CN116003469B - Preparation and use methods of pyrimidinyl antiviral compounds - Google Patents
Preparation and use methods of pyrimidinyl antiviral compounds Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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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
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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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- 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
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Abstract
The present application provides a novel pyrimidinyl antiviral compound and methods of making and using the same. The pyrimidyl antiviral compound provided by the application can be used for treating diseases caused by viruses and can be applied to the treatment of myocardial ischemia, tumors and other diseases.
Description
Technical Field
The application relates to the technical field of antiviral drugs, in particular to a preparation and use method of a novel pyrimidinyl antiviral compound. In particular, the pyrimidinyl antiviral compounds of the present application are useful for the prevention and/or treatment of viral diseases and in the treatment of myocardial ischemia and anti-tumor diseases.
Background
Hepatitis B Virus (HBV) infection is a great threat to the health of the general public, and currently, more than 3 hundred million people worldwide are infected with hepatitis b virus, and the number of people dying from hepatitis b virus infection or related liver cirrhosis disease per year reaches 100 tens of thousands. In addition, more than 3/4 of hepatitis B patients worldwide are distributed in Asia, and more than 1 hundred million people only in China are infected with hepatitis B virus, so that the health of people in China is seriously threatened.
The replication process of HBV mainly comprises the following steps: the hepatitis B virus is combined with the receptor of liver cell membrane to remove outer membrane and enter liver cell, then the DNA of the virus enters liver cell nucleus, and forms supercoiled DNA (Supercoiling DNA) with the DNA of liver cell under the action of DNA polymerase (DNB-dependent DNA polymerase, DNAp) so as to synthesize transcript. Wherein the pregenomic RNA can be used as a reverse transcription template and a translation template. Based on the characteristics of HBV replication process, the following two treatment strategies can be adopted: (1) Breaking immune tolerance and clearing supercoiled DNA in cells; (2) inhibit HBV synthesis. At present, medicines for treating hepatitis B are divided into two types, namely an immunomodulator and a DNA (deoxyribonucleic acid) polymerase inhibitor, wherein the immunomodulator mainly comprises interferon-alpha 2b and the like, and the DNA polymerase inhibitor mainly comprises nucleoside medicines such as lamivudine (Hepudine), adefovir dipivoxil and the like, and small molecular compounds with other action mechanisms also have some progress. Among them, lamivudine developed by the company glazin smith (GlaxoSmithKline, GSK) is the first effective DNA polymerase inhibitor, has the ability to rapidly inhibit viral replication in vivo, has less side effects, but is easily resistant to drug, and cannot clear cccDNA (covalently closed circular DNA) in the nucleus, so that patients have obvious rebound phenomenon after withdrawal.
Although the treatment of chronic hepatitis B has been advanced for decades, such as combined administration to stabilize the therapeutic effect and reduce the drug resistance, there is no therapeutic drug or therapeutic method for radically treating hepatitis B virus, and there is still a need to develop new safe and effective antiviral drugs.
Disclosure of Invention
The present application provides a novel class of pyrimidinyl antiviral compounds and methods of use thereof, particularly useful in the treatment of chronic hepatitis b disease.
On the other hand, the compound provided by the application has stronger antiviral activity, can obviously inhibit the replication of viral DNA in vitro and in vivo, does not show obvious toxicity to cells, and achieves obvious beneficial technical effects.
The third aspect of the application is that the compound of the application has larger water solubility, has great potential for developing into oral preparations or injections, and achieves unexpected beneficial technical effects.
The fourth aspect of the application is that the compound of the application has better stability, can reach the highest blood concentration in vivo quickly, has quicker effect and strong drug action capability, has higher bioavailability in vivo, does not show obvious toxicity, and has good clinical application prospect.
The present application provides a compound of formula I, or a solvate, isomer, pharmaceutically acceptable salt thereof:
and wherein: r is R 1 Selected from hydrogen, fluorine, chlorine, methyl, ethyl, methoxy;
w is selected from O or S;
ring A 1 Selected from C 4 -C 8 Heterocyclyl, C 6 -C 12 Aryl, C 3 -C 12 Heteroaryl;
ring A 2 Selected from C 4 -C 8 A heterocyclic group;
R 2a 、R 2b each independently selected from C substituted with one or more hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, mercapto, mercaptomethyl, mercaptoethyl, carboxy, trifluoromethyl, difluoromethyl, acetyl, amino 3 -C 8 Carbocyclyl, C 4 -C 8 Heterocyclyl, C 6 -C 12 Aryl, C 3 -C 12 Heteroaryl, or R 2a 、R 2b Are connected into a ring;
R 3 selected from the group consisting of
R 4 、R 5 Each independently selected from C substituted with one or more hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, mercapto, mercaptomethyl, mercaptoethyl, carboxy, trifluoromethyl, difluoromethyl, acetyl, amino 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 3 -C 8 Carbocyclyl, C 4 -C 8 Heterocyclyl, C 6 -C 12 Aryl, C 3 -C 12 Heteroaryl, or R 4 、R 5 Are connected into a ring;
R 6 、R 7 are independently selected from hydrogen, C 1 -C 6 Alkyl, or R 6 、R 7 Are connected into a ring;
R 8 、R 9 each independently selected from C substituted with one or more hydrogen, halogen, hydroxy, cyano, methoxy, ethoxy, mercapto, mercaptomethyl, mercaptoethyl, carboxy, trifluoromethyl, difluoromethyl, acetyl, amino 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkylamino, C 3 -C 8 Carbocyclyl, C 4 -C 8 Heterocyclyl, C 6 -C 12 Aryl, C 3 -C 12 Heteroaryl, or R 8 、R 9 Are connected into a ring.
The compound has the following structure:
the definition of each substituent in the formula II is defined as in the formula I.
The compound has the following structure:
the definition of the substituent in the formula III is defined as in the formula I.
