WO2023208200A1 - 3cl protease inhibitor - Google Patents

Abstract

The present invention relates to a 3CL^pro inhibitor having a structure represented by the following general formula (I-1) or (I-2), which is used for treating novel coronavirus infection and has better bioavailability.

Description

3CL protease inhibitor Technical field

The invention belongs to the technical field of antiviral drugs, relates to a 3CL protease inhibitor, and specifically relates to a novel 3CL ^pro inhibitor molecular entity with improved drug water solubility.

Background technique

The new coronavirus belongs to the beta coronavirus. It is enveloped and has round or oval particles with a diameter of 60-140nm. It has 5 essential genes, which target nucleoprotein (N), enveloped virus (E), and matrix protein. (M) and the structural protein and RNA-dependent RNA polymerase (RbRp) in spike protein (S)4. The nucleoprotein (N) includes the RNA genome to form the nucleocapsid, which is surrounded by the viral envelope (E). The viral envelope is embedded with proteins such as matrix protein (M) and spike protein (S), and binds to blood vessels through the spike protein. Tensin-converting enzyme 2 (ACE-2) enters cells.

Like other viruses, the genome of the new coronavirus will also undergo mutations. Some mutations will affect the biological characteristics of the virus. For example, changes in the affinity of the S protein and ACE-2 will affect the ability of the virus to invade cells, replicate, and spread. Recovered patients will recover. The production of antibodies after early vaccination and the neutralizing ability of antibody drugs have attracted widespread attention. The amino acid sequence similarity of 3CL protease (3CL ^pro ) of different coronaviruses is very high. The amino acid sequence similarity of 3CL protease between SARS and SARS-COV-2, which are both beta coronaviruses, is higher than 96% (data source: DOI: 10.1002/ med.21783).

Currently, oral anti-COVID-19 drugs that have been launched globally include Eli Lilly’s JAK inhibitor baricitinib, Merck & Co.’s RNA polymerase inhibitor monupivir, and Pfizer’s 3CL ^pro inhibitor nematvir. Among them, Pfizer's nematvir is the most clinically effective oral drug currently on the market and is used to treat mild to moderate COVID-19 patients with high risk factors for progression to severe disease, such as advanced age, chronic kidney disease, and diabetes. , cardiovascular disease, chronic lung disease and other severe high-risk factors. However, the oral bioavailability of nematvir is only 8.5%, and the half-life of intravenous injection is only 0.79 hours. P450 enzymes have a greater impact on its metabolism, so it needs to be combined with nematvir. Used in combination with tonavir.

The only drugs approved for marketing in China are Pfizer's nematvir/ritonavir and Lianhua Qingwen capsules/granules, which are used to treat mild cases.

There are many oral drugs for COVID-19 in the clinical research stage at home and abroad, such as Proxalutamide from Kintor Pharmaceuticals, Azivudine from Real Biotech/Tuoxin Pharmaceuticals, and VV-116 from Junshi Biologics ( JT001). Internationally, there are more products entering Phase 3 clinical trials, the most popular of which is 3CL ^pro inhibitors.

After Pfizer, Shionogi developed Ensitrelvir (S-217622) without ritonavir. Ensitrelvir has submitted a marketing application in Japan and approved phase 3 clinical trials in the United States. Ensitrelvir molecular structure formula is:

Although Ensitrelvir has achieved certain clinical effects, there is still an urgent need to obtain more effective new anti-COVID-19 drugs with superior pharmacokinetics.

Prodrug design is a new compound obtained by molecular modification of an active compound. It can change some characteristics of the parent drug, such as changing the drug metabolism characteristics to extend the half-life, increasing water solubility or fat solubility to facilitate drug production, and making the drug more convenient. Drug accumulation in specific organs and tissues increases drug targeting, reduces drug adverse reactions, etc. However, there is no very clear guidance on how to obtain prodrugs with specific structures and achieve the desired effects. For different types of drugs with different structures, professionals in the field need to constantly try to design from many possible structures. It has been selected from many scientific experiments in China and Canada.

For prodrug technology, published literature such as: Tycho Heimbach et al. Pharmaceutical Research 2003, Volume 20, Issue 6, pages 848-856; Tycho Heimbach et al. International Journal of Pharmaceutics 2003, 261, 81-92; Randomized comparison of etoposide pharmacokinetics after oraletoposide phosphate and oral etoposide. De Jong,R.S.; Mulder,N.H.; et al.J.of Cancer,1997,75(11),1660-1666; Etoposide bioavailability after oral administration of the prodrugetoposide phosphate in cancer patients during a phase I study. Chabot, G.G.; Armand, J.-P.; et al. J. of clinical oncology, 1996, 14(7): 2020-2030.

Contents of the invention

One or more embodiments of the present application provide Ensitrelvir and its phosphate ester prodrugs with similar structures. The inventor found that these prodrugs have significantly better solubility (such as water solubility), bioavailability, and sustained release effects than the parent molecule.

In one or more embodiments, the compounds of the present application have increased solubility.

In one or more embodiments, such prodrugs can provide higher drug exposure (AUC) and maximum blood concentration (Cmax) after administration of the compounds of the present application.

In one or more embodiments, the compounds of the present application maintain high blood concentration values for a longer period of time.

These suggest that this prodrug can provide benefits in the treatment of patients infected with new coronavirus.

In one or more embodiments, after oral administration of the compound of the present application, the amount of the compound of the present application in the form of prodrug entered into the blood is less than one ten thousandth of the amount of the compound of the present application entered into the blood in the form of the parent drug, and the prodrug of the compound of the present application is almost Metabolized to its parent drug form Blood enters after the formula.

One or more embodiments of the present application provide compounds having the following general formula (I-1) or (I-2) structure, or their stereoisomers, solvates, deuterates or pharmaceutically acceptable salts:

Wherein R ₁ is selected from alkyl, carbonyl, and -(CH ₂ ) _n -R ₁ ', wherein R ₁ ' is selected from carbonyl, amido, amidoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, n1 is 0, 1, 2 or 3, and the substitution is selected from lower alkyl, halogen, hydroxyl , and cyano substituent substitution;

Described R ₂ is selected from alkyl and -(CH ₂ ) _n -R ₂ ', wherein R ₂ ' is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl, n is 0, 1, 2 or 3, and the substitution is substituted by a substituent selected from lower alkyl, halogen, hydroxyl, and cyano;

Described R ₃ is selected from alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, the substituted Is substituted by a substituent selected from lower alkyl, halogen, hydroxyl, and cyano;

R ₄ and R ₅ are each independently selected from hydrogen and C1-C6 linear or branched alkyl.

