CN115109042A - 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 a preparation method thereofUse is provided. The compound disclosed as formula I has good inhibitory activity on 3C-like cysteine protease and has good treatment 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, large-scale epidemic of zoonosis virus, which is of the family Coronaviridae with both SARS-CoV-1 and MERS-CoV. These three viruses, unlike several other 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. Furthermore, the virus is not only highly infectious, but can be transmitted by asymptomatic infected persons and those in the symptomatic and presymptomatic stages. Although a number of different vaccines are currently approved or given emergency access worldwide, a significant portion of the population worldwide is not vaccinated due to limitations in their own physical or local medical conditions. In addition, the protective efficacy of the vaccine against the SARS-CoV-2 variant strains is reduced, especially against the recently global strain of Omicron. Thus, the development of new crown drugs effective against the variety is imminent.
Upon entry into the host cell, the coronavirus is broken down to release the nucleocapsid and viral genome. The host cell ribosome translates the Open Reading Frame (ORF) 1a and ORF1b of the viral genome into polyproteins pp1a and pp1b, respectively, for encoding 16 non-structural proteins (nsps), while the remaining ORFs encode structural and accessory proteins. 3C-like cysteine proteases (3 CLpro) and papain (PLpro) catalyze the cleavage of PP to nsp2-16, which in turn forms the replication-transcription complex (RTC). The loss of activity of these proteases leads to the cessation of the viral life cycle. Also, the structure and function of 3CLpro is highly conserved among coronaviruses. 3CLpro catalytic center has extremely low mutation rate and is not easy to generate drug resistance; the 3Clpro inhibitor does not rely on induction of an immune response, but blocks the viral replication protease 3Clpro by binding to the viral backbone, and should be effective against all variants. 3CLpro cleaves only glutamine (Gln) residues, and no known human protease has shown the same cleavage specificity as 3CLpro, so that 3CLpro inhibitors have low potential toxicity. Therefore, 3CLpro is an effective target for developing oral anti-neocoronary drugs.
The 3CLpro inhibitors reported so far include covalent peptidomimetic inhibitors represented by PF-07321332 developed by Peucedanum and non-covalent, non-peptidomimetic small molecule inhibitors represented by S-217622 developed by Shiongai (salt wild-sense) pharmaceutical Co. Currently, the new crown oral drug Paxlovid (the main component is PF-07321332) of pyroxene obtains FDA emergency use authorization and becomes the first approved oral new crown drug in the United states. PF-07321332 is a substrate for CYP3A4, is metabolically unstable and must be co-administered with the CYP3A4 enzyme inhibitor ritonavir. Changes in the activity of the CYP3a4 enzyme affect the metabolism of Paxlovid, thereby affecting the efficacy and safety of Paxlovid. S-217622 is expected to get rid of dependence on P450 enzyme inhibitor (such as ritonavir), realize single drug therapy, expand applicable population range, and avoid pharmacological reaction of other drugs due to P450 enzyme inhibition. Although S-217622 shows great potential for treating new corona, the non-covalent small-molecule inhibitors reported at present are still very deficient, and have the problems of single structure, weak enzyme inhibition activity, poor drug-forming property and the like. Therefore, the search for a novel, efficient and low-toxicity 3CLpro non-covalent small-molecule inhibitor has important significance, provides more drug treatment options which are more suitable for clinical practice for new coronary patients with different symptoms, and provides more powerful guarantee for completely overcoming the new coronary epidemic situation.
Disclosure of Invention
The invention aims to solve the technical problems that the existing broad-spectrum antiviral drugs are single in structure and lack of non-covalent efficient 3CLpro small-molecule inhibitors, and provides a triazine compound, and 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 treatment effect on coronavirus infectious diseases.
The invention solves the technical problems through the following technical scheme.
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, wherein the structure is as follows:
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 radical- (C 1-6 Alkyl) -;
R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 or R 8 Independently selected from the group consisting of hydrogen or deuterium,
at the same time, R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 Or R 8 At least one is chosen from deuterium.
In some embodiments, R 1-1 Is hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy radical- (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 3b At least one is selected from deuterium.
In some embodiments, R 2 、R 4 、R 5 、R 6 、R 7 Or R 8 At least one is chosen from deuterium.
