Methods of treating pneumoconiosis

Abstract

Method of preventing, alleviating, alleviating and / or treating pneumoconiosis comprising administering to individual in need thereof effective amount of compound of formula (I) or pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite or prodrug thereof # imgabs0 #

Description

Treatment methods for pneumoconiosis Field of the Invention

[0001] 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 to an individual in need thereof an effective amount of a compound of the present application or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof.

[0002] Background of the Invention

[0003] Pneumoconiosis is a systemic disease caused by the long-term inhalation of industrial dust (dust) during occupational activities, which accumulates in the lungs. Generally speaking, patients with early-stage pneumoconiosis have no obvious symptoms or signs, and their lung function often remains unchanged. As the disease progresses, respiratory symptoms, primarily chest pain and dyspnea, may be accompanied by varying degrees of cough, sputum production, and wheezing.

[0004] Due to long-term inhalation of mineral dust, the clearance and defense mechanisms of the respiratory system of patients with pneumoconiosis are severely damaged. In addition, due to the chronic and progressive characteristics of pneumoconiosis, the patients' resistance is significantly reduced, and various complications / comorbidities often occur, such as respiratory infections, pneumothorax, tuberculosis, chronic obstructive pulmonary disease, bronchiectasis, bronchial asthma and chronic cor pulmonale.

[0005] As a serious occupational disease, pneumoconiosis not only causes significant harm to patients' physical and mental health, but also increases the social burden and impacts the stable development of the social economy. Currently, there are no medications or measures that can clearly and effectively slow or halt the progression of pneumoconiosis.

[0006] SUMMARY OF THE INVENTION

[0007] In one aspect, the present invention provides a method for preventing, alleviating, reducing and / or treating pneumoconiosis, comprising administering to a subject 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:

[0008] in:

[0009] 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;

[0010] R is selected from H and C 1-6 alkyl;

[0011] R 1 for

[0012] R 2 Selected from H and C 1-6 alkyl;

[0013] R 3 、R 4 、R 7 and R 8 is independently selected at each occurrence from H, halogen, -NR 5 R 6 、-OH、C 1-6 Alkyl and -OR 5 ;

[0014] R 9 and R 10 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R 5 and -C 1-6 Alkylene-O(P=O)(OH)2;

[0015] The above alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl and -OR 5 Substituents substituted;

[0016] R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0017] m is independently an integer of 0, 1, 2 or 3 at each occurrence; and

[0018] n is independently an integer of 0, 1 or 2 at each occurrence.

[0019] In another aspect, the present invention provides use of a compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof in the preparation of a medicament for preventing, alleviating, alleviating and / or treating pneumoconiosis.

[0020] In another aspect, the present invention provides a compound of formula (I) above or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof for use in preventing, alleviating, reducing and / or treating pneumoconiosis.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS

[0022] 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).

[0023] Figure 2 shows the expression levels of TGF-β in BALF of mice in each group of silicosis model (Note: compared with the model group, ***p<0.001, ****p<0.0001).

[0024] FIG3 shows the Masson's Trichrome staining images of lung tissues of mice in each group of silicosis model.

[0025] Figure 4 shows the lung silica nodule scores of mice in each group of silicosis model (Note: **p<0.01, ***p<0.001 compared with the model group).

[0026] FIG5 shows H&E staining images of lung tissues of mice in each group of silicosis model.

[0027] Figure 6 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).

[0028] Detailed Description of the Invention

[0029] definition

[0030] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0031] The terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0032] As used herein, the term "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.

[0033] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, such as 1 to 6, carbon atoms. For example, as used herein, the term "C 1-6 "Alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted with one or more (e.g., one to three) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "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).

[0034] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one double bond and having 2 to 6 carbon atoms ("C 2-6 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. When the compounds of the present invention contain an alkenylene group, the compounds may be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0035] As used herein, the term "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.

