Novel pyridine derivative compounds as RON inhibitors

Abstract

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

Description

[Technical Field]

[0001] The present invention claims the benefit of priority based on Korean Patent Application No. 10-2021-0082699, filed on June 24, 2021, and all contents disclosed in the documents of this 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 activity of kinases targeting 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 objective of the present invention is to provide a compound useful for the prevention or treatment of cancer.

[0010] In still another aspect, an objective of the present invention is to provide a compound useful for the prevention or treatment of immune-related diseases.

[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 pyridine derivative compound of the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:

[0013] [ka]

[0014] In the above Chemical Formula 1, W is N or CH; wherein X is O; Y is selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Z is hydrogen, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy, carboxylic acid, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylcarbonyloxy, nitro, cyano, carbamoyl, urea, thiol, and NR 2 R 3 and one or more selected from R 1 is hydrogen or C1-C6 alkyl, A represents a substituted or unsubstituted 5-membered heteroaryl containing 1 to 4 hetero ring atoms selected from the group consisting of nitrogen, sulfur, and oxygen, and the substituents of the substituted 5-membered heteroaryl include halogen, amine, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C6-C 10Aryl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy, carboxylic acid, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylcarbonyloxy, nitro, cyano, carbamoyl, urea, thiol, or NR 2 R 3 and B is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, substituted C2-C6 heterocycloalkyl, C6-C 10 Aryl, substituted C6-C 10 aryl, where the substituents are halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, or C6-C 10 is aryl, R 2 and R 3 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)R 4 or C(O)OR 5 and R 4 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl; R 5 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl; The halogens are each independently selected from the group consisting of F, Cl, Br, and I.

[0015] 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. [Effects of the Invention]

[0016] 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 protein kinase activity of the RON receptor, but the effects of the present invention are not limited thereto. DETAILED DESCRIPTION OF THE INVENTION

[0017] According to one aspect, the present invention provides novel pyridine derivative compounds of formula 1, or pharmaceutically acceptable salts thereof, as defined above.

[0018] In the present invention, unless otherwise specified, the compound is meant to include the compound of Chemical Formula 1, its stereoisomers such as enantiomers and diastereoisomers, solvates, prodrugs, etc.

[0019] [ka]

[0020] In the above Chemical Formula 1, W is N or CH; wherein X is O; Y is selected from hydrogen, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl; Z is hydrogen, halogen, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy, carboxylic acid, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylcarbonyloxy, nitro, cyano, carbamoyl, urea, thiol, and NR 2 R 3 and one or more selected from R 1 is hydrogen or C1-C6 alkyl, A represents a substituted or unsubstituted 5-membered heteroaryl containing 1 to 4 hetero ring atoms selected from the group consisting of nitrogen, sulfur, and oxygen, and the substituents of the substituted 5-membered heteroaryl include halogen, amine, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C6-C 10 Aryl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy, carboxylic acid, C1-C6 alkylcarbonyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylcarbonyloxy, nitro, cyano, carbamoyl, urea, thiol, or NR 2 R 3 and B is hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C2-C6 heterocycloalkyl, substituted C2-C6 heterocycloalkyl, C6-C 10 Aryl, substituted C6-C 10 aryl, where the substituents are halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, or C6-C 10 is aryl, R 2 and R 3 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)R 4 or C(O)OR 5 and R 4 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl; R 5 is C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl; The halogens are each independently selected from the group consisting of F, Cl, Br, and I.

[0021] 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.

[0022] As used herein, unless otherwise defined, a "substituent" is any group including deuterium, halogen, hydroxy, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, C1-C 10 Alkoxy, C5-C 12 Aryloxy, C1-C 10 Alkylthiol, C5-C 12 Arylthioxy, C1-C 10 Alkyl sulfoxy, C5-C 12 Aryl sulfoxy, C1-C 10 Haloalkyl, C2-C 20 Alkenyl, C0-C 10 Amine, nitrile, nitro, imide, amide, oxo, carbonyl, carboxylic acid, carbamoyl, ester, C5-C 12 Aryl, and C5-C 12 It may be one or more selected from the group consisting of heteroaryl.

[0023] In this specification, the "alkyl" is linear or branched, and preferably has 1 to 20 carbon atoms, unless otherwise defined. Examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methylbutyl, ethylbutyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, n-hexyl, methylpentyl, 2-methylpentyl, 4-methyl-2-pentyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, n-heptyl, 1-methylhexyl, cyclopentylmethyl, cyclohexylmethyl, octyl, n-octyl, tert-octyl, 1-methylheptyl, 2-ethylhexyl, 2-propylpentyl, n-nonyl, 2,2-dimethylheptyl, 1-ethylpropyl, dimethylpropyl, isohexyl, 2-methylpentyl, 4-methylhexyl, and 5-methylhexyl.

[0024] In this specification, the term "cycloalkyl" refers to a cyclic saturated hydrocarbon, and unless otherwise defined, preferably has 3 to 20 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, and cyclooctyl, but are not limited thereto.

[0025] In this specification, the "alkoxy" group is linear, branched, or cyclic, and, unless otherwise defined, preferably has 1 to 20 carbon atoms. Examples of the alkoxy group include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, 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.

[0026] In this specification, the "alkenyl" group is linear or branched, and, unless otherwise defined, preferably has 2 to 20 carbon atoms. Examples include, but are not limited to, vinyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-methyl-1-butenyl, 1,3-butadienyl, allyl, 1-phenylvinyl-1-yl, 2-phenylvinyl-1-yl, 2,2-diphenylvinyl-1-yl, 2-phenyl-2-(naphthyl-1-yl)vinyl-1-yl, 2,2-bis(diphenyl-1-yl)vinyl-1-yl, a stilbenyl group, and a styrenyl group.

[0027] In this specification, the "aryl" refers to a monoaryl, biaryl, or polycyclic aryl having three or more rings. When the aryl contains two or more ring structures, the rings may be fused or may be present in a spiro form, and unless otherwise defined, preferably has 5 to 12 carbon atoms. Examples of the aryl include, but are not limited to, a phenyl group, a biphenyl group, a terphenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group, a pyrenyl group, and a perylenyl group.

[0028] As used herein, the term "hetero ring atom" refers to a non-carbon atom contained in a ring. Unless otherwise defined, the hetero ring atom may include one or more atoms selected from oxygen, nitrogen, selenium, and sulfur.

[0029] In this specification, the term "heterocycloalkyl" refers to a cyclic saturated hydrocarbon containing a hetero ring atom, and preferably has 2 to 20 carbon atoms, unless otherwise defined.

[0030] In this specification, the term "heteroaryl" refers to an aromatic hydrocarbon containing a hetero ring atom. The heteroaryl may be monocyclic or polycyclic, and when it contains two or more ring structures, the rings may be joined or may be included in a spiro form. Unless otherwise defined, it preferably has 5 to 12 carbon atoms. Examples of such groups include, but are not limited to, a thiophene group, a furanyl group, a pyrrole group, an imidazolyl group, a thiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a bipyridyl group, a pyrimidyl group, a triazinyl group, a triazolyl group, an acridyl group, a pyridazinyl group, a pyrazinyl group, a quinolinyl group, a quinazolinyl group, a quinoxalinyl group, a phthalazinyl group, a pyridopyrimidyl group, a pyridopyrazinyl group, a pyrazinopyrazinyl group, an isoquinolinyl group, an indolyl group, a carbazolyl group, a benzoxazolyl group, a benzimidazolyl group, and a benzothiazolyl group.

