Novel substituted pyridine derivative compound, method for preparing same, and pharmaceutical composition for prevention or treatment of respiratory diseases comprising same as active ingredient

Abstract

The present invention describes the synthesis and biological evaluation of new substituted pyridine derivatives as foxj1 activity enhancers. In embodiments, novel pyridine derivatives were synthesized and the ability thereof to enhance foxj1 activity was evaluated. The novel pyridine derivatives synthesized in the present invention not only exhibited excellent activity but also exhibited excellent metabolic safety and pharmacokinetic profile in a Tg (foxj1: egfp) transgenic zebrafish animal model. In addition, the novel pyridine derivatives synthesized in the present invention enhanced cilia-promoting capability in a motile ciliated cell differentiation experiment in which mouse tracheal epithelial cells (mTECs) were isolated from the airways of mice and cultured by ALI. As a result, a series of foxj1 activity enhancers with substituted pyridine skeleton has the potential to be developed as preventive and therapeutic agents for respiratory diseases.

Description

Novel substituted pyridine derivative compound, preparation method thereof, and pharmaceutical composition for preventing or treating respiratory diseases comprising the same as an active ingredient

[0001] The present invention relates to a novel pyridine derivative compound, a method for preparing the same, and a pharmaceutical composition for preventing or treating respiratory diseases comprising the same as an active ingredient.

[0002] Motile cilia are microscopic, hair-like organelles that beat rhythmically and play an essential role in various bodily functions, including respiratory mucociliary clearance, egg transport, sperm motility, and cerebrospinal fluid circulation. Motile cilia possess a complex microtubule-based 9 + 2 axoneme structure, including dynein arms and radial spokes, enabling their rhythmic movement. Dysfunction of the protein complexes that regulate motility can lead to motile ciliopathies, which can affect numerous organ systems and lead to various diseases such as infertility, hydrocephalus, fibrosis, asthma, and respiratory diseases. These diseases can be caused by mutations in genes encoding ciliary components or regulatory proteins.

[0003] The FOXJ1 transcription factor, a member of the forkhead box (FOX) transcription factor family, plays a crucial role in regulating motile cilia development. It activates genes essential for cilia formation and function. Studies have shown that multiciliated cells (MCCs) in mice lacking FOXJ1 lose axonemal cells, and overexpression of FOXJ1 leads to ectopic motile cilia in various tissues. Therefore, researchers are exploring the possibility of targeting FOXJ1 to treat motile ciliopathies. However, although treatments are known to alleviate symptoms associated with motile ciliopathies, they do not promote motile cilia and only provide temporary relief of symptoms.

[0004] To prevent and treat respiratory infections, mucociliary clearance must be improved. Aging and disease can reduce the number and function of motile cilia, leading to decreased mucociliary clearance, which increases the risk of respiratory infections and exacerbates the disease.

[0005] Accordingly, the inventors of the present invention conducted research on enhancing the activity of foxj1 for the treatment of respiratory diseases including asthma, acute respiratory distress syndrome, and chronic obstructive pulmonary disease, and discovered a novel foxj1 activity enhancer, thereby completing the present invention.

[0006] Therefore, one object of the present invention is to provide a pharmaceutical composition for preventing or treating a disease associated with foxj1 activity that can improve the number and function of motile cilia, comprising a novel pyridine derivative or a pharmaceutically acceptable salt thereof and a compound according to the present invention as an active ingredient.

[0007] Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of respiratory diseases such as asthma, acute respiratory distress syndrome, hay fever, allergic rhinitis, chronic obstructive pulmonary disease, bronchiectasis, primary ciliary dyskinesia, and cystic fibrosis, containing the novel pyridine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008]

[0009] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

[0010]

[0011] Various embodiments of the present invention are described with reference to the drawings. In the following description, various specific details, such as specific configurations, compositions, and processes, are set forth to provide a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and configurations. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the present invention. Reference throughout this specification to an embodiment means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the present invention. Therefore, the appearance of an embodiment in various places throughout this specification does not necessarily indicate the same embodiment of the present invention. Additionally, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments. In the present invention, unless otherwise specified, terms used have their ordinary meanings well known to those skilled in the art. In the present invention, all chemical formulas are intended to include any possible optical or geometric isomers (e.g., R form, S form, or racemate, or cis-trans isomers of alkenes, etc.).

[0012]

[0013] In one embodiment of the present invention, a compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] A is halogen; ; unsubstituted or C1-C5 alkyl, C1-C3 alkyl C1-C3 alkoxy, amine, C1-C3 alkyl alkoxy C1-C3 alkyl, , , , , , , , , , , (m is an integer from 1 to 5) substituted with one or more substituents selected from the group consisting of 5- to 9-membered heteroaryl rings; C6-C unsubstituted or substituted with C1-C5 alkyl or amine 10 Aryl; C6-C substituted with C1-C3 alkoxy group 10 Aryl alkyne; and,

[0018] R3 is ethoxy, alkoxy, C1-C3 alkyl alkoxy, hydroxy, C1-C3 alkyl amine, , amine, C6-C 10 aryl amine, , , , , , , , One or more substituents selected from the group consisting of,

[0019] Z is amine, C1-C5 alkyl amine, , -NR4R5 (R4 is hydrogen; R5 is amine C1-C5 alkyl, hydroxy acyl C1-C5 alkyl, C6-C 10 Cyclo, , , , (n is an integer between 1 and 5), or C6-C unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C3 alkyl or one or more halogens; 10 Heterocyclic; or R4 and R5 are connected to each other, unsubstituted, C1-C3 alkyl or C6-C substituted with one or more halogens 10is selected from the group consisting of forming a heterocyclic group, Y is oxygen or sulfur, and R1 and R2 are each independently C1-C5 alkyl or halogen.

[0020] As used herein, the term “alkyl” or “alk” refers to a straight or branched chain alkane (hydrocarbon) radical containing 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Exemplary “alkyl” groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, and the like. For example, the term “C1-C4 alkyl” refers to a straight or branched chain alkane (hydrocarbon) radical containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, and isobutyl. “Substituted alkyl” refers to an alkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.

[0021] As used herein, the term "alkenyl" refers to a linear or branched chain hydrocarbon radical containing from 2 to 12 carbon atoms and at least one carbon-carbon double bond. Exemplary such groups include ethenyl or allyl. For example, the term "C2-C6 alkenyl" refers to a linear or branched chain hydrocarbon radical having 2 to 6 carbon atoms and at least one carbon-carbon double bond, such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl, (Z)-but-2-enyl, 2-methy(E)-but-2-enyl, 2-methy(Z)-but-2-enyl, 2,3-dimethy-but-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-pent-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex-3-enyl, and (E)-hex-1,3-dienyl. "Substituted alkenyl" refers to an alkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.

[0022] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 12 carbon atoms and at least one carbon-to-carbon triple bond. Exemplary such groups include ethynyl. For example, the term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and at least one carbon-to-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl. A "substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.

[0023] As used herein, the term "alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 12 carbon atoms and at least one carbon-to-carbon triple bond. Exemplary such groups include ethynyl. For example, the term "C2-C6 alkynyl" refers to a straight or branched chain hydrocarbon radical having 2 to 6 carbon atoms and at least one carbon-to-carbon triple bond, such as ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl. A "substituted alkynyl" refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.

[0024] In this specification, the term “haloalkyl” means an alkyl group substituted with a halogen, for example, C1-C3 haloalkyl means a functional group in which at least one hydrogen in an alkyl group having 1 to 3 carbon atoms is replaced with a halogen.

[0025] As used herein, the term “halogen” refers to a halogen group element, including, for example, fluoro, chloro, bromo, and iodo.

[0026] As used herein, the term “aryl” refers to a monocyclic or polycyclic carbon ring that is wholly or partially unsaturated and has aromaticity. For example, C6-C 10Aryl refers to a monocyclic or polycyclic carbon ring having 6 to 10 carbon atoms, which is fully or partially unsaturated and aromatic. For example, when it contains two or more aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl, phenanthrenyl, etc.). "Substituted aryl" refers to an aryl group substituted with one or more substituents, preferably 1 to 3 substituents, at any available point of attachment.

[0027] As used herein, the term "carbocycle" refers to a fully saturated or partially saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring, or a cyclic, aromatic hydrocarbon group having 1 to 5 aromatic rings, in particular a monocyclic or bicyclic group such as phenyl, biphenyl or naphthyl. The term "carbocycle" encompasses cycloalkyl, cycloalkenyl, cycloalkynyl and aryl as defined above. The term "substituted carbocycle" refers to a carbocycle or carbocyclic group substituted at any available point of attachment by one or more substituents, preferably by 1 to 4 substituents.

[0028] As used herein, the term “cycloalkyl” or “cycloalkyl” refers to a fully saturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. The terms “C3-C8 cycloalkyl,” “C3-C7 cycloalkyl,” and “C3-C6 cycloalkyl” have similar meanings, for example, “C3-C7 cycloalkyl” refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. “Substituted cycloalkyl” refers to a cycloalkyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment.

[0029] As used herein, the terms "heterocycle" and "heterocyclic" refer to an aromatic (i.e., "heteroaryl") cyclic group (e.g., a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 8- to 16-membered tricyclic ring system) having at least one heteroatom within at least one carbon atom-containing ring, which is fully saturated, or partially or fully unsaturated. Each ring of the heterocyclic group including a heteroatom can have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatoms can be optionally quaternized. (The term "heteroarylium" refers to a heteroaryl group that contains a quaternary nitrogen atom and is therefore positively charged.) The heterocyclic group may be attached to any heteroatom or carbon atom of the remainder of the molecule in the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro-1,1-dioxothienyl, etc.The terms "substituted heterocycle" and "substituted heterocyclic" (e.g., "substituted heteroaryl") refer to a heterocycle or heterocyclic group substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents.

[0030] As used herein, the terms “aromatic heterocycle” or “heteroaryl” have the same meaning and refer to a heteroaromatic group containing one or more heteroatoms. The heteroatoms referred to herein include oxygen, sulfur and nitrogen. Examples thereof include furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, a heterocyclic group or a cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring. The heteroaryl is optionally substituted or unsubstituted.

[0031] The term “cycloalkenyl” as used herein refers to an unsaturated hydrocarbon ring forming a monocyclic ring or polycyclic ring, and refers to a cyclic group including at least one carbon-carbon double bond in cycloalkyl. Examples thereof include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. For example, C3-C7 cycloalkenyl refers to an unsaturated hydrocarbon ring composed of alkene units having 3 to 7 carbon atoms, and when C3-C7 alkenyl is substituted, the carbon number of the substituent is not included. “Substituted cycloalkenyl” refers to a cycloalkenyl group substituted with one or more substituents, preferably 1 to 4 substituents, at any available attachment point.

[0032] The term “alkoxy” in this specification means a radical formed by the removal of hydrogen from an alcohol, for example, C1-C5 alkoxy means an alkyl ether formed by the removal of hydrogen from an alcohol having 1 to 5 carbon atoms.

[0033] The term "alkylamino" as used herein refers to a group having the structure -NHR', wherein R' is hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl as defined above.

[0034] The term "dialkylamino" as used herein refers to a group having the structure -NRR', wherein R and R' are each independently alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocyclyl or substituted heterocyclyl as defined above. R and R' may be the same or different dialkyamino moieties. Examples of dialkylamino groups include, but are not limited to, dimethylamino, methyl ethylamino, diethylamino, methylpropylamino, di(n-propyl)amino, di(iso-propyl)amino, di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino, di(neopentyl)amino, di(n-pentyl)amino, di(hexyl)amino, di(cyclohexyl)amino, and the like. In certain embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure may be aromatic or non-aromatic. Examples of cyclic diaminoalkyl groups include, but are not limited to, aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trianolyl, and tetrazolyl.

[0035] “Alkylene” and “heteroalkylene” described in the present invention mean a divalent organic saturated radical derived by the removal of one hydrogen from “alkyl” and “heteroalkyl”, respectively, and follow the respective definitions of alkyl and heteroalkyl.

[0036] The term "substitution" herein means that one or more hydrogen atoms on a specified group are replaced by a specified substituent. The specified substituent is a substituent described correspondingly above or a substituent shown in each embodiment. Unless specifically stated otherwise, a specified substituted group may have one substituent selected from a specified group at any substitutable site of the group, and the substituents may be the same or different at each position. A cyclic substituent, such as a heterocycloalkyl, may be connected to another ring, such as a cycloalkyl, to form a spiro bicyclic system, such as two rings having one common carbon atom. It should be understood by those skilled in the art that the combinations of substituents envisaged in the present invention are stable or chemically feasible combinations. The substituents may be, for example, C 1-8 Alkyl, C 2-8 Alkenyl, C 2-8 alkynyl, C 3-8 Cycloalkyl, 3- to 12-membered heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde group, C 2-10 Asil, C 2-10 Ester group, C 1-C12 Alkoxycarbonyl, amino, alkoxy, C 1-10 Sulfonyl, etc., but are not limited to these.

