WO2023041024A1 - 治疗病毒感染的方法 - Google Patents

治疗病毒感染的方法 Download PDF

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WO2023041024A1
WO2023041024A1 PCT/CN2022/119256 CN2022119256W WO2023041024A1 WO 2023041024 A1 WO2023041024 A1 WO 2023041024A1 CN 2022119256 W CN2022119256 W CN 2022119256W WO 2023041024 A1 WO2023041024 A1 WO 2023041024A1
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days
rho
protein kinase
kinase inhibitor
associated protein
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PCT/CN2022/119256
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English (en)
French (fr)
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郑翔玲
赵焰平
王红军
周丽莹
仲伟婷
柴栋
何伊欣
候翠柳
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北京泰德制药股份有限公司
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Priority to CN202280061163.3A priority Critical patent/CN118019530A/zh
Publication of WO2023041024A1 publication Critical patent/WO2023041024A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a method for preventing and/or treating viral infection, which comprises administering an effective amount of an Rho-associated protein kinase inhibitor or an effective amount of an Rho-associated protein kinase inhibitor combined with a combination of one or more other drugs.
  • MERS-CoV Middle East respiratory syndrome coronavirus
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the present invention provides a method of preventing and/or treating a viral infection comprising administering to an individual in need thereof an effective amount of a Rho-associated protein kinase inhibitor.
  • the present invention provides a use of a Rho-associated protein kinase inhibitor in the preparation of a medicament for preventing and/or treating viral infection.
  • the present invention provides Rho-associated protein kinase inhibitors for use in the prevention and/or treatment of viral infections.
  • the invention provides methods of preventing and/or treating viral infections comprising administering to an individual in need thereof an effective amount of a Rho-associated protein kinase inhibitor in combination with one or more other drugs.
  • the present invention provides the use of a combination of a Rho-associated protein kinase inhibitor and one or more other drugs in the preparation of a medicament for preventing and/or treating viral infection.
  • the present invention provides a combination of a Rho-associated protein kinase inhibitor and one or more other drugs for the prevention and/or treatment of viral infections.
  • the present invention provides pharmaceutical compositions comprising a Rho-associated protein kinase inhibitor in combination with one or more other drugs and a pharmaceutically acceptable carrier.
  • kits comprising a plurality of containers and optionally instructions, each container containing a Rho-associated protein kinase inhibitor or one other drug, and optionally a pharmaceutically acceptable Carrier.
  • Figure 1A shows the inhibitory effect of compound 007 on the replication of SARS-CoV2 virus after 24 hours of treatment.
  • Figure 1B shows the inhibition of SARS-CoV2 viral replication after treatment with compound 007 for 48 hours.
  • Figure 2 shows the protective effect of compound 007 on mice infected with SARS-CoV-2 virus.
  • Figure 3 shows the inhibitory effect of compound 007 on the viral load in lung tissue of different strains of SARS-COV2 infection
  • Figure 3A shows the viral load in lung tissue infected by the original strain of SARS-CoV-2 (USA-WA1/2020)
  • Figure 3B shows the viral load in lung tissue infected by the SARS-CoV-2 delta variant (B.1.617.2)
  • Figure 3C shows the lung tissue infected by the SARS-CoV-2 omicron variant (BA.1.1.529) viral load in ).
  • Figure 4 shows H&E staining pictures of mouse lung tissue after SARS-CoV-2 infection (Note: a-d is the picture on the 7th day after infection, e-h is the picture on the 14th day after infection. c, d, g, h are respectively a , b, e, f magnified 2.5 times).
  • Figure 5 shows the pictures of Masson staining of mouse lung tissue after SARS-CoV-2 infection (Note: a-d is the picture on the 7th day after infection, e-h is the picture on the 14th day after infection. c, d, g, h are respectively a , b, e, f magnify the picture 2.5 times).
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • 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 radical, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally replaced by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution in which case the group is called "haloalkyl”
  • haloalkyl for example CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH 2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-butenyl, -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenylene group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclic, 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, decahydronaphthyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl,
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclopropyl) of 3 to 6 ring-forming carbon atoms. hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., with one or more double bond and/or triple bond) cyclic group.
  • a "3-10 membered (sub)heterocyclic (group)” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocyclic ring (group) of one or more (for example, 1, 2, 3 or 4) heteroatoms of , O and S.
  • heterocyclylene and heterocycle include, but are not limited to: ()oxiranyl, () aziridinyl, (azetidinyl), ()oxy Heterocyclobutyl (oxetanyl), (sub)tetrahydrofuranyl, (sub)dioxolinyl (dioxolinyl), (sub)pyrrolidinyl, (sub)pyrrolidinyl, (sub)imidazolidinyl, (sub) ) pyrazolidinyl, (sub)pyrrolinyl, (sub)tetrahydropyranyl, (sub)piperidinyl, (sub)morpholinyl, (sub)dithianyl (dithianyl), (sub) Thiomorpholinyl, piperazinyl or trithianyl.
  • the groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycle(yl) groups may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring).
  • ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • heteroarylene and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom which may be the same or different (the heteroatoms are for example oxygen, nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
  • “(y)heteroaryl” or “heteroaromatic ring” is selected from (y)thienyl, (y)furyl, (y)pyrrolyl, (y)oxazolyl, ()thiazolyl, (Yellow) imidazolyl, (lower) pyrazolyl, (lower) isoxazolyl, (lower) isothiazolyl, (lower) oxadiazolyl, (lower) triazolyl, (lower) thiadiazolyl etc., and their benzo derivatives; or (sub)pyridyl, (sub)pyridazinyl, (sub)pyrimidinyl, (sub)pyrazinyl, (sub)triazinyl, etc. derivative.
  • aralkyl preferably denotes an aryl or heteroaryl substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the heteroaryl group can have 5-14 ring atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number atomic substitution.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ).
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N); , 17 O and 18 O
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
  • stereoisomer means isomers formed as a result of at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist.
  • solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to patients in need thereof Following administration, the compound of the invention or its metabolites or residues can be provided directly or indirectly. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the 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 which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pam
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable 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, sodium, tromethamine and zinc salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperbenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions or kits 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 dextrose and glycerol solutions can also be employed 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, skim milk powder, glycerol, propylene glycol, water, ethanol etc.
  • the pharmaceutical composition can also optionally contain small amounts of wetting agents, emulsifying agents or pH buffering agents.
  • Oral formulations can contain standard carriers, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • compositions and kits of the invention may act systemically and/or locally.
  • they may be administered by a suitable route, for example by injection (e.g. intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, transdermal Nasally, transmucosally, topically, in the form of ophthalmic formulations or by inhalation.
  • the pharmaceutical composition of the present invention and each component in the kit can be administered in an appropriate dosage form.