[0036] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring 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, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C3-6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 6 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0037] As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" refer 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, (cyclo)butyl, (cyclo)pentyl, (cyclo)hexyl, (cyclo)heptyl, (cyclo)octyl, (cyclo)nonyl, (cyclo)hexenyl, and the like.

[0038] As used herein, the terms "heterocyclyl", "heterocyclylene" and "heterocycle" refer to a saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., having one or more double 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. For example, a "3-10 membered heterocyclyl" is a saturated or partially unsaturated 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. Examples of heterocyclylene and heterocyclyl groups 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 (e.g., 1, 2, 3 or 4) suitable substituents.

[0039] As used herein, the terms "arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 (E)aryl" and "C 6-10 The term "aromatic ring" means an aromatic group containing 6 to 10 carbon atoms, such as (ene)phenyl (phenyl ring) or (ene)naphthyl (naphthalene ring). The (ene)aryl group and the aromatic ring are optionally substituted by one or more (such as one to three) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0040] As used herein, the terms "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, may additionally be benzo-fused. In particular, “heteroaryl” or “heteroaromatic ring” is selected from thiophenyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0041] As used herein, the term "aralkyl" preferably refers to an alkyl group substituted with an aryl or heteroaryl group, wherein the aryl, heteroaryl, and alkyl groups are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, the heteroaryl group may have 5-14 ring atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0042] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0043] As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and at least one nitrogen atom in the ring, which may optionally further contain one or more (e.g., one, two, three or four) ring members selected from N, O, C=O, S, S=O and S(=O)2, which is linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any remaining ring atoms, the nitrogen-containing heterocycle being optionally benzo-fused and preferably linked to the rest of the molecule via the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0044] The term "substituted" means that one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0045] If a substituent is described as being "optionally substituted," the 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 substituents listed, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the substituents listed, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0046] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0047] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, where reasonable.

[0048] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0049] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0050] 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. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g. 13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotope tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0051] The term "stereoisomer" refers to 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, racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that the scope of this application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0052] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. 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 indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including 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 present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0053] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0054] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0055] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.

[0056] 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, hyphenate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate.

[0057] Suitable base addition salts are formed with bases which form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0058] For a review of suitable salts see Stahl and Wermuth, “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0059] As used herein, the term "ester" refers to esters 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 the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0060] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0061] Those skilled in the art will appreciate that not all 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. Those skilled in the art will also recognize 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 and include 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. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0062] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0063] 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 little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily 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", Volume 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)).

[0064] The present invention also encompasses compounds of the present invention that contain protecting groups. During 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 using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0065] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0066] The term "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 induction of resistance to the aforementioned diseases.

[0067] As used herein, the term "pneumoconiosis" refers to a systemic disease caused by the long-term inhalation of industrial dust (dust) during occupational activities and its accumulation in the lungs. Pneumoconiosis can be divided into inorganic pneumoconiosis and organic pneumoconiosis based on the type of dust inhaled. Pneumoconiosis caused by inhalation of inorganic dust is called inorganic pneumoconiosis. The majority of pneumoconiosis cases are inorganic pneumoconiosis. Pneumoconiosis caused by inhalation of organic dust is called organic pneumoconiosis, such as byssinosis and farmer's lung.

[0068] As used herein, unless otherwise indicated, the term "treating" means to reverse, alleviate, inhibit, slow or arrest the progression of the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0069] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein 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.).

[0070] In some embodiments, the present invention provides a method for preventing, alleviating, reducing 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:

[0071] in:

[0072] 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;

[0073] R is selected from H and C 1-6 alkyl;

[0074] R 1 for

[0075] R 2 Selected from H and C 1-6 alkyl;

[0076] R 3 、R 4 、R 7 and R 8 is independently selected at each occurrence from H, halogen, -NR 5 R 6 、-OH、C 1-6 Alkyl and -OR 5 ;

[0077] R 9 and R 10 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R 5 and -C 1-6 Alkylene-O(P=O)(OH)2;

[0078] The above alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl and -OR 5 Substituents substituted;

[0079] R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl;

[0080] m is independently an integer of 0, 1, 2 or 3 at each occurrence; and

[0081] n is independently an integer of 0, 1 or 2 at each occurrence.

