WO2023226822A1 - Method for using azetidine derivative to treat viral infections and use - Google Patents

Abstract

The present invention relates to the treatment of viral infections, in particular coronavirus infections. Specifically, provided is a compound of formula I, a pharmaceutically acceptable salt, a stereoisomer, a polymorph, a solvate, a metabolite or a prodrug thereof, or use of a composition comprising same in the preparation of a drug for treating viral infections. The present invention has a clear mechanism of action, clear efficacy and good safety, and provides more medication options for patients.

Description

Methods and uses of azetidine derivatives for treating viral infections Field of invention

The present invention relates to the use of azetidine derivatives as Janus kinase (JAK) inhibitors in the treatment of viral infection-related diseases, particularly the use of azetidine derivatives as Janus kinase (JAK) inhibitors in the treatment of coronavirus. Use in diseases related to viral infections.

Background of the invention

Viral infection seriously threatens human health. Viruses can invade the body through multiple ways, such as respiratory tract infection, genitourinary system infection, and digestive tract infection, and proliferate in susceptible host cells. Viral infection is a process of interaction between the virus and the body, and between the virus and susceptible cells. Viral infection produces varying degrees of damage or viral diseases depending on the type of virus and individual differences in the human body.

Coronaviruses are single-stranded RNA enveloped viruses, which are divided into four categories: α, β, γ and δ. The β category can be divided into four subgroups A-D. So far, 6 viral molecules (except SARS-CoV-2) have been discovered, each of which can cause different types of diseases. The main clinical manifestations are upper respiratory tract and gastrointestinal tract infections. SARS and MERS virus infections can cause pneumonia, kidney failure and other serious organ damage and death. According to statistics, the patient mortality rates caused by SARS and MERS are 9% and 36% respectively.

Coronavirus particles are covered with a fatty membrane, and there are three types of glycoproteins on the membrane surface: spike glycoprotein (S protein, which is the receptor binding site, cell lysis and main antigenic site), small envelope glycoprotein ( E protein, Envelope protein, a smaller protein that binds to the envelope), M protein, Membrane protein, which is responsible for the transport of nutrients across the membrane and the budding of new viruses. release and formation of the viral envelope). Among them, the envelope of the beta group A coronavirus also has a shorter spike protein, namely hemagglutininesterase (HE protein). Inside the virus is the nucleocapsid protein (N protein, nulceocapsid phosphor protein) of the virus, to which the single positive-strand RNA of the virus's genome is attached.

The new coronavirus SARS-CoV-2 belongs to the beta coronavirus. It is enveloped and has round or oval particles, often pleomorphic, with a diameter of 60-140nm. The clinical manifestations of infection caused by the new coronavirus are fever, fatigue, and dry cough as the main manifestations. A few patients are accompanied by symptoms such as nasal congestion, runny nose, sore throat, and diarrhea; mild patients only show low fever, mild fatigue, etc., and no symptoms of pneumonia; severe patients Dyspnea and/or hypoxemia usually occur one week after the onset of symptoms, and severe cases rapidly progress to acute respiratory distress syndrome, septic shock, metabolic acidosis, and hemorrhage and coagulation dysfunction that are difficult to correct.

At present, vaccination is still the main way to prevent COVID-19 infection, and no effective treatment has been found yet. Therefore, it is urgent and necessary to develop drugs that have inhibitory effects on the SARS-CoV-2 virus. Drugs that can effectively inhibit new coronavirus infection will provide better medication options for Covid-19 patients.

Summary of the invention

A first aspect of the present invention provides compounds of formula (I), pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof for the preparation of preventive and/or therapeutic Use in medicines for viral infections,

in:

R ₁ is selected from C(O)R ₈ and S(O) ₂ R ₉ ;

R ₂ is selected from H, CN, halogen and C _1-6 alkyl;

R ₃ and R ₄ are each independently selected from H, halogen and CN;

R ₅ , R ₆ and R ₇ are each independently selected from H, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy and C(O)NR ₁₀ R ₁₁ ;

R ₈ and R ₉ are each independently selected from C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, C _{7 -20aralkyl} and NR ₁₀ R ₁₁ ;

R ₁₀ and R ₁₁ are each independently selected on each occurrence from H and C _1-6 alkyl; and

Wherein the above-mentioned alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted by 1, 2 or 3 independently selected from halogen, CN and C _1-4 alkyl. base substitution.

A second aspect of the present invention provides a method for preventing and/or treating viral infection, the method comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a compound of the above formula (I), a pharmaceutically acceptable salt thereof , stereoisomers, polymorphs, solvates, metabolites or prodrugs.

