Novel compounds as RON inhibitors

Abstract

The present invention relates to novel compounds as protein kinase inhibitors, in particular RON inhibitors.

Description

Technical Field

[0001] Cross - Reference to Related Applications

[0002] This application claims the priority and benefit of Korean Patent Application No. 10 - 2022 - 0182613, filed on December 23, 2022, the disclosure of which is incorporated herein by reference in its entirety.

[0003] The present invention relates to a novel compound as a protein kinase inhibitor. Specifically, the present invention relates to a novel compound as a RON inhibitor. Background Art

[0004] There are known to be at least 400 protein kinases that catalyze the transfer of a phosphate group from adenosine triphosphate (ATP) to a protein substrate. Since the specific amino acid to which the phosphate group is transferred in the target protein is tyrosine, serine, or threonine, protein kinases are generally referred to as protein tyrosine kinases (PTKs) or serine / threonine kinases (STKs).

[0005] Protein kinases include a large class of structurally related proteins that are essential for regulating various signal transduction pathways within cells. The signal transduction pathways include many different signal transduction pathways by transferring a phosphate group to a target protein. These phosphorylation processes act as molecular on / off switches that can regulate the biological functions of target proteins or protein complexes. The proper function of protein kinases in signal transduction pathways is to activate or inactivate metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels and pumps, transcription factors, etc. Improper regulation of signal transduction caused by defects in protein phosphorylation regulation is associated with many diseases, including inflammation, cancer, allergies / asthma, immune system diseases, central nervous system diseases, and angiogenesis.

[0006] Most kinases include a similar catalytic site consisting of 250 to 300 amino acids. Kinases can be classified according to the substrates they phosphorylate, and sequence motifs corresponding broadly to each of these kinase families have been identified.

[0007] Meanwhile, the receptor d'origine Nantais (RON) is one of the tyrosine - protein kinase receptors, also known as macrophage - stimulating 1 receptor (MST1R), which is reported to promote the invasion and metastasis of cancer cells. Overexpression of RON has also been reported in various tumor types.

[0008] Activation of tyrosine protein kinases, such as RON mentioned above, in tumor cells enhances the proliferation, invasion and metastasis of tumor cells, and also increases the resistance of tumor cells to apoptosis and cytotoxic therapies. Therefore, it is expected that selective small molecule kinase regulators targeting tyrosine protein kinases such as RON have therapeutic potential for treating cancers in which the activation of RON receptor or other receptors plays an important role in the occurrence and progression of primary tumors and secondary metastases. Therefore, continuous research is being conducted on various inhibitors to selectively inhibit the activity of RON, one of the tyrosine protein kinases. Summary of the Invention

[0009] [Technical Problem]

[0010] An object of the present invention is to provide a novel compound having protein kinase inhibitory activity.

[0011] Another object of the present invention is to provide a compound that can be used for preventing or treating RON-mediated diseases.

[0012] Another object of the present invention is to provide a compound that can be used for preventing or treating cancers or immune diseases.

[0013] Another object of the present invention is to provide a compound that can be used as a RON inhibitor.

[0014] [Technical Solution]

[0015] To achieve the above objects,

[0016] In one aspect, the present invention provides a compound having the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0017] [Chemical Formula 1]

[0018]

[0019] In another aspect, the present invention provides a pharmaceutical composition comprising: a compound having Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0020] In yet another aspect, the present invention provides a pharmaceutical composition for preventing or treating RON-mediated diseases, comprising: a compound having Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0021] In yet another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancers or immune diseases, comprising: a compound having Chemical Formula 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

[0022] [Advantageous Effects]

[0023] According to the present invention, there is provided a novel compound or a pharmaceutically acceptable salt thereof, which can be effectively used for treating various immune-mediated diseases, such as anti-cancer agents, by inhibiting protein kinase activity, particularly the protein kinase activity of the RON receptor, but the effects of the present invention are not limited thereto. Detailed Description of the Invention

[0024] First, the terms used in the present invention are defined.

[0025] In the present specification, the term "substituted" means that a hydrogen atom bonded to a carbon atom in the structure is changed to another substituent, and the position where substitution occurs is not limited as long as it is a position where a hydrogen atom is substituted, that is, a position where a substituent can be substituted, and when substitution occurs at two or more positions, the two or more substituents may be the same or different.

[0026] In the present specification, unless otherwise defined, "substituent" may be deuterium, halogen, hydroxyl, alkyl, cycloalkyl, alkoxy, aryloxy, alkylthioxy, arylthioxy, alkylsulfonyloxy, arylsulfonyloxy, haloalkyl, alkoxyalkyl, hydroxyalkyl, alkenyl, amine, nitrile, nitro, imide, amide, oxo, carbonyl, carboxyl, carbamoyl, ester, aryl, heteroaryl, -(CO)-(CH2) n -OR c (where n is an integer from 0 to 3, and R c is hydrogen or alkyl), etc.

[0027] In the present specification, "alkyl" is an aliphatic hydrocarbon group that does not contain double bonds or triple bonds, and it may be C1 to C20, C1 to C19, C1 to C18, C1 to C17, C1 to C16, C1 to C15, C1 to C14, C1 to C13, C1 to C12, C1 to C11, C1 to C10, such as C1 to C6, particularly C1 to C4 alkyl, and may be straight-chain or branched-chain. Specific examples of alkyl include methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methylbutyl, 1-ethylbutyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, nonyl, 2,2-dimethylheptyl, 1-ethylpropyl, 1,1-dimethylpropyl, isohexyl, 4-methylhexyl, 5-methylhexyl, and benzyl, but are not limited thereto.

[0028] In this specification, "cycloalkyl" is a cyclic aliphatic hydrocarbon group that does not contain double or triple bonds. It can be C3 to C30, C3 to C28, C3 to C26, C3 to C24, C3 to C22, C3 to C20, C3 to C18, C3 to C16, C3 to C14, C3 to C12, C3 to C10, such as C3 to C8, especially C3 to C6 cycloalkyl, and it can be monocyclic or polycyclic. A polycyclic group refers to a group in which the cycloalkyl is directly linked or fused to other cyclic groups, and here, the other cyclic groups can be cycloalkyl, but can also be another type of cyclic group, such as heterocycloalkyl, aryl or heteroaryl. Specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.2]nonyl, bicyclo[4.4.0]decyl and bicyclo[4.1.0]heptyl, but are not limited thereto.

[0029] In this specification, "heterocycloalkyl" is a cyclic aliphatic hydrocarbon group that includes O, S, Se, N or Si as heteroatoms. It can be C2 to C30, C2 to C28, C2 to C26, C2 to C24, C2 to C22, C2 to C20, C2 to C18, C2 to C16, C2 to C14, C2 to C12, C2 to C10, C2 to C8, C2 to C6, such as C2 to C5 heterocycloalkyl, and can be monocyclic or polycyclic. A polycyclic group refers to a group in which the heterocycloalkyl is directly linked or fused to other cyclic groups, and here, the other cyclic groups can be cycloalkyl, but can also be another type of cyclic group, such as heterocycloalkyl, aryl or heteroaryl. Specific examples of heterocycloalkyl include aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, pyran (tetrahydropyran), oxepane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, iso oxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane and dithiane, but are not limited thereto.

[0030] In this specification, "aryl" is an aromatic hydrocarbon group, which can be C6-C30, C6-C28, C6-C26, C6-C24, C6-C22, C6-C20, C6-C18, C6-C16, C6-C14, for example, C6-C12 aryl, and can be monocyclic or polycyclic. A polycyclic group means a group in which an aryl group is directly connected or fused to other cyclic groups, and here, the other cyclic groups can be aryl groups, but can also be another type of cyclic group, such as cycloalkyl, heterocycloalkyl or heteroaryl. In addition, aryl includes spirocycles. Specific examples of aryl include phenyl, biphenyl, triphenyl, naphthyl, anthracenyl, -yl, phenanthryl, perylenyl, fluoranthenyl, tritylene, acephenanthrylenyl, pyrenyl, tetracenyl, pentacenyl, fluorenyl, indenyl, acenaphthylenyl, benzofluorenyl, spirobifluorenyl, 2,3-dihydro-1H-indenyl and its fused cyclic groups, but are not limited thereto.

