WO2024078553A1 - 治疗尘肺病的方法 - Google Patents

治疗尘肺病的方法 Download PDF

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WO2024078553A1
WO2024078553A1 PCT/CN2023/124137 CN2023124137W WO2024078553A1 WO 2024078553 A1 WO2024078553 A1 WO 2024078553A1 CN 2023124137 W CN2023124137 W CN 2023124137W WO 2024078553 A1 WO2024078553 A1 WO 2024078553A1
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days
pneumoconiosis
compound
formula
pharmaceutically acceptable
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PCT/CN2023/124137
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English (en)
French (fr)
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王红军
仲伟婷
李晶
刘伟娜
赵静
赵焰平
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北京泰德制药股份有限公司
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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
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a method for preventing, alleviating, alleviating and/or treating pneumoconiosis, which comprises administering an effective amount of the compound of the present application or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug to an individual in need thereof.
  • Pneumoconiosis is a systemic disease caused by long-term inhalation of industrial dust (dust) during occupational activities and its retention in the lungs.
  • dust industrial dust
  • patients with early pneumoconiosis have no obvious symptoms and signs, and their lung function does not change significantly.
  • chest pain and dyspnea gradually appear, accompanied by varying degrees of coughing, sputum, wheezing and other respiratory symptoms.
  • pneumoconiosis As a serious occupational disease, pneumoconiosis not only causes great harm to the patient's physical and mental health, but also increases the social burden and affects the stable development of the social economy. Currently, there is still no drug or measure that can clearly and effectively delay or block the progression of pneumoconiosis.
  • the present invention provides a method for preventing, alleviating, alleviating and/or treating pneumoconiosis, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:
  • Ring A is The above groups are attached to the pyrimidine ring through one of the two positions marked by * or **, and the other position is attached to the carbonyl group;
  • R is selected from H and C 1-6 alkyl
  • R2 is selected from H and C1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 are each independently selected at each occurrence 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 substituted at each occurrence with one or more substituents independently selected from halogen, C 1-6 alkyl and -OR 5 ;
  • R5 and R6 are each independently selected at each occurrence from H, C1-6 alkyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-14 membered heteroaryl and C6-12 aralkyl;
  • n is independently an integer of 0, 1, 2 or 3 at each occurrence;
  • n is independently an integer of 0, 1 or 2 at each occurrence.
  • the present invention provides use of the compound of formula (I) above or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug in the preparation of a medicament for preventing, alleviating, alleviating and/or treating pneumoconiosis.
  • the present invention provides a compound of the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof for use in preventing, alleviating, alleviating and/or treating pneumoconiosis.
  • Figure 1 shows the lung function index data of silicosis model mice (Note: compared with the model group, *p ⁇ 0.05, **p ⁇ 0.01, ****p ⁇ 0.0001).
  • Figure 2 shows the expression levels of TGF- ⁇ in BALF of mice in each group of silicosis model (Note: compared with the model group, ***p ⁇ 0.001, ****p ⁇ 0.0001).
  • Figure 3 shows the Masson’s Trichrome staining images of lung tissues of mice in each group of silicosis model.
  • FIG4 shows the pulmonary silica nodule scores of mice in each group of silicosis model (Note: compared with the model group, **p ⁇ 0.01, ***p ⁇ 0.001).
  • FIG5 shows H&E staining images of lung tissues of mice in each group of silicosis model.
  • FIG6 shows the lung tissue inflammation scores of mice in each group of silicosis model (Note: compared with the model group, *p ⁇ 0.05, **p ⁇ 0.01, ****p ⁇ 0.0001).
  • alkylene refers to 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. In some embodiments, the alkyl has 1 to 12, for example 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, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in this case, the group is referred to as "haloalkyl”) (e.g., CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, 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 to 6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl group is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-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 the pure E (enthafen) form, the pure Z (zusammen) form or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, 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 with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclonon
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C3-6cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) of 3 to 6 ring carbon atoms, which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.