In one or more embodiments, the linear or branched alkyl group is methyl, ethyl, propyl, or isopropyl.

In one or more embodiments, the compounds of the present application have the structure of general formula (II-1) or (II-2):

Wherein R ₁ is selected from -CH ₂ -R ₁ ', R ₁ ' is selected from -C(O)NHCH ₃ and substituted or unsubstituted aryl or heteroaryl, the aryl or heteroaryl is phenyl, Pyrrolyl, thienyl, furyl, pyrazole, thiazolyl, imidazole, triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrazolyl, benzimidazolyl, benzofuranyl , benzothienyl, indolyl, naphthyl, quinolyl, or isoquinolyl, the substitution is by lower alkyl substitution (such as methyl substitution, ethyl substitution), halogenation (such as chlorine substitution, fluorinated) substituent substitution;

R ₂ is selected from -CH ₂ -R ₂ ', where R ₂ ' is selected from substituted or unsubstituted aryl or heteroaryl, the aryl is selected from benzene, the hetero The aryl group is selected from pyrrolyl, thienyl, furyl, pyrazole, thiazolyl, imidazole, triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrazolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, naphthyl, quinolyl, or isoquinolyl; the substitution is halogenated (for example, at least chlorinated or fluorinated), and the substitution is one, Substitution of two or three positions;

R ₃ is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl substituted by a substituent selected from halogen (eg, chlorine or fluorine), and lower alkyl (eg, methyl).

In one or more embodiments, R ₁ ' is amidoalkyl or substituted or unsubstituted heteroaryl.

In one or more embodiments, the alkyl group is methyl.

In one or more embodiments, the heteroaryl group is triazolyl.

In one or more embodiments, the triazolyl group is methyltriazolyl.

In one or more embodiments, R ₁ ' is

In one or more embodiments, _R2 ' is aryl optionally substituted with one or more halogens.

In one or more embodiments, the halogen is F.

In one or more embodiments, the aryl group is phenyl.

In one or more embodiments, R ₂ ' is phenyl substituted with three F's.

In one or more embodiments, the R ₂ ' is

In one or more embodiments, _R3 is heteroaryl optionally substituted with substituents selected from C1-C3 alkyl and halogen.

In one or more embodiments, the C1-C3 alkyl group is methyl.

In one or more embodiments, the halogen is Cl.

In one or more embodiments, the R ₃ is

In one or more embodiments, R ₄ and R ₅ are each independently hydrogen or C1-C3 alkyl.

In one or more embodiments, the C1-C3 alkyl group is isopropyl.

One or more embodiments of the present application provide a compound, or a stereoisomer, solvate, deuterate or pharmaceutically acceptable salt thereof, having the structure described below:

One or more embodiments of the present application provide salts formed by compounds of the present application and alkaline earth metals, alkali metals, lysine, and trishydroxymethylaminomethane.

In one or more embodiments, the alkaline earth metal is beryllium, magnesium, calcium.

In one or more embodiments, the alkali metal is lithium, sodium, potassium.

One or more embodiments of the present application provide a pharmaceutical composition, which contains a compound described in the present application or a stereoisomer, solvate, deuterate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. form agent.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, solvate, deuterate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application for use in the treatment or prevention of coronavirus. Use in medicines for diseases caused by viral infections.

In one or more embodiments, the coronavirus is MERS, SARS or SARS-CoV-2.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, solvate, deuterate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application for use as a medicament or for Treat or prevent disease.

One or more embodiments of the present application provide a compound of the present application or a stereoisomer, solvate, deuterate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present application, which is used to treat or prevent coronavirus. Disease caused by viral infection.

One or more embodiments of the present application provide a method for treating or preventing diseases caused by coronavirus infection, which method includes using a compound of the present application or its stereoisomer, solvate, deuterated product or pharmaceutically acceptable salt , or the pharmaceutical composition of the present application is administered to a subject in need.

In one or more embodiments, the pharmaceutical compositions of the present application may be administered orally, parenterally, or via an implanted depot. Parenteral include subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, and injury area injection or infusion techniques.

In one or more embodiments, the pharmaceutical composition may be in the form of a sterile injectable preparation, for example, a sterile injectable aqueous or oleaginous suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Details regarding the preparation of these compounds are known to those skilled in the art.

In one or more embodiments, when administered orally, the pharmaceutical compositions of the present application may be in any orally acceptable form. Administration in dosage forms including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral administration, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate may also be added. For oral administration in capsule form, useful carriers/diluents include lactose, high and low molecular weight polyethylene glycols, and dry corn starch. When aqueous suspensions are administered orally, the active ingredients are mixed with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

In one or more embodiments, other suitable carriers for the compositions described above can be found in standard pharmaceutical textbooks, for example, "Remington's Pharmaceutical Sciences", 19th ed., Mack Publishing Company, Easton, Penn., 1995 middle. Further details regarding the design and preparation of suitable delivery forms for pharmaceutical compositions will be known to those skilled in the art from this disclosure.

In one or more embodiments, it also relates to the application of the compound of the present application in inhibiting coronavirus (SARS), especially the new coronavirus (SARS-CoV-2), and administering a therapeutically effective amount of the compound of the present application to virus-infected subjects. The compound can effectively inhibit the replication of the virus in the body, reduce the proportion of mild patients in the early stages of new coronavirus infection that turn into severe disease and reduce mortality.

In one or more embodiments, in addition to the compounds described in this application or their pharmaceutically acceptable salts, other antiviral compounds may also be included, such as antiviral drugs for other targets of COVID-19, other coronavirus treatments Drugs, such as JAK inhibitors such as baricitinib, RNA polymerase inhibitors such as monupivir, remdesivir, azivudine, or AR antagonists such as proxalutamide, or others Antiviral agents such as ritonavir can also be cytokine virus inhibitors such as interferons. It can also be used in combination with neuraminidase inhibitors, PB2 inhibitors, PB1 inhibitors, M2 inhibitors or other anti-influenza drugs.

