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] Cross-reference with related applications

[0002] This application claims priority to Korean Patent Application No. 10-2021-0082699, filed on June 24, 2021, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0004] This invention relates to a novel compound as a protein kinase inhibitor. Specifically, this invention relates to a novel compound as a RON inhibitor. Background Technology

[0005] At least 400 protein kinases are known to catalyze the phosphate transfer reaction from adenosine triphosphate (ATP) to a protein substrate. The specific amino acid to which the phosphate group is transferred is tyrosine, serine, or threonine; therefore, protein kinases are often referred to as protein tyrosine kinases (PTKs) or serine / threonine kinases (STKs).

[0006] Protein kinases constitute a large family of structure-associated enzymes responsible for controlling a wide variety of signaling pathways within the cell. These signaling pathways include many others involving the transfer of phosphorylation groups to target proteins. These phosphorylation events act as molecular on / off switches, regulating the biological function of target proteins or protein complexes. Suitable functions for protein kinases in signaling pathways include activating or inactivating metabolic enzymes, regulating proteins, receptors, cytoskeletal proteins, ion channels and pumps, and transcription factors. Uncontrolled signaling due to defects in protein phosphorylation control is associated with many diseases, including inflammation, cancer, allergies / asthma, immune system disorders, central nervous system disorders, and angiogenesis.

[0007] Almost all kinases contain similar catalytic domains of 250-300 amino acids. Kinases can be classified according to their phosphorylated substrates, and sequence motifs that typically correspond to each of these kinase families have been identified.

[0008] Meanwhile, RON (receptor originated from nantes), one of the tyrosine protein kinase receptors, is also known as macrophage-stimulating factor 1 receptor (MST1R) and has been reported to promote cancer cell invasion and metastasis. Overexpression of RON is also known to occur in various tumor types.

[0009] Activation of tyrosine protein kinases such as RON in tumor cells increases tumor cell proliferation, invasion, and metastasis, and also enhances tumor cell resistance to apoptosis and cytotoxic therapies. Therefore, selective small-molecule kinase modulators targeting tyrosine protein kinases such as RON are expected to have therapeutic potential in treating cancers where activation of RON receptors and other receptors plays a crucial role in the occurrence and progression of primary tumors and secondary metastases. Consequently, ongoing research is underway into various inhibitors for selectively inhibiting the kinase activity of RON, a tyrosine protein. Summary of the Invention

[0010] Technical issues

[0011] One aspect of the present invention provides a novel compound having protein kinase inhibitory activity.

[0012] Another aspect of the present invention provides a compound that can be used to prevent or treat cancer.

[0013] Another aspect of the present invention provides a compound that can be used to prevent or treat immune-related diseases.

[0014] Another aspect of the present invention provides a compound that can be used as a RON inhibitor.

[0015] Technical solutions

[0016] To achieve the above objectives, according to one aspect of the present invention, a pyridine derivative of Formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0017] [Formula 1]

[0018]

[0019] In Equation 1 above,

[0020] The above W is N or CH,

[0021] The above X is O,

[0022] The Y mentioned above is selected from hydrogen, halogens, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups.

[0023] The Z mentioned above is selected from 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 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl carbonyloxy, nitro, cyano, carbamoyl, urea, mercapto, and NR 2 R 3At least one of them,

[0024] The above R 1 It is hydrogen or C1-C6 alkyl.

[0025] The A above represents a substituted or unsubstituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen, wherein the substituents of the substituted 5-membered heteroaryl group are halogens, amines, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, C6-C6 alkyl groups, etc. 10 Aryl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy, carboxylic acid, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl carbonyloxy, nitro, cyano, carbamoyl, urea, mercapto, or NR 2 R 3 ,

[0026] The above B represents hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C2-C6 heterocyclic alkyl, substituted C2-C6 heterocyclic alkyl, C6-C 10 Aryl or substituted C6-C 10 aryl, wherein the substituent is halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, or C6-C 10 Aryl,

[0027] The above R 2 and R 3 Each of these can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, or C(O)R. 4 or C(O)OR 5 ,

[0028] The above R 4 It is a C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, and

[0029] The above R 5 It is a C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl.

