloro-2-aminopurine (294mg, 1.55mmol) and the product from the previous step were added to a mixed solution of tert-butanol/acetonitrile (10mL,1:1), and after the addition, the temperature was raised to 60 ℃ for reaction. After 1h, TLC showed complete reaction of the starting materials, the reaction mixture was concentrated, ethyl acetate was added, washed with saturated ammonium chloride and saturated brine, respectively, dried over anhydrous sodium sulfate, and column chromatography gave a white solid (130 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.24(d,J＝2.6Hz,1H),8.11–8.05(m,2H),7.96–7.89(m,2H),7.78–7.57(m,4H),7.43(t,J＝7.8Hz,2H),7.06(s,2H),6.57(dd,J＝15.8,4.6Hz,1H),6.21(dd,J＝18.8,3.4Hz,1H),5.82(dt,J＝51.3,4.0Hz,1H),4.88–4.57(m,4H),2.45–2.29(m,2H)。ESI-MS m/z:558.4[M+H]+。
Synthesis of intermediate 13-5: adding the product obtained in the previous step into ammonia/methanol solution (15mL), stirring overnight at room temperature, TLC (thin layer chromatography) shows that the raw materials completely react, evaporating to remove the solvent, and performing column chromatography separation to obtain a white solid. The product obtained1H NMR(400MHz,DMSO-d6)δ8.29(d,J＝1.8Hz,1H),7.04(s,2H),6.29(dd,J＝11.8,5.0Hz,1H),6.11(d,J＝5.0Hz,1H),5.37(t,J＝5.0Hz,0.5H),5.31(t,J＝5.5Hz,1H),5.24(t,J＝5.0Hz,0.5H),4.73–4.49(m,4H),3.58(dd,J＝11.9,5.1Hz,1H),3.52–3.46(m,1H),2.14–1.88(m,2H)。ESI-MS m/z:350.3[M+H]+。
Synthesis of Compound 13: intermediate 13-5(18mg, 0.052mmol), palladium on carbon (5mg) and triethylamine (13.1mg, 0.13mmol) were added to methanol (6mL), and the mixture was stirred at room temperature overnight with hydrogen gas being introduced. TLC showed starting material inversionThe reaction solution was filtered, the filtrate was evaporated to dryness, and the plate was prepared and isolated to give a white solid. The product obtained1H NMR(400MHz,DMSO-d6)δ8.62(s,1H),8.22(d,J＝2.0Hz,1H),6.63(s,2H),6.34(dd,J＝12.6,5.0Hz,1H),6.12(d,J＝5.0Hz,1H),5.37(t,J＝4.9Hz,0.5H),5.30(t,J＝5.5Hz,1H),5.23(t,J＝4.9Hz,0.5H),4.75–4.49(m,3H),3.58(dd,J＝11.5,4.7Hz,1H),3.53–3.46(m,1H),2.15-1.90(m,2H)。ESI-MS m/z:316.2[M+H]+。
Example 14
Figure BDA0002217910480000361
Intermediate 14-1 Synthesis: referring to the first reaction step in example 5, intermediates 2-6(600mg, 0.625mmol) were oxidized with IBX. After the reaction is completed, the reaction solution is filtered, and the filtrate is evaporated to dryness to obtain a foamy solid. The solid solution was stirred in anhydrous tetrahydrofuran (10mL) at-60 deg.C, methyllithium etherate (1.0mL, 1.6mmol, 1.6M) was slowly added dropwise, and the reaction was continued at this temperature for 2-3h after the addition was complete. Adding saturated ammonium chloride solution into the reaction solution, extracting with ethyl acetate, drying, concentrating, and separating by column chromatography to obtain 350mg of foamy solid with yield of 57%. ESI-MS M/z 972.7[ M +1 ]]+。
Intermediate 14-2 synthesis: the product of the above step was added to acetonitrile (10mL), IBX (131.6mg, 0.47mmol) was added, and the mixture was stirred at 75 ℃. After 5h, TLC showed the reaction was complete. Cooling the reaction solution, filtering, evaporating the filtrate to dryness to obtain a foamy solid, and directly carrying out the next reaction.
Intermediate 14-3 synthesis: methyltriphenylphosphonium bromide (1.29g, 3.6mmol) was added to anhydrous tetrahydrofuran (10mL) and a solution of n-butyllithium in n-hexane (1.3mL, 2.5M) was added at-78 deg.C, after stirring for 10min, the temperature was raised to 0 deg.C and stirring continued at that temperature for 1h, followed by addition of the product of the previous step in tetrahydrofuran (2mL) and reaction overnight at 35 deg.C. TLC detection reaction is complete, saturated ammonium chloride aqueous solution is added into reaction liquid, ethyl acetate extraction, drying, concentration and column chromatography separation are carried out, 200mg of foamy solid is obtained, and the yield of the two steps is 57%. ESI-MS m/z 968.7[ 2 ]M+1]+。
Intermediate 14-5 Synthesis: intermediate 14-3(97mg, 0.1mmol) was added to tetrahydrofuran (5mL), a solution of TBAF in tetrahydrofuran (0.3mL, 0.3mmol, 1M) was added, the mixture was stirred at room temperature, and after 4h the reaction was complete. The solvent is removed by evaporation, and the white solid is obtained by column chromatography separation. The resulting solid was then added to 80% aqueous acetic acid (10mL) and stirred overnight at 30 ℃. The solvent was evaporated and the preparative plate was isolated to give 20mg of a white solid in 58% yield over two steps. The product obtained1H NMR(400MHz,CD3OD)δ8.38(d,J＝1.9Hz,1H),6.53(dd,J＝15.1,4.3Hz,1H),5.27(d,J＝1.6Hz,1H),5.21(t,J＝4.1Hz,0.5H),5.12–5.05(m,1.5H),4.63(dd,J＝15.9,3.9Hz,1H),3.92(dd,J＝12.1,1.3Hz,1H),3.83(dd,J＝12.1,1.7Hz,1H),1.91(s,3H)。ESI-MS m/z:344.3[M+1]+。
Compound 14 synthesis: intermediate 14-5(20mg, 0.058mmol) was added to ethanol (3mL), hydrazine hydrate (17.1mg, 0.29mmol, 85%) was added, the reaction was allowed to proceed overnight at 40 deg.C, and TLC indicated complete reaction of the starting material. The solvent was evaporated to dryness, methanolic solution (8mL) containing NaOMe (0.5mmol) was added and the reaction was heated at reflux for about 8h and TLC showed completion. After the reaction liquid is cooled, acetic acid is added, and the pH value of the reaction liquid is adjusted to 7-8. The reaction was concentrated and separated on a plate to give an off-white solid (8 mg). The product obtained1H NMR(400MHz,CD3OD)δ8.60(s,1H),8.37(d,J＝1.9Hz,1H),6.57(dd,J＝15.4,4.2Hz,1H),5.27(s,1H),5.15(dt,J＝53.0,4.1Hz,1H),5.10(s,1H),4.64(dd,J＝15.9,3.9Hz,1H),3.92(dd,J＝12.1,1.3Hz,1H),3.84(dd,J＝12.1,1.7Hz,1H),1.92(s,3H)。ESI-MS m/z:310.3[M+1]+。
Example 15
Figure BDA0002217910480000381
Intermediate 15-1 synthesis: intermediate 5-2(476.7mg, 0.5mmol) was added to tetrahydrofuran (10mL) and a solution of TBAF in tetrahydrofuran (1.5mL, 1.5mmol, 1M) was added at room temperature and the reaction was complete after 4 h. The solvent was evaporated, water was added, extraction was performed with ethyl acetate, the organic phase was dried and concentrated to give an oil, which was directly subjected to the next reaction without purification.
