Novel compounds as RON inhibitors

Abstract

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

Description

[Technical Field]

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2022-0182613 filed on December 23, 2022, and all contents disclosed in the documents of that Korean patent application are incorporated herein by reference.

[0002] The present invention relates to novel compounds as protein kinase inhibitors. Specifically, the present invention relates to novel compounds as RON inhibitors. [Background technology]

[0003] At least 400 protein kinases are known that catalyze the transfer of a phosphate group from adenosine triphosphate (ATP) to a protein substrate. Because the specific amino acid to which the phosphate group is transferred in the target protein is tyrosine, serine, or threonine, protein kinase enzymes are usually called protein tyrosine kinases (PTKs) or serine / threonine kinases (STKs).

[0004] Protein kinases comprise a large, structurally related group of kinases necessary for regulating a wide variety of signaling pathways within cells. These signaling pathways include many other signaling pathways that rely on the transfer of phosphate groups to target proteins. These phosphorylation processes act as molecular on / off switches that can modulate the biological function of target proteins or protein complexes. The preferred function of protein kinases in signaling pathways is to activate or deactivate metabolic enzymes, regulatory proteins, receptors, cytoskeletal proteins, ion channels and pumps, transcription factors, and more. Inappropriate regulatory signaling due to defective regulation of protein phosphorylation has been linked to many diseases, including inflammation, cancer, allergies / asthma, immune system disorders, central nervous system disorders, and angiogenesis.

[0005] Most kinases contain a similar 250-300 amino acid catalytic site. Kinases can be classified by the substrates they phosphorylate, and general corresponding sequence motifs have been identified for each of these kinase families.

[0006] On the other hand, RON (receptor originated from nantes), a tyrosine protein kinase receptor also known as MST1R (macrophage stimulating 1 receptor), has been reported to promote cancer cell invasion and metastasis. Overexpression of RON is also known to occur in various tumor types.

[0007] Activation of tyrosine protein kinases such as RON in tumor cells increases tumor cell proliferation, invasion, and metastasis, and also increases tumor cell resistance to cell death and cytotoxic therapy. Therefore, selective small molecule kinase modulators that target tyrosine protein kinases such as RON are expected to have therapeutic potential for the treatment of cancers in which activation of RON receptors plays an important role in the development and progression of primary tumors and secondary metastases. Therefore, research is ongoing into various inhibitors that selectively inhibit the kinase activity of RON, a tyrosine protein. Summary of the Invention [Problem to be solved by the invention]

[0008] In one aspect, an objective of the present invention is to provide novel compounds having protein kinase inhibitory activity.

[0009] In another aspect, an object of the present invention is to provide a compound useful for the prevention or treatment of RON-mediated diseases.

[0010] In still another aspect, the present invention aims to provide a compound useful for the prevention or treatment of cancer or an infectious disease.

[0011] In still another aspect, an objective of the present invention is to provide a compound useful as a RON inhibitor. [Means for solving the problem]

[0012] In order to achieve the above objectives, In one aspect, the present invention provides a compound of Formula 1 below, or a pharmaceutically acceptable salt thereof:

[0013] [ka]

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0015] In yet another aspect, the present invention provides a pharmaceutical composition for preventing or treating a RON-mediated disease, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0016] In yet another aspect, the present invention provides a pharmaceutical composition for preventing or treating cancer or an infectious disease, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. [Effects of the Invention]

[0017] According to the present invention, a novel compound or a pharmaceutically acceptable salt thereof can be provided that can be useful in the treatment of various immune-mediated diseases, including anti-cancer drugs, by inhibiting the protein kinase activity of protein kinases, particularly the RON receptor, but the effects of the present invention are not limited thereto. DETAILED DESCRIPTION OF THE INVENTION

[0018] First, the terms used in the present invention will be defined.

[0019] As used herein, the term "substituted" means that a hydrogen atom bonded to a carbon atom in a structure is changed to another substituent, and the position of substitution is not limited as long as it is a position at which a hydrogen atom is substituted, i.e., a position at which 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.

[0020] Unless otherwise defined herein, a "substituent" may be deuterium, halogen, a hydroxy group, an alkyl group, a cycloalkyl group, an alkoxy group, an aryloxy group, an alkylthioxy group, an arylthioxy group, an alkylsulfoxy group, an arylsulfoxy group, a haloalkyl group, an alkoxyalkyl group, a hydroxyalkyl group, an alkenyl group, an amine group, a nitrile group, a nitro group, an imido group, an amide group, an oxo group, a carbonyl group, a carboxyl group, a carbamoyl group, an ester group, an aryl group, a heteroaryl group, -(CO)-(CH)-OR (wherein n is an integer of 0 to 3, and R is hydrogen or an alkyl), or the like.

[0021] In this specification, the term "alkyl group" refers to an aliphatic hydrocarbon group containing no double or triple bond, and may have 1 to 20, 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, or 1 to 10 carbon atoms, for example, 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms, and may be linear or branched. Specific examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an n-propyl group, an isopropyl group, a butyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a 1-methylbutyl group, a 1-ethylbutyl group, a pentyl group, an n-pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an n-hexyl group, a 1-methylpentyl group, a 2-methylpentyl group, a 4-methyl-2-pentyl group, a 3,3-dimethyl- Examples of alkyl groups include, but are not limited to, butyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, 1-ethylpropyl, 1,1-dimethylpropyl, isohexyl, 4-methylhexyl, 5-methylhexyl, and benzyl.