When used to prevent and/or treat novel coronavirus infection, the dosage level of the compound of the present application is generally from about 1 to about 500 milligrams per kilogram (mg/kg) of body weight per day, more specifically, from about 1 to about 50mg/kg body weight daily. Generally, the pharmaceutical composition of the present application can be administered from about once to about 3 times a day, preferably before or after the occurrence of viral infection. Alternatively, it may be administered as a continuous infusion, which may be used as chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to prepare a single dosage form will vary with the host treated and the particular mode of administration.

The present invention also includes methods of treating coronavirus infections such as COVID-19 and methods of inhibiting SARS-CoV-2 using isotopically labeled compounds of the invention that have the same structure as those described in the text, but have a Or atoms are replaced by atoms whose atomic masses or mass numbers are different from those typically found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, phosphorus, fluorine and chlorine, such as ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ O, ¹⁸ respectively. O, ³¹ P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Compounds of the present invention containing the above-mentioned isotopes and/or isotopes of other atoms, their prodrugs, and pharmaceutically acceptable salts of the compounds or the prodrugs are all within the scope of the present invention. Certain isotope-labeled compounds of the present invention, for example, incorporate radioactive isotopes such as Those of ³ H and ¹⁴ C can be used in drug and/or substrate tissue distribution assays, with tritiated (i.e. ³ H) and carbon-14 (i.e. ¹⁴ C) isotopes being particularly preferred because of their ease of preparation and detection. Additionally, substitution with more neutral isotopes (e.g., deuterium, and ^2H ) may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. Isotopically labeled compounds and their prodrugs used in the methods of the present invention can generally be prepared by performing procedures disclosed in the art for the preparation of compounds using readily available isotopically labeled reagents in place of non-isotopically labeled reagents.

One or more embodiments of the present application also relate to an article of manufacture or a kit, comprising a container and a package insert, wherein the container contains a compound of the present invention or a pharmaceutically acceptable salt thereof, or contains a compound of the present invention or a pharmaceutically acceptable salt thereof. The compound or its optional salt composition, the package insert contains instructions for the use of the drug.

In a preferred embodiment, the article of manufacture or kit further comprises one or more containers containing one or more other antiviral drugs for preventing or treating coronavirus infection. In a preferred embodiment, the other drug is a JAK inhibitor, such as baricitinib, or an RNA polymerase inhibitor, such as monupivir, remdesivir, azivudine, or AR antagonists, such as proxalutamide, or other antiviral agents, such as ritonavir, or cytokine virus inhibitors, such as interferon, etc. It can also be used in combination with neuraminidase inhibitors, PB2 inhibitors, PB1 inhibitors, M2 inhibitors or other anti-influenza drugs.

definition

The term "alkyl" refers to a linear or linear alkyl group having 1 to 6 carbons (C1-C6), such as 1, 2, 3, 4, 5 or 6 carbons, such as methane base, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., sharing pairs of adjacent carbon atoms) groups having 5 to 14 carbons (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 carbons). Non-limiting examples of aryl groups are phenyl, naphthyl and anthracenyl. Aryl groups may be substituted or unsubstituted, and when substituted, the substituents may be selected from one or more of the following groups: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl , Alkoxy group, aryloxy group, mercapto group, arylthio group, cyano group, halogen, nitro group, carbonyl group, O-carbamoyl group, N-carbamoyl group, C-amide group, N-amide group, C-carboxyl group , O-carboxy, thionyl, sulfonyl, sulfinyl, trihalomethyl, ureido, amino or -NR ^x R ^y , where R ^x and R ^y are independently selected from hydrogen, alkyl, cycloalkyl, Aryl, carbonyl, sulfonyl, trihalomethyl.

"Heteroaryl" refers to a monocyclic or fused ring having one or more (eg 1, 2, 3 or 4) atoms in the ring selected from nitrogen, oxygen and sulfur and having a fully conjugated electron system (i.e., share pairs of adjacent atoms) groups with 5 to 14 carbons (eg, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 carbons). Unless otherwise indicated, the heteroaryl group can be attached at a carbon or nitrogen atom within the heteroaryl group. It should be noted that the term "heteroaryl" includes N-oxides of the parent heteroaryl group, provided that they are as known in the art. Thus, this N-oxide is chemically feasible. Non-limiting examples of heteroaryl groups are furyl, thienyl, benzothienyl, thiazolyl, imidazolyl, oxazolyl, thiadiazolyl, benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl Azolyl, isothiazolyl, pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl, quinolyl, isoquinolyl, purinyl, benzimidazolyl, indolyl , isoindolyl, pyrazinyl, diazinyl, etc. When substituted, preferably the substituted group is one or more groups selected from the group consisting of: alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy group, mercapto group, arylthio group, cyano group, halogen, nitro group, carbonyl group, O-carbamoyl group, N-carbamoyl group, C-amide group, N-amide group, C-carboxyl group, O-carboxyl group, sulfite Acyl, sulfonyl, sulfinyl, trihalomethyl ^, ureido, amino or ^-NRxRy , where ^Rx and ^Ry are as defined above.

"Alkyl" refers to saturated aliphatic hydrocarbons including straight and branched chain groups. Preferred alkyl groups have 1 to 20 carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms), more preferably a medium-sized alkyl group with 1 to 10 carbon atoms, and most preferably a lower alkyl group with 1 to 4 (C1-C4) carbon atoms. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more groups selected from the following: trihaloalkyl, cycloalkyl, heteroaryl, hydroxyl, alkoxy, aryloxy group, heteroaryloxy group, mercapto group, alkylthio group, arylthio group, heteroarylthio group, cyano group, halogen, nitro, carbonyl group, thiocarbonyl group, O-carbamoyl group, N-carbamoyl group, C- Amide, N-amide, C-carboxy, O-carboxy, sulfinyl, sulfonyl, sulfinyl, trihalomethylsulfenamido, trihalomethanesulfonyl.