[0037] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to have sufficient hydrogen atoms to satisfy the valences.

[0038] As used herein, the term "combination" or "pharmaceutical combination" refers to a product resulting from the mixing or combining of more than one active ingredient, and including both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredients, such as a compound of the invention and one or more additional therapeutic agents, are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, such as a compound of the invention and one or more additional therapeutic agents, are administered to a patient as separate entities simultaneously, concurrently, or sequentially without a specific time limit, wherein such administration provides therapeutically effective levels of the active ingredients in the patient's body. The latter also applies to cocktail therapy, for example, the administration of three or more active ingredients.

[0039] The term "composition" or "pharmaceutical composition" as used herein refers to a mixture of at least one compound of the present invention and optionally more than one other pharmaceutically acceptable chemical component, such as a carrier, stabilizer, diluent, dispersant, suspending agent, thickener and / or excipient.

[0040] As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention, including geometric isomers. It is understood that substituents may be attached to chiral centers of carbon atoms. The term "chiral" refers to a molecule that has the property of non-superimposability on its mirror image partner, whereas the term "achiral" refers to a molecule that is superimposable on its mirror image partner. Accordingly, the present invention includes enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to designate a racemic mixture, where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and thus can produce enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0041] Salts of the compounds of the present invention having at least one salt-forming group can be prepared in a manner known to those skilled in the art. For example, salts of the compounds of the present invention having an acid group can be formed, for example, by treating the compound with a metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, for example the sodium salt of 2-ethylhexanoic acid, with an organic alkali metal or alkaline earth metal compound, such as the corresponding hydroxide, carbonate or hydrogen carbonate, such as sodium hydroxide or potassium hydroxide, carbonate or hydrogen carbonate, with the corresponding calcium compound, or with ammonia or a suitable organic amine, preferably using a stoichiometric amount or only a slight excess of a salt-forming agent. Acid addition salts of the compounds of the present invention are obtained in a conventional manner, for example by treating the compound with an acid or a suitable anion exchange reagent. Internal salts of compounds of the present invention containing acid and basic salt-forming groups, for example, free carboxyl groups and free amino groups, can be formed, for example, by neutralizing a salt, such as an acid addition salt, to its isoelectric point, for example, with a weak base, or by treating with an ion exchanger.

[0042] Salts can be converted into glass compounds by methods known to those skilled in the art. Metal and ammonium salts can be converted, for example, by treatment with a suitable acid, and acid addition salts can be converted, for example, by treatment with a suitable basic agent.

[0043] All of the process steps mentioned above can be carried out under reaction conditions known to a person skilled in the art, including those specifically mentioned, in the absence or usually the presence of a solvent or diluent (including, for example, a solvent or diluent that is inert to the reagents used and which dissolves them), in the absence or presence of a catalyst, a condensing agent or a neutralizing agent, for example, an ion exchanger such as a cation exchanger (e.g., in the form of H+), depending on the nature of the reaction and / or reactants, at reduced, moderate or elevated temperatures, for example in the temperature range of from about -100°C to about 190°C (e.g., from about -80°C to about 150°C, for example from -80°C to -60°C, room temperature, -20°C to 40°C, or reflux temperature), under atmospheric pressure or in a closed vessel, if appropriate under pressure, and / or in an inert atmosphere, for example under an argon or nitrogen atmosphere.

[0044] In one embodiment, the present invention provides a composition comprising acetate, adipate, ascorbate, aspartate, benzoate, besylate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, bromide / hydrobromide, camphorsulfonate, camsylate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, ethanedisulfonate, fumarate, gluceptate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, naphthoate, Napsilate, 2-napsilate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate, trifluoroacetate, triphenatate, triphenylacetate or xinafoate salt form.

[0045] The compounds of the present invention are inherently or by design capable of forming solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art that are known to be harmless to recipients, such as water, ethanol, and the like. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0046] Any asymmetric atom (e.g., carbon, etc.) of the compound(s) of the present invention can exist racemically or enantiomerically enriched, for example, in the (R)-, (S)-, or (R,S)- configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50%, an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, an enantiomeric excess of at least 80%, an enantiomeric excess of at least 90%, an enantiomeric excess of at least 95%, or an enantiomeric excess of at least 99% in the (R)- or (S)- configuration. Substituents at atoms having unsaturated double bonds can, where possible, exist in the cis- (Z)- or trans- (E)- configuration.

[0047] Accordingly, as used herein, the compounds of the present invention may be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0048] Any resulting mixture of isomers can be separated into pure or substantially pure geometrical or optical isomers, diastereomers, or racemates on the basis of physicochemical differences of the constituents, for example, by chromatography and / or fractional crystallization.

[0049] Any resulting racemates of the final product or intermediates can be resolved into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained using optically active acids or bases, and liberating the optically active acidic or basic compound. In particular, a basic moiety can thus be used to resolve the compounds of the invention into their optical antipodes, for example, by fractional crystallization of a salt formed using optically active acids such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. The racemic products can also be resolved by chiral chromatography, for example, high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0050] In certain embodiments, the compound is prepared as its individual stereoisomers. In other embodiments, the compound is prepared as its individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereoisomers, and recovering the optically pure enantiomers. In certain embodiments, this is accomplished using covalent diastereomeric derivatives of the enantiomers of the compound or using dissociable complexes (e.g., crystalline diastereomeric salts). Diastereoisomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivities, etc.) and are readily separated by exploiting these differences. In certain embodiments, the diastereoisomers are separated by chromatography or by separation / resolution techniques based on differences in solubility. The optically pure enantiomers are then recovered, along with the resolving agent, by any practical means that does not induce racemization. A more detailed description of techniques applicable to the resolution of stereoisomers of a compound from their racemic mixture can be found in the literature [Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley And Sons, Inc., 1981].

[0051] The mixture of isomers obtainable according to the invention can be separated into the individual isomers in a manner known to the person skilled in the art; the diastereoisomers can be separated, for example, by partitioning between multiphase solvent mixtures, recrystallization and / or chromatographic separation, for example, on silica gel, or by medium pressure liquid chromatography, for example, on a reverse-phase column, and the racemates can be separated, for example, by salt formation using an optically pure salt-forming reagent, and separation of the mixture of diastereoisomers thus obtainable, for example, by means of fractional crystallization or by chromatography on an optically active column material.

[0052] Depending on the choice of starting materials and procedures, certain embodiments of the compounds of the present invention exist in the form of one of the possible isomers, or as mixtures thereof, for example, as pure optical isomers, or as isomer mixtures, such as racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers can be prepared using chiral synthetomers or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents can be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have the cis- or trans-configuration. All tautomeric forms are also intended to be included.

[0053] Intermediates and final products can be worked up and / or purified according to standard methods, for example using chromatographic methods, partitioning methods, (re-)crystallization, etc. The present invention also relates to processes in which compounds obtainable as intermediates at any step of the process are used as starting materials and the remaining process steps are carried out, or to processes in which the starting materials are formed under the reaction conditions or are used in the form of derivatives, for example in protected form or in the form of salts, or to processes in which compounds obtainable by the process according to the invention are prepared under the process conditions and further processed in situ. All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be prepared by organic synthetic methods known to those skilled in the art.

[0054] The compounds of the present invention can form salts, which are also within the scope of the present invention. Reference to a compound of the present invention is to be understood to include reference to salts thereof, unless otherwise specified. The term "salt(s)" as used herein refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Additionally, when a compound of the present invention comprises both a basic moiety, such as, but not limited to, pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, a zwitterion ("intermolecular salt") can be formed and is included within the term "salt(s)" as used herein. Although other salts may be useful, for example, in isolation or purification steps that may be used during formulation, pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred. Salts of a compound of the present invention are formed, for example, by reacting the compound with a predetermined amount, such as an equivalent amount of acid or base, in the same medium as the salt precipitates, or in an aqueous medium, followed by lyophilization.

[0055] Compounds of the present invention comprising a basic moiety, such as, without limitation, an amine or a pyridine or imidazole ring, can form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (e.g., those formed with acetic acid or trihaloacetic acids, e.g., trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, malates, methanesulfonates, naphthalenesulfonates (e.g., 2- naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfates (e.g., those formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as tosylate, undecanoate, etc.

[0056] Compounds of the present invention comprising an acidic moiety, such as, but not limited to, a carboxylic acid, can form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (e.g., organic amines) such as benzathine, dicyclohexylamine, hydrabamine (formed from N,N-bis(dehydroabieethyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glicamide, t-butyl amine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be quaternized with substances such as lower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and the like.

[0057] Prodrugs and solvates of the compounds of the present invention are also contemplated herein. The term "prodrug," as used herein, refers to a compound that, upon administration to a subject, undergoes chemical conversion via metabolic or chemical processes to yield a compound of the present invention, or a salt and / or solvate thereof. Solvates of the compounds of the present invention include, for example, hydrates.

[0058] The compounds of the present invention, and their salts or solvates, may exist in their tautomeric forms (e.g., as amides or imino ethers). All such tautomeric forms are contemplated herein as part of the present invention.

[0059] All stereoisomers of the compounds of the invention, including enantiomeric forms and diastereomeric forms (e.g., those which may exist due to the presence of asymmetric carbons on various substituents), are contemplated within the scope of the present invention. Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers (e.g., as pure or substantially pure optical isomers having a specified activity), or may be, for example, racemates or mixed with all other, or other selected, stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 Recommendations. Racemic forms may be resolved by physical methods, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by any suitable method, including but not limited to, conventional methods, such as, for example, salt formation using an optically active acid followed by crystallization.

[0060] Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and specific functional groups are generally defined as described in said book. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, the entire contents of which are incorporated herein by reference.

[0061] Any variety of isomer ratios can be utilized in accordance with the present invention. For example, when only two isomers are combined, mixtures comprising isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 are all contemplated by the present invention. Those skilled in the art will readily appreciate that similar ratios are contemplated for more complex isomer mixtures.

[0062] The present invention also includes isotopically labeled compounds, which are identical to the compounds disclosed herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, individually. 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O,31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds of the present invention comprising the above-mentioned isotopes and / or other isotopes of other atoms, or enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Specific isotopically labeled compounds of the present invention, for example, 3 H, and, 14 Those containing radioactive isotopes such as C are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred due to their ease of preparation and detection. In addition, heavier isotopes, such as deuterium, are preferred. 2 Substitution with H may provide certain therapeutic advantages resulting from better metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and may therefore be desirable in some cases. Isotopically labeled compounds can generally be prepared by performing the procedures disclosed in the following reaction schemes and / or the examples, by substituting a readily available isotopically labeled reagent for the non-isotopically labeled reagent.

[0063] In another embodiment of the present invention, A is halogen; ; unsubstituted or C1-C3 alkyl, C1-C3 alkyl C1-C3 alkoxy, amine, C1-C3 alkyl alkoxy C1-C3 alkyl, , , , , , , , , , , (m is an integer from 1 to 3); C6-C unsubstituted or substituted with C1-C3 alkyl or amine; 10 Aryl; C6-C substituted with C1-C3 alkoxy group 10 Aryl alkyne; and,

[0064] R3 is ethoxy, alkoxy, C1-C3 alkyl alkoxy, hydroxy, C1-C3 alkyl amine, , amine, C6-C 10 aryl amine, , , , , , , , A compound, an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is at least one substituent selected from the group consisting of

[0065] In another embodiment of the present invention, in claim 2,

[0066] The above Z is amine, C1-C3 alkyl amine, , -NR4R5 (R4 is hydrogen; R5 is amine C1-C3 alkyl, hydroxy acyl C1-C3 alkyl, C6-C 10 Cyclo, , , , (n is an integer between 1 and 5), or C6-C unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C3 alkyl or one or more halogens; 10 Heterocyclic; or R4 and R5 are connected to each other, unsubstituted, C1-C3 alkyl or C6-C substituted with one or more halogens 10A compound selected from the group consisting of (forming a heterocyclic group), an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided.