[0031] In this specification, "heteroaryl" is an aromatic hydrocarbon group including O, S, Se, N or Si as heteroatoms, which can be C3-C30, C3-C28, C3-C26, C3-C24, C3-C22, C3-C20, C3-C18, C3-C16, C3-C14, C3-C12, C3-C10, C3-C8, C3-C6, for example, C3-C5 heteroaryl, and can be monocyclic or polycyclic. A polycyclic group means a group in which a heteroaryl group is directly connected or fused to other cyclic groups, and here, the other cyclic groups can be heteroaryl groups, but can also be another type of cyclic group, such as cycloalkyl, heterocycloalkyl, aryl, etc. Specific examples of heteroaryl include pyridyl, pyrrolyl, pyrimidinyl, pyridazinyl, furyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, iso oxazolyl, thiazolyl, isothiazolyl, triazolyl, furazanyl, diazolyl, thiadiazolyl, dithiazolyl, tetrazolyl, pyranyl, thiopyranyl, diazinyl, azinyl, thiazinyl, di inyl, triazinyl, tetrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, quinazolyl, naphthyridinyl, acridinyl, phenanthridinyl, imidazopyridyl, phthalazinyl, triazaindenyl, indolyl, indazolyl, benzothiazolyl, benzo oxazolyl, benzimidazolyl, benzothiophene, benzofuran, dibenzothiophene, dibenzofuran, carbazolyl, benzocarbazolyl, dibenzocarbazolyl, phenazinyl, dibenzosilanolyl, spirobis(dibenzosilanolyl), dihydro-phenazinyl, phen Quinolinyl, phenanthryl, imidazopyridinyl, thienyl, indolo[2,3-a]carbazolyl, indolo[2,3-b]carbazolyl, indolinyl, 10,11-dihydro-dibenzo[b,f]azepine, 9,10-dihydroacridinyl, phenazine, phenothiazine, phthalazine, naphthyridine, phenanthroline, benzo[c][1,2,5]thiadiazolyl, 5,10-dihydrodibenzo[b,e][1,4]azepinyl, pyrazolo[1,5-c]quinazolinyl, pyrido[1,2-b]indazolyl, pyrido[1,2-a]imidazo[1,2-e]indolyl, 5,11-dihydroindeno[1,2-b]carbazolyl. According to one embodiment, the heteroaryl may be selected from pyridinyl, pyrimidinyl, pyrazolyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, diazolyl, triazinyl, triazolyl, acridinyl, pyridazinyl, pyrazinyl, quinolinyl, quinazolyl, quin olinyl, isoquinolinyl, indolyl, indolinyl, carbazolyl, benzo oxazolyl, benzimidazolyl and benzothiazolyl, but not limited thereto.

[0032] In the present specification, "alkoxy" is a group having the chemical structure -ORa, and Ra may be a substituted or unsubstituted alkyl group, where the alkyl group is as described above. Specific examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy and p-methylbenzyl, but not limited thereto.

[0033] In the present specification, "amine" is a group having the chemical structure -NRbRc, and Rb and Rc may each independently be hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxyl group and a substituted or unsubstituted alkoxy group. The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and alkoxy groups are as described above.

[0034] In the present invention, "pharmaceutically acceptable salts" include salts commonly used to form alkali metal salts and addition salts of free acids or free bases. The nature of these salts is not critical, but they need to be pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts for the compounds of Formula 1 can be prepared from inorganic or organic acids. Examples of these inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic organic acids, examples of which include formic acid, acetic acid, adipic acid, butyric acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminosulfonic acid, camphoric acid, camphorsulfonic acid, digluconic acid, cyclopentanepropionic acid, dodecylsulfonic acid, glucoheptonic acid, glycerophosphonic acid, heptanoic acid, hexanoic acid, 2-hydroxyethanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmitic acid, pectic acid, persulfuric acid, 2-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, thiocyanic acid, methanesulfonic acid, undecanoic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactonic acid, and galacturonic acid. Pharmaceutically acceptable base addition salts suitable for the compounds of Formula 1 include metal salts, such as salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or salts prepared from organic bases including primary, secondary, or tertiary amines and substituted amines including cyclic amines, such organic bases as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucosamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, and trimethylamine. All of these salts can be prepared from the corresponding compounds of the present invention by conventional methods, such as by reacting the compounds of Formula 1 with suitable acids or bases. When basic and acidic groups are present in the same molecule, the compounds of Formula 1 can also form inner salts.

[0035] In the present invention, "solvates" can include hydrates, as well as solvates with organic solvents such as methanol, ethanol, 2-propanol, 1,2-propanediol, 1,3-propanediol, n-butanol, 1,4-butanediol, tert-butanol, acetic acid, acetone, butyl acetate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene, and mixtures thereof.

[0036] In this specification, the term "prevention" refers to reducing the risk of a disease or disorder and means all actions that inhibit or delay the onset of a disease by preventing the progression of one or more clinical symptoms of the disease in an individual who is exposed to the disease or is susceptible to the disease but has not yet developed the disease or shown symptoms of the disease.

[0037] In this specification, the term "treatment" refers to alleviating a disease or disorder and means all actions that improve or beneficially alter the symptoms of the disease by preventing or reducing the progression of the disease or one or more of its clinical symptoms.

[0038] In this specification, the term "carrier" refers to a compound that facilitates the introduction of a compound into a cell or tissue. The pharmaceutical composition can be prepared in unit dosage form by formulation with a pharmaceutically acceptable carrier or can be prepared by placing it in a multi-dose container. At this time, the dosage form can take the form of a solution, suspension or emulsion in an oily or aqueous medium, or can also take the form of an extract, powder, granule, tablet, capsule or gel (such as a hydrogel), and can also include a dispersant or stabilizer.

[0039] In this specification, the term "therapeutically effective amount" refers to an amount of each formulation that achieves the purpose of improving the severity and incidence of a disease during treatment with each formulation itself, but avoids the harmful side effects usually associated with other treatment methods. For example, an effective anti-tumor agent prolongs the survival period of a patient, inhibits the growth of rapidly proliferating cells associated with the tumor, or is effective in tumor regression.

[0040] Hereinafter, the present invention will be described in detail.

[0041] 1. Novel compounds as receptor (RON) inhibitors derived from Nantes

[0042] One aspect of the present invention provides a compound having a chemical structure of the following Chemical Formula 1 or a pharmaceutically acceptable salt, isomer, solvate or prodrug thereof.

[0043] [Chemical Formula 1]

[0044]

[0045] In Chemical Formula 1, X can be N or C.

[0046] In Chemical Formula 1, R1 can be any one selected from hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl. In particular, it can be halogen, alkyl or haloalkyl. In particular, it can be alkyl or haloalkyl, such as trifluoromethyl or ethyl.

[0047] In Chemical Formula 1, R2 can be any one selected from hydrogen and substituted or unsubstituted alkyl groups. In particular, it can be hydrogen or alkoxyalkyl, such as hydrogen or methoxypropyl.

[0048] In Chemical Formula 1, Y1 and Y2 can each independently be any one selected from hydrogen, halogen, substituted or unsubstituted alkyl groups, and substituted or unsubstituted cycloalkyl groups. In particular, they can each independently be hydrogen or halogen. In particular, they can each independently be halogen, such as fluorine. In addition, Y1 and Y2 can be connected to the 3rd and 5th carbons, 2nd and 5th carbons, or 2nd and 6th carbons of the benzene ring.

[0049] In Chemical Formula 1, Z can be any one selected from hydrogen, halogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heteroaryl groups, nitro group, cyano group, and -(CH2) n -W. In particular, it can be any one selected from hydrogen, halogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, substituted or unsubstituted aryl groups, nitro group, cyano group, and -(CH2) n -W. In particular, it can be any one selected from halogen, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted heterocycloalkyl groups, cyano group, and -(CH2) n -W. In particular, it can be any one selected from halogen, alkyl groups, alkynyl groups, hydroxyalkynyl groups, hydroxyalkylalkynyl groups, cycloalkyl groups, tetrahydropyran, cyano group, and -(CH2) n -W.

[0050] Here, n can be an integer from 0 to 3. In particular, n can be an integer from 1 to 3. In particular, n can be an integer from 1 to 2. In particular, n can be 1.

[0051] In addition, W can be -NRaRb, -ORa, or heterocycloalkyl. In particular, it can be heterocycloalkyl. In particular, it can be morpholine, and Ra and Rb can each independently be hydrogen or substituted or unsubstituted alkyl groups. In particular, Ra and Rb can be alkyl groups.

[0052] In Chemical Formula 1, A can be any one selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted and unsubstituted heteroaryl. In particular, it can be any one selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted and unsubstituted heteroaryl. In particular, it can be any one selected from substituted alkyl, substituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. For example, it can be selected from alkoxyalkyl, aryl, pyridine, halopyridine, pyrimidine, pyridazine, piperidine, alkoxyalkylpiperidine, and a piperidine group substituted by -(CO)-(CH2) n -ORc, where n can be 1 and Rc can be alkyl.

[0053] In addition, the compounds of Chemical Formula 1 can be selected from:

[0054] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0055] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0056] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0057] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-5-ethyl-1-(3-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide;

[0058] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0059] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0060] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,6-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0061] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,6-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0062] N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0063] N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0064] N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0065] N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0066] N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0067] N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0068] N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0069] N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0070] N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0071] N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0072] N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0073] N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0074] N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0075] N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0076] N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0077] N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0078] N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0079] N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0080] N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0081] N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0082] N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0083] N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0084] N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0085] N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0086] N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0087] N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0088] N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0089] N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0090] N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0091] N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0092] N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0093] N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0094] N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0095] N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0096] N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0097] N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0098] N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0099] N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0100] N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0101] N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0102] N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0103] N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0104] N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0105] N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0106] N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0107] N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0108] N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0109] N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0110] N-(4-((2-Amino-3-(3-hydroxybut-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0111] N-(4-((2-Amino-3-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0112] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(1-(3-methoxypropyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide;

[0113] N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(1-(2-ethoxyacetyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; and

[0114] N-[4-[(2-Amino-3-chloro-4-pyridinyl)oxy]-3,5-difluoro-phenyl]-1-(3-methoxypropyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, and their structures are shown in Table 1 below.