The compound is selected from the group consisting of:
the application of the compound in preparing antiviral drugs.
The compounds can have the effect of treating and/or preventing diseases caused by viruses by inhibiting viral replication.
A pharmaceutical composition, in particular comprising a therapeutically effective amount of said compound and pharmaceutically acceptable excipients.
The pharmaceutical composition can be used as AIDS (Acquired Immune Deficiency Syndrome) antiviral agent, anti-Hepatitis B virus (hepatis B) agent, anti-Hepatitis C virus (hepatis C) agent, anti-herpes virus agent, anti-human papillomavirus agent, or local advanced or metastatic solid tumor therapeutic use.
Methods of treating viral infections such as HIV infection, HBV infection, HCV (Hepatitis C Virus) and the like comprise administering to a human or other mammal a therapeutically effective amount of the compound.
The disclosure outlines only certain aspects of the application, but the application is not limited to the above aspects.
Detailed description of the application
The articles "a" and "an" as used herein are intended to include "at least one" or "one or more".
The term "drugBy "pharmaceutically acceptable salts" is meant inorganic acid salts such as hydrochloride, sulfate, phosphate, perchlorate, hydrobromide, etc., or organic acid salts such as acetate, mesylate, p-toluenesulfonate, malate, fumarate, etc., as well as salts derived from suitable bases such as alkali metal (lithium, sodium, potassium), alkaline earth (magnesium, calcium), ammonium and NM salts 4 + (wherein M is C 1 -C 6 Alkyl) salts.
The term "isomer" refers to stereoisomers that contain one or more chiral centers in the molecule and are not superimposable to each other in physical and mirror images, or non-corresponding isomers due to the multiple chiral centers.
The term "solvate" refers to a complex of a solvent with a parent compound, such as water, ethanol, acetic acid, propionic acid, etc., that is exposed to organisms without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable medical judgment.
The term "diastereoisomer" refers to stereoisomers which contain one or more chiral centers in the molecule, but which are not mirror images of each other.
The term "halogen" refers to fluorine (F), chlorine (C1), bromine (Br) or iodine (I).
The term "heteroatom" refers to oxygen (O), sulfur (S), nitrogen (N), boron (B), phosphorus (P), or silicon (Si), including N, S and the state where P is oxidized to an oxide.
For therapeutic use, it is also within the scope of the application to provide salts of compounds whose active ingredient is not a pharmaceutically acceptable acid or base.
The term "C 1 -C 6 Alkyl "refers to a straight, branched, or cyclic hydrocarbon group containing 1 to 6 carbon atoms, examples being methyl, ethyl, isopropyl, n-butyl, t-butyl, 2-pentyl, and the like.
The term "C 1 -C 6 Alkoxy "means a straight, branched, or cyclic alkyl oxy group having any number within the specified number 1-6, examples being methoxy, ethoxy, isopropoxy, 3-methoxypropyl, propyleneglycol ethylether, tetrahydropyranyl, isobutoxy, 2-ethanolyl-ethyl,(R) - (-) -1-methoxy-2-propyl, (S) - (-) -1, 2-epoxybutyl, etc.
The term "C 1 -C 6 Alkylamino "refers to a straight, branched, or cyclic alkylamino group of any number ranging from 1 to 6 carbon atoms, examples being ethylamino, t-butylamino, N-dimethylbutyl, homopiperazino, piperazino, di-N-propylamino, N-ethylisopropylamino, N-dimethylamino, and the like.
The term "C 3 -C 8 Carbocyclyl "refers to saturated, unsaturated cyclic hydrocarbon groups having the number of carbon atoms in the range of the specified number 3-8, examples being cyclopropyl, cyclohexyl, 1-cyclohex-1-enyl, cyclohexenyl, and the like.
The term "C 4 -C 8 Heterocyclic "means a saturated or unsaturated ring system containing at least one oxygen (O), sulfur (S), nitrogen (N), boron (B), phosphorus (P), or silicon (Si) and 4 to 8 carbon atoms in the ring, which may be condensed or unfused, and the condensed ring may be an aromatic ring, an unsaturated heterocycle, a saturated heterocycle, or a saturated or unsaturated aliphatic cyclic group, examples being pyrrolyl, morpholinyl, 1, 2-dimethylpiperazinyl, 1, 2-epoxycyclopentyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, morpholinyl, indolinyl, and the like.
The term "C 6 -C 12 Aryl "refers to an aromatic hydrocarbon group having 6 to 12 carbon atoms obtained by substitution of one hydrogen atom from one carbon atom of an aromatic ring system, which may be condensed or unfused, and the condensed ring is aromatic or a saturated or unsaturated aliphatic cyclic group, examples being phenyl, indenyl, indanyl, 1, 2-dihydronaphthyl, indolyl, and the like.
The term "fused" refers to a group in which two ring systems share two carbon atoms.
The term "C 3 -C 12 Heteroaryl "means an unsaturated aromatic ring system containing at least one oxygen (O), sulfur (S), nitrogen (N), phosphorus (P), or silicon (Si) and 3 to 12 carbon atoms in the ring, which may be fused or unfused, and the fused ring may be an aromatic ring, an unsaturated heterocyclic ring, a saturated heterocyclic ring, or a saturated or unsaturated aliphatic ringExamples of aliphatic cyclic groups are furyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrazinyl, indazolyl, 2, 3-benzofuryl, pyridazine, naphthyridinyl, 5-hydroxyisoquinolinyl, quinoxaline, benzofuryl and the like.
The term "independently" refers to having more than 1 variable, then each instance of a substituent is selected from the available variable definitions independent of the other selected definition variables. Thus, each substituent may be the same or different from the other substituents.
The term "pharmaceutical composition" refers to products comprising an active ingredient and inert ingredients of a pharmaceutically acceptable carrier, as well as products obtained directly or indirectly from the mixing, complexation or aggregation of any two or more of the ingredients.