  • cycloalkylene refers to saturated (i.e., “cycloalkylene” and “cycloalkyl") or unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbon atoms, including but not limited to (cyclo)propyl (ring), (cyclo)butyl (ring), (cyclo)pentyl (ring), (cyclo)hexyl (ring), (cyclo)heptyl (ring), (cyclo)octyl (ring), (cyclo)nonyl (ring), (cyclo)hexenyl (ring) and the like.
  • heterocyclyl refers to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double bonds and/or triple bonds within the ring) cyclic group having, for example, 3-10 (suitably 3-8, more suitably 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.
  • a “3-10 membered (sub)heterocyclyl” is a saturated or partially unsaturated (sub)heterocyclyl having 2-9 (e.g., 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms independently selected from N, O and S.
  • heterocyclyl and heterocyclic include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.
  • the group also encompasses bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro [4.5] decane, 3,9-diazaspiro [5.5] undecane, 2-azabicyclo [2.2.2] octane, etc.).
  • the heterocyclylene and heterocyclyl groups may be optionally substituted with one or more (eg, 1, 2, 3 or 4) suitable substituents.
  • (ylidene)aryl and “aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ electron system.
  • C 6-10 (ylidene)aryl and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as (ylidene)phenyl (benzene ring) or (ylidene)naphthyl (naphthalene ring).
  • the (ylidene)aryl and aromatic ring are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • suitable substituents e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.
  • heteroaryl(ene) 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, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being for example oxygen, nitrogen or sulfur) and, in each case additionally may be benzo-fused.
  • (ylidene)heteroaryl or “heteroaromatic ring” is selected from (ylidene)thiophenyl, (ylidene)furanyl, (ylidene)pyrrolyl, (ylidene)oxazolyl, (ylidene)thiazolyl, (ylidene)imidazolyl, (ylidene)pyrazolyl, (ylidene)isoxazolyl, (ylidene)isothiazolyl, (ylidene)oxadiazolyl, (ylidene)triazolyl, (ylidene)thiadiazolyl, etc., and their benzo derivatives; or (ylidene)pyridinyl, (ylidene)pyridazinyl, (ylidene)pyrimidinyl, (ylidene)pyrazinyl, (ylidene)triazinyl, etc., and their benzo derivatives.
  • aralkyl preferably refers to an alkyl substituted with an aryl or heteroaryl, wherein the aryl, heteroaryl and alkyl are as defined herein.
  • the aryl may have 6-14 carbon atoms
  • the heteroaryl may have 5-14 ring atoms
  • the alkyl may have 1-6 carbon atoms.
  • Exemplary aralkyls 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 the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and/or variables are permitted only if such combinations form 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 listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and/or together, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.
  • each substituent is selected independently of the other.
  • 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, where reasonable.
  • 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 are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature.
  • isotopes suitable for inclusion in the compounds of the present 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 (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32 P); and isotopes of sulfur (e.g.
  • isotopes of hydrogen e.g., deuterium ( 2H ), tritium ( 3H )
  • Certain isotopically labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (e.g., assays).
  • the radioisotopes tritium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes e.g., 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying routes and/or in the examples and preparations by using appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.
  • Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, for example, D 2 O, acetone-d 6 , or DMSO-d 6 .
  • 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, it can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention can exist as mixtures (commonly referred to as tautomers) of two or more structurally different forms in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.
  • solid lines can be used Solid wedge Virtual wedge Depicting chemical bonds of the compounds of the invention.
  • the use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the stereoisomer shown is present. When present in a racemic mixture, the solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry.
  • the compounds of the invention are intended to exist in the form of stereoisomers, which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
  • the present invention encompasses 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 ratio.
  • compositions of the present invention may exist in free form for treatment, or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which, after being administered to a patient in need thereof, can directly or indirectly provide a compound of the present invention or a metabolite or residue thereof. Therefore, when referring to "compounds of the present invention” herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • 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, hyaluronate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,
  • Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts.
  • bases include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.
  • esters means an ester derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form).
  • physiologically hydrolyzable esters which can be hydrolyzed under physiological conditions to release the compounds of the present invention in free acid or alcohol form.
  • the compounds of the present invention themselves may also be esters.