[0115] [Table 1]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125] 2. Use of the novel compounds

[0126] The novel compounds of the present invention have the activity of inhibiting tyrosine protein kinases such as RON, which increase the proliferation, invasion and metastasis of tumor cells and enhance the resistance of tumor cells to apoptosis and cytotoxic therapies.

[0127] Therefore, the novel compounds of the present invention can be used as the active ingredient of a pharmaceutical composition. Accordingly, another aspect of the present invention provides a pharmaceutical composition comprising the above compound as the active ingredient.

[0128] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0129] The pharmaceutical composition can be used for preventing or treating protein kinase-mediated diseases, but the uses of the present invention are not limited to these diseases.

[0130] The pharmaceutical composition can be used for preventing or treating RON-mediated diseases, but the uses of the present invention are not limited to these diseases.

[0131] The pharmaceutical composition according to the present invention comprises a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0132] For treating the above diseases, the pharmaceutical composition can be administered to a subject in need of preventing or treating the diseases.

[0133] The pharmaceutical composition according to the present invention can be administered orally or parenterally during clinical administration and can be used in the form of general pharmaceutical preparations. In other words, during actual clinical administration, the pharmaceutical composition of the present invention can be administered in various oral and parenteral dosage forms. In formulation, diluents or excipients such as common fillers, extenders, binders, wetting agents, disintegrants and surfactants are used for formulation. Solid preparations for oral administration include tablets, pills, powders, granules and capsules, and these solid preparations are formulated by mixing at least one excipient (such as starch, calcium carbonate, sucrose or lactose and gelatin) with a herbal extract or a herbal fermentation product. In addition, lubricants such as magnesium stearate and talc are used in addition to simple excipients. Liquid preparations for oral administration include suspensions, oral solutions, emulsions and syrups. In addition to common simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweetening agents, flavoring agents and preservatives can be incorporated. Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable esters such as ethyl oleate can be used. As the base for suppositories, Witepsol, Macrogol, Tween 61, cocoa butter, laurel oil, glycerol, gelatin, etc. can be used.

[0134] When the pharmaceutical composition is administered for clinical purposes, the effective dose of the compound of Formula 1 or a pharmaceutically acceptable salt thereof may vary depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, diet, administration time, administration route, excretion rate, drug combination, and response sensitivity of the patient, but is generally 0.01 to 20 mg / day per kg body weight in adult patients, preferably 1 to 10 mg / day, and the composition may be administered in divided doses at regular intervals several times a day, preferably 2 to 3 times a day, according to the judgment of a doctor or pharmacist.

[0135] In another aspect, the present invention provides a method for treating a protein kinase-mediated disease such as a RON-mediated disease, the method comprising administering to a subject a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0136] In another aspect, the present invention provides a method for inhibiting the activity of the RON receptor, the method comprising administering to a subject a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0137] Hereinafter, the exemplary compounds of the present invention can be prepared according to the methods described below, but the compounds of the present invention are not limited by the preparation methods.

[0138] Preparation Example 1. 4-(4-Amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine

[0139]

[0140] The compound of Preparation Example 1 was prepared according to Reaction Route 1 below.

[0141] [Reaction Route 1]

[0142]

[0143] Step 1) N-(3-Chloropyridin-2-yl)-1,1-diphenylmethanimine

[0144]

[0145] Dissolve 2,3-dichloropyridine (21 g, 142 mmol) in methyl tert-butyl ether (MTBE), then add Pd(OAc)2 (318 mg, 1.42 mmol), rac-BINAP (1.4 g, 2.13 mmol), Cs2CO3 (0.9 g, 2.84 mmol) and diphenylketimine (26 g, 142 mmol). Stir the reaction mixture at reflux at 70 °C for 12 h. Cool the reaction mixture to room temperature, filter the resulting solid through a celite filter, and concentrate the solvent. Purify the residue by column chromatography to obtain the title compound (20 g, yield: 48%).

[0146] MS m / z: 293 [M+H]

[0147] Step 2) 3-chloro-2-((diphenylmethylene)amino)pyridin-4(1H)-one

[0148]

[0149] Dissolve the compound N-(3-chloropyridin-2-yl)-1,1-diphenylmethanimine (20 g, 68.3 mmol) obtained in Step 1 in 100 ml of THF, then add triisopropyl borate (19.3 g, 102 mmol), and cool the resulting mixture to 0 °C. Slowly add lithium diisopropylamide (11 mL, 88.8 mmol) to the reaction mixture at 0 °C. Stir the reaction mixture at 0 °C for two hours, add 100 ml of water, add sodium percarbonate (16 g, 102 mmol), and then continue to stir the resulting mixture at room temperature for three hours. Slowly add 50 ml of saturated NaHSO3 to the reaction mixture, and extract the resulting mixture three times with EA. Concentrate the organic layer and use it directly in the following Step 3 without purification.

[0150] MS m / z: 309 [M+H]

[0151] Step 3) N-(3-chloro-4-(2,6-difluoro-4-nitrophenoxy)pyridin-2-yl)-1,1-diphenylmethanimine

[0152]

[0153] Dissolve the compound 3-chloro-2-((diphenylmethylene)amino)pyridin-4(1H)-one (60 g, 194 mmol) obtained in Step 2 in a DMF solution, add 1,2,3-trifluoro-5-nitrobenzene (24.9 mL, 214 mmol) and Cs2CO3 (31.7 g, 97 mmol), and stir the resulting mixture at room temperature for 12 h. Add ice to the reaction mixture and filter out the resulting solid. Wash the solid with methanol and dry it to obtain the title compound (53 g, yield: 58%).

[0154] MS m / z: 466 [M+H]

[0155] Step 4) 4-(4-Amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine

[0156]

[0157] Dissolve the compound N-(3-chloro-4-(2,6-difluoro-4-nitrophenoxy)pyridin-2-yl)-1,1-diphenylmethanimine (14 g, 29.6 mmol) obtained in Step 3 in ethanol / water (4:1), add iron powder (5.8 g, 104 mmol) and NH4Cl (5.6 g, 104 mmol), and stir the resulting mixture at 80 °C for 6 h. After cooling to room temperature, filter out the solid and wash the filtrate with water. After concentrating the organic layer, add DCM, filter out the resulting solid and dry it to obtain the title compound (5.6 g, 70%).

[0158] MS m / z: 272 [M+H]

[0159] Preparation Example 2. 4-(4-Amino-2,5-difluorophenoxy)-3-chloropyridin-2-amine

[0160]

[0161] According to Preparation Example 1, use 1,3,5-trifluoro-2-nitrobenzene instead of 1,2,3-trifluoro-5-nitrobenzene, and obtain the title compound in a similar manner to Preparation Example 1 (220 mg, yield: 45%).

[0162] MS m / z: 272 [M+H]

[0163] Preparation Example 3. 4-(4-Amino-3,5-difluorophenoxy)-3-chloropyridin-2-amine

[0164]

[0165] According to Preparation Example 1, 1,3,5-trifluoro-2-nitrobenzene was used instead of 1,2,3-trifluoro-5-nitrobenzene, and the title compound (190 mg, yield: 55%) was obtained in a similar manner to Preparation Example 1.

[0166] MS m / z: 272 [M+H]

[0167] Preparation Example 4. 6-(4-Amino-2,6-difluorophenoxy)-5-chloropyrimidin-4-amine

[0168]

[0169] Hereinafter, the compound of Preparation Example 4 was prepared according to the following Reaction Route 2.

[0170] [Reaction Route 2]

[0171]

[0172] 5,6-Dichloropyrimidin-4-amine (300 mg, 1.83 mmol) was dissolved in 5 ml of DMF, and 4-amino-2,6-difluorophenol (265 mg, 1.83 mmol) and Cs2CO3 (894 mg, 2.74 mmol) were added. The reaction mixture was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was filtered through a diatomaceous earth filter, and the filtrate was concentrated. The residue was purified by column chromatography to obtain the title compound (154 mg, 31%).

[0173] 1 1H NMR (500 MHz, DMSO-d6) δ 7.97 (d, 1H), 7.40 (brs, 2H), 6.31 (m, 2H), 5.68 (brs, 2H); MS m / z: 273 [M+H]

[0174] Preparation Example 5. 4-(4-Amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine

[0175]

[0176] Hereinafter, the compound of Preparation Example 5 was prepared according to the following Reaction Route 3.

[0177] [Reaction Route 3]

[0178]

[0179] Step 1) 4-(2,6-Difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine

[0180]

[0181] 4-Chloro-3-iodopyridin-2-amine (13 g, 51.1 mmol) was dissolved in 500 ml of N-methyl-2-pyrrolidone (NMP), and then 2,6-difluoro-4-nitrophenol (13.5 g, 76.6 mmol) and DIPEA (17.8 mL, 102 mmol) were added. The reaction mixture was stirred at reflux at 170 °C for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted three times with EA. The organic solution was washed with brine and concentrated. The residue was purified by column chromatography to give the title compound (6.4 g, yield: 32%).