[0067] In another embodiment of the present invention, a compound is provided wherein R1 and R2 are each independently C1-C3 alkyl or halogen, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[0068] In another embodiment of the present invention, the compound represented by the above chemical formula 1 is characterized in that it is selected from the group consisting of the following chemical formulas 2 to 79 (compounds 1 to 78), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[0069] [Chemical Formula 2]

[0070]

[0071] [Chemical Formula 3]

[0072]

[0073] [Chemical Formula 4]

[0074]

[0075] [Chemical Formula 5]

[0076]

[0077] [Chemical Formula 6]

[0078]

[0079] [Chemical Formula 7]

[0080]

[0081] [Chemical Formula 8]

[0082]

[0083] [Chemical Formula 9]

[0084]

[0085] [Chemical Formula 10]

[0086]

[0087] [Chemical Formula 11]

[0088]

[0089] [Chemical Formula 12]

[0090]

[0091] [Chemical Formula 13]

[0092]

[0093] [Chemical Formula 14]

[0094]

[0095] [Chemical Formula 15]

[0096]

[0097] [Chemical Formula 16]

[0098]

[0099] [Chemical Formula 17]

[0100]

[0101] [Chemical Formula 18]

[0102]

[0103] [Chemical Formula 19]

[0104]

[0105] [Chemical Formula 20]

[0106]

[0107] [Chemical Formula 21]

[0108]

[0109] [Chemical Formula 22]

[0110]

[0111] [Chemical Formula 23]

[0112]

[0113] [Chemical Formula 24]

[0114]

[0115] [Chemical Formula 25]

[0116]

[0117] [Chemical Formula 26]

[0118]

[0119] [Chemical Formula 27]

[0120]

[0121] [Chemical Formula 28]

[0122]

[0123] [Chemical Formula 29]

[0124]

[0125] [Chemical Formula 30]

[0126]

[0127] [Chemical Formula 31]

[0128]

[0129] [Chemical Formula 32]

[0130]

[0131] [Chemical Formula 33]

[0132]

[0133] [Chemical Formula 34]

[0134]

[0135] [Chemical Formula 35]

[0136]

[0137] [Chemical Formula 36]

[0138]

[0139] [Chemical Formula 37]

[0140]

[0141] [Chemical Formula 38]

[0142]

[0143] [Chemical Formula 39]

[0144]

[0145] [Chemical Formula 40]

[0146]

[0147] [Chemical Formula 41]

[0148]

[0149] [Chemical Formula 42]

[0150]

[0151] [Chemical Formula 43]

[0152]

[0153] [Chemical Formula 44]

[0154]

[0155] [Chemical Formula 45]

[0156]

[0157] [Chemical Formula 46]

[0158]

[0159] [Chemical Formula 47]

[0160]

[0161] [Chemical Formula 48]

[0162]

[0163] [Chemical Formula 49]

[0164]

[0165] [Chemical Formula 50]

[0166]

[0167] [Chemical Formula 51]

[0168]

[0169] [Chemical Formula 52]

[0170]

[0171] [Chemical Formula 53]

[0172]

[0173] [Chemical Formula 54]

[0174]

[0175] [Chemical Formula 55]

[0176]

[0177] [Chemical Formula 56]

[0178]

[0179] [Chemical Formula 57]

[0180]

[0181] [Chemical Formula 58]

[0182]

[0183] [Chemical Formula 59]

[0184]

[0185] [Chemical Formula 60]

[0186]

[0187] [Chemical Formula 61]

[0188]

[0189] [Chemical Formula 62]

[0190]

[0191] [Chemical Formula 63]

[0192]

[0193] [Chemical Formula 64]

[0194]

[0195] [Chemical Formula 65]

[0196]

[0197] [Chemical Formula 66]

[0198]

[0199] [Chemical Formula 67]

[0200]

[0201] [Chemical Formula 68]

[0202]

[0203] [Chemical Formula 69]

[0204]

[0205] [Chemical Formula 70]

[0206]

[0207] [Chemical Formula 71]

[0208]

[0209] [Chemical Formula 72]

[0210]

[0211] [Chemical Formula 73]

[0212]

[0213] [Chemical Formula 74]

[0214]

[0215] [Chemical Formula 75]

[0216]

[0217] [Chemical Formula 76]

[0218]

[0219] [Chemical Formula 77]

[0220]

[0221] [Chemical Formula 78]

[0222]

[0223] [Chemical Formula 79]

[0224]

[0225] In one embodiment of the present invention, a pharmaceutical composition for preventing or treating respiratory diseases is provided, comprising the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0226] The term "respiratory disease" of the present invention refers to a pathological condition that occurs in the respiratory organs and tissues, making gas exchange difficult. It includes all diseases that occur in the state of all respiratory organs, including the trachea, bronchi, bronchioles, alveoli, pleura, pleural space, respiratory muscles and nerves. In addition, in the present invention, the respiratory disease is a disease that affects the nasal cavity, pharynx, larynx, trachea, bronchi, lungs, thorax, diaphragm, etc., which are organs related to breathing, and examples of respiratory diseases include, but are not limited to, asthma, bronchiectasis, pulmonary fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), respiratory inflammatory lung disease, emphysema, pneumonia, cystic fibrosis, emphysema, sequelae of pulmonary tuberculosis, chronic bronchitis, allergic rhinitis, expectoration, acute lower respiratory tract infection, bronchitis, bronchiolitis, acute upper respiratory tract infection, sinusitis, pharyngitis, tonsillitis, or laryngitis.

[0227] Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating respiratory diseases, wherein the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof induces motile cilia production.

[0228] The "motile cilia" described herein are microscopic, hair-like organelles that move rhythmically and play an essential role in various bodily functions, including respiratory mucosal clearance, egg transport, sperm motility, and cerebrospinal fluid circulation. They possess a complex microtubule-based (9+2) axonemal structure, including dynein arms and radial spokes, enabling them to move rhythmically. Any dysfunction that regulates the movement of this protein complex can lead to motile ciliopathies, which can affect numerous organ systems and cause various diseases, such as infertility, hydrocephalus, fibrosis, asthma, and respiratory diseases. These disorders can be caused by mutations in genes encoding ciliary components or regulatory proteins. In conclusion, activating motile cilia production, driven by the master regulator, the transcription factor Foxj1, contributes to recovery after motile ciliary damage, thereby treating various respiratory diseases.

[0229] In another embodiment of the present invention, a pharmaceutical composition for preventing or treating a respiratory disease is provided, characterized in that the respiratory disease is at least one selected from the group consisting of acute respiratory distress syndrome, hay fever, primary ciliary dyskinesia and cystic fibrosis, kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome and pulmonary fibrosis.

[0230] The above “prevention” of the present invention may include, without limitation, any act that can block, suppress or delay symptoms caused by a disease by using the composition of the present invention.

[0231] The above "treatment" of the present invention may include, without limitation, any act that can improve symptoms caused by a disease or provide benefits by using the above composition of the present invention.

[0232] The above “improvement” of the present invention may include, without limitation, any act in which symptoms caused by a disease are improved or beneficially changed by using the composition of the present invention.

[0233] The pharmaceutical composition of the present invention is not limited thereto, but may be formulated and used in the form of oral formulations such as powders, granules, capsules, tablets, aqueous suspensions, etc., external preparations, suppositories, and sterile injection solutions, each according to a conventional method. Preferably, the pharmaceutical composition may be formulated for intratracheal administration or inhalation administration; or for use as an injection, but is not limited thereto. For the purpose of the present invention, when a disease occurs in a respiratory organ such as the lungs, it is preferable to formulate the composition for inhalation administration so that the active ingredient can reach the target organ at a yield suitable for prevention or treatment.

[0234] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may include a binder, a lubricant, a disintegrant, an excipient, a solubilizer, a dispersant, a stabilizer, a suspending agent, a pigment, a fragrance, etc. for oral administration. In the case of injections, a buffer, a preservative, an analgesic, a solubilizer, an isotonic agent, a stabilizer, etc. may be mixed and used. In the case of topical administration, a base, an excipient, a lubricant, a preservative, etc. may be used. The dosage form of the pharmaceutical composition of the present invention may be prepared in various ways by mixing it with the pharmaceutically acceptable carrier described above. For example, the composition may be prepared in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, etc. for oral administration. In the case of injections, the composition may be prepared in the form of unit dose ampoules or multiple doses. In addition, the composition may be formulated as a solution, suspension, tablet, capsule, sustained-release preparation, etc.

[0235] Meanwhile, examples of carriers, excipients, and diluents suitable for formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, malditol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, or mineral oil. In addition, fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, preservatives, and the like may be additionally included.

[0236] Routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal. Oral or parenteral administration is preferred.

[0237] The parenteral route of the present invention includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.

[0238] The pharmaceutical composition of the present invention may vary depending on various factors including the activity of the specific compound used, age, body weight, general health, sex, dosage form, administration time, administration route, excretion rate, drug combination, and severity of the specific disease to be prevented or treated, and the dosage of the pharmaceutical composition may vary depending on the patient's condition, body weight, degree of disease, form of medicine, administration route, and period, but may be appropriately selected by those skilled in the art, and may be administered at 0.0001 to 50 mg / kg or 0.001 to 50 mg / kg per day. Administration may be administered once a day or divided into several times. The dosage does not limit the scope of the present invention in any way. The pharmaceutical composition according to the present invention may be formulated as a pill, a dragee, a capsule, a liquid, a gel, a syrup, a slurry, or a suspension.

[0239] In another embodiment of the present invention, a food composition for preventing or improving respiratory diseases is provided, comprising the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0240] In another embodiment of the present invention, a food composition for preventing or improving a respiratory disease is provided, characterized in that the respiratory disease is at least one selected from the group consisting of acute respiratory distress syndrome, hay fever, primary ciliary dyskinesia, cystic fibrosis, kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome, and pulmonary fibrosis.

[0241] When the food composition of the present invention is manufactured in the form of a beverage, there are no special limitations other than including the food composition in the indicated ratio, and various flavoring agents or natural carbohydrates, etc. may be contained as additional ingredients like a typical beverage. Specifically, the natural carbohydrates may include monosaccharides such as glucose, disaccharides such as fructose, sucrose, and other polysaccharides, dextrin, cyclodextrin, and other typical sugars, and sugar alcohols such as xylitol, sorbitol, and erythritol. The flavoring agents may include natural flavoring agents (thaumatin, stevia extracts (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.).

[0242] The food composition of the present invention may further include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc.

[0243] The ingredients included in the food composition of the present invention may be used independently or in combination. The proportion of the additives is not a key element of the present invention, but may be selected within the range of 0.1 to about 50 parts by weight per 100 parts by weight of the food composition of the present invention, but is not limited thereto.

[0244] In the present invention, the "subject" refers to a subject suspected of having a respiratory disease, and the subject suspected of having a respiratory disease refers to mammals including rats, livestock, etc., including humans that have developed or may develop the disease, but subjects that can be treated with the composition of the present invention are included without limitation.

[0245] The method of the present invention may include administering the active ingredient in a pharmaceutically effective amount. The appropriate total daily dosage may be determined by the treating physician within the scope of sound medical judgment, and may be administered once or in several divided doses. However, for the purposes of the present invention, it is preferable to apply a specific therapeutically effective amount for a specific patient differently depending on various factors, including the type and degree of response to be achieved, the specific composition including whether other agents are used in some cases, the patient's age, weight, general health, sex, and diet, the time of administration, the route of administration, and the excretion rate of the composition, the treatment period, drugs used together or concurrently with the specific composition, and similar factors well known in the medical field.

[0246] The present invention describes the synthesis and biological evaluation of novel substituted pyridine derivatives as foxj1 activity potentiators. In the examples, novel pyridine derivatives were synthesized and evaluated for their ability to potentiate foxj1 activity. The novel pyridine derivatives synthesized in the present invention not only exhibited excellent activity in a Tg(foxj1:egfp) transgenic zebrafish animal model, but also exhibited excellent metabolic safety and pharmacokinetic profiles. Furthermore, the novel pyridine derivatives synthesized in the present invention enhanced ciliary stimulation in mouse tracheal epithelial cells (mTECs) isolated from the airway and cultured at an ALI in a motile ciliated cell differentiation experiment. Consequently, the series of foxj1 activity potentiators with substituted pyridine skeletons have potential for development as preventive and therapeutic agents for respiratory diseases.

[0247] Figure 1 is an overview of the phenotypic HTS. Specifically, a is Tg(foxi1a:eGFP) hsc16 Zebrafish represent crossbreeds with wild-type TL zebrafish. B represents Tg(foxi1a:eGFP) + / - Embryos were treated with chemical compounds (5 μM) or DMSO (vehicle control) at 1 day post-fertilization (dpf). The following day (2 dpf), embryos were imaged under a fluorescence stereomicroscope to evaluate EGFP expression levels in the ependymal cell region of the spinal cord. Compounds that significantly increased EGFP levels in the spinal cord compared to the DMSO control were selected as hit compounds and subjected to subsequent analysis.