In some embodiments, the compound having the structure shown in formula I is any one of the following compounds:
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 a compound II with a 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 8 As defined above;
when R is 1 Is composed of
The compound II is Boc anhydride;
when R is 1 Is R 1-1 OCH 2 When compound II is R 1-1 OCH 2 Cl, formaldehyde or paraformaldehyde.
The conditions and operation of the above-described reactions 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 salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing a 3C-like cysteine protease inhibitor.
The invention also provides an application of the triazine compound with the structure shown in the general formula I, or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing a medicament for treating and/or preventing virus infectious diseases.
Further, the viruses include, but are not limited to, severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), severe acute respiratory syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza A virus, influenza B virus, Spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, 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 the triazine compound with the structure shown in the general formula I, or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, and a pharmaceutically acceptable carrier or auxiliary material.
In the pharmaceutical composition, the dosage of the triazine compound with the structure shown in the general formula I, or the pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is therapeutically effective amount.
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 a medicament for treating and/or preventing virus infectious diseases.
Further, the viruses include, but are not limited to, severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), middle east respiratory syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza A virus, influenza B virus, Spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, 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 widely used in the field of pharmaceutical production. The excipients are primarily used to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting effective absorption of the active ingredient after administration of the composition by a subject. 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 may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled 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, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (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 preparations which can 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; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the invention contain relatively acidic functional groups, base addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of a base in neat 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 compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting free forms of such compounds with a sufficient amount of an acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogen phosphates, dihydrogen phosphates, sulfuric acid (forming sulfates or bicarbonates), hydroiodic acid, phosphorous acid, and the like, as well as salts of organic acids including similar acids such as 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, and methanesulfonic acid, salts of organic acids also including salts of amino acids such as arginine, and the like, and salts of organic acids such as glucuronic acid, certain specific compounds of the invention contain basic and acidic functional groups and thus can be converted to any base or acid addition salt. The free form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The free form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
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, such salts are prepared by the following method: prepared by reacting 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 the two. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
The term "isomers" refers to compounds having the same chemical formula but different arrangements of atoms.
The term "metabolite" refers to a pharmaceutically active product produced by the in vivo metabolism of a compound of formula I or a salt thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a method comprising contacting a compound of the invention with a mammal for a period of time sufficient to obtain a metabolite thereof.
Identification of metabolites is typically accomplished by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it at a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal, such as a rat, mouse, guinea pig, monkey, or human, 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 labelled (others are isolated by using antibodies capable of binding epitopes present in the metabolite). Metabolite structure is determined in a conventional manner, e.g., by MS, LC/MS or NMR analysis. In general, metabolismThe analysis of the analyte is carried out in the same manner as in conventional drug metabolism studies well known to those skilled in the art. Metabolite products are useful in assays for the administration of therapeutic doses of the compounds of the invention, provided that they are not otherwise detectable in vivo. The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C) and C) 3 H) Iodine-125 ( 125 I) Or C-14 ( 14 C) In that respect 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 also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the present 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 present invention. For example, compounds containing a carboxyl group may form physiologically hydrolyzable esters that act as prodrugs by hydrolyzing in vivo to give the compounds of formula I themselves. The prodrugs are preferably administered orally, since hydrolysis in many cases takes place mainly under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.
It will be understood by those skilled in the art that, in accordance with common practice used in the art, as used in the structural formulae of the radicals described herein "
"means that the corresponding group is linked 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 to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) the triazine compounds have good inhibitory activity on 3C-like cysteine protease.
(2) The triazine compound has good treatment effect on virus infectious diseases.
(3) The triazine compound has small toxic and side effects.
