CN115109042B - Triazine compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and application - Google Patents
Triazine compound or pharmaceutically acceptable salt thereof, pharmaceutical composition and application Download PDFInfo
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Abstract
The invention discloses a triazine compound with a structure shown in a general formula I, or pharmaceutically acceptable salt, a pharmaceutical composition and application thereof. The invention overcomes the defects of single structure, non-covalent, non-peptide high-efficiency small molecule inhibitor deficiency and the like of the prior broad-spectrum antiviral drugs, and the compound shown in the formula I provided by the invention has good inhibitory activity on 3C-like cysteine protease and has good therapeutic effect on infectious diseases.
Description
Technical Field
The invention belongs to the field of innovative pharmaceutical chemistry, and relates to a triazine compound, a preparation method, a pharmaceutical composition and application thereof.
Background
SARS-CoV-2 is a highly pathogenic, pandemic human and animal co-virus belonging to the coronaviridae family with SARS-CoV-1 and MERS-CoV. These three viruses, unlike the other several coronaviruses HCoV-NL63, HCoV-229E, HCoV-OC43 and HCoVHKU1, can cause severe respiratory diseases. Symptoms of SARS-CoV-2 infection range from asymptomatic disease to moderate and severe pneumonia, as well as life threatening complications including hypoxic respiratory failure, acute respiratory distress syndrome, multiple system organ failure, and ultimately death. Even more terrible, the virus is not only highly contagious, but can be transmitted by asymptomatic infected persons and those in both symptomatic and pre-symptomatic stages. Although many different vaccines are currently approved for sale or emergency use worldwide, a significant portion of the population worldwide is not vaccinated due to limitations in its own physical or local medical conditions. In addition, vaccines have reduced protective efficacy against SARS-CoV-2 variants, particularly the recently-developed worldwide Omicron strain. Thus, the development of new crown drugs that are effective against variabilities is urgent.
Coronaviruses are broken down to release nucleocapsids and viral genomes after entering host cells. The host cell ribosomes translate the Open Reading Frames (ORFs) 1a and 1b of the viral genome into the multimeric proteins pp1a and pp1b, respectively, which encode 16 nonstructural proteins (nsps), while the remaining ORFs encode structural and accessory proteins. The cleavage of PP by 3C-like cysteine protease (3 CLpro) and papain-like cysteine protease (PLpro) results in the formation of nsp2-16, which in turn forms a replication-transcription complex (RTC). These protease activity deletions lead to a viral life cycle arrest. Furthermore, the structure and function of 3CLpro are highly conserved among coronaviruses. 3CLpro catalytic center mutation rate is extremely low, and drug resistance is not easy to generate; the 3Clpro inhibitor should be effective against all variants, not dependent on inducing an immune response, but rather blocking the viral replication protease 3CLpro by binding to the viral backbone. The polypeptide after cleavage of only the glutamine (Gln) residue by 3CLpro, no known human protease has shown the same cleavage specificity as 3CLpro, and thus the potential toxicity of 3CLpro inhibitors is lower. Thus, 3CLpro is an effective target for the development of oral anti-neocrown drugs.
The 3CLpro inhibitors reported so far include covalent peptidomimetic inhibitors represented by PF-07321332 developed by the company of pyroxene and non-covalent, non-peptidomimetic small molecule inhibitors represented by S-217622 developed by the company of Shiingai, japan. Currently, the new oral drug Paxlovid (PF-07321332 as the main ingredient) of the xenia obtains FDA emergency use authorization and becomes the first new oral drug in the united states. PF-07321332 is a substrate for CYP3A4 and is metabolically unstable and must be taken together with the CYP3A4 enzyme inhibitor ritonavir. Changes in the activity of the CYP3A4 enzyme affect the metabolism of Paxlovid, and thus affect the effectiveness and safety of Paxlovid. S-217622 is hopeful to get rid of dependence on P450 enzyme inhibitors (such as ritonavir), realizes a new crown of single drug treatment, expands the applicable crowd range without taking any precaution and other drugs needing to be taken simultaneously generate pharmacological reaction due to the inhibition effect of the P450 enzyme. Although S-217622 shows great potential for treating a new crown, the currently reported non-covalent small molecule inhibitors are still very deficient, and have the problems of single structure, weak enzyme inhibition activity, poor patent medicine and the like. Therefore, the novel, efficient and low-toxicity 3CLpro non-covalent small molecule inhibitor is of great significance, more and more practical clinical drug treatment choices are provided for new coronary patients with different symptoms, and more powerful guarantee is provided for thoroughly overcoming the new coronary epidemic situation.