Intermediate 15-2 synthesis: the oil was added to 80% aqueous acetic acid (15mL) and stirred at room temperature overnight. The solvent was evaporated and column chromatography separated to give 99mg of a white solid with a two step yield of 60%. The ESI-MS M/z ratio of the product obtained is 330.2[ M +1 ]]+。
Synthesis of Compound 15: intermediate 15-2(40mg, 0.12mmol) was added to ethanol (3mL), hydrazine hydrate (35.3mg, 0.6mmol, 85%) was added, the reaction was allowed to proceed overnight at 40 deg.C, and TLC indicated complete reaction of the starting material. The solvent was evaporated to dryness, methanolic solution (8mL) containing NaOMe (1.0mmol) was added and the reaction was heated at reflux for about 8h and TLC showed completion. After the reaction liquid is cooled, acetic acid is added, and the pH value of the reaction liquid is adjusted to 7-8. The reaction mixture was concentrated and separated on a plate to give an off-white solid (18 mg). The resulting product ESI-MS M/z 296.3[ M +1 ]]+。
Example 16
Figure BDA0002217910480000382
Intermediate 16-2 synthesis: the 16-1 reference reports the synthesis (Journal of Medicinal Chemistry,2000,43(23), 4516-. 16-1(1.7g, 4.32mmol) was dissolved in ethyl acetate (20mL), acetic anhydride (2.2g, 13.0mmol) was added, concentrated sulfuric acid (86mg, 0.86mmol) was added slowly under ice bath, after addition was returned to room temperature and stirred overnight, the next day TLC showed complete reaction of starting material. To the reaction solution was added a saturated sodium bicarbonate solution, the mixture was allowed to stand for separation, the aqueous layer was extracted twice with ethyl acetate, the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a yellow oil (1.7 g).
Intermediate 16-3 synthesis: 2-amino-6-chloropurine (52mg, 0.2mmol) was added to acetonitrile (10mL), BSA (165mg, 0.81mmol) was added, and the reaction was stirred at 70 ℃ for 1h, whereupon the reaction solution became clear from turbidity. The reaction was cooled, and under ice-bath conditions, acetonitrile solution of intermediate 16-2(79mg, 0.18mmol) was added, followed by stirring for 10min, TMSOTf (140mg, 0.63mmol) was added, followed by stirring for 10min, followed by reaction at 60 ℃ overnight, and the next day TLC indicated complete reaction of the starting material. Concentrating the reaction solutionAfter condensation, water and ethyl acetate were added to separate an organic layer, a water layer was extracted with ethyl acetate 1 time, organic phases were combined, the organic phase was washed with saturated sodium bicarbonate and saturated brine successively, dried over anhydrous sodium sulfate, and separated on a preparative plate to obtain a white solid (45 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.42–7.23(m,10H),7.10(s,2H),6.17(d,J＝4.8Hz,1H),5.85–5.79(m,1H),4.80–4.70(m,2H),4.63–4.48(m,3H),3.79–3.65(m,3H),2.03(s,3H)。
Intermediate 16-4 synthesis: intermediate 16-3(984mg, 1.80mmol) was dissolved in 1, 4-dioxane (30mL) and then lithium hydroxide monohydrate (151mg, 3.60mmol) in water (10mL) was added and after about 3h TLC indicated complete reaction of starting material. Adjusting pH of the reaction solution to 6-7 with diluted hydrochloric acid, concentrating the reaction solution to small volume, extracting with ethyl acetate, extracting the water layer with ethyl acetate for 1 time, mixing ethyl acetate layers, drying, concentrating, and performing column chromatography to obtain foamed solid (850 mg).
Intermediate 16-5 synthesis: 16-4(906mg, 1.80mmol) was dissolved in dichloromethane (40mL) and DMAP (1.32g, 6mmol), pyridine (2.56g, 32.4mmol) and trifluoromethanesulfonic anhydride (1.52g, 5.4mmol) were added sequentially under ice-bath and after addition was complete, the reaction was returned to room temperature and TLC after about 1h indicated complete reaction of the starting material. The reaction mixture was diluted with dichloromethane, washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated to obtain an oily substance (1.07 g).
