CN110724140B - Dihydroquinozinone carboxylic acid compound and application thereof - Google Patents
Dihydroquinozinone carboxylic acid compound and application thereof Download PDFInfo
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- CN110724140B CN110724140B CN201911063354.XA CN201911063354A CN110724140B CN 110724140 B CN110724140 B CN 110724140B CN 201911063354 A CN201911063354 A CN 201911063354A CN 110724140 B CN110724140 B CN 110724140B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
- C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
- C07D455/06—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine containing benzo [a] quinolizine ring systems
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- 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
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention belongs to the field of medical chemistry, and relates to a dihydroquinazinone carboxylic acid compound with anti-Hepatitis B Virus (HBV) activity, a preparation method thereof, and a pharmaceutical composition containing the same for resisting HBV infection.
Description
Technical Field
The invention belongs to the field of medical chemistry, and relates to a dihydroquinazinone carboxylic acid compound with anti-Hepatitis B Virus (HBV) activity, a preparation method thereof, and a pharmaceutical composition containing the same for resisting HBV infection.
Background
Chronic Hepatitis B Virus (HBV) infection is a major public health problem worldwide. It is estimated that the infection rate of HBV accounts for about 5% of the global population, and about 100 million people die each year from HBV infection and related liver diseases. The current clinical anti-HBV infection drugs include interferon (immunomodulator) nucleoside drugs (polymerase inhibitors). Although these drugs can significantly reduce viral load (HBV DNA) and prevent progression of liver disease, there is no cure for HBV infection. Therefore, the discovery and development of anti-HBV drugs with a completely new mechanism of action has been a research hotspot in this field for many years.
Hepatitis B Virus (HBV) is an enveloped, partially double-stranded DNA virus. The infection process of HBV involves adhesion (recognition and binding), uncoating (release), coring (formation of rcDNA, repaired to cccDNA), transcription (transcription of cccDNA as template to mRNA), translation (mRNA makes viral proteins, i.e. envelope protein HBsAg, nucleocapsid protein HBeAg, HBV DNA polymerase, etc.), reverse transcription (minus strand DNA, which reverse transcribes plus strand DNA to form HBV DNA), and assembly of 7 parts. Clinically, high expression of HBsAg is considered a significant marker of chronic hepatitis b infection. The disappearance of HBsAg is defined as a "functional cure" of HBV, and the subsequent production of antibodies in the serum that can detect HBs is considered as an ideal endpoint of HBV treatment. The interferon and nucleoside drugs used in current therapies only reduce HBV DNA, but are not effective in reducing HBsAg levels. The nucleoside analogues showed HBsAg clearance comparable to those naturally observed (between-1% and 2%) even with prolonged treatment (Lancet, 2005,365, 13-9; n.engl.j.med.2004,351, 1206-17.).
The dihydroquinolizinone carboxylic acid compounds are a new anti-HBV compound reported in recent years and having activity on HBV antigen (HBsAg) and HBV DNA simultaneously, and a plurality of pharmaceutical companies across countries have researched and disclosed the compounds and disclose a plurality of patents (WO2017017042A1, WO201815446, WO2018047109, WO2017216685A1, WO2017140821A 1).
In 2017, Switzerland Roche GmbH (WO2017016960A1) disclosed 2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid compounds having the following general formula [ A ] and a preparation method thereof, and various substituents in the general formula are broadly defined. An excellent representative in the general formula [ A ] is (S) -6-isopropyl-10-methoxy-9- (3-methoxypropyl) -2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid (RG 7834). RG7834 is reported to have well-defined in vitro and in vivo anti-HBsAg and HBeAg and HBV DNA activity (j.med.chem.,2018,61, 10619-. Unfortunately, however, roche limited has currently terminated the phase I clinical trial of RG7834 (NCT02604355), possibly due to toxicity problems.
In order to overcome the defects of the prior art, the inventors of the present invention conducted extensive research to design and synthesize a series of novel dihydroquinazolinone carboxylic acid compounds, and determined their in vitro anti-HBV activity and cytotoxicity. Finally, the compounds have more excellent in vitro anti-HBV (HBsAg, HBV DNA) activity and lower cytotoxicity compared with RG 783.
Disclosure of Invention
The invention aims to provide a compound shown by a formula (I) or pharmaceutically acceptable salt, enantiomer or diastereoisomer thereof,
wherein:
a represents hydrogen or halogen;
b represents hydrogen or C1-6An alkyl group;
Z1and Z2May be the same or different, and each represents CH or N;
w represents the following group:
in the formula:
r represents 0 to 3 identical or different halogens, C1-3Alkyl, methoxy, nitro, cyano, trifluoromethyl or trifluoromethoxy;
R1represents methyl, ethyl or cyclopropyl;
x and Y may be the same or different and each represents O or CH2；
Z3And Z4May be the same or different, and each represents CH or N;
n represents 0, 1 or 2.
Preferably, the present invention specifically includes the following compounds:
1) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
2) 9- ((7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
3) 9- ((6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
4) 9- ((7-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
5) 9- ((6-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
6) 9- ((7-bromo-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
7) 9- ((6-bromo-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
8) 9- ((8-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
9) 9- ((7-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
10) 9- ((6-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
11) 9- ((5-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
12) 9- ((8-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
13) 9- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
14) 9- ((6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
15) 9- ((5-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
16) 9- ((7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
17) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
18) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) ethoxy) -6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid;
19) 9- ((3, 4-methylenedioxyphenyl) methoxy) -6-isopropyl-10-methoxy-2-oxy-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid;
20) 9- ((3, 4-methylenedioxyphenyl) ethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid;
21) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
22) 9- ((8-fluoro-2, 3-dihydroxybenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid;
23) 9- ((8-chloro-2-3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid;
24) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-2-methoxy-10-oxo-5, 10-dihydro-6H-pyrido [2,1-f ] [1,6] naphthyridine-9-carboxylic acid;
25) 9- ((2, 3-dihydro [1,4] dioxano [2,3-b ] pyridin-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid;
26) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
27) (6S) -9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
28) (6S) -9- (((R) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
29) (6S) -9- ((S) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
Another object of the present invention is to provide a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof, which process is illustrated in scheme 1.
Scheme 1:
in scheme 1, A, B, Z1、Z2And W is as previously defined.
The compounds of formula (II) and formula (II) used as starting materials in the present invention/) The compounds are known compounds, are commercially available in China or can be easily prepared according to the methods disclosed in the prior art (org. Lett.2000,2(11), 1557-1560). Another compound of formula (III) used as starting material is also known and can be easily prepared with reference to the methods disclosed in the prior art (WO2017140821, WO2018047109a 1).