[0022] In this specification, the term "cycloalkyl group" refers to a cyclic aliphatic hydrocarbon group containing no double or triple bonds, and may have 3 to 30, 3 to 28, 3 to 26, 3 to 24, 3 to 22, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, or 3 to 10 carbon atoms, for example, 3 to 8 carbon atoms, particularly 3 to 6 carbon atoms, and may be monocyclic or polycyclic. The polycyclic group refers to a group in which a cycloalkyl group is directly linked to or condensed with another cyclic group, and in this case, the other cyclic group may be a cycloalkyl group or may be another type of cyclic group, for example, a heterocycloalkyl group, an aryl group, or a heteroaryl group. Specific examples of the cycloalkyl group include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 3-methylcyclopentyl group, a 2,3-dimethylcyclopentyl group, a cyclohexyl group, a 3-methylcyclohexyl group, a 4-methylcyclohexyl group, a 2,3-dimethylcyclohexyl group, a 3,4,5-trimethylcyclohexyl group, a 4-tert-butylcyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a cyclodecyl group, a cycloundecyl group, a cyclododecyl group, a bicyclo[2.2.1]heptyl group, a bicyclo[2.2.2]octyl group, a bicyclo[3.2.2]nonyl group, a bicyclo[4.4.0]decyl group, and a bicyclo[4.1.0]heptyl group.

[0023] In this specification, the term "heterocycloalkyl group" refers to a cyclic aliphatic hydrocarbon group containing O, S, Se, N, or Si as a heteroatom, and may have 2 to 30, 2 to 28, 2 to 26, 2 to 24, 2 to 22, 2 to 20, 2 to 18, 2 to 16, 2 to 14, 2 to 12, 2 to 10, 2 to 8, or 2 to 6 carbon atoms, for example, 2 to 5 carbon atoms, and may be monocyclic or polycyclic. The polycyclic group refers to a group in which a heterocycloalkyl group is directly linked to or fused with another cyclic group, and in this case, the other cyclic group may be a cycloalkyl group or may be another type of cyclic group, for example, a heterocycloalkyl group, an aryl group, or a heteroaryl group. Specific examples of the heterocycloalkyl group include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, and dithiane.

[0024] In this specification, the term "aryl group" refers to an aromatic hydrocarbon group having 6 to 30, 6 to 28, 6 to 26, 6 to 24, 6 to 22, 6 to 20, 6 to 18, 6 to 16, or 6 to 14 carbon atoms, for example, 6 to 12 carbon atoms, and may be monocyclic or polycyclic. The polycyclic group refers to a group in which an aryl group is directly linked to or condensed with another ring group, and the other ring group may be an aryl group, but may also be another type of ring group, such as a cycloalkyl group, a heterocycloalkyl group, or a heteroaryl group. The aryl group also includes a spiro group. Specific examples of the aryl group include, but are not limited to, a phenyl group, a biphenyl group, a triphenyl group, a naphthyl group, an anthryl group, a chrysenyl group, a phenanthrenyl group, a perylenyl group, a fluoranthenyl group, a triphenylenyl group, a phenalenyl group, a pyrenyl group, a tetracenyl group, a pentacenyl group, a fluorenyl group, an indenyl group, an acenaphthylenyl group, a benzofluorenyl group, a spirobifluorenyl group, a 2,3-dihydro-1H-indenyl group, and fused ring groups thereof.

[0025] As used herein, the term "heteroaryl group" refers to an aromatic hydrocarbon group containing O, S, Se, N, or Si as a heteroatom, and may have 3 to 30, 3 to 28, 3 to 26, 3 to 24, 3 to 22, 3 to 20, 3 to 18, 3 to 16, 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or, for example, 3 to 5 carbon atoms. The heteroaryl group may be monocyclic or polycyclic. The polycyclic group refers to a group in which the heteroaryl group is directly linked to or fused with another ring group, and the other ring group may be a heteroaryl group or another type of ring group, such as a cycloalkyl group, a heterocycloalkyl group, or an aryl group. Specific examples of the heteroaryl group include a pyridyl group, a pyrrolyl group, a pyrimidyl group, a pyridazinyl group, a furanyl group, a thiophene group, an imidazolyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a triazolyl group, a furazanyl group, an oxadiazolyl group, a thiadiazolyl group, a dithiazolyl group, a tetrazolyl group, a pyranyl group, a thiopyranyl group, a diazinyl group, an oxazinyl group, a thiazinyl group, a dioxinyl group, a triazinyl group, a tetrazinyl group, a quinolyl group, an isoquinolyl group, a quinazolinyl group, an isoquinazolinyl group, a quinozolyl group, a naphthyridyl group, an acridinyl group, a phenanthridinyl group, an imidazopyridinyl group, a diazanaphthalenyl group, a triazaindene group, an indolyl group, an indolizinyl group, a benzothiazolyl group, a benzoxazolyl group, a benzophenone ... imidazolyl group, benzothiophene group, benzofuran group, dibenzothiophene group, dibenzofuran group, carbazolyl group, benzocarbazolyl group, dibenzocarbazolyl group, phenazinyl group, dibenzosilole group, spirobi(dibenzosilole), dihydrophenazinyl group, phenoxazinyl group, phenanthridyl group, imidazopyridinyl group, thienyl group, indolo[2,3-a]carbazolyl group, Indolo[2,3-b]carbazolyl group, indolinyl group, 10,11-dihydro-dibenzo[b,f]azepine group, 9,10-dihydroacridinyl group, phenanthrazinyl group, phenothiathiazinyl group, phthalazinyl group, naphthyridinyl group, phenanthrolinyl group, benzo[c][1,2,5]thiadiazolyl group, 5,10-dihydrodibenzo[b,e][1,4]azasilinyl, pyrazolo[1,5-c]quinazolinyl group, pyrido[1,2-b]indazolyl group, pyrido[1,2-a]imidazo[1,2-e]indolinyl group, 5,11-dihydroindeno[1,2-b]carbazolyl group, etc., and according to one embodiment, the heteroaryl group may be any one selected from the group consisting of a pyridyl group, a pyrimidyl group, a pyrazolyl group, a thiophene group, a furanyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a triazinyl group, a triazolyl group, an acridinyl group, a pyridazinyl group, a pyrazinyl group, a quinolyl group, a quinazolyl group, a quinoxalinyl group, an isoquinolyl group, an indolyl group, an indolinyl group, a carbazolyl group, a benzoxazolyl group, a benzimidazolyl group, and a benzothiazolyl group, but is not limited thereto.

[0026] As used herein, the term "alkoxy group" refers to a group having the chemical structure -OR, where R may be a substituted or unsubstituted alkyl group, as defined above. Specific examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propyloxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, n-hexyloxy, 3,3-dimethylbutyloxy, 2-ethylbutyloxy, n-octyloxy, n-nonyloxy, n-decyloxy, benzyloxy, and p-methylbenzyloxy.