A third aspect of the present invention provides compounds of the above formula (I), pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof, which are used for prevention and/or Treat related diseases caused by viral infections.

In a preferred embodiment, in the compound of formula (I), _R2 is selected from H, CN, F and methyl.

In a preferred embodiment, in the compound of formula (I), _R2 is selected from H and methyl.

In a preferred embodiment, in the compound of formula (I), R ₃ and R ₄ are each independently selected from H, F, Cl and CN.

In a preferred embodiment, in the compound of formula I, R ₃ and R ₄ are H.

In a preferred embodiment, in the compound of formula (I), R ₅ , R ₆ and R ₇ are each independently selected from H, F, Cl, CN, methyl, ethyl, methoxy and C(O )NH ₂ .

In a preferred embodiment, in the compound of formula I, R ₅ is H, F, Cl, CN, methyl or C(O)NH ₂ ;

R ₆ is H, Cl, CN, methyl or methoxy; and

R ₇ is H.

In a preferred embodiment, in the compound of formula (I), R ₈ and R ₉ are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl group, tert-butyl, aziridinyl, pyrrolidinyl, phenyl, benzyl and N(CH ₃ ) ₂ , wherein each of the above groups is optionally selected from 1, 2 or 3 independently from F, CN Substituted with methyl substituents.

In a preferred embodiment, in the compound of formula (I), each occurrence of R ₁₀ and R ₁₁ is independently selected from H, methyl and ethyl.

In the uses covered by the present invention, the above preferred groups can be combined in any way to obtain compounds of formula (I).

In some embodiments, the present invention provides compounds, pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof in the preparation of compounds for the prevention and/or treatment of viral infections. Use in medicine, wherein said compound is selected from:

In a preferred embodiment, the compound of formula (I) is:

In preferred embodiments, the pharmaceutically acceptable salts include selected from the group consisting of aspartate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclic Hexamethonate Salt, ethanesulfonate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroiodide/iodide, isethyl sulfonate Acid, lactate, methyl sulfate, naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, naphthalene Acid, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, glycosate, stearate, tannin, xinafoate, aluminum salt, arginine Salt, benzathine penicillin salt, calcium salt, choline salt, diethylamine salt, diethanolamine salt, glycinate, lysine salt, magnesium salt, meglumine salt, ethanolamine salt, potassium salt, sodium salt, ambutanol Trialcohol salts and zinc salts.

In a preferred embodiment, the virus is a coronavirus.

In a preferred embodiment, the coronavirus is selected from any one of SARS-CoV-1, SARS-CoV-2, MERS, 229E, NL63, OC43, HKU1 or a combination thereof.

In a preferred embodiment, the coronavirus is SARS-CoV-2.

In a preferred embodiment, the medicine of the present invention also includes pharmaceutically acceptable excipients.

In a preferred embodiment, the excipients include any one or a combination of two of excipients, diluents, carriers, flavoring agents, binders or fillers. Preferably, the carriers include liposomes. , micelles, microspheres or microcapsules, etc.

In a preferred embodiment, the dosage form of the medicine of the present invention includes tablets, capsules, granules, powders or injections. Each dosage form of medicine can be prepared according to conventional methods in the pharmaceutical field.

In a preferred embodiment, the pharmaceutical dosage form of the present invention is a capsule.

In a preferred embodiment, the pharmaceutical dosage form of the present invention is a capsule, and the capsule specifications (i.e., the compound of formula I contained in each capsule, its pharmaceutically acceptable salts, stereoisomers, polymorphs form, solvate, metabolite or prodrug) is 0.1-50 mg, such as 0.1-20 mg, e.g. Such as 0.2-10 mg, such as 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg or 6 mg, such as 0.5 mg, 1 mg or 2 mg.

In preferred embodiments, the drug also includes one or more other therapeutic drugs.

In a preferred embodiment, the one or more other therapeutic drugs are selected from one or more of antiviral drugs, hormonal drugs, immune drugs, anticoagulant drugs, Chinese herbal medicines, etc.

In a preferred embodiment, the antiviral drugs include Imdevimab, Casirivimab, Monupivir, Remdesivir, Lopinavir, Ritonavir, Nematvir, Hydroxychloroquine, Chloroquine Phosphate, Azizumab One or more of vudine, alpha-interferon, ribavirin, arbidol, tofacitinib, etc.

In a preferred embodiment, the hormonal drugs include corticosteroids and the like, such as methylprednisolone, dexamethasone and the like.

In a preferred embodiment, the immune drugs include COVID-19 human immunoglobulin, tocilizumab, etc.

In a preferred embodiment, the anticoagulant drug includes low molecular weight heparin, unfractionated heparin, etc.