[0030] The halogens mentioned therein are each independently selected from F, Cl, Br and I.

[0031] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of formula 1 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0032] Beneficial effects

[0033] The present invention may provide a novel compound or a pharmaceutically acceptable salt thereof, which can be effectively used to treat various immune-related diseases and as an anticancer drug by inhibiting the activity of protein kinases, particularly RON receptors, but the effects of the present invention are not limited thereto. Detailed Implementation

[0034] According to one aspect, the present invention provides a novel pyridine-derived compound of Formula 1 as defined above, or a pharmaceutically acceptable salt thereof.

[0035] In this invention, unless otherwise stated, the compounds are intended to include compounds of Formula 1, their stereoisomers such as enantiomers and diastereomers, solvates, prodrugs, etc.

[0036] [Formula 1]

[0037]

[0038] In Equation 1 above,

[0039] The above W is N or CH,

[0040] The above X is O,

[0041] The Y mentioned above is selected from hydrogen, halogens, C1-C6 alkyl groups, and C3-C6 cycloalkyl groups.

[0042] The Z mentioned above is selected from 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 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl carbonyloxy, nitro, cyano, carbamoyl, urea, mercapto, and NR 2 R 3 At least one of them,

[0043] The above R 1 It is hydrogen or C1-C6 alkyl.

[0044] The A above represents a substituted or unsubstituted 5-membered heteroaryl group containing 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen, wherein the substituents of the substituted 5-membered heteroaryl group are halogens, amines, C1-C6 alkyl groups, halogen-substituted C1-C6 alkyl groups, C6-C6 alkyl groups, etc. 10 Aryl, C1-C6 alkoxy, C1-C6 alkylthio, hydroxy, carboxylic acid, C1-C6 alkyl carbonyl, C1-C6 alkoxy carbonyl, C1-C6 alkyl carbonyloxy, nitro, cyano, carbamoyl, urea, mercapto, or NR 2 R 3 ,

[0045] The above B represents hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C2-C6 heterocyclic alkyl, substituted C2-C6 heterocyclic alkyl, C6-C 10 Aryl or substituted C6-C 10 aryl, wherein the substituent is halogen, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, C1-C6 alkoxy, or C6-C 10 Aryl,

[0046] The above R 2 and R 3 Each of these can be independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, or C(O)R. 4 or C(O)OR 5 ,

[0047] The above R 4 It is a C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl, and

[0048] The above R 5 It is a C1-C6 alkyl, C2-C6 alkenyl, or C3-C7 cycloalkyl.

[0049] The halogens mentioned therein are each independently selected from F, Cl, Br and I.

[0050] In this specification, the term "substitution" means that a hydrogen atom bonded to a carbon atom in a structure is replaced by another substituent, and the position of substitution is not limited, as long as it is the position of the hydrogen atom being substituted, i.e., the position that can be replaced by a substituent, and when hydrogen atoms at two or more positions are substituted, the two or more substituents can be the same or different from each other.

[0051] In this specification, unless otherwise defined, "substituent" may be selected from deuterium, halogen, hydroxyl, C1-C... 10 Alkyl, C3-C 12 cycloalkyl, C1-C 10 Alkoxy, C5-C 12 aryloxy group, C1-C 10 Alkyl sulfoxy, C5-C 12 aryl sulfoxy, C1-C 10 Alkyl sulfoxide, C5-C 12 Aryl sulfoxide group, C1-C 10 Haloalkyl, C2-C 20 alkenyl, C0-C 10 Amine, nitrile, nitro group, imide, amide, ketone group, carbonyl group, carboxylic acid, carbamoyl group, ester, C5-C 12 Aryl and C5-C 12One or more of the heteroaryl groups.

[0052] In this specification, unless otherwise defined, "alkyl" can be straight-chain or branched, and preferably has 1 to 20 carbon atoms. Examples of alkyl 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, 5-methylhexyl, etc.