"Cycloalkyl" refers to an all-carbon monocyclic or fused ring (i.e., rings sharing pairs of adjacent carbon atoms) groups in which one or more rings do not have a fully conjugated pi electron system, with 1-20 Carbon atoms (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbons). Non-limiting examples of cycloalkyl groups appear to be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexadiene, cycloheptyl, cycloheptyl triseries and adamantane. The cycloalkyl group may be substituted or unsubstituted. When substituted, it is preferred that the substituted group is one or more groups selected from the following: alkyl, cycloalkyl, aryl, heteroaryl, heteroaliphatic Ring group, hydroxyl group, alkoxy group, aryloxy group, mercapto group, arylthio group, cyano group, halogen, nitro group, carbonyl group, O-carbamoyl group, N-carbamoyl group, C-amide group, N-amide group , C-carboxy, O-carboxy, thionyl, sulfonyl, sulfinyl, trihalomethyl, ureido, amino or -NR ^x R ^y , where R ^x and R ^y are as defined above.

"Alkoxy" refers to -O-alkyl and -O-cycloalkyl, where alkyl and cycloalkyl are as defined herein.

"Hydroxy" refers to the -OH group.

"Aryloxy" refers to -O-aryl and -O-heteroaryl, where aryl and heteroaryl are as defined herein.

"Heteroaryloxy" refers to a heteroaryl-O- group, where heteroaryl is as defined herein.

"Sulfhydryl" refers to the -SH group.

"Carbonyl" refers to the group -C(=O)-R", where R" is selected from hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, and the like.

"Trihalomethyl" refers to the CZ ₃ group, where Z refers to halogen.

As used herein and in the claims, the term "pharmaceutically acceptable salts" is intended to include nontoxic base addition salts and also includes acidic base addition salts. Salts, such as carboxylates or phosphates or phosphate monoesters containing such counterions such as ammonium; alkali metal salts, especially sodium or potassium salts; alkaline earth metal salts, especially calcium or magnesium salts; transition metal salts, such as zinc Salts and salts containing suitable organic bases, such as lower alkylamines (methylamine, ethylamine, cyclohexylamine, etc.) or substituted lower alkylamines (such as hydroxyl-substituted alkylamines, such as diethanolamine, triethanolamine or monoaminobutylamine) Salts or bases of triols, lysine, arginine, histidine, N-methylglucamine, such as piperidine or morpholine. It will be understood that when isolated into solid or crystalline forms Pharmaceutically acceptable salts also include hydrates or water molecules trapped in the substance forming the compound.

The term "isomer" used herein and in the claims is well known in the art and refers to isomers resulting from different spatial arrangements of atoms in the molecule, such as cis-trans isomers. Conformers, enantiomers, diastereomers or positional isomers. Herein, typical isomers are positional isomers resulting from the "N-C=N" fragment formed with exocyclic N on the triazine ring.

In the present invention, the term "effective amount" refers to the amount of active ingredient required to cure or control the disease to a certain extent in the treatment of novel coronavirus.

The term "solvate" as used herein refers to an aggregate comprising one or more molecules of a compound of the present application and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Accordingly, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., as well as corresponding solvated forms. The compounds of the invention may be true solvates, however in other cases the compounds of the invention may remain only external water or a mixture of water plus some external solvent.

The term "deuterate" as used herein refers to a compound in which one or more hydrogen atoms in the compound of the present application are replaced by a deuterium atom. The use of deuterium substitution may yield some therapeutic advantages stemming from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

Description of drawings

The drawings described here are used to provide a further understanding of the present invention and constitute a part of the present invention. The illustrative embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the attached picture:

Figure 1 Ensitrelvir average plasma concentration and time curve (G1-G6);

Figure 2 Ensitrelvir average plasma concentration and time curve (G7-G12);

Figure 3 Ensitrelvir average plasma concentration and time curve (G13-G18);

Figure 4 Correlation between dose and AUC after a single dose of rat PK;

Figure 5 Correlation between dose and Cmax after a single administration of rat PK;

Figure 6 Ensitrelvir average plasma concentration and time curve (G1-G6);

Figure 7 Ensitrelvir average plasma concentration and time curve (G7-G12);

Figure 8 Ensitrelvir average plasma concentration and time curve (G13-G18);

Figure 9 Ensitrelvir average plasma concentration and time curve (G19-G24);

Figure 10 Compound 1 average plasma concentration and time curve (G19-G24);

Figure 11 Correlation between dosage and AUC of Ensitrelvir and Compound 1;

Figure 12 Correlation between doses of Ensitrelvir and Compound 1 and Tmax.

Detailed ways

Example 1 Synthesis of Compound 1

Main synthesis circuit

Step 1: 3-tert-butyl-6-(ethylthio)-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-di Synthesis of ketones

(1) Combine 3-tert-butyl-6-(ethylthio)-1H-1,3,5-triazine-2,4-dione (150g, 654.165mmol, 1 equivalent) and 1-(bromomethyl (161.91g, 719.582mmol, 1.1 equivalent)-2,4,5-trifluorobenzene (161.91g, 719.582mmol, 1.1 equivalent) was dissolved in ACN (1.5L);

(2) Add K ₂ CO ₃ (117.53g, 850.414mmol, 1.3 equivalent) to the mixture;

(3) Stir the reaction mixture at 75°C for 1 hour;

(4) After the reaction is completed, cool the mixture to room temperature;

(5) The resulting mixture was diluted with EtOAc (9 times volume);

(6) Filter the precipitate and concentrate the filtrate under reduced pressure;

(7) The residue was purified with n-heptane (10 times the volume) slurry;

(8) Obtain the product 3-tert-butyl-6-(ethylthio)-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4 -Diketone (185g, 75.72%) is white mud, LC-MS: (ES, m/z): 374[M+H] ⁺ .

Step 2: Synthesis of 6-(ethylthio)-1-[(2,4,5-trifluorophenyl)methyl]-3H-1,3,5-triazine-2,4-dione

(1) 3-tert-butyl-6-(ethylthio)-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4- The diketone (180 g, 482.070 mmol, 1 equiv) was dissolved in DCM (360 mL);

(2) Add TFA (540 mL, 7270.060 mmol, 15.08 equivalents) to the mixture;

(3) Stir the resulting mixture at room temperature for 6 hours;

(4) After completion, the mixture is concentrated under reduced pressure;

(5) The residue was diluted with n-heptane (5 times the volume) and purified;

(6) Obtain crude product 6-(ethylthio)-1-[(2,4,5-trifluorophenyl)methyl]-3H-1,3,5-triazine-2,4-di Ketone (184g), It is a white solid, LC-MS: (ES, m/z): 318[M+H] ⁺ .