Intermediate 16-6 synthesis: the oil from the previous step was dissolved in DMF (25mL) and reacted overnight at room temperature with the addition of tetrabutylammonium acetate (1.0g, 3.34mmol) on an ice bath, the next day TLC showed the starting material was essentially completely reacted. Adding water into the reaction solution, extracting with ethyl acetate, drying the organic layer, and concentrating to obtain oily substance. The product obtained1H NMR(400MHz,DMSO-d6)δ8.10(s,1H),7.41–7.24(m,10H),7.08(s,2H),6.41(d,J＝6.3Hz,1H),5.41(t,J＝6.6Hz,1H),4.80–4.65(m,3H),4.59(s,2H),3.89–3.77(m,3H),1.72(s,3H)。
Intermediate 16-7 synthesis: intermediate 11-6(160mg, 0.30mmol) was dissolved in 1, 4-dioxane (10mL) and then an aqueous solution of lithium hydroxide monohydrate (25mg, 0.60mmol) was added(10mL), TLC after about 3h indicated complete reaction of starting material. Adjusting pH of the reaction solution to 6-7 with diluted hydrochloric acid, concentrating the reaction solution to small volume, extracting with ethyl acetate, extracting water layer with ethyl acetate for 1 time, mixing organic phases, drying, concentrating, and separating by column chromatography to obtain foamy solid (110 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.42–7.25(m,10H),7.02(s,2H),6.21(d,J＝6.1Hz,1H),6.04(d,J＝5.4Hz,1H),4.74(s,2H),4.61–4.51(m,3H),4.37(d,J＝6.4Hz,1H),3.81–3.70(m,3H)。
Intermediate 16-8 synthesis: 11-7(100mg, 0.2mmol) was dissolved in dichloromethane (5mL), cooled to-78 deg.C, and BCl was added3After the addition was complete, the temperature was maintained and stirring was continued for 1h, followed by-15 ℃ for 2h, and TLC showed complete reaction of starting material. Cooling the reaction solution to-25 deg.C, adding mixture solution of methanol and dichloromethane (20mL, 1:1), heating to-5 deg.C, adjusting pH of the reaction solution to 7-8 with ammonia solution, stirring for 2h, concentrating the reaction solution, and separating to obtain white solid (50 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),6.98(s,2H),6.16(d,J＝6.4Hz,1H),5.85(d,J＝5.4Hz,1H),5.76(d,J＝5.5Hz,1H),5.43(t,J＝5.9Hz,1H),4.36(dd,J＝12.6,6.8Hz,1H),4.24(dd,J＝7.4,5.4Hz,1H),3.70–3.55(m,3H)。
Compound 16 synthesis: intermediate 16-8(20mg, 0.061mmol), palladium hydroxide (5mg) and triethylamine (18mg, 0.18mmol) were added to methanol (6mL), and hydrogen gas was introduced and stirred at room temperature. The reaction was completed for about 10h, the solvent was evaporated after filtration, and the plate preparation was separated to give 10mg of a white solid with a yield of 56%. The resulting product ESI-MS M/z 292.3[ M + H ]]+。
Example 17
Figure BDA0002217910480000401
Intermediate 17-2 synthesis: the starting material 17-1 reference reports the synthesis (WO2013052523A 1). 17-1(3.5g, 8.75mmol) was dissolved in DMF (30mL), NaH (700mg, 17.5mmol, 60%) was added under ice-bath, stirred for 30min, and addedInto CH3I (2.4g, 16.9mmol), stirred at room temperature and monitored by TLC to completion. The reaction mixture was added with a saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and separated by column chromatography to give 3g of a colorless oil in 83% yield.
Intermediate 17-3 synthesis: intermediate 17-2(2.9g, 7mmol) was dissolved in ethyl acetate (20mL), iced, acetic anhydride (1.9mL) was added, and concentrated H was added dropwise2SO4(87. mu.L) in ethyl acetate (1mL) was reacted at room temperature, and TLC after 5h showed substantial disappearance of starting material. Adding saturated NaHCO into the reaction solution3The aqueous solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and separated by column chromatography to give 2.6g of a colorless oil with a yield of 78.3%.
Intermediate 17-4 synthesis: 2-amino-6-chloropurine (1.3g, 7.7mmol) was dissolved in acetonitrile (30mL), BSA (3.9g, 19.2mmol) was added, and the mixture was heated at 70 ℃ for 2 h. After cooling to room temperature, 17-3(2.2g, 4.8mmol) in acetonitrile (40mL) was added followed by TMSOTf (3.7g, 16.8mmol) dropwise, stirring was continued for 20min, heating was carried out at 60 ℃ and TLC showed completion after 5 h. Adding saturated NaHCO into the reaction solution3The aqueous solution was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried, concentrated, and separated by column chromatography to give 2.2g of a white foamy solid with a yield of 74.0%.
Intermediate 17-5 synthesis: intermediate 17-4(2g, 3.5mmol) was dissolved in 1, 4-dioxane (40mL) and then lithium hydroxide monohydrate (0.3g, 7.0mmol) in water (20mL) was added and after about 3h TLC indicated complete reaction of starting material. Adjusting pH of the reaction solution to 6-7 with dilute hydrochloric acid, concentrating the reaction solution to small volume, extracting with ethyl acetate, extracting water layer with ethyl acetate for 1 time, mixing organic phases, drying, concentrating, and separating by column chromatography to obtain 1.7g foamy solid with yield of 92.5%.
Intermediate 17-6 synthesis: 17-5(564mg, 1.07mmol) was dissolved in dichloromethane (15mL) and DMAP (784mg, 6.42mmol), pyridine (1.52g, 19.26mmol) and trifluoromethanesulfonic anhydride (906mg, 3.21mmol) were added sequentially under ice-bath and returned to room temperature after addition, after about 1h TLC indicated complete reaction of starting material. Dichloromethane was added, and the reaction solution was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated for the next reaction.
Intermediate 17-7 synthesis: the product of the previous step was dissolved in DMF (25mL) and tetrabutylammonium acetate (615mg, 2.04mmol) was added under ice bath and reacted overnight at room temperature with the next day TLC showing the starting material was essentially completely reacted. Adding the reaction solution into water, extracting with ethyl acetate, drying the organic layer, and concentrating for the next reaction.
Intermediate 17-8 synthesis: the product from the previous step was dissolved in 1, 4-dioxane (5mL) and lithium hydroxide monohydrate (13mg, 0.30mmol) in water (10mL) was added and after about 3h TLC indicated complete reaction of the starting material. Adjusting pH of the reaction solution to 6-7 with diluted hydrochloric acid, concentrating to small volume, extracting with ethyl acetate, washing water layer with ethyl acetate for 1 time, mixing ethyl acetate layers, drying, concentrating, and performing column chromatography to obtain white solid (47 mg).