[0053] In this specification, unless otherwise defined, "cycloalkyl" can mean a cyclic saturated hydrocarbon and preferably has 3 to 20 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 3-methylcyclopentyl, 2,3-dimethylcyclopentyl, cyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2,3-dimethylcyclohexyl, 3,4,5-trimethylcyclohexyl, 4-tert-butylcyclohexyl, cycloheptyl, cyclooctyl, etc.

[0054] In this specification, unless otherwise defined, "alkoxy" can be straight-chain, branched, or cyclic, and preferably has 1 to 20 carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, neopentoxy, isopentoxy, n-hexyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy, n-octoxy, n-nonoxy, n-decoxy, benzoxy, p-methylbenzoxy, etc.

[0055] In this specification, unless otherwise defined, "alkenyl" can be straight-chain or branched, and preferably has 2 to 20 carbon atoms. Examples of alkenyl 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, stilbene, styryl, etc.

[0056] In this specification, unless otherwise defined, "aryl" can be monoaryl, diaryl, or polycyclic aryl having three or more rings, and when an aryl comprises two or more cyclic structures, each ring may be fused or included in a spiro compound, and the aryl preferably has 5 to 12 carbon atoms. Examples of aryl include, but are not limited to, phenyl, biphenyl, terphenyl, naphthyl, anthraceneyl, phenanthryl, pyrene, perylene, etc.

[0057] In this specification, "heterocyclic atom" means a non-carbon atom contained in a ring. Unless otherwise defined, a heterocyclic atom may include one or more atoms selected from oxygen, nitrogen, selenium, and sulfur.

[0058] In this specification, unless otherwise defined, “heterocyclic alkyl” can mean a cyclic saturated hydrocarbon containing heterocyclic atoms, and preferably has 2 to 20 carbon atoms.

[0059] In this specification, "heteroaryl" can mean an aromatic hydrocarbon containing heterocyclic atoms. Unless otherwise defined, a heteroaryl can be monocyclic or polycyclic, and when a heteroaryl comprises two or more cyclic structures, each ring can be fused or included in a spiro form, and the heteroaryl preferably has 5 to 12 carbon atoms. Examples of heteroaryl include thiophene, furanyl, pyrrole, imidazolyl, thiazolyl, and others. azole group, Diazolyl, pyridyl, bipyridyl, pyrimidinyl, triazinyl, triazolyl, acridineyl, pyridazinyl, quinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyridopyrimidinyl, pyridopyrazinyl, pyrazenopyrazinyl, isoquinolinyl, indoleyl, carbazoleyl, benzo[] Azolium, benzimidazole, benzothiazolyl, etc., but not limited to these.

[0060] According to one embodiment, the present invention provides a novel pyridine derivative compound of formula 2 below, or a pharmaceutically acceptable salt thereof.

[0061] [Equation 2]

[0062]

[0063] Where W is N or CH, and Z is selected from hydrogen, halogen, C1-C6 alkyl, and NR. 2 R 3 At least one of the above R 2 and R 3 Each of them is independently hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or substituted C3-C6 cycloalkyl, and the remaining substituents are the same as those defined in Formula 1.

[0064] According to one embodiment, A may include a subset selected from pyrazole, imidazole, triazole, azole, isotonic The heteroaryl groups of azoles, thiazoles, and thiophenes, wherein the heteroaryl group may be substituted or unsubstituted, and the substituent of the substituted heteroaryl group may be halogen, amine, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or C6-C6 alkyl. 10 Aryl.

[0065] According to one embodiment, in Formula 1 above, B may include 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.

[0066] According to one embodiment, in Formula 1 above, Y is fluorine.

[0067] According to one implementation, in Equation 1 above, the Z exists at two or more locations.

[0068] According to one implementation, in Equation 1 above, the Z exists at two locations.

[0069] According to one implementation, in formula 1 above, the aforementioned R 1 It is hydrogen.

[0070] According to one embodiment, the compound of Formula 1 above can be selected from...

