CN109748910B - Quinazolinone compound, preparation method and medical application thereof - Google Patents
Quinazolinone compound, preparation method and medical application thereof Download PDFInfo
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Abstract
The invention relates to a quinazolinone compound, a preparation method and medical application thereof, belonging to the field of pharmaceutical chemistry and pharmacotherapeutics. The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof can be applied to the preparation of anti-HBV medicines.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, in particular to quinazolinone compounds. The compounds can be used for preparing medicines with anti-Hepatitis B Virus (HBV) effect. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Hepatitis B is an infectious disease caused by Hepatitis B Virus (HBV) and transmitted through blood and body fluids in a chronic carrier state. HBV infection has become one of the major diseases endangering human health, and there are currently more than 3.5 million HBV infected people worldwide, of which about 75% are distributed in Asia Pacific region. The prognosis of chronic hepatitis B is poor, and can be developed into cirrhosis and primary liver cancer, and about 70 million people die from related diseases of HBV infection every year. Currently, anti-HBV drugs used in clinical applications mainly include immunomodulators and HBV DNA polymerase/reverse transcriptase inhibitors.
The immunomodulator mainly comprises interferon-alpha (INF-alpha) and pegylated interferon-alpha (pegylated interferon-alpha). The acting sites of the HBV DNA are HBV DNA, and the HBV DNA can be combined with a cell membrane specific receptor to generate specific antiviral protein, so that endonuclease is activated, mRNA and RNA of the virus are degraded, and the growth and the propagation of the virus are inhibited. Meanwhile, the interferon can also improve the immunity of a human body and reduce the incidence rate of liver cirrhosis and liver cancer related to HBV infection. The interferon is expensive, cannot be taken through gastrointestinal tracts, is inconvenient to use and is easy to generate side effects after being taken for a long time, so that the clinical application of the interferon is limited.
The chemical structure of nucleoside drugs is based on nucleosides, and is a series of nucleoside analogs generated by structural changes of bases or pentose rings, such as lamivudine (lamivudine), adefovir dipivoxil (adefovir dipivoxil), entecavir (entecavir), telbivudine (telbivudine), tenofovir (tenofovir), and the like. Nucleoside drugs mainly inhibit replication of HBV DNA, phosphorylate nucleosides to form nucleoside triphosphates by Thymidine Kinase (TK) produced by viruses, thereby inhibiting activity of viral DNA polymerase/reverse transcriptase, competitively incorporating deoxycytidine into viral DNA chains, terminating elongation and synthesis of DNA chains, and inhibiting replication of viruses to exert antiviral effect. However, inhibition of HBV DNA polymerase/reverse transcriptase only affects cccDNA circulation, and cccDNA cannot be completely cleared, so that relapse is easy to occur after drug withdrawal, which is also a bottleneck problem faced by nucleoside analogue to resist HBV. In addition, the replication process of HBV includes an intermediate link of reverse transcription, and reverse transcriptase does not have the function of correction and repair, so that HBV is easy to mutate in the replication process to cause drug resistance. Because the nucleoside analogue inhibits HBV replication by inhibiting HBV DNA polymerase/reverse transcriptase, the gene mutation of HBV DNA polymerase segment is more easily induced under the action of the drugs, and drug-resistant variant strains are formed, so that the disease is repeatedly even aggravated.
In summary, although there are many anti-HBV drugs in clinical practice, the existing drugs still cannot meet the requirements of treatment due to the complexity of the etiology of hepatitis b, the "bounce" caused by the inability of the drugs to completely eliminate viruses, the drug resistance of viruses, the toxic and side effects of the drugs, and other factors.
Disclosure of Invention
The invention aims to provide quinazolinone compounds based on the prior art, which have good anti-HBV activity, can effectively inhibit the replication of HBV DNA, and has stronger inhibiting effect on lamivudine and entecavir resistant HepG2A64 cells.
Another object of the present invention is to provide a process for the preparation of the above compound.
The third object of the present invention is to provide a pharmaceutical use of the above compound.
The technical scheme of the invention is as follows:
a compound, isomer, or pharmaceutically acceptable salt thereof, represented by formula I,
wherein the content of the first and second substances,
R1represents halogen, hydroxy, cyano, nitro, carboxy, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino alkoxy or C1-C6An ester group;
R2represents thiophene, furan, pyrrole, pyridine, benzene, pyran, thiazole, cyclopropane, cyclobutane, cyclopentane, cyclohexane, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino alkoxy or C1-C6An ester group;
R3represents hydrogen, halogen, hydroxyl, nitro, carboxyl, cyano, amino, C1-C6Acyl radical, C1-C6Alkyl radical, C1-C4Haloalkyl, C1-C6Alkoxy radical, C1-C6Alkylamino alkoxy or C1-C6An ester group;
n represents an integer of 1 to 3;
x represents S or CH2。
In a preferred embodiment, R1RepresentsHalogen, hydroxy, cyano, nitro, carboxy, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino alkoxy or C1-C4An ester group.
In a preferred embodiment, R1Represents fluorine, bromine, chlorine, iodine, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, methoxy, ethoxy, dimethylaminoethoxy, diethylaminoethoxy or diethylaminopropoxy.
In a more preferred embodiment, R1Represents fluorine, bromine, chlorine, iodine, hydroxyl, methyl, dimethylaminoethoxy or diethylaminoethoxy.
A compound, isomer, or pharmaceutically acceptable salt thereof of formula I, wherein, R2Represents thiophene, furan, pyridine, benzene, pyran, thiazole, cyclopentane or cyclohexane. Further, R2Represents thiophene, furan, pyridine, benzene, cyclopentane or cyclohexane.
In a preferred embodiment, R3Represents hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, carboxyl, cyano, amino, acetyl, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Alkylamino alkoxy or C1-C4An ester group.
In a preferred embodiment, R3Represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, methyl, acetyl, methoxy or ethoxy.
In a more preferred embodiment, R3Represents hydrogen, acetyl, methyl, methoxy or ethoxy.
A compound, isomer or pharmaceutically acceptable salt thereof shown in formula I, wherein n represents 1,2 or 3, preferably, n represents 1 or 2.