Intermediate 17-9 Synthesis by adding 17-8(47mg, 0.09mmol) to dichloromethane (5mL), cooling to-78 deg.C, then adding BCl3After addition was complete, the mixture was stirred at this temperature for 1h, then warmed to-15 ℃ and stirred for 2h, TLC indicated complete reaction of the starting material. The reaction was cooled to-25 deg.C, mixed solution of methanol and dichloromethane (20mL, 1:1) was added, then ammonia was added at-5 deg.C to bring the pH of the reaction to 7-8, followed by stirring at 0 deg.C for 2h, the reaction was concentrated, and preparative plate separation gave a white solid (28 mg). The product obtained1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),6.93(s,2H),6.15(d,J＝5.9Hz,1H),5.57(d,J＝5.5Hz,1H),5.51(d,J＝5.1Hz,1H),5.07(t,J＝5.5Hz,1H),4.40–4.33(m,1H),4.27–4.20(m,1H),3.57–3.46(m,3H),3.38–3.32(m,4H)。
Synthesis of Compound 17: intermediate 17-9(20mg, 0.058mmol), palladium hydroxide (5mg) and triethylamine (18mg, 0.17mmol) were added to methanol (6mL), and hydrogen gas was introduced and the mixture was stirred at room temperature. The reaction was completed for about 10h, the solvent was evaporated after filtration, and the plate preparation was separated to give 12mg of a white solid with a yield of 66%. ESI-MS M/z 312.4[ M + H ]]+。
Example 18
Figure BDA0002217910480000421
Intermediate 188-2 synthesis: entecavir monohydrate (purchased from Borna chemical Co., Ltd., Taizhou) (295mg, 1.0mmol), triethylamine (1.01g, 10mmol), DMAP (24mg, 0.2mmol) were added to acetonitrile (10mL), followed by acetic anhydride (357.3mg, 3.5mmol), and stirred at room temperature. The reaction solution gradually became clear from turbidity, and insoluble substances were gradually separated out. After overnight reaction, filtration and washing with acetonitrile gave 320mg of a white solid in 88% yield. The product obtained1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),7.74(s,1H),6.43(s,2H),5.35(t,J＝9.6Hz,1H),5.26–5.12(m,2H),4.71–4.59(m,1H),4.35–4.16(m,2H),3.01–2.88(m,1H),2.69–2.56(m 1H),2.31–2.20(m 1H),2.07(s,3H),2.04(s,3H)。
Intermediate 18-3 synthesis: intermediate 18-2(180mg, 0.5mmol), benzyltriethylammonium chloride (228mg, 1.0mmol) were added to acetonitrile (10mL), and N, N-dimethylaniline (30mg, 0.25mmol) and phosphorus oxychloride (385mg, 2.5mmol) were sequentially added under ice bath, and after completion of addition, the reaction was heated at 70 ℃. About 1h, completely reacting, evaporating reaction liquid, and performing column chromatography separation to obtain 150mg of white solid with the yield of 79%. ESI-MS M/z 380.3[ M + H ]]+。
Intermediate 18-4 synthesis: intermediate 18-3(76mg, 0.2mmol) was added to an amine methanol solution (8mL), stirred at room temperature and reacted completely in about 5 h. The solvent was evaporated to dryness and column chromatography separated to give a white solid 40mg, yield 67%. ESI-MS M/z 296.3[ M + H ]]+。
Synthesis of Compound 18: intermediate 18-4(40mg, 0.14mmol) and zinc powder (0.16g) were added to aqueous ammonia (7mL), the reaction was heated at 55 deg.C and checked by TLC until the reaction was complete. The reaction solution was evaporated to dryness and separated by column chromatography to give 24mg of a white solid with a yield of 67%. The product obtained1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.07(s,1H),6.52(s,2H),5.51(t,J＝9.4Hz,1H),5.12(s,1H),4.93(d,J＝3.1Hz,1H),4.88(t,J＝5.4Hz,1H),4.55(s,1H),4.29–4.23(m,1H),3.62–3.52(m,2H),2.60-2.53(m,1H),2.38–2.23(m,1H),2.13–2.02(m,1H)。ESI-MS m/z:262.3[M+H]+。
Example 19
Figure BDA0002217910480000431
Intermediate 19-2 synthesis: intermediate 19-1(200mg, 0.54mmol) (purchased from Shanghai Ruita pharmaceutical science, Ltd.) was dissolved in diethyl ether (10mL) under nitrogen and Et added under ice bath2Zn/cyclohexane solution (1.62mL, 1.0M) and CH2I2(608mg, 3.24mmol) was stirred at room temperature for 30min, and then the reaction was refluxed. After about 6h, TLC showed the starting material reaction was complete. Cooling to room temperature, adding saturated ammonium chloride aqueous solution, extracting with diethyl ether twice, washing the organic phase with saturated saline solution, drying with anhydrous sodium sulfate, and separating by column chromatography to obtain 180mg of waxy white solid with yield of 80%. The product obtained1H NMR(400MHz,CDCl3):δ4.35-4.28(m,1H),3.50-3.45(m,1H),3.42(dd,J＝10.3,5.8Hz,1H),3.26(dd,J＝10.3,7.5Hz,1H),2.48(br,1H),2.14-2.02(m,2H),1.84(dd,J＝13.6,1.8Hz,1H),1.02-0.94(m,1H),0.89(s,9H),0.88(s,9H),0.77-0.68(m,1H),0.55–0.45(m,1H),0.43-0.35(m,1H),0.09(m,3H),0.08(m,3H),0.02(s,6H)。
Intermediate 19-3 synthesis: intermediate 19-2(108mg, 0.28mmol), PPh3(210mg, 0.8mmol) and 6-chloro-2-aminopurine (50mg, 0.29mmol) were added to anhydrous THF (5mL), followed by slow addition of DIAD (160mg, 0.8mmol) under ice-cooling, warming to room temperature, stirring for 4h, concentration of the reaction mixture, and purification by column chromatography to give 20mg of a white solid.
Intermediate 19-4 synthesis: intermediate 19-3(65mg,0.12mmol) was dissolved in THF (5mL), TBAF in THF (0.24mL, 0.24mmol, 1M) was added and after stirring at room temperature for about 3h, TLC showed the disappearance of the starting material. The reaction solution was concentrated and separated by column chromatography to obtain 30mg of a white solid with a yield of about 80%. The product obtained1H NMR(400MHz,CD3OD):δ8.41(s,1H),4.49(q,J＝5.8Hz,1H),3.73(dd,J＝11.2,4.5Hz,1H),3.61(dd,J＝11.2,4.8Hz,1H),2.53–2.46(m,1H),2.33–2.26(m,1H),1.96(q,J＝5.0Hz,1H),0.94–0.85(m,2H),0.80–0.73(m,1H),0.05–-0.04(m,1H).13C NMR(125MHz,CD3OD):δ161.4,155.2,151.4,144.3,124.7,73.9,61.6,61.2,55.5,41.6,26.6,16.8,8.7。ESI+-MS m/z:310.7[M+1]。
Compound 19 synthesis: intermediate 19-4(20mg, 0.065mmol), palladium hydroxide (5mg) and triethylamine (20mg,0.2mmol) were added to methanol (6mL), and hydrogen gas was introduced and the mixture was stirred at room temperature. The reaction was completed in about 10h, the solvent was evaporated after filtration, and the plate was prepared for separation to give 13mg of a white solid with a yield of 73%. ESI-MS M/z 276.3[ M + H ]]+。
Example 20
Figure BDA0002217910480000441
Intermediate 20-1 synthesis: intermediate 19-1(372mg, 1.0mmol) was added to anhydrous THF (2mL), borane THF solution (2.5mL, 2.5mmol, 1M) was added, and rt was stirred overnight. Adding NaOH (120mg) water solution (1mL) and hydrogen peroxide (30%, 1.0mL), extracting with ethyl acetate after 1h, drying the organic phase, concentrating, and separating by column chromatography to obtain 20-1a (135mg, small polar product) and 20-1b (200mg, large polar product), with a yield of 84%. The product 20-1a is obtained1H NMR(400MHz,CDCl3) δ 4.38-4.28 (m,1H), 4.21-4.14 (m,1H), 3.91-3.80 (m,2H),3.51(d, J ═ 6.1Hz,2H),3.24(d, J ═ 9.8Hz,1H),2.98(t, J ═ 6.0Hz,1H), 2.14-2.03 (m,1H),1.91-1.77(m,3H),0.89(s,9H),0.88(s,9H),0.11-0.06(m,6H),0.05(s, 6H). The resulting product 20-1b1H NMR(400MHz,CDCl3):δ4.08–3.95(m,2H),3.80–3.61(m,4H),3.22(t,J＝6.2Hz,1H),2.40–2.16(m,3H),2.14–2.04(m,1H),0.90(s,9H),0.88(s,9H),0.11-0.02(m,12H)。
Intermediate 20-2 synthesis: intermediate 20-1(135mg, 0.34mmoL) was added to pyridine (1mL), MMTrCl (209mg, 0.068mmoL) was added, and the reaction was complete in about 2 h. The reaction solution was concentrated and separated by column chromatography to obtain 210mg of a foamy solid with a yield of 90%.