[0071] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0072] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0073] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide,

[0074] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide

[0075] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-phenyl-1H-pyrazole-4-carboxamide,

[0076] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide,

[0077] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide,

[0078] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0079] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide,

[0080] 5-Amino-N-(4-(((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide,

[0081] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0082] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0083] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-benzyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0084] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazol-4-carboxamide

[0085] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0086] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0087] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0088] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-chloro-1-phenyl-1H-pyrazole-4-carboxamide,

[0089] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-diphenyl-1H-pyrazole-4-carboxamide,

[0090] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-fluoro-1-phenyl-1H-pyrazole-4-carboxamide,

[0091] N-(4-((2-acrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0092] N-(4-((2-(N-acrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0093] N-(4-((3-chloro-2-(cyclopropanecarbamoyl)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0094] N-(4-((2-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0095] N-(4-((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0096] N-(4-((2-cyclopropanecarbamate)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0097] N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0098] N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0099] N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide,

[0100] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2-phenylthiazolyl-5-carboxamide,

[0101] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-2-phenylthiazolyl-5-carboxamide,

[0102] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiazolyl-2-carboxamide,

[0103] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiophene-2-carboxamide,

[0104] (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate,

[0105] (2-amino-4-(4-(5-ethyl-1-phenyl-1H-pyrazole-4-carbamate)-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate,

[0106] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0107] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0108] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3-phenyl-4-(trifluoromethyl)iso 5-oxazolium-5-carboxamide,

[0109] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide,

[0110] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-1,2,3-triazol-4-carboxamide,

[0111] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazol-4-carboxamide,

[0112] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-carboxamide,

[0113] N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0114] N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0115] N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0116] N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide,

[0117] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-5-ethyl-1-phenyl-pyrazole-4-carboxamide,

[0118] N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide,

[0119] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-(p-tolyl)-5-(trifluoromethyl)pyrazole-4-carboxamide,

[0120] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-tetrahydropyran-3-yl-5-(trifluoromethyl)pyrazole-4-carboxamide,

[0121] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-cyclohexyl-5-(trifluoromethyl)pyrazole-4-carboxamide,

[0122] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-(trifluoromethyl)pyrazole-4-carboxamide,

[0123] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-pyrazole-3-carboxamide,

[0124] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-triazol-4-carboxamide,

[0125] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-methyl-1-phenyl-triazol-4-carboxamide,

[0126] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-methyl-triazol-4-carboxamide,

[0127] N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide,

[0128] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-tert-butyl-5-(trifluoromethyl)pyrazole-4-carboxamide,

[0129] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1,5-diphenyl-pyrazole-4-carboxamide,

[0130] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(1-methyl-3-piperidinyl)-5-(trifluoromethyl)pyrazole-4-carboxamide,

[0131] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-4-methyl-2-phenyl-thiazolyl-5-carboxamide,

[0132] N-(4-((5-chloro-6-(cyclopropylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and

[0133] N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)imidazol-4-carboxamide,

[0134] And its structure is shown in Table 1 below.

[0135] [Table 1]

[0136]

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145] In this disclosure, "pharmaceutically acceptable salts" include salts commonly used to form alkali metal salts and addition salts to form free acids or free bases. The properties of these salts are not important, but they should 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 acid, and sulfonic acid groups, and examples of organic acids include formic acid, acetic acid, adipic acid, butyric acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, methanesulfonic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid, methanesulfonic acid, ethyl acetate, etc. Sulfonic acid, ethanedisulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, camphoric acid, camphorsulfonic acid, digluconic acid, cyclopentanepropionic acid, dodecyl sulfonic acid, glucoheponic acid, glycerophosphonic acid, heptanoic acid, hexanoic acid, 2-hydroxyethanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmitic acid, pectic acid, persulfate, 2-phenylpropionic acid, picric acid, neopentanoic acid, thiocyanate, undecanoic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactosidic acid, and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of the compounds of Formula 1 include metal salts, such as those made of aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or salts made of organic bases including primary, secondary, and tertiary amines, or substituted amines including cyclic amines such as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucosamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, and trimethylamine. All these salts can be prepared from the corresponding compounds of the invention by conventional methods by reacting, for example, a suitable acid or base with a compound of Formula 1. Compounds of Formula 1 can also form internal salts when a basic group and an acidic group are present in the same molecule.

