Methods for treating pneumoconiosis

Abstract

Formula (I) JPEG2025534150000026.jpg33149 or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, to an individual in need thereof.

Description

FIELD OF THE INVENTION

[0001] The present disclosure is in the field of biopharmaceuticals, and particularly relates to a method for the prevention, alleviation, reduction, and / or treatment of pneumoconiosis, comprising administering to a subject in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof. BACKGROUND OF THE INVENTION

[0002] Pneumoconiosis is a systemic disease caused by long-term inhalation of industrial dust (particulate matter) during occupational activities and its retention in the lungs. Generally, patients with early pneumoconiosis do not show significant symptoms, clinical signs, or noticeable changes in lung function. As the disease progresses, respiratory symptoms gradually appear, characterized primarily by chest pain and dyspnea, which may be accompanied by varying degrees of coughing, expectoration, and wheezing.

[0003] Due to chronic inhalation of mineral dust, pneumoconiosis patients suffer from severe impairment of the clearance and defense mechanisms of the respiratory system. Coupled with the chronic and progressive nature of the disease, patients experience significantly reduced resistance, which often leads to the development of complications / comorbidities such as respiratory infections, pneumothorax, pulmonary tuberculosis, chronic obstructive pulmonary disease, bronchiectasis, bronchial asthma, and chronic cor pulmonale.

[0004] As a serious occupational disease, pneumoconiosis not only inflicts significant physical and mental harm on patients, but also increases the social burden and undermines stable socio-economic development.To date, no drug or intervention has been conclusively and practically proven to slow or halt the progression of pneumoconiosis. Summary of the Invention

[0005] In one aspect, the present disclosure provides a compound of formula (I): [ka] [In the formula, Ring A is [ka] and the group is * or ** It is attached to the pyrimidine ring at one of the two positions labeled and to the carbonyl group at the other position. R is H and C 1~6 is selected from the group consisting of alkyl, R 1 teeth [ka] and R 2 is H and C 1~6 is selected from the group consisting of alkyl, R 3 , R 4 , R 7 , and R 8 are each, in each occurrence, H, halogen, -NR 5 R 6 , -OH, C 1~6 Alkyl and -OR 5 are independently selected from the group consisting of: R 9 and R 10 are each, in their respective occurrence, H, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R 5 , and -C 1~6 independently selected from the group consisting of alkylene-O(P=O)(OH); The alkylene, alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl each may, at each occurrence, be halogen, C 1~6 Alkyl and -OR 5 and optionally substituted with one or more substituents independently selected from the group consisting of: R 5 and R 6are each, in their respective existence, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and C 6~12 aralkyl; each m is independently, at each occurrence, an integer of 0, 1, 2, or 3; n is independently at each occurrence an integer of 0, 1, or 2. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof to a subject in need thereof.

[0006] In another aspect, the disclosure provides use of a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, in the manufacture of a medicament for the prevention, alleviation, amelioration, and / or treatment of pneumoconiosis.

[0007] In yet another aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, for use in the prevention, alleviation, amelioration, and / or treatment of pneumoconiosis. [Brief explanation of the drawings]

[0008] [Figure 1] Figure 1 shows lung function index data for silicosis model mice (note: compared with model group, *p<0.05, **p<0.01, ****p<0.0001). [Figure 2] FIG. 1 shows the expression levels of TGF-β in BALF of silicosis model mice in each group (note: comparison with model group, ***p<0.001, ****p<0.0001). [Figure 3]FIG. 1 shows Masson's trichrome stained images of lung tissues in silicosis model mice in each group. [Figure 4] FIG. 1 shows the silicotic nodule scores in the lungs of silicosis model mice in each group (note: comparison with the model group, **p<0.01, ***p<0.001). [Figure 5] FIG. 1 shows H&E stained images of lung tissues in silicosis model mice in each group. [Figure 6] FIG. 1 shows the inflammation scores of lung tissue in silicosis model mice in each group (note: comparison with model group, *p<0.05, **p<0.01, ****p<0.0001). Detailed Description of the Invention

[0009] definition Unless otherwise defined in the context, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to techniques employed herein are intended to refer to techniques commonly understood in the art, including variations of the techniques or equivalent technique substitutions that would be apparent to those skilled in the art. Although the following terms are believed to be readily understood by those skilled in the art, the following definitions are nevertheless provided to better explain the present invention.