[0082] In a preferred embodiment, 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 **, where R 10 Selected from H and C 1-6 Alkyl, preferably H or methyl.

[0083] In a preferred embodiment, 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 **.

[0084] In a preferred embodiment, R is H.

[0085] In a preferred embodiment, R 2 For H.

[0086] In a preferred embodiment, R 5 and R 6 Each occurrence is independently selected from H, methyl and ethyl.

[0087] In a preferred embodiment, R 3 、R 4 、R 7 and R 8is independently selected at each occurrence from the group consisting of H, F, Cl, Br, I, -NH2, -OH, methyl, trifluoromethyl, -CH2-Ph, methoxy, ethoxy, and -CH2OCH3.

[0088] In a preferred embodiment, R 3 For H.

[0089] In a preferred embodiment, R 4 is selected from H and halogen (such as F, Cl, Br or I), preferably H or F.

[0090] In a preferred embodiment, R 7 is selected from H and halogen (such as F, Cl, Br or I), preferably H or F.

[0091] In a preferred embodiment, R 8 For H.

[0092] In a preferred embodiment, R 9 and R 10 is independently selected at each occurrence from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, vinyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, monofluoromethyl, difluoromethyl, trifluoromethyl, acetyl, -CH2CHF2, -CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2-O(P=O)(OH)2,

[0093] In a preferred embodiment, R 9 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl, preferably H.

[0094] In a preferred embodiment, R 10 Each occurrence is independently selected from H and C 1-6 Alkyl is preferably H, methyl, ethyl, n-propyl or isopropyl, and most preferably H or methyl.

[0095] In a preferred embodiment, 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 (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof:

[0096] wherein each group is as defined above.

[0097] In a preferred embodiment, the present invention provides a method for preventing, alleviating, relieving 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:

[0098] where R 10 It is H or methyl, preferably methyl.

[0099] In a preferred embodiment, the compound has the following structure:

[0100] In some embodiments, the compound is prepared according to the method disclosed in WO 2019 / 001572 A1 (which is incorporated herein by reference).

[0101] In some embodiments, 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.

[0102] In some embodiments, 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 in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg or about 1 mg / kg to about 50 mg / kg body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 550 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5

[0014] In some embodiments, the present invention relates to an agent that is administered in an amount of about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg of body weight.

[0103] In some embodiments, 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.

[0104] In some embodiments, 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 day, 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.

[0105] In some embodiments, 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) cycles of treatment, wherein each cycle lasts 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, or more. 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 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days; and there is an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between each two courses of treatment.

[0106] In some embodiments, 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 (e.g., intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including infusion) or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of an ophthalmic preparation or by inhalation.

[0107] In some embodiments, 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.

[0108] In some embodiments, the present invention provides the use of the compounds of formula (I), formula (II) or formula (III) above, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites or prodrugs thereof, in the preparation of medicaments for preventing, alleviating, reducing and / or treating pneumoconiosis.

[0109] In some embodiments, 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 to prevent, alleviate, reduce and / or treat pneumoconiosis.

[0110] In some embodiments, the pneumoconiosis is inorganic pneumoconiosis or organic pneumoconiosis.

[0111] In a preferred embodiment, the pneumoconiosis is selected from silicosis, coal worker's pneumoconiosis, graphite pneumoconiosis, carbon black pneumoconiosis, asbestosis, talc pneumoconiosis, cement pneumoconiosis, mica pneumoconiosis, potter's pneumoconiosis, aluminum pneumoconiosis, welder's pneumoconiosis and foundry worker's pneumoconiosis.

[0112] In some embodiments, 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.

[0113] The present invention encompasses any combination of the above embodiments. Example

[0114] In order to make the purpose and technical solutions of the present invention clearer, the present invention is further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, the specific experimental methods not mentioned in the following examples are all carried out according to conventional experimental methods.