[0248] Figure 2a shows the results of confocal laser microscopy imaging of mTECs isolated from mice treated with compound 58 for 4 days after ALI-0, immunostained with anti-acetylated α-tubulin antibody (green; motile cilia) and ZO-1 antibody (purple; tight junctions). Scale bar = 25 μm. Figure 2b shows the results of quantifying multiciliated cells in a. * P < 0.05.

[0249] Figure 3a shows the results of COPD mice treated with DMSO or compound 58 after COPD was induced by intranasal administration of elastase. The trachea were then removed, immunostained with ARL13B (green; motile cilia) and γ-tubulin (red; basal bodies) antibodies, and imaged using a confocal laser microscope. Blue indicates DAPI-stained nuclei. The area within the box is enlarged in the panel below. Scale bar = 10 μm. Figure 3b shows the results of determining the number of motile cilia based on their length.

[0250]

[0251] Hereinafter, the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention more specifically, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples, in accordance with the gist of the present invention.

[0252]

[0253] [Example] Experiment Preparation

[0254] The following examples and experimental examples provide a practical and detailed explanation of the invention. These examples and experimental examples are provided to aid understanding of the invention and do not limit the scope of the invention.

[0255] Additionally, the reagents and solvents mentioned were purchased from Sigma-Aldrich unless otherwise specified. 1H NMR spectra were measured at 400 MHz (JEOL JNM-ECS400), and LCMS data were acquired using an Agilent LCMS system.

[0256]

[0257] [Example]

[0258] [Example 1] Preparation of compound 5-(3-aminophenyl)-3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)pyridin-2-amine (Compound 1)

[0259] [Reaction Formula 1]

[0260]

[0261]

[0262] Step 1: Preparation of 5-bromo-2-chloronicotinoyl chloride

[0263] To 14 g (64 mmol) of commercially available 5-bromo-hydroxynicotinic acid, 64 mL of thionyl chloride was added. Then, 1 mL of dimethylformamide was slowly added at 0°C, and the mixture was heated to 80°C and stirred for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a yellow solid compound. The next reaction was carried out without any separate purification process.

[0264]

[0265] Step 2: Preparation of 5-bromo-2-chloro-N-(2-hydroxyphenyl)nicotinamide

[0266] 2-Aminophenol 20 g (188 mmol), N,N-diisopropylethylamine 18 ml (132 mmol) and 627 mL of methylene chloride solution were added, and 32 g (126 mmol) of 5-bromo-2-chloronicotinoyl chloride dissolved in methylene chloride was slowly added at 0 °C under nitrogen gas. The temperature of the reaction mass was increased to room temperature and stirred for 18 hours. Water was added to the reaction mass to extract, the organic layer was separated, and the aqueous layer was extracted by adding methylene chloride. The separated organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel to obtain 12 g (30%) of an ivory solid compound.

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.75 (s, 1H), 8.63 (d, J = 2.5 Hz, 1H), 8.30 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.0, 1.6 Hz, 1H), 7.00-6.95 (m, 1H), 6.87 (dd, J = 8.0, 1.5 Hz, 1H), 6.81-6.77 (m, 1H).

[0268]

[0269] Step 3: Preparation of 2-(5-bromo-2-chloropyridin-3-yl)benzo[d]oxazole

[0270] 21 g (65 mmol) of 5-bromo-2-chloro-N-(2-hydroxyphenyl)nicotinamide, 3.6 g (14 mmol) of p-toluenesulfonic acid pyridine salt, and 296 mL of xylene were added and stirred at 150°C for 18 hours. The reaction mixture was cooled to 100°C and diluted with xylene. The reaction mixture was filtered to prevent the tar generated during the reaction from flowing out and washed several times with xylene. The filtrate was purified by flash chromatography on silica gel to obtain the target compound. 16.9 g, 83%.

[0271] 1 H NMR (400 MHz, DMSO-d6) δ 8.83 (d, J=2.5 Hz, 1H), 8.78 (d, J=2.5 Hz, 1H), 7.94 –7.91(m, 1H), 7.88 – 7.85 (m, 1H), 7.56 – 7.46 (m, 2H).

[0272]

[0273] Step 4: Preparation of 3-(benzo[d]oxazol-2-yl)-5-bromo-N-(tert-butyl)pyridin-2-amine

[0274] In a sealed tube, 900 mg (2.9 mmol) of 2-(5-bromo-2-chloropyridin-3-yl)benzo[d]oxazole was dissolved in a mixed solution of 4 mL of methylene chloride and 1.7 mL of tetrahydrofuran. 4.3 g (58 mmol) of tert-butylamine was added, sealed, and stirred at 70°C for 72 hours, after which the temperature was lowered to room temperature. Ethyl ether was added to the reaction mixture, stirred for 30 minutes, and the resulting solid was filtered and washed several times with ethyl ether to obtain the target compound. 250 mg, 24.8%.

[0275] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.37 (d,J= 0.9 Hz, 2H), 7.83 - 7.78 (m, 2H), 7.49-7.42 (m, 2H), 1.54 (s, 9H).

[0276]

[0277] [Example 2] Preparation of 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-indazol-4-yl)pyridin-2-amine (Compound 2)

[0278] [Reaction Formula 2]

[0279]

[0280] 3-(Benzo[d]oxazol-2-yl)-5-bromo-N-(tert-butyl)pyridin-2-amine (300 mg, 0.87 mmol), 1H-indazole-4-boronic acid (252 mg, 1.3 mmol), tetrakistriphenyl phosphine palladium (Pd(PPh3)4) (50 mg, 0.043 mmol) and 1,4-dioxane (4.3 ml) were added, 2 M aqueous sodium carbonate solution (2.6 ml) was added and the mixture was reacted at 120 °C for 1 hour using a microwave. After cooling the reaction mixture to room temperature, it was filtered and concentrated using Celite, extracted with water and methylene chloride, and the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by rapid chromatography on silica gel (eluent: EA:Hex=2:1), thereby obtaining 166 mg (57.5%) of the target compound.

[0281] 1 H NMR (400 MHz, Chloroform-d) δ 10.15 (brs, 1H), 8.92 (s, 1H), 8.69 – 8.54 (m, 2H), 8.31 (s, 1H), 7.84 – 7.62 (m, 1H), 7.59 – 7.52 (m, 1H), 7.52 – 7.41 (m, 2H), 7.39 – 7.30 (m, 2H), 7.27 (dd, J = 5.1, 2.7 Hz, 1H), 1.66 (s, 9H).

[0282]

[0283] [Examples 3 to 15] Preparation of compounds 3 to 15

[0284] Compounds 3-15 were prepared using the same method as that presented in Scheme 2 as shown in Table 1 below.

[0285] NoStructureChemical nameLCMS / NMR1 3-(benzo[d]oxazol-2-yl)-5-bromo-N-(tert-butyl)pyridin-2-amine346.0 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.33 (d,J= 0.9 Hz, 2H), 7.77 (ddd,J= 12.8, 7.4, 1.5 Hz, 2H), 7.42 (pd,J= 7.4, 1.4 Hz, 2H), 1.50 (s, 9H).2 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-indazol-4-yl)pyridin-2-amine384.1 1 H NMR (400 MHz, Chloroform-d) δ 10.15 (brs, 1H), 8.92 (s, 1H), 8.69 – 8.54 (m, 2H), 8.31 (s, 1H), 7.84 – 7.62 (m, 1H), 7.59 – 7.52 (m, 1H), 7.52 – 7.41 (m, 2H), 7.39 – 7.30 (m, 2H), 7.27 (dd,J= 5.1, 2.7 Hz, 1H), 1.66 (s, 9H).3 5-(3-aminophenyl)-3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)pyridin-2-amine3-(benzo[d]oxazol-2-yl)-5-bromo-N-(tert-butyl)pyridin-2-amine359.14 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(3-methyl-1H-pyrazol-4-yl)pyridin-2-amine348.1 1H NMR (400 MHz, DMSO-d6) δ 12.57 (brs, 1H), 8.69 (s, 1H), 8.42 (d,J= 2.5 Hz, 1H), 8.29 (d,J= 2.5 Hz, 1H), 7.80 (tt,J= 7.5, 2.9 Hz, 2H), 7.49 – 7.38 (m, 2H), 5.98 (s, 1H), 3.33 (s, 3H), 1.57 (s, 9H).5 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-((2-methoxyphenyl)ethynyl)pyridin-2-amine398.0 1 H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.47 (d,J= 2.3 Hz, 1H), 8.45 (dd,J= 2.3, 0.6 Hz, 1H), 7.76 – 7.68 (m, 1H), 7.60 – 7.53 (m, 1H), 7.50 (dd,J= 7.6, 1.7 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.30 (ddd,J= 8.4, 7.5, 1.7 Hz, 1H), 6.97 – 6.88 (m, 2H), 3.94 (s, 3H), 1.61 (s, 9H).6 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(pyrazolo[1,5-a]pyridin-3-yl)pyridin-2-amine384.0 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.76 – 8.71 (m, 1H), 8.64 (d,J= 2.5 Hz, 1H), 8.49 (d,J= 2.4 Hz, 1H), 8.40 (s, 1H), 7.95 (d,J= 8.9 Hz, 1H), 7.86 – 7.77 (m, 2H), 7.50 – 7.39 (m, 2H), 7.37 – 7.28 (m, 1H), 6.96 (td,J= 6.8, 1.3 Hz, 1H), 1.60 (s, 9H).7 3-(benzo[d]oxazol-2-yl)-5-(benzofuran-3-yl)-N-(tert-butyl)pyridin-2-amine384.0 1 H NMR (400 MHz, Chloroform-d) δ 8.88 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 1H), 7.90 – 7.84 (m, 1H), 7.81 (s, 1H), 7.79 – 7.71 (m, 1H), 7.61 – 7.54 (m, 2H), 7.41 – 7.32 (m, 4H), 1.66 (s, 9H).8 5-(benzo[b]thiophen-3-yl)-3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)pyridin-2-amine400.0 1 H NMR (400 MHz, Chloroform-d) δ 8.89 (s, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.50 (d, J = 2.4 Hz, 1H), 7.99 – 7.91 (m, 2H), 7.78 – 7.71 (m, 1H), 7.58 – 7.51 (m, 1H), 7.47 – 7.41 (m, 3H), 7.39 – 7.32 (m, 2H), 1.66 (s, 9H).9 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-indazol-3-yl)pyridin-2-amine434.1 1 H NMR (400 MHz, Chloroform-d) δ 10.06 (s, 1H), 8.96 – 8.87 (m, 3H), 8.13 – 8.06 (m, 1H), 7.79 – 7.70 (m, 1H), 7.62 – 7.50 (m, 2H), 7.45 (ddd, J = 8.2, 6.8, 1.0 Hz, 1H), 7.40 – 7.31 (m, 2H), 7.31 – 7.26 (m, 1H), 1.67 (s, 9H).10 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-indol-1-yl)pyridin-2-amine383.0 1 H NMR (400 MHz, Chloroform-d) δ 8.92 (s, 1H), 8.41 (d, J = 2.8 Hz, 1H), 8.38 (d, J = 2.7 Hz, 1H), 7.80 – 7.68 (m, 2H), 7.56 – 7.48 (m, 1H), 7.45 (dd, J = 8.2, 1.1 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.29 (d, J = 3.2 Hz, 1H), 7.25 – 7.16 (m, 2H), 6.70 (dd, J = 3.2, 0.9 Hz, 1H), 1.66 (s, 9H).11 5-(1H-benzo[d]imidazol-1-yl)-3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)pyridin-2-amine384.1 1 H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 8.39 (dd, J = 2.7, 0.8 Hz, 1H), 8.37 (dd, J = 2.7, 0.8 Hz, 1H), 8.07 (s, 1H), 7.93 – 7.86 (m, 1H), 7.80 – 7.71 (m, 1H), 7.56 – 7.48 (m, 1H), 7.51 – 7.43 (m, 1H), 7.36 (tdd, J = 6.4, 3.3, 1.8 Hz, 4H), 1.65 (s, 9H).12 5-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)pyridin-2-amine385.0 1H NMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.82 (dt, J = 1.8, 0.9 Hz, 1H), 8.54 (dd, J = 2.6, 0.9 Hz, 1H), 8.50 (dd, J = 2.6, 0.9 Hz, 1H), 8.38 (d, J = 0.9 Hz, 1H), 7.86 (dt, J = 9.2, 1.0 Hz, 1H), 7.81 (ddd, J = 9.2, 1.8, 0.9 Hz, 1H), 7.75 (ddt, J = 5.0, 3.3, 0.7 Hz, 1H), 7.64 – 7.55 (m, 1H), 7.43 – 7.33 (m, 2H), 1.65 (s, 9H).13 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(imidazo[1,2-a]pyridin-6-yl)pyridin-2-amine 2,2,2-trifluoroacetaldehyde385.0 1 H NMR (400 MHz, DMSO-d6) δ 9.38 – 9.33 (m, 1H), 8.99 (s, 1H), 8.77 (d, J = 2.6 Hz, 1H), 8.67 (d, J = 2.6 Hz, 1H), 8.36 (dd, J = 9.4, 1.8 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 7.89 – 7.78 (m, 2H), 7.67 – 7.42 (m, 3H), 1.62 (s, 9H).14 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(imidazo[1,2-a]pyrimidin-6-yl)pyridin-2-amine385.018-002 1H NMR (400 MHz, DMSO-d6) δ 9.38 (d, J = 2.6 Hz, 1H), 8.96 (d, J = 2.5 Hz, 1H), 8.92 (s, 1H), 8.73 (d, J = 2.5 Hz, 1H), 8.65 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.88 – 7.78 (m, 2H), 7.77 (d, J = 1.4 Hz, 1H), 7.52 – 7.40 (m, 2H), 1.61 (s, 9H).15 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(imidazo[1,2-b]pyridazin-6-yl)pyridin-2-amine385.0 1 H NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.03 (d, J = 2.6 Hz, 1H), 9.00 – 8.94 (m, 1H), 8.42 – 8.37 (m, 1H), 8.23 ​​– 8.16 (m, 1H), 7.96 – 7.81 (m, 3H), 7.80 (d, J = 1.2 Hz, 1H), 7.54 – 7.41 (m, 2H), 1.62 (s, 9H).