Step 3: 6-(ethylthio)-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorobenzene Synthesis of methyl)-1,3,5-triazine-2,4-dione

(1) 6-(ethylthio)-1-[(2,4,5-trifluorophenyl)methyl]-3H-1,3,5-triazine-2,4-dione (100g, 315.17mmol, 1 equivalent) dissolved in DMF (1L);

(2) Add K ₃ PO ₄ (200.70g, 945.51mmol, 3 equivalents) and 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (62.20 g, 472.75mmol, 1.5 equivalent);

(3) Stir the reaction mixture at 60°C for 16 hours;

(4) Cool the mixture to room temperature;

(5) Filter the mixture through a pad of diatomaceous earth;

(6) Drop the filtrate into water (1L) at 0-10°C;

(7) Collect the precipitated solid by filtration and wash with H ₂ O (2×150 mL);

(8) The filter cake is dried to obtain the desired product 6-(ethylthio)-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2, 4,5-Trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (60g, the yield of steps 2&3 is 55.0%), as an off-white solid, LC-MS: ( ES,m/z):413[M+H] ⁺ .

Step 4: 6-[(6-chloro-2-methylindazol-5-yl)imino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl Synthesis of ]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione

(1) 6-(ethylthio)-3-[(1-methyl-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluoro Phenyl)methyl]-1,3,5-triazine-2,4-dione (30g, 72.747mmol, 1.0 equivalent) and 6-chloro-2-methylindazole-5-amine (19.82g, 109.120 mmol, 1.5 equiv) dissolved in HOAc (60 mL, 2 times the volume) and t-BuOH (360 mL, 12 times the volume);

(2) Stir the mixture at 90°C under nitrogen for 16 hours;

(3) Cool the mixture to room temperature;

(4) Collect the precipitated solid by filtration and wash with MTBE (2×30mL);

(5) Produce about 19g of crude product with a purity of about 89%;

(6) The crude product is diluted and purified with MTBE (5 times the volume);

(7) Dry to obtain 6-[(6-chloro-2-methylindazol-5-yl)imino]-3-[(1-methyl-1,2,4-triazol-3-yl) Methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (18g, 46.56%), as a brown solid, LC -MS:(ES,m/z):532[M+H] ⁺ .

Step 5: Di-tert-butyl{2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2,4-triazole-3 -methyl]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazin-1-yl}phosphate methyl ester

(1) 6-[(6-chloro-2-methylindazol-5-yl)imino]-3-[(1-methyl-1,2,4-triazol-3-yl)methyl base]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione (75g, 141.009mmol, 1 equivalent) dissolved in ACN (750mL, 5 times volume);

(2) Add K ₂ CO ₃ (23.39g, 169.211mmol, 1.2 equivalent), TBAI (31.25g, 84.605mmol, 0.6 equivalent) and H ₂ O (3.76g, 208.693mmol, 1.48) to the solution at room temperature and nitrogen. equivalent);

(3) At 45°C, a solution of di-tert-butyl chloromethyl phosphate (91.19g, 352.522mmol, 2.5 equivalents) in ACN (5 times the volume) was slowly added dropwise to the mixture (20 minutes);

(4) Stir the mixture under nitrogen at 45°C for 36 hours;

(5) Filter the resulting mixture and wash with ACN (1 volume × 2);

(6) Concentrate the filtrate under reduced pressure to obtain 180g of crude product as a reddish-brown oil;

(7) Purification by reversed-phase flash chromatography under the following conditions: C18 silica gel; mobile phase, acetonitrile/H ₂ O, gradient from 45% to 70% in 40 minutes; detection, UV 210nm;

(8) Obtain di-tert-butyl{2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2,4-triazole- 3-yl)methyl]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazin-1-yl}methyl phosphate Ester (26g, 24.45%), as yellow solid, LC-MS: (ES, m/z): 754[M+H] ⁺ .

Step 6: {2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2,4-triazol-3-yl)methyl base]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazin-1-yl}methoxyphosphonic acid (compound 1) synthesis

(1) Di-tert-butyl{2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2,4-triazole- 3-yl)methyl]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazin-1-yl}methyl phosphate Ester (23 g, 30.5 mmol, 1 equiv) was dissolved in HOAc (92 mL) and H ₂ O (46 mL)

(2) The mixture was stirred at 35°C for 16 hours.

(3) Allow the mixture to cool to room temperature.

(4) Add H2O (5 times the volume) to the mixture to precipitate the product.

(5) Collect the precipitated solid by filtration and wash with H2O (2×2 volumes).

(6) Dry to obtain the product {2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2,4-triazole-3- methyl)methyl]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazin-1-yl}methoxyphosphine Acid (11g, 56.97%), as a white solid.

The final product obtained: LC-MS: (ES, m/z): 642[M+H] ⁺

¹ H-NMR: (300MHz, DMSO-d6, ppm) δ8.42 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.48 (ddd, J＝11.2, 8.8, 7.0Hz, 1H),7.27(td,J＝10.3,6.6Hz,1H),7.04(s,1H),5.47(d,J＝8.3Hz,2H),5.01(d,J＝17.3Hz,4H),4.11( s,3H),3.83(s,3H).

Example 2 Synthetic route of intermediate 6-chloro-2-methylindazole-5-amine

Step 1: Synthesis of 6-chloro-5-nitro-2H-indazole

(1) Dissolve 6-chloro-2H-indazole (50g, 327.697mmol, 1 equivalent) in sulfuric acid (300mL);

(2) Add potassium oxynitrite (33.13g, 327.697mmol, 1 equivalent) to the mixture in batches at 0-5°C;

(3) Stir the mixture at room temperature for 5 hours;

(4) Carefully quench the mixture with water (500 mL) at 0-10°C;

(5) Alkalization of mixture NaHCO ₃ ;

(6) The mixture is extracted with EA (200mL x 3);

(7) Combine the above organic phases, dry over Na ₂ SO ₄ , and then concentrate under vacuum;

(8) The product 6-chloro-5-nitro-2H-indazole (45g, 69.50%) was a yellow solid, LC-MS: (ES, m/z): 198 [M+H] ⁺ .