  • the dosage forms include but are not limited to tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions , Injectable solutions, elixirs, syrups.
  • container is a container for containing pharmaceutical components. This container may be used for preparation, storage, transport and/or individual/bulk sale, and it is intended to cover bottles, jars, vials, flasks, syringes, tubes (for example for cream preparations), or for preparation, containment, storage or distribution Any other containers for pharmaceutical products.
  • the term "instructions" as used herein is an insert, label, label, etc., which recites information pertaining to the pharmaceutical components located within the container.
  • the information listed is generally at the discretion of regulatory agencies (eg, the United States Food and Drug Administration) having jurisdiction in the territories in which the article is to be marketed.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert may be made of any material from which the information contained therein or thereon can be read.
  • the package insert is a printable material (eg, paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (eg, printed or applied).
  • the term "effective amount” refers to the amount sufficient to achieve the desired therapeutic effect under the administration conditions, which leads to the improvement of pathological symptoms, disease progression, physiological conditions related thereto or induces resistance to the aforementioned diseases.
  • treating 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 Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • Combination therapy of the Rho-associated protein kinase inhibitors of the present invention and one or more other drugs can provide "synergy” and “synergism", that is, the effect obtained when the active ingredients are used together is greater than that produced by the compounds alone the sum of the effects.
  • Synergistic antiviral effect means an antiviral effect that is greater than the predicted purely additive effect of the individual active ingredients in combination.
  • the present invention provides methods of preventing and/or treating viral infections comprising administering to an individual in need thereof an effective amount of a Rho-associated protein kinase inhibitor.
  • the present invention provides the use of Rho-associated protein kinase inhibitors in the preparation of medicaments for preventing and/or treating viral infections.
  • the present invention provides Rho-associated protein kinase inhibitors for use in the prevention and/or treatment of viral infections.
  • the present invention provides methods of preventing and/or treating viral infections comprising administering to an individual in need thereof an effective amount of a Rho-associated protein kinase inhibitor in combination with one or more other drugs.
  • the present invention provides the use of a combination of a Rho-associated protein kinase inhibitor and one or more other drugs in the preparation of a drug for preventing and/or treating viral infection.
  • the present invention provides a Rho-associated protein kinase inhibitor in combination with one or more other drugs for the prevention and/or treatment of viral infections.
  • the viral infection is a Coronaviridae infection
  • the Coronaviridae infection is caused by a Coronaviridae virus.
  • the Rho-associated protein kinase inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxidized Compounds, isotopically labeled compounds, metabolites or prodrugs:
  • Ring A is The above group is connected to the pyrimidine ring through one of the two positions marked with * or **, and the other position is connected to the carbonyl;
  • R is selected from H and C 1-6 alkyl
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 is independently selected from H, halogen, -NR 5 R 6 , -OH, C 1-6 alkyl and -OR 5 ;
  • alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally selected at each occurrence by one or more independently selected from halogen, C Substituents of -6 alkyl and -OR 5 ;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is independently at each occurrence an integer of 0, 1, 2 or 3;
  • n is independently an integer of 0, 1 or 2.
  • Ring A is The above groups are connected to the pyrimidine ring through the position marked with *, and connected to the carbonyl group through the position marked with **, wherein R 10 is selected from H and C 1-6 alkyl, preferably H or methyl.
  • ring A is preferably The above groups are attached to the pyrimidine ring through the positions marked with *, and to the carbonyl through the positions marked with **.
  • R is H
  • R is H
  • each occurrence of R5 and R6 is independently selected from H, methyl and ethyl.
  • each occurrence of R 3 , R 4 , R 7 and R 8 is independently selected from H, F, Cl, Br, I, -NH 2 , -OH, methyl, trifluoro Methyl, -CH2 -Ph, methoxy , ethoxy, and -CH2OCH3 .
  • R3 is H.
  • R4 is selected from H and halogen (eg F, Cl, Br or I), preferably H or F.
  • R7 is selected from H and halogen (eg F, Cl, Br or I), preferably H or F.
  • R8 is H.
  • each occurrence of R is independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl, preferably H.
  • each occurrence of R 10 is independently selected from H and C 1-6 alkyl, preferably H, methyl, ethyl, n-propyl or isopropyl, most preferably H or methyl.
  • the present invention provides a method for preventing and/or treating viral infection, wherein the Rho-associated protein kinase inhibitor is a compound having a structure of formula (II) or a pharmaceutically acceptable salt, ester, Stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • the present invention provides a method for preventing and/or treating viral infection, wherein the Rho-associated protein kinase inhibitor is a compound having a structure of formula (III) or a pharmaceutically acceptable salt, ester, Stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs:
  • R 10 is H or methyl, preferably methyl.
  • the Rho-associated protein kinase inhibitor is a compound having the following structure or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide thereof , isotope-labeled compounds, metabolites or prodrugs:
  • the Rho-associated protein kinase inhibitor is prepared according to the methods disclosed in WO 2019/001572 A1 (which is incorporated herein by reference).
  • the present invention provides methods of preventing and/or treating viral infections comprising administering to an individual in need thereof an effective amount of a Rho-associated protein kinase inhibitor in combination with one or more other drugs;
  • the other drugs are preferably selected from one or more of small molecule drugs, cytokine drugs, therapeutic antibodies, inflammatory factor storm therapy drugs, small interfering RNA and vaccines for preventing or treating viral infection.
  • the small molecule drug for preventing or treating viral infection is selected from RNA polymerase inhibitors, endonuclease inhibitors, HIV protease inhibitors, coronavirus main protease inhibitors, coronavirus 3C-like protease ( 3C-like proteinase) inhibitor, SARS-Cov-2 3-chymotrypsin (3CLpro) inhibitor, spike protease (S protease) inhibitor, transmembrane serine protease 2 (TMPRSS2) inhibitor, angiotensin conversion One or more of enzyme 2 (ACE2) blocking inhibitors, viral membrane fusion and endocytosis inhibitors, and envelope blockers.
  • the small molecule drug for preventing or treating viral infection is selected from ribavirin, favipiravir, baloxavir, BCX4430 (its structure is ), pimodivir (VX-787), nitazoxanide (also known as "nitazoxamide”), darunavir, lopinavir, ritonavir, nelfinavir, arbivir
  • ribavirin favipiravir
  • baloxavir BCX4430
  • pimodivir VX-787
  • nitazoxanide also known as "nitazoxamide”
  • darunavir darunavir
  • lopinavir lopinavir
  • ritonavir nelfinavir
  • arbivir One or more of Dole, chloroquine, hydroxychloroquine, remdesivir, vitamin B complex, vitamin C, vitamin D and zinc supplements.