Disclosure of Invention
The invention aims to solve the technical problems that the existing broad-spectrum antiviral drug is single in structure and is lack of a non-covalent high-efficiency 3CLpro small-molecule inhibitor, and provides a triazine compound, a preparation method, a pharmaceutical composition and application thereof. The triazine is a 3CLpro non-covalent small molecule inhibitor with remarkable activity and has better therapeutic effect on coronavirus infectious diseases.
The invention solves the technical problems through the following technical proposal.
The invention provides a triazine compound with a structure shown in a general formula I, or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which has the following structure:
wherein R is 1 Is R 1-1 OCH 2 -or
；
R 1-1 Is hydrogen, C 1-6 Alkyl or C 1-6 Alkoxy- (C) 1-6 Alkyl) -;
R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 or R is 8 Independently selected from the group consisting of hydrogen and deuterium,
at the same time, R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 Or R is 8 At least one is selected from deuterium.
In some embodiments, R 1-1 Is hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy- (C) 1-4 Alkyl) -.
In some embodiments, R 1 Is hydrogen, methyl, ethyl, propyl, isopropyl, or
。
In some embodiments, R 3a 、R 3b Or R is 3b At least one is selected from deuterium.
In some embodiments, R 2 、R 4 、R 5 、R 6 、R 7 Or R is 8 At least one is selected from deuterium.
In some embodiments, the compound having the structure of formula I is any one of the following:
the invention also provides a preparation method of the triazine compound with the structure shown in the general formula I, or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which is characterized by comprising the following steps: in a solvent, reacting the compound II with the compound III under the action of alkali to generate a compound I;
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 And R is 8 Is as defined above;
when R is 1 Is that
Compound II is Boc anhydride;
when R is 1 Is R 1-1 OCH 2 When the compound II is R 1-1 OCH 2 Cl, formaldehyde or paraformaldehyde.
The conditions and operation of the reactions described above are the same as those conventional in the art for such reactions.
The invention also provides application of the triazine compound with the structure shown in the general formula I or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof in preparing the 3C-like cysteine protease inhibitor.
The invention also provides application of the triazine compound with the structure shown in the general formula I or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof in preparing medicaments for treating and/or preventing virus infectious diseases.
Further, the virus includes, but is not limited to, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), middle east respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus (SARS-CoV), influenza A virus, influenza B virus, spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, polio virus, rhinovirus, adenovirus, ebola virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, japanese encephalitis virus, west Nile virus, newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackie virus, rotavirus or tobacco mosaic virus.
The invention also provides a pharmaceutical composition which contains triazine compounds with a structure shown in a general formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.
In the pharmaceutical composition, the triazine compound with the structure shown in the general formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in an amount which is effective for treatment.
The invention also provides application of the pharmaceutical composition in preparing a 3C-like cysteine protease inhibitor.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating and/or preventing viral infectious diseases.
Further, the virus includes, but is not limited to, severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), middle east respiratory syndrome-related coronavirus (MERS-CoV), severe acute respiratory syndrome-related coronavirus (SARS-CoV), influenza A virus, influenza B virus, spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, polio virus, rhinovirus, adenovirus, ebola virus, enterovirus, hepatitis A virus, hepatitis C virus, hepatitis E virus, enterovirus, HIV virus, echovirus, filovirus, measles virus, yellow fever virus, japanese encephalitis virus, west Nile virus, newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackie virus, rotavirus or tobacco mosaic virus.
The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.
The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.
The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.
Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example 3 H) Iodine-125% 125 I) Or C-14% 14 C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
As will be appreciated by those skilled in the art, the present application describes "as used in the structural formula of a group" in accordance with convention used in the art "
"means that the corresponding group is attached to other fragments, groups in the compound of formula I through this site.
The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl and the like.
The term "alkoxy" refers to the group-O-RY, wherein RY is alkyl as defined above.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
(1) The triazine compound has good inhibitory activity on 3C-like cysteine protease.
(2) The triazine compound has good therapeutic effect on virus infectious diseases.
(3) The triazine compounds have small toxic and side effects.