The term "antiviral" refers to compounds of the present application that can achieve relief or treatment of an individual in need of treatment for viral infection by a method of inhibiting viral DNA, RNA replication, which method also comprises administering to a mammal a therapeutically effective amount of a compound provided herein, and compositions thereof. Such as hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV, dengue virus, rhinovirus, west Nile virus, japanese encephalitis virus, poliovirus, bovine viral diarrhea virus, yellow fever virus, herpes virus, human papillomavirus, etc.
The term "administering" refers to providing an effective amount of a compound of the application to an individual in need of treatment and/or prophylaxis.
The term "pharmaceutically acceptable" refers to carriers, flavoring agents, diluents, preservatives, colorants, excipients and the like that are not deleterious to the recipient thereof in the case of a single use.
In practice, the compositions prepared from the compounds of structural formula I and pharmaceutically acceptable carriers may be administered in a variety of forms, such as suspensions, elixirs, powders, tablets, capsules, injections, ointments, sprays.
The term "therapeutically effective amount" means that the administration to a human or other mammal is controlled within the range of 0.01-1000mg/kg body weight to regulate the symptoms of the individual to whom it is administered.
In practice, the dosage administered to a human or other mammal may vary with the particular compound employed, the mode of administration, and the severity of the condition being treated, and the optimal therapeutic effect is achieved.
The term "treatment" refers to, in one embodiment, the modulation of at least one physical parameter, including a physical parameter that may not be identifiable by a human or other mammal.
The double bond containing compounds of the present application include all configurational isomers (e.g., cis and trans isomers).
Detailed Description
The present application will be described in more detail with reference to the following examples, but the present application is not limited to the following examples. The methods employed in the present application are all conventional methods unless otherwise specified. The materials used, unless otherwise specified, are commercially available from public sources.
Example 1: preparation of Compound NT-01
B-3: a solution of (R) -3-methylpiperidine-1-carboxylic acid tert-butyl ester (20.01 g,100 mmol) and (-) sparteine (28.12 g,120 mmol) in methyl tert-butyl ether (350 mL) was cooled to-78deg.C and butyllithium (100 mL,120mmol,1.2M cyclohexane solution) was added dropwise to the system. Stirring was carried out at-78℃for 3 hours, and a solution of zinc chloride (80 mL,80mmol,1.0M methyl tert-butyl ether solution) was added dropwise under controlled internal temperature < -65℃while stirring rapidly. The suspension was stirred at-78 ℃ for 30 minutes and then warmed to room temperature. To the resulting mixture was added 2-bromo-5-methoxypyridine (20.68 g,110 mmol), followed by the addition of palladium acetate (1.13 g,5 mmol) and tri-tert-butylphosphine tetrafluoroborate (1.74 g,6 mmol) in one portion. After stirring overnight at room temperature, 10mL of aqueous ammonia was added and stirring was continued for 1 hour. 500mL of 1.0M hydrochloric acid was added thereto and stirring was continued for 12 hours, and the resulting slurry was filtered through celite, washed with 1L of methyl tert-butyl ether, and the filtrate was washed with 500mL of saturated brine. The organic layer was filtered and concentrated, and purified by preparative liquid phase separation to give yellow oil B-3 (4.33 g,21% yield). MS (ESI) M/z=207.1 (m+h).
B-5: to the pressure reactor was added B-3 (6.19 g,30 mmol), B-4 (5.39 g,32 mmol), 150mL dry n-butanol and 20mL diisopropylethylamine. The suspension was sealed and heated to 160 ℃ for reaction overnight. The reaction was cooled to room temperature, concentrated, 200mL of ethyl acetate was added, filtered, and the filter cake was rinsed with 50mL of ethyl acetate. The filtrate was washed with 150mL of water and 150mL of brine, respectively, and the organic layer was concentrated and purified by column chromatography to give B-5 (4.26 g,42% yield). MS (ESI) M/z= 339.1 (m+h).
B-7: b-5 (6.77 g,20 mmol) and triethylamine (6.07 g,60 mmol) were added to 150mL of tetrahydrofuran, and after the addition of CDI (3.24 g,20 mmol) and reaction at 60℃for 5 hours, (R) -pyrrolidine-3-ol hydrochloride (2.47 g,20 mmol) was added, the reaction was continued at 60℃for 5 hours, cooled, filtered off with suction, and the filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from acetonitrile/water to give B-7 (3.16 g,35% yield). MS (ESI) M/z=452.2 (m+h).