  • the cytokine drug is selected from the group consisting of interferon (such as native/recombinant interferon, interferon with altered spatial conformation, interferon conjugate or interferon fusion protein), interleukin, colony-stimulating factor, tumor One or more of necrosis factor and growth factor.
  • interferon such as native/recombinant interferon, interferon with altered spatial conformation, interferon conjugate or interferon fusion protein
  • interleukin such as native/recombinant interferon, interferon with altered spatial conformation, interferon conjugate or interferon fusion protein
  • interleukin such as native/recombinant interferon, interferon with altered spatial conformation, interferon conjugate or interferon fusion protein
  • colony-stimulating factor such as tumor One or more of necrosis factor and growth factor.
  • the therapeutic antibody is one or more selected from SARS-CoV monoclonal antibody, SARS-CoV-2 monoclonal antibody and MERS-CoV monoclonal antibody.
  • the inflammatory factor storm treatment drug is selected from Vesatolimod, ketotifen, glatiramer acetate, doxycycline, roflumilast, IL-6 monoclonal antibody, IL-6R monoclonal antibody (such as tocilizumab), TLR3 mAbs, mammalian defensins, Meteorin-like protein/IL-41 fragments, glucocorticoids (eg, dexamethasone, prednisone, methylprednisone, and hydrocortisone) and one or more of broad-spectrum antibiotics such as azithromycin.
  • Vesatolimod ketotifen, glatiramer acetate, doxycycline, roflumilast
  • IL-6 monoclonal antibody such as tocilizumab
  • TLR3 mAbs such as tocilizumab
  • mammalian defensins such as tocilizumab
  • the vaccine is a vaccine against a Coronaviridae virus, particularly an inactivated vaccine, a nucleic acid vaccine, a recombinant protein/subunit vaccine, a live virus vector vaccine, an attenuated vaccine, or a DNA or RNA-based strategy or Vaccines developed using either replicating vector or non-replicating vector strategies.
  • the Coronaviridae virus is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1 and variants thereof.
  • variants of SARS-CoV-2 include, but are not limited to, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Omicron (B.1.1.529).
  • the disease caused by the coronavirus infection is Middle East Respiratory Syndrome, Severe Acute Respiratory Syndrome, or COVID-19.
  • the Coronaviridae virus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or 2019-nCoV), and the disease it causes is COVID-19.
  • SARS-CoV-2 or 2019-nCoV severe acute respiratory syndrome coronavirus 2
  • the Rho-associated protein kinase inhibitor or each active ingredient in the combination is administered in an amount of about 0.005 mg/day to about 5000 mg/day, such as about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500 or 5000 mg/day is administered.
  • the Rho-associated protein kinase inhibitor or each active ingredient in the combination is administered at about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg per day.
  • kg to about 50 mg/kg body weight for example, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg per day , about 150 ⁇ g/kg, about 175 ⁇ g/kg, about 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg , about 400 ⁇ g/kg, about 425 ⁇ g/kg, about 450 ⁇ g/kg, about 475 ⁇ g/kg/
  • the daily dose of the Rho-associated protein kinase inhibitor or each active ingredient of the combination is administered as a single dose or in two, three or four divided doses.
  • the active ingredients of the combination are administered simultaneously, sequentially or alternately.
  • the Rho-associated protein kinase inhibitor or each active ingredient in the combination is administered for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days , at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 1 year or at least 2 years.
  • one or more courses of treatment wherein each course of treatment lasts at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, At least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days days, at least 30 days, at least 35 days, at least 40 days, at least 45 days, or at least 50 days; 10 days, two weeks, three weeks or four weeks.
  • the Rho-associated protein kinase inhibitor or the individual active ingredients of the combination are administered by injection (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermally. Administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation, and the routes of administration of the active ingredients in the combination may be the same or different.
  • the present invention encompasses any combination of the above embodiments.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a Rho-associated protein kinase inhibitor and one or more other drugs and a pharmaceutically acceptable carrier; wherein the Rho-associated protein kinase inhibitor and Said other drugs are respectively as defined above.
  • the invention provides a kit comprising a plurality (eg, 2, 3 or 4) containers and optionally instructions, each container comprising a Rho-associated protein kinase inhibitor or a Other drugs, and optionally a pharmaceutically acceptable carrier; wherein the Rho-associated protein kinase inhibitor and the other drugs are respectively as defined above.
  • Compound 128 used in the examples has the following structure, which was prepared according to the method disclosed in WO 2019/001572 A1.
  • Kinase IC 50 was determined using a commercially available CISBIO Kinase Detection Kit HTRF KinEASE-STK S2 Kit (62ST2PEC).
  • Kinase ROCK2 (01-119) used in the reaction was purchased from Carna Biosciences.
  • a 10000 nM compound solution was prepared by using 1 ⁇ kinase buffer solution with a DMSO concentration of 2.5%, and the compound solution was serially diluted using the above-mentioned kinase buffer solution containing DMSO to obtain 9 solutions of the test compound with different concentrations.
  • 2 ⁇ M substrate ie 2 ⁇ L 5 ⁇ STK-S2 substrate working solution
  • 2 ⁇ M substrate ie 2 ⁇ L 5 ⁇ STK-S2 substrate working solution
  • 2 ⁇ M substrate ie 2 ⁇ L 5 ⁇ STK-S2 substrate working solution
  • 2 ⁇ M substrate ie 2 ⁇ L 5 ⁇ STK-S2 substrate working solution
  • 2 ⁇ M substrate ie 2 ⁇ L 5 ⁇ STK-S2 substrate working solution
  • 5 ⁇ ROCK2 kinase working solution containing 1.4 ng ROCK2 kinase
  • Add 2 ⁇ L of 5 ⁇ ATP working solution to all reaction wells and incubate at room temperature for 2 hours.
  • Calu-3 Human respiratory epithelial cells Calu-3 (ATCC, HTB-55) were purchased from ATCC; SARS-CoV-2 virus (2019-nCoV/USA-WA1/2020 strain) was isolated from Washington, USA 1 January 2020 COVID-19 Pharyngeal swabs of confirmed patients (BEI Resources, NR-52281). Calu-3 was cultured overnight and used for experiments when the confluence reached 80-90%.
  • Example 3 Protective effect of compound 007 on mice infected with SARS-CoV-2 virus
  • the 2019-nCoV/USA-WA1/2020 virus strain was isolated from a throat swab of a patient diagnosed with COVID-19 in Washington, USA in January 2020 (BEI Resources, NR-52281). Humanized ACE2 transgenic mice were obtained from Jackson Laboratory, USA.
  • the 12 animals were randomly divided into 2 groups (6 animals/group): SARS-CoV-2 virus infection group (ie "model group") and compound 007 treatment group (300mpk). All animals were inoculated with 10 4 PFU of SARS-CoV-2 virus, and the animals in the treatment group were given 300 mpk compound 007 by oral gavage at the same time, once a day, for 14 days; the model group was given an equal volume of 0.5% CMC-Na . Animal survival was recorded daily.