  • the compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • polar solvents as structural elements of the crystal lattice of the compounds, in particular water, methanol or ethanol.
  • the amount of polar solvents, in particular water may exist in a stoichiometric or non-stoichiometric ratio.
  • nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide; those skilled in the art will recognize nitrogen-containing heterocycles that are capable of forming N-oxides. It will be appreciated that tertiary amines are capable of forming N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxirane such as dimethyldioxirane.
  • peroxyacids such as peracetic acid and meta-chloroperbenzoic acid (MCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxirane such as dimethyldioxirane
  • metabolites of the compounds of the present invention i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a mammal for a period of time sufficient to produce a metabolic product thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have less pharmacological activity or no pharmacological activity, which when administered into or onto the body can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds that are easily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties” (e.g., as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).
  • the present invention also encompasses compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example, 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.
  • an effective amount refers to an amount sufficient to achieve the desired therapeutic effect under the conditions of administration, which results in improvement of pathological symptoms, disease progression, physiological conditions associated therewith, or inducing resistance to the aforementioned diseases.
  • the term "pneumoconiosis” refers to a systemic disease caused by long-term inhalation of industrial dust (dust) during occupational activities and its retention in the lungs. Pneumoconiosis can be divided into inorganic pneumoconiosis and organic pneumoconiosis according to the type of dust inhaled. Pneumoconiosis caused by inhalation of inorganic dust is called inorganic pneumoconiosis. Most pneumoconiosis is inorganic pneumoconiosis. Pneumoconiosis caused by inhalation of organic dust is called organic pneumoconiosis, such as cotton pneumoconiosis, farmer's lung, etc.
  • treating and “treating” mean to reverse, alleviate, inhibit, slow or arrest the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition.
  • “individual” includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • 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.).
  • the present invention provides a method for preventing, alleviating, alleviating and/or treating pneumoconiosis, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:
  • Ring A is The above groups are attached to the pyrimidine ring through one of the two positions marked by * or **, and the other position is attached to the carbonyl group;
  • R is selected from H and C 1-6 alkyl
  • R2 is selected from H and C1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 are each independently selected at each occurrence 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 substituted at each occurrence with one or more substituents independently selected from halogen, C 1-6 alkyl and -OR 5 ;
  • R5 and R6 are each independently selected at each occurrence from H, C1-6 alkyl, C3-10 cycloalkyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-14 membered heteroaryl and C6-12 aralkyl;
  • n is independently an integer of 0, 1, 2 or 3 at each occurrence;
  • n is independently an integer of 0, 1 or 2 at each occurrence.
  • Ring A is The above groups are connected to the pyrimidine ring through the position marked by *, and to the carbonyl group through the position marked by **, 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 via the position marked by * and to the carbonyl group via the position marked by **.
  • R is H
  • R2 is H.
  • R 5 and R 6 at each occurrence are each independently selected from H, methyl and ethyl.
  • R3 , R4 , R7 and R8 are each independently selected at each occurrence from H, F, Cl, Br, I, -NH2 , -OH, methyl, trifluoromethyl, -CH2 -Ph, methoxy, ethoxy and -CH2OCH3 .
  • R3 is H.
  • R 4 is selected from H and halogen (eg, F, Cl, Br or I), preferably H or F.
  • R 7 is selected from H and halogen (eg, F, Cl, Br or I), preferably H or F.
  • halogen eg, F, Cl, Br or I
  • R 8 is H.
  • R 9 is independently selected at each occurrence 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.
  • R 10 is independently selected at each occurrence 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, alleviating, alleviating and/or treating pneumoconiosis, which comprises administering to an individual in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:
  • the present invention provides a method for preventing, alleviating, alleviating and/or treating pneumoconiosis, comprising administering to an individual in need thereof an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:
  • R 10 is H or methyl, preferably methyl.
  • the compound has the following structure:
  • the compound is prepared according to the method disclosed in WO 2019/001572 A1 (which is incorporated herein by reference).
  • the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in an amount of about 0.005 mg/day to about 5000 mg/day, for example, 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.
