Novel N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives and their uses

Abstract

The present disclosure relates to: novel N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives or pharmaceutically acceptable salts thereof; methods for preparing the same; and uses thereof as active ingredients for preventing or treating ASK-1-mediated diseases.

Description

Technical Field

[0001] The present disclosure relates to novel N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives or pharmaceutically acceptable salts thereof; preparation methods thereof; and uses thereof as active ingredients for preventing or treating ASK-1-mediated diseases. Background Art

[0002] The mitogen-activated protein kinase (MAPK) signal transduction cascade is involved in directing various extracellular and intracellular queues to cellular emergency responses, including cell growth, differentiation, inflammation and apoptosis. MAPK exists in different types, such as MAP3K, MAP2K and MAPK. MAPK3 directly responds to environmental signals and phosphorylates MAP2K, which in turn phosphorylates specific MAPK. Subsequently, MAPK mediates appropriate cellular responses by phosphorylating cellular substrates, including transcription factors that regulate gene expression.

[0003] Apoptosis signal-regulating kinase 1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), is a member of the MAP kinase kinase kinase (MAP3K) family that activates c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase.

[0004] ASK1 is activated by a variety of stimuli, including oxidative stress, reactive oxygen species (ROS), LPS, TNF-α, FasL, endoplasmic reticulum (ER) stress, and intracellular calcium influx, thereby activating c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase.

[0005] Depending on the cell type, phosphorylation of the ASK1 protein can lead to apoptosis or other cellular responses. ASK1 activation has been reported to be associated with a variety of diseases, including neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, autoimmune diseases, and metabolic disorders. In addition, ASK1 has been shown to play a particularly important role in psychosomatic diseases, such as kidney disease, diabetic nephropathy, chronic kidney disease, fibrosis (including pulmonary fibrosis and renal fibrosis), respiratory diseases (including chronic obstructive pulmonary disease (COPD) and acute lung injury), and acute and chronic liver diseases.

[0006] Therefore, it would be desirable to develop therapeutic agents that act to inhibit the ASK1 signaling complex to remedy or improve the lives of patients in need of prevention and treatment of this wide range of diseases. Summary of the invention

[0007] Technical issues

[0008] The present inventors have made great efforts to develop novel compounds that can inhibit the activity of ASK-1, and thus they have confirmed that a series of N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives can effectively inhibit the activity of ASK-1 and can therefore be used to prevent and treat ASK-1-mediated diseases, thereby completing the present invention.

[0009] Technical Solution

[0010] The object of the present disclosure is to provide N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives or pharmaceutically acceptable salts thereof.

[0011] Another object of the present disclosure is to provide a method for preparing the aforementioned N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives.

[0012] Another object of the present disclosure is to provide a pharmaceutical composition for preventing or treating ASK-1-mediated diseases, comprising the aforementioned N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] Yet another object of the present disclosure is to provide a method for preventing or treating an ASK-1-mediated disease, comprising administering the aforementioned pharmaceutical composition to a subject in need thereof.

[0014] Beneficial effects

[0015] Novel N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives or pharmaceutically acceptable salts thereof exhibit an inhibitory effect on ASK-1 activity and thus can be effectively used for preventing and treating ASK-1-mediated diseases.

[0016] Best Mode for Carrying Out the Invention

[0017] In one aspect of the present disclosure to achieve the above object, there is provided an N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivative or a pharmaceutically acceptable salt thereof.

[0018] In another aspect of the present disclosure, a method for preparing N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivatives is provided.

[0019] In yet another aspect of the present disclosure, provided is a pharmaceutical composition for preventing or treating ASK-1-mediated diseases, comprising an N-(isopropyl-triazolyl)pyridinyl)-heteroaryl-carboxamide derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0020] In yet another aspect of the present disclosure, provided is a method for preventing or treating an ASK-1-mediated disease, comprising administering a pharmaceutical composition to a subject in need thereof.

[0021] Hereinafter, the present disclosure will be described in detail. DETAILED DESCRIPTION

[0022] Listed below are definitions of various concepts used to describe compounds of the present disclosure.

[0023] These definitions apply to the terms as they are used throughout the specification, whether individually or as part of a larger group, unless otherwise limited to specific instances.

[0024] The term "alkyl" refers to a straight chain, branched chain or cyclic hydrocarbon group, and each carbon atom may be optionally substituted with one or more substituents.

[0025] The term "alkoxy" refers to an -O-alkyl group, and alkyl is as defined above.

[0026] The term "aryl" refers to an aromatic group including phenyl, naphthyl, etc. The aryl group may be optionally substituted with one or more substituents.

[0027] The term "heteroaryl" refers to a saturated, partially saturated or aromatic group containing 1 to 4 heteroatoms selected from N, O and S, which may be optionally fused with a benzo or cycloalkyl group.

[0028] The term "halo" refers to a substituent selected from the group consisting of fluoro, chloro, bromo or iodo.

[0029] Unless otherwise defined, the terms and abbreviations used herein have their original meanings.