[0115] Example 1

[0116] After acclimation, 6-8 week-old male C57BL / 6J mice were acclimated and then instilled with 40 μl of SiO2 suspension (600 mg / kg) into the airways on day 1 to establish the model. On day 1, the mice were randomly divided into three groups based on body weight and administered vehicle (model group) or compound 007 (100 mg / kg or 150 mg / kg, once daily) by oral gavage for 28 consecutive days. A control group was also established, receiving 40 μl of saline solution instilled into the airways on day 1 and sterile water by oral gavage. No mortality was observed in any of the groups during the dosing period.

[0117] Two hours after the last administration, the mice's lung function-related test data were read. As shown in Figure 1, compared with the model group, daily administration of 100 mg / kg and 150 mg / kg of Compound 007 significantly increased the mice's deep inspiratory volume (p<0.05, p<0.01), and reduced respiratory system resistance (p<0.05, p<0.05) and respiratory system elastance (p<0.05, p<0.05).

[0118] After administration, the animals were euthanized, and bronchoalveolar lavage fluid (BALF) was collected from randomly selected animals in each group for TGF-β assay. The results are shown in Figure 2, which demonstrates that daily administration of 100 mg / kg and 150 mg / kg of Compound 007 significantly reduced TGF-β levels (Figure 2, p<0.001, p<0.0001).

[0119] Lung tissues were collected from all mice, and tissue sections were prepared for Masson's Thricome staining and H&E staining to perform silica nodule scoring and inflammation scoring. The silica nodule scoring was based on King's five-point method [Zhujie Cao, et al. Acta Pharmacologica Sinica, 2021. The severity of silica nodules in lung tissue is graded on a scale of 0-5, with higher scores indicating greater severity of tissue nodules. H&E pathology is scored using the Szapiel's inflammation scoring system, with higher scores for inflammatory cell infiltration (0-3) in lung tissue indicating greater inflammation (0: none, no alveolitis; 1: mild, mononuclear cell infiltration with thickening of alveolar septa, focal involvement, pleural space-occupying lesions less than 20% of the lung, and good alveolar structure; 2: moderate, more extensive alveolitis involving 20%-50% of the lung, primarily pleural lesions; 3: severe, diffuse alveolitis involving more than 50% of the lung, occasionally accompanied by intraalveolar mononuclear cells and interstitial and / or intraalveolar hemorrhage). The results are shown in Tables 1-2 and Figures 3-6.

[0120] The results show that daily administration of 100 mg / kg and 150 mg / kg of Compound 007 reduced silica-induced nodule formation and collagen fiber deposition, and significantly reduced silica nodule scores (Figures 3-4, p<0.01, p<0.01). The silica nodule scores of each group are shown in Table 1. In addition, 100 mg / kg and 150 mg / kg of Compound 007 significantly improved lung tissue inflammation in mice and reduced inflammation scores (p<0.01 and p<0.05) (Figures 5-6, Table 2).

[0121] Table 1 Silica nodule scores in the lungs of mice in each group of silicosis model

[0122] Table 2 Inflammation scores of lung tissues in each group of mice in the silicosis model

[0123] In summary, in a silica-induced mouse pulmonary nodule model, Compound 007 improved lung function, specifically by increasing deep inspiratory capacity and reducing respiratory resistance and elastance. Furthermore, Compound 007 reduced silica nodule and inflammation scores in the mice's lungs and decreased TGF-β levels in BALF.