[0182] MS m / z: 394 [M+H]

[0183] Step 2) 4-(4-Amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine

[0184]

[0185] The compound 4-(2,6-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (6 g, 15.3 mmol) obtained in Step 1 was dissolved in 300 ml of ethanol, and then SnCl2 (11.6 g, 61.2 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 4 h. After cooling to room temperature, the ethanol was concentrated and diluted with EA. A saturated aqueous NaHCO3 solution was added, and the resulting mixture was extracted three times with EA. The organic layer was concentrated, and then the residue was purified by column chromatography to give the title compound (4.2 g, yield: 76%).

[0186] 1 1H NMR (500 MHz, DMSO-d6) δ 7.74 (d, 1H), 6.37 (d, 2H), 6.17 (brs, 2H), 5.79 (m, 3H); MS m / z: 364 [M+H]

[0187] Preparation Example 6. 1-(3-Fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0188]

[0189] Hereinafter, the compound of Preparation Example 6 was prepared according to Reaction Route 4 below.

[0190] [Reaction Route 4]

[0191]

[0192] Step 1) Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate

[0193]

[0194] Ethyl 4,4,4-trifluoro-3-oxobutyrate (2.0 g, 10.9 mmol) and triethoxymethane (2.0 g, 14.1 mmol) were dissolved in acetic anhydride (3.3 g, 32.6 mmol), and the resulting mixture was stirred at 130 °C for 4 h. The reaction mixture was concentrated to give the title compound (2.0 g, yield: 77%).

[0195] MS m / z: 241 [M+H]

[0196] Step 2) Ethyl 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0197]

[0198] Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (0.5 g, 2.08 mmol) obtained in Step 1 and 4-fluoro-2-hydrazinopyridine (0.24 g, 1.87 mmol) were dissolved in 6 ml of ethanol, and the resulting mixture was stirred at 60 °C for 12 h, and then the reaction mixture was extracted with EA and water. The residue was purified by column chromatography to give the title compound (0.35 g, yield: 55%).

[0199] MS m / z: 304 [M+H]

[0200] Step 3) 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0201]

[0202] Ethyl 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.35 g, 2.01 mmol) obtained in Step 2 was dissolved in 4 ml of ethanol, 2 ml of 6N sodium hydroxide solution was added at room temperature, and the resulting mixture was stirred for 1 h. Ice water was added to the reaction product, and the resulting solid was filtered out to give the title compound (0.26 g, yield: 82%).

[0203] MS m / z: 276 [M+H]

[0204] Example 1. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0205]

[0206] In the following, the compound of Example 1 was prepared according to Reaction Route 5 below.

[0207] [Reaction Route 5]

[0208]

[0209] Step 1) 1-Phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride

[0210]

[0211] To 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (46 mg, 0.18 mmol) was added 2 ml of SOCl2, and the resulting mixture was stirred at 60 °C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to obtain 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride.

[0212] Step 2) N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0213]

[0214] The compound 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine (40 mg, 0.15 mmol) obtained in Preparation Example 1 was dissolved in 3 m THF, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride (49 mg, 0.18 mmol) and TEA (31 μl, 0.22 mmol) obtained in Step 1 were added, and the resulting mixture was stirred at room temperature for 12 h. The reaction solution was diluted with water, extracted three times with EA and concentrated. The residue was purified by preparative HPLC (0.1% formic acid / acetonitrile in water) to obtain the title compound (53 mg, yield: 71%).

[0215] 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.35 (s, 1H), 7.82 (d, 1H), 7.70 (m, 6H), 6.84 (brs, 2H), 6.15 (d, 1H); MS m / z: 511 [M+H]

[0216] Example 2. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0217]

[0218] According to Example 1, 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (14 mg, yield: 28%) was obtained in a similar manner to Example 1.

[0219] 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.47 (d, 1H), 8.52 (s, 1H), 8.26 (d, 1H), 8.12 (m, 1H), 7.78 (d, 1H), 7.67 (m, 2H), 6.50 (s, 2H), 6.06 (d, 1H); MS m / z: 513 [M+H]

[0220] Example 3. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0221]

[0222] According to Example 1, 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (11 mg, yield: 20%) was obtained in a similar manner to Example 1.

[0223] 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.10 (d, 1H), 8.43 (s, 1H), 7.82 (d, 2H), 7.67 (m, 2H), 6.52 (s, 2H), 6.06 (d, 1H); MS m / z: 513 [M+H]

[0224] Example 4. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-5-ethyl-1-(3-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide

[0225]

[0226] According to Example 1, 5-ethyl-1-(3-fluoropyridin-2-yl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (30 mg, yield: 40%) was obtained in a similar manner to Example 1.

[0227] 1 H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.54 (d, 1H), 8.37 (s, 1H), 8.16 (t, 1H), 7.78 (m, 4H), 6.49 (s, 2H), 6.04 (d, 1H), 2.34 (q, 2H), 1.08 (t, 3H); MS m / z: 489 [M+H]

[0228] Example 5. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0229]

[0230] According to Example 1, 4-(4-amino-2,5-difluorophenoxy)-3-chloropyridin-2-amine obtained in Preparation Example 2 was used instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, and the title compound (28 mg, yield: 61%) was obtained in a similar manner to Example 1.

[0231] 1 H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.56 (d, 1H), 8.47 (d, 1H), 8.21 (t, 1H), 7.98 (m, 1H), 7.87 (m, 1H), 7.78 (m, 1H), 7.55 (t, 1H), 6.48 (brs, 2H), 6.08 (brs, 1H); MS m / z: 529 [M+H]

[0232] Example 6. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0233]

[0234] According to Example 5, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (22 mg, yield: 57%) was obtained in a similar manner to Example 5.

[0235] 1 1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.32 (s, 1H), 7.97 (m, 1H), 7.80 (d, 1H), 7.63 (m, 3H), 7.55 (m, 3H), 6.48 (brs, 2H), 6.07 (brs, 1H); MS m / z: 510 [M + H]

[0236] Example 7. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,6-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0237]

[0238] According to Example 1, 4-(4-Amino-3,5-difluorophenoxy)-3-chloropyridin-2-amine obtained in Preparation Example 3 was used instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, and the title compound (14 mg, yield: 42%) was obtained in a similar manner to Example 1.

[0239] 1 1H NMR (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.56 (d, 1H), 8.49 (d, 1H), 8.23 (t, 1H), 7.88 (m, 2H), 7.14 (m, 2H), 6.52 (brs, 2H), 6.26 (d, 1H); MS m / z: 529 [M + H]

[0240] Example 8. N-(4-((6-Amino-5-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0241]

[0242] According to Example 7, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (16 mg, yield: 46%) was obtained in a similar manner to Example 7.

[0243] 11H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.34 (s, 1H), 7.88 (m, 1H), 7.62 (m, 3H), 7.56 (m, 2H), 7.13 (m, 2H), 6.52 (brs, 2H), 6.26 (brs, 1H); MS m / z: 510 [M+H]

[0244] Example 9. N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0245]

[0246] According to Example 1, 6-(4-Amino-2,6-difluorophenoxy)-5-chloropyrimidin-4-amine obtained in Preparation Example 4 was used instead of 4-(4-Amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, and the title compound (35 mg, yield: 62%) was obtained in a similar manner to Example 1.

[0247] 1 1H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.63 - 7.50 (m, 9H); MS m / z: 511 [M+H]

[0248] Example 10. N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0249]

[0250] According to Example 9, 1-(3-Fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (45 mg, yield: 77%) was obtained in a similar manner to Example 9.

[0251] 1 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.56 (d, 1H), 8.49 (m, 1H), 8.23 (t, 1H), 7.99 (d, 1H), 7.88 (m, 1H), 7.62 (m, 4H); MS m / z: 530 [M+H]

[0252] Example 11. N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0253]

[0254] According to Example 9, 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (45 mg, yield: 76%) was obtained in a similar manner to Example 9.

[0255] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.68 (brs, 1H), 8.50 (d, 1H), 8.40 (d, 1H), 7.99 (s, 1H), 7.82 (t, 1H), 7.61 (m, 4H); MS m / z: 547 [M+H]

[0256] Example 12. N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0257]

[0258] According to Example 9, 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (40 mg, yield: 71%) was obtained in a similar manner to Example 9.

[0259] 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.10 (brs, 2H), 8.43 (s, 1H), 7.99 (d, 1H), 7.82 (m, 1H), 7.62 (m, 4H); MS m / z: 513 [M+H]

[0260] Example 13. N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0261]

[0262] According to Example 1, 4-(4-amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine obtained in Preparation Example 5 was used instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, and the title compound (720 mg, yield: 63%) was obtained in a similar manner to Example 1.

[0263] 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.36 (s, 1H), 7.76 (d, 1H), 7.74 (m, 5H), 7.59 (m, 2H), 6.28 (s, 2H), 5.89 (d, 1H); MS m / z: 601 [M+H]

[0264] Example 14. N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0265]

[0266] According to Example 13, 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (705 mg, yield: 55%) was obtained in a similar manner to Example 13.