[0031] According to one embodiment, the present invention provides a novel pyridine derivative compound of the following formula 2, or a pharmaceutically acceptable salt thereof:

[0032] [ka]

[0033] wherein W is N or CH, and Z is hydrogen, halogen, C1-C6 alkyl, and NR 2 R 3 and R is one or more selected from 2 and R 3 are each independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or substituted C3-C6 cycloalkyl, and the remaining substituents are as defined in Chemical Formula 1.

[0034] According to one embodiment, A may comprise a heteroaryl group selected from the group consisting of pyrazole, imidazole, triazole, oxazole, isoxazole, thiazole, and thiophene, wherein the heteroaryl group is substituted or unsubstituted, and the substituted heteroaryl group has substituents selected from halogen, amine, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or C6-C 10 It may also be aryl.

[0035] According to one embodiment, in Chemical Formula 1, B may include a C3-C6 alkyl, C3-C6 cycloalkyl, phenyl, halogen-substituted phenyl, C1-C3 alkoxy-substituted phenyl, C1-C6 alkyl-substituted phenyl, benzyl, tolyl, C1-C3 alkyl-substituted piperidine, or tetrahydropyranyl group.

[0036] According to one embodiment, in Formula 1, Y is fluoro.

[0037] According to one embodiment, in Formula 1, Z is present in two or more positions.

[0038] According to one embodiment, in the formula 1, Z is present in two positions.

[0039] According to one embodiment, in Formula 1, the R 1 is hydrogen.

[0040] According to one embodiment, the compound of Formula 1 is N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1H-pyrazole-4- )-1-methyl-1H-pyrazole-4-carboxamide, 5-amino-N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3 -chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-benzyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-chloro-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-Diphenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-fluoro-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-acrylamido-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-(N-acrylamido-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((3-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide N-(4-((2-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-cyclopropanecarboxamido)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl) oxy)-3-fluorophenyl)-2-phenylthiazole-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-2-phenylthiazole-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiazole-2-carboxamide, N-(4-(( 2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiophene-2-carboxamide, ethyl (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate, ethyl (2-amino-4-(4-(5-ethyl-1-vinyl-1H-pyrazole-4-carboxamide) N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide oxy)-3-fluorophenyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, N-( 4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide H-pyrazole-4-carboxamide, N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-5-ethyl-1-phenyl-pyrazole-4-carboxamide, N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-3,5-Dimethyl-1-phenyl-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-(p-tolyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-tetrahydropyran-3-yl-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino -5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-cyclohexyl-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-pyrazole- 3-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-triazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-methyl-1-phenyl-triazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-methyl- riazole-4-carboxamide, N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-tert-butyl-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1,5-Diphenyl-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(1-methyl-3-piperidyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-4-methyl-2-phenyl-thiazole-5-carboxamide, N-(4-((5-chloro-6-(cyclopropylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trif, and N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)imidazole-4-carboxamide, the structures of which are set forth in Table 1 below.

[0041] [Table 1A] [Table 1B] [Table 1C] [Table 1D] [Table 1E] [Table 1F] [Table 1G] [Table 1H]

Table 1I

Table 1J

Table 1L

Table 1N

Table 1O

Table 1P

Table 1Q

Table 1R

Table 1S

Table 1T

Table 1U

[0042] In the present invention, the term "pharmaceutically acceptable salts" includes 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, and the like. Acids include 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, camphoric acid, camphorsulfonic acid, digluconic acid, cyclopentanepropionic acid, dodecylsulfonic acid, glucoheptanoic acid, glycerophosphonic acid, heptanoic acid, hexanoic acid, 2-hydroxyethanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmoic acid, pectinic acid, persulfuric acid, 2-phenylpropionic acid, picric acid, pivalic acid, thiocyanic acid, undecanoic acid, stearic acid, algenic acid, beta-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.Suitable pharmaceutically acceptable base addition salts of the compounds of Chemical 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, histidine, glucamine, 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 the compound of Chemical Formula 1. When a basic group and an acidic group are present in the same molecule, the compounds of Chemical Formula 1 can also form internal salts.

[0043] 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.

[0044] According to another aspect, the present invention provides a pharmaceutical composition comprising a novel compound of formula 1 as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0045] The pharmaceutical composition 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.

[0046] In one embodiment, the pharmaceutical composition may be useful for the prevention or treatment of a RON-mediated disease.

[0047] The pharmaceutical composition of the present invention comprises a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0048] In one embodiment, the disease may be, but is not limited to, a cancer selected from the group consisting of lung cancer, breast cancer, colorectal cancer, kidney cancer, pancreatic cancer, head cancer, neck cancer, hereditary papillary renal cell carcinoma, pediatric hepatocellular carcinoma, and gastric cancer.

[0049] In other embodiments, the disease may be an infectious disease selected from the group consisting of, but not limited to, inflammatory disorders, cardiovascular diseases, virally induced diseases, circulatory system diseases, fibroproliferative diseases, and pain sensations.

[0050] 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.

[0051] As used herein, the term "prevention" refers to reducing the risk of contracting a disease or disorder, and refers to any action that suppresses 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 has not yet contracted the disease or has not yet shown symptoms of the disease.

[0052] As used herein, the term "treatment" means to alleviate 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 improves or favorably alters the symptoms of a disease.

[0053] 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 a solution, suspension, or emulsion in an oil or aqueous medium, or an extract, powder, granules, tablets, capsules, or gel (e.g., hydrogel), and may further contain a dispersant or stabilizer.

[0054] The compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition can be delivered by a pharmaceutically acceptable carrier such as a colloidal suspension, powder, saline, lipid, liposome, microsphere, or nanosphere. These can be complexed or associated with a delivery means and delivered into the body using a delivery system known in the art, such as lipid, liposome, microparticle, gold, nanoparticle, polymer, condensation reaction agent, polysaccharide, polyamino acid, dendrimer, saponin, adsorption enhancer, or fatty acid.

[0055] Other pharmaceutically acceptable carriers may include, but are not limited to, commonly used ingredients in pharmaceutical formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the formulation may further include lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

[0056] 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 also 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.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] 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 harmful side effects associated with other conventional therapies. For example, an effective tumor treatment agent is one that prolongs the patient's survival time, inhibits the growth of rapidly proliferating cells associated with tumors, or is effective in causing tumor regression.

[0061] 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.

[0062] Preparation Example 1: 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine [ka] The compound of the following Preparation Example 1 was prepared according to the following Reaction Scheme 1.