[0124] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. 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: in: Ring A is The above groups are connected to the pyrimidine ring through one of the two positions marked by * or **, and the other position is connected to the carbonyl group; preferably, 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 **; R is selected from H and C 1-6 alkyl; R 1 for R 2 Selected from H and C 1-6 alkyl; R 3 、R 4 、R 7 and R 8 is independently selected at each occurrence from H, halogen (eg, F, Cl, Br, or I), -NR 5 R 6 、-OH、C 1-6 Alkyl and -OR 5 ; R 9 and R 10 Each occurrence is independently selected from H, halogen, C 1-6 Alkyl (such as methyl), C 2-6 Alkenyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl, C 6-12 Aralkyl, -C(=O)R 5 and -C 1-6 Alkylene-O(P=O)(OH)2; The above alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl groups are each optionally substituted by one or more independently selected from halogen, C 1-6 Alkyl and -OR 5 Substituents substituted; R 5 and R 6 Each occurrence is independently selected from H, C 1-6 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-14 membered heteroaryl and C 6-12 Aralkyl; m is independently an integer of 0, 1, 2 or 3 at each occurrence; and n is independently an integer of 0, 1 or 2 at each occurrence.

2. The method of claim 1, wherein the compound has the structure of formula (II): wherein each group is as defined in claim 1; Preferably, the compound has the structure of formula (III): where R 10 H or C 1-6 The alkyl group is preferably H or methyl, more preferably methyl.

3. The method of claim 1 or 2, wherein the compound has the following structure:

4. The method of any one of claims 1 to 3, wherein the compound of formula (I), 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.

5. The method of any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is administered in an amount of about 1 ng / kg to about 200 mg / kg, about 1 μg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg body weight per day, for example, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 75 μg / kg, or about 100 μg / kg per day. g / kg, about 100 μg / kg, about 125 μg / kg, about 150 μg / kg, about 175 μg / kg, about 200 μg / kg, about 225 μg / kg, about 250 μg / kg, about 275 μg / kg, about 300 μg / kg, about 325 μg / kg, about 350 μg / kg, about 375 μg / kg, about 400 μg / kg, about 425 μg / kg, about 450 μg / kg, about 475 μg / kg, about 500 μg / kg, about 525 μg / kg, about 55 0 μg / kg, about 575 μg / kg, about 600 μg / kg, about 625 μg / kg, about 650 μg / kg, about 675 μg / kg, about 700 μg / kg, about 725 μg / kg, about 750 μg / kg, about 775 μg / kg, about 800 μg / kg, about 825 μg / kg, about 850 μg / kg, about 875 μg / kg, about 900 μg / kg, about 925 μg / kg, about 950 μg / kg, about 975 μg / kg, about 1 mg / kg, about 5 mg / kg. g / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 60 mg / kg, about 70 mg / kg, about 80 mg / kg, about 90 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg or about 300 mg / kg body weight.

6. The method of any one of claims 1 to 5, wherein the daily dose of the compound of formula (I) 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.

7. The method of any one of claims 1 to 6, wherein the compound of Formula (I) 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 day, 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.

8. The method of any one of claims 1 to 7, wherein the compound of Formula (I) 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 , 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 30 days, at least 35 days, at least 40 days, at least 45 days or at least 50 days; and there is an interval of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks or four weeks between each two courses of treatment.

9. The method of any one of claims 1 to 8, wherein the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite or prodrug thereof is administered by injection (e.g., 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.

10. The method of any one of claims 1 to 9, wherein the compound of formula (I) 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 the group consisting of tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.

11. The method according to any one of claims 1 to 10, wherein the pneumoconiosis is inorganic pneumoconiosis or organic pneumoconiosis; Preferably, the pneumoconiosis is selected from silicosis, coal worker's pneumoconiosis, graphite pneumoconiosis, carbon black pneumoconiosis, asbestosis, talc pneumoconiosis, cement pneumoconiosis, mica pneumoconiosis, potter's pneumoconiosis, aluminum pneumoconiosis, welder's pneumoconiosis and foundry worker's pneumoconiosis.

12. The method according to any one of claims 1 to 11, wherein the prevention, alleviation, reduction and / or treatment of pneumoconiosis comprises the prevention, alleviation, reduction and / or treatment of the following symptoms: cough, sputum production, chest pain and / or dyspnea.

Images