Further, the compound of formula I is selected from the following compounds:
2- ((5-acetyl-2-methoxybenzyl) thio) -6-fluoro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)1)；
2- ((5-acetyl)-2-methoxybenzyl) thio) -6-chloro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)2)；
2- ((5-acetyl-2-methoxybenzyl) thio) -6-bromo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)3)；
2- ((5-acetyl-2-methoxybenzyl) thio) -6-iodo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)4)；
2- ((5-acetyl-2-methoxybenzyl) thio) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)5)；
2- ((5-acetyl-2-methoxybenzyl) thio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)6)；
2- ((5-acetyl-2-methoxybenzyl) thio) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)7)；
2- ((5-acetyl-2-methoxybenzyl) thio) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)8)；
6-fluoro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)9)；
6-chloro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)10)；
6-bromo-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)11)；
6-iodo-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)12)；
2- ((2-methoxybenzyl) thio) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)13)；
6-hydroxy-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)14)；
6- (2- (dimethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)15)；
6- (2- (diethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one(I16)；
2- (benzylsulfanyl) -6-fluoro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)17)；
2- (benzylsulfanyl) -6-chloro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)18)；
2- (benzylsulfanyl) -6-bromo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)19)；
2- (benzylsulfanyl) -6-iodo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)20)；
2- (benzylsulfanyl) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)21)；
2- (benzylsulfanyl) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)22)；
2- (benzylsulfanyl) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)23)；
2- (benzylthio) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)24)；
6-fluoro-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)25)；
6-chloro-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)26)；
6-iodo-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)27)；
6-methyl-2- (2-methoxyphenylethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)28)。
Still further, the compound of formula I is selected from the following compounds:
6-fluoro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)9)；
6- (2- (diethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)16)；
2- (benzylsulfanyl) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)23)；
2- (benzylthio) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)24)；
The invention discloses a preparation method of a compound shown in a general formula I,
a) when X is S, the synthesis route of the compound shown in the general formula I is as follows:
the specific preparation method of the route comprises the following steps: reacting methyl anthranilate or a derivative thereof with an isothiocyanate derivative under an alkaline condition to prepare a 2-sulfo-2, 3-dihydroquinazoline-4 (1H) ketone derivative (II), and reacting the II with a chlorobenzyl or bromobenzyl derivative in a dioxane solution to generate a 2- (benzylthio) quinazoline-4 (3H) ketone derivative (I); alternatively, 2- (benzylthio) quinazolin-4 (3H) one derivatives are reacted with alkyl halides containing amino substituents to form R1Is C1-C6The 2- (benzylthio) quinazoline-4 (3H) ketone derivative (I) of the alkylamino alkoxy has the following specific synthetic route:
b) when X is CH2The synthetic route of the compound shown in the general formula I is as follows:
the specific preparation method of the route comprises the following steps: performing condensation reaction on methyl anthranilate or a derivative thereof and phenylpropionic acid or a derivative thereof to prepare methyl 2- (3-phenylpropionamido) benzoate or a derivative (III) thereof, performing hydrolysis reaction on the III to generate 2- (3-phenylpropionamido) benzoic acid or a derivative (II ') thereof, reacting the II' with an amine compound in an organic solvent for 6-12 hours, and performing reflux reaction to generate a target product (I); or, R1Is the reaction of a target product of hydroxyl with an alkyl halide containing an amino substituent to form R1Is C1-C6The specific synthetic route of the target product (I) of the alkylamino alkoxy is as follows:
in the step of preparing the compound of formula I from II, the organic solvent used is selected from one or more of chloroform, dichloromethane, ethylene glycol, methanol, ethanol, ethyl acetate, acetone, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), acetonitrile, tetrahydrofuran, pyridine, 1, 2-dichloroethane, toluene or dioxane, preferably dioxane, N-Dimethylformamide (DMF); the reaction temperature employed is from-5 ℃ to reflux.
The preparation of compounds of formula I from II' is characterized in that the solvent used is selected from one or more of toluene, chloroform, dichloromethane, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), acetonitrile, tetrahydrofuran, pyridine, 1, 2-dichloroethane, toluene or dioxane, preferably toluene; the reaction temperature employed is from 0 ℃ to reflux.
These intermediates or the target compounds can be purified according to conventional isolation techniques and, if desired, converted into addition salts with pharmaceutically acceptable acids.
The invention also provides a pharmaceutical composition which takes the compound, the isomer or the pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient and is assisted by pharmaceutically acceptable auxiliary materials. In the composition, the active ingredient can also comprise other anti-HBV drugs or nucleoside anti-HBV drugs besides the compound, the isomer or the pharmaceutically acceptable salt thereof, such as lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir, and can also be combined with interferon and the like.
The invention also provides application of the compound, the isomer or the pharmaceutically acceptable salt thereof in preparing medicaments for treating diseases related to hepatitis B, in particular application in preparing anti-HBV medicaments.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"alkyl" means a saturated aliphatic radical of 1 to 20 carbon atoms, including straight and branched chain radicals (a numerical range referred to herein, e.g., "1 to 20", means that the radical, in this case alkyl, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"hydroxy" means an-OH group.
"cyano" means a-CN group.
"nitro" means-NO2A group.
"carboxyl" means a-COOH group.
"haloalkyl" denotes halogen-substituted alkyl, preferably halogen-substituted lower alkyl as defined above, which is substituted by one or more identical or different halogen atoms, e.g. -CH2Cl、-CF3、-CH2CF3、-CH2CCl3And the like.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"alkylamino" denotes-NH- (alkyl), -N (alkyl)2Wherein the alkyl group herein may be a substituted or unsubstituted alkyl group. Representative examples include, but are not limited to, methylamino, ethylamino, dimethylamino, and the like.
"Alkylaminoalkoxy" means a group in which at least one hydrogen on the alkoxy group is substituted by an alkylamino group, such as dimethylaminomethoxy, dimethylaminoethoxy, methylaminoethoxy, and the like.
"ester group" means a-C (O) O-alkyl group.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid and the like, or with organic acids including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, benzoic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid and the like.
(2) The acidic protons present in the parent compound are replaced with metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or are complexed with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, quinine, and the like.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to an animal.
By adopting the technical scheme of the invention, the advantages are as follows:
the quinazolinone compounds provided by the invention not only have good anti-HBV activity, can effectively inhibit the replication of HBV DNA, but also have strong inhibiting effect on lamivudine and entecavir drug-resistant HepG2A64 cells (mutation site: rtLl80M + rtM204V + rtTl 84L). The quinazolinone compound, the isomer thereof or the pharmaceutically acceptable salt thereof provided by the invention can be applied to the preparation of anti-HBV drugs, and has excellent potential application prospects.
Drawings
FIG. 1 shows ETV, 3TC and Compound I23、I24Inhibition of HepG2a64 HBV DNA;
in the figure, from the left, ETV, 3TC, I are shown in sequence23And I24(ii) a Active compound I is measured by taking lamivudine and entecavir combined drug-resistant cell HepG2A64 (mutation site: rtLl80M + rtM204V + rtTl84L) constructed in China civil liberty military 302 hospital as a test research object23And I24Determining the sensitivity of the three drug-resistant mutation sites to a target compound and evaluating the anti-drug-resistant HBV activity of the target compound on the influence of the drug-resistant cell HBV DNA replication; anti-HBV drugs Entecavir (ETV) and lamivudine (3TC) were used as drug controls.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
Example 1
2- ((5-acetyl-2-methoxybenzyl) thio) -6-fluoro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)1)
A mixture of methyl 2-amino-5-fluorobenzoate (1.69g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.84g,12mmol) and triethylamine (2mL) in ethanol (50mL) was heated under reflux for 4 hours. After cooling, the reaction mixtureAnd (3) carrying out suction filtration and drying on the compound to obtain a compound 6-fluoro-3- (thiophene-2-ylmethyl) -2-sulfo-2, 3-dihydroquinazoline-4 (1H) -ketone. A solution of 6-fluoro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.44g, 1.5mmol) and anhydrous potassium carbonate (1.24g,9mmol) in 1.4-dioxane (1.5mL) was mixed, 3- (chloromethyl) -4-methoxyacetophenone (0.3g,1.5mmol) was added to reflux for 10 hours, 5mL of water was added to terminate the reaction, and the solvent was recovered under reduced pressure. Dissolving the residue in CH2Cl2The organic layer was washed with water several times, dried over anhydrous sodium sulfate, and recrystallized from ethanol to give the title compound (0.16g, 17%).