Drawings
FIG. 1 shows the anti-infective activity of the positive control group and compound S3 in a mouse infection model of example 25.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
EXAMPLE 1 Synthesis of Compound S1
Step one: synthesis of Compound 2
Compound 1 (18 g,78.8 mmol) was dissolved in acetonitrile (240 mL), and to the above solution were added compound 5 (26 g,118.8 mmol) and K 2 CO 3 (16.4 g,118.8 mol) and the reaction mixture was heated to reflux for reaction 3. 3 h. The reaction solution was cooled to room temperature, suction filtration, concentration of the filtrate, and separation and purification by column chromatography (PE: ea=30:1) gave compound 2 (23.5 g, 80%). 1 H NMR (300 MHz, CDCl 3 ) δ 1.33 (3H, t, J = 7.4 Hz), 1.65 (9H, s), 3.15 (2H, q, J = 7.4 Hz), 5.03 (2H, s), 6.91−7.01 (2H, m).
Step two: synthesis of Compound 3
Compound 2 (20 g,51.9 mmol) was dissolved in TFA (39 mL), the reaction was stirred at room temperature for 6 h, stirring was stopped, TFA was distilled off under reduced pressure, diethyl ether was slurried, suction filtration was performed, the filter cake was collected, and vacuum drying was performed to obtain Compound 3 (14.8 g, 90%). 1 H NMR (300 MHz, CDCl 3 ) δ 1.37 (3H, t, J = 7.4 Hz), 3.23 (2H, q, J = 7.4 Hz), 5.15 (2H, s), 6.95−7.09 (2H, m), 8.23 (1H, br).
Step three: synthesis of Compound 4
Compound 3 (14.5 g,45.6 mmol) was dissolved in anhydrous DMF (80 mL), and Compound 6 (12.4 g,68.4 mmol) and K were added to the above solution 2 CO 3 (18.9 g,136.8 mol), the reaction mixture was warmed to 60℃and stirred for reaction 4. 4 h. The reaction mixture was cooled to room temperature and quenched with water (100 mL)The reaction was extracted with DCM (100 mL. Times.3), the organic phases were combined, washed with saturated brine (200. 200 mL), and dried over Na 2 SO 4 Drying, filtration, concentration, column chromatography purification (DCM: meoh=80:1) afforded compound 4 (7.7 g, 40%).
Step four: synthesis of Compound 5
0. To a tetrahydrofuran solution of compound 4 (300 mg, 0.727 mmol) and compound 7 (172 mg, 0.946 mmol) was added dropwise LiHMDS (1M, 1.46 mL, 1.46 mmol) at C, stirred at 0deg.C for 2h, and then transferred to room temperature for 2h. After completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (2 ml), extracted with ethyl acetate (2 ml. Times.3), the organic phases were combined, washed with saturated brine, and dried over Na 2 SO 4 Drying, filtration, concentration, and column chromatography purification gave compound II-1 (97 mg, 25%). 1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.91 (s, 3H).
Step five: synthesis of Compound S1
Compound II-1 (97 mg,0.182 mmol) was dissolved in acetonitrile, and potassium carbonate (75 mg, 0.546 mmol) and MOMCl (22 mg,0.273 mmol) were added sequentially to the above solution at 0℃and heated under reflux for reaction 3 h. After completion of the reaction, ethyl acetate extraction (10 mL ×3), the organic phases were combined, washed with saturated brine, and dried over Na 2 SO 4 Drying, filtering, concentrating, and separating and purifying by column chromatography to obtain the compound S1. 1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.91 (s, 3H), 3.44(s, 3H). MS (ESI, m/z): 577.2 (M + +1).
The synthesis of the compounds S2 to S15 in examples 2 to 15 below refers to the synthesis method of example 1, and only the corresponding raw materials need to be replaced.
EXAMPLE 2 Synthesis of Compound S2
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.91 (s, 3H), 3.72 (t, J = 6.1 Hz, 1H), 3.52 (t, J = 6.2 Hz, 1H), 3.44 (s, 3H). MS (ESI, m/z): 621.2 (M + +1).
EXAMPLE 3 Synthesis of Compound S3
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 7.36 (s, 1H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.44 (s, 3H). MS (ESI, m/z): 579.2 (M + +1).