[0063] Reaction Scheme 1. [ka] 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]

[0064] Step 2) N-(3-chloropyridin-2-yl)-1,1-diphenylmethanimine [ka] N-(3-chloropyridin-2-yl)-1,1-diphenylmethanimine (20 g, 68.3 mmol), the compound obtained in Step 1, was dissolved in THF (100 mL) 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 water (100 mL) was added. Sodium percarbonate (16 g, 102 mmol) was added, followed by further stirring at room temperature for 3 hours. Saturated aqueous NaHSO3 (50 mL) was slowly added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layer was concentrated and used in Step 3 below without further purification. MS m / z: 309 [M+H]

[0065] Step 3) N-(3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl-1,1-diphenylmethanimine [ka] N-(3-chloropyridin-2-yl)-1,1-diphenylmethanimine (20 g, 65 mmol), the compound obtained in Step 2, was dissolved in DMF, and then 3,4-difluoronitrobenzene (9.3 ml, 84.5 mmol) and Cs2CO3 (27.5 g, 84.5 mmol) were added. The mixture was stirred at 90 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic solution was washed with brine and concentrated. The residue was purified by column chromatography to obtain the title compound (21 g, yield: 72%). MS m / z: 448 [M+H]

[0066] Step 4) 4-((3-chloro-2-(diphenylmethylene)amino)pyridin-4-yl)oxy-3-fluoroaniline [ka] N-(3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl-1,1-diphenylmethanimine) (20 g, 44.6 mmol), the compound obtained in step 3, was dissolved in isopropanol, and then ammonium sulfide (30.4 ml, 446 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was then stirred at 70°C for an additional 3 hours. After the reaction was completed, water was added and the mixture was cooled to room temperature. The resulting solid was collected by filtration, and butyl acetate was added and dissolved by heating to 80°C. Heptane was added and the mixture was cooled to room temperature. The reaction mixture was cooled to room temperature, and the resulting solid was filtered and dried to obtain the title compound (14 g, 75%). MS m / z: 418 [M+H]

[0067] Step 5) 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine [ka] The compound obtained in Step 4, 4-((3-chloro-2-(diphenylmethylene)amino)pyridin-4-yl)oxy-3-fluoroaniline (14 g, 33 mmol), was dissolved in THF, and then 1 M HCl (14 ml) was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then saturated NaHCO3 was added and extracted three times with ethyl acetate. The organic solution was washed with brine and concentrated. The residue was purified by column chromatography to obtain the title compound (7.1 g, yield: 84%). MS m / z: 254 [M+H]

[0068] Preparation Example 2. 1-(2-Fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ka] The compound of the following Preparation Example 2 was prepared according to the following Reaction Scheme 2.

[0069] Reaction Scheme 2. [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].

[0070] Step 2) Ethyl 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [ka] Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutanoate (0.5 g, 2.1 mmol), the compound obtained in Step 1, and (2-fluorophenyl)hydrazine (0.263 g, 2.1 mmol) were dissolved in 7 mL of ethanol and stirred at 70°C for 4 hours. The reaction mixture was then extracted with ethyl acetate and water. The residue was purified by column chromatography to obtain the title compound (0.38 g, yield: 60%). MS m / z: 303[M+H].

[0071] Step 3) 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid [ka] Ethyl 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.38 g, 1.3 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 (0.18 g, yield: 52%). MS m / z: 275[M+H].

[0072] Example 1. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound of Example 1 below was prepared according to the following Reaction Scheme 3.

[0073] Reaction Scheme 3. [ka] 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine (50 mg, 0.20 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-imidazole-4-carboxylic acid (61 mg, 0.24 mmol), HATU (114 mg, 0.3 mmol), and DIPEA (52 μL, 0.3 mmol). The mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to give the title compound (72 mg, yield: 74%). 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.36 (s, 1H), 8.06 (m, 1H), 7.85 (d, 1H), 7.64 (m, 1H), 7.57 (m, 4H), 7.41 (m, 1H), 7.22 (m, 1H), 6.18 (d, 1H); MS m / z : 492[M+H]

[0074] Example 2. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (4 mg, yield: 36%) was obtained in the same manner as in Example 1, except that 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.88 (m, 1H), 7.76 (d, 1H), 7.61 (m, 3H), 7.54 (m, 3H), 7.29 (m, 1H), 7.22 (m, 1H), 6.07 (d, 1H); MS m / z : 492[M+H]

[0075] Example 3. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (7 mg, yield: 50%) was obtained in the same manner as in Example 1, except that 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.32 (s, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.59 (m, 5H), 7.53 (m, 1H), 7.36 (m, 1H), 6.41 (brs, 2H), 5.96 (d, 1H), 2.56 (s, 3H); MS m / z : 438[M+H]

[0076] Example 4. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (11 mg, yield: 60%) was obtained in the same manner as in Example 1, except that 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.92 (d, 1H), 7.77 (d, 1H), 7.58 (m, 2H), 7.52 (m, 4H), 7.32 (m, 1H), 6.41 (brs, 2H), 5.95 (d, 1H), 2.42 (s, 3H), 2.38 (s, 3H); MS m / z : 452[M+H]

[0077] Example 5. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (8 mg, yield: 55%) was obtained in the same manner as in Example 1, except that 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.32 (s, 1H), 7.97 (d, 1H), 7.78 (d, 1H), 7.62 (m, 4H), 7.52 (m, 2H), 7.34 (t, 1H), 6.42 (brs, 2H), 5.96 (d, 1H), 2.97 (q, 2H), 1.08 (t, 3H); MS m / z : 452[M+H]

[0078] Example 6. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (51 mg, yield: 68%) was obtained in the same manner as in Example 1, except that 5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.47 (s, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.61 (m, 6H), 7.39 (m, 1H), 6.45 (brs, 2H), 5,97 (d, 1H); MS m / z : 474 [M+H]

[0079] Example 7. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (51 mg, yield: 77%) was obtained in the same manner as in Example 1, except that 1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.12 (s, 1H), 8.34 (s, 1H), 7.97 (d, 1H), 7.95 (m, 2H), 7.78 (d, 1H), 7.58 (m, 3H), 7.41 (m, 2H), 6.48 (brs, 2H), 5,98 (d, 1H); MS m / z : 424 [M+H]

[0080] Example 8. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (46 mg, yield: 58%) was obtained in the same manner as in Example 1, except that 1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.11 (d, 1H), 7.87 (d, 1H), 7.77 (d, 1H), 7.50 (m, 1H), 7.38 (m, 1H), 6.54 (brs, 2H), 5.98 MS m / z : 500[M+H]

[0081] Example 9. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide [ka] The title compound (54 mg, yield: 83%) was obtained in the same manner as in Example 1, except that 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.22 (s, 1H), 7.93 (d, 1H), 7.80 (d, 1H), 7.65 (m, 1H), 7.59 (m, 1H), 7.39 (m, 1H), 6.67 (brs, 2H), 6.01 (d, 1H), 4.04 (s, 3H); MS m / z : 412[M+H]

[0082] Example 10. 5-Amino-N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (29 mg, yield: 42%) was obtained in the same manner as in Example 1, except that 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 8.18 (s, 1H), 7.96 (d, 1H), 7.80 (d, 1H), 7.60 (m, 5H), 7.44 (m, 1H), 7. 36 (m, 1H), 6.67 (brs, 2H), 6.55 (brs, 2H), 6.02 (d, 1H); MS m / z : 439[M+H]