[0010] The terms "containing," "include," "comprise," "having," or "related to," and other variations as used herein, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0011] As used herein, the term "alkylene" refers to a divalent saturated hydrocarbyl, preferably having 1, 2, 3, 4, 5, or 6 carbon atoms, for example, methylene, ethylene, propylene, or butylene.

[0012] As used herein, the term "alkyl" is defined as a straight-chain or branched-chain saturated aliphatic hydrocarbon. In some embodiments, alkyl has 1 to 12, e.g., 1 to 6, carbon atoms. For example, as used herein, the term "C 1~6 "Alkyl" refers to a straight or branched chain group having 1 to 6 carbon atoms (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group may be referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl, or CH2CH2CF3, etc.). 1~4 "Alkyl" refers to a straight or branched aliphatic hydrocarbon chain having 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0013] As used herein, the term "alkenyl" refers to a straight- or branched-chain monovalent hydrocarbyl group having a double bond and 2 to 6 carbon atoms ("C 2~6 The term "alkenyl" refers to, 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, they may exist as the pure E (entgegen) form, the pure Z (zusammen) form, or any mixture thereof.

[0014] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl containing one or more triple bonds and preferably having 2, 3, 4, 5, or 6 carbon atoms, for example, ethynyl or propynyl.

[0015] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or cyclononyl, or bicyclic, containing spiro, fused, or bridged ring systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, or decahydronaphthalene) optionally substituted with one or more (e.g., 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms. For example, the term "C 3~6 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 6 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), optionally substituted with one or more (e.g., 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0016] As used herein, the terms "cyclic hydrocarbylene," "cyclic hydrocarbyl," and "hydrocarbon ring" refer to saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and / or triple bonds in the ring) monocyclic or polycyclic hydrocarbon rings, for example, having 3 to 10 ring carbon atoms (suitably having 3 to 8, more suitably having 3 to 6), including, but not limited to, cyclopropyl(ene)(ring), cyclobutyl(ene)(ring), cyclopentyl(ene)(ring), cyclohexyl(ene)(ring), cycloheptyl(ene)(ring), cyclooctyl(ene)(ring), cyclononyl(ene)(ring), cyclohexenyl(ene)(ring), and the like.

[0017] 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 in the ring) cyclic group having, for example, 3 to 10 ring atoms (suitably 3 to 8, more suitably 3 to 6), in which at least one ring atom is a heteroatom selected from the group consisting of N, O, and S, and the remaining ring atoms are C. For example, the "3- to 10-membered heterocyclyl(ene)" of a "3- to 10-membered heterocycle" refers to a saturated or partially unsaturated heterocyclyl(ene) or heterocycle having 2 to 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 the group consisting of N, O, and S. Examples of heterocyclylene, heterocyclyl, and heterocycle include, but are not limited to, oxiranyl(ene), aziridinyl(ene), azetidinyl(ene), oxetanyl(ene), tetrahydrofuranyl(ene), dioxolinyl(ene), pyrrolidinyl(ene), pyrrolidonyl(ene), imidazolidinyl(ene), pyrazolidinyl(ene), pyrrolinyl(ene), tetrahydropyranyl(ene), piperidinyl(ene), morpholinyl(ene), dithianyl(ene), thiomorpholinyl(ene), piperazinyl(ene), or trithianyl(ene). The group also encompasses bicyclic systems, including spiro, fused, or bridged systems (e.g., 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azabicyclo[2.2.2]octane, etc.) Heterocyclylene, heterocyclyl, and heterocycle may be optionally substituted with one or more (e.g., 1, 2, 3, or 4) suitable substituents.