m.p.158.3-162.8℃；1H NMR(400MHz,CDCl3)δppm:8.24(d,J＝2.0Hz,1H,Ar-H),8.00(s,1H,Ar-H),7.89(dd,J＝8.4Hz,2.4Hz,1H,Ar-H),7.84(dd,J＝8.4,3.2Hz,1H,Ar-H),7.68(dd,J＝8.8,4.8Hz,1H,Ar-H),7.44(m,1H,Ar-H),7.20(m,1H,Ar-H),6.91(m,2H,Ar-H),5.42(s,2H,CH2),4.56(s,2H,CH2),3.96(s,3H,CH3),2.50(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:196.65,162.64,161.58,155.27,144.18,136.98,132.01,130.48,129.93,128.87,128.40,126.47,126.31,125.07,123.35,123.11,112.06,111.83,110.11,56.01,42.52,31.56,26.39。
Example 2
2- ((5-acetyl-2-methoxybenzyl) thio) -6-chloro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)2)
In a similar manner to example 1, methyl 2-amino-5-chlorobenzoate (1.85g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.84g,12mmol) were reacted to give the compound 6-chloro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-chloro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.92g,3mmol) and 3- (chloromethyl) -4-methoxyacetophenone (0.59g,3mmol) were reacted to give the title compound (0.23g, 16%).
m.p.170.3-173.6℃；1H NMR(400MHz,DMSO)δppm:8.21(s,1H,Ar-H),8.04(s,1H,Ar-H),7.93(d,J＝8.8Hz,1H,Ar-H),7.88(d,J＝8.4Hz,1H,Ar-H),7.73(d,J＝8.4Hz,1H,Ar-H),7.44(d,J＝5.2Hz,1H,Ar-H),7.13-7.18(m,2H,Ar-H),6.97(t,1H,Ar-H),5.36(s,2H,CH2),4.55(s,2H,CH2),3.95(s,3H,CH3),2.48(s,3H,CH3)；13C NMR(100MHz,DMSO)δppm:201.44,167.58,166.48,164.82,162.05,150.70,142.23,140.39,136.69,135.74,136.48,134.62,133.76,133.47,131.85,130.76,129.45,125.22,116.12,61.51,41.07,36.06,31.68。
Example 3
2- ((5-acetyl-2-methoxybenzyl) thio) -6-bromo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)3)
In a similar manner to example 1, methyl 2-amino-5-bromobenzoate (2.29g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.84g,12mmol) were reacted to give the compound 6-bromo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-bromo-3- (thiophen-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.06g,3mmol) and 3- (chloromethyl) -4-methoxyacetophenone (0.59g,3mmol) were reacted to give the title compound (0.23g, 15%).
m.p.143.3-150.6℃；1H NMR(400MHz,CDCl3)δppm:8.33(d,J＝2.4Hz,1H,Ar-H),8.23(d,J＝2.0Hz,1H,Ar-H),8.00(s,1H,Ar-H),7.88(dd,J＝8.8Hz,2.0Hz,1H,Ar-H),7.78(dd,J＝8.4,2.0Hz,1H,Ar-H),7.55(d,J＝8.8Hz,1H,Ar-H),7.20(m,1H,Ar-H),6.91(m,2H,Ar-H),5.41(s,2H,CH2),4.55(s,2H,CH2),3.96(s,3H,CH3),2.50(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:196.64,162.65,161.57,160.53,156.63,146.23,137.80,136.87,132.02,130.51,129.93,129.68,128.91,127.96,126.41,124.94,120.84,119.04,110.12,56.01,42.55,31.61,26.40.
Example 4
2- ((5-acetyl-2-methoxybenzyl) thio) -6-iodo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)4)
In a similar manner to example 1, methyl 2-amino-5-bromobenzoate (2.77g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.84g,12mmol) were reacted to give the compound 6-iodo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-iodo-3- (thiophen-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.20g,3mmol) and 3- (chloromethyl) -4-methoxyacetophenone (0.59g,3mmol) reacted to give the title compound (0.27g, 16%).
m.p.170.3-177.6℃；1H NMR(400MHz,CDCl3)δppm:8.54(s,1H,Ar-H),8.23(br,1H,Ar-H),7.96(d,J＝8.4Hz,1H,Ar-H),7.89(d,J＝6.8Hz,1H,Ar-H),7.42(d,J＝8.8Hz,1H,Ar-H),7.20(br,2H,Ar-H),6.90-6.93(m,2H,Ar-H),5.41(s,2H,CH2),4.56(s,2H,CH2),3.96(s,3H,CH3),2.51(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:196.67,161.57,160.29,156.83,146.69,143.37,136.88,135.98,132.04,130.51,129.93,128.90,128.00,126.48,126.35,124.95,121.16,116.31,110.12,56.02,42.56,31.61,26.41.
Example 5
2- ((5-acetyl-2-methoxybenzyl) thio) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)5)
In a similar manner to example 1, methyl 2-amino-5-methylbenzoate (1.65g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.84g,12mmol) were reacted to give the compound 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.86g,3mmol) and 3- (chloromethyl) -4-methoxyacetophenone (0.59g,3mmol) were reacted to give the title compound (0.26g, 6%).
m.p.218.5-220.0℃；1H NMR(400MHz,CDCl3)δppm:8.20(d,J＝2.4Hz,1H,Ar-H),7.91(dd,J＝8.8,2.4Hz,1H,Ar-H),7.57(d,J＝8.8Hz,1H,Ar-H),7.38-7.40(m,2H,Ar-H),7.28(dd,J＝8.8Hz,3.2Hz,1H,Ar-H),7.15(dd,J＝7.6Hz,1.2Hz,1H,Ar-H),7.12(d,J＝8.8Hz,1H,Ar-H),6.94(dd,J＝4.8Hz,3.2Hz,1H,Ar-H),5.35(s,2H,CH2),4.51(s,2H,CH2),3.95(s,3H,CH3),2.48(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:196.52,161.67,160.87,156.18,152.37,140.79,138.01,131.85,130.77,129.78,128.67,128.09,126.93,126.89,125.05,124.82,120.21,111.18,109.77,55.31,49.15,31.23,26.86.
Example 6
2- ((5-acetyl-2-methoxybenzyl) thio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)6)
In a similar manner to example 1, methyl 2-amino-5-hydroxybenzoate (1.67g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.84g,12mmol) were reacted to give the compound 6-hydroxy-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-hydroxy-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.87g,3mmol) and 3- (chloromethyl) -4-methoxyacetophenone (0.59g,3mmol) were reacted to give the title compound (0.16g, 12%).
m.p.218.5-220.0℃；1H NMR(400MHz,CDCl3)δppm:8.20(d,J＝2.4Hz,1H,Ar-H),7.91(dd,J＝8.8,2.4Hz,1H,Ar-H),7.57(d,J＝8.8Hz,1H,Ar-H),7.38-7.40(m,2H,Ar-H),7.28(dd,J＝8.8Hz,3.2Hz,1H,Ar-H),7.15(dd,J＝7.6Hz,1.2Hz,1H,Ar-H),7.12(d,J＝8.8Hz,1H,Ar-H),6.94(dd,J＝4.8Hz,3.2Hz,1H,Ar-H),5.35(s,2H,CH2),4.51(s,2H,CH2),3.95(s,3H,CH3),2.48(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:196.52,161.67,160.87,156.18,152.37,140.79,138.01,131.85,130.77,129.78,128.67,128.09,126.93,126.89,125.05,124.82,120.21,111.18,109.77,55.31,49.15,31.23,26.86.