[0083] Example 11. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (40 mg, yield: 50%) was obtained in the same manner as in Example 1, except that 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.34 (s, 1H), 7.78 (m, 1H), 7.65 (d, 1H), 7.53 (m, 2H), 7.48 (m, 1H), 7.45 (m, 2H), 7.39 (m, 1H), 6.49 (brs, 2H), 5.98 (d, 1H); MS m / z : 510[M+H]

[0084] Example 12. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (20 mg, yield: 33%) was obtained in the same manner as in Example 1, except that 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid obtained in Production Example 2 was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, MeOD-d4) δ 10.86 (s, 1H), 8.43 (s, 1H), 7.90 (d, 1H), 7.77 (d, 1H), 7.73 (m, 2H), 7.57 (dd, 1H), 7.47 (t, 1H), 7.38 (t, 1H), 6.44 (s, 2H), 5.96 (d, 1H); MS m / z : 510[M+H]

[0085] Example 13. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-benzyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (38 mg, yield: 48%) was obtained in the same manner as in Example 1, except that 1-benzyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.18 (s, 1H), 7.88 (m, 1H), 7.76 (d, 1H), 7.51 (m, 1H), 7.41 (m, 4H), 7.21 (m, 2H), 6.43 (brs, 2H), 5.95 (d, 1H), 5.61 (s, 2H); MS m / z : 506[M+H]

[0086] Example 14. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide [ka] The title compound (21 mg, yield: 30%) was obtained in the same manner as in Example 1, except that 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.09 (d, 1H), 7.79 (m, 2H), 7.64 (m, 3H), 7.48 (m, 2H), 7.31 (m, 1H), 6.41 (brs, 2H), 5.93 (d, 1H), 2.31 (s, 3H), 2.19 (s, 3H); MS m / z : 452[M+H]

[0087] Example 15. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (51 mg, yield: 51%) was obtained in the same manner as in Example 1, except that 1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.31 (s, 1H), 7.89 (dd, 1H), 7.76 (d, 1H), 7.53 (d, 1H), 7.44-7.35 (m, 5H), 6.43 (s, 2H), 5.95 (d, 1H); MS m / z : 506[M+H]

[0088] Example 16. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (58 mg, yield: 56%) was obtained in the same manner as in Example 1, except that 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.33 (s, 1H), 7.90 (dd, 1H), 7.77 (d, 1H), 7.61-7.54 (m, 2H), 7.46 (dd, 1H), 7.37 (t, 1H), 7.29 (d, 1H), 7.14 (t, 1H), 6.43 (s, 2H), 5.95 (d, 1H); MS m / z : 522[M+H]

[0089] Example 17. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (69 mg, yield: 74%) was obtained in the same manner as in Example 1, except that 1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 7.95 (s, 1H), 7.85 (dd, 1H), 7.75 (d, 1H), 7.48 (d, 1H), 7.35 (t, 1H), 6.42 (s, 2H), 5.94 (d, 1H); MS m / z : 472[M+H]

[0090] Example 18. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-chloro-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (18 mg, yield: 20%) was obtained in the same manner as in Example 1, except that 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 8.45 (s, 1H), 7.92 (dd, 1H), 7.77 (d, 1H), 7.62-7.55 (m, 6H), 7.36 (t, 1H), 6.43 (s, 2H), 5.95 (d, 1H); MS m / z : 458[M+H]

[0091] Example 19. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-diphenyl-1H-pyrazole-4-carboxamide [ka] The title compound (27 mg, yield: 34%) was obtained in the same manner as in Example 1, except that 1,5-diphenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.34 (s,1H), 7.82 (d, 1H), 7.71 (s, 1H), 7.44 (m, 1H), 7.38 - 7.26 (m, 9H), 7.18 (m, 2H), 6.36 (brs, 2H), 5.88 (d, 1H); MS m / z : 500[M+H]

[0092] Example 20. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-fluoro-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (3.0 mg, yield: 3%) was obtained in the same manner as in Example 1, except that 5-fluoro-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ10.60 (s, 1H), 8.77 (d, 1H), 8.75 (s, 1H), 8.36 (dd, 1H), 7.86 (dd, 1H), 7.74 (d, 1H), 7.70 (dd, 1H), 7.48-7.41 (m, 6H), 7.30 (t, 1H), 6.41 (s, 2H), 5.90 (d, 1H); MS m / z : 442[M+H]

[0093] Example 21. N-(4-((2-acrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound of Example 21 below was prepared according to the following Reaction Scheme 4.

[0094] Reaction Scheme 4. [ka] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide (100 mg, 0.20 mmol), the compound of Example 1, was dissolved in DCM, and DIPEA (43 μL, 0.24 mmol) was added. The reaction mixture was cooled to −78° C., and acryloyl chloride (17 μL, 0.24 mmol) was added. The reaction mixture was stirred at 0° C. for 10 minutes, diluted with DCM, and washed with brine. The organic layer was concentrated, and the residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to give the title compound (23 mg, yield: 21%). 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 10.51 (s, 1H), 8.36 (s, 1H), 8.25 (d, 1H), 8.09 (d, 1H), 7.81 (m, 1H), 7.64 (m, 5H), 7.48 (t, 1H), 6.74 (d, 1H), 6.54 (m, 1H), 6.33 (m, 1H), 5.84 (d, 1H); MS m / z : 546[M+H]

[0095] Example 22. N-(4-((2-(N-acrylacrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The title compound (9 mg, yield: 8%) was obtained as a by-product of Example 21. 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.39 (m, 2H), 8.12 (m, 1H), 7.83 (m, 1H), 7.64 (m, 5H), 7.54 (t, 1H), 7.02 (d, 1H), 6.51 (m, 4H), 5.96 (m, 2H); MS m / z : 600[M+H]

[0096] Example 23. N-(4-((3-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound of Example 23 below was prepared according to the following Reaction Scheme 5.

[0097] Reaction Scheme 5. [ka] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide (40 mg, 0.08 mmol), the compound of Example 1, was dissolved in pyridine, and cyclopropanecarbonyl chloride (9 μl, 0.09 mmol) was slowly added at 0° C. The reaction mixture was stirred at 0° C. for 1 hour, diluted with ethyl acetate, and washed with brine. The organic layer was concentrated, and the residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to give the title compound (16 mg, yield: 34%). 1 H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 10.44 (s, 1H), 8.31 (s, 1H), 8.17 (d, 1H), 8.06 (m, 1H), 7.72 (m, 1H), 7.59 (m, 5H), 7.40 (t, 1H), 6.66 (d, 1H), 1.87 (m, 1H), 0.80 (m, 4H); MS m / z : 560[M+H]

[0098] Example 24. N-(4-((2-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound of Example 24 below was prepared according to the following Reaction Scheme 6.