[0018] As used herein, the terms "aryl(ene)" 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 Aryl(ene) and C 6~10"Aromatic ring" refers to an aromatic group containing 6 to 10 carbon atoms, such as a phenyl(ene) (benzene ring) or a naphthyl(ene) (naphthalene ring). The aryl(ene) or aromatic ring may contain one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO, and C 1~6 alkyl).

[0019] 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, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom (such as O, N, or S), which may be the same or different. In addition, the aromatic ring system, in each case, may be benzo-fused. In particular, the "heteroaryl(ene)" or "heteroaromatic ring" is selected from the group consisting of thienyl(ene), furyl(ene), pyrrolyl(ene), oxazolyl(ene), thiazolyl(ene), imidazolyl(ene), pyrazolyl(ene), isoxazolyl(ene), isothiazolyl(ene), oxadiazolyl(ene), triazolyl(ene), thiadiazolyl(ene), etc. and their benzo derivatives or pyridinyl(ene), pyridazinyl(ene), pyrimidinyl(ene), pyrazinyl(ene), triazinyl(ene), etc. and their benzo derivatives.

[0020] As used herein, the term "aralkyl" preferably refers to aryl- or heteroaryl-substituted alkyl, where aryl, heteroaryl, and alkyl are as defined herein. Typically, aryl groups can have 6 to 14 carbon atoms, heteroaryl groups can have 5 to 14 ring atoms, and alkyl groups can have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0021] As used herein, the term "halo" or "halogen" is defined to include F, Cl, Br, or I.

[0022] 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, and optionally further containing one or more (e.g., 1, 2, 3, or 4) ring members selected from the group consisting of N, O, C=O, S, S=O, and S(=O)2. The nitrogen-containing heterocycle is bonded to the remainder of the molecule through the nitrogen atom and any other ring atoms in the nitrogen-containing heterocycle. The nitrogen-containing heterocycle is optionally benzo-fused, and is preferably bonded to the remainder of the molecule through the nitrogen atom in the nitrogen-containing heterocycle and any carbon atom in the fused benzene ring.

[0023] The term "substituted" means the replacement of one or more (e.g., 1, 2, 3, or 4) hydrogens on a specified atom with one selected from the indicated group, provided that the substitution does not exceed the normal valence of the specified atom in the existing environment and results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0024] When a substituent is described as "optionally substituted," the substituent may be either (1) unsubstituted or (2) substituted. When a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, one or more (to some extent) of the hydrogens on the carbon may be replaced individually and / or together with independently selected optional substituents. When a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, one or more (to some extent) of the hydrogens on the nitrogen may each be replaced with independently selected optional substituents.

[0025] When substituents are described as being "independently selected" from a group, each substituent is selected independently of the other substituent(s). Thus, each substituent can be the same or different from the other substituent(s).

[0026] As used herein, the term "one or more" means one or more than one (eg, 2, 3, 4, 5, or 10), as appropriate.

[0027] As used herein, unless specified, the point of attachment of a substituent may be based on any suitable position on the substituent.

[0028] When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any of the substitutable ring-forming atoms in that ring.

[0029] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds that 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 that predominates in nature. Examples of isotopes suitable for inclusion in compounds of the present invention include: 2 H and 3 Isotopes of hydrogen such as H, 11 C. 13 C, and 14 Carbon, such as C, 36 chlorine such as Cl, 18 Fluorine such as F, 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O, and 18 Oxygen, such as O 32 Phosphorus such as P, 35Certain isotopically labeled compounds of the present invention, for example those incorporating a radioactive isotope, 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 given their ease of incorporation and ready means of detection. 11 C. 18 F, 15 O, and 13 Substitution with positron-emitting isotopes, such as N, can be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by processes analogous to those described in the accompanying schemes and / or examples and preparations, by substituting the appropriate isotopically labeled reagent for the previously employed unlabeled reagent. Pharmaceutically acceptable solvates according to the present invention include those in which the solvent of crystallization may be isotopically substituted, e.g., DO, acetone-d6, or DMSO-d6.

[0030] The term "stereoisomer" refers to an isomer having at least one asymmetric center. Compounds having one or more (e.g., one, two, three, or four) asymmetric centers can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules can exist as geometric isomers (cis / trans). Similarly, compounds of the present invention can exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) that are in rapid equilibrium. Typical examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. It will be understood that all such isomers and mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, and 99%) are encompassed within the scope of the present invention.