Step 2: Synthesis of 6-chloro-2-methyl-5-nitroindazole

(1) Dissolve 6-chloro-5-nitro-2H-indazole (71g, 359.348mmol, 1 equivalent) in tetrahydrofuran (710ml, 10 times the volume);

(2) Add sodium hydride (28.75g, 718.696mmol, 2 equivalents, 60%) to the mixture in batches at 0-5°C;

(3) Stir the mixture at 0-10°C for 30 minutes;

(4) Add methyl iodide (127.51g, 898.370mmol, 2.5 equivalents) to the mixture at 0-10°C;

(5) Stir the mixture at room temperature for 3 hours;

(6) Quench the mixture with water (500 mL);

(7) The mixture was extracted with EA (3×300mL);

(8) Combine the above organic phases, dry with Na ₂ SO ₄ , and then concentrate in vacuo;

(9) The residue is purified using a silica gel column;

(10) The product 6-chloro-2-methyl-5-nitroindazole (30g, 39.45%) is a light yellow solid, LC-MS: (ES, m/z): 212[M+H] ⁺ .

Step 3: Synthesis of 6-chloro-2-methylindazole-5-amine

(1) Add Fe (71.25g, 1275.930mmol, 9 equivalents) and NH4Cl (68.25g, 1275.930mmol, 9 equivalents) to a mixture of EtOH (300mL) and H2O (300mL);

(2) Heat the mixture to 80°C;

(3) Add 6-chloro-2-methyl-5-nitroindazole (30g, 141.770mmol, 1 equivalent) to the mixture in batches;

(4) Stir the mixture at 80°C for 2 hours;

(5) Cool the mixture to room temperature;

(6) Filter the mixture and wash with EtOH (300 mL) and EA (300 mL);

(7) Extract the filtrate with EA (300mL x 3);

(8) Combine the above organic phases, dry with Na ₂ SO ₄ and concentrate in vacuo;

(9) The residue is purified with a silica gel column;

(10) The product 6-chloro-2-methylindazol-5-amine (20g, 77.67%) was a brown solid, LC-MS: (ES, m/z): 181 [M+H] ⁺ .

Example 3 Salt form screening of compound 1

We conducted a series of explorations on the salt form of compound 1, and conducted a preliminary evaluation of the stability of the salt form of compound 1 under different solvents, temperatures and time conditions. Among them, 4-6 are the non-salt form of compound 1. Experimental results show that the Tris salt of compound 1 has the best stability at room temperature (as shown in Table 1), and the stability of other salts also basically meets the requirements.

Table 1 Compound 1 salt form stability

Synthetic route of Tris salt of compound 1 in Example 4

(1) 2-amino-2-(hydroxymethyl)propane-1,3-diol (0.756g, 1.0 equivalent) was dissolved in H ₂ O (40 mL) at room temperature and nitrogen atmosphere;

(2) Add {2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2, 4-Triazol-3-yl)methyl]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-1- Methoxyphosphonic acid (4.0g, 1.0 equivalent);

(3) Stir the mixture for 30 minutes;

(4) Add acetonitrile (40 mL) and acetone (12 mL) to the mixture at room temperature;

(5) Stir the resulting mixture in nitrogen at room temperature for 1 hour;

(6) Dilute the resulting mixture with water (72 mL);

(7) Stir the mixture for 10 minutes and then freeze-dry;

(8) Obtain the product [(2Z)-2-[(6-chloro-2-methylindazol-5-yl)imino]-5-[(1-methyl-1,2,4-triazole) -3-yl)methyl]-4,6-dioxo-3-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazin-1-yl]methyl Oxyphosphonic acid; tris buffer (4.6g, 95.49%), as a white solid.

The final product obtained: LC-MS: (ES, m/z): 642[M+H] ⁺ /640[MH] ^-

¹ H-NMR: (400MHz, DMSO d6, ppm) δ8.41(s,1H),8.17(s,1H),7.64(s,1H),7.53(ddd,J＝11.2,8.9,7.1Hz,1H ),7.37(td,J＝10.2,6.6Hz,1H),7.16(s,1H),5.05(d,J＝15.1Hz,6H),4.10(s,3H),3.83(s,3H),3.43 (s,6H).

Example 5 Ensitrelvir, Compound 1, and Tris salt solubility determination of Compound 1

(a) Kinetic solubility:

(1) Weigh the test compound to measure solubility (approximately 1.0 mg each in three separate 1.5 mL glass vials);

(2) One vial is used as a standard, and the other two are used to measure solubility, in duplicate;

(3) Using a pipette, add the appropriate volume (~1000 μL) of PBS pH 2.0, pH 6.5, or pH 7.4 to each vial of the solubility sample plate. Add a stir rod to each vial and seal the vial with a molded PTFE/silicone stopper;

(4) Transfer the solubility sample plate to a shaker and shake at 1100RPM at 25°C for 24 hours;

(5) After 24 hours is completed, use a large magnet to remove the stir bar and use a pipette to transfer the sample from the solubility sample plate to the filter plate. Filter all compounds using a vacuum manifold. The filtrate was diluted 1000 times with a mixture of H ₂ O and acetonitrile (1:1 v/v). The dilution factor changes based on the solubility value and LC-MS signal response;

(6) Place the solubility sample plate and standard plate in a well plate autosampler at 4°C and evaluate by LC-MS/MS analysis.

(b) Thermodynamic solubility:

(1) Stock solutions of test compounds and control compounds were prepared in DMSO at a concentration of 10mM;

(2) 30 μL of stock solution (10 mM) of each sample is placed sequentially into its appropriate 96-well rack. Add 970 μL of PBS pH 2.0, pH 6.5, or pH 7.4 to each vial of the solubility sample plate. The assay was performed in duplicate. Add a stir rod to each vial and seal with a molded PTFE/silicone stopper. The solubility sample plate was then transferred to a shaker and shaken at 1100 RPM for 2 hours at 25°C. Once the 2 hours are complete, remove the stopper and use a large magnet to remove the stir bar and transfer the sample from the solubility sample plate to the filter plate. Filter all samples using a vacuum manifold. Take a 5 μL aliquot from the filtrate and add 5 μL DMSO and 490 μL H ₂ O and acetonitrile mixture (1:1 v/v). The dilution factor changes based on the solubility value and LC-MS signal response;

(3) Place the plate into a well plate autosampler and evaluate the sample by LC-MS/MS analysis.