Example 7
2- ((5-acetyl-2-methoxybenzyl) thio) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)7)
2- ((5-acetyl-2-methoxybenzyl) thio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (2.26g,5mmol), dimethylaminoethyl chloride hydrochloride (0.86g,6mmol) and K2CO3(4.1g,30mmol) was reacted in 30mL1, 4-dioxane under reflux for 3h, the solvent was recovered under reduced pressure, ethyl acetate was added to dissolve the solvent, the solution was washed twice with water, the saturated sodium bicarbonate solution and saturated sodium chloride solution were washed and then dried over anhydrous sodium sulfate, ethyl acetate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the title compound (0.26g, 10%).
m.p.70.2-72.8℃；1H NMR(400MHz,CDCl3)δppm:8.23(d,J＝2.4Hz,1H,Ar-H),7.89(dd,J＝8.8Hz,2.4Hz,1H,Ar-H),7.61(d,J＝9.2Hz,1H,Ar-H),7.57(d,J＝2.8Hz,1H,Ar-H),7.35(dd,J＝8.8Hz,2.8Hz,1H,Ar-H),7.18-7.25(m,2H,Ar-H),6.88-6.92(m,2H,Ar-H),5.41(s,2H,CH2),4.54(s,2H,CH2),4.32(t,2H,OCH2),3.95(s,3H,CH3),3.09(t,2H,NCH2),2.59(s,6H,CH3),2.49(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:196.77,161.58,161.53,155.96,153.68,142.72,137.23,132.06,130.36,129.87,128.77,127.97,126.45,126.25,125.20,125.00,120.06,110.12,107.58,64.71,57.13,56.01,44.67(2C),42.52,31.41,26.46.
Example 8
2- ((5-acetyl-2-methoxybenzyl) thio) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)8)
In a similar manner to example 7, 2- ((5-acetyl-2-methoxybenzyl) thio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (2.26g,5mmol) and diethylaminochloroethane hydrochloride (1.03g,6mmol) were reacted to give the title compound (0.25g, 9%).
1H NMR(400MHz,CDCl3)δppm:8.24(d,J＝2.4Hz,1H,Ar-H),7.91(dd,J＝8.4Hz,2.0Hz,1H,Ar-H),7.61(m,2H,Ar-H),7.34(dd,J＝8.4Hz,3.2Hz,1H,Ar-H),7.18-7.22(m,2H,Ar-H),6.89-6.93(m,2H,Ar-H),5.42(s,2H,CH2),4.55(s,2H,CH2),4.16(t,2H,OCH2),3.96(s,3H,CH3),2.94(t,2H,NCH2),2.65-2.70(m,4H,N(CH2CH3)2),2.50(s,3H,CH3),1.09(t,6H,N(CH2CH3)2)；13C NMR(100MHz,CDCl3)δppm:196.76,162.64,161.66,161.57,156.86,153.18,142.34,137.35,132.09,130.30,129.89,128.73,127.69,126.43,126.21,125.28,120.07,110.13,107.25,66.70,56.00,51.45,47.83(2C),42.50,31.37,26.46,11.72(2C).
Example 9
6-fluoro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)9)
In a similar manner to example 1, methyl 2-amino-5-fluorobenzoate (1.08g,6.4mmol) and 2- (methylthioisothiocyanato) thiophene (1g,6.4mmol) were reacted to give the compound 6-fluoro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-fluoro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (2.25g,7mmol) and 2-methoxybenzyl chloride (1.2g,7mmol) were reacted to give the title compound (0.566g, 23%).
m.p.116.1-122.8℃；1H NMR(400MHz,CDCl3)δppm:7.86(dd,J＝8.4Hz,2.8Hz,1H,Ar-H),7.61(dd,J＝8.8Hz,4.8Hz,1H,Ar-H),7.49(d,J＝7.2Hz,1H,Ar-H),7.39-7.44(m,1H,Ar-H),7.18-7.29(m,3H,Ar-H),6.87-6.92(m,3H,Ar-H),5.43(s,2H,CH2),4.57(s,2H,CH2),3.89(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:157.82,155.78,144.28,137.06,131.16,129.35,128.93,128.49,128.40,126.46,126.32,124.48,123.19,122.95,120.53,112.05,111.81,110.68,55.63,42.53,31.89.
Example 10
6-chloro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)10)
In a similar manner to example 1, methyl 2-amino-5-chlorobenzoate (1.18g,6.4mmol) and 2- (methylthioisothiocyanato) thiophene (1g,6.4mmol) were reacted to give the compound 6-chloro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.894g, 45%), 6-chloro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.894g,3mmol) and 2-methoxybenzyl chloride (0.455g,3mmol) to give the title compound (0.742g, 25%).
m.p.114.8-122.9℃；1H NMR(400MHz,CDCl3)δppm:8.18(d,J＝2.4Hz,1H,Ar-H),7.61(dd,J＝8.8Hz,2.4Hz,1H,Ar-H),7.54(d,J＝8.8Hz,1H,Ar-H),7.47(d,J＝8.0Hz,1H,Ar-H),7.28(d,J＝6.4Hz,1H,Ar-H),7.19-7.22(m,2H,Ar-H),6.87-6.91(m,3H,Ar-H),5.42(s,2H,CH2),4.57(s,2H,CH2),3.89(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:156.01,153.05,152.20,141.24,132.20,130.17,126.48,126.43,124.64,124.22,123.06,121.71,121.62,119.60,115.78,115.68,105.91,105.52,50.88,37.79,27.19.
Example 11
6-bromo-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)11)
In a similar manner to example 1, methyl 2-amino-5-bromobenzoate (1.47g,6.4mmol) and 2- (methylthioisothiocyanato) thiophene (1.0g,6.4mmol) were reacted to give the compound 6-bromo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.12g, 5%), 6-bromo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.11g,0.48mmol) and 2-methoxybenzyl chloride (0.07g,0.48mmol) to give the title compound (0.117g, 25%).
m.p.134.2-139.3℃；1H NMR(400MHz,CDCl3)δppm:8.35(dd,J＝6.8Hz,2.8Hz,1H,Ar-H),7.75(dd,J＝8.4Hz,2.0Hz,1H,Ar-H),7.47-7.49(m,2H,Ar-H),7.20-7.30(m,3H,Ar-H),6.87-6.93(m,3H,Ar-H),5.42(s,2H,CH2),4.57(s,2H,CH2),3.89(s,3H,CH3)；13C NMR(100MHz,DMSO)δppm:159.91,157.94,157.66,146.20,138.25,137.47,131.52,129.91,129.03,128.91(2C),127.19,127.08,123.96,120.79,120.77,118.68,111.58,56.13,42.94,31.90.
Example 12
6-iodo-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)12)
In a similar manner to example 1, methyl 2-amino-5-iodobenzoate (1.77g,6.4mmol) and 2- (methylthioisothiocyanato) thiophene (0.9g,6.4mmol) were reacted to give the compound 6-iodo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.277g, 11%). 6-iodo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.25g,0.64mmol) and 2-methoxybenzyl chloride (0.1g,0.64mmol) were reacted to give the title compound (0.21g, 7%).
m.p.126.6-131.7℃；1H NMR(400MHz,CDCl3)δppm:8.55(s,1H,Ar-H),7.93(d,J＝8.0Hz,1H,Ar-H),7.48(d,J＝8.0Hz,2H,Ar-H),7.35(d,J＝8.0Hz,1H,Ar-H),7.28(d,J＝8.0Hz,1H,Ar-H),7.20-7.22(m,2H,Ar-H),6.87-6.92(m,3H,Ar-H),5.42(s,2H,CH2),4.58(s,2H,CH2),3.89(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:160.31,157.82,157.40,146.73,143.19,136.95,135.95,131.19,129.40,128.98,128.03,126.46,126.38,124.35,121.14,120.55,110.68,89.46,55.64,42.56,31.99.