NT-01: b-7 (0.45 g,1 mmol), 60% sodium hydrogen (0.08 g,2 mmol) and 10mL of solvent DMF are added into a reactor under stirring, stirring is carried out for 1h at room temperature, dibenzyl phosphate chloride (0.30 g,1 mmol) is added under the condition of controlling the temperature to be 0-10 ℃,60 mL of water is slowly added dropwise under ice bath after the reaction of the mixture is completed, solid precipitation, filtration, column chromatography separation and purification of a filter cake are carried out, the obtained solid is added into 20mL of solvent methanol, 10% palladium carbon (0.02 g) is added, the reaction is carried out for 16 h at room temperature under hydrogen atmosphere, filtration and concentration are carried out, and the obtained solid preparation column is separated and purified to obtain NT-01 (0.05 g, 10%). MS (ESI) M/z= 532.3 (m+h). (M+H). 1 H NMR(DMSO)δ：8.60(s,1H),8.01(s,1H),7.84(s,1H),7.33(d,1H),7.18-7.17(m,1H),7.11-7.10(m,1H),6.42(s,1H),4.30-4.29(m,1H),3.82(s,3H),4.00-3.99(m,1H),3.60-3.52(m,3H),3.38-3.36(m,2H),3.10-3.08(m,2H),2.02-1.97(m,2H),1.84-1.81(m,1H),1.55-1.52(m,2H),1.41-1.39(m,2H),0.92(d,J＝12.1Hz,3H)。
Example 2: preparation of Compound NT-02
NT-02: NT-01 (0.53 g,1 mmol), thionyl chloride (0.24 g,2 mmol), and 10mL of tetrahydrofuran as a solvent were added to the reactor with stirring, and stirred at room temperature under nitrogen for 1 hour, methanol 1mL and triethylamine (0.30 g,3 mmol) were slowly added under ice bath conditions, and stirring was continued for 2 hours, followed by filtration, concentration, and separation and purification of the liquid phase were performed to give NT-02 (0.05 g, 9%). MS (ESI) M/z=560.0 (m+h). 1 H NMR(DMSO)δ：8.63(s,1H),8.05(s,1H),7.87(s,1H),7.35(d,1H),7.19-7.18(m,1H),7.15-7.14(m,1H),6.47(s,1H),4.36-4.34(m,1H),3.85(s,3H),3.73(s,3H),3.71(s,3H),4.03-4.02(m,1H),3.64-3.56(m,3H),3.39-3.36(m,2H),3.13-3.10(m,2H),2.04-1.99(m,2H),1.86-1.83(m,1H),1.59-1.56(m,2H),1.45-1.40(m,2H),0.96(d,J＝12.3Hz,3H)。
Example 3: preparation of Compound NT-03
NT-03: NT-01 (0.53 g,1 mmol), sodium hydroxide (0.20 g,5 mmol), and 10mL of solvent acetone were added to the reactor with stirring, stirred at room temperature for 15h, filtered, and the resulting solid was purified by recrystallization from acetone/water to give NT-03 (0.03 g, 6%). MS (ESI) M/z= 598.4 (m+na). 1 H NMR(DMSO)δ：8.59(s,1H)，8.02(s,1H)，7.80(s,1H)，7.30(d,1H)，7.15-7.14(m,1H)，7.12-7.11(m,1H)，6.43(s,1H)，4.36-4.34(m,1H)，3.81(s,3H)，4.01-4.00(m,1H)，3.62-3.57(m,3H)，3.36-3.34(m,2H)，3.16-3.11(m,2H)，2.01-1.96(m,2H)，1.82-1.79(m,1H)，1.53-1.50(m,2H)，1.43-1.40(m,2H)，0.94(d,J＝12.5Hz,3H)。
Example 4: preparation of Compound NT-04
NT-04: NT-01 (0.53 g,1 mmol), thionyl chloride (0.24 g,2 mmol), and 10mL of solvent tetrahydrofuran were added to the reactor with stirring, stirred at room temperature under nitrogen for 1 hour, and ethylene glycol 1mL and triethylamine were slowly added under ice bath conditions(0.30 g,3 mmol) and stirring for 2 hours, filtering, concentrating, separating and purifying the liquid phase to obtain NT-04 (0.04 g, 8%). MS (ESI) M/z=558.1 (m+h). 1 H NMR(DMSO)δ：8.66(s,1H),8.07(s,1H),7.85(s,1H),7.34(d,1H),7.18-7.17(m,1H),7.15-7.14(m,1H),6.46(s,1H),4.39-4.35(m,5H),3.87(s,3H),4.04-4.01(m,1H),3.65-3.59(m,3H),3.33-3.31(m,2H),3.13-3.10(m,2H),2.06-1.99(m,2H),1.85-1.80(m,1H),1.56-1.52(m,2H),1.46-1.42(m,2H),0.97(d,J＝12.0Hz,3H)。
Example 5: preparation of Compound NT-05
B-10: a solution of B-8 (22.00 g,100 mmol) and B-9 (19.83 g,100 mmol) in THF (450 mL) was cooled to 0deg.C, triethylamine (30.30 g,300 mmol) was slowly added to the system and after the addition was completed, the temperature was raised to room temperature. The reaction was carried out at 50℃for 4 hours, cooled to room temperature, filtered through celite, the filtrate was concentrated, 400mL of methylene chloride was added to the residue, and the residue was washed with 300mL of saturated brine, and the organic phase was concentrated and purified by column chromatography to give B-10 as a yellow solid (11.38 g,33% yield). MS (ESI) M/z= 346.1 (m+h).
B-11: b-10 (3.45 g,10 mmol) was added to 200mL of methanol, iron powder (5.60 g,50 mmol) and ammonium chloride (5.85 g,50 mmol) were added, the reaction was warmed to reflux for 4 hours, cooled to room temperature, celite was filtered, the filter cake was rinsed with 100mL of methanol, the filtrates were combined and concentrated, the resulting residue was added to 200mL of dichloromethane, washed with 100mL of saturated brine, the organic phase was concentrated, and column chromatography was purified to give B-11 as a yellow solid (0.69 g,22% yield). MS (ESI) M/z=316.1 (m+h).
B-12: b-11 (3.15 g,10 mmol) and triethylamine (3.03 g,30 mmol) were added to 100mL of tetrahydrofuran, and after the addition of CDI (3.24 g,20 mmol) and reaction at 60℃for 5 hours, (R) -pyrrolidine-3-ol hydrochloride (1.24 g,10 mmol) was added, the reaction was continued at 60℃for 5 hours, cooled, filtered off with suction, the filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from acetonitrile/water to give B-12 (2.35 g,55% yield). MS (ESI) M/z=429.0 (m+h).