  • Example 4 Antiviral effect of compound 007 on SARS-CoV2 in Vero E6 cells
  • Example 5 In vivo antiviral effect of compound 007 on SARS-CoV-2
  • Humanized K18-hACE2 transgenic mice purchased from Jackson Laboratory, USA. Nasal inoculation of 1000 PFU of the original SARS-COV-2 strain (USA-WA1/2020), Delta variant (B.1.617.2) or Omicron variant (BA.1.1.529), on the day of virus inoculation, orally
  • the vehicle (0.5% CMC-Na aqueous solution, model group), 100 mg/kg, 300 mg/kg of compound 007 was given by intragastric administration, or 25 mg/kg of remdesivir was given by subcutaneous injection, once a day for 21 consecutive days.
  • the lung tissues of the mice were collected for detection, homogenized, and the viral load in the lung tissues of animals in each group was detected by qPCR.
  • the lung tissues of the model group and the compound 007 treatment group were fixed, embedded in paraffin, and sectioned, and H&E staining and Masson staining were performed on the lung tissue sections to evaluate Anti-inflammatory and anti-fibrotic effects of compound 007.

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Abstract

提供预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂或者有效量的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合。

Description

治疗病毒感染的方法 发明领域
本发明属于生物医药领域，并具体涉及预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂或者有效量的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合。
发明背景
[根据细则26改正23.09.2022]　
人类冠状病毒最早是在20世纪60年代中期发现的，它们是在他们生活中的某个时间感染大多数人的普通病毒，通常会导致轻度到中度的上呼吸道和胃肠道疾病。称为“中东呼吸综合症冠状病毒”(MERS-CoV或MERS)的新型冠状病毒于2012年在沙特阿拉伯首次报道，并已蔓延至其他几个国家。
严重急性呼吸综合征冠状病毒2(SARS-CoV-2)导致的疾病为COVID-19。目前，尚没有针对SARS-CoV-2感染的有效治疗手段或疫苗，疾病控制主要依赖与严格的物理隔离切断传播途径，这会直接造成严重的经济损失。
发明概述
在一个方面中，本发明提供预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂。
在另一方面中，本发明提供Rho相关蛋白激酶抑制剂在制备用于预防和/或治疗病毒感染的药物中的用途。
在另一方面中，本发明提供Rho相关蛋白激酶抑制剂，其用于预防和/或治疗病毒感染。
在一个方面中，本发明提供预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合。
在另一方面中，本发明提供Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合在制备用于预防和/或治疗病毒感染的药物中的用途。
在另一方面中，本发明提供Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合，其用于预防和/或治疗病毒感染。
在另一方面中，本发明提供药物组合物，其包含Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合以及药学上可接受的载体。
在另一方面中，本发明提供药盒，其包含多个容器以及任选存在的说明书，每个容器中包含Rho相关蛋白激酶抑制剂或者一种其它药物，以及任选存在的药学上可接受的载体。
附图简要说明
图1A显示用化合物007处理24小时后对SARS-CoV2病毒复制的抑制作用。
图1B显示用化合物007处理48小时后对SARS-CoV2病毒复制的抑制作用。
图2显示化合物007对SARS-CoV-2病毒感染小鼠的保护作用。
图3显示化合物007对SARS-COV2不同毒株感染模型肺组织病毒载量抑制作用(图3A显示SARS-CoV-2原始毒株(USA-WA1/2020)感染的肺组织中的病毒载量；图3B显示SARS-CoV-2 delta变异株(B.1.617.2)感染的肺组织中的病毒载量；图3C显示SARS-CoV-2 omicron变异株(BA.1.1.529)感染的肺组织中的病毒载量)。
图4显示SARS-CoV-2感染后小鼠肺组织H&E染色图片(注：a-d为感染后第7天的图片，e-h为感染后第14天的图片。c、d、g、h分别为a、b、e、f放大2.5倍的图片)。
图5显示SARS-CoV-2感染后小鼠肺组织Masson染色图片(注：a-d为感染后第7天的图片，e-h为感染后第14天的图片。c、d、g、h分别为a、b、e、f放大2.5倍图片)。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员 通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为线性或支化饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CH 2F、CHF 2、CF 3、CCl 3、C 2F 5、C 2Cl 5、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所使用，术语“环烷基”指饱和的单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等))，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和的单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“杂环基”、“亚杂环基”和“杂环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3-10元(亚)杂环(基)”是具有2-9个(如2、3、4、5、6、7、8或9个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和(亚)杂环(基)。亚杂环基和杂环(基)的实例包括但不限于：(亚)环氧乙烷基、(亚)氮丙啶基、(亚)氮杂环丁基(azetidinyl)、(亚)氧杂环丁基(oxetanyl)、(亚)四氢呋喃基、(亚)二氧杂环戊烯基(dioxolinyl)、(亚)吡咯烷基、(亚)吡咯烷酮基、(亚)咪唑烷基、(亚)吡唑烷基、(亚)吡咯啉基、(亚)四氢吡喃基、(亚)哌啶基、(亚)吗啉基、(亚)二噻烷基(dithianyl)、(亚)硫吗啉基、(亚)哌嗪基或(亚)三噻烷基(trithianyl)。所述基团也涵盖双环系统，包括螺环、稠合或桥连系统(诸如8-氮杂螺[4.5]癸烷、3,9-二氮杂螺[5.5]十一烷、2-氮杂双环[2.2.2]辛烷等)。亚杂环基和杂环(基)可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子系统的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-10(亚)芳基”和“C 6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基、(亚)呋喃基、(亚)吡咯基、(亚)噁唑基、(亚)噻唑基、(亚)咪唑基、(亚)吡唑基、(亚)异噁唑基、(亚)异噻唑基、(亚)噁二唑基、(亚)三唑 基、(亚)噻二唑基等，以及它们的苯并衍生物；或(亚)吡啶基、(亚)哒嗪基、(亚)嘧啶基、(亚)吡嗪基、(亚)三嗪基等，以及它们的苯并衍生物。