[0027] As used herein, an "amine group" has the chemical structure -NRbRc, where Rb and Rc can 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, or a substituted or unsubstituted alkoxy group, where the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, and alkoxy group are as defined above.

[0028] In the present invention, "pharmaceutically acceptable salts" include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. The identity of these salts is not critical, but they must be pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts of compounds of Formula 1 can be prepared from inorganic or organic acids. Examples of such 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, mesylic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethoxybenzoic acid, ... The following acidic acids are known: benzoic acid, benzoic acid, benzoyl sulfonic acid, benzoic acid, benzoyl benzoate ...Suitable pharmaceutically acceptable base addition salts of compounds of Formula 1 include salts prepared from metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or from organic bases containing substituted amines, including primary, secondary, or tertiary amines and cyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, 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 a suitable acid or base with a compound of Formula 1. When a basic group and an acidic group are present in the same molecule, compounds of Formula 1 can also form internal salts.

[0029] In the present invention, the "solvate" may include hydrates; and 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, t-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene, and mixtures thereof.

[0030] As used herein, the term "prevention" means reducing the risk of contracting a disease or disorder, and refers to any action that inhibits or delays the onset of a disease by preventing the development of one or more clinical signs of the disease in a subject who has been exposed to or is susceptible to the disease but who has not yet contracted or shown symptoms of the disease.

[0031] As used herein, the term "treatment" means alleviating a disease or disorder, and refers to any action that prevents or reduces the progression of a disease or one or more of its clinical symptoms, or that improves or favorably alters the symptoms of a disease.

[0032] As used herein, the term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. The pharmaceutical composition can be formulated with a pharmaceutically acceptable carrier to be prepared in a unit dose form or in a multi-dose container. In this case, the dosage form may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granules, tablets, capsules, or gel (e.g., hydrogel), and may further contain a dispersant or stabilizer.

[0033] As used herein, the term "therapeutically effective amount" refers to the amount of each agent that achieves the goal of improving the severity and frequency of disease during treatment and avoids the harmful side effects associated with other conventional therapies. For example, an effective tumor treatment agent is one that prolongs patient survival, inhibits the growth of rapidly proliferating cells associated with tumors, or is effective in causing tumor regression.

[0034] The present invention will be described in detail below.

[0035] 1. Novel compounds as RON inhibitors One aspect of the present invention provides a compound having the chemical structure of Formula 1 below, or a pharmaceutically acceptable salt, isomer, solvate, or prodrug thereof:

[0036] [ka]

[0037] In the above formula 1, X may be N or C.

[0038] In the above Chemical Formula 1, R1 may be any one selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, particularly halogen, alkyl, or haloalkyl, particularly alkyl or haloalkyl, for example, trifluoromethyl or ethyl.

[0039] In the above formula 1, R2 may be any one selected from the group consisting of hydrogen and substituted or unsubstituted alkyl, and in particular may be hydrogen or alkoxyalkyl, for example, hydrogen or methoxypropyl.

[0040] In Formula 1, Y1 and Y2 may each independently represent any one selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl, and may each independently represent hydrogen or halogen, and may each independently represent halogen, such as fluoro. Y1 and Y2 may be linked to the 3- and 5-position carbons, the 2- and 5-position carbons, or the 2- and 6-position carbons of the benzene ring.

[0041] In the above Chemical Formula 1, Z is 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 -(CH) n -W may be any one selected from the group consisting 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 -(CH) n-W may be any one selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, and -(CH) n -W may be any one selected from the group consisting of halogen, alkyl, alkynyl, hydroxyalkynyl, hydroxyalkylalkynyl, cycloalkyl, tetrahydropyran, cyano, and -(CH) n -W.

[0042] Here, n may be an integer of 0 to 3, particularly n may be an integer of 1 to 3, particularly n may be an integer of 1 to 2, particularly n may be 1.

[0043] Also, W is -NR a R b , -OR a or heterocycloalkyl, in particular heterocycloalkyl, in particular morpholine; R a and R b may each independently be hydrogen or substituted or unsubstituted alkyl, and in particular, R a and R b can be alkyl.

[0044] In the above Chemical Formula 1, A may be any one selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted and unsubstituted heteroaryl, particularly any one selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, particularly any one selected from the group consisting of substituted alkyl, substituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, such as alkoxyalkyl, aryl, pyridine, halopyridine, pyrimidine, pyridazine, piperidine, alkoxyalkylpiperidine, and -(CO)-(CH) n -OR c wherein n is 1 and R c can be alkyl.

[0045] In addition, the compound of Chemical Formula 1 is 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-pyridyl)oxy]-3,5-difluoro-phenyl]-1-(3-methoxypropyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, the structure of which is shown in Table 1 below.

[0046] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11]

[0047] 2. Uses of the new compound The novel compounds of the present invention have activity in inhibiting tyrosine protein kinases such as RON, which increase tumor cell proliferation, invasion and metastasis, and increase tumor cell resistance to cell killing and cytotoxic therapy.

[0048] Therefore, the novel compound of the present invention can be used as an active ingredient in a pharmaceutical composition. Therefore, another aspect of the present invention provides a pharmaceutical composition containing the compound as an active ingredient.

[0049] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.

[0050] The pharmaceutical compositions may be useful for the prevention or treatment of protein kinase-mediated diseases, although the use of the present invention is not limited to these diseases alone.

[0051] The pharmaceutical composition may be useful for the prevention or treatment of RON-mediated diseases, but the application of the present invention is not limited to only these diseases.

[0052] The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0053] For the treatment of the above-mentioned diseases, the pharmaceutical composition can be administered to a subject in need of prevention or treatment of the disease.