NT-05: under stirringB-12 (0.43 g,1 mmol), 60% sodium hydrogen (0.08 g,2 mmol) under nitrogen protection and 10mL of solvent DMF are added into a reactor, the mixture is stirred for 1h at room temperature, dibenzyl phosphate chloride (0.30 g,1 mmol) is added at the temperature of 0-10 ℃,60 mL of water is slowly added dropwise under ice bath after the reaction of the mixture at room temperature for 16 hours after the dripping, solid is separated and filtered, the obtained solid is added into 20mL of solvent methanol for separation and purification by column chromatography of a filter cake, 10% palladium carbon (0.02 g) is added, the mixture is subjected to reflux reaction for 16 hours under hydrogen atmosphere, the mixture is filtered and concentrated, and the obtained solid is prepared for separation and purification by column to obtain NT-05 (0.06 g, 12%). MS (ESI) M/z=509.2 (m+h). 1 H NMR(CDCl 3 )δ：8.46(s,1H),7.83(s,1H),7.33(s,1H),7.14(s,1H),6.89(s,1H),5.36(s,1H),4.88(s,1H),3.97(s,1H),3.83-3.25(m,8H),2.18-1.82(m,5H)。
Example 6: preparation of Compound NT-07
NT-07: NT-05 (0.51 g,1 mmol), sodium hydroxide (0.20 g,5 mmol), and 10mL of solvent acetone were added to the reactor with stirring, stirred at room temperature for 15h, filtered, and the resulting solid was purified by recrystallization from acetone/water to give NT-07 (0.04 g, 8%). MS (ESI) M/z=575.0 (m+na). 1 H NMR(DMSO)δ：8.41(s,1H)，7.81(s,1H)，7.30(s,1H)，7.11(s,1H)，6.85(s,1H)，5.33(s,1H)，4.82(s,1H)，3.93(s,1H)，3.80-3.22(m,8H)，2.14-1.80(m,5H)。
Example 7: preparation of Compound NT-08
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NT-08: NT-05 (0.51 g,1 mmol), thionyl chloride (0.24 g,2 mmol), and 10mL of solvent tetrahydrofuran were added to the reactor with stirring, and stirred at room temperature under nitrogen for 1 hour, ethylene glycol 1mL and triethylamine (0.30 g,3 mmol) were slowly added under ice bath conditions, stirring was continued for 2 hours, filtration, concentration, and separation and purification of the liquid phase were performed to give NT-08 (0.05 g, 10%). MS (ESI) M/z=535.1 (m+h). 1 H NMR(DMSO)δ： 1 H NMR(DMSO)δ：8.45(s,1H)，7.84(s,1H)，7.35(s,1H)，7.13(s,1H)，6.8(s,1H)，5.36(s,1H)，4.86(s,1H)，4.47-4.43(m,4H)，3.97(s,1H)，3.85-3.27(m,8H)，2.16-1.88(m,5H)。
Example 8: preparation of Compound NT-09
B-14: a solution of B-2 (20.01 g,100 mmol) and (-) sparteine (28.12 g,120 mmol) in methyl tert-butyl ether (350 mL) was cooled to-78deg.C and butyllithium (100 mL,120mmol,1.2M cyclohexane solution) was added dropwise to the system. Stirring was carried out at-78℃for 3 hours, and a solution of zinc chloride (80 mL,80mmol,1.0M methyl tert-butyl ether solution) was added dropwise under controlled internal temperature < -65℃while stirring rapidly. The suspension was stirred at-78 ℃ for 30 minutes and then warmed to room temperature. B-13 (22.60 g,100 mmol) was added to the resulting mixture, followed by the addition of palladium acetate (1.13 g,5 mmol) and tri-tert-butylphosphine tetrafluoroborate (1.74 g,6 mmol) in one portion. After stirring overnight at room temperature, 10mL of aqueous ammonia was added and stirring was continued for 1 hour. 500mL of 1.0M hydrochloric acid was added thereto and stirring was continued for 12 hours, and the resulting slurry was filtered through celite, washed with 1L of methyl tert-butyl ether, and the filtrate was washed with 500mL of saturated brine. The organic layer was filtered and concentrated, and purified by preparative liquid phase separation to give yellow oil B-14 (4.40 g,18% yield). MS (ESI) M/z=245.3 (m+h).
B-15: to the pressure reactor was added B-14 (7.33 g,30 mmol), B-4 (5.39 g,32 mmol), 150mL dry n-butanol and 20mL diisopropylethylamine. The suspension was sealed and heated to 160 ℃ for reaction overnight. The reaction was cooled to room temperature, concentrated, 200mL of ethyl acetate was added, filtered, and the filter cake was rinsed with 50mL of ethyl acetate. The filtrate was washed with 150mL of water and 150mL of brine, respectively, and the organic layer was concentrated and purified by column chromatography to give B-15 (3.95 g,35% yield). MS (ESI) M/z= 377.2 (m+h).
B-16: b-15 (7.52 g,20 mmol) and triethylamine (6.07 g,60 mmol) were added to 150mL of tetrahydrofuran, and after the addition of CDI (3.24 g,20 mmol) and reaction at 60℃for 5 hours, (R) -pyrrolidine-3-ol hydrochloride (2.47 g,20 mmol) was added, the reaction was continued at 60℃for 5 hours, cooled, filtered off with suction, and the filtrate was concentrated under reduced pressure, and the obtained solid was recrystallized from acetonitrile/water to give B-16 (2.94 g,30% yield). MS (ESI) M/z=490.0 (m+h).