Intermediate 20-3 synthesis: intermediate 20-2(210mg, 0.32mmol), 2-amino-6-chloropurine (94.3mg, 0.56mmol) and PPh3(168mg, 0.64mmol) was added to anhydrous THF (2mL), DIAD (129mg, 0.64mmol) was slowly added, and after 3h reaction at room temperatureAnd performing column chromatography separation to obtain 240mg of white solid.
Intermediate 20-4 synthesis: intermediate 20-3(240mg, 0.3mmol) was added to THF (2mL), TBAF in THF (0.9mL, 1M) was added, and rt reacted overnight. Evaporating to remove solvent, adding water to precipitate insoluble substances, adding filtered solid into water (2mL), stirring at room temperature for 2 hr, filtering, and oven drying to obtain white solid. The resulting product ESI-MS M/z 586.2[ M + H ]]+。
Synthesis of Compound 20: intermediate 20-4(100mg, 0.17mmol) was added to 80% aqueous acetic acid (10mL) and stirred at room temperature overnight. The solvent was evaporated and purified by column chromatography to give 50mg of a white solid. The solid was added to methanol (10mL), palladium hydroxide (10mg) and triethylamine (48mg, 0.47mmol) were added, hydrogen gas was introduced, and the mixture was stirred at room temperature. After overnight the reaction was complete, the solvent was evaporated to dryness after filtration and plate separation to give 29mg of a white solid. The resulting product ESI-MS M/z 280.3[ M + H ]]+。
Example 21
Figure BDA0002217910480000451
Intermediate 21-1 synthesis: intermediate 19-1(400mg, 1.7mmol) was dissolved in methanol (10mL), platinum dioxide (10mg) was added, and the reaction was allowed to proceed overnight at room temperature with hydrogen gas. The reaction solution was filtered, and the filtrate was concentrated and separated by column chromatography to give a pair of diastereoisomers 21-a (170mg, small in polarity) and 21-b (170mg, large in polarity). The resulting product 21-1a1H NMR(400MHz,CDCl3) δ 4.26 to 4.19(m,1H),4.08 to 3.98(m,1H),3.66(dd, J ═ 10.1,4.4Hz,1H),3.42(dd, J ═ 10.1,6.1Hz,1H),1.84 to 1.73(m,2H),1.72 to 1.52(m,2H),1.14(d, J ═ 6.9Hz,3H),0.91(s,9H),0.90(s,9H),0.08(s,6H),0.07 to 0.04(m, 6H). . The resulting product 21-1b1H NMR(400MHz,CDCl3):δ4.23-4.15(m,1H),3.86-3.75(m,1H),3.63(dd,J＝10.2,5.6Hz,1H),3.51(dd,J＝10.2,6.0Hz,1H),2.35–2.06(m,4H),0.99(d,J＝7.3Hz,3H),0.91(s,9H),0.90(s,9H),0.09–0.03(m,12H)。
Intermediate 21-2 synthesis: intermediate 21-1(68mg, 0.18mmol), 2-amino-6-chloropurine (47mg, 0.28mmol), PPh3(98mg, 0.37mmol) was added to dry THF (10mL), DIAD (75mg, 0.37mmol) was added dropwise, the reaction was allowed to proceed at room temperature, monitored by TLC, and the starting material disappeared after 3 h. The solvent was evaporated and column chromatography gave 70mg of oil in 74% yield.
Intermediate 21-3 synthesis: intermediate 21-2(64mg, 0.12mmol) was added to THF (2mL), TBAF in THF (0.36mL, 1M) was added, and rt reacted overnight. The solvent was evaporated and column chromatography separated to give 28mg of a white solid with a yield of 80%.
Synthesis of Compound 21: intermediate 21-3(28mg, 0.09mmol) was added to methanol (5mL), palladium hydroxide (8mg) and triethylamine (28mg, 0.28mmol) were added, hydrogen gas was introduced, and the mixture was stirred at room temperature. After overnight the reaction was complete, the solvent was evaporated to dryness after filtration and plate separation to give 15mg of a white solid. ESI-MS M/z 264.2[ M + H ]]+。
Example 22
Figure BDA0002217910480000461
Intermediate 22-1 synthesis: intermediate 20-1(150mg, 0.38mmol), TEMPO (0.5mg) and a saturated sodium bicarbonate solution (0.5mL) containing potassium bromide (3.6 mg)/tetrabutylammonium bromide (4.9mg) were added to dichloromethane (6mL), and a sodium hypochlorite (0.38mL) solution and a saturated sodium bicarbonate solution (0.35mL) were added in that order under ice bath to continue the reaction for 1 h. Dichloromethane and water were added, the organic phase was separated, dried and concentrated, and the next reaction was carried out without purification.
Intermediate 22-2 synthesis: methyltriphenylphosphine bromide (236mg, 0.66mmol) was added to anhydrous tetrahydrofuran (10mL) and a solution of n-butyllithium (0.22mL, 0.55mmol, 2.5M) was added at-78 deg.C and stirred while warming to ice. After 30min, adding the tetrahydrofuran solution of the aldehyde in the last step, and then stirring at room temperature for about 3h to complete the reaction. Adding saturated solution of ammonium chloride, extracting with ethyl acetate, drying, concentrating, and purifying by column chromatography to obtain 40mg oily substance.
Intermediate 22-3 synthesis: intermediate 22-2(40mg, 0.10mmol), 2-amino-6-chloropurine (34mg, 0.20mmol), PPh3(52.5mg, 0.20mmol) was added to dry THF (8mL)DIAD (44.5mg, 0.22mmol) was added dropwise, the reaction was carried out at room temperature, monitored by TLC, and the starting material disappeared after 2 h. The solvent was distilled off, and column chromatography separation was carried out to obtain 36mg of a foamy solid in a yield of 67%.
Intermediate 22-4 synthesis: intermediate 22-2(36mg, 0.067mmol) was added to THF (2mL), TBAF in THF (0.20mL, 1M) was added, and rt reacted overnight. The solvent was evaporated and column chromatography separated to give 17mg of a white solid in 81% yield.