[0054] The pharmaceutical composition of the present invention can be administered orally or parenterally during clinical administration and can be used in the form of a common pharmaceutical formulation. That is, the pharmaceutical composition of the present invention can be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using commonly used diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid formulations are prepared by mixing herbal extracts or fermented herbal products with at least one or more excipients, such as starch, calcium carbonate, sucrose or lactose, and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral administration include suspensions, liquid solutions, emulsions, syrups, and the like. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients, such as wetting agents, sweeteners, flavoring agents, and preservatives, may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include witepsol, macrogol, Tween 61, cocoa butter, laurin butter, glycerol, and gelatin.

[0055] When the pharmaceutical composition is administered for clinical purposes, the effective dosage of the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, diet, administration time, administration route, excretion rate, drug mixture, and reaction sensitivity of the patient. In general, the effective dosage of the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof is 0.01 to 20 mg / kg / day, preferably 1 to 10 mg / kg / day, for an adult patient. The effective dosage may be administered several times a day at regular intervals, preferably 2 to 3 times a day, according to the judgment of a physician or pharmacist.

[0056] In yet another aspect, the present invention provides a method for treating a protein kinase-mediated disease, particularly a RON-mediated disease, comprising administering to a subject a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0057] In yet another aspect, the present invention provides a method for inhibiting the activity of RON receptor, comprising administering to a subject a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0058] The compounds of the examples of the present invention can be prepared by the following methods, but the compounds of the present invention are not limited by the preparation methods.

[0059] Preparation Example 1: 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine [ka] The compound of Preparation Example 1 was prepared according to the following Reaction Scheme 1.

[0060] [ka] [Reaction Scheme 1] Step 1) N-(3-chloropyridin-2-yl)-1,1-diphenylmethanimine [ka] 2,3-Dichloropyridine (21 g, 142 mmol) was dissolved in methyl tert-butyl ether (MTBE) and then Pd(OAc) (318 mg, 1.42 mmol), rac-BINAP (1.4 g, 2.13 mmol), CsCO (0.9 g, 2.84 mmol), and benzophenone imine (26 g, 142 mmol) were added. The reaction mixture was refluxed at 70 °C for 12 hours. The reaction mixture was cooled to room temperature, and the resulting solid was filtered through Celite. The solvent was concentrated. The residue was purified by column chromatography to give the title compound (20 g, yield: 48%). MS m / z: 293[M+H]

[0061] Step 2) 3-chloro-2-((diphenylmethylene)amino)pyridin-4(1H)-one [ka] N-(3-chloropyridin-2-yl)-1,1-diphenylmethanimine (20 g, 68.3 mmol), the compound obtained in Step 1, was dissolved in 100 mL of THF, and triisopropyl borate (19.3 g, 102 mmol) was added. The mixture was then cooled to 0°C. Lithium diisopropylamide (11 mL, 88.8 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 2 hours, and then 100 mL of water was added. Sodium percarbonate (16 g, 102 mmol) was added, followed by further stirring at room temperature for 3 hours. 50 mL of saturated NaHSO3 was slowly added to the reaction mixture, and the mixture was extracted three times with EA. The organic layer was concentrated and used in Step 3 below without further purification. MS m / z: 309[M+H]

[0062] Step 3) N-(3-chloro-4-(2,6-difluoro-4-nitrophenoxy)pyridin-2-yl)-1,1-diphenylmethanimine [ka] 3-Chloro-2-((diphenylmethylene)amino)pyridin-4(1H)-one (60 g, 194 mmol), the compound obtained in Step 2, was dissolved in DMF, and then 1,2,3-trifluoro-5-nitrobenzene (24.9 ml, 214 mmol) and Cs2CO3 (31.7 g, 97 mmol) were added and stirred at room temperature for 12 hours. Ice was added to the reaction mixture, and the resulting solid was filtered. The solid was washed with methanol and dried to obtain the title compound (53 g, yield: 58%). MS m / z: 466[M+H]

[0063] Step 4) 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine [ka] N-(3-chloro-4-(2,6-difluoro-4-nitrophenoxy)pyridin-2-yl)-1,1-diphenylmethanimine (14 g, 29.6 mmol), the compound obtained in Step 3, was dissolved in ethanol / water (4:1), and then iron powder (5.8 g, 104 mmol) and NHCl (5.6 g, 104 mmol) were added and stirred at 80°C for 6 hours. After cooling to room temperature, the solid was filtered and the filtrate was washed with water. The organic layer was concentrated, and DCM was added. The resulting solid was filtered and dried to obtain the title compound (5.6 g, 70%). MS m / z: 272[M+H]

[0064] Preparation Example 2: 4-(4-amino-2,5-difluorophenoxy)-3-chloropyridin-2-amine [ka] The title compound (220 mg, 45%) was obtained in the same manner as in Production Example 1, except that 1,2,3-trifluoro-5-nitrobenzene was used instead of 1,2,3-trifluoro-5-nitrobenzene. MS m / z: 272[M+H]

[0065] Preparation Example 3. 4-(4-amino-3,5-difluorophenoxy)-3-chloropyridin-2-amine [ka] The title compound (190 mg, 55%) was obtained in the same manner as in Production Example 1, except that 1,3,5-trifluoro-2-nitrobenzene was used instead of 1,2,3-trifluoro-5-nitrobenzene. MS m / z: 272[M+H]

[0066] Preparation Example 4. 6-(4-amino-2,6-difluorophenoxy)-5-chloropyrimidin-4-amine [ka] The compound of the following Preparation Example 4 was prepared according to the following Reaction Scheme 2.

[0067] Reaction Scheme 2. [ka] 5,6-Dichloropyrimidin-4-amine (300 mg, 1.83 mmol) was dissolved in 5 mL of DMF, followed by the addition of 4-amino-2,6-difluorophenol (265 mg, 1.83 mmol) and CsCO (894 mg, 2.74 mmol). The reaction mixture was stirred at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (154 mg, 31%). 1 H 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]

[0068] Preparation Example 5: 4-(4-amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine [ka] The compound of the following Preparation Example 5 was prepared according to the following Reaction Scheme 3.