EXAMPLE 4 Synthesis of Compound S4
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 7.36 (s, 1H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.72 (t, J = 6.1 Hz, 1H), 3.52 (t, J = 6.2 Hz, 1H), 3.44 (s, 3H). MS (ESI, m/z): 623.2 (M + +1).
EXAMPLE 5 Synthesis of Compound S5
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.54 (q, J = 7.0 Hz, 1H), 1.16 (t, J = 6.9 Hz, 1H). MS (ESI, m/z): 593.2 (M + +1).
EXAMPLE 6 Synthesis of Compound S6
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.91 (hept, J = 6.2 Hz, 1H), 1.19 (d, J = 6.2 Hz, 6H). MS (ESI, m/z): 607.2 (M + +1).
EXAMPLE 7 Synthesis of Compound S7
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.41 (t, J = 6.0 Hz, 1H), 1.54 (qt, J = 7.6, 6.1 Hz, 1H), 0.90 (t, J = 7.7 Hz, 2H). MS (ESI, m/z): 607.2 (M + +1).
EXAMPLE 8 Synthesis of Compound S8
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.91 (s, 2H), 3.44 (s, 3H). MS (ESI, m/z): 579.1 (M + +1).
EXAMPLE 9 Synthesis of Compound S9
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.68-7.54 (m, 2H), 7.43 (s, 1H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.44 (s, 3H). MS (ESI, m/z): 580.1 (M + +1).
EXAMPLE 10 Synthesis of Compound S10
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.79 (s, 1H), 7.68-7.54 (m, 2H), 7.43 (s, 1H), 5.24 (s, 2H), 5.11(s, 2H), 4.14 (s, 3H), 3.44 (s, 3H). MS (ESI, m/z): 581.1 (M + +1).
EXAMPLE 11 Synthesis of Compound S11
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.79 (s, 1H), 7.68-7.54 (m, 2H), 7.43 (s, 1H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.44 (s, 3H). MS (ESI, m/z): 581.1 (M + +1).
EXAMPLE 12 Synthesis of Compound S12
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.79 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 1H), 5.11(s, 2H), 4.14 (s, 3H), 3.44 (s, 3H). MS (ESI, m/z): 582.2 (M + +1).
EXAMPLE 13 Synthesis of Compound S13
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 1H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.44 (s, 3H). MS (ESI, m/z): 581.2 (M + +1).
EXAMPLE 14 Synthesis of Compound S14
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.72 (t, J = 6.1 Hz, 1H), 3.52 (t, J = 6.2 Hz, 1H), 3.44 (s, 3H). MS (ESI, m/z): 624.2 (M + +1).
EXAMPLE 15 Synthesis of Compound S15
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.68-7.54 (m, 2H), 7.35 (s, 1H), 5.24 (s, 2H), 5.11(s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.72 (t, J = 6.1 Hz, 1H), 3.52 (t, J = 6.2 Hz, 1H), 3.44 (s, 3H). MS (ESI, m/z): 624.2 (M + +1).
EXAMPLE 16 Synthesis of Compound S16
Compound II-16 was obtained by the synthesis method of Compound II-1 in example 1. Compound II-1 (97 mg,0.182 mmol) was dissolved in acetonitrile, and an aqueous formaldehyde solution (37%, 270. Mu.L) and potassium carbonate (75 mg, 0.546 mmol) were added sequentially thereto, followed by reaction at room temperature of 12 h. After completion of the reaction, ethyl acetate extraction (10 mL ×3), the organic phases were combined, washed with saturated brine, and dried over Na 2 SO 4 Drying, filtering, concentrating, and separating and purifying by column chromatography to obtain the compound S16. 1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 7.36 (s, 1H), 6.07 (t, J = 7.0 Hz, 1H), 5.71 (d, J = 6.9 Hz, 2H), 5.24 (s, 2H), 5.03 (s, 2H), 4.14 (s, 3H). MS (ESI, m/z): 565.2 (M + +1).
The synthesis of the compounds S17 to S21 in examples 17 to 21 below refers to the synthesis method of example 1, and only the corresponding raw materials need to be replaced.
EXAMPLE 17 Synthesis of Compound S17
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.73 (s, 1H), 7.68-7.54 (m, 2H), 7.36 (s, 1H), 6.07 (t, J = 7.0 Hz, 1H), 5.71 (d, J = 6.9 Hz, 2H), 5.24 (s, 2H), 5.03 (s, 2H), 4.14 (s, 3H), 3.93 (s, 2H). MS (ESI, m/z): 564.2 (M + +1).