Example 13
2- ((2-methoxybenzyl) thio) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)13)
In a similar manner to example 1, methyl 2-amino-5-methylbenzoate (1.05g,6.4mmol) and 2- (methylthioisothiocyanato) thiophene (1g,6.4mmol) were reacted to give the compound 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.077g, 47%), 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.05g,3.64mmol) and 2-methoxybenzyl chloride (0.57g,3.64mmol) to give the title compound (1.01g, 32%).
m.p.108.1-110.2℃；1H NMR(400MHz,CDCl3)δppm:8.02(s,1H,Ar-H),7.50-7.56(m,3H,Ar-H),7.27(d,J＝8.0Hz,1H,Ar-H),7.18-7.22(m,2H,Ar-H),6.86-6.90(m,3H,Ar-H),5.44(s,2H,CH2),4.61(s,2H,CH2),3.88(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:161.76,157.82,155.42,145.47,137.48,136.00,135.86,131.22,129.26,128.72,126.67,126.39,126.18,125.91,124.74,120.54,119.17,110.65,55.63,42.43,31.85,21.34.
Example 14
6-hydroxy-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)14)
In a similar manner to example 1, methyl 2-amino-5-hydroxybenzoate (1.67g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.5g,10mmol) were reacted to give the compound 6-hydroxy-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.45g,5mmol) and 2-methoxybenzyl chloride (0.78g,5mmol) were reacted to give the title compound (0.57g, 28%).
1H NMR(400MHz,DMSO)δppm:7.50(d,J＝8.8Hz,1H,Ar-H),7.50(dd,J＝7.2Hz,1.6Hz,1H,Ar-H),7.37-7.38(m,2H,Ar-H),7.21-7.27(m,2H,Ar-H),7.10(d,J＝1.6Hz,1H,Ar-H),6.99(d,J＝8.1Hz,1H,Ar-H),6.82-6.91(m,3H,Ar-H),5.30(s,2H,CH2),4.44(s,2H,CH2),3.79(s,3H,CH3)；13C NMR(100MHz,DMSO)δppm:160.90,157.93,156.27,152.70,140.81,138.14,131.40,129.76,128.68,128.19,127.03,126.95,124.94,124.41,120.78,120.17,111.59,109.79,55.45,42.65,31.56.
Example 15
6- (2- (dimethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)15)
Analogously to example 7, 6-hydroxy-2- ((2-methoxybenzyl) thio) -3- (thiophen-2-methylidene) quinazolin-4 (3H) -one (I)14) (2.05g,5mmol) and dimethylaminoethyl chloride hydrochloride (0.86g,6mmol) to give the title compound (0.60g, 25%).
m.p.82.5-83.2℃；1H NMR(400MHz,DMSO)δppm:7.57(d,J＝8.8Hz,1H,Ar-H),7.45-7.47(m,2H,Ar-H),7.38-7.41(m,2H,Ar-H),7.22-7.26(m,1H,Ar-H),7.11(d,J＝3.2Hz,1H,Ar-H),6.99(d,J＝8.0Hz,1H,Ar-H),6.91(dd,J＝5.2Hz,3.6Hz,1H,Ar-H),6.84(t,1H,Ar-H),5.33(s,2H,CH2),4.45(s,2H,CH2),4.15(t,2H,OCH2),3.80(s,3H,CH3),2.69(t,2H,NCH2),2.24(s,6H,CH3)；13C NMR(100MHz,DMSO)δppm:160.87,157.94,156.90,153.97,142.04,137.94,131.46,129.82,128.82,128.32,127.05(2C),125.34,124.30,120.79,119.92,111.60,107.65,66.59,57.90,56.13,45.85(2C),42.77,31.64.
Example 16
6- (2- (diethylamino)Yl) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)16)
Analogously to example 7, 6-hydroxy-2- ((2-methoxybenzyl) thio) -3- (thiophen-2-methylidene) quinazolin-4 (3H) -one (I)14) (2.05g,5mmol) and diethylaminoethyl chloride hydrochloride (1.03g,6mmol) to give the title compound (0.64g, 25%).
1H NMR(400MHz,DMSO)δppm:7.57(d,J＝8.8Hz,1H,Ar-H),7.45-7.47(m,2H,Ar-H),7.37-7.39(m,2H,Ar-H),7.24(t,1H,Ar-H),7.11(d,J＝2.4Hz,1H,Ar-H),6.99(d,J＝8.0Hz,1H,Ar-H),6.91(dd,J＝5.2Hz,3.6Hz,1H,Ar-H),6.85(t,1H,Ar-H),5.33(s,2H,CH2),4.45(s,2H,CH2),4.10(t,2H,OCH2),3.80(s,3H,CH3),2.80(t,2H,NCH2),2.55(m,4H,N(CH2CH3)2),0.95(t,6H,N(CH2CH3)2)；13C NMR(100MHz,DMSO)δppm:162.85,160.87,157.93,156.97,153.94,141.99,137.93,131.46,129.83,128.82,128.32,127.06,125.32,124.28,120.79,119.91,111.59,107.66,56.13,55.45,51.61,47.52(2C),42.77,31.64,12.25(2C).
Example 17
2- (benzylsulfanyl) -6-fluoro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)17)
In a similar manner to example 1, methyl 2-amino-5-fluorobenzoate (0.42g,2.5mmol) and 2- (methylthioisothiocyanato) thiophene (0.4g,3mmol) were reacted to give the compound 6-fluoro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-fluoro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.271g,0.93mmol) and benzyl bromide (0.16mL,0.93mmol) were reacted to give the title compound (81mg, 8%).
m.p.157.2-167.1℃；1H NMR(400MHz,CDCl3)δppm:7.87(dd,J＝8.4Hz,2.8Hz,1H,Ar-H),7.58(dd,J＝8.8Hz,4.8Hz,1H,Ar-H),7.47(d,J＝6.8Hz,2H,Ar-H),7.28-7.47(m,4H,Ar-H),7.21-7.25(m,2H,Ar-H),6.92(t,1H,Ar-H),5.45(s,2H,CH2),4.55(s,2H,CH2)；13C NMR(100MHz,CDCl3)δppm:160.46,155.81,144.21,137.59,137.06,129.96(2C),129.44,129.36,128.99(3C),127.99,127.19,127.13,124.17,123.93,111.80,43.00,36.30.
Example 18
2- (benzylsulfanyl) -6-chloro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)18)
In a similar manner to example 1, methyl 2-amino-5-chlorobenzoate (1.18g,6.4mmol) and 2- (methylthioisothiocyanato) thiophene (1g,6.4mmol) were reacted to give the compound 6-chloro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-chloro-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.894g,3mmol) and benzyl bromide (0.45mL,3mmol) were reacted to give the title compound (0.5g, 18%).
m.p.139.6-145.5℃；1H NMR(400MHz,CDCl3)δppm:8.20(d,J＝2.0Hz,1H,Ar-H),7.62(dd,J＝8.8Hz,2.4Hz,1H,Ar-H),7.52(d,J＝8.8Hz,1H,Ar-H),7.46(d,J＝7.2Hz,2H,Ar-H),7.28-7.35(m,3H,Ar-H),7.22(d,J＝4.4Hz,2H,Ar-H),6.92(t,1H,Ar-H),5.45(s,2H,CH2),4.55(s,2H,CH2)；13C NMR(100MHz,DMSO)δppm:160.09,157.10,145.93,137.49,136.96,135.64,130.74,129.97(2C),129.00(3C),128.81,128.02,127.22,127.14,125.99,120.48,43.06,36.36.