  • the compound of Formula (I), Formula (II) or Formula (III) or its pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg body weight per day, 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, 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 1 ng/kg
  • the daily dose of the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered once or divided into two, three or four doses.
  • the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered continuously 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 26 days, at least 27 days, at least 28 days, at least 29 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.
  • the compound of Formula (I), Formula (II) or Formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered for one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) 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, or more.
  • the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is administered by injection (such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic preparation or by inhalation.
  • injection such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation
  • transdermal administration or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic preparation or by inhalation.
  • the compound of Formula (I), Formula (II) or Formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof is administered in a dosage form selected from tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.
  • the present invention provides the use of the above-mentioned compounds of formula (I), formula (II) or formula (III) or their pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs in the preparation of drugs for preventing, alleviating, reducing and/or treating pneumoconiosis.
  • the present invention provides a compound of the above-mentioned formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof, which is used for preventing, alleviating, reducing and/or treating pneumoconiosis.
  • the pneumoconiosis is inorganic pneumoconiosis or organic pneumoconiosis.
  • the pneumoconiosis is selected from silicosis, coal workers' pneumoconiosis, graphite pneumoconiosis, carbon black pneumoconiosis, asbestosis pneumoconiosis, talc pneumoconiosis, cement pneumoconiosis, mica pneumoconiosis, potters' pneumoconiosis, aluminum pneumoconiosis, welders' pneumoconiosis and foundry workers' pneumoconiosis.
  • the prevention, alleviation, reduction and/or treatment of pneumoconiosis includes the prevention, alleviation, reduction and/or treatment of the following symptoms: cough, sputum, chest pain and/or dyspnea.
  • the present invention covers any combination of the above embodiments.
  • mice After adaptive feeding, 6-8 week old male C57BL/6J mice were instilled with 40 ⁇ l SiO 2 suspension (600mg/kg) in the D1 airway to establish the model.
  • day 1 On the day of modeling (day 1), the animals were randomly divided into 3 groups according to their body weight and given vehicle (model group) and compound 007 (100mg/kg or 150mg/kg, once a day) by oral gavage for 28 consecutive days.
  • a normal control group was also set up, and 40 ⁇ l of normal saline was instilled in the D1 airway, and sterile water was given by oral gavage. No death was observed in any group of animals during the administration period.
  • Lung tissues were collected from all mice, and tissue sections were prepared for Masson’s Thricome staining and H&E staining for silica nodule scoring and inflammation scoring.
  • the silica nodule scoring used King’s five-point method [Zhujie Cao, et al. Acta Pharmacologica Sinica, 2021].
  • the degree of silica nodules in lung tissue was scored from 0 to 5. The higher the score, the more severe the tissue nodules.
  • the H&E pathology score was scored using the Szap method.
  • iel inflammation scoring standard, the higher the score of inflammatory cell infiltration in lung tissue (0-3), the higher the degree of inflammation in lung tissue (0 points, no, no alveolitis; 1 point, mild, mononuclear cell infiltration, thickening of alveolar septa, local involvement, pleural space-occupying lesions less than 20% of the lung, good alveolar structure; 2 points: moderate, more extensive alveolitis, involving 20%-50% of the lung, mainly pleural lesions; 3 points: severe, diffuse alveolitis, involving more than 50% of the lung, occasionally combined with intra-alveolar mononuclear cells and interstitial and/or some intra-alveolar hemorrhage areas). The results are shown in Table 1-2 and Figure 3-6.
  • compound 007 has the effect of improving mouse lung function, specifically increasing deep inspiration volume, reducing respiratory system resistance value and respiratory system elasticity.
  • compound 007 reduces mouse lung silica nodules and inflammation scores, and reduces TGF- ⁇ levels in BALF.