如本文中所使用，术语“芳烷基”优选表示芳基或杂芳基取代的烷基，其中所述芳基、杂芳基和烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，所述杂芳基可具有5-14个环原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员，其通过所述含氮杂环中的氮原子以及任一其余环原子与分子的其余部分连接，所述含氮杂环任选地为苯并稠合的，并且优选通过所述含氮杂环中的氮原子以及所稠合的苯环中的任一碳原子与分子的其余部分连接。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘( 2H)、氚( 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如一个、两个、三个或四个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本文中可使用实线(——)、实楔形
Figure PCTCN2022119256-appb-000001
或虚楔形
Figure PCTCN2022119256-appb-000002
描绘本发明的化合物的化学键。使用实线以描绘键连至不对称碳原子的键欲表明，包括该碳原子处的所有可能的立体异构体(例如，特定的对映异构体、外消旋混合物等)。使用实或虚楔形以描绘键连至不对称碳原子的键欲表明，存在所示的立体异构体。当存在于外消旋混合物中时，使用实及虚楔形以定义相对立体化学，而非绝对立体化学。除非另外指明，否则本发明的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻 转异构体及其混合物)的形式存在。本发明的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、丁二酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐及昔萘酸盐(xinofoate)。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、苄星青霉素盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐及锌盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保 护的形式。这可以通过常规的保护基实现，例如，在T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物或药盒中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述药物组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物及药盒中的各组分可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物及药盒中的各组分。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
本文所用的术语“容器”为用于容纳药物组分的容器。此容器可用于制备、储存、运输和/或独立/批量销售，其意图涵盖瓶、罐、小瓶、烧瓶、注射器、管(例如用于乳膏制品)，或者用于制备、容纳、储存或分配药物产品的任何其它容器。
本文所用的术语“说明书”为插页、标签、标示等，其列举了与位于所述容器内的药物组分相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组分获准用于的适应症。所述包装说明书可由任何材料制成，可从所述材料上读取包含于其中或其上的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等)，其上可形成(例如印刷或施涂)所需信息。
术语“有效量”是指在施用条件下足以达到所需治疗效果的量，其导致病理学症状、疾病进展、与之相关的生理状况改善或诱导对前述疾病进行的抵抗力。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
本发明中的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合治疗可以提供“协同作用”和“协同增效作用”，即当一起使用活性成分时获得的效果大于单独使用化合物产生的作用总和。协同增效抗病毒作用表示抗病毒效应，其大于组合中单个活性成分的预测的纯加和效应。
治疗方法和用途
在一些实施方案中，本发明提供预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂。
在另一些实施方案中，本发明提供Rho相关蛋白激酶抑制剂在制备用于预防和/或治疗病毒感染的药物中的用途。
在另一些实施方案中，本发明提供Rho相关蛋白激酶抑制剂，其用于预防和/或治疗病毒感染。
在一些实施方案中，本发明提供预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合。
在另一些实施方案中，本发明提供Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合在制备用于预防和/或治疗病毒感染的药物中的用途。
在另一些实施方案中，本发明提供Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合，其用于预防和/或治疗病毒感染。
在一些实施方案中，所述病毒感染为冠状病毒科感染，并且所述冠状病毒科感染由冠状病毒科病毒引起。
在优选的实施方案中，所述Rho相关蛋白激酶抑制剂为式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2022119256-appb-000003
其中：
环A为
Figure PCTCN2022119256-appb-000004
以上基团通过*或**标记的两个位置之一与嘧啶环连接，并且另一位置与羰基连接；
R选自H和C 1-6烷基；
R 1为
Figure PCTCN2022119256-appb-000005
R 2选自H和C 1-6烷基；
R 3、R 4、R 7和R 8在每次出现时各自独立地选自H、卤素、-NR 5R 6、-OH、C 1-6烷基和-OR 5；
R 9和R 10在每次出现时各自独立地选自H、卤素、C 1-6烷基、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5和-C 1-6亚烷基-O(P＝O)(OH) 2；
上述亚烷基、烷基、烯基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自卤素、C 1-6烷基和-OR 5的取代基取代；
R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
m在每次出现时各自独立地为0、1、2或3的整数；
n在每次出现时各自独立地为0、1或2的整数。
在优选的实施方案中，环A为
Figure PCTCN2022119256-appb-000006
以上基团通过*标记的位置与嘧啶环连接，并且通过**标记的位置与羰基连接，其中R 10选自H和C 1-6烷基，优选为H或甲基。
在优选的实施方案中，环A优选为
Figure PCTCN2022119256-appb-000007
以上基团通过*标记的位置与嘧啶环连接，并且通过**标记的位置与羰基连接。