The compounds of formula (IV) may be prepared by: carrying out Mitsunobu reaction on the compound of the formula (II) and the compound of the formula (III) in a non-polar solvent; or adding acid-binding agent into dipolar solvent to obtain the compound of formula (II)/) The compound and the compound of the formula (III) are added into the solvent to carry out condensation reaction.
To improveEfficiency of reaction of the noble starting material of the compound of formula (IIII), use of an excess of the reactants of the compound of formula (II) and of the compound of formula (II)/) The compound is, for example, in an equimolar to 10-fold molar amount, preferably in an equimolar to 3-fold molar amount, relative to the starting material. Stirring and reacting for 2-30 hours at 0-100 ℃ with or without pressure to prepare the compound of formula (IV). The nonpolar solvent used in the reaction is selected from tetrahydrofuran, dioxane or chloroform; the dipolar solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or acetonitrile; the acid-binding agent is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
The compounds of formula (IV) may be prepared by hydrolysis of an ester to produce the compounds of formula (I). The method is generally realized by placing the compound of the formula (IV) in a protic solvent, adding an inorganic base, and stirring for reaction for 2-10 hours at room temperature to 50 ℃. The alkali is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide; the protic solvent is selected from water, alcohol or alcohol-water mixed solvent.
The invention also provides a pharmaceutical composition which takes the compound shown in the formula (I) or the medicinal salt thereof as an active ingredient.
In the pharmaceutical composition, the weight ratio of the compound shown in the formula (I) or the medicinal salt thereof is 0.1-99.9%, and the weight ratio of the pharmaceutically acceptable carrier in the composition is 0.1-99.9%.
The pharmaceutical compositions of the present invention are in the form of preparations suitable for pharmaceutical use. The pharmaceutical composition of the invention can be prepared into any pharmaceutically acceptable dosage form. Preferably, the pharmaceutical preparation is a tablet, a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a capsule, a hard capsule, a soft capsule, a sustained-release capsule, or a powder.
The pharmaceutical composition of the present invention is in the form of a preparation, wherein each preparation contains 0.1-1000 mg of the compound of the present invention, and each preparation unit, such as each tablet of a tablet, each capsule, or each dose, such as 100mg per dose.
The pharmaceutical composition of the invention can be prepared into any pharmaceutically acceptable dosage form.
Preferably, the pharmaceutical dosage form of the invention is selected from: tablet, capsule, granule, syrup, powder for injection, and injection.
Solid carriers are used in the preparation of solid or semi-solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories, and ointments. The solid carrier which may be used is preferably one or more substances selected from diluents, flavouring agents, solubilising agents, lubricants, suspending agents, binders, bulking agents and the like, or may be an encapsulating substance. In the powdery preparation, 5-70% of micronized active ingredients are contained in a carrier. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling waxes, cocoa butter, and the like. Because of their ease of administration, tablets, powders, cachets, capsules and the like represent the most advantageous oral solid dosage forms.
Liquid formulations of the present invention include solutions, suspensions and emulsions. For example, parenteral injection preparations may be in the form of water or water-propylene glycol solutions, which are adjusted in isotonicity, pH, etc. to suit the physiological conditions of the living body. The liquid preparation can also be prepared into solution in polyethylene glycol or water solution. Aqueous solutions for oral administration can be prepared by dissolving the active ingredient in water, followed by the addition of suitable amounts of coloring, flavoring, stabilizing and thickening agents. Aqueous suspensions suitable for oral administration can be prepared by dispersing the micronized active ingredient in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.
It is particularly advantageous to formulate the above pharmaceutical preparations in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of a formulation refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect. Such dosage unit forms may be in the form of a pack, such as a tablet, capsule or powder in a small tube or vial, or an ointment, gel or cream in a tube or bottle.
Although the amount of active ingredient contained in the dosage unit form may vary, it is generally adjusted within the range of 1 to 800mg, depending on the potency of the active ingredient selected.
The preferred dosage for a given situation can be determined by one skilled in the art in a routine manner. Generally, the amount of the active ingredient to be initially treated is lower than the optimum dose of the active ingredient, and then the dose to be administered is gradually increased until the optimum therapeutic effect is achieved. The total daily dose may be administered once or in divided doses for therapeutic purposes.
Detailed Description
The following examples are presented to further illustrate and explain the present invention and are not intended to limit the scope of the invention.
In the following preparation methods, the starting compounds and intermediate compounds referred to are known compounds, and can be prepared by existing methods or can be purchased in the market.
Example 1.9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
a)2-bromomethyl-1,4-benzodioxane,K2CO3,KI,ACN,80℃；b)LiOH,CH3OH,H2O,rt.
Step a: to a solution of compound A (45mg, 0.16mmol, synthesized by the method described in WO2017017042A 1) in acetonitrile at room temperature was added 2-bromomethyl-1, 4-benzodioxan (87mg, 0.38mmol), potassium carbonate (35mg,0.25mmol), and the mixture was stirred at 80 ℃ overnight, cooled at room temperature, filtered, and concentrated. The residue was diluted with dichloromethane, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound B by preparative thin chromatography (dichloromethane: methanol ═ 10:1) (53.6mg, yield 84.2%).
Step b: to a solution of Compound B (50mg,0.09mmol) in aqueous methanol (5mL, MeOH: H) at room temperature2O is 3: 2) adding lithium hydroxide (11.8mg,0.49mmol), stirring at the same temperature for 2h, adjusting pH to 1-2 with 1N hydrochloric acid aqueous solution, extracting with dichloromethane, washing with saturated sodium chloride aqueous solution, and adding anhydrous sulfuric acidSodium dried and preparative thin layer chromatography (dichloromethane: methanol ═ 10:1) afforded title compound C (36mg, yield 81.3%); melting point, 223-;1H NMR(500MHz,CDCl3)15.99(s,1H),8.50(s,1H),7.23(s,1H),7.10(s,1H),6.92-6.90(m,4H),6.83(s,1H),4.68(brs,1H),4.45-4.45(d,J＝11.60Hz),4.43-4.29(m,3H),3.95(s,3H),3.38-3.34(d,J＝16.26Hz,1H),3.09-3.06(d,J＝16.26Hz,1H),1.83(brs,1H),0.96-0.95(d,J＝6.72Hz,3H),0.85-0.84(d,J＝6.72Hz,3H)；13C NMR(400MHz,CDCl3)177.95,165.87,150.41,148.59,145.55,145.06,141.63,141.60,124.73,120.89,120.68,118.85,116.37,113.51,112.90,112.54,107.78,70.24,70.14,68.05,66.61,66.40,63.96,63.91(d,J＝7.80Hz),55.23,29.31,28.47,28.46(d,J＝1.56Hz),18.76,18.57；MS-ESI(m/z):478(M+H)+。
example 2.9- ((7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
a) TsCl, Et3N, DCM; b) 5-methylsalicylaldehyde, K2CO3,DMF,50℃；c)mCPBA,DCM,reflux；d)K2CO3,MeOH；e)E,Ph3P,DIAD,THF；f)LiOH,MeOH,H2O.