[0267] 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.36 (s, 1H), 7.76 (d, 1H), 7.74 (m, 5H), 7.59 (m, 2H), 6.28 (s, 2H), 5.89 (d, 1H); MS m / z: 601 [M+H]

[0268] Example 15. N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0269]

[0270] According to Example 13, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (700 mg, yield: 53%) was obtained in a similar manner to Example 13.

[0271] 11H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.23 (t, 1H), 7.88 (m, 1H), 7.76 (d, 1H), 7.68 (m, 2H), 6.29 (s, 2H), 5.89 (d, 1H); MS m / z: 621 [M+H]

[0272] Example 16. N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0273]

[0274] According to Example 13, 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (710 mg, yield: 58%) was obtained in a similar manner to Example 13.

[0275] 1 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.67 (d, 1H), 8.51 (s, 1H), 8.41 (d, 1H), 7.83 (m, 1H), 7.76 (d, 1H), 7.68 (m, 2H), 6.29 (s, 2H), 5.89 (d, 1H); MS m / z: 637 [M+H]

[0276] Example 17. N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0277]

[0278] According to Example 13, 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (690 mg, yield: 59%) was obtained in a similar manner to Example 13.

[0279] 11H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.47 (d, 1H), 8.52 (s, 1H), 8.26 (d, 1H), 8.11 (m, 1H), 7.76 (d, 1H), 7.66 (d, 2H), 6.29 (s, 2H), 5.90 (d, 1H); MS m / z: 604 [M+H]

[0280] Example 18. N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0281]

[0282] According to Example 13, 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (580 mg, yield: 57%) was obtained in a similar manner to Example 13.

[0283] 1 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.10 (d, 1H), 8.44 (s, 1H), 7.81 (t, 1H), 7.76 (d, 1H), 7.66 (d, 2H), 6.29 (s, 2H), 5.90 (d, 1H); MS m / z: 604 [M+H]

[0284] Example 19. N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0285]

[0286] Hereinafter, the compound of Example 19 was prepared according to the following Reaction Route 6.

[0287] [Reaction Route 6]

[0288]

[0289] Step 1) 4-(4-Amino-2,6-difluorophenoxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine

[0290]

[0291] 4-(4-Amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine (1 g, 2.75 mmol) was dissolved in 20 ml of 1,4-d ane, 2-(3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (694 mg, 3.30 mmol), Pd(PPh3)4 (318 mg, 0.27 mmol) and 2 M sodium acetate (4.1 mL, 8.26 mmol) were added, and the resulting mixture was stirred at 95 °C for 12 h. The reaction mixture was cooled to room temperature, filtered through a celite filter, and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (800 mg, yield: 91%).

[0292] MS m / z: 320 [M+H]

[0293] Step 2) 4-(4-Amino-2,6-difluorophenoxy)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine

[0294]

[0295] The compound 4-(4-Amino-2,6-difluorophenoxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine (800 mg, 2.51 mmol) obtained in Step 1 was dissolved in 20 ml of methanol, Pd(OH)2 (2.46 g, 17.54 mmol) was added, and the resulting mixture was stirred under hydrogen for 12 h. The reaction solution was filtered through a celite filter, the filtrate was concentrated, and the residue was purified by column chromatography to give the title compound (400 mg, yield: 50%).

[0296] MS m / z: 322 [M+H]

[0297] Step 3) N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0298]

[0299] According to Example 1, using the compound 4-(4-Amino-2,6-difluorophenoxy)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine obtained in Step 2 instead of 4-(4-Amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, the title compound (18 mg, yield: 34%) was obtained in a similar manner to Example 1.

[0300] 1 1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.36 (d, 1H), 7.67 (m, 6H), 7.57 (m, 2H), 5.99 (brs, 2H), 5.86 (d, 1H), 3.94 (m, 2H), 3.48 (t, 2H), 3.09 (m, 1H), 2.33 (m, 2H), 1.52 (m, 2H); MS m / z: 560 [M+H]

[0301] Example 20. N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0302]

[0303] According to Example 19, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (14 mg, yield: 26%) was obtained in a similar manner to Example 19.

[0304] 1 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.56 (d, 1H), 8.51 (s, 1H), 8.23 (t, 1H), 7.88 (m, 1H), 7.66 (m, 3H), 5.99 (brs, 2H), 5.86 (d, 1H), 3.93 (m, 2H), 3.48 (t, 2H), 3.07 (m, 1H), 2.31 (m, 2H), 1.53 (m, 2H); MS m / z: 579 [M+H]

[0305] Example 21. N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0306]

[0307] According to Example 19, 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (23 mg, yield: 41%) was obtained in a similar manner to Example 19.

[0308] 11H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.68 (d, 1H), 8.52 (s, 1H), 8.42 (m, 1H), 7.84 (m, 1H), 7.67 (m, 3H), 5.99 (brs, 2H), 5.86 (d, 1H), 3.94 (m, 2H), 3.46 (t, 2H), 3.07 (m, 1H), 2.33 (m, 2H), 1.52 (m, 2H); MS m / z: 595 [M+H]

[0309] Example 22. N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0310]

[0311] According to Example 19, 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (13 mg, yield: 25%) was obtained in a similar manner to Example 19.

[0312] 1 1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 9.10 (d, 1H), 8.44 (s, 1H), 7.82 (m, 1H), 7.66 (m, 3H), 5.99 (brs, 2H), 5.85 (d, 1H), 3.94 (m, 2H), 3.45 (t, 2H), 3.09 (m, 1H), 2.31 (m, 2H), 1.50 (m, 2H); MS m / z: 562 [M+H]

[0313] Example 23. N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0314]

[0315] According to Example 19, 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (12 mg, yield: 24%) was obtained in a similar manner to Example 19.

[0316] 11H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.47 (d, 1H), 8.55 (m, 1H), 8.26 (m, 1H), 8.12 (m, 1H), 7.75 (m, 1H), 7.66 (m, 3H), 5.99 (brs, 2H), 5.86 (d, 1H), 3.94 (m, 2H), 3.46 (t, 2H), 3.07 (m, 1H), 2.33 (m, 2H), 1.53 (m, 2H); MS m / z: 562 [M+H]

[0317] Example 24. N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0318]

[0319] According to Example 19, 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (8 mg, yield: 14%) was obtained in a similar manner to Example 19.

[0320] 1 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.64 (m, 1H), 8.40 (m, 1H), 8.22 (m, 2H), 7.85 (d, 1H), 7.66 (m, 4H), 5.99 (brs, 2H), 5.86 (d, 1H), 3.94 (m, 2H), 3.48 (t, 2H), 3.07 (m, 1H), 2.33 (m, 2H), 1.52 (m, 2H); MS m / z: 561 [M+H]

[0321] Example 25. N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0322]

[0323] Hereinafter, the compound of Example 25 was prepared according to the following Reaction Route 7.

[0324] [Reaction Route 7]

[0325]

[0326] Step 1) N-(4-((2-Amino-3-((trimethylsilyl)ethynyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0327]

[0328] Dissolve N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (70 mg, 0.12 mmol) in 1.5 ml of DMF / TEA (1:1) solution, add ethynyltrimethylsilane (32 μl, 0.24 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol) and CuI (4.4 mg, 0.02 mmol), and stir the resulting mixture at room temperature for 4 hours. Dilute the reaction solution with water, extract it three times with EA and concentrate. Purify the residue by column chromatography to obtain the title compound (30 mg, yield: 45%).

[0329] MS m / z: 572 [M+H]

[0330] Step 2) N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0331]

[0332] Dissolve the compound N-(4-((2-Amino-3-((trimethylsilyl)ethynyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (40 mg, 0.07 mmol) obtained in Step 1 in 4 ml of methanol, add K2CO3 (40 mg, 0.28 mmol), and stir the resulting mixture at room temperature for 4 hours. Dilute the reaction solution with water, extract it three times with EA and concentrate. Purify the residue by column chromatography to obtain the title compound (21 mg, yield: 57%).

[0333] 1 1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.35 (s, 1H), 7.77 (d, 1H), 7.66 (m, 5H), 7.57 (m, 2H), 6.39 (s, 2H), 5.96 (d, 1H), 4.64 (s, 1H); MS m / z: 500 [M+H]

[0334] Example 26. N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0335]

[0336] According to Example 25, using N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound (8 mg, yield: 46%) was obtained in a similar manner to Example 25.

[0337] 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.23 (t, 1H), 7.87 (m, 1H), 7.83 (d, 1H), 7.66 (m, 2H), 6.40 (s, 2H), 5.96 (d, 1H), 4.65 (s, 1H); MS m / z: 519 [M+H]

[0338] Example 27. N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0339]

[0340] According to Example 25, using N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound (20 mg, yield: 57%) was obtained in a similar manner to Example 25.