EXAMPLE 18 Synthesis of Compound S18
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.68-7.54 (m, 2H), 7.36 (s, 1H), 6.07 (t, J = 7.0 Hz, 1H), 5.71 (d, J = 6.9 Hz, 2H), 5.24 (s, 2H), 5.03 (s, 2H), 4.14 (s, 3H). MS (ESI, m/z): 566.2 (M + +1).
EXAMPLE 19 Synthesis of Compound S19
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.63 (s, 1H), 7.68-7.54 (m, 2H), 6.07 (t, J = 7.0 Hz, 1H), 5.71 (d, J = 6.9 Hz, 2H), 5.24 (s, 2H), 5.03 (s, 2H), 4.14 (s, 3H). MS (ESI, m/z): 566.2 (M + +1).
EXAMPLE 20 Synthesis of Compound S20
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.63 (s, 1H), 7.68-7.54 (m, 2H), 7.33 (s, 1H), 6.07 (t, J = 7.0 Hz, 1H), 5.71 (d, J = 6.9 Hz, 2H), 5.03 (s, 2H), 4.14 (s, 3H). MS (ESI, m/z): 567.2 (M + +1).
EXAMPLE 21 Synthesis of Compound S21
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.63 (s, 1H), 7.68-7.54 (m, 2H), 7.33 (s, 1H), 6.07 (t, J = 7.0 Hz, 1H), 5.71 (d, J = 6.9 Hz, 2H), 5.23 (s, 2H), 4.14 (s, 3H). MS (ESI, m/z): 567.2 (M + +1).
EXAMPLE 22 Synthesis of Compound S22
Compound II-16 (97 mg,0.182 mmol) was dissolved in anhydrous THF (3 mL), and Boc anhydride (44 mg,0.2 mmol) and DMAP (24 mg,0.2 mmol) were added to the above solution at 0deg.C, then transferred to room temperature and reacted overnight. The next day, saturated sodium bicarbonate solution was added to the reaction, extracted with ethyl acetate (10 mL ×3), the organic phases were combined, washed with saturated brine, and dried over Na 2 SO 4 Drying, filtering, concentrating, and separating and purifying by column chromatography to obtain the compound S22.
1 H NMR (500 MHz, DMSO-d 6 , DCl in D 2 O) δ9.43 (s, 1H), 8.42 (s, 1H), 7.63 (s, 1H), 7.68-7.54 (m, 2H), 7.33 (s, 1H), 5.23 (s, 2H), 4.14 (s, 3H), 1.45 (s, 9H). MS (ESI, m/z): 635.2 (M + +1).
Example 23: test of SARS-CoV-2 Virus 3C-like cysteine protease (3 CLpro) enzyme inhibitory Activity
1.3 expression and purification of CLpro protein
The gene sequence of the full-length 3CLpro protein was constructed in the expression vector pET28a (+) vector and transferred into competent cells of E.coli BL21 (DE 3), and after induction for 12 hours at a final concentration of 0.5 mM IPTG at 25℃was purified using a Ni-NTA column. The purified protein is detected by SDS, the part with the purity of more than 90 percent is further purified by Superdex 200 10/300 GL of AKTA Pure of GE protein chromatography purification system, the protein with the purity of more than 95 percent is obtained, the protein concentration is measured by Nano Drop, and the protein is packaged and quick frozen by liquid nitrogen and then is stored at the temperature of minus 80 ℃.