[0099] Reaction Scheme 6. [ka] Step 1) 4-((2-chloropyridin-4-yl)oxy-3-fluoroaniline [ka] 4-Amino-2-fluorophenol (400 mg, 3.15 mmol) was dissolved in DMF, and then NaH (140 mg, 3.46 mmol) was added and stirred at room temperature for 30 minutes. 2-Chloro-4-nitropyridine (500 mg, 3.15 mmol) was added and stirred at 90°C for 12 hours. The reaction mixture was cooled to room temperature, diluted with brine, and extracted three times with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give the title compound (690 mg, yield: 92%). MS m / z: 239[M+H]

[0100] Step 2) N-(4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] Using 4-((2-chloropyridin-4-yl)oxy-3-fluoroaniline (100 mg, 0.42 mmol), the compound obtained in Step 1, and 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (130 mg, 0.50 mmol), the title compound (180 mg, yield: 90%) was obtained in the same manner as in Example 1. 1H NMR (400 MHz, MeOH-d4) δ 8.28 (d, 1H), 8.02 (s, 1H), 7.98 (m, 1H), 7.63 (m, 4H), 7.53 (m, 2H), 7.36 (t, 1H), 7.01 (d, 1H), 6.96 (m, 1H); MS m / z : 477[M+H]

[0101] Example 25. N-(4-((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound of Example 25 below was prepared according to the following Reaction Scheme 7.

[0102] Reaction Scheme 7. [ka] N-(4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide (100 mg, 0.21 mmol), the compound of Example 24, was dissolved in 1,4-dioxane, and tert-butyl carbamate (74 mg, 0.63 mmol), CsCO (137 mg, 0.42 mmol), Xantphos (12 mg, 0.02 mmol), and Pddba (20 mg, 0.02 mmol) were added. Nitrogen was bubbled through the solution for 10 minutes. The mixture was stirred at 100°C for 12 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The organic layer was concentrated, and the residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to obtain the title compound (10 mg, yield: 11%). 1H NMR (400 MHz, MeOH-d4) δ 8.06 (s, 1H), 7.92 (d, 1H), 7.81 (d, 1H), 7.63 (m, 3H), 7.56 (m, 3H), 7.28 (t, 1H), 6.29 (d, 1H), 6.02 (brs, 1H); MS m / z : 458[M+H]

[0103] Example 26. N-(4-((2-cyclopropanecarboxamido)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] According to Example 23, instead of the compound N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide (Example 25) was used, and the title compound (2 mg, yield: 23%) was obtained in the same manner as in Example 23. 1 H NMR (400 MHz, MeOH-d4) δ 8.16 (d, 1H), 8.02 (s, 1H), 7.93 (d, 1H), 7.71 (d, 1H), 7.63 (m, 4H), 7.53 (m, 2H), 7.29 (t, 1H), 6.72 (d, 1H), 1.86 (m, 1H), 0.96 (m, 2H), 0.89 (m, 2H); MS m / z : 526[M+H]

[0104] Example 27. N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound of Example 27 below was prepared according to the following Reaction Scheme 8.

[0105] Reaction Scheme 8. [ka] Step 1) 4-(4-amino-2-fluorophenoxy)-3-nitropyridin-2-amine [ka] 4-Amino-2-fluorophenol (1.6 g, 12.6 mmol) was dissolved in DMF, and then potassium tert-butoxide (140 mg, 3.46 mmol) and 4-chloro-3-nitropyridin-2-amine (2 g, 11.5 mmol) were added and stirred at 80 °C for 1 hour. The reaction mixture was cooled to room temperature, diluted with brine, and extracted three times with ethyl acetate. The organic layer was concentrated, and the residue was purified by column chromatography to give the title compound (1.9 g, yield: 62%). MS m / z: 265[M+H]

[0106] Step 2) N-(4-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (120 mg, yield: 63%) was obtained in the same manner as in Example 1 using 4-(4-amino-2-fluorophenoxy)-3-nitropyridin-2-amine (100 mg, 0.38 mmol), the compound obtained in Step 1, and 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (116 mg, 0.45 mmol). MS m / z: 502[M+H]

[0107] Step 3) N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The compound obtained in Step 2, N-(4-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (120 mg, 0.24 mmol) was dissolved in methanol, Pd / C (25 mg, 0.24 mmol) was added, and the mixture was stirred under hydrogen gas for 12 hours. After removing the catalyst using a Celite filter and concentrating, the residue was purified by column chromatography to obtain the title compound (83 mg, yield: 74%). 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.34 (s, 1H), 7.96 (d, 1H), 7.67 (m, 6H), 7.23 (m, 1H), 7.17 (t, 1H), 5.93 (d, 1H), 5.59 (brs, 2H), 4.58 (brs, 2H); MS m / z : 473[M+H]

[0108] Example 28. N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (90 mg, yield: 80%) was obtained in the same manner as in Example 27, except that 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1H NMR (400 MHz, MeOH-d4) δ 8.41 (s, 1H), 7.89 (d, 1H), 7.62 (m, 3H), 7.54 (m, 3H), 7.29 (m, 2H), 6.29 (d, 1H); MS m / z : 473[M+H]

[0109] Example 29. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide [ka] The title compound (700 mg, yield: 77%) was obtained in the same manner as in Example 1, except that 4-(4-amino-2-fluorophenoxy)-3-iodopyridin-2-amine was used instead of 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine. 1 H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.31 (s, 1H), 7.94 (d, 1H), 7.69 (m, 2H), 7.54 (m, 5H), 7.29 (t, 1H), 6.17 (brs, 2H), 5.78 (d, 1H); MS m / z : 584[M+H]

[0110] Example 30. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2-phenylthiazole-5-carboxamide [ka] The title compound (35 mg, yield: 51%) was obtained in the same manner as in Example 1, except that 2-phenylthiazole-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 8.69 (d, 1H), 8.06 (m, 2H), 7.93 (m, 1H), 7.78 (m, 1H), 7.57 (m, 4H), 7.40 (m, 1H), 6.44 (brs, 2H), 5.97 (d, 1H); MS m / z : 441[M+H]

[0111] Example 31. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-2-phenylthiazole-5-carboxamide [ka] The title compound (24 mg, yield: 34%) was obtained in the same manner as in Example 1, except that 4-methyl-2-phenylthiazole-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.01 (m, 2H), 7.89 (d, 1H), 7.78 (d, 1H), 7.56 (m, 4H), 7.38 (t, 1H), 6.43 (brs, 2H), 5.96 (d, 1H), 2.67 (s, 3H); MS m / z : 455[M+H]

[0112] Example 32. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiazole-2-carboxamide [ka] The title compound (30 mg, yield: 35%) was obtained in the same manner as in Example 1, except that 5-phenylthiazole-2-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.55 (s, 1H), 8.03 (dd, 1H), 7.85-7.77 (m, 4H), 7.52 (m, 2H), 7.46 (d, 1H), 7.38 (t, 1H), 6.43 (s, 2H), 5.95 (d, 1H); MS m / z : 441[M+H]

[0113] Example 33. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiophene-2-carboxamide [ka] The title compound (35 mg, yield: 40%) was obtained in the same manner as in Example 1, except that 5-phenylthiophene-2-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.05 (d, 1H), 7.93 (dd, 1H), 7.78-7.76 (m, 3H), 7.66 (d, 1H), 7.48 (m, 2H), 7.42-7.35 (m, 2H), 6.43 (s, 2H), 5.96 (d, 1H); MS m / z : 440[M+H]

[0114] Example 34. Ethyl (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate [ka] The compound of Example 34 below was prepared according to the following Reaction Scheme 9.