[0030] The N-(isopropyl-triazolyl)pyridyl)-heteroaryl-carboxamide derivative disclosed herein may be a compound represented by the following Chemical Formula 1:

[0031] [Chemical formula 1]

[0032]

[0033] In the chemical formula 1,

[0034] X is NH, O or S,

[0035] R1 is hydrogen, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 alkoxy or halogen, and

[0036] R2 and R3 are each independently hydrogen, C 1-6 Alkyl, C1-6 Heteroalkyl, C 1-6 Alkoxy, halogen, cyano, nitro, amino, C 1-6 Alkoxy-C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Arylamino, C 5-10 Heteroaryl or C 5-10 Heteroarylamino,

[0037] wherein the aryl or heteroaryl is unsubstituted or substituted by at least one selected from the group consisting of: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, halogen, nitro, cyano, amino, C 1-6 Alkylamino, acetylamino, formyl, C 1-6 Alkylcarbonyl, morpholinocarbonyl, morpholinyl, piperazinyl, piperidinyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, C 1-6 Alkyl-thio, cyano-C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Dihaloalkyl, C 1-6 Alkylsulfonyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 (alkyl)aminosulfonyl, C 1-6 Heteroalkyl and heteroaryl-C 1-6 alkyl.

[0038] Specifically, in Chemical Formula 1, X may be NH, and R1 may be hydrogen.

[0039] For example, in Chemical Formula 1, R2 and R3 can each independently be hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 Alkyl, C 6-10 Aryl or C 5-10 Heteroaryl.

[0040] Specifically, in Chemical Formula 1, R2 and R3 may each independently be hydrogen, methyl, ethyl, methoxymethyl, or unsubstituted or substituted phenyl, thienyl, or pyrimidinyl.

[0041] For example, in the compounds of the present disclosure, the aryl group or heteroaryl group may be unsubstituted or substituted with at least one selected from the group consisting of methyl, chloro, fluoro, ethoxy, methylthio, and methylsulfonyl, but is not limited thereto.

[0042] More specifically, the compounds of the present disclosure may be:

[0043] 1. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxamide,

[0044] 2. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-m-tolyl-1H-pyrrole-2-carboxamide,

[0045] 3. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(methoxymethyl)-1H-pyrrole-2-carboxamide,

[0046] 4.4-ethyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0047] 5. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-p-tolyl-1H-pyrrole-2-carboxamide,

[0048] 6. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-phenyl-1H-pyrrole-2-carboxamide,

[0049] 7. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0050] 8. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-2-carboxamide, 9. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-phenyl-1H-pyrrole-2-carboxamide,

[0051] 10. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-p-tolyl-1H-pyrrole-2-carboxamide,

[0052] 11.5-ethyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0053] 12. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(2-methylpyrimidin-5-yl)-1H-pyrrole-2-carboxamide,

[0054] 13. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrole-2-carboxamide,

[0055] 14. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-m-tolyl-1H-pyrrole-2-carboxamide,

[0056] 15.5-(3,5-dimethylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0057] 16. 5-(4-chlorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0058] 17. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(thiophen-2-yl)-1H-pyrrole-2-carboxamide,

[0059] 18.5-(3,4-dimethylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0060] 19.5-(3-Fluoro-4-methylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0061] 20.5-(3-chloro-4-fluorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide,

[0062] 21. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(4-(methylthio)phenyl)-1H-pyrrole-2-carboxamide,

[0063] 22. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-o-tolyl-1H-pyrrole-2-carboxamide,

[0064] 23. 5-(4-Fluorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, or

[0065] 24. 5-(4-ethoxyphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, but not limited thereto.

[0066] In addition, the compounds of the present disclosure may exist in the form of pharmaceutically acceptable salts. Acid addition salts formed from pharmaceutically acceptable free acids may be used as salts. As used herein, the term "pharmaceutically acceptable salt" refers to any organic or inorganic addition salt of a compound, the concentration of which makes it exhibit an effective effect that is relatively nontoxic and harmless to the patient, and the side effects caused by the salt do not impair the beneficial effects of the compound represented by Chemical Formula 1. Pharmaceutically acceptable salts may include acid addition salts formed from acids that can form nontoxic acid addition salts containing pharmaceutically acceptable anions, the acid being, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; organic carbonic acid such as tartaric acid, formic acid, citric acid, acetic acid, adipic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc.; or sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc. The compound of Chemical Formula 1 according to the present disclosure may be converted into its salt by conventional methods.

[0067] Acid addition salts can be prepared by conventional methods, for example, by dissolving the compound in an excess of aqueous acid solution, followed by precipitation of the salt using an organic solvent miscible with water such as methanol, ethanol, acetone or acetonitrile. Acid or alcohol (for example, ethylene glycol monomethyl ether) and water equimolar to the compound can be heated, and the mixture can be dried by evaporation subsequently, or suction filtration can be carried out on the precipitated salt.

[0068] In addition, a pharmaceutically acceptable metal salt can be prepared using a base, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, then filtering out the undissolved compound salt, and evaporating and drying the filtrate to obtain an alkali metal salt or an alkaline earth metal salt.

[0069] Unless otherwise specified, pharmaceutically acceptable salts of the compounds of the present disclosure may include salts having an acidic or basic group that may be present in the compound of Chemical Formula 1, and may be prepared by methods for preparing salts known in the art.

[0070] Furthermore, the present disclosure is intended to include not only the compound of Chemical Formula 1 and pharmaceutically acceptable salts thereof, but also possible solvates that may be prepared therefrom.