[0286]

[0287] [Example 16] Preparation of N1-(3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride (Compound 16)

[0288] [Reaction Formula 3]

[0289]

[0290]

[0291] Step 1: Preparation of tert-butyl (3-((3-(benzo[d]oxazol-2-yl)-5-bromopyridin-2-yl)amino)propyl)carbamate

[0292] In a sealed tube, 170 mg (0.55 mmol) of 2-(5-bromo-2-chloropyridin-3-yl)benzo[d]oxazole was dissolved in a mixed solution of 2 mL of methylene chloride and 1 mL of tetrahydrofuran. 115 mg (0.66 mmol) of tert-butyl(3-aminopropyl)carbamate was added, sealed, and stirred at 125°C for 72 hours, after which the temperature was lowered to room temperature. Ethyl ether was added to the reaction mixture, stirred for 30 minutes, and the resulting solid was filtered and washed several times with ethyl ether to obtain the target compound. 191 mg, 78%.

[0293] MS(ESI) m / z= 447.1 [M+H] +

[0294]

[0295] Step 2: Preparation of N1-(3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride

[0296] Tert-butyl (3-((3-(benzo[d]oxazol-2-yl)-5-bromopyridin-2-yl)amino)propyl)carbamate (110 mg, 0.25 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (57 mg, 0.30 mmol), tetrakistriphenyl phosphine palladium (Pd(PPh3)4) (28 mg, 0.025 mmol) and 1,4-dioxane (1.2 ml) were added, and a 2 M sodium carbonate aqueous solution (0.25 ml) was added and the mixture was reacted at 120°C for 1 hour using a microwave. After cooling the reaction mixture to room temperature, the mixture was filtered and concentrated using Celite, extracted with water and methylene chloride, and the organic layer obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel (eluent: EA:Hex=2:1) ​​to obtain 34 mg (32%) of tert-butyl (3-((3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)amino)propyl)carbamate.

[0297] 1 H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.87 (s, 2H), 7.76 (dd, J = 6.0, 3.1 Hz, 1H), 7.63 – 7.56 (m, 1H), 7.42 – 7.33 (m, 2H), 5.32 (s, 1H), 3.77 (q, J = 6.4 Hz, 2H), 3.28 (d, J = 7.4 Hz, 2H), 1.98 – 1.90 (m, 2H), 1.46 (s, 9H).

[0298]

[0299] Step 3: Preparation of target compound

[0300] To tert-butyl (3-((3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)amino)propyl)carbamate (33 mg, 0.08 mmol) dissolved in 0.4 mL of tetrahydrofuran was added a 4 M hydrogen chloride solution in 1,4-dioxane (0.4 mL). The reaction mixture was stirred at room temperature overnight. The product was collected by filtration and washed with diethyl ether. After drying under vacuum, the target compound was obtained (7 mg, 27%).

[0301] 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.62 – 8.54 (m, 2H), 8.18 (s, 2H), 7.96 (s, 3H), 7.85 (ddd,J= 15.0, 6.9, 2.2 Hz, 2H), 7.53 – 7.42 (m, 2H), 4.03 (q,J= 7.1 Hz, 1H), 3.75 (d,J= 13.6 Hz, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 2.92 (s, 2H), 2.05 – 1.94 (m, 2H).

[0302]

[0303] [Examples 17 to 27] Preparation of compounds 17 to 29

[0304] Compounds 17 to 29 were prepared as shown in Table 2 below using the same method as the process presented in Scheme 3.

[0305] NoStructureChemical nameMS or NMR16 N1-(3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)propane-1,3-diamine hydrochloride335.1 1H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.62 – 8.54 (m, 2H), 8.18 (s, 2H), 7.96 (s, 3H), 7.85 (ddd,J= 15.0, 6.9, 2.2 Hz, 2H), 7.53 – 7.42 (m, 2H), 4.03 (q,J= 7.1 Hz, 1H), 3.75 (d,J= 13.6 Hz, 1H), 3.74 (s, 2H), 3.66 (s, 2H), 2.92 (s, 2H), 2.05 – 1.94 (m, 2H).17 2-(2-(piperidin-1-yl)-5-(1H-pyrazol-4-yl)pyridin-3-yl)benzo[d]oxazole346.118 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-pyrazol-3-yl)pyridin-2-amine 1 H NMR (400 MHz, Chloroform-d) δ 8.87 (brs, 1H), 8.67 (s, 2H), 7.75-7.71 (m, 1H), 7.58-7.53 (m, 1H), 7.35 (m, 3H), 6.63-6.61 (m, 1H), 1.63 (d, J = 3.6 Hz, 12H).19 2-(2,5-di(1H-pyrazol-4-yl)pyridin-3-yl)benzo[d]oxazole329.120 (3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)-L-leucine392.221 tert-butyl 4-((3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)amino)piperidine-1-carboxylate 1H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 7.4 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.86 (s, 2H), 7.78 – 7.70 (m, 1H), 7.59 (dd, J = 6.1, 3.2 Hz, 1H), 7.37 (dt, J = 7.1, 3.6 Hz, 2H), 4.52 – 4.23 (m, 1H), 4.03 (d, J = 13.7 Hz, 2H), 3.23 – 3.11 (m, 2H), 2.15 (d, J = 7.9 Hz, 2H), 1.73 – 1.59 (m, 2H), 1.50 (d, J = 5.1 Hz, 9H).22 3-(benzo[d]oxazol-2-yl)-N-(piperidin-4-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine hydrogen chloride361.1 1 H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 2H), 8.64 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.52 (s, 1H), 8.12 (d, J = 4.7 Hz, 2H), 7.86 – 7.78 (m, 1H), 7.81 – 7.73 (m, 1H), 7.49 – 7.38 (m, 2H), 4.38 (s, 1H), 3.31 (d, J = 12.7 Hz, 2H), 3.08 (d, J = 11.2 Hz, 2H), 2.26 (dd, J = 14.0, 4.0 Hz, 2H), 1.90 – 1.79 (m, 2H).23 3-(benzo[d]oxazol-2-yl)-N-(1-methylpiperidin-4-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine375.124 3-((3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)amino)propanoic acid350.025 3-(benzo[d]oxazol-2-yl)-N-(1-ethylpiperidin-4-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.60 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.80 (s, 2H), 7.44 (p, J = 7.5 Hz, 2H), 4.31 (s, 1H), 3.54 (s, 2H), 3.12 (s, 2H), 2.27 (s, 2H), 2.10 (s, 2H), 1.74 (s, 2H), 1.21 (s, 3H).26 N1-(3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)butane-1,4-diamine349.127 3-(benzo[d]oxazol-2-yl)-N-cyclohexyl-5-(1H-pyrazol-4-yl)pyridin-2-amine 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 7.86 (s, 2H), 7.79 – 7.71 (m, 1H), 7.59 (dd, J = 6.0, 3.2 Hz, 1H), 7.41 – 7.32 (m, 2H), 4.23 (s, 1H), 2.13 (d, J = 9.4 Hz, 2H), 1.83 (dd, J = 9.7, 4.9 Hz, 2H), 1.70 – 1.32 (m, 6H).28 ethyl (3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)-L-valinate406.029 methyl (S)-2-((3-(benzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-yl)amino)-3,3-dimethylbutanoate406.0

[0306]

[0307] [Example 30] Preparation of 3-(5-(benzo[d]oxazol-2-yl)-6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)aniline (Compound 30)

[0308] A solid of 23 mg (45%) was obtained by manufacturing it using the same method as the process presented in the above reaction scheme 2.

[0309] 1 H NMR (400 MHz, Chloroform-d) δ 8.58 (d,J= 2.4 Hz, 1H), 8.49 (d,J= 2.5 Hz, 1H), 7.85 – 7.76 (m, 1H), 7.65 – 7.56 (m, 1H), 7.44 – 7.35 (m, 2H), 7.26 (t,J= 7.8 Hz, 1H), 7.01 (ddd,J= 7.6, 1.7, 0.9 Hz, 1H), 6.92 (t,J= 2.0 Hz, 1H), 6.71 (ddd,J= 8.0, 2.4, 0.9 Hz, 1H), 3.79 (s, 2H), 3.57 – 3.50 (m, 4H), 2.18 (td,J= 13.8, 6.8 Hz, 4H).

[0310]

[0311] [Examples 31 to 33] Preparation of compounds 31 to 33

[0312] As shown in Table 3 below, it was manufactured using the same method as the process presented in Scheme 3.

[0313] NoStructureChemical nameNMR / MS30 3-(5-(benzo[d]oxazol-2-yl)-6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)aniline407.131 3-(5-(benzo[d]oxazol-2-yl)-6-(4-methylpiperazin-1-yl)pyridin-3-yl)aniline386.132 2-(5-(benzo[d]oxazol-2-yl)-6-(piperidin-1-yl)pyridin-3-yl)aniline371.233 5-(benzo[d]oxazol-2-yl)-6-(piperidin-1-yl)-[3,4'-bipyridin]-2'-amine371.4

[0314] [Examples 34 to 37] Preparation of compounds 34 to 37

[0315] Compounds 34 to 37 described in Table 4 below were prepared using the same method as the process presented in the above reaction schemes 1 and 2.

[0316] NoStructureChemical nameNMR / MS34 N-(tert-butyl)-3-(6-fluorobenzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine352.235 N-(tert-butyl)-3-(4-methylbenzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine348.136 N-(tert-butyl)-3-(5-methylbenzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine347.437 N-(tert-butyl)-3-(6-methylbenzo[d]oxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine348.1

[0317]

[0318] Example 38: Preparation of ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoate (Compound 38)

[0319] [Reaction Formula 4]

[0320]

[0321]

[0322] Step 1: Preparation of compound 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-pyrazol-4-yl)pyridin-2-amine

[0323] 3-(Benzo[d]oxazol-2-yl)-5-bromo-N-(tert-butyl)pyridin-2-amine (300 mg, 0.87 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (252 mg, 1.3 mmol), tetrakistriphenyl phosphine palladium (Pd(PPh3)4) (50 mg, 0.043 mmol) and 1,4-dioxane (4.3 ml) were added, and a 2 M sodium carbonate aqueous solution (2.6 ml) was added and the mixture was reacted at 120°C for 1 hour using a microwave. After cooling the reaction mixture to room temperature, the mixture was filtered and concentrated using Celite, extracted with water and methylene chloride, and the organic layer obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel (eluent: EA:Hex=2:1), thereby obtaining 166 mg (57.5%) of the target compound.

[0324] 1H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.48 (d, J = 2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 7.87 (s, 2H), 7.76 – 7.67 (m, 1H), 7.61 – 7.52 (m, 1H), 7.38-7.33 (m, 2H), 1.62 (s, 9H).