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Abstract

提供一种预防、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的式(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，

Description

治疗尘肺病的方法 发明领域
本发明属于生物医药领域，并具体涉及预防、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的本申请中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。
发明背景
尘肺病是由于在职业活动中长期吸入生产性粉尘(灰尘)，并在肺内潴留而引起的全身性疾病。一般来说，早期尘肺病患者多无明显症状和体征，肺功能也多无明显变化。随着病情的进展，逐渐出现以胸痛、呼吸困难为主并可伴有不同程度的咳嗽、咳痰、喘息等呼吸系统症状。
尘肺病患者由于长期吸入矿物性粉尘，呼吸系统的清除和防御机制受到严重损害，加之尘肺病慢性、进行性的特点，患者的抵抗力明显降低，常常发生各种并发症/合并症，如呼吸系统感染、气胸、肺结核、慢性阻塞性肺疾病、支气管扩张、支气管哮喘和慢性肺源性心脏病等。
尘肺病作为一种严重的职业病不仅会对患者的身心健康造成巨大伤害，还会加重社会负担，影响社会经济的稳定发展。目前仍没有药物或措施可以明确有效地延缓或阻断尘肺病的进展。
发明概述
在一个方面中，本发明提供预防、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的式(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：
其中：
环A为以上基团通过*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C1-6烷基；
R1为
R2选自H和C1-6烷基；
R3、R4、R7和R8在每次出现时各自独立地选自H、卤素、-NR5R6、-OH、C1-6烷基和-OR5；
R9和R10在每次出现时各自独立地选自H、卤素、C1-6烷基、C2-6烯基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)R5和-C1-6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、C1-6烷基和-OR5的取代基取代；
R5和R6在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
m在每次出现时各自独立地为0、1、2或3的整数；并且
n在每次出现时各自独立地为0、1或2的整数。
在另一方面中，本发明提供上述式(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、代谢物或前药在制备用于预防、缓解、减轻和/或治疗尘肺病的药物中的用途。
在另一方面中，本发明提供上述式(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，其用于预防、缓解、减轻和/或治疗尘肺病。
附图简要说明
图1显示矽肺模型小鼠肺功能指标数据(注：与模型组相比，*p<0.05,**p<0.01,****p<0.0001)。
图2显示矽肺模型各组小鼠BALF中TGF-β表达水平(注：与模型组相比，***p<0.001,****p<0.0001)。
图3显示矽肺模型各组小鼠肺组织Masson’s Trichrome染色图像。
图4显示矽肺模型各组小鼠肺二氧化硅结节评分(注：与模型组相比，**p<0.01,***p<0.001)。
图5显示矽肺模型各组小鼠肺组织H&E染色图像。
图6显示矽肺模型各组小鼠肺组织炎症评分(注：与模型组相比，*p<0.05,**p<0.01,****p<0.0001)。
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“C1-6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CH2F、CHF2、CF3、CCl3、C2F5、C2Cl5、CH2CF3、CH2Cl或-CH2CH2CF3等)。术语“C1-4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(“C2-6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“C3-6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“C6-10(亚)芳基”和“C6-10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、-NO2、C1-6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，D2O、丙酮-d6或DMSO-d6。
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或虚楔形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。
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。
如本文中所使用，术语“尘肺病”是指由于在职业活动中长期吸入生产性粉尘(灰尘)，并在肺内潴留而引起的全身性疾病。尘肺病按其吸入粉尘的种类不同，可分为无机尘肺病和有机尘肺病。吸入无机粉尘所致的尘肺病，称为无机尘肺病。尘肺病大部分为无机尘肺病。吸入有机粉尘所致的尘肺病称为有机尘肺病，如棉尘肺、农民肺等。
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、延缓或阻断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。
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)。
在一些实施方案中，本发明提供预防、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的式(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：
其中：
环A为以上基团通过*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C1-6烷基；