[0071] In addition, since the compounds of the present disclosure have asymmetric carbon centers in the parent structure and its substituents, it can exist as R or S isomers, racemic mixtures, diastereomeric mixtures and individual diastereomers, and all of these isomers and mixtures are within the scope of the present disclosure. That is, if there are one or more asymmetric carbons in the structure of Chemical Formula 1, it should be understood that all stereoisomers are included in the scope of the present disclosure as long as the direction is not described separately.

[0072] The compound represented by Chemical Formula 1 of the present disclosure can be prepared by a method comprising the following:

[0073] A compound represented by the following Chemical Formula 2 is reacted with 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine:

[0074] [Chemical formula 2]

[0075]

[0076] In the chemical formula 2,

[0077] X is NH, O or S,

[0078] Y is OH or halogen, and

[0079] R1 to R3 are as defined above.

[0080] Specifically, if Y is OH, the above reaction can be carried out in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and a base, but is not limited thereto.

[0081] In particular, N-methylmorpholine may be used as a base, and N,N-dimethylformamide may be used as a solvent, but these are not limited thereto. In addition, the reaction may be performed by adjusting the temperature to 90° C. to 110° C., but is not limited thereto.

[0082] Meanwhile, if Y is halogen, then the reaction can be carried out in the presence of triethylamine, but these are not limited thereto. In addition, the reaction can be carried out by further adding a nucleophilic catalyst, and in this article, 4-dimethylaminopyridine (DMAP) can be used as a nucleophilic catalyst, but these are not limited thereto.

[0083] For example, the reaction may be performed using dichloromethane as a solvent at room temperature (eg, 10° C. to 35° C.), but is not limited thereto.

[0084] Specifically, the compound of Chemical Formula 2 wherein Y is halogen may be prepared by reacting the compound of Chemical Formula 2 wherein Y is OH (ie, a benzoic acid derivative compound) with oxalyl halide, but is not limited thereto.

[0085] For example, the reaction may be performed using dichloromethane containing N,N-dimethylformamide as a solvent at room temperature (eg, 10° C. to 35° C.), but is not limited thereto.

[0086] More specifically, the compound of Chemical Formula 1 of the present disclosure can be prepared according to the following Reaction Scheme 1 or 2, using the compound of Chemical Formula 2 (ie, benzoic acid derivative compound) in which Y is OH as a starting material.

[0087] [Reaction Scheme 1]

[0088]

[0089] [Reaction Scheme 1]

[0090]

[0091] The type of reaction scheme used in this article can be selected according to the position of the substituent of the target compound to be synthesized. For example, when preparing a compound in which R1 and R3 are both hydrogen and R2 is any substituent other than hydrogen, reaction scheme 1 can be selected, and when preparing a compound in which R1 and R2 are both hydrogen and R3 is any substituent other than hydrogen, reaction scheme 2 can be selected, but it is not limited thereto.

[0092] For example, after each reaction is completed, a separation and / or purification process may be further performed to improve reaction efficiency or increase product purity. The separation and purification process may be performed using any method known in the art without limitation.

[0093] Meanwhile, the series of reaction schemes described above are only used to illustrate the preparation method of the compounds of the present disclosure, and the preparation method of the compounds of the present disclosure is not limited thereto and can be carried out using methods known in the art or with appropriate modifications.

[0094] In addition, the present disclosure provides a pharmaceutical composition for preventing or treating an ASK-1-mediated disease, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0095] In addition, the present disclosure provides a method for preventing or treating an ASK-1-mediated disease, comprising administering a pharmaceutical composition to a subject in need thereof.

[0096] Specifically, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have the characteristic of inhibiting ASK-1 activity.

[0097] As used herein, the term "preventing" or "prevention" refers to all actions that inhibit or delay the onset, spread and recurrence of ASK-1-mediated diseases by administering a pharmaceutical composition. In addition, the term "treating" or "treatment" refers to all actions that alleviate or beneficially change the symptoms of the above-mentioned diseases by administering a pharmaceutical composition.

[0098] For example, the pharmaceutical composition according to the present disclosure may contain the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient in an amount of 0.1 to 75 wt %, specifically 1 to 50 wt %, based on the total weight of the composition.

[0099] ASK-1-mediated diseases that can be prevented or treated by administering a pharmaceutical composition comprising the compound of Chemical Formula 1 according to the present disclosure include diabetes, diabetic nephropathy, kidney disease, renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute lung injury, non-alcoholic steatohepatitis, liver disease, alcoholic liver disease, alcoholic hepatitis, inflammatory disorders, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, or diseases associated with excessive secretion of IL6, but the diseases are not limited thereto.

[0100] In one embodiment of the present disclosure, it was confirmed that ASK-1 activity can be effectively inhibited by administering the compound of Chemical Formula 1 according to the present disclosure. Based on this finding, it was found that the compound of Chemical Formula 1 according to the present disclosure can be used to prevent or treat diseases caused by ASK-1 activation.

[0101] As used herein, the term "subject" refers to all animals and humans that suffer from or are at risk of suffering from ASK-1-mediated diseases, including monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, and guinea pigs, and the diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present disclosure to the subject. The pharmaceutical composition of the present disclosure can be administered in combination with conventional therapeutic agents.