[0325]

[0326] Step 2. Ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoate

[0327] 3-(Benzo[d]oxazol-2-yl)-5-bromo-N-(tert-butyl)pyridin-2-amine (50 mg, 0.14 mmol), ethyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (55 mg, 0.18 mmol), Tetrakistriphenyl phosphine palladium (Pd(PPh3) 4 ) (8 mg, 0.007 mmol) and 1,4-dioxane (0.7 ml) were added, 2 M sodium carbonate aqueous solution (0.2 ml) was added, and the mixture was reacted at 120 °C for 1 hour using a microwave. After cooling the reaction mixture to room temperature, it was filtered and concentrated using Celite, extracted with water and methylene chloride, and the obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel (eluent: EA:Hex=2:1), thereby obtaining 21 mg (34%) of the target compound.

[0328] 1H NMR (400 MHz, CD3OD) δ 8.45-8.35 (m, 2H), 8.01 – 7.93 (m, 1H), 7.83 (m, 1H), 7.75 – 7.67 (m, 1H), 7.67 – 7.60 (m, 1H), 7.44 – 7.31 (m, 2H), 4.51 – 4.39 (m, 2H), 4.21 – 4.06 (m, 2H), 2.99 – 2.83 (m, 2H), 1.20 (s, 9H).

[0329]

[0330] Example 39: 3-(4-(5-(Benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoic acid (Compound 39)

[0331] [Reaction Formula 5]

[0332]

[0333] Ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoate (step 2) (20 mg, 0.046 mmol) was dissolved in a mixture of tetrahydrofuran (0.2 mL) and methanol (0.2 mL), and 0.09 ml of 2 M aqueous lithium hydroxide solution was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Water was added to the concentrate, and it was acidified by adding 1 N hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel to give 15 mg (82%) of the title compound.

[0334] 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 8.37 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.77 (td, J = 6.9, 2.3 Hz, 2H), 7.41 (tt, J = 7.6, 5.8 Hz, 2H), 4.30 (t, J = 6.6 Hz, 2H), 2.80 (t, J = 6.8 Hz, 2H), 1.53 (s,9H).

[0335]

[0336] Example 45: Preparation of compound 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-morpholinopropan-1-one (Compound 45)

[0337] [Reaction Formula 6]

[0338]

[0339] 3-(4-(5-(Benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoic acid (50 mg, mmol), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) (93 mg, 0.25 mmol) and dimethylformamide (0.6 ml) were added and stirred at room temperature for 30 min. Amine (16 mg, 0.18 mmol) and DIPEA (0.13 mL, 0.74 mmol) were added and stirred for 16 h, and then extracted with ethyl acetate, water, 1 N-HCl and brine. The organic layer was dried over anhydrous Mg2SO4, concentrated under reduced pressure, and purified by column chromatography (EtOAc: n-Hexane: MeOH = 1: 2: 7%).

[0340] 1H NMR (400 MHz, Chloroform-d) δ 9.68 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 7.88 (s, 1H), 7.84 (s, 1H), 7.79 – 7.74 (m, 1H), 7.68 – 7.61 (m, 1H), 7.48 – 7.39 (m, 2H), 4.59 (t,J= 6.2 Hz, 2H), 3.37 (q,J= 7.0 Hz, 2H), 3.25 (q,J= 7.2 Hz, 2H), 2.94 (t,J= 6.2 Hz, 2H), 1.67 (s, 9H), 1.28-1.07 (m, 4H).

[0341]

[0342] Example 57: Preparation of compound ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoate (Compound 57)

[0343] [Reaction Formula 7]

[0344]

[0345]

[0346] Step 1: Preparation of ethyl 3-methylbut-2-enoate

[0347] 3-Methyl-2-butenoic acid (100 mg, 1.00 mmol) was dissolved in ethanol (0.6 ml), and 10 drops of H2SO4 were added while stirring. The solution was heated at 90 °C overnight. The reaction mixture was concentrated under reduced pressure, diluted with diethyl ether (1 ml), and the organic layer was washed with NaHCO3 (3 x 30 ml) and H2O (2 x 30 ml). The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain the target compound. 110 mg, 85%

[0348]

[0349] Step 2: Preparation of ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoate

[0350] In an oven-dried flask, K2CO3 (36 mg, 0.27 mmol) was added to a stirred solution of 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-pyrazol-4-yl)pyridin-2-amine (30 mg, 0.09 mmol) in anhydrous DMF (0.9 mL). After stirring for 30 min, ethyl 3-methylbut-2-enoate (57 mg, 0.45 mmol) was added. The solution was stirred for 48 h and then extracted with EtOAc (3 x 100 mL). The extract was washed with saturated ammonium chloride (100 mL) and water (2 x 100 mL), dried (MgSO4), filtered, and evaporated. The residue was subjected to flash chromatography. The target compound (45 g, >99%) was obtained as a yellow oil by eluting with 1:5 EtOAc / hexane.

[0351] 1 H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 8.45 (d,J= 2.4 Hz, 1H), 8.34 (d,J= 2.5 Hz, 1H), 7.80 (s, 1H), 7.76 (d,J= 1.0 Hz, 1H), 7.72 (dt,J= 7.5, 3.7 Hz, 1H), 7.58 (dt,J= 6.2, 3.6 Hz, 1H), 7.35 (dd,J= 6.0, 3.2 Hz, 2H), 4.05 (q,J= 7.1 Hz, 2H), 2.95 (s, 2H), 1.79 (s, 6H), 1.62 (s, 9H), 1.16 (t,J= 7.2 Hz, 1H).

[0352]

[0353] Example 58: Preparation of compound 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoic acid (Compound 58)

[0354] [Reaction Formula 8]

[0355]

[0356] Ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoate (Step 2) (45 mg, 0.098 mmol) was dissolved in a mixture of tetrahydrofuran (0.2 mL) and methanol (0.2 mL), and 0.09 ml of 2 M aqueous lithium hydroxide solution was added. The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. Water was added to the concentrate, and it was acidified by adding 1 N hydrochloric acid. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by flash chromatography on silica gel to give 17 mg (41%) of the title compound.

[0357] 1 H NMR (400 MHz, DMSO-d6) δ 12.09 (brs, 1H), 8.65 (s, 1H), 8.58 (t,J= 1.9 Hz, 1H), 8.43 (t,J= 2.0 Hz, 1H), 8.32 (s, 1H), 7.88 (s, 1H), 7.77 (t,J= 6.9 Hz, 2H), 7.46 – 7.34 (m, 2H), 2.83 (s, 2H), 1.63 (d,J= 1.5 Hz, 6H), 1.53 (d,J= 1.5 Hz, 9H).

[0358]

[0359] [Examples 39 to 70] Preparation of compounds 39 to 70

[0360] The compounds described in Table 5 below were prepared using the same method as the process presented in the above reaction schemes 4 to 8.

[0361] NoStructureChemical nameMS or NMR38 ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoate434.039 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoic acid406.040 ethyl 2-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)acetate420.141 2-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)acetic acid392.142 ethyl 2-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoate434.143 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyridin-2-amine392.144 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1-(2-morpholinoethyl)-1H-pyrazol-4-yl)pyridin-2-amine447.145 ethyl 4-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)butanoate447.546 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-N-ethylpropanamide433.147 4-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)butanoic acid 2,2,2-trifluoroacetic acid420.048 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-morpholinopropan-1-one405.049 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanamide481.150 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-N-phenylpropanamide 2,2,2-trifluoroacetate461.151 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-N,N-diethylpropanamide 2,2,2-trifluoroacetate447.152 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-N-isopropylpropanamide 2,2,2-trifluoroacetate447.1 1H NMR (400 MHz, Chloroform-d) δ 10.11 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 7.91 (d, J = 15.4 Hz, 1H), 7.82 – 7.76 (m, 1H), 7.68 (d, J = 127.8 Hz, 1H), 7.54 – 7.41 (m, 2H), 5.87 (s, 1H), 4.56 (s, 2H), 4.02 (s, 1H), 2.81 (s, 2H), 1.69 (s, 9H), 1.07 (d, J = 6.3 Hz, 6H).53 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(4-methylpiperazin-1-yl)propan-1-one488.154 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(piperidin-1-yl)propan-1-one473.155 ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)butanoate448.1 1H NMR (400 MHz, Chloroform-d) δ 9.31 (s, 1H), 8.52 (d, J = 2.4 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 7.82 (s, 1H), 7.79 – 7.71 (m, 2H), 7.67 – 7.58 (m, 1H), 7.46 – 7.34 (m, 2H), 4.93 – 4.80 (m, 1H), 4.12 (qd, J = 7.2, 1.1 Hz, 2H), 3.07 (dd, J = 16.1, 7.9 Hz, 1H), 2.78 (dd, J = 16.2, 6.0 Hz, 1H), 1.65 (s, 9H), 1.63 (d, J = 6.8 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H).56 ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoate462.117-034 1 H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 8.45 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.80 (s, 1H), 7.76 (d, J = 1.0 Hz, 1H), 7.72 (dt, J = 7.5, 3.7 Hz, 1H), 7.63 – 7.50 (m, 1H), 7.40 – 7.31 (m, 2H), 4.05 (q, J = 7.1 Hz, 2H), 2.95 (s, 2H), 1.79 (s, 6H), 1.62 (s, 9H), 1.20 – 1.11 (m, 3H).57 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)butanoic acid420.058 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoic acid434.0 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.62 (t, J = 1.9 Hz, 1H), 8.47 (t, J = 2.0 Hz, 1H), 8.36 (s, 1H), 7.92 (s, 1H), 7.81 (t, J = 6.9 Hz, 2H), 7.50 – 7.39 (m, 2H), 2.87 (s, 2H), 1.67 (d, J = 1.5 Hz, 6H), 1.57 (d, J = 1.5 Hz, 9H).59 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(pyrrolidin-1-yl)propan-1-one459.1 1 H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 1.5 Hz, 2H), 7.75 – 7.66 (m, 1H), 7.62 – 7.53 (m, 1H), 7.39 – 7.29 (m, 2H), 4.53 (t, J = 6.4 Hz, 2H), 3.44 (t, J = 6.8 Hz, 2H), 3.31 (t, J = 6.7 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H), 1.94 – 1.73 (m, 4H), 1.60 (s, 9H).60 tert-butyl 4-(3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoyl)piperazine-1-carboxylate574.1 1H NMR (400 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.44 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.73 (dt, J = 3.7, 2.5 Hz, 2H), 7.63 – 7.54 (m, 1H), 7.40 – 7.31 (m, 2H), 4.54 (t, J = 6.4 Hz, 2H), 3.62 – 3.55 (m, 2H), 3.38 (d, J = 4.4 Hz, 6H), 2.97 (t, J = 6.5 Hz, 2H), 1.61 (s, 9H), 1.44 (s, 9H).61 N-(2-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)acetamide419.1 1 H NMR (400 MHz, Chloroform-d) δ 8.77 (s, 1H), 8.44 (d, J = 2.5 Hz, 2H), 8.34 (d, J = 2.5 Hz, 1H), 7.80 (s, 1H), 7.73 (dd, J = 6.0, 3.2 Hz, 1H), 7.63 (s, 1H), 7.61 – 7.53 (m, 1H), 7.36 (dq, J = 7.0, 4.0 Hz, 2H), 6.11 (s, 1H), 4.34 – 4.26 (m, 2H), 3.75 (q, J = 5.7 Hz, 2H), 2.00 (s, 3H), 1.62 (s, 9H).62 N-(2-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)methanesulfonamide455.0 1H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 8.46 – 8.41 (m, 1H), 8.36 – 8.31 (m, 1H), 7.80 (s, 1H), 7.76 – 7.69 (m, 1H), 7.68 (s, 1H), 7.59 (dt, J = 5.3, 3.7 Hz, 1H), 7.36 (ddd, J = 6.6, 4.3, 2.4 Hz, 2H), 5.15 (s, 1H), 4.39 – 4.32 (m, 2H), 3.68 – 3.63 (m, 2H), 2.95 (d, J = 1.1 Hz, 3H), 1.62 (d, J = 1.1 Hz, 9H).63 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1-(2-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl)-1H-pyrazol-4-yl)pyridin-2-amine444.1 1 H NMR (400 MHz, Chloroform-d) δ 9.04 (s, 1H), 8.47 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 7.81 (s, 1H), 7.78 – 7.71 (m, 1H), 7.69 (s, 1H), 7.63 – 7.56 (m, 1H), 7.43 – 7.33 (m, 2H), 4.66 (t, J = 6.9 Hz, 2H), 3.51 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H), 1.63 (s, 9H).64 N-((3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoyl)oxy)acetamide406.0 1H NMR (400 MHz, Chloroform-d) δ 10.40 (s, 1H), 8.77 (s, 1H), 8.32 – 8.23 (m, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.79 (dd, J = 7.5, 1.5 Hz, 1H), 7.71 – 7.65 (m, 1H), 7.48 (dtd, J = 18.2, 7.5, 1.3 Hz, 2H), 4.59 (s, 2H), 3.06 (s, 2H), 2.05 (s, 3H), 1.70 (s, 9H).65 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(piperazin-1-yl)propan-1-one474.166 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(4-(methylsulfonyl)piperazin-1-yl)propan-1-one552.1 1 H NMR (400 MHz, Chloroform-d) δ 9.88 (s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 7.81 – 7.75 (m, 1H), 7.70 – 7.63 (m, 1H), 7.45 (pd, J = 7.4, 1.4 Hz, 2H), 4.58 (t, J = 6.1 Hz, 2H), 3.74 (t, J = 5.2 Hz, 2H), 3.55 (t, J = 4.9 Hz, 2H), 3.18 (t, J = 4.9 Hz, 4H), 2.99 (t, J = 6.2 Hz, 2H), 2.75 (s, 3H), 1.67 (s, 9H).67 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-1-(3-hydroxypyrrolidin-1-yl)propan-1-one475.1 1 H NMR (400 MHz, Chloroform-d) δ 8.71 (d, J = 2.4 Hz, 1H), 8.34 (dd, J = 8.7, 2.5 Hz, 1H), 8.25 (dd, J = 6.9, 2.5 Hz, 1H), 7.75 (s, 1H), 7.73 – 7.61 (m, 2H), 7.58 – 7.49 (m, 1H), 7.31 (dt, J = 6.2, 3.3 Hz, 2H), 4.55 (s, 2H), 4.45 (d, J = 20.6 Hz, 1H), 3.71 – 3.52 (m, 2H), 3.50 – 3.35 (m, 2H), 2.93 (d, J = 18.8 Hz, 1H), 2.90 – 2.81 (m, 2H), 1.95 (d, J = 33.0 Hz, 2H), 1.59 (d, J = 1.7 Hz, 9H).