[0115] Reaction Scheme 9. [ka] Step 1) tert-Butyl (4-((2-amino-3-nitropyridin-4yl)oxy-3-fluorophenyl)carbamate [ka] 4-(4-amino-2-fluorophenoxy)-3-nitropyridin-2-amine (1.6 g, 4.5 mmol) was dissolved in THF, and then Boc anhydride (1.9 g, 9.0 mmol) was added and stirred at room temperature for 12 hours. The organic layer was concentrated, and the residue was purified by column chromatography to give the title compound (1.6 g, yield: 98%). MS m / z: 365[M+H]

[0116] Step 2) tert-butyl (4-((2,3-aminopyridin-4yl)oxy-3-fluorophenyl)carbamate [ka] The compound obtained in Step 1, tert-butyl (4-((2-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)carbamate (1.6 g, 4.4 mmol), was dissolved in methanol, and Pd / C (0.46 g, 4.4 mmol) was added. The mixture was stirred under hydrogen gas for 12 hours. The catalyst was removed using a Celite filter and the mixture was concentrated. The residue was purified by column chromatography to obtain the title compound (1.3 g, yield: 89%). MS m / z: 335[M+H]

[0117] Step 3) tert-butyl (4-((2-amino-3-((ethoxycarbonyl)amino)pyridin-4-yl)oxy-3-fluorophenyl)carbamate [ka] tert-Butyl (4-((2,3-aminopyridin-4-yl)oxy-3-fluorophenyl)carbamate (900 mg, 2.7 mmol) obtained in Step 2 above was dissolved in THF, pyridine (430 μl, 5.4 mmol) was added, and the mixture was cooled to 0°C. Ethyl chloroformate (320 mg, 2.9 mmol) was added, and the mixture was stirred at 0°C for 30 minutes, then warmed to room temperature and stirred for 12 hours. The reaction mixture was concentrated, diluted with DCM, washed with NaCO, and washed with brine. The organic layer was concentrated, and the residue was purified by column chromatography to obtain the title compound (800 mg, yield: 73%). MS m / z: 407[M+H]

[0118] Step 4) Ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)carbamate [ka] tert-Butyl (4-((2-amino-3-((ethoxycarbonyl)amino)pyridin-4-yl)oxy-3-fluorophenyl)carbamate (800 mg, 2.0 mmol), the compound obtained in Step 3, was dissolved in 7 ml of DCM, and 3.5 ml of TFA was added and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate 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 (540 mg, yield: 90%). MS m / z: 307 [M+H]

[0119] Step 5) Ethyl (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate [ka] Using ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)carbamate (500 mg, 1.6 mmol) obtained in Step 4 above and 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, the title compound (500 mg, yield: 56%) was obtained in the same manner as in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.67 (brs, 1H), 8.34 (s, 1H), 7.92 (m, 1H), 7.81 (t, 1H), 7.64 (m, 3H), 7.56 (m, 3H), 7.30 (t, 1H), 7.01 (brs, 2H), 6.18 (d, 1H), 4.10 (q, 2H), 1.25 (t, 3H); MS m / z : 545[M+H]

[0120] Example 35. Ethyl (2-amino-4-(4-(5-ethyl-1-vinyl-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate [ka] The compound of Example 35 below was prepared according to the following Reaction Scheme 10.

[0121] Reaction Scheme 10. [ka] Step 1) Ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate [ka] Ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)carbamate (280 mg, 0.91 mmol) was dissolved in DMF, and NaH (46 mg, 1.14 mmol) was added at 0°C and stirred for 30 minutes. 2-Bromopropane (103 μl, 1.1 mmol) was slowly added at 0°C and stirred at room temperature for 12 hours. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was concentrated, and the residue was purified by column chromatography to obtain the title compound (260 mg, yield: 82%). MS m / z: 349[M+H]

[0122] Step 2) Ethyl (2-amino-4-(4-(5-ethyl-1-vinyl-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate [ka] The title compound (26 mg, yield: 64%) was obtained in the same manner as in Example 1 using ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate (30 mg, 0.086 mmol) obtained in Step 1 and 5-ethyl-1H-pyrazole-4-carboxylic acid. 1 H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.32 (s, 1H), 7.94 (d, 1H), 7.74 (d, 1H), 7.62 (m, 6H), 7.19 (t, 1H), 5.98 (brs, 2H), 5.85 (d, 1H), 4.28 (m, 1H), 4.06 (m, 2H), 2.98 (m, 2H), 1.24 (m, 6H), 1.09 (m, 6H); MS m / z : 547[M+H]

[0123] Example 36. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (35 mg, yield: 56%) was obtained in the same manner as in Example 1, except that 1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.44 (s, 1H), 7.90 (d, 1H), 7.78 (m, 2H), 7.72 (m, 2H), 7.61 (t, 1H), 7.56 (d, 1H), 7.38 (t, 1H), 6.43 (s, 2H), 5.96 (d, 1H); MS m / z : 527[M+H]

[0124] Example 37. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (34 mg, yield: 55%) was obtained in the same manner as in Example 1, except that 1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.51 (s, 1H), 7.89 (d, 1H), 7.83 (t, 1H), 7.7 (d, 1H), 7.52 (m, 3H), 7.38 (t, 1H), 6.43 (s, 2H), 5.96 (d, 1H); MS m / z: 528[M+H]

[0125] Example 38. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide [ka] The title compound (29 mg, yield: 91%) was obtained in the same manner as in Example 1, except that 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.65 (m, 6H), 7.40 (t, 1H), 6.44 (s, 2H), 6.00 (d, 1H).

[0126] Example 39. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide [ka] The title compound (11 mg, yield: 16%) was obtained in the same manner as in Example 1, except that 1-phenyl-1H-pyrazole-3-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.67 (s, 1H), 8.02 (m, 3H), 7.74 (m, 2H), 7.57 (m, 2H), 7.44 (m, 1H), 7.34 (m, 1H), 7.07 (s. 1H), 6.41 (s, 2H), 5.96 (d, 1H).

[0127] Example 40. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamide [ka] The title compound (45 mg, yield: 64%) was obtained in the same manner as in Example 1, except that 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.50 (s, 1H), 8.03 (m, 3H), 7.82 (m, 2H), 7.67 (m, 2H), 7.55 (m, 1H), 7.35 (m, 1H), 6.41 (s, 2H), 5.96 (d, 1H).

[0128] Example 41. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide [ka] The title compound (50 mg, yield: 68%) was obtained in the same manner as in Example 1, except that 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.07 (d, 1H), 7.81 (m, 2H), 7.76 (m, 5H), 7.33 (t, 1H), 6.41 (s, 2H), 5.96 (d, 1H), 2.59 (s, 3H).

[0129] Example 42. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide [ka] The title compound (20 mg, yield: 26%) was obtained in the same manner as in Example 1, except that 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.06 (d, 1H), 7.80 (m, 4H), 7.66 (m, 1H), 7.53 (t, 1H), 7.34 (t, 1H), 6.41 (s, 2H), 5.96 (d, 1H), 2.59 (s, 3H).