[0102] As used herein, the term "administer" refers to introducing a predetermined substance into a patient by any appropriate method. The composition of the present disclosure can be administered by any common route, as long as it can reach the desired tissue. The composition can be administered by an intraperitoneal route, an intravenous route, an intramuscular route, a subcutaneous route, an intradermal route, an oral route, a topical route, an intranasal route, an intrapulmonary route, or an intrarectal route, but is not limited thereto. In addition, the pharmaceutical composition can be administered by any device capable of delivering the active ingredient to the target cell.

[0103] The pharmaceutical composition according to the present disclosure may contain a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and may further include a pharmaceutically acceptable carrier, diluent or excipient. As used herein, the term "pharmaceutically acceptable carrier or diluent" refers to a carrier or diluent that neither causes significant stimulation to an organism nor eliminates the biological activity or characteristics of the compound to be administered thereto. In addition, as used herein, the term "pharmaceutically acceptable excipient" refers to an inert material added to a pharmaceutical composition to facilitate the administration of the compound represented by Chemical Formula 1 of the present disclosure. Examples of excipients may include calcium carbonate, calcium phosphate, various types of sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol, but are not limited thereto. In addition, the composition may be prepared into various preparations, including oral preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., and injections of sterile injectable solutions, etc., according to conventional methods, according to the desired purpose.

[0104] The pharmaceutical composition of the present disclosure can be applied in a pharmaceutically effective amount or a therapeutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease with a reasonable effect / risk ratio that can be used for any medical treatment but does not cause adverse effects, and the level of the effective dose can be determined based on factors including the following: the patient's health, disease type and severity, drug activity, sensitivity to drugs, administration methods, administration time, administration routes and excretion rates, treatment duration, drugs used simultaneously or in combination, and other factors well known in the medical field. Taking into account all of the above elements, it is important to administer the composition in a dosage that can achieve the maximum effect in a minimum amount without adverse effects. Therefore, those skilled in the art can easily determine the dosage of the composition. The daily dose of the compound represented by Chemical Formula 1 or its pharmaceutically acceptable salt can be specifically 1mg / kg to 1000mg / kg, and the composition can be applied once a day or several times a day as needed.

[0105] Invention Mode

[0106] Hereinafter, preferred embodiments are provided to help understand the present disclosure. However, these embodiments are given only for illustrative purposes to help better understand the present disclosure, and the scope of the present disclosure is not intended to be limited by these embodiments.

[0107] Various synthetic methods for the starting materials for synthesizing the disclosed compounds are known, and if commercially available, the starting materials can be purchased from suppliers. Examples of reagent suppliers include Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Dae-Jung, Combi-Blocks, etc., but are not limited thereto. In addition, unless otherwise specified, all commercially available materials were used without further purification.

[0108] First, the compounds used for synthesis in the examples are prepared according to the following preparation examples. The preparation examples are exemplary embodiments of the compounds represented by Chemical Formula 1 in the above reaction scheme 1, and may be appropriately adjusted according to the structures of the compounds in the examples to be prepared.

[0109] Preparation Example 1: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxamide

[0110] Step 1-1) Preparation of 4-methyl-1H-pyrrole-2-carbonyl chloride

[0111]

[0112] 4-Methyl-1H-pyrrole-2-carboxylic acid (200 mg, 1.60 mmol) was dissolved in 3 mL of dichloromethane and 0.1 mL of N,N-dimethylformamide, and oxalyl chloride (0.18 mL, 2.08 mmol) was slowly added dropwise thereto. The mixture was stirred at room temperature for 1 hour to synthesize 4-methyl-1H-pyrrole-2-carbonyl chloride.

[0113] Step 1-2) Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxamide

[0114]

[0115] The reaction solution containing 4-methyl-1H-pyrrole-2-carbonyl chloride synthesized according to step 1-1) was concentrated under reduced pressure and then redissolved in 3 mL of dichloromethane. 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (360 mg, 1.76 mmol) was added to the reaction solution, and triethylamine (0.29 mL, 2.08 mmol) was slowly added dropwise, and then the reaction solution was stirred at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, 6 mL of a 1:1 mixed solution of acetonitrile and distilled water was added thereto to obtain 100 mg of the title compound N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxamide.

[0116] 1 H NMR (400MHz, DMSO-d6) δ11.54(br s,1H),10.07(s,1H),8.87(s,1H),8.17(d,J=8.6Hz,1H),7.96(t,J=8.0Hz,1H),7.77(d,J=7.7Hz,1H),7.01(br s,1H),6.82(br s,1H),5.65(br d,J=6.6Hz,1H),2.07(s,3H),1.44(d,J=6.8Hz,6H);

[0117] MS (ESI+) m / z 311 (M+H) + .

[0118] Preparation Example 2: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0119]

[0120] 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine (100 mg, 0.492 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and 1H-pyrrole-2-carboxylic acid (66 mg, 0.590 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 225 mg, 0.590 mmol) and N-methylmorpholine (162 μL, 1.476 mmol) were added thereto, and the mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with saturated aqueous ammonium chloride solution and ethyl acetate. The extracted solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by preparative TLC (dichloromethane:methanol=15:1) to obtain 11 mg of the title compound N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide.

[0121] 1 H NMR (400MHz, CDCl3) δ9.82 (s, 1H), 8.37 (s, 1H), 8.33 (d, J = 1.2Hz, 1H), 8.32 (s, 1H), 7.92-7.84 (m, 2H),7.18-7.04(m,1H),6.94(s,1H),6.35-6.33(m,1H),5.48-5.40(m,1H),1.59(d,J=1.0Hz,6H);

[0122] MS (ESI+) m / z 297 (M+H) + .