Step a, adding 4-tosyl chloride (5.1g,27mmol) and triethylamine (3.6g,35.1mmol) to a dichloromethane (30mL) solution of compound A (2g,27mmol) at room temperature, stirring at the same temperature for 5h, washing with a 1N hydrochloric acid aqueous solution, washing with a saturated sodium carbonate solution, washing with water, drying over anhydrous sodium sulfate, filtering, concentrating to obtain a pale yellow oily substance B (6.8g), and directly using the crude product in the next reaction.
Step b: to a solution of 5-methylsalicylaldehyde (1g,7.35mmol) in N, N-dimethylformamide (10mL) was added potassium carbonate (1.21g,8.82mmol), crude compound B (2.1g,9.55mmol) at room temperature, stirred at 50 ℃ for 3.5h, cooled at room temperature, and filtered. The filtrate was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give yellow oil C (1.8g), which was used directly in the next reaction.
Step C to a solution of Compound C (1.8g, 9.37mmol) in dichloromethane (30mL) at room temperature was added m-chloroperoxybenzoic acid (2.58g,10.31mmol), refluxed for 5h, and cooled at room temperature. To the reaction solution was added saturated aqueous sodium carbonate solution, quenched with 10% aqueous sodium thiosulfate solution, washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated to give colorless oil D (1.7g), which was used directly in the next reaction.
Step D Potassium carbonate (4.4g,31.61mmol) was added to a solution of Compound D (2.0g, 9.56mmol) in methanol (30mL) at room temperature, stirred at the same temperature for 18h, diluted with water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give E (1.2g) as a yellow oil which was used directly in the next reaction.
Step E compound E (28mg, 0.16mmol), triphenylphosphine (55mg, 0.2mmol) were added to a solution of compound F (30mg, 0.08mmol) in anhydrous tetrahydrofuran (5mL) at room temperature under argon protection, stirred at the same temperature for 30min, added diisopropyl azodicarboxylate (43mg, 0.2mmol), stirred at the same temperature for 5h, and concentrated. The residue was subjected to preparative thin chromatography (dichloromethane: methanol ═ 10:1) to give compound G (21mg, yield 48%) as a white solid.
Step f, adding lithium hydroxide (6mg, 0.25mmol) into a methanol aqueous solution of a compound G (21mg, 0.04mmol) at room temperature, stirring at the same temperature for 2 hours, adding a 1N hydrochloric acid solution into a reaction solution to adjust the pH value to 1-2, extracting dichloromethane, washing a dichloromethane layer with water, washing a saturated sodium chloride solution with water, drying by anhydrous sodium sulfate, and preparing a white solid target compound H (17mg, yield 85%) by thin layer chromatography (dichloromethane: methanol ═ 10: 1); melting point, 167-;1H NMR(500MHz,CDCl3)16.05(d,J＝29.51Hz,1H),8.52(s,1H),7.24(s,1H),7.12(s,1H),7.11(s,1H),6.88-6.70(m,3H),4.43-4.37(m,3H),4.02-3.96(m,6H),3.73(d,J＝27.11Hz,1H),3.37(d,J＝4.82Hz,1H),3.10(d,J＝16.66Hz,1H),1.65(m,3H),0.98(s,3H),0.87(s,3H)；MS-ESI(m/z):492(M+H)+。
example 3.9- ((6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 4-methyl salicylaldehyde is used as a raw material to replace 5-methyl salicylaldehyde, the target compound is prepared, and the yield is 79 percent (two-step reaction); melting point, 207-;1H NMR(500MHz,DMSO)8.80(s,1H),7.57(s,1H),7.50(s,1H),7.17(s,1H),6.81-6.67(m,3H),4.61(s,1H),4.45-4.43(m,4H),4.17(s,1H),3.91(s,3H),3.32-3.14(m,2H),2.22(s,3H),1.64(s,1H),0.89(s,3H),0.72(s,3H)；MS-ESI(m/z):430(M+H)+。
example 4.9- ((7-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, the above target compound is prepared by using 5-methoxysalicylaldehyde instead of 5-methylsalicylaldehyde as a raw material, and the white solid is obtained with a yield of 46% (two-step reaction); melting point, 244-;1H NMR(500MHz,DMSO)8.80(s,1H),7.57(s,1H),7.50(s,1H),7.18(s,1H),6.84(d,J＝8.35Hz,1H),6.53(s,1H),6.46(d,J＝8.35Hz,1H),4.65(s,1H),4.46-4.33(m,4H),4.16-4.15(m,1H),3.92(s,3H),3.69(s,3H),3.34-3.14(m,2H),1.64(s,1H),0.89(s,3H),0.72(s,3H)；MS-ESI(m/z):508(M+H)+。
example 5.9- ((6-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
Preparation method according to example 2, 4-methoxy salicylaldehyde instead of 5-methyl salicylaldehyde prepared the above target compound as a white solid with a yield of 66% (two-step reaction); melting point, 105-;1H NMR(500MHz,CDCl3)16.11(s,1H),8.53(s,1H),7.41-7.249(m,3H),7.12(s,1H),6.87-6.80(m,1H),6.53-6.48(m,1H),4.76-4.71(d,J＝26.29Hz,1H),4.39-4.30(d,J＝44.90Hz,2H),4.01-3.97(m,6H),3.78(s,2H),3.39-3.28(m,3H),3.13(d,J＝14.24Hz,1H),1.84(brs,1H),0.99(s,3H),0.87(s,3H)；MS-ESI(m/z):508(M+H)+。
example 6.9- ((7-bromo-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 5-bromosalicylaldehyde is used as a raw material to replace 5-methyl salicylaldehyde, the target compound is prepared, white solid is obtained, and the yield is 61% (two-step reaction); melting point, 244-;1H NMR(500MHz,DMSO)8.80(s,1H),7.57(s,1H),7.50(s,1H),7.16(d,J＝13.55Hz,2H),7.03(s,1H),6.91(d,J＝8.62Hz,1H),4.70(s,1H),4.46(d,J＝9.56Hz,2H),4.32(brs,2H),4.23-4.20(m,1H),3.91(s,3H),3.34-3.30(m,2H),1.62(s,1H),0.73(s,3H),0.72(s,3H)；MS-ESI(m/z):556(M+H)+。