R1为
R2选自H和C1-6烷基；
R3、R4、R7和R8在每次出现时各自独立地选自H、卤素、-NR5R6、-OH、C1-6烷基和-OR5；
R9和R10在每次出现时各自独立地选自H、卤素、C1-6烷基、C2-6烯基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)R5和-C1-6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、C1-6烷基和-OR5的取代基取代；
R5和R6在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
m在每次出现时各自独立地为0、1、2或3的整数；并且
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R10选自H和C1-6烷基，优选为H或甲基。
在优选的实施方案中，环A优选为以上基团通过*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，R2为H。
在优选的实施方案中，R5和R6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，R3、R4、R7和R8在每次出现时各自独立地选自H、F、Cl、Br、I、-NH2、-OH、甲基、三氟甲基、-CH2-Ph、甲氧基、乙氧基和-CH2OCH3。
在优选的实施方案中，R3为H。
在优选的实施方案中，R4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，R7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，R8为H。
在优选的实施方案中，R9和R10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、-CH2CHF2、-CH2OH、-CH2OCH3、-CH2CH2OCH3、-CH2-O(P＝O)(OH)2、
在优选的实施方案中，R9在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基，优选为H。
在优选的实施方案中，R10在每次出现时各自独立地选自H和C1-6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、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的式(II)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：
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、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的式(III)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：
其中R10为H或甲基，优选为甲基。
在优选的实施方案中，所述化合物具有以下结构：

在一些实施方案中，所述化合物根据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，将所述式(I)、式(II)或式(III)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，将所述式(I)、式(II)或式(III)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，将所述式(I)、式(II)或式(III)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，将所述式(I)、式(II)或式(III)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26天、至少27天、至少28天、至少29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，将所述式(I)、式(II)或式(III)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26天、至少27天、至少28天、至少29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，将所述式(I)、式(II)或式(III)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。
在一些实施方案中，将所述式(I)、式(II)或式(III)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、代谢物或前药以选自片剂、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、酏剂和糖浆剂的剂型给药。
在一些实施方案中，本发明提供上述式(I)、式(II)或式(III)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、代谢物或前药在制备用于预防、缓解、减轻和/或治疗尘肺病的药物中的用途。
在一些实施方案中，本发明提供上述式(I)、式(II)或式(III)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，其用于预防、缓解、减轻和/或治疗尘肺病。
在一些实施方案中，所述尘肺病为无机尘肺病或有机尘肺病。
在优选的实施方案中，所述尘肺病选自矽肺、煤工尘肺、石墨尘肺、碳黑尘肺、石棉尘肺、滑石尘肺、水泥尘肺、云母尘肺、陶工尘肺、铝尘肺、电焊工尘肺和铸工尘肺。
在一些实施方案中，所述尘肺病的预防、缓解、减轻和/或治疗包括对以下症状的预防、缓解、减轻和/或治疗：咳嗽、咳痰、胸痛和/或呼吸困难。
本发明涵盖以上实施方案的任意组合。
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1
将经适应性饲养的6-8周龄雄性C57BL/6J小鼠适应性饲养后，于D1气道内滴注40μl SiO2混悬液(600mg/kg)造模，造模当天(day 1)根据体重大小将动物随机分为3组，分别经口灌胃给予溶媒(模型组)和化合物007(100mg/kg或150mg/kg，每天一次)，连续给药28天。另设正常对照组，于D1气道内滴注40μl生理盐水，口服灌胃给予灭菌水。给药期间，各组动物均未见死亡。