[0123] Example 1: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxamide

[0124]

[0125] In the same manner as in Preparation Example 1, the above compound was obtained.

[0126] 1H NMR (400MHz, DMSO-d6) δ11.54(br s,1H),10.07(s,1H),8.87(s,1H),8.17(d,J=8.6Hz,1H),7.96(t,J=8.0Hz,1H),7.77(d,J=7.7Hz,1H),7.01(br s,1H),6.82(br s,1H),5.65(br d,J=6.6Hz,1H),2.07(s,3H),1.44(d,J=6.8Hz,6H);

[0127] MS (ESI+) m / z 311 (M+H) + .

[0128] Example 2: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-m-tolyl-1H-pyrrole-2-carboxamide

[0129]

[0130] In the same manner as in Preparation Example 1, the above compound was obtained.

[0131] 1 H NMR(400MHz,DMSO-d6)δ12.03-12.11(m,1H),10.28-10.34(m,1H),8.89(s,1H),8.20(br d,J=8.2Hz,1H),7.97-8.03(m,1H),7.77-7.81(m,1H),7.59-7.65(m,2H),7.53-7.57(m,1H),7 .33-7.39(m,2H),7.16-7.21(m,1H),5.61-5.67(m,1H),2.16-2.32(m,3H),1.41-1.51(m,6H);

[0132] MS (ESI+) m / z 387 (M+H) + .

[0133] Example 3: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(methoxymethyl)-1H-pyrrole-2-carboxamide

[0134]

[0135] In the same manner as in Preparation Example 1, the above compound was obtained.

[0136] 1H NMR(400MHz,DMSO-d6)δ11.78(br s,1H),10.18(s,1H),8.86(s,1H),8.16(d,J=8.2Hz,1H),7.97(t,J=8.1Hz,1H),7.79(d,J=7.5Hz, 1H),7.20(s,1H),7.01(s,1H),5.63-5.74(m,1H),4.28(s,2H),3.23(s,3H),1.45(d,J=6.8Hz,6H);

[0137] MS (ESI+) m / z 341 (M+H) + .

[0138] Example 4: Preparation of 4-ethyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0139]

[0140] In the same manner as in Preparation Example 1, the above compound was obtained.

[0141] 1 H NMR(400MHz,DMSO-d6)δ11.49-11.62(m,1H),10.08(br s,1H),8.86(s,1H),8.16(d,J=8.2Hz,1H),7.93-8.03(m,1H),7.76(d,J=7.7Hz,1H),7.05(s,1H),6.84(s,1H),5.60-5.70(m,1H),2.55(br d,J=3.1Hz,1H),2.39-2.48(m,2H),1.44(d,J=6.6Hz,6H),1.16(t,J=7.6Hz,3H);

[0142] MS (ESI+) m / z 325 (M+H) + .

[0143] Example 5: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-p-tolyl-1H-pyrrole-2-carboxamide

[0144]

[0145] In the same manner as in Preparation Example 1, the above compound was obtained.

[0146] 1H NMR (400MHz, DMSO-d6) δ11.97-12.08(m,1H),10.28(br s,1H),8.88(s,1H),8.19(br d,J=8.4Hz,1H),7.99(br t,J=8.1Hz,1H),7.78(br d,J=7.3Hz,1H),7.43-7.64(m,3H),7.09-7.25(m,2H),5.85-5.98(m,1H),5.60-5.71(m,1H),2.16-2.32(m,3H),1.31-1.64(m,6H);

[0147] MS (ESI+) m / z 387 (M+H) + .

[0148] Example 6: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-phenyl-1H-pyrrole-2-carboxamide

[0149]

[0150] In the same manner as in Preparation Example 1, the above compound was obtained.

[0151] 1H NMR(400MHz,DMSO-d6)δ12.03-12.11(m,1H),10.28-10.34(m,1H),8.89(s,1H),8.20(br d,J=8.2Hz,1H),7.97-8.03(m,1H),7.77-7.81(m,1H),7.59-7.65(m,3H),7.53-7.57 (m,1H),7.33-7.39(m,2H),7.16-7.21(m,1H),5.61-5.67(m,1H),1.41-1.51(m,6H);

[0152] MS (ESI+) m / z 373 (M+H) + .

[0153] Example 7: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0154]

[0155] In the same manner as in Preparation Example 2, the above compound was obtained.

[0156] 1H NMR (400MHz, CDCl3) δ9.82 (s, 1H), 8.37 (s, 1H), 8.33 (d, J = 1.2Hz, 1H), 8.32 (s, 1H), 7.92-7.84 (m, 2H),7.18-7.04(m,1H),6.94(s,1H),6.35-6.33(m,1H),5.48-5.40(m,1H),1.59(d,J=1.0Hz,6H);

[0157] MS (ESI+) m / z 297 (M+H) + .

[0158] Example 8: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-2-carboxamide

[0159]

[0160] In the same manner as in Preparation Example 2, the above compound was obtained.

[0161] 1 H NMR (400MHz, CDCl3) δ9.54 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.0Hz, 1H), 8.11 (s, 1H), 7.92-7.83 (m, 2H),6.74-6.73(m,1H),5.99-5.98(m,1H),5.49-5.42(m,1H),2.36(s,3H),1.55(d,J=6.8Hz,6H);

[0162] MS (ESI+) m / z 311 (M+H) + .