NT-09: b-16 (0.49 g,1 mmol), 60% sodium hydrogen (0.08 g,2 mmol) and 10mL of solvent DMF are added into a reactor under the protection of nitrogen, stirring is carried out for 1h at room temperature, dibenzyl phosphate chloride (0.30 g,1 mmol) is added under the control of temperature of 0-10 ℃, the mixture is reacted for 15 hours at room temperature, 60mL of water is slowly added dropwise under ice bath, solid is separated out, filtration is carried out, the filter cake column chromatography is carried out for separation and purification, the obtained solid is added into 20mL of solvent methanol, 10% palladium carbon (0.02 g) is added, reflux reaction is carried out for 20 hours under hydrogen atmosphere, filtration and concentration are carried out, and the obtained solid is prepared for separation and purification to obtain NT-09 (0.05 g, 9%). MS (ESI) M/z= 570.1 (m+h). 1 H NMR(DMSO)δ：8.55(s,1H),8.00(s,1H),7.81(s,1H),7.32(d,1H),7.13-7.12(m,1H),7.09-7.08(m,1H),6.43(s,1H),4.28-4.26(m,1H),4.00-3.98(m,1H),3.57-3.50(m,3H),3.34-3.31(m,2H),3.07-3.04(m,2H),2.00-1.94(m,2H),1.83-1.80(m,1H),1.52-1.50(m,2H),1.39-1.37(m,2H),0.93(d,J＝12.2Hz,3H)。
Example 9: preparation of Compound NT-25
B-17: b-5 (6.77 g,20 mmol) and triethylamine (6.07 g,60 mmol) were added to 150mL of tetrahydrofuran, and after the addition of bis (1H-imidazol-1-yl) methylthioketone (3.56 g,20 mmol) and reaction at 60℃for 5 hours, (R) -pyrrolidin-3-ol hydrochloride (2.47 g,20 mmol) was added and reaction was continued at 60℃for 5 hours, cooled, suction filtered, and the filtrate was concentrated under reduced pressure, and the resulting solid was recrystallized from acetonitrile/water to give B-17 (2.90 g,31% yield). MS (ESI) M/z= 468.2 (m+h).
NT-25: b-17 (0.47 g,1 mmol), 60% sodium hydrogen (0.08 g,2 mmol) and 10mL of solvent DMF are added into a reactor under stirring, stirring is carried out for 1h at room temperature, dibenzyl phosphate chloride (0.30 g,1 mmol) is added under the temperature of 0-10 ℃,60 mL of water is slowly added dropwise under ice bath after the dropwise addition, the solid is separated out, and the filtration and the filter cake column chromatography are carried outThe solid was separated and purified, and 10% palladium on carbon (0.02 g) was added to 20mL of methanol as a solvent, and reacted at room temperature under a hydrogen atmosphere for 10 hours, filtered, and concentrated to obtain NT-25 (0.04 g, 8%) as a solid by column separation and purification. MS (ESI) M/z= 548.2 (m+h). 1 H NMR(DMSO)δ：8.62(s,1H),8.03(s,1H),7.85(s,1H),7.37(d,1H),7.19-7.18(m,1H),7.13-7.12(m,1H),6.45(s,1H),4.33-4.31(m,1H),3.84(s,3H),4.03-4.00(m,1H),3.65-3.59(m,3H),3.39-3.37(m,2H),3.12-3.09(m,2H),2.05-1.99(m,2H),1.86-1.84(m,1H),1.57-1.53(m,2H),1.46-1.44(m,2H),0.98(d,J＝12.0Hz,3H)。
Example 10: preparation of Compound NT-31
NT-31: to the reactor was added B-7 (0.45 g,1 mmol), potassium carbonate (0.27 g,2 mmol) and 10mL of solvent DMF under nitrogen protection, tetra (n-butyl) ammonium iodide (0.37 g,1 mmol), after stirring at room temperature for 30 min, di-tert-butylchloromethyl phosphate (0.52 g,2 mmol), stirring at room temperature for 24 hours, then toluene 20mL and water 10mL, after separation the organic phase was washed with 10mL of saturated saline solution, then with 10mL of citric acid solution (0.1M), then with 10mL of sodium bicarbonate solution (15%) solution, concentrated, then the residue was added to n-hexane (2 mL) and MTBE (3 mL), placed under ice bath for 24 hours, the precipitated solid was filtered, the obtained solid was added to 5mL of tetrahydrofuran, 2mL of trifluoroacetic acid was added, reacted at room temperature under nitrogen protection for 16 hours, neutralized with sodium bicarbonate solution (15%) and after neutralization was concentrated, the obtained residue was separated from the preparation liquid phase to obtain-31 (0.04 g, 7%). MS (ESI) M/z= 562.0 (m+h). 1 H NMR(DMSO)δ：8.55(s,1H),8.01(s,1H),7.77(s,1H),7.28(d,1H),7.13-7.12(m,1H),7.10-7.09(m,1H),6.40(s,1H),6.19(s,2H),4.32-4.30(m,1H),3.78(s,3H),4.00-3.98(m,1H),3.60-3.54(m,3H),3.33-3.30(m,2H),3.13-3.10(m,2H),2.00-1.95(m,2H),1.84-1.81(m,1H),1.57-1.55(m,2H),1.46-1.44(m,2H),0.96(d,J＝12.4Hz,3H)。
Example 11: preparation of Compound NT-34
NT-34: to the reactor was added B-12 (0.43 g,1 mmol), potassium carbonate (0.27 g,2 mmol) and 10mL of solvent DMF under nitrogen protection, tetra (n-butyl) ammonium iodide (0.37 g,1 mmol), after stirring at room temperature for 30 min, di-tert-butylchloromethyl phosphate (0.52 g,2 mmol), stirring at room temperature for 24 hours, then toluene 20mL and water 10mL, after separation the organic phase was washed with 10mL of saturated saline solution, then with 10mL of citric acid solution (0.1M), then with 10mL of sodium bicarbonate solution (15%) solution, concentrated, then the residue was added to n-hexane (2 mL) and MTBE (3 mL), placed under ice bath for 24 hours, the precipitated solid was filtered, the obtained solid was added to 5mL of tetrahydrofuran, 2mL of trifluoroacetic acid was added, reacted at room temperature under nitrogen protection for 16 hours, neutralized with sodium bicarbonate solution (15%) and after neutralization was concentrated, the obtained residue was separated from the preparation liquid phase to obtain-34 (0.05 g, 10%) under ice bath. MS (ESI) M/z= 539.2 (m+h). 1 H NMR(DMSO)δ：8.44(s,1H)，7.84(s,1H)，7.32(s,1H)，7.15(s,1H)，6.87(s,1H)，6.27(s,2H)，5.36(s,1H)，4.84(s,1H)，3.97(s,1H)，3.83-3.29(m,8H)，2.17-1.88(m,5H)。
Example 12: preparation of Compound NT-35