[0031] The chemical bonds of the compounds of the present invention are represented herein by solid lines. [ka] , solid wedge line [ka] , or dotted wedge line [ka] The use of a solid line to depict bonds to an asymmetric carbon atom is meant to indicate that all possible stereoisomers at that carbon atom (e.g., a specific enantiomer, a racemic mixture, etc.) are included. The use of either a solid wedge line or a dotted wedge line to depict bonds to an asymmetric carbon atom is meant to indicate that the depicted stereoisomer exists. When present in a racemic compound, the solid wedge line and dotted wedge line are used to define relative rather than absolute stereochemistry. Unless otherwise stated, it is intended that the compounds of the present invention may exist as stereoisomers, including optical isomers such as cis and trans isomers, R and S enantiomers, diastereomers, geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one isomeric type and may consist of mixtures thereof (such as racemates and diastereomeric pairs).

[0032] The present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph in any ratio.

[0033] It should also be understood that certain compounds of the present invention can be used for treatment in free form or, where appropriate, in the form of a pharmaceutically acceptable derivative. In the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable salt, ester, solvate, N-oxide, metabolite, or prodrug, which can directly or indirectly provide the compound of the present invention or its metabolite or residue after administration to a patient in need thereof. Therefore, the "compound of the present invention" referred to herein is also intended to encompass various derivative forms of the above-mentioned compounds.

[0034] Pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and the base addition salts thereof.

[0035] Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Specific examples include acetic, adipic, aspartic, benzoic, besylic, bicarbonate / carbonic, bisulfate / sulfuric, boric, camphorsulfonic, citric, cyclamic, edisylic, esylic, formic, fumaric, gluceptic, gluconic, glucuronic, hexafluorophosphate, hybenzic, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionic, lactic, malic, maleic, malonic, mesylic, methylsulfate, naphthylic, 2-napsylic, nicotinic, nitric, orotic, oxalic, palmitic, pamoic, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamic, saccharinic, stearic, succinic, tannic, tartaric, tosylic, trifluoroacetic, and xinofoate salts.

[0036] Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts, particular examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

[0037] For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.

[0038] As used herein, the term "ester" refers to compounds derived from various formulae in this application that contain physiologically hydrolyzable esters (which may be hydrolyzed under physiological conditions to release the compounds of the invention in the free acid or alcohol form). The compounds of the invention themselves may also be esters.

[0039] The compounds of the present invention may exist as solvates (preferably hydrates) in which the compounds of the present invention contain polar solvents, particularly water, methanol, or ethanol, as structural elements of the compound's crystal lattice. The amount of polar solvent, particularly water, may be present in a stoichiometric or non-stoichiometric ratio.

[0040] As can be recognized by those skilled in the art, not all nitrogen-containing heterocycles can form N-oxides, because nitrogen requires an available lone pair of electrons for oxidation to an oxide, and those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides.Those skilled in the art will also recognize that tertiary amines can form 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 m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane. These methods for the preparation of N-oxides have been extensively described and reviewed in the literature, see, for example, T. L. Gilchrist, Comprehensive Organic Synthesis, Vol. 7, pp. 748-750; A. R. Katrittzky and A. J. Boulton, eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, Vol. 22, pp. 390-392, A. R. Katrittzky and A. J. Boulton, eds., Academic Press.