[0163] Example 9: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-phenyl-1H-pyrrole-2-carboxamide

[0164]

[0165] In the same manner as in Preparation Example 2, the above compound was obtained.

[0166] 1H NMR (400MHz, CDCl3) δ10.58(s,1H),8.59(s,1H),8.37(s,1H),8.25(d,J=8.2Hz,1H),7.82(d,J=7.6Hz,1H),7.74-7.62(m, 3H),7.50-7.34(m,2H),7.30-7.28(m,1H),7.06-7.04(m,1H),6.63-6.62(m,1H),5.40-5.32(m,1H),1.44(d,J=6.6Hz,6H);

[0167] MS (ESI+) m / z 373 (M+H) + .

[0168] Example 10: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-p-tolyl-1H-pyrrole-2-carboxamide

[0169]

[0170] In the same manner as in Preparation Example 2, the above compound was obtained.

[0171] 1 H NMR (400MHz, CDCl3) δ10.32(s,1H),8.44(s,1H),8.39(s,1H),8.27(d,J=8.2Hz,1H),7.85(d,J=7.3Hz,1H),7.77(t,J=7.3Hz,1H),7.6 4(d,J=7.7Hz,2H),7.19(d,J=8.0Hz,2H),7.06-6.99(m,1H),6.63-6.59(m,1H),5.48-5.37(m,1H),2.34(s,3H),1.50(d,J=6.8Hz,6H);

[0172] MS (ESI+) m / z 387 (M+H) + .

[0173] Example 11: Preparation of 5-ethyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0174]

[0175] In the same manner as in Preparation Example 2, the above compound was obtained.

[0176] 1H NMR (400MHz, CDCl3) δ9.38 (s, 1H), 8.38 (s, 1H), 8.33 (d, J = 8.2Hz, 1H), 8.17 (s, 1H), 7.92-7.73 (m, 2H), 6.73-6.7 1(m,1H),6.06-6.04(m,1H),5.50-5.42(m,1H),2.74-2.65(m,2H),1.57(d,J=6.8Hz,6H),1.29(t,J=8.0Hz,3H);

[0177] MS (ESI+) m / z 325 (M+H) + .

[0178] Example 12: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(2-methylpyrimidin-5-yl)-1H-pyrrole-2-carboxamide

[0179]

[0180] In the same manner as in Preparation Example 2, the above compound was obtained.

[0181] 1 H NMR (400MHz, CDCl3) δ8.96 (s, 2H), 8.38 (s, 1H), 8.29 (d, J = 7.5Hz, 1H), 7.85-7.74 (m, 2H), 7.0 1(d,J=4.0Hz,1H),6.66(d,J=3.6,1H),5.37-5.34(m,1H),2.74(s,3H),1.50(d,J=6.8Hz,6H);

[0182] MS (ESI+) m / z 389 (M+H) + .

[0183] Example 13: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrole-2-carboxamide

[0184]

[0185] In the same manner as in Preparation Example 2, the above compound was obtained.

[0186] 1H NMR (400MHz, CDCl3) δ8.46(s,1H),8.23(d,J=6.8Hz,1H),7.90-7.83(m,2H),7.80-7.75(m,3H),7.71(d,J=7 .5Hz,1H),6.89(d,J=4.0Hz,1H),6.68(d,J=4.0,1H),5.41-5.32(m,1H),3.03(s,3H),1.45(d,J=6.8Hz,6H);

[0187] MS (ESI+) m / z 451 (M+H) + .

[0188] Example 14: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-m-tolyl-1H-pyrrole-2-carboxamide

[0189]

[0190] In the same manner as in Preparation Example 2, the above compound was obtained.

[0191] 1 H NMR (400MHz, CDCl3) δ8.61(s,1H),8.37(s,1H),8.23(d,J=7.3Hz,1H),7.80(d,J=6.8Hz,1H),7.68(t,J=6.8Hz,1H),7.52-7 .46(m,2H),7.27-7.20(m,1H),7.12-7.01(m,2H),6.61-6.54(m,1H),5.40-5.31(m,1H),2.38(s,3H),1.49(d,J=6.8Hz,6H);

[0192] MS (ESI+) m / z 387 (M+H) + .

[0193] Example 15: Preparation of 5-(3,5-dimethylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0194]

[0195] In the same manner as in Preparation Example 2, the above compound was obtained.

[0196] 1H NMR (400MHz, CDCl3) δ10.45(s,1H),8.52(s,1H),8.36(s,1H),8.25(d,J=6.6Hz,1H),7.83-7.69(m,2H),7.28 (s,2H),7.01(s,1H),6.94(s,1H),6.60-6.58(m,1H),5.40-5.30(m,1H),2.32(s,6H),1.48(d,J=7.6Hz,6H);

[0197] MS (ESI+) m / z 401 (M+H) + .

[0198] Example 16: Preparation of 5-(4-chlorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0199]

[0200] In the same manner as in Preparation Example 2, the above compound was obtained.