Example 19
2- (benzylsulfanyl) -6-bromo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)19)
In a similar manner to example 1, methyl 2-amino-5-bromobenzoate (1g,6mmol) and 2- (methylthioisothiocyanato) thiophene (0.8g,6mmol) were reacted to give the compound 6-bromo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-bromo-3- (thiophen-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (1.212g,3.4mmol) and benzyl bromide (0.58mL,3.4mmol) were reacted to give the title compound (0.43g, 16%).
m.p.145.3-147.6℃；1H NMR(400MHz,CDCl3)δppm:8.35(d,J＝2.0Hz,1H,Ar-H),7.76(dd,J＝8.0Hz,2.0Hz,1H,Ar-H),7.45(d,J＝6.8Hz,3H,Ar-H),7.21-7.34(m,5H,Ar-H),6.92(t,1H,Ar-H),5.44(s,2H,CH2),4.54(s,2H,CH2)；13C NMR(100MHz,DMSO)δppm:159.95,157.22,146.18,138.34,137.48,136.94,129.98(2C),129.08,129.00(3C),128.95,128.02,127.22,127.14,120.85,118.80,43.07,36.37.
Example 20
2- (benzylsulfanyl) -6-iodo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)20)
In a similar manner to example 1, methyl 2-amino-5-iodobenzoate (0.55g,2mmol) and 2- (methylthioisothiocyanato) thiophene (0.4g,3mmol) were reacted to give the compound 6-iodo-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-iodo-3- (thiophen-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.374g,0.9mmol) and benzyl bromide (0.16mL,0.9mmol) reacted to give the title compound (0.123g, 13%).
m.p.144.6-145.2℃；1H NMR(400MHz,CDCl3)δppm:8.56(d,J＝1.6Hz,1H,Ar-H),7.93(dd,J＝8.4Hz,2.0Hz,1H,Ar-H),7.45(d,J＝6.8Hz,2H,Ar-H),7.27-7.34(m,4H,Ar-H),7.20-7.22(m,2H,Ar-H),6.91(t,1H,Ar-H),5.43(s,2H,CH2),4.54(s,2H,CH2)；13C NMR(100MHz,DMSO)δppm:159.73,157.17,146.44,143.80,137.51,136.93,135.20,129.98(2C),129.00(3C),128.71,128.02,127.22,127.13,121.06,91.27,43.03,36.37.
Example 21
2- (benzylsulfanyl) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)21)
In a similar manner to example 1, methyl 2-amino-5-methylbenzoate (0.33g,2mmol) and 2- (methylthioisothiocyanato) thiophene (0.4g,3mmol) were reacted to give the compound 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-methyl-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (0.213g,0.74mmol) and benzyl bromide (0.12mL,0.74mmol) were reacted to give the title compound (0.143g, 18%).
m.p.151.9-152.7；1H NMR(400MHz,CDCl3)δppm:8.04(s,1H,Ar-H),7.46-7.50(m,4H,Ar-H),7.21-7.33(m,5H,Ar-H),6.91(br,1H,Ar-H),5.46(s,2H,CH2),4.56(s,2H,CH2),2.45(s,3H,CH3)；13C NMR(100MHz,CDCl3)δppm:161.73,154.54,145.53,137.44,136.43,136.03(2C),129.53(2C),128.74(3C),127.75,126.61,126.48,126.27,126.03,119.31,42.52,36.97,21.37.
Example 22
2- (benzylsulfanyl) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)22)
In a similar manner to example 1, methyl 2-amino-5-hydroxybenzoate (1.67g,10mmol) and 2- (methylthioisothiocyanato) thiophene (1.5g,10mmol) were reacted to give the compound 6-hydroxy-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one. 6-hydroxy-3- (thien-2-ylmethyl) -2-thioxo-2, 3-dihydroquinazolin-4 (1H) -one (2.9g,10mmol) and benzyl bromide (1.18mL,10mmol) were reacted to give the title compound (0.57g, 15%).
1H NMR(400MHz,CDCl3)δppm:10.01(s,1H,OH),7.45-7.47(m,3H,Ar-H),7.39(dd,J＝5.2Hz,1.2Hz,1H,Ar-H),7.35(d,J＝3.6Hz,1H,Ar-H),7.19-7.30(m,4H,Ar-H),7.12(d,J＝3.6Hz,1H,Ar-H),6.92(dd,J＝5.2Hz,3.6Hz,1H,Ar-H),5.33(s,2H,CH2),4.48(s,2H,CH2)；13C NMR(100MHz,CDCl3)δppm:160.88,156.22,152.29,140.79,138.10,137.29,129.92(2C),128.96(2C),128.72,128.26,127.91,127.08,127.04,124.92,120.23,109.75,42.76,36.16.
Example 23
2- (benzylsulfanyl) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)23)
In a similar manner to example 7, 2- (benzylthio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)22) (1.9g,5mmol) and dimethylaminoethyl chloride hydrochloride (0.86g,6mmol) to give the title compound (0.29g, 13%).
m.p.75.8-77.2℃；1H NMR(400MHz,CDCl3)δppm:7.55(d,J＝8.8Hz,1H,Ar-H),7.45-7.47(m,3H,Ar-H),7.37-7.40(m,2H,Ar-H),7.25-7.30(m,2H,Ar-H),7.19-7.23(m,1H,Ar-H),7.13(dd,J＝3.6Hz,1.2Hz,1H,Ar-H),6.92(dd,J＝5.2Hz,3.2Hz,1H,Ar-H),5.35(s,2H,CH2),4.50(s,2H,CH2),4.14(t,2H,OCH2),2.67(t,2H,NCH2),2.20(s,6H,CH3)；13C NMR(100MHz,DMSO)δppm:160.87,156.98,153.48,141.96,137.91,137.22,129.95(2C),128.97(2C),128.83,128.32,127.94,127.10(2C),125.38,119.97,107.63,66.65,57.90,45.89(2C),42.87,36.20.
Example 24
2- (benzylthio) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)24)
In a similar manner to example 7, 2- (benzylthio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)22) (1.9g,5mmol) and diethylaminoethyl chloride hydrochloride (1.03g,6mmol) to give the title compound (0.31g, 13%).
m.p.108.8-110.2℃；1H NMR(400MHz,CDCl3)δppm:7.55(d,J＝8.8Hz,1H,Ar-H),7.45-7.48(m,3H,Ar-H),7.36-7.40(m,2H,Ar-H),7.26-7.30(m,2H,Ar-H),7.20-7.24(m,1H,Ar-H),7.13(d,J＝2.4Hz,1H,Ar-H),6.92(dd,J＝5.2Hz,3.6Hz,1H,Ar-H),5.35(s,2H,CH2),4.50(s,2H,CH2),4.08(t,2H,OCH2),2.76(t,2H,NCH2),2.49-2.54(m,4H,N(CH2CH3)2),0.94(t,6H,CH3)；13C NMR(100MHz,CDCl3)δppm:165.63,161.84,158.19,146.67,142.68,141.97,134.70(2C),133.73(2C),133.59,133.06,132.70,131.85(2C),130.09,124.74,112.40,72.20,56.42,52.27(2C),47.62,40.97,17.17(2C).