[0069] [Reaction Scheme 3] [ka] Step 1) 4-(2,6-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine [ka] 4-Chloro-3-iodopyridin-2-amine (13 g, 51.1 mmol) was dissolved in 500 mL of N-methyl-2-pyrrolidone (NMP), followed by the addition of 2,6-difluoro-4-nitrophenol (13.5 g, 76.6 mmol) and DIPEA (17.8 mL, 102 mmol). The reaction mixture was refluxed at 170 °C for 12 hours. 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%). MS m / z: 394[M+H]

[0070] Step 2) 4-(4-amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine [ka] The compound obtained in Step 1, 4-(2,6-difluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (6 g, 15.3 mmol), was dissolved in 300 mL of ethanol and SnCl2 (11.6 g, 61.2 mmol) was added. The reaction mixture was heated to 80°C and stirred for 4 hours. After cooling to room temperature, the ethanol was concentrated and diluted with EA. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted three times with EA. The organic layer was concentrated, and the residue was purified by column chromatography to obtain the title compound (4.2 g, yield: 76%). 1 H 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]

[0071] Preparation 6. 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ka] The compound of the following Preparation Example 6 was prepared according to the following Reaction Scheme 4.

[0072] [Reaction Scheme 4] [ka] Step 1) Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate [ka] Ethyl 4,4,4-trifluoro-3-oxobutanoate (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 stirred at 130° C. for 4 hours. The reaction mixture was concentrated to give the title compound (2.0 g, yield: 77%). MS m / z: 241[M+H].

[0073] Step 2) Ethyl 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [ka] Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.5 g, 2.08 mmol), the compound obtained in Step 1, and 4-fluoro-2-hydrazineylpyridine (0.24 g, 1.87 mmol) were dissolved in 6 mL of ethanol and stirred at 60°C for 12 hours. The reaction mixture was then extracted with EA and water. The residue was purified by column chromatography to obtain the title compound (0.35 g, yield: 55%). MS m / z: 304[M+H].

[0074] Step 3) 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ka] Ethyl 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.35 g, 2.01 mmol), the compound obtained in step 2, was dissolved in 4 ml of ethanol, and then 2 ml of 6N sodium hydroxide solution was added at room temperature and stirred for 1 hour. Ice water was added to the reaction mixture, and the resulting solid was filtered to obtain the title compound (0.26 g, yield: 82%). MS m / z: 276[M+H].

[0075] Example 1. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The compound of Example 1 below was prepared according to the following Reaction Scheme 5.

[0076] [Reaction Scheme 5] [ka] Step 1) 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride [ka] 1-Phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (46 mg, 0.18 mmol) was added to 2 mL of SOCl2 and stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and concentrated to give 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride.

[0077] Step 2) N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine (40 mg, 0.15 mmol), the compound obtained in Preparation Example 1, was dissolved in 3 mL of THF, followed by the addition of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride (49 mg, 0.18 mmol) obtained in Step 1 and TEA (31 μL, 0.22 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water, extracted three times with EA, and concentrated. The residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to give the title compound (53 mg, yield: 71%). 1H 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]

[0078] Example 2. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 1, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (14 mg, yield: 28%) was obtained in the same manner as in Example 1. 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]

[0079] Example 3. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 1, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (11 mg, yield: 20%) was obtained in the same manner as in Example 1. 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]

[0080] 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 [ka] According to Example 1, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 5-ethyl-1-(3-fluoropyridin-2-yl)-1H-pyrazole-4-carbonyl chloride, and the title compound (30 mg, yield: 40%) was obtained in the same manner as in Example 1. 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]

[0081] 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 [ka] According to Example 1, instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, 4-(4-amino-2,5-difluorophenoxy)-3-chloropyridin-2-amine obtained in Preparation Example 2 was used, and the title compound (28 mg, yield: 61%) was obtained in the same manner as in Example 1. 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]

[0082] Example 6. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 5, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (22 mg, yield: 57%) was obtained in the same manner as in Example 5. 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]

[0083] 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 [ka] According to Example 1, using 4-(4-amino-3,5-difluorophenoxy)-3-chloropyridin-2-amine obtained in Production Example 3 instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, in the same manner as in Example 1, the title compound (14 mg, yield: 42%) was obtained. 1 H 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]

[0084] Example 8. N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 7, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (16 mg, yield: 46%) was obtained in the same manner as in Example 7. 1 H 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]

[0085] Example 9. N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 1, the title compound (35 mg, yield: 62%) was obtained in the same manner as in Example 1, except that 6-(4-amino-2,6-difluorophenoxy)-5-chloropyrimidin-4-amine, the compound obtained in Production Example 4, was used instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine. 1 H NMR (500 MHz, DMSO-d6) δ 810.96 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.63 - 7.50 (m, 9H); MS m / z : 511[M+H]

[0086] 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 [ka] According to Example 9, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (45 mg, yield: 77%) was obtained in the same manner as in Example 9. 1 H 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]

[0087] 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 [ka] 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 the same manner as in Example 9. 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]

[0088] Example 12. N-(4-((6-amino-5-chloropyrimidin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 9, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (40 mg, yield: 71%) was obtained in the same manner as in Example 9. 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]

[0089] Example 13. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 1, instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, 4-(4-amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine, the compound obtained in Production Example 5, was used in the same manner as in Example 1 to obtain the title compound (720 mg, yield: 63%). 1H 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]

[0090] Example 14. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 13, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (705 mg, yield: 55%) was obtained in the same manner as in Example 13. 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]

[0091] 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 [ka] According to Example 13, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (700 mg, yield: 53%) was obtained in the same manner as in Example 13. 1 H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.56 (d, 1H), 8.50 (s, 1H), 8.23 ​​(t, 1H), 7.88 (m, 1H), 7.76 (d, 1H), 7.68 (m, 2H), 6.29 (s, 2H), 5.89 (d, 1H); MS m / z : 621[M+H]

[0092] 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 [ka] According to Example 13, 11-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (710 mg, yield: 58%) was obtained in the same manner as in Example 16. 1 H 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]

[0093] Example 17. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 13, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (690 mg, yield: 59%) was obtained in the same manner as in Example 13. 1 H 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]

[0094] Example 18. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 13, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (580 mg, yield: 57%) was obtained in the same manner as in Example 13. 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]