In a preferred embodiment, the Chinese herbal medicine includes one or more of Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Shufeng Jiedu Capsules, Qingfei Paidu Decoction, etc.

In a preferred embodiment, the compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof is present in an amount of less than about 100 nM, for example less than about 90 nM , 80nM, 70nM, 60nM, 50nM, 40nM, 30nM, 20nM, 19nM, 18nM, 17nM, 16nM, 15nM, 14nM, 13nM, 12nM, 11nM, 10nM or less inhibit AAK1 with _IC50 .

In a preferred embodiment, the compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof is present in an amount of less than about 1000 nM, for example less than about _IC50 inhibits GAK at 950nM, 900nM, 850nM, 800nM, 750nM, 700nM, 650nM, 600nM, 550nM, 500nM, 450nM, 400nM, 350nM, 340nM, 330nM, 320nM, 310nM, 300nM or less.

In a preferred embodiment, the prevention and/or treatment includes administering to the patient a prophylactically or therapeutically effective amount of a compound of formula (I), its pharmaceutically acceptable salts, stereoisomers, polymorphs, solvents The compound, metabolite or prodrug is preferably administered at a daily dose of 0.0001-100mg/kg body weight, and the preferred dose is 0.0001-100mg/kg, 0.0001-90mg/kg, 0.0001-80mg/kg, 0.0001-70mg daily /kg, 0.0001-60mg/kg, 0.0001-50mg/kg, 0.0001-40mg/kg, 0.0001-30mg/kg, 0.0001-20mg/kg, 0.001-100mg/kg, 0.001-90mg/kg, 0.001-80mg/kg , 0.001-70mg/kg, 0.001-60mg/kg, 0.001-50mg/kg, 0.001-40mg/kg, 0.001-30mg/kg, 0.001-20mg/kg, 0.001-10mg/kg, 0.01-90mg/kg, 0.01 -80mg/kg, 0.01-70mg/kg, 0.01-60mg/kg, 0.01-50mg/kg, 0.01-40mg/kg, 0.01-30mg/kg, 0.01-20mg/kg, 0.01-10mg/kg, 0.1-90mg /kg, 0.1-80mg/kg, 0.1-70mg/kg, 0.1-60mg/kg, 0.1-50mg/kg, 0.1-40mg/kg, 0.1-30mg/kg, 0.1-20mg/kg, 0.1-10mg/kg , 1-90mg/kg, 1-80mg/kg, 1-70mg/kg, 1-60mg/kg, 1-50mg/kg, 1-40mg/kg, 1-30mg/kg, 1-20mg/kg, 1 -10 mg/kg, more preferably 0.0001 mg/kg to about 50 mg/kg per day, such as about 0.01 mg/kg to about 10 mg/kg, about 0.005 mg/kg to about 0.1 mg/kg, about 0.005 mg/kg per day kg to about 0.05mg/kg, about 0.007mg/kg to about 0.035mg/kg.

In a preferred embodiment, the frequency of administration is once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, once every five weeks, or once every six weeks.

In a preferred embodiment, the dosing cycle is 1-200d, such as 3d, 4d, 5d, 6d, 7d, 8d, 9d, 10d, 11d, 12d, 13d, 14d, 21d, 28d, 60d, 90d, 180d.

In preferred embodiments, administration routes include oral administration, parenteral administration, and transdermal administration. The parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection.

In a preferred embodiment, a compound of formula (I), a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, metabolite or prodrug thereof is combined with one or more other therapeutic agents Combined administration.

In a preferred embodiment, the one or more other therapeutic drugs are selected from one or more of antiviral drugs, hormonal drugs, immune drugs, anticoagulant drugs, Chinese herbal medicines, etc.

In a preferred embodiment, the antiviral drugs include Imdevimab, Casirivimab, Monupivir, Remdesivir, Lopinavir, Ritonavir, Nematvir, Hydroxychloroquine, Chloroquine Phosphate, Azizumab One or more of vudine, alpha-interferon, ribavirin, arbidol, tofacitinib, etc.

In a preferred embodiment, the hormonal drugs include corticosteroids and the like, such as methylprednisolone, dexamethasone and the like.

In a preferred embodiment, the immune drugs include COVID-19 human immunoglobulin, tocilizumab, etc.

In a preferred embodiment, the anticoagulant drug includes low molecular weight heparin, unfractionated heparin, etc.

In a preferred embodiment, the Chinese herbal medicine includes one or more of Jinhua Qinggan Granules, Lianhua Qingwen Capsules, Shufeng Jiedu Capsules, Qingfei Paidu Decoction, etc.

In a preferred embodiment, the patient is a COVID-19 patient.