在优选的实施方案中，R为H。
在优选的实施方案中，R 2为H。
在优选的实施方案中，R 5和R 6在每次出现时各自独立地选自H、甲基和乙基。
在优选的实施方案中，R 3、R 4、R 7和R 8在每次出现时各自独立地选自H、F、Cl、Br、I、-NH 2、-OH、甲基、三氟甲基、-CH 2-Ph、甲氧基、乙氧基和-CH 2OCH 3。
在优选的实施方案中，R 3为H。
在优选的实施方案中，R 4选自H和卤素(例如F、Cl、Br或I)，优选为H或F。
在优选的实施方案中，R 7选自H和卤素(例如F、Cl、Br或I)，优选为H或F。
在优选的实施方案中，R 8为H。
在优选的实施方案中，R 9和R 10在每次出现时各自独立地选自H、F、Cl、Br、甲基、乙基、正丙基、异丙基、乙烯基、环丙基、环丁基、环戊基、氧杂环丁烷基、单氟甲基、二氟甲基、三氟甲基、乙酰基、-CH 2CHF 2、-CH 2OH、-CH 2OCH 3、-CH 2CH 2OCH 3、-CH 2-O(P＝O)(OH) 2、
Figure PCTCN2022119256-appb-000008
Figure PCTCN2022119256-appb-000009
在优选的实施方案中，R 9在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，优选为H。
在优选的实施方案中，R 10在每次出现时各自独立地选自H和C 1-6烷基，优选为H、甲基、乙基、正丙基或异丙基，最优选为H或甲基。
在优选的实施方案中，本发明提供预防和/或治疗病毒感染的方法，其中所述Rho相关蛋白激酶抑制剂为具有式(II)的结构的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2022119256-appb-000010
其中各基团如上文所定义。
在优选的实施方案中，本发明提供预防和/或治疗病毒感染的方法，其中所述Rho相关蛋白激酶抑制剂为具有式(III)的结构的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2022119256-appb-000011
其中R 10为H或甲基，优选为甲基。
在优选的实施方案中，所述Rho相关蛋白激酶抑制剂为具有以下结构的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
Figure PCTCN2022119256-appb-000012
Figure PCTCN2022119256-appb-000013
在一些实施方案中，所述Rho相关蛋白激酶抑制剂根据WO 2019/001572 A1(将其通过援引加入本文)中公开的方法制备。
在一些实施方案中，本发明提供预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合；
其中所述其它药物优选为选自预防或治疗病毒感染的小分子药物、细胞因子药物、治疗性抗体、炎症因子风暴治疗药物、小干扰RNA和疫苗中的一种或多种。
在一些实施方案中，所述预防或治疗病毒感染的小分子药物为选自RNA聚合酶抑制剂、内切酶抑制剂、HIV蛋白酶抑制剂、冠状病毒主蛋白酶抑制剂、冠状病毒3C样蛋白酶(3C-like proteinase)抑制剂、SARS-Cov-2 3-胰糜样蛋白酶(3CLpro)抑制剂、刺突蛋白酶(S蛋白酶)抑制剂、跨膜丝氨酸蛋白酶2(TMPRSS2)抑制剂、血管紧张素转化酶2(ACE2)阻断抑制剂、病毒膜融合和内吞抑制剂和囊膜阻断剂中的一种或多种。
在一些实施方案中，所述预防或治疗病毒感染的小分子药物为选自利巴韦林、法匹拉韦、巴洛沙韦、BCX4430(其结构为
Figure PCTCN2022119256-appb-000014
)、匹莫地韦(VX-787)、硝唑尼特(也称作“硝唑克酰胺”)、达芦那韦、洛匹那韦、利托那韦、奈非那韦、阿比朵尔、氯喹、羟氯喹、瑞德西韦、复合维生素B、维生素C、维生素D和补锌剂中的一种或多种。
在一些实施方案中，所述细胞因子药物为选自干扰素(例如天然/重组干扰素、空间构象改变的干扰素、干扰素偶联物或干扰素融合蛋白)、白介素、集落刺激因子、肿瘤坏死因子和生长因子中的一种或多种。
在一些实施方案中，所述治疗性抗体为选自SARS-CoV单抗、SARS-CoV-2单抗和MERS-CoV单抗中的一种或多种。
在一些实施方案中，所述炎症因子风暴治疗药物为选自Vesatolimod、酮替芬、醋酸格拉替雷、多环西素、罗氟司特、IL-6单抗、IL-6R单抗(例如托珠单抗)、TLR3单抗、哺乳动物防御素、镍纹蛋白样蛋白/IL-41片段、糖皮质激素(例如地塞米松、泼尼松、甲基泼尼松和氢化可的松)和广谱抗生 素(如阿奇霉素)中的一种或多种。
在一些实施方案中，所述疫苗为针对冠状病毒科病毒的疫苗，特别地为灭活疫苗、核酸疫苗、重组蛋白/亚单位疫苗、活病毒载体疫苗、减毒疫苗或者基于DNA或RNA策略或者复制载体或非复制载体策略开发的疫苗。
在一些实施方案中，所述冠状病毒科病毒选自SARS-CoV、SARS-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43、HCoV-HKU1及其变体。
在一些实施方案中，SARS-CoV-2的变体包括但不限于Alpha(B.1.1.7)、Beta(B.1.351)、Gamma(P.1)、Delta(B.1.617.2)和Omicron(B.1.1.529)。
在一些实施方案中，由所述冠状病毒感染引起的疾病为中东呼吸综合症、严重急性呼吸系统综合症或者COVID-19。
在一些实施方案中，所述冠状病毒科病毒是严重急性呼吸综合征冠状病毒2(SARS-CoV-2或者2019-nCoV)，其导致的疾病为COVID-19。
在一些实施方案中，将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分以约0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
在一些实施方案中，将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg或约300mg/kg体重的量给药。
在一些实施方案中，将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分的每日剂量一次性给予或分两次、三次或四次给予。
在一些实施方案中，将所述组合中的活性成分同时、顺序或交替给药。
在一些实施方案中，将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少1个月、至少2个月、至少3个月、至少4个月、至少5个月、至少6个月、至少1年或至少2年。
在一些实施方案中，将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
在一些实施方案中，将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药，并且所述组合中的活性成分的给药途径可以相同或不同。
本发明涵盖以上实施方案的任意组合。
药物组合物和药盒
在另一实施方案中，本发明提供药物组合物，其包含Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合以及药学上可接受的载体；其中所述Rho相关蛋白激酶抑制剂以及所述其它药物分别如上文所定义。
在另一实施方案中，本发明提供药盒，其包含多个(例如2个、3个或4个)容器以及任选存在的说明书，每个容器中包含Rho相关蛋白激酶抑制剂或者一种其它药物，以及任选存在的药学上可接受的载体；其中所述Rho相关蛋白激酶抑制剂以及所述其它药物分别如上文所定义。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
实施例中所使用化合物128具有以下结构，其根据WO 2019/001572 A1中公开的方法制备。
Figure PCTCN2022119256-appb-000015
实施例1.ROCK2激酶活性检测
采用商品化的CISBIO激酶检测试剂盒HTRF KinEASE-STK S2试剂盒(62ST2PEC)进行激酶IC 50测定。反应所用的激酶ROCK2(01-119)购自Carna Biosciences。