[0130] Example 43. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (300 mg, yield: 89%) was obtained in the same manner as in Example 29, except that 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.34 (s, 1H), 7.87 (m, 1H), 7.74 (s, 1H), 7.63 (m, 3H), 7.53 (m, 3H), 7.32 (t, 1H), 6.22 (s, 2H), 5.83 (d, 1H).

[0131] Example 44. N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (5 mg, yield: 13%) was obtained in the same manner as in Example 25, except that 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.34 (s, 1H), 7.89 (m, 1H), 7.80 (d, 1H), 7.64 (m, 3H), 7.56 (m, 3H), 7.36 (m, 1H), 6.19 (d, 1H), 5.96 (s, 2H), 5.81 (s, 1H).

[0132] Example 45. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] The title compound (32 mg, yield: 71%) was obtained in the same manner as in Example 2, except that 4-(4-amino-3-fluorophenoxy)-3-chloropyridin-2-amine was used instead of 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 7.76 (m, 1H), 7.62 (m, 3H), 7.56 (m, 2H), 7.26 (m, 1H), 7.02 (m, 1H), 6.46 (brs, 2H), 6.13 (d, 1H); MS m / z : 492[M+H]

[0133] Example 46. N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] 6-(4-amino-2-fluorophenoxy)-5-chloropyrimidin-4-amine (40 mg, 0.16 mmol) was dissolved in 3 mL of THF, followed by the addition of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (45 mg, 0.18 mmol), HATU (90 mg, 0.24 mmol), and DIPEA (41 μL, 0.24 mmol). The mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to give the title compound (32 mg, yield: 44%). 1 H NMR (500 MHz, DMSO-d6) δ 10.78 (s, 1H), 8.34 (s, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.64 (m, 3H), 7.56 (m, 2H), 7.48 (t, 1H), 7.36 (m, 3H); MS m / z : 493[M+H]

[0134] Example 47. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-5-ethyl-1-phenyl-pyrazole-4-carboxamide [ka] The title compound (33 mg, yield: 37%) was obtained in the same manner as in Example 46, except that 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.85 (d, 1H), 7.62 (m, 3H), 7.52 (m, 3H), 7.34 (m, 3H), 2.99 (q, 2H), 1.07 (t, 3H); MS m / z : 453[M+H]

[0135] Example 48. N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (40 mg, yield: 57%) was obtained in the same manner as in Example 46, except that 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.96 (s, 1H), 7.83 (d, 1H), 7.58 (m, 2H), 7.46 (m, 4H), 7.32 (m, 3H), 2.51 (s, 3H), 2.38 (s, 3H); MS m / z : 453[M+H]

[0136] Example 49. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-(p-tolyl)-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] The title compound (32 mg, yield: 40%) was obtained in the same manner as in Example 46, except that 1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.26 (s, 1H), 7.76 (d, 1H), 7.44 (d, 1H), 7.37 (m, 4H), 7.32 (t, 1H) 2.38 (s, 3H); MS m / z: 507[M+H]

[0137] Example 50. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-tetrahydropyran-3-yl-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] According to Example 46, using 1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, the title compound (47 mg, yield: 60%) was obtained in the same manner as in Example 46. 1 H NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.78 (d, 1H), 7.44 (m, 1H), 7.36 (m, 3H), 4.43 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 3.69 (t, 1H), 3.43 (m, 1H), 2.21 (m, 2H), 1.81 (m, 2H); MS m / z : 501[M+H]

[0138] Example 51. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-cyclohexyl-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] The title compound (38 mg, yield: 49%) was obtained in the same manner as in Example 46, except that 1-cyclohexyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.05 (s, 1H), 7.95 (s, 1H), 7.78 (d, 1H), 7.49 (m, 1H), 7.33 (m, 3H), 4.30 (m, 1H), 1.94 (m, 3H), 1.89 (m, 3H), 1.70 (m, 1H), 1.46 (m, 2H), 1.25 (m, 1H); MS m / z : 499[M+H]

[0139] Example 52. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] In Example 46, instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, the compound obtained in Production Example 2, was used, and the title compound (31 mg, yield: 39%) was obtained in the same manner as in Example 46. 1H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.43 (s, 1H), 7.97 (s, 1H), 7.83 (d, 1H), 7.73 (m, 2H), 7.60 (m, 1H), 7.49 (m, 2H), 7.37 (m, 3H); MS m / z : 511[M+H]

[0140] Example 53. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-pyrazole-3-carboxamide [ka] The title compound (33 mg, yield: 66%) was obtained in the same manner as in Example 46, except that 1-phenyl-1H-pyrazole-3-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.67 (s, 1H), 8.02 (d, 2H), 7.95 (m, 2H), 7.69 (m, 1H), 7.60 (m, 2H), 7.33 (m, 3H), 7.07 (s, 1H).

[0141] Example 54. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-triazole-4-carboxamide [ka] The title compound (30 mg, yield: 58%) was obtained in the same manner as in Example 46, except that 1-phenyl-1H-1,2,3-triazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.49 (s, 1H), 8.03 (d, 2H), 7.97 (m, 2H), 7.74 (d, 1H), 7.66 (m, 2H), 7.36 (m, 1H), 7.34 (m, 2H).

[0142] Example 55. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-methyl-1-phenyl-triazole-4-carboxamide [ka] The title compound (45 mg, yield: 87%) was obtained in the same manner as in Example 46, except that 5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.97 (d, 2H), 7.64 (m, 6H), 7.66 (m, 2H), 7.32 (m, 2H), 2.59 (s, 3H).

[0143] Example 56. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-methyl-triazole-4-carboxamide [ka] The title compound (285 mg, yield: 52%) was obtained in the same manner as in Example 46, except that 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.97 (d, 2H), 7.78 (m, 3H), 7.66 (m, 1H), 7.32 (m, 3H), 2.50 (s, 3H).

[0144] Example 57. N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide [ka] The title compound (32 mg, yield: 48%) was obtained in the same manner as in Example 46, except that 1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.12 (s, 1H), 8.34 (s, 1H), 7.97 (m, 1H), 7.90 (m, 2H), 7.88 (d, 1H), 7.58 (m, 2H), 7.42 (m, 1H), 7.37 (m, 1H), 7.30 (m, 3H); MS m / z : 425[M+H]

[0145] Example 58. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-tert-butyl-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] The title compound (53 mg, yield: 72%) was obtained in the same manner as in Example 46, except that 1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1H NMR (500 MHz, DMSO-d6) δ 10.74 (s, 1H), 7.95 (s, 2H), 7.77 (d, 1H), 7.44 (m, 2H), 7.33 (m, 2H), 1.67 (s, 9H); MS m / z : 473[M+H]

[0146] Example 59. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1,5-diphenyl-pyrazole-4-carboxamide [ka] The title compound (39 mg, yield: 50%) was obtained in the same manner as in Example 46, except that 1,5-diphenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.38 (s, 1H), 7.95 (s, 1H), 7.76 (d, 1H), 7.43-7.33 (m, 8H), 7.29-7.20 (m, 6H); MS m / z: 501[M+H]

[0147] Example 60. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(1-methyl-3-piperidyl)-5-(trifluoromethyl)pyrazole-4-carboxamide [ka] According to Example 46, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was replaced with 1-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid, and the title compound (35 mg, yield: 44%) was obtained in the same manner as in Example 46. MS m / z: 514[M+H]