[0201] 1 H NMR (400MHz, MeOD) δ8.80(s,1H),8.26(d,J=6.8Hz,1H),7.93-7.84(m,1H),7.72(d,J=6.8Hz,1H),7.65(d,J=4. 0Hz,2H),7.37(d,J=4.0Hz,2H),7.15-7.12(m,1H),6.62-6.58(m,1H),5.78-5.72(m,1H),1.51(d,J=8.0Hz,6H);

[0202] MS (ESI+) m / z 407 (M+H) + .

[0203] Example 17: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(thiophen-2-yl)-1H-pyrrole-2-carboxamide

[0204]

[0205] In the same manner as in Preparation Example 2, the above compound was obtained.

[0206] 1H NMR (400MHz, CDCl3) δ10.87(s,1H),8.71(s,1H),8.36(s,1H),8.20(d,J=8.2Hz,1H),7.79-7.62(m,2H),7.38-7 .32(m,1H),7.20-7.16(m,1H),7.06-7.01(m,1H),6.79-6.49(m,1H),5.32-5.23(m,1H),1.51(d,J=6.8Hz,6H);

[0207] MS (ESI+) m / z 379 (M+H) + .

[0208] Example 18: Preparation of 5-(3,4-dimethylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0209]

[0210] In the same manner as in Preparation Example 2, the above compound was obtained.

[0211] 1 H NMR (400MHz, CDCl3) δ10.53(s,1H),8.57(s,1H),8.34(s,1H),8.22(d,J=8.2Hz,1H),7.81(d,J=7.3Hz,1H),7.70-7.63(m,1H),7.4 4-7.38(m,2H),7.11(d,J=8.2Hz,1H),7.07-7.01(m,1H),6.57-6.55(m,1H),5.40-5.30(m,1H),2.24(s,6H),1.46(d,J=6.8Hz,6H);

[0212] MS (ESI+) m / z 401 (M+H) + .

[0213] Example 19: Preparation of 5-(3-fluoro-4-methylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0214]

[0215] In the same manner as in Preparation Example 2, the above compound was obtained.

[0216] 1H NMR (400MHz, CDCl3) δ11.02(s,1H),8.78(s,1H),8.34(s,1H),8.19(d,J=6.6Hz,1H),7.76-7.70(m,1H),7.68-7.63(m ,1H),7.41-7.32(m,2H),7.13-7.07(m,2H),6.62-6.58(m,1H),5.33-5.23(m,1H),2.22(s,3H),1.43(d,J=6.8Hz,6H);

[0217] MS (ESI+) m / z 405 (M+H) + .

[0218] Example 20: Preparation of 5-(3-chloro-4-fluorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0219]

[0220] In the same manner as in Preparation Example 2, the above compound was obtained.

[0221] 1 H NMR (400MHz, CDCl3) δ11.05(s,1H),8.79(s,1H),8.38(s,1H),8.16(d,J=6.8Hz,1H),7.81-7.64(m,3H ),7.60-7.54(m,1H),7.17-7.09(m,2H),6.60-6.56(m,1H),5.24-5.17(m,1H),1.48(d,J=7.6Hz,6H);

[0222] MS (ESI+) m / z 425 (M+H) + .

[0223] Example 21: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(4-(methylthio)phenyl)-1H-pyrrole-2-carboxamide

[0224]

[0225] In the same manner as in Preparation Example 2, the above compound was obtained.

[0226] 1H NMR (400MHz, CDCl3) δ10.57(s,1H),8.56(s,1H),8.35(s,1H),8.22(d,J=8.2Hz,1H),7.81(d,J=7.6Hz,1H),7.73(m,1H),7.57(d, J=6.8Hz,2H),7.24(d,J=6.6Hz,2H),7.02-7.00(m,1H),6.59-6.57(m,1H),5.35-5.30(m,1H),2.46(s,3H),1.47(d,J=6.8Hz,6H);

[0227] MS (ESI+) m / z 419 (M+H) + .

[0228] Example 22: Preparation of N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-o-tolyl-1H-pyrrole-2-carboxamide

[0229]

[0230] In the same manner as in Preparation Example 2, the above compound was obtained.

[0231] 1 H NMR (400MHz, CDCl3) δ10.33(s,1H),8.51(s,1H),8.34(s,1H),8.14(d,J=4.0Hz,1H),7.85(d,J=6.6Hz,1H),7.71(t,J=6.8Hz,1H), 7.47-7.45(m,1H),7.29-7.20(m,3H),7.04-7.01(m,1H),6.43-6.41(m,1H),5.43-5.38(m,1H),2.47(s,3H),1.49(d,J=6.8Hz,6H);

[0232] MS (ESI+) m / z 387 (M+H) + .

[0233] Example 23: Preparation of 5-(4-fluorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0234]

[0235] In the same manner as in Preparation Example 2, the above compound was obtained.

[0236] 1H NMR(400MHz,MeOD)δ10.62(s,1H),8.60(s,1H),8.34(s,1H),8.22(d,J=6.8Hz,1H),7.81-7.72(m,2H ),7.68-7.61(m,2H),7.09-6.99(m,3H),6.56-6.51(m,1H),5.36-5.28(m,1H),1.47(d,J=8.0Hz,6H);

[0237] MS (ESI+) m / z 391 (M+H) + .

[0238] Example 24: Preparation of 5-(4-ethoxyphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide

[0239]

[0240] In the same manner as in Preparation Example 2, the above compound was obtained.