实验开始前，根据需要，按照激酶检测试剂盒说明书用相应试剂配制如下工作液：1×激酶缓冲液，5×STK-S2底物工作液(1.5μM)和5×ATP工作液(1.5μM)、5×ROCK2激酶工作液、4×抗生蛋白链菌素-XL665工作液、4×STK-Ab-穴状化合物2检测液，然后进行如下操作。
采用DMSO浓度为2.5％的1×激酶缓冲液配制得到10000nM的化合物溶液，采用上述含DMSO的激酶缓冲液再对化合物进行逐级稀释，得到9个不同浓度的待测化合物溶液。除测试化合物孔外，设置阳性孔(含有除化合物之外的所有试剂)和阴性孔(含有除待测化合物和激酶外的所有试剂)。除对照孔(阳性孔和阴性孔)外，向所有反应孔中加入4μL的待测化合物溶液，向对照孔中加入4μL 2.5％的DMSO溶液。然后，再向所有反应孔中加入2μM底物(即2μL 5×STK-S2底物工作液)。向除阴性孔外的所有反应孔中加入2μL的5×ROCK2激酶工作液(含1.4ng ROCK2激酶)，阴性孔用2μL的1×激酶缓冲液补足体积。向所有反应孔中加入2μL 5×ATP工作液，室温孵育2小时。待激酶反应结束后，向所有反应孔中加入5μL 4×抗生蛋白链菌素-XL665工作液，混匀后立即加入5μL 4×STK-Ab-穴状化合物2检测液，室温孵育1小时后，用ENVISION(Perkinelmer)仪器检测荧光信号(激发波长为320nm，发射波长为665nm和615nm)。通过各孔荧光强度值计算出每个孔中的抑制率：ER(Emission Ratio,发射光比率)＝(665nm处荧光强度/615nm处荧光强度)；抑制率＝(ER阳性-ER待测化合物)/(ER阳性-ER阴性)*100％，用软件PRISM 5.0绘制曲线图，同时用PRISM 5.0拟合得到各待测化合物的半数抑制浓度(IC 50)。化合物IC 50值如下表所示。
表1
化合物 ROCK2 IC 50nM 化合物 ROCK2 IC 50nM
化合物006 34 化合物011 9
化合物007 33 化合物020 44
化合物008 24 化合物021 45
化合物009 12 化合物022 75
化合物010 61 化合物128 27
实施例2：化合物007体外抗SARS-CoV-2作用
人呼吸道上皮细胞Calu-3(ATCC，HTB-55)购于ATCC；SARS-CoV-2病毒(2019-nCoV/USA-WA1/2020病毒株)分离自美国华盛顿1位2020年1月COVID-19确诊患者咽拭子(BEI Resources，NR-52281)。Calu-3培养过夜，待融合度达到80-90％用于实验。取适量细胞接种于96孔培养板中，加入含SARS-CoV-2病毒上清液10μL进行感染，同时加入1、5、10和25μM化合物007，在培养24小时和48小时后分别取上清液，通过QPCR方法检测病毒RNA水平，评价化合物007体外抗病毒作用，0.1％DMSO作为阴性对照。结果显示，24小时和48小时后，1、5、10和25μM的化合物007均能显著抑制SARS-CoV-2病毒增殖(与阴性对照相比，****p<0.0001)，1-25μM化合物007的抑制率在90％以上(参见图1A和图1B)。
实施例3：化合物007对SARS-CoV-2病毒感染小鼠的保护作用
2019-nCoV/USA-WA1/2020病毒株分离自美国华盛顿1位2020年1月COVID-19确诊患者咽拭子(BEI Resources，NR-52281)。人源化ACE2转基因小鼠获得自美国杰克逊实验室。
将12只动物随机分为2组(6只/组)：SARS-CoV-2病毒感染组(即“模型组”)和化合物007治疗组(300mpk)。所有动物接种10 4PFU SARS-CoV-2病毒，治疗组动物同时经口灌胃给予300mpk剂量的化合物007，每日一次，给药14天；模型组平行地给予等体积的0.5％CMC-Na。每日记录动物生存率。
结果显示：病毒感染后第10天模型组动物全部死亡，化合物007治疗组仅1只动物死于第11天，第14天动物生存率为83.3％(参见图2)。结果表明化合物007在体内具有显著抗病毒作用，可显著降低动物死亡率。
实施例4：在Vero E6细胞中化合物007对SARS-CoV2的抗病毒作用
首先将Vero E6细胞接种于96孔板中，加入不同剂量的化合物007(0.04-20μM)或瑞德西韦(0.04-20μM)，孵育72h后通过CCK-8方法检测细胞活力，计算化合物对Vero E6细胞的抑制率(CC 50)，评估化合物对细胞生长的影响。抑制率计算公式为：抑制率(％)＝100×(A 对照孔-A 检测孔)/A 对照孔，应用Graph prism 8.0软件计算化合物对细胞生长抑制的CC 50值。
将Vero E6细胞接种到48孔板，每孔加入100μL原始毒株(序列登录号NIMDCN0000HUI)或Delta变异株(序列登录号NMDC60042793)病毒稀释液(MOI＝0.01)与100μL不同浓度受试物化合物007(0.04-20μM)或瑞德西韦(0.02-10μM)，37℃，5％CO 2共孵育1h，吸弃病毒-样品混合培养基，并用1×PBS清洗两次后换成只含化合物007或瑞德西韦的培养基继续培养。37℃，5％CO 2培养48h后，收集细胞上清液，提取病毒RNA，用于Real-time PCR病毒定量，计算待测样品对病毒复制的抑制率(EC 50)。病毒复制抑制率计算公式为：病毒复制抑制率(％)＝(对照组病毒量-样品组病毒量)/对照组病毒量×100％，应用Graph prism 8.0软件画拟合曲线，计算化合物抗病毒的EC 50值。
结果显示，如表2所示，化合物007和瑞德西韦对Vero E6细胞的CC 50均>20μM；化合物007对原始毒株和Delta变异株的EC 50值均<40nM(SI>500)，瑞德西韦对原始毒株和Delta变异株的EC 50值分别为150nM(SI>133)和60nM(SI>333)。
表2 Vero E6细胞中化合物对SARS-CoV-2的抗病毒作用
Figure PCTCN2022119256-appb-000016
实施例5：化合物007对SARS-CoV-2的体内抗病毒作用
人源化K18-hACE2转基因小鼠(购自美国杰克逊实验室)。经鼻接种1000PFU的SARS-COV-2原始毒株(USA-WA1/2020)、Delta变异株(B.1.617.2)或Omicron变异株(BA.1.1.529)，病毒接种当天，分别经口灌胃给予溶媒(0.5％CMC-Na水溶液，模型组)、100mg/kg、300mg/kg的化合物007，或皮下注射给予25mg/kg的瑞德西韦，每天1次，连续给予21天。分别于给药后第7、14和21天取小鼠肺组织检测，匀浆并利用qPCR法检测各组动物肺组织病毒载量。同时，1000PFU SARS-CoV-2原始毒株感染模型中，取模型组和化合物007治疗组的动物肺组织进行固定、石蜡包埋、切片，并对肺组织切片分别进行H&E染色和Masson染色，评估化合物007的抗炎和抗纤维化作用。
结果显示，在SARS-COV-2原始毒株(USA-WA1/2020)、Delta变异株(B.1.617.2)或Omicron变异株(BA.1.1.529)感染模型中，与溶媒组相比，100mg/kg和300mg/kg的化合物007、瑞德西韦治疗7天、14天或21天均能显著降低小鼠病毒载量，结果详见图3A、图3B和图3C。
组织切片H&E染色结果如图4所示。结果表明，1000PFU SARS-CoV-2原始毒株感染7天(图4a-c)和14天(图4e-g)后，化合物007治疗组小鼠肺组织在肺间质性炎性细胞浸润、肺泡壁增厚、肺泡塌陷、坏死细胞碎片等方面的病理学改变明显减轻。
组织切片Masson染色结果如图5所示。1000PFU SARS-CoV-2原始毒株感染7天和14天后，模型组中小鼠的肺组织可见明显胶原堆积；而在化合物007治疗组中，SARS-CoV-2感染引起的小鼠肺组织胶原堆积明显降低。
除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (21)

  1. 预防和/或治疗病毒感染的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂，
    其中所述Rho相关蛋白激酶抑制剂优选为式(I)的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    Figure PCTCN2022119256-appb-100001
    其中：
    环A为