Synthesis of Compound 22: the product 22-4(17mg, 0.055mmol) obtained in the above step was added to ethanol (3mL), and hydrazine hydrate (17.1mg, 0.29mmol, 85%) was added, followed by reaction at 40 ℃ overnight. The solvent was evaporated to dryness, methanolic solution (8mL) containing NaOMe (0.5mmol) was added and the reaction was heated at reflux for about 8h and TLC showed completion. Cooling the reaction liquid to room temperature, adding acetic acid, and adjusting the pH value of the reaction liquid to 7-8. The reaction was concentrated and isolated on preparative plates to give a white solid (8 mg). The resulting product ESI-MS M/z 276.2[ M + H ]]+。
Example 23
Figure BDA0002217910480000471
Intermediate 23-2 synthesis: intermediate 23-1(164.6mg, 0.2mmol) (purchased from Shangham bright Biotech Co., Ltd.) was added to anhydrous THF (10mL), NaH (12mg,0.3mmol, 60%) was added under ice bath, and after 10min, methyl iodide (57mg, 0.4mmol) was added and TLC checked until the reaction was complete. Adding saturated ammonium chloride aqueous solution, extracting with ethyl acetate, drying, and concentrating to obtain oily substance.
Intermediate 23-3 synthesis: the oil obtained in the above step was added to acetonitrile (10mL), 2M hydrochloric acid solution (2mL) was added, stirred at 45 ℃ and checked by TLC until the reaction was complete. Adding water, extracting with ethyl acetate, drying the organic phase, concentrating, and purifying by column chromatography to obtain 62mg of white solid with the yield of 65%.
Intermediate 23-4 synthesis: adding intermediate 23-3(62mg, 0.13mmol), benzyltriethylammonium chloride (59mg, 0.26mmol) to acetonitrile (5mL), adding N, N-dimethylaniline (8.5mg, 0.07mmol) and phosphorus oxychloride (100mg, 0.65mmol) in sequence under ice bath, and heating at 70 deg.C to reactShould be used. About 1h, completely reacting, evaporating reaction liquid, and performing column chromatography separation to obtain 44mg of white solid with the yield of 68%. The resulting product ESI-MS M/z 494.3[ M + H ]]+。
Intermediate 23-5 synthesis: intermediate 23-3(44mg, 0.089mmol) was added to dichloromethane (5mL), cooled to-78 deg.C, and BCl was added3After addition of dichloromethane solution (0.9mL,0.9mmol, 1M), the temperature was raised to-20 ℃ and stirring was continued until TLC indicated complete reaction of the starting material. Isopropanol (0.5mL) was added to the reaction solution, the reaction solution was concentrated, and separation was performed on a preparative plate to obtain 20mg of a white solid with a yield of 70%.
Compound 23 synthesis: intermediate 23-5(20mg, 0.064mmol) was added to methanol (5mL), palladium on carbon (8mg) and triethylamine (19.2mg, 0.19mmol) were added, hydrogen gas was introduced, and the mixture was stirred at room temperature. After overnight the reaction was complete, the solvent was evaporated to dryness after filtration and plate separation to give 12mg of a white solid. ESI-MS M/z 280.3[ M + H ]]+。
The compounds of the invention were evaluated in standard pharmacological test protocols.
The following are pharmacological tests and results of the compounds of the present invention.
In vitro anti-HBV activity
HepG2.2.15 cells were used to evaluate the in vitro anti-HBV activity of the compounds. HepG2.2.15 cells were seeded in a 96-well plate, and after one day of incubation, the test compound was added, and after five days, a new compound-containing culture solution was replaced, cultured for three days, and the supernatant was collected. Extracting DNA in the supernatant, and detecting the content of HBV DNA in the supernatant by using quantitative PCR. The percentage of inhibition of HBV DNA by the compound was calculated and the half-Effective Concentration (EC) of the compound was calculated using GraphPad Prism software50) And simultaneously determining half the toxic concentration (CC) of the compound on the test cells50)。
Figure BDA0002217910480000481
Figure BDA0002217910480000491
Figure BDA0002217910480000501
A represents 0.5nM<EC50<10 nM; b represents 10nM<EC50<100 nM; c represents 100nM<EC50
The results show that the compound of the invention has obvious inhibition effect on hepatitis B virus replication in vitro. The compound can be used for preparing medicaments for preventing and treating infectious diseases caused by hepatitis B virus.

Claims (9)

1. A compound represented by the following general formula (I), pharmaceutically acceptable salts, crystalline hydrates and solvates thereof:
Figure FDA0002217910470000011
wherein:
a is O, -C ═ CH2or-CX1X2，
When A is O, R1Is selected from C1-6Alkyl, halo C1-6Alkyl, azido C1-6Alkyl, cyano C1-6Alkyl, hydroxy C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl, halo C2-6Alkenyl radical, C2-6Alkynyl, halo C2-6Alkynyl, C3-6Cycloalkyl radical C2-6Alkynyl, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C1-3Alkyl radical C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl, azido, cyano, halogen, -CHR4CH(CH2CH2)；
R2Selected from hydroxyl, fluorine;
R3selected from hydrogen, amino, halogen, R5OCONH-；
Y1Selected from hydrogen,
Figure FDA0002217910470000012
Y2Selected from hydrogen,
Figure FDA0002217910470000013
Figure FDA0002217910470000014
Or Y1And Y2Are connected with each other to form
Figure FDA0002217910470000015
R4Selected from hydroxy, halogen, cyano, azide;
R5is selected from C1-18Alkyl radical, C3-6Cycloalkyl, aryl, heteroaryl;
R6is selected from C1-18Alkyl radical, C3-6A cycloalkyl group;
R7is selected from C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-20Aryl radical, C5-20A heteroaryl group;
R8is selected from C1-6Alkyl radical, C3-6Cycloalkyl radical, C6-20Aryl radical, C5-20A heteroaryl group;
R9is selected from C1-18Alkyl radical, C3-6Cycloalkyl radical, C6-20Aryl radical, C5-20A heteroaryl group;
when A is-C ═ CH2When R is1Selected from hydrogen, hydroxy, amino, C1-6Alkylamino radical, C1-6Alkylamide group, C3-6Cycloalkyl amide group, C6-20Aryl amide group, C1-6Alkyl, halo C1-6Alkyl, azido C1-6Alkyl, cyano C1-6Alkyl, hydroxy C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl, halo C2-6Alkenyl radical, C2-6Alkynyl, halo C2-6Alkynyl, C3-6Cycloalkyl radical C2-6Alkynyl radical、C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C1-3Alkyl radical C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl, azido, cyano, halogen, -CHR4CH(CH2CH2)；
R2Selected from hydrogen, hydroxy, fluorine;
R3、Y1、Y2、R4、R5、R6、R7、R8、R9the definition is the same as that when A is O;
when A is CX1X2When, X1And X2Each independently selected from hydrogen, hydroxy, halogen, azido, amino, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Alkylcarboxamide radical, C2-6Cycloalkyl carboxamido radical, C6-20Aryl carboxamido radical, C5-20Heteroaryl carboxamido, azido C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, and X1And X2Not being simultaneously hydrogen, or X1And X2Are linked to each other to form- (CH)2)n-, or halogen substituted- (CH)2)n-, wherein n is an integer of 2 to 5, thereby comprising a 5-membered ring of A and X1And X2Together form a spiro ring;
R1selected from hydrogen, C1-6Alkyl, halo C1-6Alkyl, azido C1-6Alkyl, cyano C1-6Alkyl, hydroxy C1-6Alkyl, methoxy C1-6Alkyl radical, C2-6Alkenyl, halo C2-6Alkenyl radical, C2-6Alkynyl, halo C2-6Alkynyl, C3-6Cycloalkyl radical C2-6Alkynyl, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C1-3Alkyl radical C3-6Cycloalkyl radical, C3-6Cycloalkyl radical C1-3Alkyl, azido, cyano, halogen, -CHR4CH(CH2CH2)；
R2Selected from hydrogen, hydroxy, fluorine;
R3、Y1、Y2、R4、R5、R6、R7、R8、R9the definition is the same as that when A is O.