于最后一次给药2小时后，读取小鼠肺功能相关检测指标数据。结果如图1所示，与模型组相比，每天给药100mg/kg和150mg/kg的化合物007显著增加小鼠深吸气量(p<0.05,p<0.01)，降低呼吸系统阻力(p<0.05,p<0.05)和呼吸系统弹性(p<0.05,p<0.05)。
给药结束后，将动物实施安乐死，每组随机选取部分动物收集支气管肺泡灌洗液(BALF)，用于TGF-β检测。结果如图2所示，其表明，每天给药100mg/kg、150mg/kg的化合物007显著降低TGF-β水平(图2，p<0.001，p<0.0001)。
对全部小鼠收集肺组织，制备组织切片进行Masson’s Thricome染色和H&E染色用于进行二氧化硅结节评分和炎症评分，二氧化硅结节评分采用King’s五分法[Zhujie Cao,et al.Acta Pharmacologica Sinica,2021]，肺组织二氧化硅结节程度等级分数0-5，分数越高，说明组织结节严重程度越高；H&E病理评分采用Szapiel’s炎症评分标准，肺组织中炎症细胞浸润(0-3)分数越高，说明肺组织炎症程度越高(0分，无，无肺泡炎；1分，轻度，单核细胞浸润肺泡间隔增厚，局部受累，胸膜占位病变少于肺的20％，肺泡结构良好；2分：中度，更广泛的肺泡炎，累及肺20％-50％，主要是胸膜病变；3分：重度，弥漫性肺泡炎，累及肺50％以上，偶尔合并肺泡内单核细胞和间质和/或肺泡内的一些出血区域)。结果如表1-2和图3-6所示。
由结果可见，每天给药100mg/kg和150mg/kg的化合物007减少了二氧化硅诱导的结节形成和胶原纤维的沉积，并显著降低二氧化硅结节评分(图3-4，p<0.01,p<0.01)，各组二氧化硅结节评分如表1中所示。此外，100mg/kg和150mg/kg的化合物007对小鼠肺组织炎症具有明显改善作用，并降低炎症评分(p<0.01和p<0.05)(图5-6，表2)。
表1矽肺模型各组小鼠肺二氧化硅结节评分

表2矽肺模型各组小鼠肺组织炎症评分
综上，在二氧化硅诱导的小鼠肺结节模型中，化合物007具有改善小鼠肺功能作用，具体表现为增加深吸气量，降低呼吸系统阻力值和呼吸系统弹性。此外，化合物007降低小鼠肺二氧化硅结节和炎症评分，并降低BALF中TGF-β水平。
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 (12)

  1. 预防、缓解、减轻和/或治疗尘肺病的方法，其包括向需要其的个体给药有效量的式(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：
    其中：
    环A为以上基团通过*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；
    R选自H和C1-6烷基；
    R1为
    R2选自H和C1-6烷基；
    R3、R4、R7和R8在每次出现时各自独立地选自H、卤素(例如F、Cl、Br或I)、-NR5R6、-OH、C1-6烷基和-OR5；
    R9和R10在每次出现时各自独立地选自H、卤素、C1-6烷基(例如甲基)、C2-6烯基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)R5和-C1-6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、C1-6烷基和-OR5的取代基取代；
    R5和R6在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
    m在每次出现时各自独立地为0、1、2或3的整数；并且
    n在每次出现时各自独立地为0、1或2的整数。
  2. 权利要求1的方法，其中所述化合物具有式(II)的结构：
    其中各基团如权利要求1中所定义；
    优选地，所述化合物具有式(III)的结构：

    其中R10为H或C1-6烷基，优选为H或甲基，更优选为甲基。
  3. 权利要求1或2的方法，其中所述化合物具有以下结构：
  4. 权利要求1-3中任一项的方法，其中将所述式(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。
  5. 权利要求1-3中任一项的方法，其中将所述式(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。
  6. 权利要求1-5中任一项的方法，其中将所述式(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、代谢物或前药的每日剂量一次性给予或分两次、三次或四次给予。
  7. 权利要求1-6中任一项的方法，其中将所述式(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26天、至少27天、至少28天、至少29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。
  8. 权利要求1-7中任一项的方法，其中将所述式(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26天、至少27天、至少28天、至少29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。
  9. 权利要求1-8中任一项的方法，其中将所述式(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。
  10. 权利要求1-9中任一项的方法，其中将所述式(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、代谢物或前药以选自片剂、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、酏剂和糖浆剂的剂型给药。
  11. 权利要求1-10中任一项的方法，其中所述尘肺病为无机尘肺病或有机尘肺病；
    优选地，所述尘肺病选自矽肺、煤工尘肺、石墨尘肺、碳黑尘肺、石棉尘肺、滑石尘肺、水泥尘肺、云母尘肺、陶工尘肺、铝尘肺、电焊工尘肺和铸工尘肺。
  12. 权利要求1-11中任一项的方法，其中所述尘肺病的预防、缓解、减轻和/或治疗包括对以下症状的预防、缓解、减轻和/或治疗：咳嗽、咳痰、胸痛和/或呼吸困难。
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