[0041] Also included within the scope of the invention are metabolic products of the compounds of the invention, i.e., substances formed in vivo upon administration of a compound of the invention. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic degradation, etc. of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0042] Also within the scope of the present invention are prodrugs of the compounds of the present invention, which are specific derivatives of the compounds of the present invention that may have little or no biological activity themselves but that, upon administration to or onto the body, can be converted, for example, by hydrolytic cleavage, into compounds of the present invention having the desired activity. Generally, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into compounds having the desired therapeutic activity. Further information regarding the use of prodrugs can be found in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs according to the present invention can be produced, for example, by replacing appropriate functional groups present in the compounds of the present invention with specific moieties known to those skilled in the art as "promoieties," as described, for example, in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0043] The present invention further encompasses compounds of the present invention having protecting groups. During any of the processes for preparing the compounds of the present invention, it may be necessary and / or desirable to create chemically protected forms of the compounds of the present invention by protecting sensitive or reactive groups on any of the molecules of interest. This can be achieved by conventional protecting groups, for example, those described in TW Greene & PG M Buts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is incorporated herein by reference. The protecting groups can be removed at a later convenient stage using methods known in the art.

[0044] The term "about" refers to a range within ±10%, preferably within ±5%, and more preferably within ±2% of the specified value.

[0045] The term "effective amount" refers to an amount sufficient, under the conditions of administration, to achieve the desired therapeutic effect, ameliorating pathological symptoms, disease progression, or associated physiological condition, or inducing resistance to the aforementioned disorder.

[0046] As used herein, the term "pneumoconiosis" refers to a systemic disease caused by long-term inhalation of industrial dust (particulate matter) during occupational activities and its retention in the lungs. Based on the type of dust inhaled, pneumoconiosis can be classified into inorganic pneumoconiosis and organic pneumoconiosis. Pneumoconiosis caused by inhalation of inorganic dust is called inorganic pneumoconiosis, which accounts for the majority of pneumoconiosis cases. Pneumoconiosis resulting from inhalation of organic dust is known as byssinosis or organic pneumoconiosis, such as farmer's lung disease.

[0047] Unless otherwise specified, the term "treatment" as used herein means reversing, alleviating, inhibiting, slowing, or arresting the progression of the disorder or condition to which such term applies, or one or more symptoms thereof.

[0048] As used herein, the term "subject" includes a human or a non-human animal. Exemplary human subjects include a human subject (referred to as a patient) with a disease (such as a disease described herein) or a normal subject. The term "non-human animal," as used herein, includes all vertebrates, such as mammals, including non-mammals (e.g., birds, amphibians, and reptiles) and non-human primates, livestock, and / or domesticated animals (such as sheep, dogs, cats, cows, and pigs).

[0049] In some embodiments, the present disclosure provides a compound of formula (I): [ka] [In the formula, Ring A is [ka] and the group is * or **It is attached to the pyrimidine ring at one of the two positions labeled and to the carbonyl group at the other position. R is H and C 1~6 is selected from the group consisting of alkyl, R 1 teeth [ka] and R 2 is H and C 1~6 is selected from the group consisting of alkyl, R 3 , R 4 , R 7 , and R 8 are each, in each occurrence, H, halogen, -NR 5 R 6 , -OH, C 1~6 Alkyl and -OR 5 are independently selected from the group consisting of: R 9 and R 10 are each, in their respective occurrence, H, halogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5-14 membered heteroaryl, C 6~12 Aralkyl, -C(=O)R 5 , and -C 1~6 independently selected from the group consisting of alkylene-O(P=O)(OH); The alkylene, alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl each may, at each occurrence, be halogen, C 1~6 Alkyl and -OR 5 and optionally substituted with one or more substituents independently selected from the group consisting of: R 5 and R 6 are each, in their respective existence, H, C 1~6 Alkyl, C 3~10Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and C 6~12 aralkyl; each m is independently, at each occurrence, an integer of 0, 1, 2, or 3; n is independently at each occurrence an integer of 0, 1, or 2. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof to a subject in need thereof.

[0050] In a preferred embodiment, ring A is [ka] and the group is * and attached to the pyrimidine ring at the position labeled ** and binds to the carbonyl group at the position labeled R 10 is H and C 1~6 It is selected from the group consisting of alkyl, preferably H or methyl.

[0051] In a preferred embodiment, ring A is preferably [ka] and the group is * and attached to the pyrimidine ring at the position labeled ** It is attached to the carbonyl group at the position labeled as

[0052] In a preferred embodiment, R is H.

[0053] In a preferred embodiment, R 2 is H.