[0341] 11H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.67 (d, 1H), 8.50 (s, 1H), 8.41 (d, 1H), 7.83 (m, 2H), 8.41 (m, 2H), 6.39 (s, 2H), 5.96 (d, 1H), 4.64 (s, 1H); MS m / z: 535 [M+H]

[0342] Example 28. N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0343]

[0344] According to Example 25, using N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound (8 mg, yield: 31%) was obtained in a similar manner to Example 25.

[0345] 1 1H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.10 (d, 1H), 8.36 (s, 1H), 7.82 (m, 2H), 7.66 (m, 2H), 6.39 (s, 2H), 5.97 (d, 1H), 4.64 (s, 1H); MS m / z: 502 [M+H]

[0346] Example 29. N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0347]

[0348] According to Example 25, using N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound (3 mg, yield: 34%) was obtained in a similar manner to Example 25.

[0349] 1 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.63 (s, 1H), 8.39 (s, 1H), 8.16 (t, 1H), 7.84 (m, 2H), 7.67 (m, 3H), 6.39 (s, 2H), 5.96 (d, 1H), 4.64 (s, 1H); MS m / z: 501 [M+H]

[0350] Example 30. N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0351]

[0352] According to Example 25, using N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound (17 mg, yield: 65%) was obtained in a similar manner to Example 25.

[0353] 1 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.47 (d, 1H), 8.52 (s, 1H), 8.24 (d, 1H), 8.11 (t, 1H), 7.83 (d, 1H), 7.66 (m, 2H), 6.39 (s, 2H), 5.97 (d, 1H), 4.64 (s, 1H); MS m / z: 502 [M+H]

[0354] Example 31. N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0355]

[0356] Hereinafter, the compound of Example 31 was prepared according to the following Reaction Route 8.

[0357] [Reaction Route 8]

[0358]

[0359] Dissolve N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (50 mg, 0.08 mmol) in 1 ml of N-methyl-2-pyrrolidone, add Pd(PPh3)4 (20 mg, 0.02 mmol) and ZnCN2 (10 mg, 0.08 mmol), and stir the resulting mixture at 140 °C for 12 h. Dilute the reaction solution with water, extract it three times with EA and concentrate. Purify the residue by column chromatography to obtain the title compound (9 mg, yield: 22%).

[0360] 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.36 (s, 1H), 8.06 (d, 1H), 7.71 (d, 2H), 7.56 (m, 5H), 7.18 (br s, 2H), 6.09 (d, 1H); MS m / z: 501 [M+H]

[0361] Example 32. N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0362]

[0363] According to Example 31, use N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and obtain the title compound (20 mg, yield: 48%) in a similar manner to Example 31.

[0364] 1 H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.63 (d, 1H), 8.39 (s, 1H), 8.17 (t, 1H), 8.06 (d, 1H), 7.85 (d, 1H), 7.66 (m, 3H), 7.18 (br s, 2H), 6.09 (d, 1H); MS m / z: 502 [M+H]

[0365] Example 33. N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0366]

[0367] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in a similar manner to Example 31.

[0368] 1 H NMR (500 MHz, DMSO-d6) 11.13 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.23 (t, 1H), 8.06 (d, 1H), 7.87 (m, 1H), 7.71 (m, 2H), 7.18 (brs, 2H), 6.09 (d, 1H); MS m / z: 520 [M+H]

[0369] Example 34. N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0370]

[0371] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 47%) was obtained in a similar manner to Example 31.

[0372] 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.67 (d, 1H), 8.52 (s, 1H), 8.41 (d, 1H), 8.06 (d, 1H), 7.83 (m, 1H), 7.71 (m, 2H), 7.18 (brs, H), 6.09 (d, 1H); MS m / z: 536 [M+H]

[0373] Example 35. N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0374]

[0375] According to Example 31, N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in a similar manner to Example 31.

[0376] 1 H NMR (500 MHz, DMSO-d6) δ 11.17 (s, 1H), 9.10 (d, 1H), 8.44 (s, 1H), 8.06 (d, 1H), 7.83 (m, 1H), 7.71 (m, 2H), 7.18 (brs, H), 6.09 (d, 1H); MS m / z: 503 [M+H]

[0377] Example 36. N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0378]

[0379] According to Example 31, N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in a similar manner to Example 31.

[0380] 1 H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.47 (d, 1H), 8.53 (s, 1H), 8.26 (d, 1H), 8.12 (m, 1H), 8.07 (d, 1H), 7.72 (m, 2H), 7.19 (brs, H), 6.09 (d, 1H); MS m / z: 503 [M+H]

[0381] Example 37. N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0382]

[0383] According to Example 19, using cyclopropylboronic acid instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, the title compound was obtained in a similar manner to Example 19 (15 mg, yield: 18%).

[0384] 1 H NMR (500 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.31 (s, 1H), 7.59 (m, 8H), 5.87 (brs, H), 5.78 (d, 1H), 1.40 (m, 1H), 0.96 (m, 2H), 0.56 (m, 2H); MS m / z: 516 [M+H]

[0385] Example 38. N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0386]

[0387] According to Example 37, using N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound was obtained in a similar manner to Example 37 (15 mg, yield: 17%).

[0388] 1 H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.23 (t, 1H), 7.88 (m, 1H), 7.66 (m, 3H), 5.91 (brs, 2H), 5.82 (d, 1H), 1.46 (m, 1H), 1.02 (m, 2H), 0.61 (m, 2H); MS m / z: 535 [M+H]

[0389] Example 39. N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0390]

[0391] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (15 mg, yield: 17%) was obtained in a similar manner to Example 37.

[0392] 1 H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.67 (d, 1H), 8.50 (s, 1H), 8.41 (d, 1H), 7.83 (m, 1H), 7.66 (m, 3H), 5.91 (brs, 2H), 5.82 (d, 1H), 1.46 (m, 1H), 1.02 (m, 2H), 0.61 (m, 2H); MS m / z: 551 [M+H]

[0393] Example 40. N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0394]

[0395] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 35%) was obtained in a similar manner to Example 37.

[0396] 11H NMR (500 MHz, DMSO-d6) δ 8 11.00 (s, 1H), 8.63 (d, 1H), 8.39 (s, 1H), 8.16 (m, 1H), 7.85 (d, 1H), 7.66 (m, 4H), 5.91 (brs, 2H), 5.82 (d, 1H), 1.46 (m, 1H), 1.02 (m, 2H), 0.61 (m, 2H); MS m / z: 517 [M+H]

[0397] Example 41. N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0398]

[0399] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (10 mg, yield: 12%) was obtained in a similar manner to Example 37.

[0400] 1 1H NMR (500 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.10 (d, 1H), 8.43 (s, 1H), 7.83 (m, 1H), 7.66 (m, 3H), 5.91 (brs, 2H), 5.82 (d, 1H), 1.46 (m, 1H), 1.02 (m, 2H), 0.61 (m, 2H); MS m / z: 518 [M+H]

[0401] Example 42. N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0402]

[0403] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (15 mg, yield: 17%) was obtained in a similar manner to Example 37.

[0404] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.47 (d, 1H), 8.52 (s, 1H), 8.25 (d, 1H), 8.11 (m, 1H), 7.69 (m, 3H), 5.91 (brs, 2H), 5.82 (d, 1H), 1.46 (m, 1H), 1.02 (m, 2H), 0.61 (m, 2H); MS m / z: 518 [M+H]

[0405] Example 43. N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0406]

[0407] According to Example 19, 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane was used instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and the title compound (13 mg, yield: 25%) was obtained in a similar manner to Example 19.

[0408] 1 H NMR (500 MHz, DMSO-d6) δ 10.95 (s, 1H), 8.36 (d, 1H), 7.65 (m, 5H), 7.56 (m, 2H), 5.85 (brs, 3H), 3.23 (m, 1H), 1.35 (d, 6H); MS m / z: 518 [M+H]

[0409] Example 44. N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0410]

[0411] According to Example 43, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (6 mg, yield: 20%) was obtained in a similar manner to Example 43.

[0412] 1 H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.68 (d, 1H), 8.51 (s, 1H), 8.42 (d, 1H), 7.82 (m, 1H), 7.65 (m, 3H), 5.85 (brs, 3H), 3.22 (m, 1H), 1.34 (d, 6H); MS m / z: 553 [M+H]

[0413] Example 45. N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0414]

[0415] According to Example 43, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (2.3 mg, yield: 12%) was obtained in a similar manner to Example 43.

[0416] 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (brs, 1H), 9.09 (m, 2H), 8.43 (s, 1H), 7.82 (m, 1H), 7.64 (m, 3H), 5.85 (brs, 3H), 3.23 (m, 1H), 1.35 (d, 6H); MS m / z: 520 [M+H]

[0417] Example 46. N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0418]

[0419] According to Example 43, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (9 mg, yield: 22%) was obtained in a similar manner to Example 43.

[0420] 1 H NMR (500 MHz, DMSO-d6) 11.07 (s, 1H), 8.56 (m, 1H), 8.51 (m, 1H), 8.23 (m, 1H), 7.87 (m, 1H), 7.65 (m, 3H), 5.84 (brs, 3H), 3.23 (m, 1H), 1.34 (d, 6H); MS m / z: 537 [M+H]

[0421] Example 47. N-(4-((2-amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0422]

[0423] Hereinafter, the compound of Example 47 was prepared according to the following Reaction Route 9.