[0095] 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 [ka] The compound of Example 19 below was prepared according to the following Reaction Scheme 6. [ka] Step 1) 4-(4-amino-2,6-difluorophenoxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine [ka] 4-(4-Amino-2,6-difluorophenoxy)-3-iodopyridin-2-amine (1 g, 2.75 mmol) was dissolved in 20 mL of 1,4-dioxane, and 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. The mixture was stirred at 95 °C for 12 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated. The residue was purified by column chromatography to give the title compound (800 mg, 91% yield). MS m / z: 320[M+H]

[0096] Step 2) 4-(4-amino-2,6-difluorophenoxy)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine [ka] The compound obtained in Step 1, 4-(4-amino-2,6-difluorophenoxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-amine (800 mg, 2.51 mmol), was dissolved in 20 mL of methanol, and then Pd(OH) (2.46 g, 17.54 mmol) was added and stirred under hydrogen gas for 12 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography to give the title compound (400 mg, yield: 50%). MS m / z: 322[M+H]

[0097] 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 [ka] According to Example 1, instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine, 4-(4-amino-2,6-difluorophenoxy)-3-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine, the compound obtained in Step 2 was used, and the title compound (18 mg, yield: 34%) was obtained in the same manner as in Example 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]

[0098] 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 [ka] According to Example 19, 11-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (14 mg, yield: 26%) was obtained in the same manner as in Example 19. 1 H 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]

[0099] 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 [ka] According to Example 19, using 1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride instead of 11-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, the title compound (23 mg, yield: 41%) was obtained in the same manner as in Example 19. 1 H 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]

[0100] 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 [ka] According to Example 19, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (13 mg, yield: 25%) was obtained in the same manner as in Example 19. 1 H 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]

[0101] 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 [ka] According to Example 19, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (12 mg, yield: 24%) was obtained in the same manner as in Example 19. 1 H 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]

[0102] 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 [ka] According to Example 19, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (8 mg, yield: 14%) was obtained in the same manner as in Example 19. 1 H 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]

[0103] Example 25. N-(4-((2-amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The compound of Example 25 below was prepared according to the following Reaction Scheme 7.

[0104] [ka] Step 1) N-(4-((2-amino-3-((trimethylsilyl)ethynyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] 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) was dissolved in 1.5 mL of DMF / TEA (1:1) solution, and ethynyltrimethylsilane (32 μL, 0.24 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol), and CuI (4.4 mg, 0.02 mmol) were added. The mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with water, extracted three times with EA, and concentrated. The residue was purified by column chromatography to obtain the title compound (30 mg, yield: 45%). MS m / z: 572[M+H]

[0105] Step 2) N-(4-((2-amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The compound obtained in Step 1, 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), was dissolved in 4 mL of methanol, and then K2CO3 (40 mg, 0.28 mmol) was added and stirred at room temperature for 4 hours. The reaction solution was diluted with water, extracted three times with EA, and concentrated. The residue was purified by column chromatography to obtain the title compound (21 mg, yield: 57%). 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]

[0106] 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 [ka] According to Example 25, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (8 mg, yield: 46%) was obtained in the same manner as in Example 25. 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]

[0107] 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 [ka] According to Example 25, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 57%) was obtained in the same manner as in Example 25. 1 H 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]

[0108] Example 28. N-(4-((2-amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 25, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (8 mg, yield: 31%) was obtained in the same manner as in Example 25. 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]

[0109] Example 29. N-(4-((2-amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 25, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (3 mg, yield: 34%) was obtained in the same manner as in Example 25. 1 H 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]

[0110] Example 30. N-(4-((2-amino-3-ethynylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 25, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (17 mg, yield: 65%) was obtained in the same manner as in Example 25. 1 H 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]

[0111] Example 31. N-(4-((2-amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The compound of Example 31 below was prepared according to the following Reaction Scheme 8.

[0112] [ka] 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) was dissolved in 1 ml of N-methyl-2-pyrrolidone, and Pd(PPh3)4 (20 mg, 0.02 mmol) and ZnCN2 (10 mg, 0.08 mmol) were added, followed by stirring at 140°C for 12 hours. The reaction solution was diluted with water, extracted three times with EA, and concentrated. The residue was purified by column chromatography to obtain the title compound (9 mg, yield: 22%). 1 MS m / z : 501[M+H]

[0113] Example 32. N-(4-((2-amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in the same manner as in Example 31. 1H 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 (brs, 2H), 6.09 (d, 1H); MS m / z : 502[M+H]

[0114] 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 [ka] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in the same manner as in Example 31. 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]

[0115] 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 [ka] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 47%) was obtained in the same manner as in Example 31. 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]

[0116] Example 35. N-(4-((2-amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in the same manner as in Example 31. 1H 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]

[0117] Example 36. N-(4-((2-amino-3-cyanopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 31, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (20 mg, yield: 48%) was obtained in the same manner as in Example 31. 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]

[0118] Example 37. N-(4-((2-amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] 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 (15 mg, yield: 18%) was obtained in the same manner as in Example 19. 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]

[0119] 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 [ka] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (15 mg, yield: 17%) was obtained in the same manner as in Example 37. 1H 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]

[0120] 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 [ka] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (15 mg, yield: 17%) was obtained in the same manner as in Example 37. 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]

[0121] Example 40. N-(4-((2-amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 35%) was obtained in the same manner as in Example 37. 1 H 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]

[0122] Example 41. N-(4-((2-amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (10 mg, yield: 12%) was obtained in the same manner as in Example 37. 1 H 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]

[0123] Example 42. N-(4-((2-amino-3-cyclopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 37, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (15 mg, yield: 17%) was obtained in the same manner as in Example 37. 1H 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]

[0124] Example 43. N-(4-((2-amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 19, using 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane instead of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, the title compound (13 mg, yield: 25%) was obtained in the same manner as in Example 19. 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]

[0125] 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 [ka] According to Example 43, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (6 mg, yield: 20%) was obtained in the same manner as in Example 43. 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]

[0126] Example 45. N-(4-((2-amino-3-isopropylpyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 43, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (2.3 mg, yield: 12%) was obtained in the same manner as in Example 43. 1H 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]