[0054] In a preferred embodiment, R 5 and R 6 is each, at each occurrence, independently selected from the group consisting of H, methyl, and ethyl.

[0055] In a preferred embodiment, R 3 , R 4 , R 7 , and R 8 is each, at each occurrence, independently selected from the group consisting of H, F, Cl, Br, I, —NH 2 , —OH, methyl, trifluoromethyl, —CH 2 -Ph, methoxy, ethoxy, and —CH 2 OCH 3 .

[0056] In a preferred embodiment, R 3 is H.

[0057] In a preferred embodiment, R 4 is selected from the group consisting of H and halogen (e.g., F, Cl, Br, or I), preferably H or F.

[0058] In a preferred embodiment, R 7 is selected from the group consisting of H and halogen (e.g., F, Cl, Br, or I), preferably H or F.

[0059] In a preferred embodiment, R 8 is H.

[0060] In a preferred embodiment, R 9 and R 10 each, in each occurrence, is 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, [ka] are independently selected from the group consisting of:

[0061] In a preferred embodiment, R 9 are each, in their respective existence, H, C 1~6 Alkyl, C 3~10 Cyclic hydrocarbyl, 3-10 membered heterocyclyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and C 6~12 and aralkyl, and preferably H.

[0062] In a preferred embodiment, R 10 are each, in their respective occurrences, H and C 1~6 alkyl, preferably H, methyl, ethyl, n-propyl, or isopropyl, and most preferably H or methyl.

[0063] In a preferred embodiment, the present disclosure provides a compound of formula (II) [ka] wherein each group is as defined above. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof to a subject in need thereof.

[0064] In a preferred embodiment, the present disclosure provides a compound of formula (III) [ka] [In the formula, R 10 is H or methyl, preferably methyl] or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof to a subject in need thereof.

[0065] In a preferred embodiment, the compound has the structure: [Table 1] It has.

[0066] In some embodiments, the compounds are prepared according to the methods disclosed in WO 2019 / 001572A1, which is incorporated herein by reference.

[0067] In some embodiments, a compound of Formula (I), (II), or (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, e.g., 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.

[0068] In some embodiments, a compound of Formula (I), (II), or (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 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 of body weight per day, e.g., about 1 μg / kg of body weight per day. , about 10μg / kg, about 25μg / kg, about 50μg / kg, about 75μg / kg, about 100μg / kg, about 125μg / kg, about 150μg / kg, about 175μg / kg, about 200μg / kg, about 225μg / kg, about 25 0μg / kg, approximately 275μg / kg, approximately 300μg / kg, approximately 325μg / kg, approximately 350μg / kg, approximately 375μg / kg, approximately 400μg / kg, approximately 425μg / kg, approximately 450μg / kg, approximately 475μg / kg, approximately 50 0μg / kg, approximately 525μg / kg, approximately 550μg / kg, approximately 575μg / kg, approximately 600μg / kg, approximately 625μg / kg, approximately 650μg / kg, approximately 675μg / kg, approximately 700μg / kg, approximately 725μg / kg, approximately 75 0μg / kg, approximately 775μg / kg, approximately 800μg / kg, approximately 825μg / kg, approximately 850μg / kg, approximately 875μg / kg, approximately 900μg / kg, approximately 925μg / kg, approximately 950μg / kg, approximately 975μg / kg, approximately 1m g / kg, about 5 mg / 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.

[0069] In some embodiments, the daily dose of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered once, or in two, three, or four doses.

[0070] In some embodiments, a compound of Formula (I), (II), or (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.

[0071] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered during one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, each treatment course lasting 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, or at least Both treatment courses last for 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 the interval between any two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

[0072] In some embodiments, a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered via injection (e.g., intravenous, arterial, subcutaneous, intraperitoneal, intramuscular, including infusion) or transdermal administration, or via topical administration in oral, buccal, nasal, transmucosal, or ophthalmic formulations, or via inhalation.

[0073] In some embodiments, a compound of Formula (I), (II), or (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 the group consisting of a tablet, capsule, lozenge, hard candy, powder, spray, cream, salve, suppository, gel, paste, lotion, ointment, aqueous suspension, injectable solution, elixir, and syrup.