[0424] [Reaction Route 9]

[0425]

[0426] Step 1) tert-Butyl (4-(2,6-difluoro-4-nitrophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate

[0427]

[0428] Dissolve tert-butyl (4-(2,6-difluoro-4-nitrophenoxy)-3-formylpyridin-2-yl)carbamate (1 g, 2.53 mmol) in 50 ml of DCM, add morpholine (264 μl, 3.04 mmol) and acetic acid (174 μl, 3.04 mmol), and stir the resulting mixture at room temperature. After 30 minutes, add sodium triacetoxyborohydride (1.07 g, 5.06 mmol), and allow the resulting mixture to react at room temperature for 12 h. Dilute the reaction solution with saturated aqueous NaHCO3, extract three times with DCM and concentrate. Purify the residue by column chromatography to obtain the title compound (0.7 g, yield: 59%).

[0429] MS m / z: 467 [M+H]

[0430] Step 2) tert-butyl (4-(4-amino-2,6-difluorophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate

[0431]

[0432] Dissolve the compound tert-butyl (4-(2,6-difluoro-4-nitrophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate (600 mg, 1.29 mmol) obtained in Step 1 in 15 ml of methanol, add Pd / C (98 mg, 0.92 mmol), and stir the resulting mixture under hydrogen for 12 h. Filter the reaction solution through a celite filter, concentrate the filtrate, and purify the residue by column chromatography to obtain the title compound (500 mg, yield: 57%).

[0433] MS m / z: 437 [M+H]

[0434] Step 3) tert-butyl (4-(2,6-difluoro-4-(1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate

[0435]

[0436] According to Example 1, use tert-butyl (4-(4-amino-2,6-difluorophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate obtained in Step 2 instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, and obtain the title compound (80 mg, yield: 62%) in a similar manner to Example 1.

[0437] MS m / z: 694 [M+H]

[0438] Step 4) N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0439]

[0440] Dissolve tert-butyl (4-(2,6-difluoro-4-(1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate (80 mg, 0.12 mmol) obtained in Step 3 in 3 ml of DCM, add 3 ml of TFA, and stir the resulting mixture at room temperature for 2 hours. Concentrate the reaction mixture, then dilute the residue with EA and wash with saturated aqueous NaHCO3. Wash the organic layer again with brine and concentrate, and purify the residue by column chromatography to obtain the title compound (21 mg, yield: 31%).

[0441] 1 1H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.23 (t, 1H), 7.88 (brs, 1H), 7.77 (d, 1H), 7.65 (m, 2H), 6.21 (s, 2H), 5.90 (d, 1H), 3.59 (brs, 6H), 2.43 (s, 4H); MS m / z: 594 [M+H]

[0442] Example 48. N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0443]

[0444] According to Example 47, use 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and obtain the title compound (20 mg, yield: 29%) in a similar manner to Example 47.

[0445] 11H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.10 (d, 1H), 8.43 (s, 1H), 7.82 (t, 1H), 7.77 (d, 1H), 7.64 (d, 1H), 6.20 (s, 2H), 5.91 (d, 1H), 3.59 (s, 6H), 2.08 (s, 4H); MS m / z: 577 [M+H]

[0446] Example 49. N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0447]

[0448] According to Example 47, 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (50 mg, yield: 58%) was obtained in a similar manner to Example 47.

[0449] 1 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.67 (d, 1H), 8.51 (s, 1H), 8.41 (d, 1H), 7.82 (t, 1H), 7.77 (d, 1H), 7.66 (m, 2H), 6.20 (s, 2H), 5.90 (d, 1H), 3.59 (m, 6H), 2.44 (s, 4H); MS m / z: 610 [M+H]

[0450] Example 50. N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0451]

[0452] According to Example 47, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (30 mg, yield: 44%) was obtained in a similar manner to Example 47.

[0453] 11H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 8.35 (s, 1H), 7.77 (d, 1H), 7.63 (m, 5H), 7.57 (m, 2H), 6.20 (s, 2H), 5.90 (d, 1H), 3.60 (m, 6H), 2.43 (s, 4H); MS m / z: 575 [M+H]

[0454] Example 51. N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0455]

[0456] According to Example 25, using prop-2-yn-1-ol instead of ethynyltrimethylsilane, the title compound (30 mg, yield: 68%) was obtained in a similar manner to Example 25.

[0457] 1 1H NMR (500 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.34 (s, 1H), 7.80 (d, 1H), 7.62 (m, 6H), 6.04 (brs, 2H), 5.93 (d, 1H), 5.31 (t, 1H), 4.36 (d, 2H); MS m / z: 530 [M+H]

[0458] Example 52. N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0459]

[0460] According to Example 51, using N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, the title compound (30 mg, yield: 69%) was obtained in a similar manner to Example 51.

[0461] 11H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.63 (d, 1H), 8.39 (s, 1H), 8.14 (t, 1H), 7.85 (d, 1H), 7.79 (d, 1H), 7.63 (m, 3H), 6.41 (brs, 2H), 5.93 (d, 1H), 5.76 (s, 1H), 5.31 (t, 1H), 4.36 (d, 2H); MS m / z: 531 [M+H]

[0462] Example 53. N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0463]

[0464] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 66%) was obtained in a similar manner to Example 51.

[0465] 1 1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.56 (d, 1H), 8.49 (s, 1H), 8.23 (t, 1H), 7.87 (t, 1H), 7.79 (d, 1H), 7.65 (d, 2H), 6.41 (brs, 2H), 5.93 (d, 1H), 5.31 (t, 1H), 4.36 (d, 2H); MS m / z: 549 [M+H]

[0466] Example 54. N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0467]

[0468] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 67%) was obtained in a similar manner to Example 51.

[0469] 1 H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.67 (d, 1H), 8.50 (s, 1H), 8.41 (d, 1H), 7.83 (m, 2H), 7.65 (d, 2H), 6.41 (brs, 2H), 5.93 (d, 1H), 5.31 (t, 1H), 4.36 (d, 2H); MS m / z: 565 [M+H]

[0470] Example 55. N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0471]

[0472] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 68%) was obtained in a similar manner to Example 51.

[0473] 1 H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.10 (d, 1H), 8.43 (s, 1H), 7.82 (m, 2H), 7.64 (d, 2H), 6.41 (brs, 2H), 5.93 (d, 1H), 5.31 (t, 1H), 4.36 (d, 2H); MS m / z: 532 [M+H]

[0474] Example 56. N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0475]

[0476] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used in place of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 68%) was obtained in a manner similar to Example 51.

[0477] 1 H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.47 (d, 1H), 8.52 (s, 1H), 8.25 (d, 1H), 8.11 (m, 1H), 7.81 (d, 2H), 7.67 (d, 1H), 6.41 (brs, 2H), 5.93 (d, 1H), 5.31 (t, 1H), 4.36 (d, 2H); MS m / z: 532 [M+H]

[0478] Example 57. N-(4-((2-Amino-3-(3-hydroxybut-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0479]

[0480] According to Example 53, 3-butyn-2-ol was used in place of prop-2-yn-1-ol, and the title compound (25 mg, yield: 43%) was obtained in a manner similar to Example 53.

[0481] 1 H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 8.52 (d, 1H), 8.45 (s, 1H), 8.25 (t, 1H), 7.81 (2m, 2H), 7.67 (d, 2H), 6.35 (brs, 2H), 5.93 (d, 1H), 5.45 (d, 1H), 4.75 (m, 1H), 1.35 (d, 3H); MS m / z: 563 [M+H]

[0482] Example 58. N-(4-((2-Amino-3-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0483]

[0484] According to Example 53, 2-methylbut-3-yn-2-ol was used instead of prop-2-yn-1-ol, and the title compound (25 mg, yield: 54%) was obtained in a similar manner to Example 53.

[0485] 1 H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.52 (d, 1H), 8.45 (s, 1H), 8.25 (t, 1H), 7.81 (m, 2H), 7.60 (d, 2H), 6.27 (brs, 2H), 5.94 (d, 1H), 5.52 (s, 1H), 1.39 (s, 6H); MS m / z: 577 [M+H]

[0486] Example 59. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(1-(3-methoxypropyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0487]

[0488] According to Example 1, 1-(1-(3-methoxypropyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (6 mg, yield: 7%) was obtained in a similar manner to Example 1.

[0489] 1 H NMR (500 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.77 (m, 2H), 7.60 (m, 2H), 6.05 (d, 1H), 4.60 (m, 1H), 5.52 (s, 1H), 2.85 (m, 2H), 2.75 (m, 2H), 2.42 (m, 2H), 2.15 (m, 2H), 1.95 (m, 2H); MS m / z: 590 [M+H]

[0490] Example 60. N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(1-(2-ethoxyacetyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0491]

[0492] According to Example 1, 1-(1-(2-Ethoxyacetyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (12 mg, yield: 24%) was obtained in a similar manner to Example 1.