2. The compound of claim 1, wherein,
when A is O, R1Selected from the group consisting of methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxymethyl, methoxyethyl, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, vinyl, 2-fluorovinyl, 2, 2-difluorovinyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-fluoroethynyl, 2-methylethynyl, 2-cyclopropylethynyl, vinylmethyl, 3-fluorovinylmethyl, 3-difluorovinylmethyl, trifluoromethyl, and mixtures thereof, Ethynylmethyl, cyclopropyl, 2-difluorocyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, 1-cyclopropyl-1-hydroxymethyl, 1-cyclopropyl-1-fluoromethyl, azido, fluoro, cyano;
R2selected from hydroxyl, fluorine;
R3selected from hydrogen, amino, halogen;
Y1selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure FDA0002217910470000031
Y2Selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure FDA0002217910470000032
Figure FDA0002217910470000033
Or Y1And Y2Are connected with each other to form
Figure FDA0002217910470000034
R7Is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R8is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R9is selected from C2-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl radical, C5-10A heteroaryl group;
when A is-C ═ CH2When R is1Selected from the group consisting of hydrogen, hydroxy, fluoro, azido, amino, methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxymethyl, methoxyethyl, methylamino, acetylamino, cyclopropylamino, benzamido, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, vinyl, 2-fluorovinyl, 2, 2-difluorovinyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-fluoroethynyl, 2-methylethynyl, 2-cyclopropylethynyl, methyl, fluoromethylethynyl, methyl, trifluoromethyl, methyl, 2-azido, 2-methyl, 2-cyanoethyl, vinylmethyl, 3-fluorovinylmethyl, 3-difluorovinylmethyl, ethynylmethyl, cyclopropyl, 2-difluorocyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, 1-cyclopropyl-1-hydroxymethyl, 1-cyclopropyl-1-fluoromethyl, azido, fluoro, cyano;
R2selected from hydrogen, hydroxy, fluorine;
R3selected from hydrogen, amino, halogen;
Y1selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure FDA0002217910470000035
Y2Selected from hydrogen, acetyl,Propionyl group, isobutyryl group, pivaloyl group, b,
Figure FDA0002217910470000041
Figure FDA0002217910470000042
Or Y1And Y2Are connected with each other to form
Figure FDA0002217910470000043
R7Is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R8is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R9is selected from C2-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl radical, C5-10A heteroaryl group;
when A is CX1X2When, X1And X2Each independently selected from hydrogen, hydroxy, fluoro, azido, amino, methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 2,2, 2-trifluoroethyl, methoxy, ethoxy, methylamino, acetylamino, cyclopropylamino, benzamido, azidomethyl, 2-azidoethyl, 1-azidoethyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, cyanomethyl, 2-cyanoethyl, 1-cyanoethyl, methoxymethyl, methoxyethyl, vinyl, 1-methylvinyl, 2, 2-dimethylvinyl, ethynyl, 2-methylethynyl, but not both simultaneously hydrogen, or X1And X2Are linked to each other to form-CH2CH2-，-CF2CH2-or-CH2CH2CH2-, thereby containing the 5-membered ring of A and X1And X2Together form a spiro ring;
R1selected from hydrogen, hydroxy, fluoro, azido, amino, methyl, ethyl, isopropyl, chloromethyl, fluoromethyl, difluoromethylA group, trifluoromethyl group, 2-fluoroethyl group, 1-fluoroethyl group, 2, 2-difluoroethyl group, 2,2, 2-trifluoroethyl group, methoxymethyl group, methoxyethyl group, methylamino group, acetylamino group, cyclopropylamino group, benzamido group, azidomethyl group, 2-azidoethyl group, 1-azidoethyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, cyanomethyl group, 2-cyanoethyl group, 1-cyanoethyl group, vinyl group, 2-fluorovinyl group, 2, 2-difluorovinyl group, 1-methylvinyl group, 2, 2-dimethylvinyl group, ethynyl group, 2-fluoroethynyl group, 2-methylethynyl group, 2-cyclopropylethynyl group, vinylmethyl group, 3-fluorovinylmethyl group, 3-difluorovinylmethyl group, alkynylmethyl, cyclopropyl, 2-difluorocyclopropyl, 1-methylcyclopropyl, cyclopropylmethyl, 1-cyclopropyl-1-hydroxymethyl, 1-cyclopropyl-1-fluoromethyl, azido, fluoro, cyano;
R2selected from hydrogen, hydroxy, fluorine;
R3selected from hydrogen, amino, halogen;
Y1selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure FDA0002217910470000051
Y2Selected from the group consisting of hydrogen, acetyl, propionyl, isobutyryl, pivaloyl, and the like,
Figure FDA0002217910470000052
Figure FDA0002217910470000053
Or Y1And Y2Are connected with each other to form
Figure FDA0002217910470000054
R7Is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R8is selected from C6-10Aryl radical, C5-10A heteroaryl group;
R9is selected from C2-6Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl radical, C5-10A heteroaryl group.
3. The compound according to claim 1 or 2, wherein,
a is O.
4. The compound according to claim 1 or 2, wherein,
a is-C ═ CH2。
5. The compound according to claim 1 or 2, wherein,
a is-CX1X2。
6. The compound of claim 1, wherein the compound of formula I has the structure:
Figure FDA0002217910470000055
Figure FDA0002217910470000061
Figure FDA0002217910470000071
Figure FDA0002217910470000081
Figure FDA0002217910470000091
Figure FDA0002217910470000101
Figure FDA0002217910470000111
Figure FDA0002217910470000121
Figure FDA0002217910470000131
Figure FDA0002217910470000141
Figure FDA0002217910470000151
7. a pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound of general formula (I), pharmaceutically acceptable inorganic or organic salts, crystalline hydrates and solvates thereof as claimed in any one of claims 1 to 6, optionally together with a pharmaceutically acceptable carrier or excipient.