In a preferred embodiment, the COVID-19 patients are asymptomatic, mild, common, severe, or critical patients.

In preferred embodiments, the COVID-19 patient is a hospitalized COVID-19 adult patient requiring supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).

In a preferred embodiment, the COVID-19 patient has at least one elevated inflammatory marker, such as CRP, D-dimer, LHD, ferritin, etc.

Detailed description of the invention

Definition of Terms

Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technology as used herein are intended to mean technology as commonly understood in the art, including those variations or equivalent technology that would be apparent to those skilled in the art. Although the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

All patents, published patent applications, publications, references, and other materials mentioned herein are incorporated by reference in their entirety.

Unless the context clearly dictates otherwise, references to "or" herein mean the term "and/or" and may be used interchangeably with the term "and/or".

As used herein, the term "alkyl" is defined to include saturated aliphatic hydrocarbons, including straight and branched chains. In some embodiments, an alkyl group has 1 to 6, such as 1 to 4 carbon atoms. For example, as used herein, the term "C _1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl (isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (e.g. CF ₃ , C ₂ F ₅ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ Cl or -CH ₂ CH ₂ CF ₃ , etc.). The term "C _1-4 alkyl" refers to a linear or branched fat of 1 to 4 carbon atoms Family hydrocarbon chain (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).

As used herein, the term "alkoxy" refers to a linear, branched or cyclic saturated monovalent hydrocarbon radical of the formula -O-alkyl, where the term "alkyl" is as defined above or as defined below "Cycloalkyl", such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, cyclobutoxy, pentyloxy, isopentyloxy or n-hexyloxy, or their isomers.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclo, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[ 3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents. Said cycloalkyl having 3 to 15 carbon atoms. For example, the term "C _3-10 cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring-forming carbon atoms ( for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bicyclo[1.1.1]pentyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the ring and one or more (eg one, two, three or four) heteroatom-containing compounds selected from C(=O), O, S, S(=O), S ₍ =O) and _NR group, wherein _Ra represents a hydrogen atom or a C _1-6 alkyl group or a halo-C _1-6 alkyl group; the heterocycloalkyl group can be passed through any one of the carbon atoms or a nitrogen atom (if present) ) is connected to the rest of the molecule. In particular, 3-10 membered heterocyclyl groups have 3-10 carbon atoms and heteroatoms in the ring. Groups such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl ( dioxolinyl), pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl.

As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi electron system. For example, as used herein, the term "C _6-14 aryl" means an aromatic group containing 6 to 14 carbon atoms, such as phenyl or naphthyl. Aryl groups are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.

As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, In particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and it contains at least one heteroatom which may be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and, additionally In each case it may be benzo-fused. In particular, the heteroaryl group is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl Diazolyl, etc. and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.

The term "aralkyl" preferably means an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein. Typically, the aryl group may have 6 to 14 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.

The term "substituted" refers to one or more (e.g., one, two, three or four) hydrogens are replaced by a selection from the groups indicated, provided that the normal valencies of the atoms indicated in the present case are not exceeded and that said substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.

The term "optionally substituted" means optionally substituted with specified groups, radicals or moieties.

When the bond of a substituent is shown as a bond connecting two atoms in the ring, then such substituent may be bonded to any ring-forming atom in the substitutable ring.

The compounds of the invention may also contain one or more (eg one, two, three or four) isotopic substitutions. For example, in the compound, H can be in any isotopic form, including ¹ H, ² H (D or deuterium), and ³ H (T or tritium); C can be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O can be in any isotope form, including ¹⁶ O, ¹⁸ O, etc.

The term "stereoisomer" means an isomer formed due to at least one asymmetric center. In compounds with one or more (e.g., one, two, three or four) asymmetric centers, they may give rise to racemates, racemic mixtures, single enantiomers, diastereomers Conformational mixtures and individual diastereomers. Certain individual molecules may also exist as geometric isomers (cis/trans). Similarly, compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, and imine-enamine tautomers. wait. It is to be understood that the scope of this application encompasses all such products in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99 %) isomers or mixtures thereof.

The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

It will also be understood that certain compounds of the present invention may exist in free form for therapeutic use, or, where appropriate, as pharmaceutically acceptable derivatives thereof. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites or prodrugs that, upon administration to a patient in need thereof, can directly or Compounds of the invention or metabolites or residues thereof are indirectly provided.

Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include aspartate, bicarbonate/carbonate, bisulfate, borate, camphorsulfonate, citrate, cyclamate, ethylenedisulfonate, ethanesulfonate , fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydroiodide/iodide, isethionate, lactate, methyl sulfate, Naphthylate, 2-naphthalene sulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/diphosphate Hydrogen salts, pyroglutamate, glycolates, stearates, tannins and xinofoate.