[0362]

[0363] [Examples 68 to 70] Preparation of compounds 68 to 70

[0364] Compounds 68 to 70 described in Table 6 below were prepared using the same method as the process presented in Scheme 3 above.

[0365] NoStructureChemical nameNMR / MS68 ethyl 3-(4-(5-(benzo[d]oxazol-2-yl)-6-((3-((tert-butoxycarbonyl)amino)propyl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)propanoate535.1 1H NMR (400 MHz, Chloroform-d) δ 8.71 (s, 1H), 8.42 (d, J = 2.4 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.71 (d, J = 0.8 Hz, 1H), 7.64 – 7.55 (m, 1H), 7.41 – 7.32 (m, 2H), 5.32 (s, 1H), 4.48 (t, J = 6.5 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 3.76 (q, J = 6.4 Hz, 2H), 3.27 (d, J = 6.8 Hz, 2H), 2.95 (t, J = 6.5 Hz, 2H), 1.93 (p, J = 6.5 Hz, 2H), 1.46 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).69 3-(4-(6-((3-aminopropyl)amino)-5-(benzo[d]oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)propanoic acid hydrogen chloride407.1 1 H NMR (400 MHz, Methanol-d4) δ 8.53 (d, J = 2.2 Hz, 1H), 8.47 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.47 – 7.35 (m, 2H), 4.45 (s, 2H), 3.79 (t, J = 6.3 Hz, 2H), 3.05 (t, J = 6.9 Hz, 2H), 2.91 (s, 2H), 2.09 (d, J = 7.1 Hz, 2H).70 tert-butyl 4-(3-(4-(6-amino-5-(benzo[d]oxazol-2-yl)pyridin-3-yl)-1H-pyrazol-1-yl)propanoyl)piperazine-1-carboxylate517 1H NMR (400 MHz, Chloroform-d) δ 9.90 (brs, 3H), 7.94 (d, J = 4.7 Hz, 2H), 7.47 (dt, J = 8.3, 1.1 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.32 – 7.27 (m, 1H), 4.66 (t, J = 6.1 Hz, 2H), 3.58 (dd, J = 6.7, 4.0 Hz, 2H), 3.39 (d, J = 9.1 Hz, 6H), 3.02 (t, J = 6.1 Hz, 2H), 1.45 (s, 9H), 1.41 (dt, J = 10.7, 4.7 Hz, 1H).

[0366]

[0367] [Examples 61 to 78] Preparation of compounds 71 ​​to 78

[0368] Compounds 71 ​​to 78 described in Table 7 below were prepared using the same method as the process presented in Scheme 3 above.

[0369] NoStructureChemical nameNMR / MS71 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1H-pyrrol-3-yl)pyridin-2-amine 1 H NMR (400 MHz, Chloroform-d) δ 8.67 (s, 1H), 8.52 (s, 1H), 8.41 (s, 1H), 8.28 (s, 1H), 7.73 (s, 1H), 7.58 (s, 1H), 7.33 (s, 3H), 7.08 (s, 1H), 6.87 (s, 1H), 6.55 (s, 1H), 1.59 (s, 9H).72 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(1-methyl-1H-pyrrol-3-yl)pyridin-2-amine 1H NMR (400 MHz, Chloroform-d) δ 8.64 (s, 1H), 8.46 (t,J= 3.5 Hz, 1H), 8.35 (dd,J= 4.5, 2.5 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.60 – 7.50 (m, 1H), 7.37 – 7.28 (m, 2H), 6.87 (dt,J= 4.6, 2.1 Hz, 1H), 6.64 (dt,J= 4.5, 2.4 Hz, 1H), 6.41 (ddd,J= 4.5, 2.7, 1.8 Hz, 1H), 3.70 (d,J= 4.5 Hz, 3H), 1.61 (s, 9H).73 3-(3-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrrol-1-yl)propanoic acid405.274 3-(benzo[d]oxazol-2-yl)-N-(tert-butyl)-5-(2H-1,2,3-triazol-4-yl)pyridin-2-amine 1 H NMR (400 MHz, Chloroform-d) δ 12.17 (s, 1H), 8.70 (q,J= 2.3, 1.6 Hz, 1H), 7.75 – 7.65 (m, 1H), 7.39 – 7.30 (m, 1H), 4.11 (qd,J= 7.2, 0.7 Hz, 3H), 2.04 (d,J= 0.8 Hz, 5H), 1.62 (d,J= 0.8 Hz, 3H), 1.25 (td,J= 7.1, 0.8 Hz, 5H).75 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-2H-1,2,3-triazol-2-yl)propanoic acid 1H NMR (400 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 7.80 (t,J= 7.8 Hz, 2H), 7.42 (t,J= 7.5 Hz, 2H), 4.59 (d,J= 7.6 Hz, 2H), 2.75 (s, 2H), 1.54 (s, 9H).76 3-(4-(5-(benzo[d]oxazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-1,2,3-triazol-1-yl)propanoic acid 1 H NMR (400 MHz, Chloroform-d) δ 9.00 (s, 1H), 8.73 – 8.62 (m, 2H), 7.82 (s, 1H), 7.75 – 7.63 (m, 1H), 7.61 – 7.51 (m, 1H), 7.50 – 7.30 (m, 2H), 4.77 (t,J= 6.9 Hz, 2H), 3.14 (t,J= 7.0 Hz, 2H), 1.62 (s, 9H).77 3-(benzo[d]thiazol-2-yl)-N-(tert-butyl)-5-(1H-pyrazol-4-yl)pyridin-2-amine 1 H NMR (400 MHz, Chloroform-d) δ 9.43 (s, 1H), 8.42 (d,J= 2.3 Hz, 1H), 7.99 – 7.92 (m, 2H), 7.90 – 7.84 (m, 1H), 7.82 (s, 2H), 7.47 (ddd,J= 8.2, 7.2, 1.3 Hz, 1H), 7.37 (ddd,J= 8.2, 7.2, 1.3 Hz, 1H), 7.25 (d,J= 4.2 Hz, 1H), 1.60 (s, 9H).78 3-(4-(5-(benzo[d]thiazol-2-yl)-6-(tert-butylamino)pyridin-3-yl)-1H-pyrazol-1-yl)-3-methylbutanoic acid 1H NMR (400 MHz, Chloroform-d) δ 9.47 (s, 1H), 8.38 (d,J= 2.4 Hz, 1H), 7.96 (d,J= 8.1 Hz, 1H), 7.94 – 7.84 (m, 2H), 7.80 (d,J= 0.8 Hz, 1H), 7.74 (d,J= 0.8 Hz, 1H), 7.52 – 7.44 (m, 1H), 7.43 – 7.34 (m, 1H), 3.09 (s, 2H), 1.74 (s, 6H), 1.60 (s, 9H).

[0370]

[0371] [Experimental Example] Measurement of Pharmacological Activity of Compounds 1-78

[0372]

[0373] [Experimental Example 1] Tg(foxj1a:eGFP) promotes Foxjla expression by promoting motile cilia production hsc16 Screening in a zebrafish model

[0374] To identify a promoter for motile cilia, the present inventors screened using a transgenic zebrafish model. Transgenic zebrafish expressing EGFP by the foxj 1a promoter (Tg(foxj1a:eGFP) hsc16 ), Grimes DT et al., Zebrafish models of idiopathic scoliosis link cerebrospinal fluid flow defects to spine curvature. Science. 2016 Jun 10:352(6291): 1341-4.) were utilized. Foxjla is a transcription factor involved in the production of motile cilia, and as its expression increases, the production of motile cilia increases, so it was selected as a model suitable for use in screening.

[0375]

[0376] 1. Breeding and mating of zebrafish

[0377] Normal zebrafish (TL) were obtained from the Zebrafish International Resource Center (ZIRC) (Eugene, USA), and Tg(foxj1a:eGFP) hsc16 Transgenic zebrafish were provided by Dr. Brian Ciruna, Ontario, Canada.

[0378] All zebrafish were bred and maintained at the experimental animal facility at Chonnam National University College of Medicine in Hwasun, South Korea, and maintained using standard conventional procedures (Westerfield et al., THE ZEBRAFISH BOOK: A guide for the laboratory use of zebrafish 5 (Danio rerio), 5th ed. University of Oregon Press. 2007). Standard conditions were maintained at 28°C with a 14-h photoperiod / 10-h dark cycle. Larval zebrafish were fed a diet of self-cultured rotifers, and after swim bladder maturation, artemia was provided twice daily as an adult diet until the digestive tract was fully developed. Zebrafish less than 1 year of age, regardless of sex, were used for all matings. Transgenic or wild-type embryos were collected by natural spawning, with males and females separated in mating boxes the day before mating and then combined early the next morning.

[0379] The collected embryos were cultured in petri dishes using E3 media (5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2·2H2O and 0.4 mM MgCl2·6H2O, pH 7.2) at 28°C, and screening experiments were performed using embryos 1 to 2 days after fertilization (dpf). Tg(foxj1a:eGFP) hsc16Among the transgenic embryos generated by crossing transgenic mothers (AB background) with TL zebrafish, those with confirmed eGFP fluorescence were used in small molecule compound screening experiments. Embryonic developmental stages were classified according to standard methods based on hours post-fertilization (hpf) or days post-fertilization (dpf).

[0380]

[0381] 2. Tg(foxj1a:eGFP) hsc16 Compound screening using transgenic zebrafish

[0382] After dechorionation, 24 hpf Tg(foxjla:egfp) zebrafish embryos were plated in E3 medium (5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2_ 2H,0 0.4 mM MgCl2_ 6H,0, pH 7.2) in a 96-well plate (SPL Life Sciences, Korea, Cat. No: 30096), with three embryos per well using a glass Pasteur pipette. 78 small molecule compounds dissolved in DMSO were diluted to 500 μM and then individually added 2 μL to each well to a final concentration of 5 μM. For the control group, 2 μL of DMSO (final concentration 1%) was added. Embryos were cultured for 24 hours after drug treatment, and at 2 days post-fertilization (dpf), the presence of increased EGFP expression in the spinal cord region was observed using a fluorescence microscope (MZ16 FA, Leica). Embryos with morphological abnormalities or developmental defects were excluded from the analysis. As shown in Fig. 1, compounds that increased EGFP expression in the spinal cord region of transgenic zebrafish compared to the DMSO-treated group were judged to be compounds that have the activity of promoting the production of motile cilia.

[0383]

[0384] [Experimental Example 2] Measurement of Biological Activity: Structure-Activity Relationship (SAR) of Pyridine Derivatives

[0385] A series of pyridine derivatives synthesized in the above examples are Tg(foxj1a:eGFP) hsc16 The efficacy of increasing Foxj1a expression in the zebrafish spinal cord was evaluated. GM-90371 was used as the reference compound. The activity of the compounds of the present invention (compounds 1 to 78, chemical formulas 2 to 79) was tested at a concentration of 5 μM, and the measured activity values ​​are shown in Table 8 below. The degree of activity of increasing EGFP in the spinal cord was scored according to the following criteria: - No significant activity, + minimal, ++ weak, +++ mild, ++++ moderate, +++++ high, ++++++ < marked. 'ND' means not determined.