Example 25
6-fluoro-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)25)
Methyl 2-amino-5-fluoro-benzoate (1.69g,10mmol) was dissolved in dichloromethane (5mL), 3- (2-methoxyphenyl) propionic acid (1.80g,10mmol) was added, dissolved with stirring, and cooled to 0 ℃ in an ice-water bath. N-methylmorpholine (2.7mL,24mmol) was added thereto, isobutyl chloroformate (1.5mL,12mmol) was slowly added dropwise, the mixture was stirred and reacted for 2 hours, then 1mL of water was added to stop the reaction, the mixture was extracted with methylene chloride, the organic layer was washed with a saturated common salt solution and a saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to give methyl 5-fluoro-2- [3- (2-methoxyphenyl) propionylamino ] benzoate. Dissolving the raw materials in 5mL of methanol, adding 5N sodium hydroxide, refluxing for half an hour, cooling to room temperature, adding 6N concentrated hydrochloric acid until a large amount of light yellow solid is separated out, filtering to separate out the solid, washing the solid with water for multiple times, and drying to obtain the 5-fluoro-2- [3- (2-methoxyphenyl) propionylamino ] benzoic acid. 5-fluoro-2- [3- (2-methoxyphenyl) propionylamino ] benzoic acid (1.44g,5mmol) was dissolved in 5mL of toluene, thiophene-2-methylamine (0.56g,5mmol) was added under nitrogen protection, phosphorus trichloride (0.05mL,0.4mmol) was added and the reaction was refluxed for 4 hours, and then 10mL of 20% sodium carbonate solution was added to terminate the reaction. Extraction with dichloromethane and washing of the organic layer with saturated brine, drying over anhydrous sodium sulfate, filtration and removal of the solvent under reduced pressure gave a solid which was chromatographed on silica gel to give the title compound as a white product (0.47g, 24%).
m.p.110.9-116.1℃；1H NMR(400MHz,DMSO)δppm:7.82(dd,J＝8.0,2.8Hz,1H,Ar-H),7.65-7.72(m,2H,Ar-H),7.42(dd,J＝4.8,1.2Hz,1H,Ar-H),7.15-7.20(m,2H,Ar-H),7.04(d,J＝3.2Hz,1H,Ar-H),6.91-6.96(m,2H,Ar-H),6.81-6.85(t,,.1H,Ar-H),5.47(s,2H,CH2),3.71(s,3H,CH3),3.15(t,2H,CH2),3.02(t,2H,CH2)；13C NMR(100MHz,DMSO)δppm:161.69,161.16,159.26,157.73,156.32,144.27,139.16,130.50,128.79,128.24,127.46,127.38,126.78,123.81,123.57,120.88,111.53,111.11,55.73,42.03,34.39,28.00.
Example 26
6-chloro-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)26)
Using methyl 2-amino-5-chlorobenzoate (0.93g,5mmol), 3- (2-methoxyphenyl) propionic acid (0.90g,5mmol) and 5N sodium hydroxide, 2- [3- (2-methoxyphenyl) propionylamino ] -5-chlorobenzoic acid was reacted by a similar manner to example 25. 2- [3- (2-methoxyphenyl) propionylamino ] -5-chlorobenzoic acid (1.52g,5mmol), thiophene-2-methanamine (0.48g,5mmol) to give the title compound (0.59g, 29%).
1H NMR(400MHz,DMSO)δppm:8.08(d,J＝2.8Hz,1H,Ar-H),7.83(dd,J＝8.8Hz,2.8Hz,1H,Ar-H),7.66(d,J＝8.4Hz,1H,Ar-H),7.42(dd,J＝4.8Hz,2.8Hz,1H,Ar-H),7.15-7.20(m,2H,Ar-H),7.04(dd,J＝3.6Hz,1.2Hz,1H,Ar-H),6.91-6.96(m,1H,Ar-H),6.83(t,1H,Ar-H),5.46(s,2H,CH2),3.71(s,3H,CH3),3.13(t,2H,CH2),3.00(t,2H,CH2)；13C NMR(100MHz,DMSO)δppm:160.81,157.70,157.49,146.05,139.04,135.31,131.37,130.52,129.76,128.71,128.27,127.63,127.33,126.86,125.82,121.60,120.87,111.08,55.72,42.07,34.46,27.96.
Example 27
6-iodo-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)27)
Using methyl 2-amino-5-iodo-benzoate (2.77g,10mmol), 3- (2-methoxyphenyl) propanoate (1.80g,10mmol), and 5N sodium hydroxide, 5-iodo-2- [3- (2-methoxyphenyl) propionylamino ] benzoic acid was reacted by a similar manner to example 25. 5-iodo-2- [3- (2-methoxyphenyl) propionylamino ] benzoic acid (2.00g,5mmol), thiophene-2-methanamine (0.56g,5mmol) reacted to give the title compound as a white color (0.65g, 26%).
m.p.102.1-109.0℃；1H NMR(400MHz,DMSO)δppm:8.40(d,J＝2.0Hz,1H,Ar-H),8.08(dd,J＝8.8Hz,2.4Hz,1H,Ar-H),7.40-7.42(m,2H,Ar-H),7.14-7.19(m,2H,Ar-H),7.03(dd,J＝3.6Hz,1.2Hz,1H,Ar-H),6.93-6.95(m,2H,Ar-H),6.83(t,1H,Ar-H),5.45(s,2H,CH2),3.71(s,3H,CH3),3.12(t,2H,CH2),2.99(t,2H,CH2)；13C NMR(100MHz,DMSO)δppm:160.47,157.72,157.67,146.60,143.49,139.10,135.10,130.50,129.66,128.74,128.25,127.46,127.33,126.80,122.20,120.87,111.11,92.05,55.74,42.07,34.54,27.93.
Example 28
6-methyl-2- (2-methoxyphenylethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one (I)28)
Similar to example 25, using methyl 2-amino-5-methylbenzoate (1.65g,10mmol), 3- (2-methoxyphenyl) propionic acid (1.80g,10mmol), and 5N sodium hydroxide, reaction was carried out to give 2- [3- (2-methoxyphenyl) propionylamino ] -5-methylbenzoic acid. 2- [3- (2-methoxyphenyl) propionylamino ] -5-methylbenzoic acid (1.44g,5mmol), thiophene-2-methanamine (0.56g,5mmol) to give the title compound (0.27g, 14%).
m.p.106.1-111.2℃；1H NMR(400MHz,DMSO)δppm:7.93(s,1H,Ar-H),7.63(d,J＝8.0Hz,1H,Ar-H),7.54(d,J＝8.4Hz,1H,Ar-H),7.41(d,J＝5.2Hz,1H,Ar-H),7.15-7.20(m,2H,Ar-H),7.01(br,1H,Ar-H),6.92-6.95(m,2H,Ar-H),6.83(t,1H,Ar-H),5.46(s,2H,CH2),3.72(s,3H,CH3),3.11(t,2H,CH2),2.99(t,2H,CH2)；13C NMR(100MHz,DMSO)δppm:161.65,157.71,155.92,145.37,139.55,136.84,136.45,130.50,128.87,128.22,127.28(3C),126.72,126.19,120.87,120.12,111.07,55.71,41.79,34.41,28.08,21.34。
The following are some of the pharmacological tests and results of representative compounds of the invention:
1. MTT assay
MTT assay the cytotoxicity of compounds was studied in vitro. The experimental method is as follows: taking a flask of HepG22.2.15 cells in exponential growth phase, preparing the flask to contain 5X 10 cells per milliliter4～7×104A suspension of individual cells. Inoculating the cell suspension to a 96-well plate at a volume of 160 μ L per well, and placing in a constant temperature CO2The culture was carried out in an incubator for 24 hours. After changing the medium, 200. mu.L of test compound (compound dissolved in DMSO and diluted with culture medium) was added at different concentrations, and the culture was continued for 72 hours. 20. mu.L of MTT 5mg/mL was added to a 96-well plate and reacted in an incubator for 6 hours. The supernatant was discarded, the precipitate was completely dissolved in 200. mu.L of DMSO, the absorbance was measured by a microplate reader, and the inhibition of the compound on 2.2.15 cell growth was observed. anti-HBV drug lamivudine (3TC) was selected as a positive control. The results of the experiment are shown in table 1.