Suitable base addition salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium salt, sodium salt, tromethamine salt and zinc salt.

For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

The compounds of the invention may exist in the form of hydrates or solvates, wherein the compounds of the invention comprise as a structural element of the crystal lattice of the compound a polar solvent, in particular such as water, methanol or ethanol. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.

Also included within the scope of the invention are metabolites of the compounds of the invention, ie compounds formed in the body upon administration of the drug.

The prodrugs of the invention can be prepared, for example, by using certain groups known to those skilled in the art (e.g. "pro-moieties" as described in H. Bundgaard, Design of Prodrugs (Elsevier, 1985)) are produced by replacing the appropriate functional groups present in the compounds of formula I.

In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered with a therapeutic agent and is suitable for contact with humans and/or within the scope of reasonable medical judgment. Tissues from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable carriers that may be used in the compositions/medicines of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, Mineral oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous glucose and glycerol solutions may also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol etc. The compositions may also, if desired, contain minor amounts of wetting agents, emulsifying agents, or pH buffering agents. Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

The compounds/compositions/drugs of the present invention may act systemically and/or locally. For this purpose, they may be administered by suitable routes, for example by injection, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly or transdermally; or by oral, buccal, nasal, transmucosal, topical, Administered as an ophthalmic preparation or by inhalation.

For these routes of administration, the compounds/compositions/medicaments of the invention may be administered in suitable dosage forms.

The dosage forms include, but are not limited to, tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, and aqueous suspensions. , injectable solutions, elixirs, syrups.

The term "therapeutically effective amount" as used herein refers to an amount of a compound that, when administered, alleviates to a certain extent one or more symptoms of the condition being treated.

Dosage regimens can be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dosage may be proportionally reduced or increased as the exigencies of the therapeutic situation indicate. It is noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that, for any particular individual, specific dosage regimens should be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.

The amount of a compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, disposition of the compound, and the judgment of the prescribing physician. Generally speaking, the effective dose is about 0.0001 to about 50 mg per kg of body weight per day, for example, about 0.01 to about 10 mg/kg/day (single or divided administration). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, for example about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels no higher than the lower end of the foregoing ranges may be sufficient, while in other cases, larger dosages may still be employed without causing any deleterious side effects, provided that the larger dosage is first The dose is divided into several smaller doses to be administered throughout the day.

The content or amount of the compound of the present invention in the pharmaceutical composition/drug may be about 0.01 mg to about 1000 mg, suitably 0.1-500 mg, preferably 0.1-300 mg, more preferably 0.1-150 mg, particularly preferably 0.3-50 mg, such as 0.5 mg, 1mg, 1.5mg, 2mg, 4mg, 10mg, 25mg wait.

Unless otherwise stated, the term "treating" as used herein means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Preventing such a disease or condition or one or more symptoms of such a disease or condition.

"Subject" as used herein includes humans or non-human animals. Exemplary human subjects include human individuals (referred to as patients) suffering from a disease, such as a disease described herein, or normal individuals. In the present invention, "non-human animals" include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.). When a subject refers to a human being, the terms "subject" and "patient" are used interchangeably herein.

As used in this article, the clinical classification of COVID-19 refers to the "Diagnosis and Treatment Plan for Novel Coronavirus Pneumonia (Trial Eighth Edition)", with specific definitions as follows:

(1) Lightweight.

The clinical symptoms were mild, and no pneumonia was found on imaging.

(2) Ordinary type.

Have fever, respiratory symptoms, etc., and pneumonia manifestations can be seen on imaging.

(3) Heavy duty.

Adults meet any of the following criteria:

1. Shortness of breath occurs, RR ≥ 30 times/min;

2. In the resting state, when breathing air, the oxygen saturation is ≤93;

3. Arterial blood oxygen partial pressure (PaO ₂ )/oxygen concentration (FiO ₂ ) ≤ 300mmHg

(1mmHg=0.133kPa); in high-altitude areas (over 1,000 meters above sea level), PaO ₂ /FiO ₂ should be corrected according to the following formula: PaO ₂ /FiO ₂ × [760/atmosphere (mmHg)].

4. Clinical symptoms progressively worsen, and lung imaging shows significant progression of >50 lesions within 24 to 48 hours.

Children meet any of the following conditions:

1. High fever persists for more than 3 days;

2. Shortness of breath occurs (<2 months old, RR ≥ 60 times/min; 2 to 12 months old, RR ≥ 50 times/min; 1 to 5 years old, RR ≥ 40 times/min; > 5 years old, RR ≥ 30 times/min), excluding the effects of fever and crying;

3. In the resting state, when breathing air, the oxygen saturation is ≤93;

4. Assisted breathing (nostril flaring, three concave signs);

5. Drowsiness and convulsions occur;

6. Refusing to eat or having difficulty feeding, with signs of dehydration.

(4) Critical illness.