[0493] 1 H NMR (500 MHz, DMSO-d6) 10.93 (s, 1H), 8.10 (s, 1H), 7.61 (d, 2H), 6.50 (s, 2H), 6.02 (d, 1H), 4.67 (m, 1H), 4.54 (m, 2H), 4.06 (m, 2H), 3.62 (m, 2H), 3.45 (m, 3H), 3.24 (m, 2H), 2.96 (m, 1H), 2.85 (m, 1H), 2.79 (m, 1H), 2.05 (m, 6H); MS m / z: 603 [M+H]

[0494] Example 61. N-[4-[(2-Amino-3-chloro-4-pyridinyl)oxy]-3,5-difluoro-phenyl]-1-(3-methoxypropyl)-5-(trifluoromethyl)pyrazole-4-carboxamide

[0495]

[0496] According to Example 1, 1-(3-Methoxypropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (32 mg, yield: 44%) was obtained in a similar manner to Example 1.

[0497] 1 H NMR (500 MHz, DMSO-d6) δ10.88 (s, mH), 8.59 (m, 1H), 7.78 (m, 2H), 7.66 (d, 2H), 6.50 (d, 2H), 6.03 (d, 1H), 4.37 (m, 2H), 3.36 (s, 3H), 3.25 (m, 2H), 2.08 (m, 2H); MS m / z: 506 [M+H]

[0498] Experimental Example 1. Evaluation of RON and MET Inhibitory Activities

[0499] [1-1]Evaluation of RON Inhibitory Activity

[0500] To measure the RON inhibitory activity of the compounds of the examples, the IC of the compounds was measured using time-resolved fluorescence energy transfer (TR-FRET). 50 .

[0501] Specifically, the compounds at a concentration of 1 mM were prepared with 100% DMSO and serially diluted 10 times by 3-fold dilution. 2 μl of the serially diluted compounds were added to a 96-well plate containing 48 μl of 1x kinase reaction buffer (50 mM HEPES (pH 7.4), 0.01% Tween-20, 5 mM DTT, 0.5 mM Na3VO4, 2 mM EGTA, 10 mM MgCl2).

[0502] The RON protein was diluted to a concentration of 49.3 nM with RON storage buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.5 mM EDTA, 0.02% Triton X-100) and then further diluted to 0.4 nM with 1x kinase reaction buffer. As a substrate mixture, a RON-specific substrate mixture (40 μM ULight-labeled Poly GT, 100 nM ATP) was prepared at twice the final reaction concentration.

[0503] Subsequently, a 384-well plate was prepared, 2.5 μl of the diluted compound of the example was added to each experimental group well, and 2.5 μl of 4% DMSO solution was dispensed into the high control well and the low control well.

[0504] Subsequently, 2.5 μl of 0.4 nM RON was dispensed into the high control well and the experimental group wells, and 2.5 μl of 1x kinase reaction buffer was added to the low control well. After centrifuging the mixture at 1000 RPM for 40 seconds at room temperature, the mixture was incubated at room temperature for 20 to 30 minutes. Then, 5 μl of the substrate mixture (2x) was dispensed into all wells. After centrifuging the mixture at 1000 RPM for 40 seconds at room temperature, the mixture was incubated at room temperature for 60 minutes. Then, 5 μl of 30 mM EDTA was added to all wells to terminate the reaction, and the mixture was incubated at room temperature for another 5 minutes. Thereafter, 5 μl of a 4x europium-containing anti-phosphotyrosine antibody (PerkinElmer) was added to all wells and incubated at room temperature for 60 minutes. After incubation, the 384-well plate was read with a Vison plate reader. At this time, the excitation wavelength was 340 nm and the emission wavelengths were 620 nm and 665 nm. The IC of each compound of the example was obtained using the GraphPd Prism7 program. 50 value.

[0505] [1-2] Evaluation of MET inhibitory activity

[0506] In addition, to measure the inhibition of cMET enzyme activity, experiments were conducted by the same method as the experiments for measuring the inhibition of RON enzyme activity.

[0507] Specifically, compounds with a concentration of 1 mM were prepared using 100% DMSO and serially diluted 10 times by 3-fold dilution. 2 μl of the serially diluted compounds were added to a 96-well plate containing 48 μl of 1x kinase reaction buffer (50 mM HEPES (pH 7.4), 0.05% BSA, 0.005% Tween-20, 1 mM DTT, 0.5 mM MnCl2, 20 mM MgCl2).

[0508] The cMET protein was diluted to a concentration of 263 nM in cMET storage buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.05% Brij35, 1 mM DTT, 10% glycerol) and then further diluted to 2 nM with 1x kinase reaction buffer. As a substrate mixture, a MET-specific substrate mixture (5 μM TK peptide, 10 mM ATP) was prepared at a concentration twice the final reaction concentration.

[0509] Subsequently, a 384-well plate was prepared. 2.5 μl of the diluted example compounds were added to each experimental group well, and 2.5 μl of a 4% DMSO solution was dispensed into the high control well and the low control well.

[0510] Subsequently, 2.5 μl of 2 nM cMET was dispensed into the high control well and the experimental group wells, and 2.5 μl of 1x kinase reaction buffer was added to the low control well. After centrifuging the mixture at 1000 RPM for 40 seconds at room temperature, the mixture was incubated at room temperature for 20 to 30 minutes. Then, 5 μl of the substrate mixture (2x) was dispensed into all wells. After centrifuging the mixture at 1000 RPM for 40 seconds at room temperature, the mixture was incubated at room temperature for 60 minutes. Then, 5 μl of 90 mM EDTA was added to all wells to terminate the reaction, and the mixture was incubated at room temperature for another 5 minutes. Thereafter, 5 μl of a 4x phosphotyrosine antibody containing europium (PerkinElmer) was added to all wells and incubated at room temperature for 60 minutes. After incubation, the 384-well plate was read using a Vison plate reader. At this time, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm. The IC 50 value of each example compound was obtained using the GraphPd Prism7 program.

[0511] The evaluation results of the RON or cMET enzyme inhibitory activities of the example compounds are shown in Table 2 below.

[0512] (A: <50 nM, B: 50 to 500 nM, C: 500 to 5000 nM, D: >5000 nM)

[0513] [Table 2]

[0514]

[0515]

Claims

1. A compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In Chemical Formula 1, X is N or C; R1 is any one selected from hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R2 is any one selected from hydrogen and substituted or unsubstituted alkyl; Y1 and Y2 are each independently any one selected from hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; Z is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, nitro, cyano, and -(CH2) n -W, where n is an integer from 0 to 3 and W is -NR a R b -, -OR a or heterocycloalkyl, where R a and R b are each independently hydrogen or substituted or unsubstituted alkyl; A is any one selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted and unsubstituted heteroaryl; and The substituted functional group is a group substituted by at least one selected from halogen, alkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkyl, alkoxyalkyl, -(CO)-(CH2) n -OR c and aryl, where n is an integer from 0 to 3, and R c is hydrogen or alkyl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is hydrogen, halogen, alkyl, or haloalkyl; R2 is hydrogen or alkoxyalkyl; Y1 and Y2 are each independently hydrogen or halogen; Z is selected from any one of hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, nitro, cyano and -(CH2) n -W, wherein W is heterocycloalkyl, and n is an integer from 1 to 3; A is any one selected from substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and The substituted functional group is a group substituted by at least one selected from halogen, alkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkyl, alkoxyalkyl, -(CO)-(CH2) n -OR c and aryl, where n is an integer from 1 to 3, and R c is hydrogen or alkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is halogen, alkyl, or haloalkyl; R2 is hydrogen or alkoxyalkyl; Y1 and Y2 are each halogen; Z is any one selected from halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano and -(CH2) n -W, where n is an integer from 1 to 2, and W is heterocycloalkyl; A is any one selected from substituted alkyl, substituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and The substituted functional group is a group substituted by at least one selected from halogen, alkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkyl, alkoxyalkyl, and -(CO)-(CH2) n -OR c , where n is an integer from 1 to 2, and R c is hydrogen or alkyl.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is alkyl or haloalkyl; R2 is hydrogen or alkoxyalkyl; Y1 and Y2 are each fluorine; Z is selected from any of halogen, alkyl, alkynyl, hydroxyalkynyl, hydroxyalkylalkynyl, cycloalkyl, tetrahydropyran, cyano, and -(CH2) n -W, where W is morpholine and n is 1; and A is selected from any of alkoxyalkyl, aryl, pyridine, halopyridine, pyrimidine, pyridazine, piperidine, alkoxyalkylpiperidine and a piperidine group substituted by -(CO)-(CH2) n -OR c and wherein n is 1, R c is alkyl.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from: N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-5-ethyl-1-(3-fluoropyridin-2-yl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,6-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-2,6-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((6-Amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxyprop-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxybut-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(1-(3-methoxypropyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; N-(4-((2-Amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(1-(2-ethoxyacetyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide; and N-[4-[(2-Amino-3-chloro-4-pyridinyl)oxy]-3,5-difluoro-phenyl]-1-(3-methoxypropyl)-5-(trifluoromethyl)pyrazole-4-carboxamide.

6. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

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