Drawings
FIG. 1 is a graph of the anti-infective activity of the positive control group and Compound S3 in example 25 in a mouse infection model.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
EXAMPLE 1 Synthesis of Compound S1
The method comprises the following steps: synthesis of Compound 2
Compound 1 (18 g, 78.8 mmol) was dissolved in acetonitrile (240 mL), and to the above solution was added compound 5 (26 g, 118.8 mmol) and K 2 CO 3 (16.4 g, 118.8 mol), and the reaction solution was heated under reflux for 3 hours. The reaction was cooled to room temperature, filtered under suction, the filtrate was concentrated, and purified by column chromatography (PE: EA =30: 1) to obtain 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) and the reaction stirred at room temperature for 6 h, stirring was stopped, TFA was evaporated under reduced pressure, ether slurried, suction filtered, the filter cake collected and dried in vacuo to give 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 to the above solution was added compound 6 (12.4 g, 68.4 mmol) and K 2 CO 3 (18.9 g, 136.8 mol), the reaction mixture was heated to 60 ℃ and stirred for 4 hours. The reaction was cooled to room temperature, quenched with water (100 mL), extracted with DCM (100 mL. times.3), the combined organic phases washed with brine (200 mL), anhydrous Na 2 SO 4 Drying, filtration, concentration, and column chromatography purification (DCM: MeOH =80: 1) afforded compound 4 (7.7 g, 40%).
Step four: synthesis of Compound 5
LiHMDS (1M, 1.46 mL, 1.46 mmol) was added dropwise to a solution of compound 4 (300 mg, 0.727 mmol) and compound 7 (172 mg, 0.946 mmol) in tetrahydrofuran at 0 ℃ and stirred for 2h while maintaining 0 ℃ before being transferred to room temperature and stirred for 2 h. After completion of the reaction, the reaction was quenched by addition of saturated ammonium chloride solution (2 ml), extracted with ethyl acetate (2 ml. times.3), and the organic phases were combined, washed with saturated brine, and washed with anhydrous Na 2 SO 4 Drying, filtration, concentration and purification by column chromatography 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 to the above solution at 0 ℃ in this order, followed by heating and refluxingAnd reacting for 3 h. After completion of the reaction, extraction with ethyl acetate (10 mL. times.3) was carried out, and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating, and purifying by column chromatography to obtain 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).
Synthesis of Compounds S2 to S15 in examples 2 to 15 below, the synthesis method of example 1 was referred to, and only the corresponding raw materials were 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 according to the synthetic method of Compound II-1 in example 1. Compound II-1 (97 mg, 0.182 mmol) was dissolved in acetonitrile, and to the above solution were added aqueous formaldehyde (37%, 270. mu.L) and potassium carbonate (75 mg, 0.546 mmol) in this order, and the reaction was carried out at room temperature for 12 hours. After completion of the reaction, ethyl acetate extraction (10 mL. times.3) was carried out, and the organic phases were combined, washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, filtering, concentrating, and purifying by column chromatography to obtain 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).
Synthesis of Compounds S17 to S21 in examples 17 to 21 below, the synthesis method in example 1 was referred to, and only the corresponding raw materials were 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), placed at 0 deg.C, to the above solution was added Boc anhydride (44 mg, 0.2 mmol) and DMAP (24 mg, 0.2 mmol), and then transferred to room temperature for overnight reaction. The next day, saturated sodium bicarbonate solution was added to the reaction, extracted with ethyl acetate (10 mL. times.3), the organic phases were combined, washed with saturated brine, and anhydrous Na 2 SO 4 Drying, filtering, concentrating, and purifying by column chromatography to obtain 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: SARS-CoV-2 virus 3C-like cysteine protease (3 CLpro) enzyme inhibitory Activity test experiment
1.3 CLpro protein expression and purification
The gene sequence of the full-length 3CLpro protein was constructed in the expression vector pET28a (+) vector and transformed into E.coli BL21(DE3) competent cells, and purified using Ni-NTA column after 12 hours of induction at 25 ℃ with a final concentration of 0.5 mM IPTG. And detecting the purified protein by SDS, purifying the part with the purity of more than 90 percent by Superdex 20010/300 GL of AKTA Pure of a GE protein chromatography purification system to obtain the protein with the purity of more than 95 percent, determining the protein concentration by using Nano Drop, subpackaging, quick-freezing by liquid nitrogen, and storing at-80 ℃.