[0127] 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 [ka] According to Example 43, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (9 mg, yield: 22%) was obtained in the same manner as in Example 43. 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]

[0128] 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 [ka] The compound of Example 47 below was prepared according to the following Reaction Scheme 9. [ka] Step 1) tert-butyl (4-(2,6-difluoro-4-nitrophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate [ka] tert-Butyl (4-(2,6-difluoro-4-nitrophenoxy)-3-formylpyridin-2-yl)carbamate (1 g, 2.53 mmol) was dissolved in 50 mL of DCM, followed by the addition of morpholine (264 μL, 3.04 mmol) and acetic acid (174 μL, 3.04 mmol) and stirring at room temperature. After 30 minutes, sodium triacetoxyborohydride (1.07 g, 5.06 mmol) was added and the reaction was continued at room temperature for 12 hours. The reaction solution was diluted with saturated aqueous NaHCO3, extracted three times with DCM, and concentrated. The residue was purified by column chromatography to obtain the title compound (0.7 g, yield: 59%). MS m / z: 467[M+H]

[0129] Step 2) tert-butyl (4-(4-amino-2,6-difluorophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate [ka] The compound obtained in Step 1, tert-butyl (4-(2,6-difluoro-4-nitrophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate (600 mg, 1.29 mmol), was dissolved in 15 ml of methanol, and then Pd / C (98 mg, 0.92 mmol) was added and stirred under hydrogen gas for 12 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography to obtain the title compound (500 mg, yield: 57%). MS m / z: 437[M+H]

[0130] 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 [ka] According to Example 1, the title compound (80 mg, yield: 62%) was obtained in the same manner as in Example 1, except that tert-butyl (4-(4-amino-2,6-difluorophenoxy)-3-(morpholinomethyl)pyridin-2-yl)carbamate, the compound obtained in Step 2, was used instead of 4-(4-amino-2,6-difluorophenoxy)-3-chloropyridin-2-amine. MS m / z: 694[M+H]

[0131] 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 [ka] The compound obtained in 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 (80 mg, 0.12 mmol), was dissolved in 3 ml of DCM, and then 3 ml of TFA was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was diluted with EA and washed with saturated aqueous NaHCO3. The organic layer was further washed with brine and concentrated, and the residue was purified by column chromatography to obtain the title compound (21 mg, yield: 31%). 1 H 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]

[0132] 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 [ka] According to Example 47, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (20 mg, yield: 29%) was obtained in the same manner as in Example 47. 1H 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]

[0133] 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 [ka] 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 the same manner as in Example 47. 1 H 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]

[0134] Example 50. N-(4-((2-amino-3-(morpholinomethyl)pyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] According to Example 47, 1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (30 mg, yield: 44%) was obtained in the same manner as in Example 47. 1 H 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]

[0135] 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 [ka] The same procedure as in Example 25 was followed, except that prop-2-yn-1-ol was used instead of ethynyltrimethylsilane, to give the title compound (30 mg, yield: 68%). 1 H 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]

[0136] 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 [ka] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 69%) was obtained in the same manner as in Example 51. 1 H 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]

[0137] 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 [ka] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-fluoropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 66%) was obtained in the same manner as in Example 51. 1 H 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]

[0138] 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 [ka] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl) oxy)-3,5-difluorophenyl)-1-(3-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 67%) was obtained in the same manner as in Example 51. 1H 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]

[0139] 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 [ka] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyrimidin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 68%) was obtained in the same manner as in Example 51. 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]

[0140] 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 [ka] According to Example 51, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide was used instead of N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3,5-difluorophenyl)-1-(pyridazin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and the title compound (30 mg, yield: 68%) was obtained in the same manner as in Example 51. 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]

[0141] 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 [ka] The same procedure as in Example 53 was followed, except that but-3-yn-2-ol was used instead of prop-2-yn-1-ol, to give the title compound (25 mg, yield: 43%). 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]

[0142] 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 [ka] The same procedure as in Example 53 was followed, except that 2-methylbut-3-yn-2-ol was used instead of prop-2-yn-1-ol, to give the title compound (25 mg, yield: 54%). 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]

[0143] 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 [ka] According to Example 1, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride was replaced with 1-(1-(3-methoxypropyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, and the title compound (6 mg, yield: 7%) was obtained in the same manner as in Example 1. 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]

[0144] 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 [ka] According to Example 1, using 1-(1-(2-ethoxyacetyl)piperidin-4-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, the title compound (12 mg, yield: 24%) was obtained in the same manner as in Example 1. 1H 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, MS m / z : 603[M+H]

[0145] Example 61. N-[4-[(2-amino-3-chloro-4-pyridyl)oxy]-3,5-difluoro-phenyl]-1-(3-methoxypropyl)-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] According to Example 1, using 1-(3-methoxypropyl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl chloride, the title compound (32 mg, yield: 44%) was obtained in the same manner as in Example 1. 1 H NMR (500 MHz, DMSO-d6) δ 10.88 (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]

[0146] Experimental Example 1. Evaluation of inhibitory activity against RON and MET [1-1] Evaluation of inhibitory activity against RON To measure the inhibitory activity of the compounds of the examples against RON, the IC 50was measured using TR-FRET (Time-Resolved Fluorescence Energy Transfer).

[0147] Specifically, the compounds were prepared at a concentration of 1 mM in 100% DMSO and serially diluted 10 times by 3-fold dilution. 2 μL of the serially diluted compounds was added to a 96-well plate containing 48 μL of 1× 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).

[0148] RON protein was diluted to a concentration of 49.3 nM in RON storage buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.5 mM EDTA, 0.02% Triton X-100) and further diluted to 0.4 nM in 1x kinase reaction buffer. A RON-specific substrate mixture (40 μM ULight-labeled Poly GT, 100 nM ATP) was prepared at twice the final reaction concentration.

[0149] Then, a 384-well plate was prepared, and 2.5 μl of the diluted example compound was added to each well of the experimental group wells, and 2.5 μl of 4% DMSO solution was dispensed into the high control wells and the low control wells.