The cell inhibition rate (negative control OD value-test substance OD value)/negative control OD value × 100%.
TABLE 1 Toxicity (TC) of representative compounds of the invention against HepG22.2.15 cells50,μM)
The results show that except for compound I1、I2、I4、I7、I8、I15、I16、I23And I24In addition, TC for the majority of compounds50More than 100 mu M, less cytotoxicity and higher safety.
2. anti-HBV DNA Activity
According to the result of cytotoxicity of the compound on HepG22.2.15 cells, non-toxic concentration of each compound is taken as a high-dose group, a medium-dose group and a low-dose group are set, DMEM containing 2% FBS is used for preparing liquid medicine, and a lamivudine (3TC) positive control group and a virus control group which are anti-HBV medicines are set and are respectively added into a 96-well cell culture plate, wherein each concentration is 0.2 mL/well and 3 wells. The cells were lysed with 0.5% NP-40 by collecting cell supernatants every 3 days with a change of medium and day 6. Extracting total DNA of the cell from the cell lysate by using a DNA Extraction Soln 1.0 extracting solution, and detecting the carrying capacity of HBV DNA in the cell by using an RT-PCR method. The results of the experiment are shown in table 2.
TABLE 2 inhibitory Activity of the representative Compounds of the invention on HepG22.2.15 cell HBV DNA replication
Table 2 shows that the compounds have certain inhibitory activity on HBV DNA replication, and the compound I23And I24The inhibition rates are 83.28 percent and 98.42 percent respectively, and the compound I has better anti-HBV activity24The inhibition rate is higher than that of a contrast medicament lamivudine, the effect is obvious, and the method has further research and development values.
3. Anti-drug-resistant HBV activity
Active compound I is measured by taking lamivudine and entecavir combined drug-resistant cell HepG2A64 (mutation site: rtLl80M + rtM204V + rtTl84L) constructed in China civil liberty military 302 hospital as a test research object23And I24The influence on the HBV DNA replication of drug-resistant cells, the sensitivity of the three drug-resistant mutation sites to the target compound is judged, and the anti-drug-resistant HBV activity of the target compound is evaluated.
According to the cytotoxicity result of the compound on HepG2A64, 0.001, 0.01, 0.1, 1 and 10 mu mol/L5 concentrations of the compound are respectively taken, DMEM containing 2% FBS is used for preparing liquid medicine, a lamivudine (3TC) positive control group and an Entecavir (ETV) positive control group and a virus control group are additionally arranged, and the liquid medicine and the virus control group are respectively added into a 96-well cell culture plate, 0.2 mL/well and 3 wells per concentration. The cells were lysed with 0.5% NP-40 by collecting cell supernatants every 3 days with a change of medium and day 6. Extracting total DNA of the cell from the cell lysate by using a DNA Extraction Soln 1.0 extracting solution, and detecting the carrying capacity of HBV DNA in the cell by using an RT-PCR method. The results of the experiment are shown in FIG. 1.
The experimental results show that the compound I23And I24The compound I can effectively inhibit the replication of HBV DNA of HepG2A64 cells at the concentration of 4 mu M, the inhibition rates are respectively 80.91 percent and 93.99 percent, and compared with the inhibition rates of 81.95 percent and 96.09 percent of HepG22.2.15 cells, the compound I can be considered as23And I24No drug resistance was developed. The positive controls lamivudine (lamivudine,3TC) and entecavir (entecavir, ETV) are not ideal for inhibiting drug-resistant virus, and the inhibition rates of lamivudine (100 μ M) and entecavir (10 μ M) on HepG2A64 cell HBV DNA replication are 22.58% and 17.73%, respectively (the inhibition rates of HepG22.2.15 cells are 90.67% and 98.07%, respectively).
Claims (14)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
wherein the content of the first and second substances,
R1represents halogen, hydroxy, cyano, nitro, carboxy, C1-C6Alkyl radical, C1-C6Alkoxy radical, C1-C6Alkylamino alkoxy or C1-C6An ester group;
R3represents hydrogen, halogen, hydroxyl, nitro, carboxyl, cyano, amino, C1-C6Acyl radical, C1-C6Alkyl radical, C1-C4Haloalkyl, C1-C6Alkoxy radical, C1-C6Alkylamino alkoxy or C1-C6An ester group;
n represents an integer of 1 to 3;
x represents S or CH2。
2. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R1Represents halogen, hydroxy, cyano, nitro, carboxy, C1-C4Alkyl radical, C1-C4Alkoxy radical, C1-C4Alkylamino alkoxy or C1-C4An ester group.
3. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R1Represents fluorine, bromine, chlorine, iodine, hydroxyl, cyano, nitro, carboxyl, methyl, ethyl, methoxy, ethoxy, dimethylaminoethoxy, diethylaminoethoxy or diethylaminopropoxy.
4. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R1Represents fluorine, bromine, chlorine, iodine, hydroxyl, methyl, dimethylaminoethoxy or diethylaminoethoxy.
5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R3Represents hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, nitro, carboxyl, cyano, amino, acetyl, C1-C4Alkyl radical, C1-C4Haloalkyl, C1-C4Alkoxy radical, C1-C4Alkylamino alkoxy or C1-C4An ester group.
6. A compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R3Represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, methyl, acetyl, methoxy or ethoxy.
7. A compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R3Represents hydrogen, acetyl, methyl, methoxy or ethoxy.
8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein n represents 1 or 2.
9. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from:
2- ((5-acetyl-2-methoxybenzyl) thio) -6-fluoro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6-chloro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6-bromo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6-iodo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((5-acetyl-2-methoxybenzyl) thio) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-fluoro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-chloro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-bromo-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-iodo-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- ((2-methoxybenzyl) thio) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-hydroxy-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6- (2- (dimethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6- (2- (diethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6-fluoro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6-chloro-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6-bromo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6-iodo-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6-methyl-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6-hydroxy-3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-fluoro-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-chloro-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-iodo-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6-methyl-2- (2-methoxyphenethyl) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one.
10. A compound or pharmaceutically acceptable salt thereof according to claim 6, wherein the compound is selected from:
6-fluoro-2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
6- (2- (diethylamino) ethoxy) -2- ((2-methoxybenzyl) thio) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6- (2- (dimethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one;
2- (benzylsulfanyl) -6- (2- (diethylamino) ethoxy) -3- (thiophene-2-methylene) quinazolin-4 (3H) -one.
11. A process for the preparation of a compound according to claim 1,
a) when X is S, the synthesis route of the compound shown in the general formula I is as follows:
b) when X is CH2The synthetic route of the compound shown in the general formula I is as follows:
12. a pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient or as a major active ingredient, together with a pharmaceutically acceptable carrier.
13. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with hepatitis b.
14. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an anti-HBV agent.
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