2. Establishment of SARS-CoV-23 CLpro enzyme activity screening system and inhibitor inhibition rate and medicine IC 50 Is calculated by
The activity of SARS-CoV-23 CLpro and the inhibitory activity of the compound to SARS-CoV-23 CLpro are determined by Fluorescence Resonance Energy Transfer (FRET) technique. Fluorescent substrate (Dabcyl-KTSAVLQ ↓. SGFRKM-E (Edans) -NH) with SARS-CoV-23 CLpro cleavage site (indicated by arrow) was used in the assay 2 ) And Tris-HCl buffer (20 mM Tris-HCl, 150mM NaCl, 10 mM EDTA, pH 7.5). Compounds were dissolved by 100% DMSO. Mu.l of the compound was incubated with 40. mu.l of SARS-CoV-23 CLpro (final concentration 0.5. mu.M, diluted in 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 fluorescence signal generated due to 3 CLpro-catalyzed cleavage of the substrate was detected using a radio resonance energy transfer fluorescence spectrophotometer at an excitation wavelength of 340nm and an absorption wavelength of 490 nm. The kinetic constants (Vmax and Km) for SARS-CoV-23 CLpro were obtained by fitting the data to the Michaelis Menten equation, V = Vmax × [ S ]]/(Km + [S]). Then kcat = Vmax/[ E ] according to the formula]Calculating kcat. Compounds were diluted in gradient by fold dilution using Tris-HCl buffer and assayed using the same final concentration of SARS-CoV-23 CLpro and fluorogenic substrate system described above. The values of the intrinsic (V0 i) and apparent (Vappi, kappa) catalytic parameters for the hydrolysis of a polypeptide substrate catalyzed by 3CLpro were determined in the presence and absence, respectively, of the target compound. Apparent inhibition constant (kappa) of binding of target compound to Mpro from Vappi to fixed substrate concentration ([ S ] S)]) Lower inhibitor concentration ([ I ]]) Is/are as followsDependence according to the equation Vappi = Vapp × [ I × []/（Kappi +[I]) And (6) obtaining. The value of the intrinsic inhibition constant (Ki) of binding of a compound of interest to 3CLpro is according to the equation kappa = Ki x (1 + [ S + ])]/Km) was calculated. Inhibition curves for compounds were plotted by GraphPad Prism 8.0 software and IC calculated 50 The value is obtained.
The results are shown in the following table 1, and the compound of the embodiment has better inhibitory activity to SARS-CoV-2 virus 3CLpro, and the activity is better than that of positive control S-217622.
Example 24: cytotoxicity and test of drug effect against SARS-CoV-2 virus infection
Vero E6 cytotoxicity test: the CCK8 method is adopted to detect the cytotoxicity of the test compound on mammalian Vero E6 cells. Vero E6 cells were added to 96-well plates and cultured overnight. The cells were then incubated with different concentrations of test compound for 48 h. The medium in the well plate was removed, replaced with fresh serum-free medium, 10% CCK8 reagent was added, incubated at 37 ℃ for 1h, and absorbance at 450 nm was measured using a microplate reader.
Screening compounds without cytotoxicity or with low cytotoxicity for testing antiviral infection, and the specific operation comprises the following steps:
inoculating cells: taking Vero-E6 cells in logarithmic growth phase, sucking out the culture solution, digesting the cells with pancreatin, and counting the cells as follows: 1 × 106/mL; 4 mL of the above cells were taken, and 6 mL of the culture medium was added to prepare a cell suspension having a cell density of 4X 105 cells/mL, which was then inoculated into a 96-well plate at 100. mu.l per well and at 4X 10 cells per well 4 And (4) respectively. ② pretreating cells with drugs: the cell culture medium was replaced with DMEM medium containing 2% FBS, and 100. mu.l of the drug and DMSO were added at the corresponding concentrations, followed by pretreatment in an incubator at 37 ℃ for 1 hour. ③ infection with viruses: taking 0.3 mL of virus, adding 45 mL of culture medium, uniformly mixing, and diluting the virus to 100TCID 50/0.05 mL; discarding the drug culture medium vertical hanging drop virus diluent in the cell plate to a 96-well plateAdding 50 mul/hole of sample volume, adding corresponding drug culture medium (containing drugs with corresponding concentration) at the same time, adding 50 mul/hole of sample volume, and mixing uniformly; fourthly, incubation: and (3) uniformly mixing the well-added cell culture plate on a shaker, placing the cell culture plate in an incubator at 37 ℃, and incubating for 1 h. After the incubation was completed, the virus-serum mixture inoculated with the cells was aspirated, the drug and control DMSO were added at the corresponding concentrations, the volume of the sample was 100. mu.l/well (100 TCID 50/well), and the mixture was placed at 37 ℃ in CO 2 Culturing for 48 h in an incubator; collecting supernatant to detect virus RNA, fixing and dyeing with 4% paraformaldehyde for immunofluorescence dyeing analysis.