[0074] In some embodiments, the disclosure provides use of a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, in the manufacture of a medicament for the prevention, alleviation, mitigation, and / or treatment of pneumoconiosis.

[0075] In some embodiments, the present disclosure provides a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, for use in the prevention, alleviation, amelioration, and / or treatment of pneumoconiosis.

[0076] In some embodiments, the pneumoconiosis is inorganic pneumoconiosis or organic pneumoconiosis.

[0077] In preferred embodiments, the pneumoconiosis is selected from the group consisting of 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.

[0078] In some embodiments, preventing, alleviating, reducing, and / or treating pneumoconiosis includes preventing, alleviating, reducing, and / or treating the following symptoms: coughing, expectoration, chest pain, and / or shortness of breath.

[0079] The present disclosure encompasses any combination of the above embodiments. [Example]

[0080] In order to make the objectives and technical solutions of the present invention clearer, the present invention will be further described below with reference to specific examples. It should be understood that the following examples are merely intended to illustrate the present invention and should not be understood as limiting the scope of the present invention. Furthermore, certain experimental methods not mentioned in the following examples are carried out according to conventional experimental methods.

[0081] Example 1 After acclimation, 6- to 8-week-old male C57BL / 6J mice were intratracheally instilled with 40 μL of SiO2 suspension (600 mg / kg) on ​​day 1 (D1) to establish the silicosis model. On the same day (D1), the animals were randomly divided into three groups based on body weight and administered either vehicle (model group) or compound 007 (100 mg / kg or 150 mg / kg, once daily) by oral gavage for 28 consecutive days. A normal control group was also established and administered 40 μL of saline intratracheally on D1 followed by oral administration of sterile water. No deaths were observed in any of the groups during the administration period.

[0082] Two hours after the final administration, the lung function indexes of the mice were measured. As shown in Figure 1, the daily administration of compound 007 at 100 mg / kg and 150 mg / kg significantly increased deep inspiratory capacity (p<0.05, p<0.01), reduced respiratory resistance (p<0.05, p<0.05), and reduced respiratory elasticity (p<0.05, p<0.05) compared with the model group.

[0083] After administration was completed, the animals were euthanized, and bronchoalveolar lavage fluid (BALF) was collected from randomly selected animals in each group for TGF-β detection. The results are shown in Figure 2, demonstrating that daily administration of compound 007 at 100 mg / kg and 150 mg / kg significantly reduced TGF-β levels (Figure 2, p<0.001, p<0.0001).

[0084] Lung tissues from all mice were harvested, sectioned, and stained with Masson's trichrome and H&E for silicotic nodule scoring and inflammation scoring. Silicotic nodule scoring was performed using King's five-point scale (Zhujie Cao et al., Acta Pharmacologica Sinica, 2021). The severity of silicotic nodules in lung tissue was scored from 0 to 5, with higher scores indicating more severe nodules. H&E pathological scoring was performed according to the Szapiel inflammation scoring criteria, where the degree of inflammatory cell infiltration in the lung tissue was scored from 0 to 3, with higher scores indicating greater inflammation in the lung tissue (0: no inflammation or alveolitis; 1: mild mononuclear cell infiltration with thickened alveolar septa, localized disease, pleural involvement involving less than 20% of the lung, and well-preserved alveolar architecture; 2: moderate, more extensive alveolitis involving 20% ​​to 50% of the lung, primarily pleural involvement; 3: severe, diffuse alveolitis involving more than 50% of the lung, sometimes with mononuclear cell infiltration in the alveoli and interstitium and / or some hemorrhagic areas within the alveoli). The results are shown in Tables 1 and 2 and Figures 3 to 6.

[0085] As demonstrated by the results, daily administration of compound 007 at 100 mg / kg and 150 mg / kg significantly reduced silica-induced nodule formation and collagen fiber deposition, leading to a significant decrease in silicosis nodule scores (Figures 3-4, p<0.01, p<0.01), as shown in Table 1. Furthermore, 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).