Table 2 Determination of solubility of compound 1 and compound 1 Tris salt

(c) Experimental results and conclusions:

As shown in Table 2, under different pH conditions, Compound 1 and the Tris salt of Compound 1 were more soluble than Ensitrelvir. The solubility has been greatly improved, especially the kinetic solubility value of the Tris salt of compound 1 at pH 6.5 and 7.4 has exceeded the detection limit.

Example 6 Pharmacokinetic Test

(a) Drugs and reagents: Prepare the compounds to be tested into solutions using the following solvents (the preparation process of the drug solution is: weigh an appropriate amount of Ensitrelvir, Compound 1 and the Tris salt of Compound 1 at room temperature, and add it to a container of appropriate size. , add an appropriate volume of solvent. If necessary, vortex or ultrasonicize to obtain a suspension of target concentration), see Table 3.

Table 3 Preparation of solutions of compounds to be tested

(b) Test animals: male SPF grade SD rats (3 rats in each group). The rats were purchased from Spefford (Beijing) Biotechnology Co., Ltd.

(c) Dosage and animal grouping: The compound solution to be tested was administered to rats by gavage. All animals had a normal diet before and after administration. The dosage of each group of animals is shown in Table 4.

Table 4 Grouping and Dosage

(d) Pharmacokinetic test:

Blood samples of animals in each group were collected through the jugular vein. About 0.20mL of whole blood was collected from each animal at each time point. EDTA-K2 anticoagulation was used. The blood collection time points were as follows: 0.083h, 0.25h, 0.5h, 1h, 2h, after administration. At 4h, 6h, 8h, and 24h, after blood collection, invert the blood collection tube containing anticoagulant several times to mix thoroughly. After blood samples are collected, place them in a cryogenic storage box. After all samples are collected at that time point, the plasma will be separated by centrifugation (centrifugation conditions: 4000 rpm, 5 minutes, 4°C). The collected plasma was stored at -75 ± 15°C until analysis. All plasma samples were analyzed by LC-MS/MS. The standard curve was used to determine the concentration of the drug to be tested in the sample. The software WinNonlin5.2 (PhoenixTM) was used to calculate the pharmacokinetic parameters of the plasma measurement results and calculate the compounds to be tested respectively. The blood drug concentration (Cmax), peak time (Tmax), area under the curve (AUC) (AUC _last : represents the blood drug concentration from the beginning of the administration time to the last point; AUC _inf : from the beginning of administration Plasma drug concentration), half-life (t _1/2 ) and mean residence time (MRT) at the time to theoretical extrapolation to infinity. The time-varying curves of Ensitrelvir plasma concentration in each group are shown in Figures 1 to 3; the correlation between dosage and AUC and Cmax is shown in Figures 4 to 5; the specific experimental data are shown in Table 5.

Table 5 Compound 1, Compound 1 Tris salt pharmacokinetics

"—" means that the value has not been measured

(e) Analysis of pharmacokinetic experimental results

The above data show that at each dose, the AUC and Cmax values of Compound 1 are significantly improved compared with Ensitrelvir. The AUC value can be increased by about 30 times at most, and the Cmax value can be increased by about 65 times at most. Compared with Ensitrelvir, the Tris salt of Compound 1 also has significantly improved AUC and Cmax values at each dose. At high doses, the AUC and Cmax values can be increased up to 30-40 times (see Figures 4 and 5). Experimental results show that compound 1 and compound 1 Tris salt are both Revealed unexpected levels of drug exposure.

Example 7 Rat PK BE comparative experiment

(a) Drugs and reagents: Prepare the compounds to be tested into solutions using the following solvents:

Table 6 Preparation of solutions of compounds to be tested

(b) Test animals: male SPF level SD rats (3 rats in each group), purchased from Spefford (Beijing) Biotechnology Co., Ltd., and fed normally.

(c) Animal grouping and administration: Dissolve the compound to be tested in the solvent, and administer different doses of the drug to the rats by gavage (see Table 7 for details). The rats in each group eat a normal diet.

Table 7 Grouping and Dosage

(d) Pharmacokinetic test: Blood samples from each experimental group were collected from the jugular vein. About 0.20mL of whole blood was collected from each animal at each time point. EDTA-K2 anticoagulant was used. The blood collection time points were as follows: 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, 336, 360, 384, 408, 432, 456, 480, 504, 528, 552, 576, 600, 624, 648, 672, 696, 720h. After blood samples are collected, they are placed in a low-temperature storage box. After all samples are collected within this time, the plasma is separated by centrifugation (centrifugation conditions: 4000 rpm, 5 minutes, 4°C). The collected plasma was frozen at -75 ± 15°C before analysis. Plasma samples were analyzed by LC-MS/MS, and the concentration of the drug to be tested in the sample was determined by the standard curve method. For the plasma measurement results, the pharmacokinetic calculation software WinNonlin (PhoenixTM) was used to calculate the plasma concentration of the compound to be tested ( Cmax), time to peak (Tmax), area under the curve (AUC), half-life (t _1/2 ) and mean residence time (MRT). The blood concentration versus time curves of Ensitrelvir in each group are shown in Figures 6 to 9, and the average plasma concentration versus time curve of Compound 1 is shown in Figure 10. After a single dose of rat PK, the correlation between the dose and AUC and Tmax is shown in Figures 11 and 12. The specific experimental data are shown in Table 8.

Table 8 Pharmacokinetics

Table 9: Pharmacokinetic parameters of compound 1 in blood given the Tris salt of compound 1

(e) Analysis of pharmacokinetic experimental results

Experimental results show that compared to fumaric acid-Ensitrelvir, the Tris salt form of Compound 1 has an AUC that is approximately 2 times higher and a Tmax that is approximately 3 times that of Ensitrelvir (see Figures 11 and 12). The plasma concentration of Compound 1 (prodrug) in the Tris salt of Compound 1 was measured. The results showed (Table 9) that the exposure (AUC) of Compound 1 (prodrug) was approximately one ten thousandth of the drug exposure of Ensitrelvir (parent drug). 1. It is suggested that Compound 1 (prodrug) can hardly be absorbed through the digestive tract, and most of it is metabolized into Ensitrelvir (parent drug) in the body, and Ensitrelvir is directly absorbed into the blood.