example 7.9- ((6-bromo-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 4-bromosalicylaldehyde is used as a raw material to replace 5-methyl salicylaldehyde, the target compound is prepared, white solid is obtained, and the yield is 72% (two-step reaction); melting point, 231-;1H NMR(500MHz,CDCl3)16.01(s,1H),8.48(s,1H),7.30(s,2H),7.22(s,1H),7.10(s,1H),6.88(s,1H),6.82(s,1H),6.15(s,1H),4.46-4.28(m,4H),4.02(s,3H),3.90-3.87(m,1H),3.36-3.32(m,1H),3.10(d,J＝16.17Hz,1H),1.87-1.84(m,1H),0.98(d,J＝6.49Hz,3H),0.86(d,J＝6.55Hz,3H)；MS-ESI(m/z):556(M+H)+。
example 8.9- ((7-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 5-chlorosalicylaldehyde is used for replacing 5-methyl salicylaldehyde as a raw material, the target compound is prepared, white solid is obtained, and the yield is 65% (two-step reaction); melting point, 221-;1H NMR(500MHz,CDCl3)16.01(s,1H),8.53(s,1H),7.31(s,1H),7.25(s,1H),7.13-6.85(m,4H),4.69(s,1H),4.46-4.31(m,4H),3.97(s,4H),3.38(d,J＝14.03Hz,1H),3.10(d,J＝16.58Hz,1H),1.85(s,1H),0.99(d,J＝4.97Hz,3H),0.87(d,J＝5.18Hz,3H)；MS-ESI(m/z):512(M+H)+。
example 9.9- ((6-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 4-chlorosalicylaldehyde replaces 5-methyl salicylaldehyde to be used as a raw material, the target compound is prepared, white solid is obtained, and the yield is 72% (two-step reaction); melting point, 229-;1H NMR(500MHz,CDCl3)15.86(s,1H),8.38(s,1H),7.15(s,1H),7.09(s,1H),6.97-6.88(m,4H),4.51(s,1H),4.31-4.15(m,4H),3.81(s,4H),3.22(d,J＝15.53Hz,1H),2.96(d,J＝16.03Hz,1H),1.68(s,1H),0.83(d,J＝5.25Hz,3H),0.71(d,J＝5.50Hz,3H)；MS-ESI(m/z):512(M+H)+。
example 10.9- ((8-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation was carried out as in example 2, to6-chlorosalicylaldehyde replaces 5-methyl salicylaldehyde to serve as a raw material, the target compound is prepared, white solid is obtained, and the yield is 76% (two-step reaction); melting point, 230-;1H NMR(500MHz,CDCl3)16.09(s,1H),8.56(s,1H),7.25(s,1H),7.13(s,1H),6.96(s,2H),6.82(s,2H),4.73(s,1H),4.49-4.32(m,4H),3.99-3.95(s,4H),3.38(d,J＝15.82Hz,1H),3.10(d,J＝16.51Hz,1H),1.83(s,1H),0.96(s,3H),0.83(s,3H)；MS-ESI(m/z):512(M+H)+。
example 11.9- ((5-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 3-chlorosalicylaldehyde replaces 5-methyl salicylaldehyde to be used as a raw material, the target compound is prepared, white solid is obtained, and the yield is 87% (two-step reaction); melting point, 292-;1H NMR(500MHz,CDCl3)16.01(s,1H),8.52(s,1H),7.24(s,1H),7.12(s,1H),7.01(s,1H),6.99-6.84(m,3H),4.71(s,1H),4.57-4.32(m,4H),4.02-3.96(m,4H),3.35(d,J＝15.66Hz,1H),3.10(d,J＝16.03Hz,1H),1.75(s,1H),0.98-0.97(d,J＝5.55Hz,3H),0.86-0.85(d,J＝5.55Hz,3H)；MS-ESI(m/z):512(M+H)+。
example 12.9- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 3-chlorosalicylaldehyde replaces 5-methyl salicylaldehyde to be used as a raw material, the target compound is prepared, white solid is obtained, and the yield is 58% (two-step reaction); melting point, 188-;1H NMR(500MHz,CDCl3)15.98(s,1H),8.52(s,1H),7.32(s,1H),7.26(s,1H),7.13(s,1H),6.90-6.64(m,3H),4.71(s,1H),4.46-4.37(m,3H),4.04-3.94(m,5H),3.39(d,J＝13.14Hz,1H),3.12(d,J＝16.27Hz,1H),1.87(s,1H),1.00(d,J＝5.88Hz,3H),0.89(d,J＝5.37Hz,3H)；MS-ESI(m/z):496(M+H)+。
example 13.9- ((7-Nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, with 5-nitro salicylaldehyde replacing 5-methyl salicylaldehyde as raw materials, the above target compound is prepared, white solid, yield 43% (two-step reaction); melting point, 185-187 deg.C;1H NMR(500MHz,CDCl3)15.90(s,1H),8.49(s,1H),7.87(s,1H),7.30(s,1H),7.25(s,1H),7.11(s,1H),7.04(d,J＝8.32Hz,1H),6.86(d,J＝4.08Hz,1H),4.72(s,1H),4.61-4.30(m,4H),3.96(s,3H),3.92(s,1H),3.40-3.36(dd,J＝10.96Hz,J＝11.35Hz,1H),3.10(d,J＝15.96Hz,1H),1.84(d,J＝7.36Hz,1H),0.99(d,J＝6.53Hz,3H),0.88(d,J＝6.72Hz,3H)；MS-ESI(m/z):523(M+H)+。
example 14.9- ((6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in example 2, 4-fluorosalicylaldehyde is used as a raw material to replace 5-methyl salicylaldehyde, the target compound is prepared, white solid is obtained, and the yield is 55% (two-step reaction); melting point, 222-224 ℃;1H NMR(500MHz,CDCl3)16.01(s,1H),8.53(s,1H),7.25(s,1H),7.12(s,1H),6.86(d,2H),6.68(s,1H),6.62(s,1H),4.65(s,1H),4.47-4.31(m,4H),3.97(s,4H),3.38(s,1H),3.12(s,1H),1.84(brs,1H),0.98(s,3H),0.87-0.86(d,J＝4.60Hz,3H)；MS-ESI(m/z):496(M+H)+。
example 15.9- ((8-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in implementation 2, 6-fluorosalicylaldehyde is used as a raw material to replace 5-methyl salicylaldehyde, the target compound is prepared, white solid is obtained, and the yield is 49% (two-step reaction); melting point, 219-;1H NMR(500MHz,CDCl3)16.02(s,1H),8.53(s,1H),7.24(s,1H),7.12(s,1H),6.91-.89(d,J＝6.04Hz,1H),6.82-6.79(m,1H),6.71-6.72(m,1H),4.72-4.71(m,1H),4.52-4.44(m,2H),4.40-4.32(m,2H),3.96(s,1H),3.39(d,J＝15.38Hz,1H),3.10(d,J＝16.25Hz,1H),1.85-1.82(m,1H),0.98-0.97(m,3H),0.86-0.84(d,J＝5.71Hz,3H)；MS-ESI(m/z):496(M+H)+。
example 16.9- ((5-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation method is as in implementation 2, 3-fluorosalicylaldehyde is used as a raw material to replace 5-methyl salicylaldehyde, the target compound is prepared, white solid is obtained, and the yield is 54% (two-step reaction); melting point, 281-;1H NMR(500MHz,CDCl3)16.00(s,1H),8.52(s,1H),7.24(s,1H),7.12(s,1H),6.84(s,1H),6.74(s,1H),4.73(d,J＝4.63Hz,1H),4.51(d,J＝11.63Hz,1H),4.41-4.33(m,3H),3.96(s,4H),3.39(d,J＝15.86Hz,1H),3.11-3.08(d,J＝15.86Hz,1H),1.84(brs,1H),0.98(d,J＝6.55Hz,3H),0.86(d,J＝6.67Hz,3H)；MS-ESI(m/z):496(M+H)+。
example 17.9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
The preparation was carried out according to the procedure of example 1, substituting 2-hydroxymethyl-1, 4-benzodioxan for 2-oxan-7-aza-spiro [4.4]Nonane as a raw material to obtain the target compound as a white solid with a yield of 77% (two-step reaction); melting point, 262-;1H NMR(500MHz,DMSO)8.79(s,1H),7.55(s,1H),7.48(s,1H),7.20(s,1H),6.99(brs,1H),6.94(s,1H),6.90(d,J＝8.07Hz,2H),5.09-5.03(m,2H),4.26(s,4H),3.89(s,3H),3.12(d,J＝16.52Hz,1H),2.05-2.02(m,1H),0.98(d,J＝6.40Hz,3H),0.73(d,J＝6.57Hz,3H)；13C NMR(400MHz,DMSO)178.75,166.72,151.52,149.00,147.69,147.02,143.81,129.75,127.24,121.83,119.02,117.66,117.44,113.75,113.29,109.84,70.11,64.56,64.52,56.49,31.75,29.53,29.36(d,J＝26.03Hz),19.49,19.40；MS-ESI(m/z):478(M+H)+。
example 18.9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) ethoxy) -6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid
Preparation method according to example 1, with 2- (2, 3-dihydrobenzo [ B ]][1,4]The above target compound was prepared as a white solid in 64% yield from (R) -2- (hydroxymethyl) -1, 4-benzodioxan as a starting material, dioxan-6-yl) ethanol; melting point, 208-;1H NMR(500MHz,CDCl3)16.09(s,1H),8.51(s,1H),7.20(s,1H),7.08(s,1H),6.82-6.80(m,2H),6.77-6.75(m,1H),6.71(s,1H),4.25-4.21(m,6H),3.94(s,4H),3.33(d,J＝11.52Hz,1H),3.10-3.02(m,3H),1.81-1.79(m,1H),0.93(d,J＝6.69Hz,3H),0.82(d,J＝6.83Hz,3H)；MS-ESI(m/z):492(M+H)+。
example 19.9- ((3, 4-methylenedioxyphenyl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid
Preparation method according to example 1, the above-mentioned object compound was prepared from piperonyl alcohol instead of (R) -2- (hydroxymethyl) -1, 4-benzodioxaneWhite solid, yield 54% (two-step reaction); melting point, 210 ℃ and 212 ℃;1H NMR(500MHz,CDCl3)16.00(s,1H),8.48(s,1H),7.23(s,1H),7.10(s,1H),6.98(s,1H),6.94(s,1H),6.86(s,1H),6.81(s,1H),5.18-5.12(m,2H),3.98(s,1H),3.88(s,1H),3.36-3.33(m,1H),3.06(d,J＝16.26Hz,1H),1.85(m,1H),0.96(d,J＝6.54Hz,3H),0.88(d,J＝6.54Hz,3H)；MS-ESI(m/z):464(M+H)+。
example 20.9- ((3, 4-methylenedioxyphenyl) ethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid
Preparation method the above target compound was prepared as a white solid in 63% yield (two-step reaction) according to example 1, starting from (3, 4-methylenedioxyphenyl) ethanol instead of (R) -2- (hydroxymethyl) -1, 4-benzodioxane; melting point, 125-127 ℃;1H NMR(500MHz,CDCl3)16.04(s,1H),8.47(s,1H),7.20-7.19(m,1H),7.08(s,1H),6.90-6.81(m,H),6.66(s,1H),5.98(d,2H),5.34(s,1H),3.99(s,3H),3.85(s,1H),3.28(d,J＝16.53Hz,1H),2.98-2.97(m,1H),1.75(s,4H),0.96-091(m,3H),0.86-0.77(m,3H)；MS-ESI(m/z):478(M+H)+。
example 21.9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
Preparation method according to example 1, the target compound C was prepared from a (synthesized according to patent WO 2017140821) and commercially available B as starting materials to obtain the target compound as a white solid in a yield of 45% (two-step reaction); melting point, 238-;1H NMR(500MHz,CDCl3)15.10(s,1H),8.45(s,1H),7.67(s,1H),7.00(s,1H),6.3-6.89(m,2H),6.83(s,1H),5.15(s,2H),4.29(s,4H),3.96(s,4H),3.52(s,1H),3.35(s,1H),3.07(d,J＝13.42Hz,1H),2.04(s,1H),0.93(d,J＝4.88Hz,3H),0.86(d,J＝5.83Hz,3H)；MS-ESI(m/z):496(M+H)+。
example 22.9- ((8-fluoro-2, 3-dihydroxybenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-A ] isoquinoline-3-carboxylic acid
The preparation method is that according to the embodiment 21 and the embodiment 2, the target compound can be prepared by taking 6-fluorosalicylaldehyde as a raw material, and the target compound is prepared and is white solid with the yield of 34 percent (two-step reaction); melting point, 102-;1H NMR(500MHz,CDCl3)15.12(s,1H),8.52(s,1H),7.70(s,1H),6.98(d,J＝8.05Hz,1H),6.86(m,1H),6.77(m,2H),4.75-4.74(m,1H),4.00(d,J＝6.63Hz,1H),3.96(s,3H),3.42(d,J＝13.97Hz,1H),3.15(d,J＝15.55Hz,1H),1.80(s,1H),1.00(d,J＝3.53Hz,3H),0.89(d,J＝5.15Hz,3H)；MS-ESI(m/z):514(M+H)+。
example 23.9- ((8-chloro-2-3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid
Preparation method according to example 21 and example 2, the target compound can be prepared by using 6-chlorosalicylaldehyde as a raw material, and the target compound is prepared and is white solid with the yield of 53% (two-step reaction); the melting point is 89-91 ℃;1H NMR(500MHz,CDCl3)15.07(s,1H),8.48(s,1H),7.68(s,1H),7.00(s,2H),6.86-6.83(m,2H),4.75(d,J＝16.5Hz,1H),4.51-4.37(m,4H),3.90(s,4H),3.37(d,J＝15.68Hz,1H),3.14(d,J＝16.05Hz,1H),2.05-2.04(m,1H),0.98-0.96(m,3H),0.87-0.86(m,3H)；MS-ESI(m/z):530(M+H)+。
example 24.9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-2-methoxy-10-oxo-5, 10-dihydro-6H-pyrido [2,1-f ] [1,6] naphthyridine-9-carboxylic acid
Preparation method according to example 21, the target compound C was obtained as a white solid in a yield of 57% from compound a (obtained by the method of WO2018047109a1) and compound B (commercially available) as starting materials (two-step reaction);1H NMR(500MHz,CDCl3)15.07(s,1H),8.48(s,1H),7.68(s,1H),7.02-6.89(m,3H),4.75-4.74(d,1H),4.51-4.37(m,4H),3.90(s,4H),3.39-3.36(d,J＝15.68Hz,1H),3.12(d,J＝16.05Hz,1H),2.05(d,J＝15.43Hz,1H),0.98-0.96(m,3H),0.87-0.86(m,3H)；MS-ESI(m/z):479(M+H)+。
example 25.9- ((2, 3-dihydro [1,4] dioxano [2,3-b ] pyridin-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid
Preparation method according to example 21, the target compound C was obtained as a white solid in a yield of 39% from compound A (obtained by the method described in CN 201580003570.9) and compound B (obtained by the method described in org. Lett.2000,2(11), 1557-E1560);1H NMR(500MHz,CDCl3)15.07(s,1H),8.48(s,1H),7.68(s,1H),7.02(s,2H),6.76-6.69(m,2H),4.75-4.74(d,1H),4.51-4.37(m,4H),3.90(s,4H),3.37(d,J＝15.68Hz,1H),3.14-3.11(d,J＝16.05Hz,1H),2.05-2.04(m,1H),0.98-0.96(m,3H),0.87-0.86(m,3H)；MS-ESI(m/z):479(M+H)+。
example 26.9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
Preparation method according to example 21, compound A (see patent method US 2015)210682) and the commercially available compound B as starting materials to give the target compound C as a white solid in 71% yield (two-step reaction),1H NMR(500MHz,CDCl3)15.07(s,1H),8.48(s,1H),7.68(s,1H),7.02(s,2H),6.76-6.69(m,2H),4.75-4.74(d,1H),4.51-4.37(m,4H),3.90(s,4H),3.37(d,J＝15.68Hz,1H),3.12(d,J＝16.05Hz,1H),2.05-2.04(m,1H),0.87(s,9H)；MS-ESI(m/z):492(M+H)+。
EXAMPLE 27 (6S) -9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
a)2-bromomethyl-1,4-benzodioxane,K2CO3,KI,ACN,80℃；b)LiOH,CH3OH,H2O,rt.
Preparation method referring to example 1, the target compound C can be prepared by using the compound A with S configuration (J.Med.chem.,2018,61,10619-10634 can be prepared by the literature method) as the raw material,1H NMR(500MHz,CDCl3)15.99(s,1H),8.50(s,1H),7.23(s,1H),7.10(s,1H),6.92-6.90(m,4H),6.83(s,1H),4.68(brs,1H),4.45-4.45(d,J＝11.60Hz),4.43-4.29(m,3H),3.95(s,3H),3.38-3.34(d,J＝16.26Hz,1H),3.09-3.06(d,J＝16.26Hz,1H),1.83(brs,1H),0.96-0.95(d,J＝6.72Hz,3H),0.85-0.84(d,J＝6.72Hz,3H)；MS-ESI(m/z):478(M+H)+。
EXAMPLE 28 (6S) -9- (((R) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
a)(R)-2-bromomethyl-1,4-benzodioxane,K2CO3,KI,ACN,80℃；b)LiOH,CH3OH,H2O,
rt.
Preparation method referring to example 1, Compound A in S configuration (prepared by the literature method)J.Med.chem.,2018,61,10619-10634) and R-configuration 2-bromomethyl-benzodioxan as raw materials to prepare a target compound C,1HNMR(500MHz,CDCl3)15.99(s,1H),8.50(s,1H),7.23(s,1H),7.10(s,1H),6.92-6.90(m,4H),6.83(s,1H),4.68(brs,1H),4.45-4.45(d,J＝11.60Hz),4.43-4.29(m,3H),3.95(s,3H),3.38-3.34(d,J＝16.26Hz,1H),3.09-3.06(d,J＝16.26Hz,1H),1.83(brs,1H),0.96-0.95(d,J＝6.72Hz,3H),0.85-0.84(d,J＝6.72Hz,3H)；MS-ESI(m/z):478(M+H)+。
EXAMPLE 29 (6S) -9- (((S) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
a)(S)-2-bromomethyl-1,4-benzodioxane,K2CO3,KI,ACN,80℃；b)LiOH,CH3OH,H2O,rt.
The preparation method refers to example 1, the target compound C can be prepared by taking the compound A with S configuration (J.Med.chem.,2018,61,10619-10634 can be prepared by the literature method) and the 2-bromomethyl-benzodioxan with S configuration as raw materials,1HNMR(500MHz,CDCl3)15.99(s,1H),8.50(s,1H),7.23(s,1H),7.10(s,1H),6.92-6.90(m,4H),6.83(s,1H),4.68(brs,1H),4.45-4.45(d,J＝11.60Hz),4.43-4.29(m,3H),3.95(s,3H),3.38-3.34(d,J＝16.26Hz,1H),3.09-3.06(d,J＝16.26Hz,1H),1.83(brs,1H),0.96-0.95(d,J＝6.72Hz,3H),0.85-0.84(d,J＝6.72Hz,3H)；MS-ESI(m/z):478(M+H)+。
biological example 1
In vitro anti-HBsAg Activity assay
The HBsAg detection kit (Beijing Korea biotechnology Co., Ltd.) was taken out of the refrigerator at 2-8 ℃ and equilibrated at room temperature for 30 minutes while the concentrated washing solution was made to 1: 20, diluting; taking the microporous plate out of the sealed bag, setting blank reference two holes and a calibrator hole, and placing the microporous plate strips on the plate frame according to the designed number of samples; taking out from a refrigerator at minus 80 ℃, collecting supernatant for 6d, and adding 50 mu L of calibrator or supernatant to be tested into the other holes except blank control; adding 50 mu L of enzyme label into each hole except the blank control hole; shaking and mixing uniformly for 5s with a micro-oscillator, sealing the reaction plate with a sealing plate membrane, and incubating at 37 ℃ for 1 h; adding 350 mu L of washing liquid into each hole, washing the plate for 5 times, soaking for 10s each time, and finally drying on clean absorbent paper; adding 100 μ L of chemiluminescent substrate working solution (equal volume mixing of two luminescent substrates) into each well, and mixing with micro oscillator for 5 s; standing and reacting for 5min at room temperature in a dark place, and immediately sequentially measuring the luminous value of each hole on an EnVision multifunctional microplate reader (Perkinelmer); and drawing a standard curve according to the numerical value of the standard substance, and calculating the content of the HBsAg in each hole.
The inhibition rate of HBsAg was calculated.
Calculation of IC Using Reed-Muench method50And compared with RG7834 (racemate), the results are shown in Table 1.
Biological example 2
In vitro anti-HBV-DNA Activity and cytotoxicity test
1. Cell culture
Hep2.2.15 cell passage/plating/dilution medium for drug: MEM (Gibco) medium containing 10% fetal bovine serum (Gbico), 380. mu.g/ml G418(Gibco), penicillin and streptomycin diabody 100U/ml (Gibco).
When Hep2.2.15 cell confluence reaches 90%, 0.25% pancreatin-EDTA (Gibco) is added into a culture flask, the mixture is digested for 5 minutes at 37 ℃, the pancreatin is discarded, the residual liquid is continuously digested for 5 minutes at 37 ℃, the mixture is passed at 1:3, and the passage is carried out once in 3-4 days.
2. Determination of anti-HBV efficacy of compounds
Hep2.2.15 cells were seeded in 24-well plates at 1X 105/well and cultured at 37 ℃ in 5% CO 2; after 24h, the medium in the well plate was discarded and different concentrations of drug diluted in complete medium were added. Control groups (culture medium without drug) and experimental drug groups (culture medium with different concentrations of drug) were set. Adding the same culture solution at 3d, changing once, observing cytotoxicity after administration for 6d, collecting cells and supernatant, centrifuging the supernatant at 2000rpm for 10min, collecting supernatant, and storing at-80 deg.C for testing.
2.1 cytotoxicity assays
After 6 days of administration, the growth state of the cells in each well was observed under an inverted microscope, the cells at different administration concentrations were compared with normal cells, and the cell CPE in each well was observed, and the cell state change or death ratio was labeled 4+ (75% -100% of cell death ratio), 3+ (50% -75% of cell death ratio), 2+ (25% -50% of cell death ratio), 1+ (0-25% of cell death ratio), and 0+ (no difference between the cell state and the control group), respectively. Calculation of half Toxic Concentration (TC) by Reed-Muench method50) And compared with RG7834 (racemate), the results are shown in Table 1.
2.2 intracellular HBV core DNA content determination
Preparing a cell lysate: 10mM Tris-HCl/pH 8.0, 1mM EDTA, 1% NP 40;
cell HBV core DNA extraction: adding 300uL cell lysate into each well, performing lysis at room temperature for 5-10min, and centrifuging at 12000rpm for 5 min; collecting supernatant, performing protease K (Sigma), extracting with phenol (chloroform) and isoamyl alcohol, precipitating with anhydrous alcohol, dissolving the precipitate with 20 μ L ddH2O to obtain HBV core DNA, and storing at-20 deg.C.
qPCR method for intracellular HBV core DNA determination and calculation: HBV core DNA content was detected using a kit TransStart Tip GreenqPCR SuperMix (Beijing Quanji Co., Ltd.) in an ABI7500Fast type high throughput real-time fluorescent quantitative PCR (qPCR) instrument, and each DNA sample was assayed 2 times.
HBV core DNA qPCR primers: 5'-GGCTTTCGGAAAATTCCTATG-3' (upstream); 5'-AGCCCTACGAACCACTGAAC-3' (downstream).
The reaction system is as follows:
real-time PCR reaction system
| Composition (I) | Amount of addition |
| HBV upstream primer (10. mu.M) | 0.2μL |
| HBV downstream primer (10. mu.M) | 0.2μL |
| 2×SYBR Green Reaction Mix | 10μL |
| Rox Dye | 0.2μL |
| DNA | 1μL |
| Deionized water | 8.4μL |
| In total | 20μL |
Reaction conditions are as follows: 20uL system, 94 ℃, 30s, 1 cycle; 94 ℃ for 5s, 60 ℃ for 30s, 40 cycles.
Two reactions were run in parallel for each DNA sample.
After the reaction is finished, the content of HBV core DNA of each sample relative to the content of the control group is calculated by a delta Ct method, and the calculation formula is as follows:
the relative content (%) < 2^ (HBV Ct control group-HBV Ct drug group) < 100% (HBV Ct control group represents Ct value of HBV core DNA of virus control group; HBV Ct drug group represents Ct value of HBV core DNA of drug groups with different concentrations). Then, the inhibition rate is calculated, and finally, the half Inhibition Concentration (IC) is calculated by a Reed-Muench method50) And compared with RG7834 (racemate), the results are shown in Table 1.
TABLE 1 in vitro Activity and cytotoxicity of some of the example Compounds
NT not measured
As can be seen from Table 1, the activity (IC) of the compounds of the formula (I) of the present application of the compounds of examples 1, 3,4, 9-13, 15-17, 20-22, 25 on HBeAg50: 0.0002-0.0046. mu.M) greater than RG7834 (racemate) (IC)50: 0.0055. mu.M), in vitro activity (IC) of the compounds of examples 3,4, 8, 9, 11, 12 on HBV-DNA50: 0.0057-0.0101 μ M) greater than RG7834 (racemate) (IC)50: 0.0102 μ M), cytotoxicity (CC)50：>100. mu.M) are all less than RG7834 (racemate) (CC)50：>50μM)。
The in vitro activity and cytotoxicity of some compounds of the present invention are listed in the table, and other compounds of the present invention have similar structures and also have the same or similar in vitro activity as the above compounds and have lower cytotoxicity, which are not listed herein.
Composition examples
EXAMPLE 1 coated tablet
Tablet core prescription:
mixing the above materials, granulating, sieving, grading, drying, and tabletting to obtain 100 tablet cores.
The prescription of the coating liquid is as follows: opadry (Opadry)5g, 80% ethanol in appropriate amount.
EXAMPLE 2 capsules
Prescription:
the preparation method comprises the following steps:
taking the formula amount of raw and auxiliary materials, respectively sieving, adding 5% of polyvinylpyrrolidone alcohol solution and tween 80 to prepare soft materials, granulating by using a 20-mesh sieve, airing at room temperature of 15 ℃, adding sodium dodecyl sulfate, uniformly mixing, filling 0.27g/S into a No. 0 gastric soluble capsule, sampling and testing, wherein the dissolution limit is 80% and the content is 90-110% of the marked amount.
Example 3 granules
Taking 100g of the compound in the embodiment 17, adding a proper amount of dextrin and steviosin, carrying out dry granulation, finishing granules and subpackaging to obtain the compound.
EXAMPLE 4 injection
150g of the compound obtained in example 19 was dissolved in water, and sodium chloride and ethyl p-hydroxybenzoate were dissolved in hot water, followed by mixing and adjusting the pH to 5 to 7. Diluting the injection water to 1000ml, filtering with hollow fiber membrane, bottling, and sterilizing.
EXAMPLE 5 lyophilized powder for injection
Dissolving 150g of the compound in example 21 in water, adding 500g of mannitol, dissolving in hot water, mixing, diluting with water for injection to 5000ml, filtering with hollow fiber membrane, bottling, sterilizing, and lyophilizing to obtain lyophilized powder for injection.
EXAMPLE 6 dropping pills
Taking 20g of the compound in the embodiment 21 as a raw material medicine for standby; weighing 200g of dripping pill matrix, heating to 80 deg.C for melting, and stirring; adding the raw materials into the adjuvant matrix while stirring, stirring for 30min to make it uniform, and keeping the temperature of the liquid medicine not lower than 60 deg.C; injecting the prepared medicinal liquid into a dripping pill machine, and dripping into dripping pills.
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
wherein:
a represents hydrogen or halogen;
b represents hydrogen or C1-6An alkyl group;
Z1and Z2May be the same or different, and each represents CH or N;
w represents the following group:
in the formula:
r represents 0 to 3 identical or different halogens, C1-3Alkyl, methoxy, nitro, cyano, trifluoromethyl or trifluoromethoxy;
R1represents methyl, ethyl or cyclopropyl;
x and Y may be the same or different and each represents O or CH2；
Z3And Z4May be the same or different, and each represents CH or N;
n represents 0, 1 or 2.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that said compound is selected from:
1) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
2) 9- ((7-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
3) 9- ((6-methyl-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
4) 9- ((7-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
5) 9- ((6-methoxy-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
6) 9- ((7-bromo-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
7) 9- ((6-bromo-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
8) 9- ((8-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
9) 9- ((7-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
10) 9- ((6-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
11) 9- ((5-chloro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
12) 9- ((8-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
13) 9- ((7-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
14) 9- ((6-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
15) 9- ((5-fluoro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
16) 9- ((7-nitro-2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
17) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
18) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-6-yl) ethoxy) -6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid;
19) 9- ((3, 4-methylenedioxyphenyl) methoxy) -6-isopropyl-10-methoxy-2-oxy-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid;
20) 9- ((3, 4-methylenedioxyphenyl) ethoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid;
21) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
22) 9- ((8-fluoro-2, 3-dihydroxybenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6, 7-dihydro-2H-pyridine [2,1-a ] isoquinoline-3-carboxylic acid;
23) 9- ((8-chloro-2-3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -1-fluoro-6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid;
24) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-2-methoxy-10-oxo-5, 10-dihydro-6H-pyrido [2,1-f ] [1,6] naphthyridine-9-carboxylic acid;
25) 9- ((2, 3-dihydro [1,4] dioxano [2,3-b ] pyridin-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6-, 7-dihydro-2H-pyrido [2,1-a ] isoquinoline-3-carboxylic acid;
26) 9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-tert-butyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid;
27) (6S) -9- ((2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
28) (6S) -9- (((R) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid
29) (6S) -9- ((S) -2, 3-dihydrobenzo [ b ] [1,4] dioxan-2-yl) methoxy) -6-isopropyl-10-methoxy-2-oxo-6, 7-dihydrobenzo [ a ] quinolizine-3-carboxylic acid.
3. A process for the preparation of a compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, comprising the steps of:
1) carrying out Mitsunobu reaction on the compound of the formula (II) and the compound of the formula (III) in a non-polar solvent; or adding acid-binding agent into dipolar solvent to obtain the compound of formula (II)/) Adding the compound and the compound of formula (III) into the solvent for condensation reaction, and using excessive compound of formula (II) or formula (II)/) The compound meets the reaction requirement, is stirred and reacts for 2 to 30 hours at the temperature of between 0 and 100 ℃ with or without pressure to obtain a compound shown in a formula (IV),
wherein:
A、B、Z1、Z2and W is as defined in claim 1,
2) then placing the compound of the formula (IV) in a protic solvent, adding an inorganic base, stirring and reacting for 2-10 hours at the temperature of room temperature to 50 ℃, then adjusting the pH value to 1-2 by using 1N hydrochloric acid to obtain the compound of the formula (I),
wherein the nonpolar solvent is selected from tetrahydrofuran, dioxane or chloroform; the dipolar solvent is selected from N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide or acetonitrile; the acid-binding agent is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate; the protic solvent is selected from water, alcohol or alcohol-water mixed solvent; the inorganic alkali is selected from lithium hydroxide, sodium hydroxide or potassium hydroxide.
4. Use of a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment and/or prevention of Hepatitis B Virus (HBV) infection.
5. A pharmaceutical composition comprising the compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.
6. Use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment and/or prevention of HBV infection.
7. The pharmaceutical composition of claim 5, wherein the composition is formulated into any pharmaceutically acceptable dosage form.
8. The pharmaceutical composition of claim 5, wherein the composition is formulated as: tablet, capsule, granule, syrup, powder for injection, and injection.
9. The pharmaceutical composition according to claim 5, wherein the weight ratio of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is 0.1-99.9%.
10. A process for the preparation of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it comprises the following steps:
A、B、Z1、Z2and W is as defined in claim 1.
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| WO2018047109A1 (en) * | 2016-09-09 | 2018-03-15 | Novartis Ag | Polycyclic pyridone compounds as antivirals |
| CN106928245B (en) * | 2017-03-06 | 2019-06-11 | 河南春风医药科技有限公司 | A kind of Quinolizinone type compounds and its preparation method and application |
| CN108976223B (en) * | 2017-06-01 | 2020-08-07 | 广东东阳光药业有限公司 | Fused tricyclic compound and application thereof in medicines |
| CN110066278B (en) * | 2017-06-01 | 2021-06-08 | 广东东阳光药业有限公司 | Fused tricyclic compound and application thereof in medicines |
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