[0086] [Table 2]

[0087] [Table 3]

[0088] In summary, in a mouse model of silica-induced pulmonary nodules, Compound 007 improved pulmonary function by increasing deep inspiratory capacity and reducing respiratory resistance and elasticity. Furthermore, Compound 007 reduced silicotic nodule and inflammation scores in the lungs of mice and reduced TGF-β levels in BALF.

[0089] Various modifications to the present invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each reference, including all patents, applications, journal articles, books, and any other disclosures referred to in this specification, is hereby incorporated by reference in its entirety.

Claims

1. Formula (I) 【Chemical 1】 [In the formula, Ring A is 【Chemistry 2】 and the group is ＊ or ＊＊ and the other position is attached to the carbonyl group, and preferably ring A is 【Chemistry 3】 and the group is ＊ and attached to the pyrimidine ring at the position labeled ＊＊ It binds to the carbonyl group at the position labeled R is H and C １～６ is selected from the group consisting of alkyl, R １ teeth 【Chemistry 4】 and R ２ is H and C １～６ is selected from the group consisting of alkyl, R ３ , R ４ , R ７ , and R ８ each, in each occurrence, is H, halogen (e.g., F, Cl, Br, or I), —NR ５ R ６ , -OH, C １～６ Alkyl, and —OR ５ are independently selected from the group consisting of: R ９ and R １０ are each, in each occurrence, H, halogen, C １～６ Alkyl (e.g., methyl), C ２～６ Alkenyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, C ６～１２ Aralkyl, —C(═O)R ５ , and -C １～６ Alkylene-O(P=O)(OH) ２ are independently selected from the group consisting of: The alkylene, alkyl, alkenyl, cyclic hydrocarbyl, heterocyclyl, aryl, heteroaryl, and aralkyl each may, at each occurrence, be halogen, C １～６ Alkyl, and —OR ５ and optionally substituted with one or more substituents independently selected from the group consisting of: R ５ and R ６ are each, in their respective existence, H, C １～６ Alkyl, C ３～１０ Cyclic hydrocarbyl, 3- to 10-membered heterocyclyl, C ６～１０ Aryl, 5- to 14-membered heteroaryl, and C ６～１２ aralkyl; m is independently at each occurrence an integer of 0, 1, 2, or 3; n is independently at each occurrence an integer of 0, 1, or 2. or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, to a subject in need thereof.

2. The compound is represented by formula (II) 【Chemistry 5】 wherein each group is as defined in claim 1. having the structure Preferably, the compound has the formula (III) 【Chemistry 6】 [In the formula, R １０ is H or C １～６ alkyl, preferably H or methyl, more preferably methyl. having the structure The method of claim 1.

3. The compound has the following structure: 【Table 1】 3. The method of claim 1 or 2, comprising:

4. 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, e.g., 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 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 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 of body weight per day, e.g., about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg of body weight per day. g, 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 / k g, 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 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, about 10 mg / kg, 4. The method of any one of claims 1 to 3, wherein the compound is administered in an amount of 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.

6. 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 in two, three, or four doses.

7. 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 continuously administered for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 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. A compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug thereof, is administered during one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) treatment courses, each treatment course lasting 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, 8. The method of any one of claims 1 to 7, wherein the treatment courses last for at least 1 day, 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 the interval between any two treatment courses is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, 2 weeks, 3 weeks, or 4 weeks.

9. 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, isotopically labeled compound, metabolite, or prodrug thereof, is administered via injection (e.g., intravenous, arterial, subcutaneous, intraperitoneal, intramuscular, including infusion) or transdermal administration, or via topical administration in an oral, buccal, nasal, transmucosal, ophthalmic formulation, or via inhalation.

10. 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 a tablet, capsule, lozenge, hard candy, powder, spray, cream, salve, suppository, gel, paste, lotion, ointment, aqueous suspension, injectable solution, elixir, and syrup.

11. The pneumoconiosis is inorganic pneumoconiosis or organic pneumoconiosis, Preferably, the pneumoconiosis is selected from the group consisting of 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. The method according to any one of claims 1 to 10.

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

Images