[0148] Example 61. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-4-methyl-2-phenyl-thiazole-5-carboxamide [ka] The title compound (22 mg, yield: 30%) was obtained in the same manner as in Example 46, except that 4-methyl-2-phenylthiazole-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.00 (s, 2H), 7.97 (s, 1H), 7.80 (d, 1H), 7.56 (m, 3H), 7.49 (m, 1H), 7.34 (m, 3H), 2.68 (s, 3H); MS m / z : 456[M+H]

[0149] Example 62. N-(4-((5-chloro-6-(cyclopropylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide [ka] 6-(4-amino-2-fluorophenoxy)-5-chloro-N-cyclopyrimidin-4-amine (40 mg, 0.14 mmol) was dissolved in 3 mL of THF, followed by the addition of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (42 mg, 0.16 mmol), HATU (77 mg, 0.20 mmol), and DIPEA (47 μL, 0.27 mmol). The mixture was stirred at room temperature for 12 hours. The reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The residue was purified by prep-HPLC (0.1% formic acid in water / acetonitrile) to give the title compound (30 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 7.89 (m, 1H), 7.58 (m, 3H), 7.52 (m, 3H), 7.51 (m, 1H), 7.31 (t, 1H), 2.85 (m, 1H), 0.68 (m, 2H), 0.61 (m, 2H).

[0150] Example 63. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)imidazole-4-carboxamide [ka] The title compound (40 mg, yield: 51%) was obtained in the same manner as in Example 46, except that 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylic acid. 1 H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.93 (d, 1H), 7.69 (m, 1H), 7.59 (m, 5H), 7.36 (m, 3H); MS m / z: 493[M+H]

[0151] 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 example compounds against RON, the IC50 of the compounds was measured using TR-FRET (Time-Resolved Fluorescence Energy Transfer).

[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), 0.01% Tween-20, 5 mM DTT, 0.5 mM Na3VO4, 2 mM EGTA, 10 mM MgCl2).

[0153] 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.

[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 high control wells and low control wells.

[0155] 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. The IC50 value of each example compound was calculated using the GraphPd Prism7 program.

[0156] [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.

[0157] 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).

[0158] 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.

[0159] 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 high control wells and low control wells.

[0160] 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. The IC50 value of each example compound was calculated using the GraphPd Prism7 program.

[0161] 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)

[0162] [Table 2A] [Table 2B] [Table 2C]

Claims

1. A pyridine derivative compound represented by the following formula 2 or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (In the above chemical formula 2, W is N or CH; wherein X is O; The Y is hydrogen, halogen, C １ -C ６ Alkyl, and C ３ -C ６ cycloalkyl; The Z exists in two positions, one of which is NR 2 R 3 or halogen, and the other of which is hydrogen, halogen, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ６ -C １０ Aryl, halogen-substituted C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, hydroxy, carboxylic acid, C １ -C ６ Alkylcarbonyl, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ alkylcarbonyloxy, nitro, cyano, carbamoyl, urea, thiol, or NR ２ R3, The R １ is hydrogen or C １ -C ６ is alkyl, A represents a substituted or unsubstituted 5-membered heteroaryl containing 1 to 4 hetero ring atoms selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the substituted 5-membered heteroaryl has a substituent such as a halogen, an amine, C １ -C ６ Alkyl, halogen-substituted C １ -C ６ Alkyl, C ６ -C １０ Aryl, C １ -C ６ Alkoxy, C １ -C ６ Alkylthio, hydroxy, carboxylic acid, C １ -C ６ Alkylcarbonyl, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ alkylcarbonyloxy, nitro, cyano, carbamoyl, urea, thiol, or NR ２ R ３ and The B is hydrogen, C １ -C ６ Alkyl, substituted C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, C ２ -C ６ Heterocycloalkyl, substituted C ２ -C ６ Heterocycloalkyl, C ６ -C １０ Aryl, substituted C ６ -C １０ aryl, where the substituents are halogen, C １ -C ６ Alkyl, halogen-substituted C １ -C ６ Alkyl, or C １ -C ６ is an alkoxy, The R ２ and R ３ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ Cycloalkyl, C(O)R ４ or C(O)OR ５ and The R ４ is C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ３ -C ７ is cycloalkyl, The R ５ is C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ３ -C ７ is cycloalkyl, The halogens are each independently selected from the group consisting of F, Cl, Br, and I.

2. W is N or CH, Z exists in two positions, one is NR 2 R 3 or halogen, and the other is hydrogen, halogen, C １ -C ６ alkyl, or NR ２ R3, and the R ２ and R ３ are each independently hydrogen, C １ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, substituted C ３ -C ６ 2. The compound of claim 1, wherein R is cycloalkyl and the remaining substituents are as defined in Formula 2, or a pharmaceutically acceptable salt thereof.

3. A comprises a heteroaryl group selected from the group consisting of pyrazole, imidazole, triazole, oxazole, isoxazole, thiazole, and thiophene, and the heteroaryl group is substituted or unsubstituted, and the substituents of the substituted heteroaryl group are halogen, amine, C １ -C ６ Alkyl, halogen-substituted C １ -C ６ Alkyl, or C ６ -C １０ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

4. The B is C ３ -C ６ Alkyl, C ３ -C ６ Cycloalkyl, phenyl, halogen-substituted phenyl, C １ -C ６ Alkyl-substituted phenyl, C １ -C ３ Alkoxy-substituted phenyl, benzyl, tolyl, C １ -C ３ 2. The compound of claim 1, which is an alkyl-substituted piperidine or tetrahydropyran, or a pharmaceutically acceptable salt thereof.

5. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is F.

6. The R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

7. The compounds include N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1H-pyrazole-4- )-1-methyl-1H-pyrazole-4-carboxamide, 5-amino-N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3 N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-benzyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-chloro-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-diphenyl-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-fluoro-1-phenyl-1H-pyrazole-4-carboxamide, N-(4-((2-acrylamido-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazo N-(4-((2-(N-acrylacrylamido)-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((3-chloro-2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide N-(4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide , N-(4-((2-cyclopropanecarboxamido)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2,3-diaminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2,3-diaminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazole-4-carboxamide )oxy)-3-fluorophenyl)-2-phenylthiazole-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-2-phenylthiazole-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiazole-2-carboxamide, N-(4-(( 2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiophene-2-carboxamide, ethyl (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate, ethyl (2-amino-4-(4-(5-ethyl-1-phenyl-1H-pyrazole-4-carboxamide) N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-1,2,3-triazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxamide, N- (4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1-phenyl-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide, N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-ethyl-1-phenyl-pyrazole-4-carboxamide, N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(p-tolyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-tetrahydropyran-3-yl-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino- 5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-cyclohexyl-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-pyrazole-3 -carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-triazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-methyl-1-phenyl-triazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-methyl- riazole-4-carboxamide, N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-tert-butyl-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1,5-diphenyl-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(1-methyl-3-piperidyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-4-methyl-2-phenyl-thiazole-5-carboxamide, N-(4-((5-chloro-6-(cyclopropylamino)pyrimidin-4-yl, 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)imidazole-4-carboxamide,

8. 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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