A further analysis of the rat PK data showed:

At low doses (Compound 1 Tris salt 35.9 mg/kg and fumarate-Ensitrelvir 30.5 mg/kg, equivalent to Ensitrelvir 25 mg/kg), Compound 1 Tris salt form compared with fumarate-Ensitrelvir at 24 hours, The respective plasma drug concentrations were 854±286ng/mL and 1142±648ng/mL, respectively, with similar blood drug concentrations.

At the same time, at high doses (Table 10, Compound 1 Tris salt 287 mg/kg, fumaric acid-Ensitrelvir 244 mg/kg, Ensitrelvir 200 mg/kg), the blood drug concentrations at each time point (the measured blood drug concentrations are all Ensitrelvir blood The drug concentration) is significantly higher than the blood drug concentration of fumaric acid-Ensitrelvir or Ensitrelvir. The blood drug concentration of Compound 1 Tris salt at 120 hours still has the same blood drug concentration as fumaric acid-Ensitrelvir or Ensitrelvir at 48 hours. concentration, indicating that the release rate of the Tris salt of Compound 1 is significantly delayed; at the same medium dose (equivalent to the 100mg/kg dosage group of the parent drug), a similar high-dose delayed release effect was also observed, and the Tris salt of Compound 1 The plasma concentration at 96 hours (2267±2325ng/mL) was comparable to the plasma concentration of fumarate-Ensitrelvir at 48 hours (1754±1458ng/mL). From Example 6, we know that Compound 1 and the Tris salt of Compound 1 have similar pharmacokinetic characteristics in the body, so Compound 1 also has a delayed release rate effect similar to that of the Tris salt of Compound 1; and, high Comparing doses of the Tris salt of Compound 1 with a 30.5 mg/kg dose of fumarate-Ensitrelvir, plasma exposure at 120 hours was similar to 24-hour plasma concentrations of fumarate-Ensitrelvir.

Table 10 Parent drug plasma concentration values at various time points after administration of different compounds

BLOQ: Indicates that the concentration is lower than the lower detection limit and the data is not detected.

Claims (10)

Compounds with the following general formula (I-1) or (I-2) structure, or their stereoisomers, solvates, deuterated products or pharmaceutically acceptable salts:
Wherein R ₁ is selected from alkyl, carbonyl, and -(CH ₂ ) _n -R ₁ ', wherein R ₁ ' is selected from carbonyl, amido, amidoalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Substituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, n1 is 0, 1, 2 or 3, and the substitution is selected from lower alkyl, halogen, hydroxyl , and cyano substituent substitution; Described R ₂ is selected from alkyl and -(CH ₂ ) _n -R ₂ ', wherein R ₂ ' is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Aryl, and substituted or unsubstituted heteroaryl, n is 0, 1, 2 or 3, and the substitution is substituted by a substituent selected from lower alkyl, halogen, hydroxyl, and cyano; Described R ₃ is selected from alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, the substituted Is substituted by a substituent selected from lower alkyl, halogen, hydroxyl, and cyano; R ₄ and R ₅ are each independently selected from hydrogen and C1-C6 linear or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl. The compound according to claim 1, or its stereoisomer, solvate, deuterate or pharmaceutically acceptable salt, wherein the compound has the structure of general formula (II-1) or (II-2):
Wherein R ₁ is selected from -CH ₂ -R ₁ ', R ₁ ' is selected from -C(O)NHCH ₃ and substituted or unsubstituted aryl or heteroaryl, the aryl or heteroaryl is phenyl, Pyrrolyl, thienyl, furyl, pyrazole, thiazolyl, imidazole, triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrazolyl, benzimidazolyl, benzofuranyl , benzothienyl, indolyl, naphthyl, quinolyl, or isoquinolyl, the substitution is by lower alkyl substitution (such as methyl substitution, ethyl substitution), halogenation (such as chlorine, Fluorinated) substituent substitution; R ₂ is selected from -CH ₂ -R ₂ ', where R ₂ ' is selected from substituted or unsubstituted aryl or heteroaryl, the aryl is selected from benzene, the hetero The aryl group is selected from pyrrolyl, thienyl, furyl, pyrazole, thiazolyl, imidazole, triazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzopyrazolyl, benzimidazolyl, benzofuryl, benzothienyl, indolyl, naphthyl, quinolyl, or isoquinolyl; the substitution is halogenated (such as at least chlorinated or fluorinated), and the substitution is one, Substitution of two or three positions; R ₃ is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, which is substituted by a substituent selected from halogen (such as chlorine or fluorine), and lower alkyl (such as methyl). The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₁ ' is an amidoalkyl group or a substituted or unsubstituted heteroaryl group; preferably, the alkyl group The radical is methyl; preferably, the heteroaryl group is a triazolyl group, more preferably, the triazolyl group is a methyltriazolyl group; more preferably, the R ₁ ' is The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₂ ' is an aryl group optionally substituted by one or more halogens; preferably, the halogen is F; Preferably, the aryl group is phenyl; Preferably, R ₂ ' is a phenyl group substituted by three F; More preferably, R ₂ ' is The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₃ is a heteroaryl optionally substituted by a substituent selected from C1-C3 alkyl and halogen; Preferably, the C1-C3 alkyl group is methyl; preferably, the halogen is Cl; more preferably, the R ₃ is The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R ₄ and R ₅ are each independently hydrogen or C1-C3 alkyl; preferably, the C1-C3 alkyl The base is isopropyl. Compounds, or stereoisomers, solvates, deuterates or pharmaceutically acceptable salts thereof, having the following structure:
The compound of any one of claims 1-7 or its stereoisomer, solvate, deuterate or pharmaceutically acceptable salt, wherein the salt is with an alkaline earth metal (such as calcium), an alkali metal ( Such as potassium, sodium), lysine or tris(hydroxymethylaminomethane), preferably salts with tris(hydroxymethylaminomethane). A pharmaceutical composition containing the compound of any one of claims 1 to 8 or its stereoisomer, solvate, deuterated product or pharmaceutically acceptable salt, and pharmaceutically acceptable excipients. The compound of any one of claims 1 to 8 or its stereoisomer, solvate, deuterate or pharmaceutically acceptable salt, or the pharmaceutical composition of claim 9 when prepared for treatment or prevention Use in medicines for diseases caused by coronavirus infection; preferably, the coronavirus is MERS, SARS or SARS-CoV-2.