Those who meet one of the following conditions:

1. Respiratory failure occurs and mechanical ventilation is required;

2. Shock occurs;

3. Combined with other organ failure, ICU monitoring and treatment is required.

Description of the drawings

Figure 1 Inhibitory effect of compound 8 on AAK1

Example

The invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the invention.

The abbreviations in this invention have the following meanings:

The structure of the compound is confirmed by nuclear magnetic resonance spectroscopy ( ¹ H NMR) or mass spectrometry (MS).

The reaction is monitored by thin layer chromatography (TLC) or LC-MS. The developing solvent systems used are: methylene chloride and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system.

Column chromatography generally uses 200 to 300 mesh silica gel (Qingdao Ocean) as the stationary phase. The eluent system includes: methylene chloride and methanol system and n-hexane and ethyl acetate system.

In the following examples, unless otherwise specified, the reaction temperature is room temperature (20°C to 30°C).

Reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company Or companies like Tebo Chemical.

Example 1: 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)nitrogen Hetetane-3-yl)acetonitrile (8)

Step 1: 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (8b)

Add 4-bromo-7-azaindole (8a) (10g, 50.7mmol) and DMF (100mL) into a 250mL three-neck flask, cool the reactant through ice-salt bath cooling to below -10°C, and use _N2 protection, stir the reaction solution evenly, and then add sodium hydride (60%, 2.64g, 54.4mmol) to the reactant in batches within 1 hour, keeping the temperature not exceeding -5°C. Stir the reactant for 1 hour, then add 2-(trimethylsilyl)ethoxymethyl chloride dropwise to the reactant, keep the temperature at no more than 10°C, and complete the dropwise addition in about 1.5 hours. Stir the reactant for 1 hour. . The reaction was monitored by thin layer chromatography, and the raw materials basically disappeared. The reaction solution was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 4-bromo-1-((2-(trimethylsilane) (ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (8b) (14.57 g, yield: 88.0%). MS(ESI,m/z):326.1[M+H] ⁺ .

Step 2: 4-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b] Pyridine(8c)

Compound 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (8b) (4g, 12.3mmol), Pinacol 4-pyrazole borate (3.86g, 19.9mmol) and dioxane (300mL) were added to the 500mL reaction bottle in sequence, and then potassium carbonate (4.58g, 33.1mmol) solution (60mL) was added to complete the reaction. The solution was stirred evenly, then Pd(dppf)Cl ₂ (0.97g, 1.33mmol) was added, protected with N ₂ , the reactant was heated to 95°C, and reacted under reflux overnight. After the reaction was completed, thin layer chromatography was used to monitor the reaction. The reaction solution was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 4-(1H-pyrazol-4-yl)-1-(( 2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (8c) (1.67g, yield: 43.5%). MS(ESI,m/z):314.2[M+H] ⁺ .

Step 3: 2-(1-(ethylsulfonyl)-3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2 ,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (8d)

Compound 4-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine ( 8c) (200mg, 0.64mmol), 2-[1-(ethylsulfonyl)-3-azetidinylidene]acetonitrile (118mg, 0.64mmol) and acetonitrile (15mL) were added to the 50mL reaction bottle, and the reaction solution was Stir evenly, then add DBU (116 mg, 0.76 mmol), react the above reaction solution at room temperature for 1 hour, monitor the reaction with thin layer chromatography, quench the reaction solution with water, concentrate the reaction solution under reduced pressure, and use a silica gel column to Purification by chromatography gave compound 2-(1-(ethylsulfonyl)-3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl))-1H-pyrrolo [2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (8d) (285 mg, yield: 89.1%). MS(ESI,m/z):500.2[M+H] ⁺ .

Step 4: 2-(3-(4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl) nitrogen Hetetane-3-yl)acetonitrile (8)

Compound 2-(1-(ethylsulfonyl)-3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl))-1H-pyrrolo [2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (8d) (345 mg, 0.69 mmol) and TFA/DCM (1: 1) (6 mL) of the mixed solution was added to a 50 mL reaction bottle, and stirred at room temperature for 1 h under Ar protection. After monitoring the reaction with LC-MS, extract with ethyl acetate, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a yellow oil. Add tetrahydrofuran (7.6 mL) at room temperature, stir evenly, and add 1M hydroxide. Sodium solution (7.6 mL), stirred at room temperature for 2 h. After monitoring the reaction by thin layer chromatography, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by TLC chromatography to obtain 2-(3-(4-(1H-pyrrolo[2, 3-b]pyridin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (8) (40 mg, yield: 15.7 %).