[0241] 1 H NMR (400MHz, CDCl3) δ10.56(s,1H),8.54(s,1H),8.32(s,1H),8.25(d,J=8.0Hz,1H),7.82-7.80(m,1H),7.78-7.71(m,1H),7.56(d,J=6.6 ,2H),7.01(s,1H),6.86(d,J=8.8Hz,2H),6.51(s,1H),5.41-5.34(m,1H),4.03-3.98(m,2H),1.48(d,J=6.8Hz,6H),1.37(t,J=8.0Hz,3H);

[0242] MS (ESI+) m / z 417 (M+H) + .

[0243] Experimental Example 1: Determination of the inhibitory ability on ASK-1 enzyme activity (ADP-Glo TM Kinase assay)

[0244] In order to evaluate the inhibitory ability of the compounds of Examples 1 to 24 on ASK-1 enzyme activity, ADP-Glo TM(Promega, catalog number V9101) was used for the following experiment. Each compound was prepared into a solution with a concentration of 0.32nM, 1.6nM, 8nM, 40nM, 200nM, 1,000nM by adding a kinase buffer solution (H2O containing 40mM Tris, 20mM MgCl2, 0.1mg / mL bovine serum albumin). Subsequently, 250μM ATP (Promega, catalog number V915A) and 0.5μg / μL MBP substrate (Signal Chem, catalog number 42-51N) were added thereto, and the mixture was reacted at 30°C for 40 minutes in the presence of 15ng ASK-1 enzyme (Signal Chem, catalog number M13-11G-10). Then, ADP-Glo ​​was added thereto in sequence. TM Reagent and kinase detection reagent were added and reacted for 40 minutes and 10 minutes respectively. TM The luminescence was measured by NEO microplate reader (BioTEK, NEOB-1311189).

[0245] The ability of the compounds of Examples 1 to 24 to inhibit ASK-1 enzyme activity was verified by analyzing the data from the measured RLU values. Specifically, the ability to inhibit ASK-1 enzyme activity was evaluated by deriving the residual activity percentage of the ASK-1 enzyme in the samples treated with the tested concentrations of the compounds while using the RLU values ​​of the samples not treated with the compounds as a 100% control. The IC values ​​of the ASK-1 inhibitors were calculated. 50 The IC value (nM) was determined as the compound concentration that induced 50% inhibition of ASK-1 enzyme activity compared to the control, and the results are shown in the following Table 1. As shown in Table 1, all compounds of Examples 1 to 24 showed excellent inhibitory activity against ASK-1, IC 50 The value was 100 nM or lower.

[0246] Table 1

[0247]

[0248]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

1. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methyl-1H-pyrrole-2-carboxamide, 2. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-m-tolyl-1H-pyrrole-2-carboxamide, 3. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-(methoxymethyl)-1H-pyrrole-2-carboxamide, 4.4-ethyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 5.N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-p-tolyl-1H-pyrrole-2-carboxamide, 6. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-phenyl-1H-pyrrole-2-carboxamide, 7. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 8. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methyl-1H-pyrrole-2-carboxamide, 9. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-phenyl-1H-pyrrole-2-carboxamide, 10. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-p-tolyl-1H-pyrrole-2-carboxamide, 11.5-ethyl-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 12. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(2-methylpyrimidin-5-yl)-1H-pyrrole-2-carboxamide, 13. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(4-(methylsulfonyl)phenyl)-1H-pyrrole-2-carboxamide, 14. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-m-tolyl-1H-pyrrole-2-carboxamide, 15.5-(3,5-dimethylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 16. 5-(4-chlorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 17. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(thiophen-2-yl)-1H-pyrrole-2-carboxamide, 18.5-(3,4-dimethylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 19.5-(3-Fluoro-4-methylphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 20.5-(3-chloro-4-fluorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, 21. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-(4-(methylthio)phenyl)-1H-pyrrole-2-carboxamide, 22. N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-o-tolyl-1H-pyrrole-2-carboxamide, 23. 5-(4-Fluorophenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide, or 24. 5-(4-Ethoxyphenyl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-1H-pyrrole-2-carboxamide.

2. A method for preparing the compound according to claim 1, comprising: A compound represented by the following Chemical Formula 2 is reacted with 6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-amine: [Chemical formula 2] In the chemical formula 2, X is NH, Y is OH or Cl, R1 is H, and R2 and R3 are as defined in the compound of claim 1.

3. The method according to claim 2, wherein: If Y is OH, the reaction is carried out in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and a base.

4. The method according to claim 2, wherein: If Y is Cl, the reaction is carried out in the presence of triethylamine.

5. The method according to claim 4, wherein: The compound of Chemical Formula 2 wherein Y is Cl is prepared by reacting the compound of Chemical Formula 2 wherein Y is OH with oxalyl halide.

6. A pharmaceutical composition for preventing or treating an ASK-1-mediated disease, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to claim 6 , which inhibits ASK-1 activity.

8. The pharmaceutical composition of claim 6, wherein the ASK-1 mediated disease is selected from the group consisting of diabetes, diabetic nephropathy, kidney disease, renal fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute lung injury, nonalcoholic steatohepatitis, liver disease, alcoholic liver disease, alcoholic hepatitis, inflammatory disorders, autoimmune diseases, proliferative diseases, transplant rejection, diseases associated with impaired cartilage turnover, congenital cartilage malformations, diseases associated with excessive secretion of IL6, and combinations thereof.

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