[0150] Next, 2.5 μL of 0.4 nM RON was added to the high control and experimental wells, and 2.5 μL of 1x kinase reaction buffer was added to the low control wells. The wells were centrifuged at 1000 RPM for 40 seconds at room temperature and then incubated for 20–30 minutes. 5 μL of substrate cocktail (2x) was then added to all wells. The wells were centrifuged at 1000 RPM for 40 seconds at room temperature and then incubated for 60 minutes at room temperature. The reaction was terminated by adding 5 μL of 30 mM EDTA to all wells, followed by an additional 5 minutes of incubation at room temperature. 5 μL of 4x phosphotyrosine antibody (Perkin Elmer) containing europium was then added to all wells and incubated for 60 minutes at room temperature. After incubation, the 384-well plate was read using a Vision plate reader. In this case, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm. 50 Values ​​were derived using the GraphPd Prism7 program.

[0151] [1-2] Evaluation of MET inhibitory activity Furthermore, the inhibition of the enzyme activity against cMET was measured in the same manner as in the experiment for measuring the inhibition of the enzyme activity against RON.

[0152] Specifically, the compounds were prepared at a concentration of 1 mM in 100% DMSO and serially diluted 10 times by 3-fold dilution. 2 μL of the serially diluted compounds was added to a 96-well plate containing 48 μL of 1× kinase reaction buffer (50 mM HEPES (pH 7.4), 0.05% BSA, 0.005% Tween-20, 1 mM DTT, 0.5 mM MnCl, 20 mM MgCl).

[0153] 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% Brij 35, 1 mM DTT, 10% glycerol) and further diluted to 2 nM in 1x kinase reaction buffer. A substrate cocktail containing MET-specific substrates (5 μM TK peptide, 10 mM ATP) was prepared at twice the final reaction concentration.

[0154] Then, a 384-well plate was prepared, and 2.5 μl of the diluted example compound was added to each well of the experimental group wells, and 2.5 μl of 4% DMSO solution was dispensed into the high control wells and the low control wells.

[0155] Next, 2.5 μL of 2 nM cMET was added to the high control and experimental wells, and 2.5 μL of 1x kinase reaction buffer was added to the low control wells. The wells were centrifuged at 1000 RPM for 40 seconds and then incubated at room temperature for 20–30 minutes. 5 μL of substrate cocktail (2x) was then added to all wells. The wells were centrifuged at 1000 RPM for 40 seconds and then incubated at room temperature for 60 minutes. The reaction was terminated by adding 5 μL of 90 mM EDTA to all wells, followed by an additional 5 minutes of incubation at room temperature. 5 μL of 4x phosphotyrosine antibody (Perkin Elmer) containing europium was then added to all wells and incubated at room temperature for 60 minutes. After incubation, the 384-well plate was read using a Vision plate reader. In this case, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm. 50 Values ​​were derived using the GraphPd Prism7 program.

[0156] The results of evaluating the enzyme inhibitory activity of the compounds of the above examples against RON or cMET are shown in Table 2 below. (A:<50nM, B:50~500nM, C:500~5000nM, D:>5,000nM)

[0157] [Table 2-1] [Table 2-2]

Claims

1. A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the above Chemical Formula 1, X is N or C; R １ is any one selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl, and substituted or unsubstituted cycloalkyl; R ２ is any one selected from the group consisting of hydrogen and substituted or unsubstituted alkyl; Y １ and Y ２ are each independently any one selected from the group consisting of 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 —(CH ２ ) ｎ -W, where n is an integer of 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 the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted and unsubstituted heteroaryl; The substituted functional group may be a halogen, alkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkyl, alkoxyalkyl, -(CO)-(CH ２ ) ｎ -OR ｃ and aryl, where n is an integer from 0 to 3; ｃ is hydrogen or alkyl.

2. The R １ is hydrogen, halogen, alkyl, or haloalkyl; The R ２ is hydrogen or alkoxyalkyl; The Y １ and Y ２ are each independently hydrogen or halogen; Z is selected from the group consisting 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 —(CH ２ ) ｎ - any one selected from the group consisting of W, where W is heterocycloalkyl, and where n is an integer from 1 to 3; A is any one selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted and unsubstituted heteroaryl; The substituted functional group may be a halogen, alkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkyl, alkoxyalkyl, -(CO)-(CH ２ ) ｎ -OR ｃ and aryl, where n is an integer from 1 to 3; R ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen or alkyl.

3. The R １ is halogen, alkyl, or haloalkyl; The R ２ is hydrogen or alkoxyalkyl; The Y １ and Y ２ is a halogen; Z is selected from the group consisting of halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, cyano, and —(CH ２ ) ｎ - any one selected from the group consisting of W, where n is an integer from 1 to 2 and W is heterocycloalkyl; A is any one selected from the group consisting of substituted alkyl, substituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; The substituted functional groups include halogen, alkyl, hydroxyalkyl, hydroxy, alkoxy, haloalkyl, alkoxyalkyl, and —(CO)—(CH ２ ) ｎ -OR ｃ where n is an integer from 1 to 2, and R ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is hydrogen or alkyl.

4. The R １ is alkyl or haloalkyl; The R ２ is hydrogen or alkoxyalkyl; The Y １ and Y ２ is fluoro; Z is selected from halogen, alkyl, alkynyl, hydroxyalkynyl, hydroxyalkylalkynyl, cycloalkyl, tetrahydropyran, cyano, and —(CH ２ ) ｎ - any one selected from the group consisting of W, where W is morpholine and where n is 1; A is an alkoxyalkyl, an aryl, a pyridine, a halopyridine, a pyrimidine, a pyridazine, a piperidine, an alkoxyalkylpiperidine, or —(CO)—(CH ２ ) ｎ -OR ｃ wherein n is 1; and R ｃ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: is alkyl.

5. The compound is 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 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of N-[4-[(2-amino-3-chloro-4-pyridyl)oxy]-3,5-difluoro-phenyl]-1-(3-methoxypropyl)-5-(trifluoromethyl)pyrazole-4-carboxamide.

6. 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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