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 11.72 (s, 1H), 8.78 (s, 1H), 8.35 (s, 1H), 8.21 (d, J = 5.00Hz, 1H), 7.54 (t, J＝3.04Hz,1H),7.34(d,J＝5.00Hz,1H),6.90(dd,J ₁ ＝3.62Hz,J ₂ ＝1.84Hz,1H),4.59(d,J＝9.02Hz,2H) ,4.24(d,J＝9.02Hz,2H),3.68(s,2H),3.24(q,2H),1.25(t,J＝7.29Hz,3H).MS(ESI,m/z):370.1[ M+H] ⁺ .

The preparation of the remaining compounds of the present invention can be found in WO2017/097224A1.

biology test

When the SARS-CoV-2 virus binds to the host cell surface receptor angiotensin-converting enzyme 2 (ACE2), AAK1 and GAK are activated, thereby mediating virus entry into cells. AAK1 and GAK Inhibitors prevent viruses from entering host cells.

Test raw materials:

AAK1 kinase (Tag-tagged), GAK kinase (Tag-tagged), Eu-tagged anti-Tag antibody, Alexa 647 dye-labeled tracers, etc., are all from Thermo Fisher Scientific.

Test Example 1 GAK Inhibition Experiment

First, compound 8 prepared in Example 1 and the control compound baricitinib were added to the 384-well plate respectively, so that the final concentrations were 10000nM, 3330nM, 1110nM, 370nM, 123nM, 41.2nM, 13.7nM, 4.57nM, and 1.52nM respectively. ,0.5nM. Then add kinase buffer and kinase/Eu-labeled anti-Tag antibody mixture. The final concentration of GAK kinase is 5nM. Then join Alexa Tracer 236 labeled with 647 dye, the final concentration is 100nM. After incubation at room temperature for 60 minutes, read using a fluorescence plate reader.

Use the following formula to calculate the substitution rate: Fluorescence signal ratio (ER) = AF647 fluorescence signal (665nM)/Eu fluorescence signal (615nM); Substitution rate (%) = 100*{(ER _{0% substitution rate control} well-ER _{test well} ) /(ER _{0% substitution rate control well} -ER _{100% substitution rate control well} )}.

Among them, the 0% substitution rate control well did not add any inhibitor. The GAK inhibitor Staurosporine was added to the 100% substitution rate control well.

Use IDBS XFfit to perform curve fitting on the substitution rate, and calculate the IC ₅₀ value of the compound against the kinase GAK. The measurement results are shown in Table 1.

Table 1 Inhibitory effects of compounds on GAK

The results show that the compounds of the present invention (such as compound 8) have good inhibitory effects on GAK.

Test Example 2 AAK1 Inhibition Experiment

Compound 8 prepared in Example 1 was added to a 384-well plate to a final concentration of 10000 nM, 3330 nM, 1110 nM, 370 nM, 123 nM, 41.2 nM, 13.7 nM, 4.57 nM, 1.52 nM, and 0.5 nM. Then add kinase buffer and kinase/Eu-labeled anti-Tag antibody mixture. The final concentration of AAK1 kinase is 5nM. Then join Alexa 647 dye-labeled tracer Tracer222, the final concentration is 100nM. After incubation at room temperature for 60 minutes, read using a fluorescence plate reader.

Use the following formula to calculate the substitution rate: Fluorescence signal ratio (ER) = AF647 fluorescence signal (665nM)/Eu fluorescence signal (615nM); Substitution rate (%) = 100*{(ER _{0% substitution rate control} well-ER _{test well} ) /(ER _{0% substitution rate control well} -ER _{100% substitution rate control well} )}.

Among them, the 0% substitution rate control well did not add any inhibitor. The AAK1 inhibitor sunitinib was added to the 100% substitution rate control well.

IDBS XFfit was used to perform curve fitting on the substitution rate (the results are shown in Figure 1), and the IC ₅₀ value of compound 8 for inhibiting kinase AAK1 was calculated to be 11.5nM.

Various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is hereby incorporated by reference in its entirety.