[0386] No.Activity (foxj1a)1++++2++++3++++4++++5++6++++++++7+8+++9+++10-11++12+++13-14-15-16++++17++++18++++19++++20++++21 ++++22++++23++++24++++25++++26++++27+++28++++29++++30++++31++++32++++33++++34++++35++++36++++37++++38+++ +++39ND40-41++42++++43++++44-45++++46+++++47ND48++++++49++++++50+51++++52++++53-54++++55++++56++++57ND5 8++++++59++++60++++61+++++62++++63++++64+++65+++66-67+++68ND69++70++++71++++72++++73ND74-75-76ND77ND78ND

[0387]

[0388] [Experimental Example 3] Measurement of Biological Activity in a Mammalian Model

[0389] 1. Air-liquid interface (ALI) culture of mouse tracheal epithelial cells (mTECs)

[0390] Tracheal epithelial cells were isolated from 68-week-old adult C57BL / 6 wild-type (WT) mice and cultured using a method slightly modified from the literature. The epithelial cells isolated from the mouse trachea were digested with pronase overnight at 4°C. The isolated cells were suspended in mTEC-basic medium and transferred to Primaria™ culture dishes and cultured for 45 h at 37°C and 5% CO₂ conditions to remove fibroblasts. Non-attached cells were collected by centrifugation at 220 xg for 5 min at room temperature, resuspended in mTEC-plus medium, and seeded at a density of 5 x 10⁴ cells cm⁻² onto transparent PET porous (0.4 ㎛) transwell membrane inserts coated with collagen (50 ㎍ mL⁻¹). Afterwards, the cells were submerged in the medium in both the upper and lower chambers at 37°C and 5% CO₂ until they reached complete confluency. The mTEC-plus medium was replaced every other day.

[0391] When cells reached a complete monolayer in the upper chamber of the transwell, the medium in the upper chamber was removed to form an air-liquid interface (ALI). The medium in the lower chamber was replaced with mTEC differentiation medium without FBS and ROCK inhibitor. The differentiation medium was replaced every two days, and the upper chamber was washed with 1x PBS every 2–3 days to remove mucus.

[0392] For small molecule compound treatment, the hit compound was added to the lower chamber of the transwell at a final concentration of 5 μM starting from ALI-0. The final DMSO concentration was 0.1% [v / v]. The hit compound was administered along with the differentiation medium, which was replaced every two days.

[0393]

[0394] 2. mTEC immunofluorescence staining

[0395] The upper chamber of the transwell was washed twice with 1x PBS, pH 7.4, to remove any remaining mucus. Both the upper and lower chambers were then treated with 4% PFA and fixed for 15 minutes at room temperature. After fixation, the cells were washed three times with PBS and then permeabilized with PBSTX (1x PBS and 0.5% Triton X-100) for 1 hour on a shaker (50–80 rpm).

[0396] The upper chamber was washed twice with PBS and then blocked with a blocking solution consisting of 1x PBS containing 2% BSA, 5% goat serum, and 0.2% Triton X-100 for 1 hour at room temperature or overnight at 4°C. After blocking, the upper chamber was washed three times with a washing buffer consisting of 1x PBS and 0.02% Triton X-100, and then treated with acetylated α-tubulin antibody (1:500) or ZO-1 antibody (1:500) diluted in blocking buffer, and primary antibody reaction was performed overnight at 4°C.

[0397] The next day, cells were washed with washing buffer and then incubated with goat anti-mouse and anti-rabbit secondary antibodies (1:1,000) diluted in blocking buffer in a darkroom at room temperature for 12 hours or overnight at 4°C. After secondary antibody reaction, cells were washed three times for 10 minutes each with washing buffer (using a shaker at 5080 rpm).

[0398] The membranes with stained mTECs attached were carefully excised with forceps and a scalpel and placed on a clean slide with the cell side facing upward. A few drops of mounting solution containing Vectashield antifade reagent and DAPI were placed on the membranes and left to stand at room temperature for 5 minutes. The membranes were then covered with a coverslip, the edges sealed with nail polish remover, and the slides were dried at room temperature for 10 minutes.

[0399] As a result, the number of MCCs significantly increased in mTECs treated with compound 58 compared to the DMSO control (Figure 2). This indicates that compound 58 indeed activates the FOXJ1 motor cilia production pathway in mammalian airway epithelia. These results demonstrate that compound 58 has the ability to enhance motor cilia production.

[0400]

[0401] [Experimental Example 4] Verification of efficacy in an in vivo mouse model

[0402] Adult C57BL / 6 mice (6-8 weeks old) were used for in vivo experiments. To generate a mouse chronic obstructive pulmonary disease (COPD) model, 30 μg of porcine pancreatic elastase (PPE) (Sigma-Aldrich, Cat. No: E1250) dissolved in phosphate-buffered saline (PBS) was administered intranasally to the mice weekly for 4 weeks. In COPD, motile cilia are reported to be damaged by shortening and alteration of ciliary beats. The control group was injected with PBS. The presence of COPD was confirmed through tracheal sections from elastase-treated mice. After the COPD model was established, the mice were divided into two groups. The first group received intraperitoneal injections of 400 μL of compound 16 (2 mg kg⁻¹; dissolved in DMSO:DW:PEG400 = 5:55:40) every other day for 2 weeks. The second group received an equal volume of control solution. One day after the last compound injection, mice were sacrificed, and the trachea was removed for immunohistochemistry. Ciliary length was measured.

[0403] As shown in Figure 3, immunofluorescence analysis revealed a decrease in motile cilia along the trachea in airway damage and COPD mice, but not in mice administered PBS (control). However, this phenotype was nearly abolished in COPD mice treated with compound 58. Taken together, these results indicate that compound 58 can restore damaged motile cilia in vivo.

[0404]

[0405] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A compound represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, A is halogen; ; unsubstituted or C1-C5 alkyl, C1-C3 alkyl C1-C3 alkoxy, amine, C1-C3 alkyl alkoxy C1-C3 alkyl, , , , , , , , , , , (m is an integer from 1 to 5) substituted with one or more substituents selected from the group consisting of 5- to 9-membered heteroaryl rings; C6-C unsubstituted or substituted with C1-C5 alkyl or amine 10 Aryl; C6-C substituted with C1-C3 alkoxy group 10 Aryl alkyne; and, R3 is ethoxy, alkoxy, C1-C3 alkyl alkoxy, hydroxy, C1-C3 alkyl amine, , amine, C6-C 10 aryl amine, , , , , , , , One or more substituents selected from the group consisting of, Z is amine, C1-C5 alkyl amine, , -NR4R5 (R4 is hydrogen; R5 is amine C1-C5 alkyl, hydroxy acyl C1-C5 alkyl, C6-C 10 Cyclo, , , , (n is an integer between 1 and 5), or C6-C unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C3 alkyl or one or more halogens; 10 Heterocyclic; or R4 and R5 are connected to each other, unsubstituted, C1-C3 alkyl or C6-C substituted with one or more halogens 10 is selected from the group consisting of forming a heterocyclic group, Y is oxygen or sulfur, R1 and R2 are each independently C1-C5 alkyl or halogen.

2. In paragraph 1, The above A is halogen; ; unsubstituted or C1-C3 alkyl, C1-C3 alkyl C1-C3 alkoxy, amine, C1-C3 alkyl alkoxy C1-C3 alkyl, , , , , , , , , , , (m is an integer from 1 to 3) substituted with one or more substituents selected from the group consisting of N, O, S, a 5-membered to 9-membered heteroaryl ring containing one or more heteroatoms; C6-C unsubstituted or substituted with C1-C3 alkyl or amine 10 Aryl; C6-C substituted with C1-C3 alkoxy group 10 Aryl alkyne; and, R3 is ethoxy, alkoxy, C1-C3 alkyl alkoxy, hydroxy, C1-C3 alkyl amine, , amine, C6-C 10 aryl amine, , , , , , , , A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound comprises one or more substituents selected from the group consisting of:

3. In paragraph 2, The above Z is amine, C1-C3 alkyl amine, , -NR4R5 (R4 is hydrogen; R5 is amine C1-C3 alkyl, hydroxy acyl C1-C3 alkyl, C6-C 10 Cyclo, , , , (n is an integer between 1 and 5), or C6-C unsubstituted or substituted with one or more substituents selected from the group consisting of C1-C3 alkyl or one or more halogens; 10 Heterocyclic; or R4 and R5 are connected to each other, unsubstituted, C1-C3 alkyl or C6-C substituted with one or more halogens 10 A compound selected from the group consisting of (forming a heterocyclic group), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

4. In paragraph 3, The above R1 and R2 are each independently a C1-C3 alkyl or halogen compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, The compound represented by the above chemical formula 1 is a compound characterized by being selected from the group consisting of the following chemical formulas 2 to 79, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 9] [Chemical Formula 10] [Chemical Formula 11] [Chemical Formula 12] [Chemical Formula 13] [Chemical Formula 14] [Chemical Formula 15] [Chemical Formula 16] [Chemical Formula 17] [Chemical Formula 18] [Chemical Formula 19] [Chemical Formula 20] [Chemical Formula 21] [Chemical Formula 22] [Chemical Formula 23] [Chemical Formula 24] [Chemical Formula 25] [Chemical Formula 26] [Chemical Formula 27] [Chemical Formula 28] [Chemical Formula 29] [Chemical Formula 30] [Chemical Formula 31] [Chemical Formula 32] [Chemical Formula 33] [Chemical Formula 34] [Chemical Formula 35] [Chemical Formula 36] [Chemical Formula 37] [Chemical Formula 38] [Chemical Formula 39] [Chemical Formula 40] [Chemical Formula 41] [Chemical Formula 42] [Chemical Formula 43] [Chemical Formula 44] [Chemical Formula 45] [Chemical Formula 46] [Chemical Formula 47] [Chemical Formula 48] [Chemical Formula 49] [Chemical Formula 50] [Chemical Formula 51] [Chemical Formula 52] [Chemical Formula 53] [Chemical Formula 54] [Chemical Formula 55] [Chemical Formula 56] [Chemical Formula 57] [Chemical Formula 58] [Chemical Formula 59] [Chemical Formula 60] [Chemical Formula 61] [Chemical Formula 62] [Chemical Formula 63] [Chemical Formula 64] [Chemical Formula 65] [Chemical Formula 66] [Chemical Formula 67] [Chemical Formula 68] [Chemical Formula 69] [Chemical Formula 70] [Chemical Formula 71] [Chemical Formula 72] [Chemical Formula 73] [Chemical Formula 74] [Chemical Formula 75] [Chemical Formula 76] [Chemical Formula 77] [Chemical Formula 78] [Chemical Formula 79] 6. A pharmaceutical composition for preventing or treating respiratory diseases, comprising a compound of any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

7. In paragraph 6, A pharmaceutical composition for preventing or treating respiratory diseases, wherein the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof induces motile cilia production.

8. In paragraph 7, A pharmaceutical composition for preventing or treating a respiratory disease, characterized in that the respiratory disease is at least one selected from the group consisting of kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome, and pulmonary fibrosis.

9. A food composition for preventing or improving respiratory diseases, comprising a compound of any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

10. In paragraph 9, A food composition for preventing or improving a respiratory disease, characterized in that the respiratory disease is at least one selected from the group consisting of acute respiratory distress syndrome, hay fever, primary ciliary dyskinesia and cystic fibrosis, acute respiratory distress syndrome, hay fever, primary ciliary dyskinesia and cystic fibrosis, kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome and pulmonary fibrosis.

11. A method for preventing or treating a respiratory disease, comprising administering to a subject a compound of any one of claims 1 to 5, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

12. In paragraph 11, A method for preventing or treating respiratory diseases, wherein the compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof induces the production of motile cilia.

13. In paragraph 12, A method for preventing or treating a respiratory disease, characterized in that the above respiratory disease is at least one selected from the group consisting of kennel cough, bronchopneumonia, respiratory inflammatory lung disease, chronic obstructive pulmonary disease, sinusitis, allergic rhinitis, lower respiratory tract infection, acute and chronic bronchitis, emphysema, pneumonia, bronchial asthma, bronchiectasis, emphysema, sequelae of pulmonary tuberculosis, acute respiratory distress syndrome, and pulmonary fibrosis.

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