2. Establishment of SARS-CoV-2 3CLpro enzyme activity screening system, inhibitor inhibition rate and medicine IC 50 Calculation of (2)
The SARS-CoV-2 3CLpro activity and the inhibitory activity of the compound on SARS-CoV-2 3CLpro are determined by Fluorescence Resonance Energy Transfer (FRET) technique. In the assay, a fluorogenic substrate (Dabcyl-KTSAVLQ +.SGFRKM-E (Edans) -NH) with SARS-CoV-2 3CLpro cleavage site (arrow) 2 ) And Tris-HCl buffer (20 mM Tris-HCl,150mM NaCl,10 mM EDTA,pH 7.5). The compound was dissolved in 100% DMSO. 10. Mu.l of the compound was incubated with 40. Mu.l of SARS-CoV-2 3CLpro (final concentration 0.5. Mu.M, tris-HCl buffer) at 25℃for 10 min, and the reaction was initiated by addition of 50. Mu.l of fluorogenic substrate (final concentration 20. Mu.M). The Dabcyl fluorescent signal resulting from the cleavage of the substrate catalyzed by 3CLpro was detected using a radioresonance energy transfer fluorescence spectrophotometer at an excitation wavelength of 340nm and an absorption wavelength of 490 nm. The SARS-CoV-2 3CLpro kinetic constants (Vmax and Km) are obtained by fitting the data to the Michaelis Menten equation, V=Vmax× [ S ]]/(Km + [S]). Then according to the formula kcat=vmax/[ E ]]Kcat was calculated. Compounds were diluted in a gradient by fold dilution using Tris-HCl buffer and assayed using the same final concentration of SARS-CoV-2 3CLpro and fluorogenic substrate system as described above. Values of intrinsic (V0 i) and apparent (Vappi, kappi) catalytic parameters of 3CLpro catalytic polypeptide substrate hydrolysis were determined in the presence and absence, respectively, of the compound of interest. Apparent inhibition constant (kappa) for binding of the target compound to Mpro is determined by Vappi versus the fixed substrate concentration ([ S)]) Lower inhibitor concentration ([ I)]) According to the equation vappi=vappx [ I ]]/（Kappi +[I]) And obtaining the product. The value of the intrinsic inhibition constant (Ki) of the binding of the target compound to 3CLpro is determined according to the equation kappi=ki× (1+ [ S ]]Km) is calculated. Inhibition curves for compounds were plotted by GraphPad Prism 8.0 software and IC was calculated 50 Values.
As a result, as shown in Table 1 below, the compound of the example had a better inhibitory activity against SARS-CoV-2 virus 3CLpro, which was superior to that of the positive control S-217622.
Example 24: cytotoxicity and anti-SARS-CoV-2 virus infection efficacy test experiment
Vero E6 cytotoxicity test: the CCK8 method is used for detecting cytotoxicity of the compound to be detected in Vero E6 cells of mammals. Vero E6 cells were added to 96-well plates and cultured overnight. The cells were then incubated 48 h with different concentrations of the test compound. The medium in the well plate was removed, replaced with fresh serum-free medium, 10% CCK8 reagent was added, and then incubated at 37 ℃ for 1h, followed by detection of absorbance at 450 nm using an enzyme-labeled instrument.
Screening compounds with no cytotoxicity or less cytotoxicity for testing antiviral infection, the specific operation comprises the following steps:
(1) inoculating cells: taking Vero-E6 cells in logarithmic growth phase, sucking out the culture solution, and digesting the cells with pancreatin, wherein the cell count is as follows: 1X 106/mL; taking the above cell 4 mL, adding culture medium 6 mL, preparing into cell suspension with cell density of 4×105/mL, inoculating into 96-well plate, 100 μl/well, and 4×10/well cell 4 And each. (2) Drug pretreatment cells: the cell culture medium was replaced with DMEM medium containing 2% FBS, and 100 μl of the corresponding concentration of drug and DMSO was added to each well, followed by pretreatment in a 37 ℃ incubator of 1h. (3) Viral infection: taking virus 0.3 and mL, adding 45-mL culture medium, uniformly mixing, and diluting the virus to 100TCID 50/0.05mL; discarding the medicine culture medium vertical hanging drop virus diluent in the cell plate, adding 50 μl/hole of sample volume, adding corresponding medicine culture medium (containing medicine with corresponding concentration), adding 50 μl/hole of sample volume, and mixing; (4) incubation: the cell culture plates with the added samples are evenly mixed on a shaker and placed in a 37 ℃ incubator for incubation for 1h. After the incubation, the virus-serum mixture inoculated with cells was aspirated, the drug and the control DMSO at the corresponding concentrations were added, and the sample volume was 100. Mu.l/well (100 TCID 50/well) and placed in CO at 37 ℃ 2 Culturing 48 h in an incubator; (5) collecting supernatant to detect virusRNA was subjected to immunofluorescent staining analysis by 4% paraformaldehyde fixation staining.