NT-35: NT-31 (0.54 g,1 mmol), sodium hydroxide (0.20 g,5 mmol), and 10mL of solvent acetone were added to the reactor with stirring, stirred at room temperature for 10h, filtered, and the resulting solid was purified by recrystallization from acetone/water to give NT-35 (0.04 g, 7%). MS (ESI) M/z=605.3 (m+na). 1 H NMR(DMSO)δ：8.42(s,1H)，7.81(s,1H)，7.30(s,1H)，7.12(s,1H)，6.86(s,1H)，6.17(s,2H)，5.32(s,1H)，4.81(s,1H)，3.94(s,1H)，3.80-3.23(m,8H)，2.16-1.85(m,5H)。
In a similar manner, the following compounds can be synthesized:
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example 13: cytotoxicity of the Compounds
HepG 2.2.15 cells were cultured in Eagle's MEM medium (10% fetal bovine serum, 1% glutamine) at 37℃C 5% CO 2 Incubator culture for 24 hours at 1X 10 5 Density of each mL was grown in 96-well plates and culture was continued for 24 hours, replacing with compound and positive control solutions (0.02% DMSO) in Eagle's MEM medium, each compound and positive control (lamivudine) set at 6 concentrations: 0.5. Mu.M, 2.5. Mu.M, 12.5. Mu.M, 62.5. Mu.M, 125.0. Mu.M, 312.5. Mu.M, three duplicate wells were set for each concentration. Cell control wells were not added with compound and positive control solution, and only the corresponding volumes of Eagle's MEM broth were added. After the addition was completed, the culture was continued for 96 hours, during which time the culture broth was discarded every 48 hours, and replaced with a compound solution or positive control solution or Eagle's MEM culture broth of the corresponding concentration diluted with fresh Eagle's MEM culture broth. After 96 hours, the cytopathic effect was observed with a microscope according to Reed&The Muench method calculates the median Toxicity Concentration (TC) 50 ) The calculation results are shown in Table 1:
table 1: toxicity of Compounds against HepG 2.2.15 cells
The data indicate that the compounds of the application have no significant toxicity, TC, in HepG 2.2.15 cells 50 The values are above 95.0 mu M, especially the compounds NT-03, NT-05, NT-22,TC of NT-30, NT-32 50 Larger values, TC in HepG 2.2.15 cells by Gao Yula Mivudine 50 The compounds of the present application are expected to have higher safety.
Example 14: inhibition of HBV-DNA by Compounds in vitro
2.2.15 cell lines transfected with Hepatitis B Virus (HBV) DNA clones (HepG 2) were used to test the activity, and after resuscitation, the cells were added to Eagle's MEM medium (containing 10% fetal bovine serum) and incubated in an incubator (5% CO) at 37 ℃ 2 ) Culturing for 8 days. Mother liquor according to 10 5 The cells/wells were seeded in 96-well plates, three wells were set for each experimental group, and the cells were incubated in an incubator at 37 ℃ (5% CO) 2 ) Culturing for 1 day, adding NT-02, NT-03, NT-05, NT-22, NT-30, NT-32, lamivudine liquid medicine (containing 0.02% DMSO to aid dissolution), adding culture medium, controlling final concentration to 30mg/mL, adding culture medium only into control hole, and culturing in 37 deg.C incubator (5% CO) 2 ) Culturing for 8 days, and changing the liquid medicine and the culture medium once on the 4 th day. After the culture is finished, the culture solution of the cell supernatant of each group is subjected to precipitation and cleavage by adopting a molecular cloning experiment technology, HBV-DNA is repeatedly extracted, HBV-DNA copy number of each sample is measured by Taqman fluorescent quantitative PCR, and the inhibition ratio (%) of the compound to HBV-DNA is calculated according to the following formula:
inhibition (%) = (control Kong Kaobei number-dosing well copy number)/control well copy number x 100%
The calculation results are shown in Table 2:
table 2: inhibition of HBV-DNA by Compounds in vitro
The data show that the synthesized pyrimidine derivatives NT-03, NT-05, NT-22, NT-30 and NT-32 can significantly inhibit HBV-DNA synthesis in HepG2 cells, and compared with lamivudine, the synthesized pyrimidine derivatives NT-03, NT-05, NT-22, NT-30 and NT-32 have stronger inhibition effect on HBV-DNA in HepG2 cells.
Example 15: solubility test of Compounds in Water
The solubility of the compound in water was tested according to the chinese pharmacopoeia 2020 edition of method for measuring the solubility of the valve:
the test method comprises the following steps: 0.1000g of the sample ground into fine powder is weighed, added into water with a certain volume at 15+/-2 ℃, shaken vigorously for 30 seconds every 5 minutes, and observed for dissolution within 30 minutes, and if solute particles are not visible, the solution is regarded as complete dissolution. The test results are shown in table 3:
table 3: solubility of Compounds in Water
| Compounds of formula (I) | Solubility (mg/mL) | Compounds of formula (I) | Solubility (mg/mL) |
| NT-03 | 989.6 | NT-30 | 1020.5 |
| NT-05 | 1249.3 | NT-32 | 1100.7 |
| NT-22 | 977.9 |
The results show that the synthesized pyrimidinyl derivatives NT-03, NT-05, NT-22, NT-30, NT-32 have greater solubility in water. It is well known that solubility is a key factor affecting drug availability, while the increased solubility more facilitates dissolution of drug molecules in the gastrointestinal tract, and thus the pyrimidinyl derivatives NT-03, NT-05, NT-22, NT-30, NT-32 of the present application have great potential for development as oral formulations or injections. Meanwhile, the solubility is obviously improved, so that the method is suitable for developing true solution preparations.