Claims (15)

1. The use of the compound of formula I, its pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs in the preparation of medicaments for the prevention and/or treatment of viral infections, wherein The compound has the structure shown in formula I:
   

   in:

   R ₁ is selected from C(O)R ₈ and S(O) ₂ R ₉ ;

   R ₂ is selected from H, CN, halogen and C _1-6 alkyl;

   R ₃ and R ₄ are each independently selected from H, halogen and CN;

   R ₅ , R ₆ and R ₇ are each independently selected from H, halogen, CN, C _1-6 alkyl, C _1-6 alkoxy and C(O)NR ₁₀ R ₁₁ ;

   R ₈ and R ₉ are each independently selected from C _1-6 alkyl, C _3-10 cycloalkyl, 3-10 membered heterocyclyl, C _6-14 aryl, 5-14 membered heteroaryl, C _{7 -20aralkyl} and NR ₁₀ R ₁₁ ;

   R ₁₀ and R ₁₁ are each independently selected on each occurrence from H and C _1-6 alkyl; and

   Wherein the above-mentioned alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally substituted by 1, 2 or 3 independently selected from halogen, CN and C _1-4 alkyl. base substitution.
2. The use of claim 1, wherein R ₂ is selected from H, CN, F and methyl;

   Preferably, _R2 is selected from H and methyl.
3. The use of claim 1 or 2, wherein R ₃ and R ₄ are each independently selected from H, F, Cl and CN;

   Preferably, R ₃ and R ₄ are H.
4. The use of any one of claims 1-3, wherein R ₅ , R ₆ and R ₇ are each independently selected from H, F, Cl, CN, methyl, ethyl, methoxy and C(O )NH ₂ ;

   Preferably, R ₅ is H, F, Cl, CN, methyl or C(O)NH ₂ ;

   R ₆ is H, Cl, CN, methyl or methoxy; and

   R ₇ is H.
5. The use of any one of claims 1-4, wherein R ₈ and R ₉ are each independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl group, tert-butyl, aziridinyl, pyrrolidinyl, phenyl, benzyl and N(CH ₃ ) ₂ , wherein each of the above groups is optionally selected from 1, 2 or 3 independently from F, CN Substituted with methyl substituents.
6. The use of any one of claims 1 to 5, wherein R ₁₀ and R ₁₁ are each independently selected from H, methyl and ethyl at each occurrence.
7. Use of compounds, pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, metabolites or prodrugs thereof in the preparation of medicaments for the prevention and/or treatment of viral infections, wherein the compound Selected from:
   
   
   
8. The use of any one of claims 1 to 7, wherein the drug further includes pharmaceutically acceptable excipients.
9. The use according to any one of claims 1 to 8, wherein the dosage form of the drug includes tablets, capsules, granules, powders or injections. Preferably, the dosage form of the drug is capsules.
10. The use according to claim 9, wherein the capsule specification is 0.1-50mg, such as 0.1-20mg, such as 0.2-10mg, such as 0.5mg, 1mg, 1.5mg, 2mg, 2.5mg, 3mg, 3.5mg, 4mg, 4.5 mg, 5 mg, 5.5 mg or 6 mg, such as 0.5 mg, 1 mg or 2 mg.
11. The use of any one of claims 1-10, wherein the virus is a coronavirus; preferably any one of SARS-CoV-1, SARS-CoV-2, MERS, 229E, NL63, OC43, HKU1 or Combinations thereof; more preferably SARS-CoV-2.
12. The use of any one of claims 1-11, wherein the medicine also includes one or more other therapeutic drugs, preferably one of antiviral drugs, hormone drugs, immunological drugs, anticoagulant drugs, Chinese herbal medicines, etc. Kind or variety.
13. The use of any one of claims 1 to 12, further comprising administering the compound or a composition containing it to the patient at a frequency of once a day, twice a day, three times a day, once a week, or twice a day. Once a week, once every three weeks, once every four weeks, or once a month, once every five weeks, or once every six weeks; preferably, the dosing cycle is 1-200d, preferably 3d, 4d, 5d, 6d, 7d, 8d, 9d, 10d, 11d, 12d, 13d, 14d, 21d, 28d, 60d, 90d, 180d; preferably, the dosage is 0.0001-100mg/kg body weight per day, more preferably 0.0001mg/kg to about 50mg/kg per day, for example About 0.01 mg/kg to about 10 mg/kg, about 0.005 mg/kg to about 0.1 mg/kg, about 0.005 mg/kg to about 0.05 mg/kg, and about 0.007 mg/kg to about 0.035 mg/kg per day.
14. The use according to claim 13, wherein the administration route includes oral administration, parenteral administration, and transdermal administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular administration. injection.
15. The use of any one of claims 13-14, wherein the patient is a COVID-19 patient; preferably an asymptomatic, mild, common, severe, or critical COVID-19 patient; preferably, the COVID-19 The patient is a hospitalized adult patient with COVID-19 who requires supplemental oxygen, non-invasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO); preferably, the COVID-19 patient has at least one elevated inflammatory marker, such as CRP , D-dimer, LHD, ferritin, etc.