The specific experimental results are shown in Table 2, and the compounds in the examples have low cytotoxicity, good inhibitory activity on SARS-CoV-2 virus infection, better selectivity index than positive control S-217662 and good selectivity index
Example 25: in vivo anti-infective activity test of Compound S3
Female BALB/c mice were anesthetized by intraperitoneal injection of ketamine/xylazine (50 mg/kg/5 mg/kg), followed by SARS-CoV-2. gamma. strain (1X 10) 4 TCID 50 /only) infection model was constructed by intranasal inoculation, and negative control group mice were dropped with the same volume of physiological saline. After the molding is successful, the test pieces are divided into a blank control group, an S-217622 positive control group and an administration group, and each group comprises 6 pieces. The compounds S-217622 and S3 were suspended in 0.5% methylcellulose, respectively, and were administered once orally immediately after molding was successful and once after 12 h. S3 was administered at 2mg/kg, 8 mg/kg, 16mg/kg and 32mg/kg, and S-217622 at 32 mg/kg. 24 h after viral infection, mice were sacrificed and lung viral titers were observed.
As shown in fig. 1, compound S3 significantly reduced viral titers in lung homogenates of infected mice after two administrations, relative to the blank control group, and was dose-dependent. The positive control S-217622 and Compound S3 reached the lowest detectable limit for viral titers at 16mg/kg and 32mg/kg doses.
It should be noted that the above detailed description is only for exemplary purposes, and the present invention is not limited to the above described embodiments. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent alterations and modifications are intended to be included within the scope of the present invention, without departing from the spirit and scope of the invention.
Claims (13)
1. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof 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 radical- (C 1-6 Alkyl) -;
R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 or R 8 Independently selected from the group consisting of hydrogen or deuterium,
at the same time, R 2 、R 3a 、R 3b 、R 3c 、R 4 、R 5 、R 6 、R 7 Or R 8 At least one is selected from deuterium;
the compound of formula I is other than
。
2. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1-1 Is hydrogen, C 1-4 Alkyl or C 1-4 Alkoxy radical- (C 1-4 Alkyl) -.
3. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is 1 Is hydrogen, methyl, ethyl, propyl, isopropyl, or
。
4. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is 3a 、R 3b Or R 3b At least one is chosen from deuterium.
5. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein R is 2 、R 4 、R 5 、R 6 、R 7 Or R 8 At least one is chosen from deuterium.
6. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound shown in the formula I is any one of the following compounds:
7. a process for the preparation of triazines having the structure of formula I according to any one of claims 1 to 6, which comprises the steps of: in a solvent, reacting a compound II with a 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 8 As defined in claims 1-6;
when R is 1 Is composed of
The compound II is Boc anhydride;
when R is 1 Is R 1-1 OCH 2 When compound II is R 1-1 OCH 2 Cl, formaldehyde or paraformaldehyde.
8. A pharmaceutical composition, which comprises a therapeutically effective amount of one or more triazine compounds with a structure shown in a general formula I in any one of claims 1 to 6 or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or adjuvant.
9. Triazine compounds of formula I according to any one of claims 1 to 6, or pharmaceutically acceptable salts thereof, for the preparation of 3C-like cystatins.
10. The triazine compound with the structure shown in the general formula I or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is used for preparing a medicament for treating and/or preventing virus 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 prevention of a viral infectious disease.
13. Use according to claim 10 or 12, wherein the virus is selected from severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), middle east respiratory syndrome-associated coronavirus (MERS-CoV), severe acute respiratory syndrome-associated coronavirus (SARS-CoV), influenza a virus, influenza b virus, spanish influenza virus, arenavirus, bunyavirus, rabies virus, avian influenza virus, poliovirus, 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.
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