    Figure PCTCN2022119256-appb-100002
    以上基团通过*或**标记的两个位置之一与嘧啶环连接，并且另一位置与羰基连接；优选地，环A为
    Figure PCTCN2022119256-appb-100003
    以上基团通过*标记的位置与嘧啶环连接，并且通过**标记的位置与羰基连接，其中R 10选自H和C 1-6烷基，优选为H或甲基；
    R选自H和C 1-6烷基；
    R 1为
    Figure PCTCN2022119256-appb-100004
    R 2选自H和C 1-6烷基；
    R 3、R 4、R 7和R 8在每次出现时各自独立地选自H、卤素(例如F、Cl、Br或I)、-NR 5R 6、-OH、C 1-6烷基和-OR 5；
    R 9和R 10在每次出现时各自独立地选自H、卤素、C 1-6烷基(例如甲基)、C 2-6烯基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R 5和-C 1-6亚烷基-O(P＝O)(OH) 2；
    上述亚烷基、烷基、烯基、环烃基、杂环基、芳基、杂芳基和芳烷基在每次出现时各自任选地被一个或多个独立地选自卤素、C 1-6烷基和-OR 5的取代基取代；
    R 5和R 6在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基；
    m在每次出现时各自独立地为0、1、2或3的整数；
    n在每次出现时各自独立地为0、1或2的整数；并且
    所述病毒感染优选为冠状病毒科感染，并且所述冠状病毒科感染由冠状病毒科病毒引起。
  2. 权利要求1的方法，其中所述Rho相关蛋白激酶抑制剂为具有式(II)的结构的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    Figure PCTCN2022119256-appb-100005
    其中各基团如权利要求1中所定义；
    优选地，所述Rho相关蛋白激酶抑制剂为具有式(III)的结构的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    Figure PCTCN2022119256-appb-100006
    其中R 10为H或甲基，优选为甲基。
  3. 权利要求1或2的方法，其中所述Rho相关蛋白激酶抑制剂为具有以下结构的化合物或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    Figure PCTCN2022119256-appb-100007
  4. 权利要求1-3中任一项的方法，其包括向需要其的个体给药有效量的Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合；
    其中所述其它药物优选为选自预防或治疗病毒感染的小分子药物、细胞因子药物、治疗性抗体、炎症因子风暴治疗药物、小干扰RNA和疫苗中的一种或多种。
  5. 权利要求4的方法，其中所述预防或治疗病毒感染的小分子药物为选自RNA聚合酶抑制剂、内切酶抑制剂、HIV蛋白酶抑制剂、冠状病毒主蛋白酶抑制剂、冠状病毒3C样蛋白酶抑制剂、SARS-Cov-2 3-胰糜样蛋白酶(3CLpro)抑制剂、刺突蛋白酶(S蛋白酶)抑制剂、跨膜丝氨酸蛋白酶2(TMPRSS2)抑制剂、血管紧张素转化酶2(ACE2)阻断抑制剂、病毒膜融合和内吞抑制剂和囊膜阻断剂中的一种或多种。
  6. 权利要求4或5的方法，其中所述预防或治疗病毒感染的小分子药物为选自利巴韦林、法匹拉韦、巴洛沙韦、BCX4430、匹莫地韦(VX-787)、硝唑尼特、达芦那韦、洛匹那韦、利托那韦、奈非那韦、阿比朵尔、氯喹、羟氯喹、瑞德西韦、复合维生素B、维生素C、维生素D和补锌剂中的一种或多种。
  7. 权利要求4的方法，其中所述细胞因子药物为选自干扰素(例如天然/重组干扰素、空间构象改变的干扰素、干扰素偶联物或干扰素融合蛋白)、白介素、集落刺激因子、肿瘤坏死因子和生长因子中的一种或多种。
  8. 权利要求4的方法，其中所述治疗性抗体为选自SARS-CoV单抗、SARS-CoV-2单抗和MERS-CoV单抗中的一种或多种。
  9. 权利要求4的方法，其中所述炎症因子风暴治疗药物为选自Vesatolimod、酮替芬、醋酸格拉替雷、多环西素、罗氟司特、IL-6单抗、IL-6R单抗(例如托珠单抗)、TLR3单抗、哺乳动物防御素、镍纹蛋白样蛋白/IL-41片段、糖皮质激素(例如地塞米松、泼尼松、甲基泼尼松和氢化可的松)和广谱抗生素(如阿奇霉素)中的一种或多种。
  10. 权利要求4的方法，其中所述疫苗为针对冠状病毒科病毒的疫苗，特别地为灭活疫苗、核酸疫苗、重组蛋白/亚单位疫苗、活病毒载体疫苗、减毒疫苗或者基于DNA或RNA策略或者复制载体或非复制载体策略开发的疫苗。
  11. 权利要求1-10中任一项的方法，其中所述冠状病毒科病毒选自SARS-CoV、SARS-CoV-2、MERS-CoV、HCoV-229E、HCoV-NL63、HCoV-OC43、HCoV-HKU1及其变体；
    优选地，SARS-CoV-2的变体为Alpha(B.1.1.7)、Beta(B.1.351)、Gamma(P.1)、Delta(B.1.617.2)或Omicron(B.1.1.529)。
  12. 权利要求1-11中任一项的方法，其中由所述冠状病毒感染引起的疾病为中东呼吸综合症、严重急性呼吸系统综合症或者COVID-19。
  13. 权利要求1-12中任一项的方法，其中将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分以约0.005mg/日至约5000mg/日的量，例如约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450、500、550、600、650、700、750、800、850、900、950、1000、1500、2000、2500、3000、3500、4000、4500或5000mg/日的量给药。
  14. 权利要求1-13中任一项的方法，其中将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800 μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg或约300mg/kg体重的量给药。
  15. 权利要求1-14中任一项的方法，其中将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分的每日剂量一次性给予或分两次、三次或四次给予。
  16. 权利要求4-15中任一项的方法，其中将所述组合中的活性成分同时、顺序或交替给药。
  17. 权利要求1-16中任一项的方法，其中将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少1个月、至少2个月、至少3个月、至少4个月、至少5个月、至少6个月、至少1年或至少2年。
  18. 权利要求1-17中任一项的方法，其中将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
  19. 权利要求1-18中任一项的方法，其中将所述Rho相关蛋白激酶抑制剂或者所述组合中的各个活性成分通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药，并且所述组合中的活性成分的给药途径可以相同或不同。
  20. 药物组合物，其包含Rho相关蛋白激酶抑制剂与一种或多种其它药物的组合以及药学上可接受的载体；
    其中：
    所述Rho相关蛋白激酶抑制剂如权利要求1-3中任一项所定义；并且
    所述其它药物如权利要求4-10中任一项所定义。
  21. 药盒，其包含多个(例如2个、3个或4个)容器以及任选存在的说明书，每个容器中包含Rho相关蛋白激酶抑制剂或者一种其它药物，以及任选存在的药学上可接受的载体；
    其中：
    所述Rho相关蛋白激酶抑制剂如权利要求1-3中任一项所定义；并且
    所述其它药物如权利要求4-10中任一项所定义。
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