Example 16: anti-HBV activity in vivo
Taking 70 rats with the age of 10 weeks, randomly dividing the weight of the rats into 7 groups, namely a blank group, a NT-03 group, a NT-05 group, a NT-22 group, a NT-30 group, a NT-32 group and a lamivudine group (positive control group), adaptively feeding the rats for 15 days, adopting foot intravenous injection of DHBV positive serum, injecting 0.1mL of the serum into the rats, feeding the rats into the corresponding feeding groups according to the dosage of 30mg/kg after feeding for 15 days, filling the blank group with normal saline with the corresponding dosage of the stomach only, continuously feeding the rats for 30 days, collecting blood in a vein, standing in warm water at 37 ℃, separating upper serum, detecting HBV-DNA in the serum by adopting a standard TaqMan real-time fluorescent PCR method, taking an internal standard calibrated in a laboratory as a reference, and determining HBV-DNA quantitative results of each experimental group, wherein the experimental data results are shown in table 4:
table 4: determination of HBV-DNA content in rat serum
The data show that after 30 days of continuous dosing, the HBV-DNA content in the serum of the rats of the dosed group is significantly lower than that of the blank group, and compared with the lamivudine group, the HBV-DNA content in the serum of the rats of the compounds NT-03 group, NT-05 group, NT-22 group, NT-30 group and NT-32 group of the application is significantly reduced, which means that the compounds NT-03, NT-05, NT-22, NT-30 and NT-32 have more significant anti-HBV effect in the rats than lamivudine.
Example 17: stability of the Compounds in solution
Preparing a solution A: weigh 20gHS 15 is dissolved in 50mL of warm water (deionized water), and after shaking to dissolve completely, diluted to 100mL with deionized water for use.
10.0mg of each of the compounds NT-03, NT-05, NT-22, NT-30 and NT-32 was weighed and added to 1.0mL of solution A, respectively, and after shaking for complete dissolution, the mixture was placed in a 40 ℃/75% RH stability box, and the stability of the compound in solution A was tested by using high performance liquid phases on days 0, 3 and 10, respectively, under the following chromatographic conditions:
chromatographic column: inert sustein TM C18-AQ 4.6×250mm,5μm；
Mobile phase: 0.1% phosphoric acid in water-methanol (35:65);
wavelength: 280nm; flow rate: 1.0mL/min; column temperature: 30 ℃;
sample injection volume: 10. Mu.L;
the test results are shown in Table 5:
table 5: stability of the Compounds in solution A
The data show that the compounds NT-03, NT-05, NT-22, NT-30 and NT-32 have better stability, have no obvious impurity generation in the stability placing process, and are suitable for being used as lead drug molecules to continue the subsequent development.
Example 18: in vivo pharmacokinetic experiments of compounds by intragastric administration in rats
Compound solution preparation: weigh 20gHS 15, dissolving in 50mL warm water (deionized water), shaking to dissolve completely, diluting with deionized water to 100mL, dissolving the compounds NT-18, NT-20, NT-30 in the aboveIn the HS 15 solution, compound solution with the concentration of 5.0mg/mL is prepared for standby.
18 male SD rats were fed adaptively for 3 days with free feeding of water, the experimental temperature was controlled at 20-26 ℃, the laboratory humidity was controlled at 40-70%, and the light was illuminated: dark = 12h: and 12h. After 3 days, 9 male SD rats weighing 180g-220g are taken and divided into three groups of 3 rats, wherein the three groups are respectively: the NT-05 group, the NT-22 group and the NT-30 group were administered by gastric lavage to each group of mice after 16 hours of fasting (without water control) at a dose of 36mg/kg. Free feeding and drinking after administration, respectively after administration: venous blood is taken from the eyeballs of the rats for 0.25h, 0.5h, 1h, 1.5h, 2h, 3h, 4h, 8h and 24h, the blood taking volume is about 300 mu L each time, the venous blood is added into a chilled heparin sodium centrifuge tube, the centrifugal tube is placed in an ice bath for 1 hour, and after centrifugation (4000 rpm) is carried out for 10 minutes, upper serum is taken and placed in a sterile EP tube for standby at-80 ℃. In the experimental process, general state observation is carried out on experimental animals, and the content comprises: the rats have abnormal eating and water intake, abnormal hair color, abnormal behavior and mental state, abnormal secretion of eyes, ears, mouth and nose, abnormal urination and defecation. And if so, recording in detail. After all the rats were bled, the concentration of the test compound in the plasma was measured as soon as possible and the calculated results are shown in table 6:
table 6: intragastric administration of compounds in vivo PK parameters in rats
The data show that the compounds NT-05, NT-22 and NT-30 can reach the highest blood concentration in the rat body within 0.5h after being administrated by gastric lavage, and have the advantages of quick effect, high exposure in the body and strong drug action. The calculation result shows that the bioavailability of the compound in vivo by gastric administration is above 66%, especially the bioavailability of the compound NT-05 in rats is above 70%. Meanwhile, the general physiological conditions of the rats in each group are observed in the experimental process, and the rats in each group have free movement, luster and luster, good appetite, normal urination and defecation and no other obvious adverse reaction. The data above together show that the compounds of the application have good prospects for development as clinical drugs.
The features of the present application will be more fully understood from the foregoing detailed description of the application, and the modified forms of the application will fall within the scope of the appended claims.
Claims (5)
1. A compound selected from the group consisting of:
。
2. the use of a compound according to claim 1 for the preparation of a medicament against hepatitis b virus.
3. The use according to claim 2, wherein the medicament treats and/or prevents diseases caused by viruses by inhibiting viral replication.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable adjuvant.
5. The use of the pharmaceutical composition of claim 4 for the preparation of an anti-hepatitis b virus medicament.
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