The specific experimental results are shown in Table 2, the compound of the example has smaller cytotoxicity, better inhibition activity on SARS-CoV-2 virus infection, better than positive control S-217662 and better selection index
Example 25: in vivo anti-infective Activity test of Compound S3
Female BALB/c mice were first anesthetized by intraperitoneal injection of ketamine/xylazine (50 mg/kg/5 mg/kg), and then SARS-CoV-2 gamma strain (1X 10) 4 TCID 50 The infection model was constructed by intranasal inoculation, and the negative control mice were instilled with the same volume of physiological saline. After successful molding, the blank control group, the S-217622 positive control group and the administration group are divided into 6 groups. Compounds S-217622 and S3 were each suspended in 0.5% methylcellulose and administered once orally immediately after molding, 12 h. S3 was administered at doses of 2mg/kg, 8 mg/kg,16mg/kg and 32mg/kg, and S-217622 was administered at doses of 32mg/kg. After 24 h viral infection, mice were sacrificed and observed for pulmonary viral titers.
As shown in fig. 1, compound S3 significantly reduced viral titer in lung homogenates of infected mice relative to the placebo group after two administrations, and was dose dependent. Positive control S-217622 and Compound S3 reached the lowest detection limit at the doses given of 16mg/kg and 32mg/kg.
Finally, it should be noted that the above describes in detail specific embodiments of the invention, but is only exemplary and the invention is not limited to the above described specific embodiments. Any equivalent modifications and substitutions for the present invention will occur to those skilled in the art, and are also within the scope of the present invention. Accordingly, equivalent changes and modifications are intended to be included within the scope of the present invention without departing from the spirit and scope thereof.
Claims (13)
1. The triazine compound with the structure shown in the general formula I or pharmaceutically acceptable salt thereof has the following structure:
wherein R is 1 Is R 1-1 OCH 2 -or
；
R 1-1 Is C 1-6 Alkyl or C 1-6 Alkoxy- (C) 1-6 Alkyl) -;
R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 or R is 8 Independently selected from the group consisting of hydrogen and deuterium,
R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 or R is 8 At least one is selected from deuterium.
2. The triazine compound having a structure represented by the general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1-1 Is C 1-4 Alkyl or C 1-4 Alkoxy- (C) 1-4 Alkyl) -.
3. The triazine compound having a structure represented by the general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1-1 Is methyl, ethyl, propyl, isopropyl, or
。
4. The triazine compound having a structure represented by the general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 3a 、R 3b Or R is 3c At least one is selected from deuterium.
5. The triazine compound having a structure represented by the general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 、R 4 、R 5 、R 6 、R 7 Or R is 8 At least one is selected from deuterium.
6. The triazine compound having a structure shown in the general formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound shown in the general formula I is any one of the following compounds:
7. a process for the preparation of a triazine compound of formula I according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, which comprises the steps of: in a solvent, reacting the compound II with the compound III under the action of alkali to generate a compound I;
wherein R is 1 、R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 And R is 8 Is as defined in claims 1-6;
when R is 1 Is that
Compound III is Boc anhydride;
when R is 1 Is R 1-1 OCH 2 When the compound III is R 1-1 OCH 2 Cl, formaldehyde or paraformaldehyde.
8. A pharmaceutical composition comprising a therapeutically effective amount of one or more triazine compounds having a structure according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.
9. A triazine compound having a structure according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for use in the preparation of a 3C-like cysteine protease inhibitor.
10. A triazine compound having a structure represented by general formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, for use in the preparation of a medicament for the treatment and/or prevention of viral infectious diseases.
11. Use of a pharmaceutical composition according to claim 8 for the preparation of a 3C-like cysteine protease inhibitor.
12. Use of a pharmaceutical composition according to claim 8 for the preparation of a medicament for the treatment and/or prophylaxis of viral infectious diseases.
13. Use according to claim 11 or 12, characterized in that the virus is selected from severe acute respiratory syndrome related coronavirus-2 (SARS-CoV-2), middle eastern respiratory syndrome related coronavirus (MERS-CoV), severe acute respiratory syndrome related coronavirus (SARS-CoV), influenza a virus, influenza b virus, spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, polio virus, rhinovirus, adenovirus, ebola virus, enterovirus, hepatitis a virus, hepatitis c virus, hepatitis e virus, enterovirus, HIV virus, ico virus, filovirus, measles virus, yellow fever virus, japanese encephalitis virus, west nile virus, newcastle disease virus, RS virus, vesicular stomatitis virus, mumps virus, dengue virus, coxsackievirus, rotavirus or tobacco mosaic virus.
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