8. Use of a compound of general formula (I) as defined in any one of claims 1 to 6, and pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, or a pharmaceutical composition as defined in claim 7 for the preparation of a medicament against viruses.
9. The use according to claim 8, wherein,
the virus is hepatitis B virus, human immunodeficiency virus, and influenza virus.
CN201910922150.0A 2019-09-27 2019-09-27 Purine nucleoside compound and application thereof Pending CN112574269A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910922150.0A CN112574269A (en) 2019-09-27 2019-09-27 Purine nucleoside compound and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910922150.0A CN112574269A (en) 2019-09-27 2019-09-27 Purine nucleoside compound and application thereof

Publications (1)

Publication Number Publication Date
CN112574269A true CN112574269A (en) 2021-03-30

Family

ID=75109656

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910922150.0A Pending CN112574269A (en) 2019-09-27 2019-09-27 Purine nucleoside compound and application thereof

Country Status (1)

Country Link
CN (1) CN112574269A (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114796229A (en) * 2022-05-11 2022-07-29 中国科学院大学 Application of 6-Thioinosine in inhibition of ZIKV replication
WO2022198195A1 (en) * 2021-03-16 2022-09-22 The Scripps Research Institute Anitiviral prodrugs of entecavir (etv) and formulations thereof
CN116462728A (en) * 2021-12-15 2023-07-21 南京知和医药科技有限公司 Novel purine nucleoside derivative for resisting virus infection, pharmaceutical composition and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006007A1 (en) * 2001-09-28 2004-01-08 Gilles Gosselin Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
WO2018181102A1 (en) * 2017-03-29 2018-10-04 ヤマサ醤油株式会社 Nucleoside derivative or salt thereof, and pharmaceutical composition containing same
US20190185510A1 (en) * 2017-12-20 2019-06-20 Institute Of Organic Chemistry And Biochemistry Ascr,V.V.I. 2'3' cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2019133712A1 (en) * 2017-12-27 2019-07-04 Schinazi Raymond F Combined modalities for nucleosides and/or nadph oxidase (nox) inhibitors as myeloid-specific antiviral agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040006007A1 (en) * 2001-09-28 2004-01-08 Gilles Gosselin Methods and compositions for treating hepatitis C virus using 4'-modified nucleosides
WO2018181102A1 (en) * 2017-03-29 2018-10-04 ヤマサ醤油株式会社 Nucleoside derivative or salt thereof, and pharmaceutical composition containing same
US20190185510A1 (en) * 2017-12-20 2019-06-20 Institute Of Organic Chemistry And Biochemistry Ascr,V.V.I. 2'3' cyclic dinucleotides with phosphonate bond activating the sting adaptor protein
WO2019133712A1 (en) * 2017-12-27 2019-07-04 Schinazi Raymond F Combined modalities for nucleosides and/or nadph oxidase (nox) inhibitors as myeloid-specific antiviral agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TIANWEI MA等: "《Synthesis and Anti-Hepatitis B Virus Activity of 9-(2-Deoxy-2-fluoro-β-L-arabinofuranosyl)purine Nucleosides》", 《JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022198195A1 (en) * 2021-03-16 2022-09-22 The Scripps Research Institute Anitiviral prodrugs of entecavir (etv) and formulations thereof
CN116462728A (en) * 2021-12-15 2023-07-21 南京知和医药科技有限公司 Novel purine nucleoside derivative for resisting virus infection, pharmaceutical composition and application thereof
CN116462728B (en) * 2021-12-15 2023-12-12 南京知和医药科技有限公司 Purine nucleoside derivative for resisting virus infection, pharmaceutical composition and application thereof
CN114796229A (en) * 2022-05-11 2022-07-29 中国科学院大学 Application of 6-Thioinosine in inhibition of ZIKV replication

Similar Documents

Publication Publication Date Title
CN110177785B (en) Dihydroisoquinoline compound
TWI518085B (en) Prodrug of substituted polycyclic carbamoyl pyridone derivative
WO2021023154A1 (en) Tetracyclic compound, preparation method therefor and use thereof
CN112574269A (en) Purine nucleoside compound and application thereof
WO2018019297A1 (en) Isoquinolinone compound and use thereof in preparation of antiviral drugs
CN111051281A (en) Compounds, compositions and methods for synthesis
CN106543253B (en) Anti-viral nucleoside phosphoramidate and its pharmaceutical composition and purposes
JP2019516714A (en) Novel pyrazine compounds with oxygen, sulfur and nitrogen linkers for the treatment of infections
WO2015124063A1 (en) Hepatitis c virus inhibitors and uses thereof in preparation of drugs
WO2012031539A1 (en) Nucleoside derivatives, synthesis methods and uses thereof for preparing anti-tumor and anti-virus medicaments
CN102199181A (en) Preparation of alkyl-substituted 2-deoxy-2-fluoro-D-ribofuranosyl pyrimidines and purines and their derivatives
KR0144865B1 (en) New 2&#39;-halomethylidene, 2&#39;-ethenylidene and 2&#39;ethynyl cytidine, uridine and guanosine derivatives
CN110642874B (en) Cell necrosis inhibitor and preparation method and application thereof
CN106883279B (en) A kind of prodrug, preparation method, medical composition and its use
CN111032644B (en) Diarylthiohydantoin compounds useful as androgen receptor antagonists
CN108473477A (en) The pyrimidine of aryl substitution for being used in influenza infection
CN114375293A (en) Isoquinoline compounds and preparation method and application thereof
KR102502749B1 (en) Liver Delivery Entecavir Prodrug Nucleotide Cyclophosphate Compounds and Applications
WO2013107428A1 (en) 7-substituted hanfangichin b derivative, and preparation method and use thereof
CN113045569B (en) Compounds useful as RET kinase inhibitors and uses thereof
CN108350007B (en) Substituted adenine compound and pharmaceutical composition thereof
JPH02160769A (en) Novel 2&#39;-halomethylidene, 2&#39;-ethenylidene and
CN102286048A (en) 4-amino-6-(3-(3-bromophenyl) phenyl-5-cyano-7-(beta-L-xylofuranose) pyrrolo [2,3-d] pyrimidine, like derivatives and application for preparing antitumor drugs
CN115947758A (en) Nucleotide derivative and pharmaceutical composition and application thereof
CN110088098B (en) Quinazolinone PARP-1 inhibitor and preparation method, pharmaceutical composition and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination