CN111393366B - Tetrahydroisoquinoline derivatives, preparation method, pharmaceutical composition and application - Google Patents
Tetrahydroisoquinoline derivatives, preparation method, pharmaceutical composition and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Abstract
The invention relates to a tetrahydroisoquinoline derivative, a preparation method, a pharmaceutical composition and application, wherein the tetrahydroisoquinoline derivative has a structure shown in a formula I:
(ii) a Wherein the content of the first and second substances,
is a substituted or unsubstituted aromatic ring or aromatic heterocycle,
Description
Technical Field
The invention relates to a tetrahydroisoquinoline derivative, a preparation method, a pharmaceutical composition and application, and belongs to the technical field of chemical medicines.
Background
Viral hepatitis B is one of the diseases with the highest incidence, the number of hepatitis B virus carriers is up to 3 hundred million, and the currently clinically effective anti-hepatitis B virus drugs mainly comprise interferon, lamivudine, adefovir dipivoxil, tenofovir disoproxil fumarate and recently marketed tenofovir alafenamide fumarate. However, the effective rate of the interferon is only 30-50%, and the interferon has toxic and side effects of dose limitation; lamivudine has definite anti-hepatitis B virus effect, but is easy to generate drug resistance, and after 2 years of continuous use, the incidence rate of the drug resistance is as high as 40-50%; adefovir dipivoxil has certain renal toxicity, and tenofovir disoproxil fumarate and recently marketed tenofovir alafenamide fumarate have higher effect of treating hepatitis B, but can not effectively eliminate hepatitis B virus; entecavir is suitable for treating chronic adult hepatitis B with active virus replication, continuous elevation of serum transaminase ALT or active pathological changes shown in liver histology, but has certain renal toxicity. Therefore, it is of great importance to find new compounds that are effective against antiviral drugs, especially as drugs for treating or preventing hepatitis b.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a tetrahydroisoquinoline derivative, a preparation method, a pharmaceutical composition and an application, and the specific technical scheme is as follows:
the tetrahydroisoquinoline derivative has a structure shown in a formula I:
wherein the content of the first and second substances,
is a substituted or unsubstituted aromatic ring or aromatic heterocycle,
represents cyclohexylamino, 4-methyl-1, 4-diazepan-1-yl, 3-oxo-1, 4-diazepan-1-yl.
As an improvement of the technical scheme, the tetrahydroisoquinoline derivatives are selected from any compound in the following formula 1-formula 30,
the structural formula of the compound is as follows:
formula 1
Formula 2
Formula 3
Formula 4
Formula 5
Formula 6
Formula 7
Formula 8
Formula 9
Formula 10
Formula 11
Formula 12
Formula 13
Formula 14
Formula 15
Formula 16
Formula 17
Formula 18
Formula 19
Formula 20
Formula 21
Formula 22
Formula 23
Formula 24
Formula 25
Formula 26
Formula 27
Formula 28
Formula 29
And (6) formula 30.
The invention also aims to provide a preparation method of the compound shown in the formula I and the pharmaceutically acceptable salt, and the reaction principle is as follows:
the preparation method comprises the following steps:
(1) reacting a compound shown in a formula II under the action of chlorosulfonic acid to obtain a compound shown in a formula III, wherein the reaction is carried out at the temperature of 20-100 ℃, a reaction solvent is selected from one or more of dichloromethane, trichloromethane and toluene, and the reaction formula is as follows:
(2) reacting a compound shown in a formula IV with a compound shown in a formula III under the action of alkali to obtain a compound shown in a formula V, wherein the reaction is carried out at the temperature of 20-100 ℃, the alkali is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide and sodium hydroxide, the reaction solvent is one or more of acetonitrile, dichloromethane, acetone and N, N-dimethylformamide, and the reaction formula is as follows:
(3) the compound shown in the formula V is subjected to reduction reaction under the catalysis of palladium carbon to obtain a compound shown in the formula VI, the reaction is carried out at the temperature of 20-100 ℃, the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran and dioxane, and the reaction formula is as follows:
(4) carrying out condensation reaction on a compound shown as a formula VI and a compound shown as a formula VII to obtain a compound shown as a formula I, wherein the reaction is carried out at the temperature of 20-100 ℃ by base catalysis, and the base is selected from triethylamine, Diisopropylethylamine (DIPEA), pyridine and 4-dimethylaminopyridine; the condensing agent is one or more of O- (7-azabenzotriazole-1-yl) -N, N, N ' -tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N ' -tetramethylurea Hexafluorophosphate (HATU), dicyclohexylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole; the reaction solvent is one or more of dichloromethane, N-Dimethylformamide (DMF) and N, N-dimethylacetamide, and the reaction formula is as follows:
it is another object of the present invention to provide methods for the treatment and prevention of hepatitis b virus, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of one or more compounds of the present invention, or pharmaceutically acceptable salts, stereoisomers, or tautomers thereof.
A pharmaceutical composition comprising: the tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or diluents.
The tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof can be applied to the preparation of the drugs for treating or preventing hepatitis viruses.
In an improvement of the above aspect, the hepatitis virus is selected from any one of hepatitis b virus and hepatitis c virus.
The application of the tetrahydroisoquinoline derivatives or the pharmaceutically acceptable salts thereof in preparing medicines for treating or preventing HIV virus.
The tetrahydroisoquinoline derivatives or pharmaceutically acceptable salts thereof can be used for preparing medicines for treating or preventing HPV virus.
The invention has the beneficial effects that:
1) the tetrahydroisoquinoline derivatives belong to non-nucleotide cytotoxic drugs, can obviously and effectively inhibit hepatitis B viruses, and have important significance and great research value in the research field of medicaments for treating or preventing hepatitis B.
2) The synthesis method of the tetrahydroisoquinoline derivatives has the advantages of few byproducts in the synthesis reaction process, high yield and great application value.
3) The tetrahydroisoquinoline derivatives or pharmaceutically acceptable salts thereof can also obviously and effectively inhibit HIV viruses and HPV viruses, and have important significance and great research value in the research field of treating or preventing HIV antiviral drugs and HPV antiviral drugs.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
In the chemical compounds of the invention, when any variable (e.g. R)1、R2Etc.) occur more than one time in any constituent, then the definition of each occurrence is independent of the definition of each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. The line drawn from a substituent into the ring system indicates that the indicated bond can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that such a bond is only attached to any suitable carbon atom of the adjacent ring. It is to be understood that substituents and substitution patterns on the compounds of the present invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by those skilled in the art and by the methods set forth below from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms,as long as the structure is stabilized.
The term "aromatic heterocycle" is a heterocycle with flat structure, wherein atoms in the heterocycle form a closed-loop conjugated system, molecules are planar, the upper side and the lower side of the plane are provided with annular delocalized electron clouds, and the number of P electrons in the conjugated system conforms to the Huckel rule. For example, pyridine, furan ring, thiazole ring, pyrimidine ring, etc.
The term "pharmaceutical composition" means a composition comprising a compound of formula I and, depending on the mode of administration and the nature of the dosage form, at least one pharmaceutically acceptable ingredient selected from the group consisting of: carriers, diluents, adjuvants, excipients or excipients, for example preservatives, fillers, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, antibacterial agents, antifungal agents, lubricating agents and dispersing agents. Examples of suspending agents include ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example sugars, sodium chloride and the like are preferably included. Prolonged absorption of the injectable form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. Examples of suitable carriers, diluents, solvents or excipients include water, ethanol, polyols, suitable mixtures thereof, vegetable oils (e.g. olive oil), and injectable organic esters such as ethyl oleate. Examples of excipients include lactose, sodium citrate, calcium carbonate, dicalcium phosphate. Examples of disintegrants include starch, alginic acid and some complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycols.
The invention comprises free forms of compounds shown as formulas 1-30, and also comprises pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine-based compounds. The term "free form" refers to the amine compound in a non-salt form. Included pharmaceutically acceptable salts include not only the exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a dilute aqueous solution of a suitable base, such as a dilute aqueous NaOH solution, a dilute aqueous potassium carbonate solution, dilute aqueous ammonia, and a dilute aqueous sodium bicarbonate solution. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with suitable inorganic or organic bases.
Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts of the compounds of the present invention formed by the reaction of a basic compound of the present invention and an inorganic or organic acid. For example, conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as those prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-monobenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and the like.
If a compound of the invention is acidic, an appropriate "pharmaceutically acceptable salt" refers to a salt prepared by a pharmaceutically acceptable non-toxic base including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, piperdine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
Berg et al, "Pharmaceutical Salts," J.pharm.Sci.1977:66:1-19. the preparation of the pharmaceutically acceptable Salts described above and other typical pharmaceutically acceptable Salts is described in more detail.
Since acidic moieties such as carboxyl groups deprotonated in a compound under physiological conditions may be anionic and such charge may then be balanced out by a protonated or alkylated basic moiety such as a quaternary nitrogen atom bearing a cation internally, it should be noted that the compounds of the present invention are potential internal salts or zwitterions.
In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using reactions as shown in the following schemes. The following illustrative schemes are therefore for illustrative purposes and are not limited to the compounds listed or any particular substituents. The number of substituents shown in the schemes does not necessarily correspond to the number used in the claims and for the sake of clarity a single substituent is shown attached to the compound allowing for multiple substituents under the definition of formula I above.
Example 1
A compound of formula 1: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (4-fluorobenzoyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the following reaction formula:
the first step is as follows: dissolving the compound 1a (62.2 g, 200.0 mmol) in dichloromethane (1000 ml), cooling to-10 ℃, adding chlorosulfonic acid (27.8 g, 240.0 mmol), stirring at 20 ℃ for reaction for 10 hours, detecting the reaction by Thin Layer Chromatography (TLC), adding water (300 ml) after the reaction is finished, quenching the reaction, and concentrating an organic layer to obtain a light yellow solid 54.3g with the yield of 66.4%. (wherein, it is to be noted that the compound 1a refers to the compound shown in the formula 1 a; and so on, which will not be described in detail below).
The second step is that: dissolving the compound 1b (54.0 g, 132.0 mmol), cycloheximide (13.1 g, 132.0 mmol) and triethylamine (16.0, 158.4 mmol) in dichloromethane (1000 ml), stirring at 30 ℃ for reaction for 12 hours, detecting by TLC, adding water (200 ml) after the reaction is finished, performing extraction and quenching reaction, layering, drying an organic layer, concentrating, and performing column chromatography to obtain an off-white solid 42.1g with the yield of 67.6%.
The third step: dissolving compound 1c (42.0 g, 89.0 mmol) and palladium carbon (4.0 g) in methanol (500 ml), charging hydrogen gas, stirring for reaction for 10 hours, detecting the reaction by TLC, adding water after the reaction is finished, filtering, concentrating the filtrate, and separating by column chromatography to obtain off-white solid 25.3g with yield of 74.4%.
The fourth step: compound 1d (1.9 g, 5.0 mmol), 1e (700 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 mlx 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.8g of an off-white solid with a yield of 71.4%, MS-ESI: M/z =505.2 [ M +1 ].
Example 2
A compound of formula 2: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (4-cyanobenzoyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 2a (735 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.4g of an off-white solid with a yield of 54.8%, MS-ESI: M/z =512.2[ M +1 ].
Example 3
A compound of formula 3: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (4-aminocarbonylbenzoyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 3a (825 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.6g of off-white solid with a yield of 60.5%, MS-ESI: M/z =530.2[ M +1 ].
Example 4
A compound of formula 4: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (3, 4-difluorobenzoyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate, the reaction formula is as follows:
compound 1d (1.9 g, 5.0 mmol), 4a (790 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, reaction was carried out at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.9g of an off-white solid with a yield of 72.8%, MS-ESI: M/z =523.2 [ M +1 ].
Example 5
A compound of formula 5: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (4-methoxycarbamoyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate, the reaction scheme being as follows:
compound 1d (1.9 g, 5.0 mmol), compound 5a (760 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.5g of an off-white solid with a yield of 58.1%, MS-ESI: M/z =517.2[ M +1 ].
Example 6
A compound of formula 6: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) 2- (6-methoxypyridine-3-formyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 6a (765 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.3g of off-white solid with a yield of 50.4%, MS-ESI: M/z =518.2[ M +1 ].
Example 7
A compound of formula 7: a process for the preparation of methyl 2- (4-acetamidobenzoyl) -7- (cycloheximide-1-ylsulfonyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 7a (895.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, reaction was carried out at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.8g of an off-white solid with a yield of 66.3%, MS-ESI: M/z =544.2 [ M +1 ].
Example 8
A compound represented by formula 8: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2-pyridine-4-formyl-6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the following reaction formula:
compound 1d (1.9 g, 5.0 mmol), 8a (615 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.5g of an off-white solid with a yield of 61.6%, MS-ESI: M/z =488.2 [ M +1 ].
Example 9
A compound of formula 9: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (2-methoxypyridine-4-formyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 9a (765 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.8g of an off-white solid with a yield of 69.6%, MS-ESI: M/z =518.2[ M +1 ].
Example 10
A compound according to formula 10: a process for the preparation of methyl 7- (cycloheximide-1-ylsulfonyl) -2- (3-fluoro-4-methoxybenzoyl) -6-methoxy-1, 2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 10a (850 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.7g of an off-white solid with a yield of 63.7%, MS-ESI: M/z =535.2 [ M +1 ].
Example 11
A compound of formula 11: a process for the preparation of methyl 2- (4-fluorobenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 11a (700 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 2.1g of an off-white solid with a yield of 80.9%, MS-ESI: M/z =520.2 [ M +1 ].
Example 12
A compound of formula 12: a process for the preparation of methyl 2- (4-cyanobenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 1d (1.9 g, 5.0 mmol), 11a (735 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml. times.2) was added for extraction, and the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.9g of an off-white solid with a yield of 72.2%, MS-ESI: M/z =527.2 [ M +1 ].
Example 13
A compound of formula 13: a process for the preparation of methyl 2- (4-aminocarbonylbenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
the first step is as follows: compound 1b (40.9 g, 100.0 mmol), 1-methyl-1, 4-diazepane (11.4 g, 100.0 mmol), triethylamine (12.1 g, 120.0 mmol) were dissolved in dichloromethane (1000 ml), stirred at 30 ℃ for 14 hours, detected by TLC, after the reaction was complete, water (200 ml) was added to quench the reaction, the layers were separated, the organic layer was dried, concentrated, and isolated by column chromatography to give 33.7g of off-white solid in 69.2% yield.
The second step is that: dissolving the compound 13b (33.0 g, 67.7 mmol) and palladium carbon (4.0 g) in methanol (500 ml), charging hydrogen gas, stirring for reaction for 10 hours, detecting the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain 18.5g of off-white solid with the yield of 68.8%.
The third step: compound 13c (2.0 g, 5.0 mmol), 3a (825 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.9g of off-white solid with a yield of 69.9%. MS-ESI: M/z =545.2 [ M +1 ].
Example 14
A compound of formula 14: a process for the preparation of methyl 2- (3, 4-difluorobenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 13c (2.0 g, 5.0 mmol), 4a (790 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.6g of off-white solid with a yield of 59.6%. MS-ESI: M/z =538.2[ M +1 ].
Example 15
A compound according to formula 15: a process for the preparation of methyl 2- (4-methoxybenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 13c (2.0 g, 5.0 mmol), 5a (760 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.7g of off-white solid with a yield of 75.0%. MS-ESI: M/z =532.2[ M +1 ].
Example 16
A compound according to formula 16: a process for the preparation of methyl 2- (6-methoxypyridine-3-formyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 13c (2.0 g, 5.0 mmol), 6a (765 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added and extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.5g of off-white solid with a yield of 56.4%. MS-ESI: M/z =533.2 [ M +1 ].
Example 17
A compound according to formula 17: a process for the preparation of methyl 2- (4-acetamidobenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 13c (2.0 g, 5.0 mmol), 7a (895 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 2.0g of an off-white solid with a yield of 71.7%. MS-ESI: M/z =559.2[ M +1 ].
Example 18
A compound according to formula 18: a process for the preparation of methyl 2- (pyridine-4-formyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 13c (2.0 g, 5.0 mmol), 8a (615 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.7g of off-white solid with a yield of 67.7%. MS-ESI: M/z =503.2[ M +1 ].
Example 19
A compound according to formula 19: a process for the preparation of methyl 2- (2-methoxypyridine-4-formyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 13c (2.0 g, 5.0 mmol), 9a (765 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added and extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give off-white solid 1.4g, yield 52.6%. MS-ESI: M/z =533.2 [ M +1 ].
Example 20
A compound represented by formula 20: a process for the preparation of methyl 2- (3-fluoro-4-methoxybenzoyl) -6-methoxy-7- ((4-methyl-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 13c (2.0 g, 5.0 mmol), 10a (850 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added and extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.7g of off-white solid with a yield of 61.9%. MS-ESI: M/z =550.2 [ M +1 ].
Example 21
A compound of formula 21: a process for the preparation of methyl 2- (4-fluorobenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
the first step is as follows: compound 1b (40.9 g, 100.0 mmol), 1, 4-diazepan-2-one (11.4 g, 100.0 mmol) and triethylamine (12.1 g, 120.0 mmol) were dissolved in dichloromethane (1000 ml), stirred at 30 ℃ for 10 hours, subjected to TLC detection, and after completion of the reaction, water (200 ml) was added to the solution to effect extraction and quenching, followed by separation, drying of the organic layer, concentration and column chromatography to obtain an off-white solid (36.3 g) with a yield of 74.5%.
The second step is that: dissolving the compound 21b (36.0 g, 73.9 mmol) and palladium carbon (4.0 g) in methanol (500 ml), charging hydrogen gas, stirring for reaction for 10 hours, detecting the reaction by TLC, filtering after the reaction is finished, concentrating the filtrate, and separating by column chromatography to obtain an off-white solid 24.2g with the yield of 82.5%.
The third step: compound 21c (2.0 g, 5.0 mmol), 11a (700 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.6g of off-white solid with a yield of 61.5%. MS-ESI: M/z =520.2 [ M +1 ].
Example 22
A compound represented by formula 22: a process for the preparation of methyl 2- (4-cyanobenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 21c (2.0 g, 5.0 mmol), 11a (735 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was allowed to react at room temperature for 4 hours, the reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.9g of off-white solid with a yield of 72.2%. MS-ESI: M/z =527.2 [ M +1 ].
Example 23
A compound according to formula 23: a process for the preparation of methyl 2- (4-aminocarbonylbenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 21c (2.0 g, 5.0 mmol), 3a (825 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.2g of off-white solid with a yield of 44.1%. MS-ESI: M/z =545.2 [ M +1 ].
Example 24
A compound represented by formula 24: a process for the preparation of methyl 2- (3, 4-difluorobenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 21c (2.0 g, 5.0 mmol), 4a (790 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.9g of off-white solid with a yield of 70.8%. MS-ESI: M/z =538.2[ M +1 ].
Example 25
A compound according to formula 25: a process for the preparation of methyl 2- (4-methoxybenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 21c (2.0 g, 5.0 mmol), 5a (760 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.4g of off-white solid with a yield of 52.7%. MS-ESI: M/z =532.2[ M +1 ].
Example 26
A compound according to formula 26: a process for the preparation of methyl 2- (6-methoxypyridine-3-formyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 21c (2.0 g, 5.0 mmol), 6a (765 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added and extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give off-white solid 1.7g, yield 63.9%. MS-ESI: M/z =533.2 [ M +1 ].
Example 27
A compound according to formula 27: a process for the preparation of methyl 2- (4-acetamidobenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate having the formula:
compound 21c (2.0 g, 5.0 mmol), 7a (895 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, reaction was performed at room temperature for 4 hours, reaction was detected by TLC, after completion of the reaction, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.8g of off-white solid with a yield of 64.5%. MS-ESI: M/z =559.2[ M +1 ].
Example 28
A compound according to formula 28: a process for the preparation of methyl 2- (pyridine-4-formyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 21c (2.0 g, 5.0 mmol), 8a (615 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.5g of off-white solid with a yield of 59.8%. MS-ESI: M/z =503.2[ M +1 ].
Example 29
A compound according to formula 29: a process for the preparation of methyl 2- (2-methylpyridine-4-formyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 21c (2.0 g, 5.0 mmol), 9a (765 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added and extracted, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give off-white solid 1.6g, yield 60.2%. MS-ESI: M/z =533.2 [ M +1 ].
Example 30
A compound represented by formula 30: a process for the preparation of methyl 2- (3-fluoro-4-methoxybenzoyl) -6-methoxy-7- ((3-oxo-1, 4-diazepan-1-yl) sulfonyl) -1,2,3, 4-tetrahydroisoquinoline-1-carboxylate by the reaction of the formula:
compound 21c (2.0 g, 5.0 mmol), 10a (850 mg, 5.0 mmol), DIPEA (774 mg, 6.0 mmol) were dissolved in DMF (50 ml), HATU (2.3 g, 6.0 mmol) was added, the reaction was reacted at room temperature for 4 hours, the reaction was detected by TLC, after the reaction was completed, the reaction was quenched with water (50 ml), ethyl acetate (50 ml × 2) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to give 1.9g of off-white solid with a yield of 69.1%. MS-ESI: M/z =550.2 [ M +1 ].
Example 31 anti-hepatitis B Virus Activity assay
The determination of the inhibitory effect of the target compound on HBV DNA and the anti-hepatitis B virus activity is determined by a Hep G2.2.15 cell in vitro experiment method.
The inhibitory effect of the target compound on HBV DNA was determined by the quantitative PCR method: hep G2.2.15 cells were cultured in DMEN medium containing 10% calf serum in 5% CO2Incubate in incubator, then inoculate cells in 96-well plate, cell number 3 × 104Continuing the culture, when the cell density reaches about 80%, discarding the old culture solution, adding new culture solution containing different concentrations, setting 3 parallel holes, and replacing the culture solution every 2 days. On the 10 th day after administration, 100ul of the supernatant was removed, the HBV DNA content was determined by quantitative PCR, and the 50% inhibitory concentration was calculated as IC50A value; specific results are shown in table 1: (Note: Compound 1 in Table 1 means a compound represented by the formula 1, and so on.)
TABLE 1 test results for anti-HBV activity
| Compound (I) | IC50 | Compound (I) | IC50 |
| 1 | B | 16 | A |
| 2 | B | 17 | A |
| 3 | A | 18 | C |
| 4 | C | 19 | C |
| 5 | C | 20 | C |
| 6 | A | 21 | B |
| 7 | A | 22 | B |
| 8 | B | 23 | A |
| 9 | B | 24 | A |
| 10 | C | 25 | C |
| 11 | C | 26 | B |
| 12 | A | 27 | A |
| 13 | B | 28 | B |
| 14 | C | 29 | B |
| 15 | A | 30 | C |
Note: a is less than 50nM, B is more than or equal to 50nM and less than or equal to 500nM, C is more than 500nM
In this example, compound 1-compound 30 all had good inhibitory effects against hepatitis b virus. Among them, the inhibitory activity of compound 3, compound 6, compound 7, compound 12, compound 15, compound 16, compound 17, compound 23, compound 24 and compound 27 on HBV DNA is less than 50nM, and the inhibitory activity of some compounds such as compound 6, compound 7, compound 12, compound 15 and compound 23 on HBV DNA is less than 10nM, so that compound 3, compound 6, compound 7, compound 12, compound 15, compound 16, compound 17, compound 23, compound 24 and compound 27 have great guiding value in clinical trial research of drugs, and especially 5 compounds with inhibitory activity on HBV DNA less than 10nM have significant clinical research value.
Example 32 anti-HIV Activity assay
293T cells at 6X 10 per well4Was applied to a 96 well plate, test compounds were dissolved in dimethyl sulfoxide (DMSO) and prepared at 8 different concentrations, added to the cell culture medium 15 minutes prior to infection, DMSO was used as a blank, and 0.5ml virus stock was added (virus stock was diluted to 0.1-0.5ng p24/ml based on p24 concentration). 48 hours after infection, the supernatant was removed, 50. mu.l of cell lysate (Triton) was added to each well to lyse the cells, the cell lysate was added to 30. mu.l of luciferase substrate (Biotium), the relative activity of cellular luciferase was measured with a fluorescence detector (Agilent), DMSO was used as a control, and the half inhibitory concentration of the compound on wild-type HIV-I replication was calculated as IC50A value; specific results are shown in table 2: (Note: Compound 1 in Table 2 means a compound represented by the formula 1, and so on.)
TABLE 2 anti-HIV Activity test results
| Compound (I) | IC50 | Compound (I) | IC50 |
| 1 | B | 16 | A |
| 2 | B | 17 | A |
| 3 | A | 18 | C |
| 4 | C | 19 | C |
| 5 | C | 20 | C |
| 6 | A | 21 | B |
| 7 | A | 22 | B |
| 8 | B | 23 | A |
| 9 | B | 24 | A |
| 10 | C | 25 | C |
| 11 | C | 26 | B |
| 12 | A | 27 | A |
| 13 | B | 28 | B |
| 14 | C | 29 | B |
| 15 | A | 30 | C |
Note: a is less than 50nM, B is more than or equal to 50nM and less than or equal to 500nM, C is more than 500nM
In this example, compound 1-compound 30 all had good inhibitory effects against the HIV virus. Among them, the inhibitory activity of compound 3, compound 6, compound 7, compound 12, compound 15, compound 16, compound 17, compound 23, compound 24 and compound 27 on HBV DNA is less than 50nM, and the inhibitory activity of some compounds such as compound 6, compound 7, compound 12, compound 15 and compound 23 on HIV is less than 10nM, so that compound 3, compound 6, compound 7, compound 12, compound 15, compound 16, compound 17, compound 23, compound 24 and compound 27 have great guiding value in clinical trial research of drugs, and especially 5 compounds with the inhibitory activity on HIV less than 10nM have significant clinical research value.
Example 33 anti-HPV Activity assay
A reporter "replicon" vector containing the HPV11/HPV6 viral origin of replication (also known as LCR, which carries the binding sites for the E1 and E2 proteins of HPV) and a gene encoding firefly luciferase under the transcriptional control of the SV40 promoter was constructed. The presence of the HPV origin of replication and the presence or absence of viral E1 or E2 protein had no transcriptional effect on luciferase gene expression. Cotransfection of this replicon swivel with a swivel expressing HPV E1 and E2 proteins resulted in enhanced luciferase activity depending on the presence of E1 and E2 and increased expression of the replicon vector. This is due to the activity of the viral E1 and E2 proteins that cause this replicon vector, which contains the viral origin of replication, to replicate in mammalian cells.
The inhibitory activity of the compounds against HPV11/HPV 6-dependent E1 and E2 viral replication was evaluated in a cell assay by co-transfection of a replicon-reporter vector and paired HPV11/HPV 6E 1 and E2 expression vectors in a human cell line derived from cervical cancer cells. After transfection, compound DMSO solutions with different concentrations were added to the cell culture medium, incubated for 2-6 days, the relative activity of the luciferase of the cells was measured with a fluorescence detector (Agilent), DMSO was used as a control, and the half inhibitory concentration of the compound on HPV genome replication was calculated as IC50A value; specific results are shown in table 3: (Note: Compound 1 in Table 3 means a compound represented by the formula 1, and so on.)
TABLE 3 test results for anti-HPV Activity
| Compound (I) | IC50 | Compound (I) | IC50 |
| 1 | A | 16 | A |
| 2 | B | 17 | B |
| 3 | A | 18 | C |
| 4 | C | 19 | B |
| 5 | B | 20 | C |
| 6 | A | 21 | A |
| 7 | A | 22 | B |
| 8 | B | 23 | B |
| 9 | A | 24 | A |
| 10 | C | 25 | C |
| 11 | C | 26 | B |
| 12 | A | 27 | A |
| 13 | B | 28 | B |
| 14 | C | 29 | B |
| 15 | A | 30 | C |
Note: a is less than 50nM, B is more than or equal to 50nM and less than or equal to 500nM, C is more than 500nM
In this example, compound 1-compound 30 all had good inhibitory effects against HPV virus. Among them, the inhibitory activity of compound 1, compound 3, compound 6, compound 7, compound 9, compound 12, compound 15, compound 16, compound 21, compound 24 and compound 27 on HPV genome replication is less than 50nM, and the inhibitory activity of some compounds such as compound 1, compound 3, compound 7, compound 12, compound 15, compound 21 and compound 24 on HPV genome replication is less than 10nM, so that compound 1, compound 3, compound 6, compound 7, compound 9, compound 12, compound 15, compound 16, compound 21, compound 24 and compound 27 have great guiding value in the pharmaceutical clinical trial research, and especially, the above 7 compounds with the inhibitory activity on HPV genome replication less than 10nM have significant clinical research value.
In the above embodiment, compared with the currently clinically used hepatitis B drugs which are mostly nucleotide cytotoxic drugs, the tetrahydroisoquinoline derivatives of the present invention belong to non-nucleotide cytotoxic drugs, can significantly and effectively inhibit hepatitis B viruses, and have important significance and great research value in the research field of drugs for treating or preventing hepatitis B.
Meanwhile, the tetrahydroisoquinoline derivatives or pharmaceutically acceptable salts thereof can also obviously and effectively inhibit HIV viruses and HPV viruses, and have important significance and great research value in the research field of treating or preventing HIV antiviral drugs and HPV antiviral drugs.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (7)
1. A tetrahydroisoquinoline derivative or a pharmaceutically acceptable salt thereof, wherein the tetrahydroisoquinoline derivative is selected from any one of the following compounds of formula 1, formula 2, formula 3, formula 5, formula 6, formula 7, formula 8, formula 9, formula 12, formula 13, formula 15, formula 16, formula 17, formula 19, formula 21, formula 22, formula 23, formula 24, formula 26, formula 27, formula 28, and formula 29,
the structural formula of the compound is as follows:
formula 1
Formula 2
Formula 3
Formula 5
Formula 6
Formula 7
Formula 8
Formula 9
Formula 12
Formula 13
Formula 15
Formula 16
Formula 17
Formula 19
Formula 21
Formula 22
Formula 23
Formula 24
Formula 26
Formula 27
Formula 28
And (9) formula 29.
2. The method for preparing tetrahydroisoquinoline derivatives or pharmaceutically acceptable salts thereof according to claim 1, comprising the steps of:
(1) reacting a compound shown in a formula II under the action of chlorosulfonic acid to obtain a compound shown in a formula III, wherein the reaction is carried out at the temperature of 20-100 ℃, a reaction solvent is selected from one or more of dichloromethane, trichloromethane and toluene, and the reaction formula is as follows:
(2) reacting a compound shown in a formula IV with a compound shown in a formula III under the action of alkali to obtain a compound shown in a formula V, wherein the reaction is carried out at the temperature of 20-100 ℃, the alkali is selected from triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide and sodium hydroxide, the reaction solvent is one or more of acetonitrile, dichloromethane, acetone and N, N-dimethylformamide, and the reaction formula is as follows:
(3) the compound shown in the formula V is subjected to reduction reaction under the catalysis of palladium carbon to obtain a compound shown in the formula VI, the reaction is carried out at the temperature of 20-100 ℃, the reaction solvent is selected from one or more of methanol, ethanol, isopropanol, tetrahydrofuran and dioxane, and the reaction formula is as follows:
(4) carrying out condensation reaction on a compound shown as a formula VI and a compound shown as a formula VII to obtain a compound shown as a formula I, wherein the reaction is carried out at the temperature of 20-100 ℃ by base catalysis, and the base is selected from one or more of triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine; the condensing agent is one or more of O- (7-azabenzotriazole-1-yl) -N, N, N ' -tetramethylurea hexafluorophosphate, benzotriazole-N, N, N ', N ' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole; the reaction solvent is one or more of dichloromethane, N-dimethylformamide and N, N-dimethylacetamide, and the reaction formula is as follows:
wherein R is1、R2、R3The tetrahydroisoquinoline derivatives or the pharmaceutically acceptable salts thereof according to claim 1 have the same meanings as defined in the corresponding groups.
3. A pharmaceutical composition characterized by comprising: the tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof according to claim 1, and one or more pharmaceutically acceptable carriers or diluents.
4. The use of the tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof according to claim 1 for the preparation of a medicament for the treatment or prevention of hepatitis virus.
5. The use of the tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof according to claim 4 for preparing a medicament for treating or preventing hepatitis virus, wherein the hepatitis virus is selected from any one of hepatitis b virus and hepatitis c virus.
6. Use of the tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating or preventing the HIV virus.
7. The use of the tetrahydroisoquinoline derivative or the pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a medicament for treating or preventing HPV virus.
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| CN101039662A (en) * | 2004-08-20 | 2007-09-19 | 密执安州立大学董事会 | Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
| CN101146808A (en) * | 2005-01-26 | 2008-03-19 | 弗·哈夫曼-拉罗切有限公司 | Phenyl methanone derivatives and their use as glycine transporter 1 inhibitors |
| WO2017059191A1 (en) * | 2015-09-30 | 2017-04-06 | Quartet Medicine, Inc. | Heteroaryl derivatives as sepiapterin reductase inhibitors |
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| CN101039662A (en) * | 2004-08-20 | 2007-09-19 | 密执安州立大学董事会 | Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof |
| CN101146808A (en) * | 2005-01-26 | 2008-03-19 | 弗·哈夫曼-拉罗切有限公司 | Phenyl methanone derivatives and their use as glycine transporter 1 inhibitors |
| WO2017059191A1 (en) * | 2015-09-30 | 2017-04-06 | Quartet Medicine, Inc. | Heteroaryl derivatives as sepiapterin reductase inhibitors |
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