[0146] In this invention, "solvent" 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, tert-butyl acetate, isobutyl acetate, methyl ethyl ketone, 2-pentanone, tetrahydrofuran, acetonitrile, chloroform, toluene, and mixtures thereof.

[0147] 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.

[0148] The pharmaceutical composition may be used to prevent or treat protein kinase-mediated diseases, but the uses of the present invention are not limited to these diseases.

[0149] In one embodiment, the pharmaceutical composition can be used to prevent or treat RON-mediated diseases.

[0150] The pharmaceutical compositions according to the invention comprise a therapeutically effective amount of a compound of formula 1 above or a pharmaceutically acceptable salt thereof.

[0151] In one embodiment, the disease may be selected from cancers such as lung cancer, breast cancer, colorectal cancer, kidney cancer, pancreatic cancer, head cancer, neck cancer, hereditary papillary renal cell carcinoma, childhood hepatocellular carcinoma, and stomach cancer, but is not limited thereto.

[0152] In another embodiment, the disease may be selected from inflammatory disorders, cardiovascular diseases, virus-induced diseases, circulatory system diseases, fibroproliferative diseases, and pain-sensitizing immune diseases, but is not limited thereto.

[0153] To treat the above-mentioned diseases, the pharmaceutical composition may be administered to a subject who needs to prevent or treat the above-mentioned diseases.

[0154] In this specification, the term "prevention" means reducing the risk of developing a disease or disorder, and refers to any action that inhibits or delays the onset of a disease by preventing the progression of one or more clinical symptoms of the disease in a subject who is susceptible to or prone to a disease but has not yet experienced the disease or exhibited symptoms of the disease.

[0155] In this specification, the term "treatment" means to alleviate a disease or disorder, and refers to any action that improves or beneficially alters the symptoms of a disease by preventing or reducing the progression of the disease or one or more of its clinical symptoms.

[0156] In this specification, the term "carrier" refers to a compound that facilitates the introduction of a compound into cells or tissues. Pharmaceutical compositions can be prepared in unit dose form by using a pharmaceutically acceptable carrier, or by incorporating it into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension, or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granules, tablet, capsule, or gel (e.g., hydrogel), and may additionally include dispersants or stabilizers.

[0157] Furthermore, compounds of Formula 1 or pharmaceutically acceptable salts thereof contained in the pharmaceutical composition can be delivered in pharmaceutically acceptable carriers, such as colloidal suspensions, powders, saline solutions, lipids, liposomes, or microspheres or nanospheres. These can be complexed or bound to a medium and can be delivered in vivo using delivery systems known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensing agents, polysaccharides, polyamino acids, dendritic macromolecules, saponins, adsorption enhancers, or fatty acids.

[0158] In addition, pharmaceutically acceptable carriers may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylparaben, propylparaben, talc, magnesium stearate, mineral oil, etc., commonly used in formulations. Furthermore, in addition to the above components, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc., may also be included.

[0159] The pharmaceutical compositions according to the present invention can be administered orally or parenterally in clinical administration and can be used in the form of general pharmaceutical formulations. That is, the pharmaceutical compositions of the present invention can be administered in various formulations for oral and parenteral administration in actual clinical administration, and are prepared using commonly used diluents or excipients such as fillers, expanders, binders, wetting agents, disintegrants, and surfactants during formulation. Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid dosage forms are prepared by mixing herbal extracts or herbal fermentation products with at least one excipient such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc., in addition to water and liquid paraffin as commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. For non-aqueous solutions and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate can be used. As a base for suppositories, Wiptsol can be used. TM Polyethylene glycol, Tween TM 61. Cocoa butter, lauryl fat, glycerin, gelatin, etc.

[0160] When the pharmaceutical composition is administered for clinical purposes, the effective dose of the compound of Formula 1 above or a pharmaceutically acceptable salt thereof may vary with a variety of factors, such as the method of formulation, method of administration, patient's age, weight, sex, condition and diet, time of administration, route of administration, excretion rate, drug combination and sensitivity of response, but may generally be from 0.01 mg / day to 20 mg / day per kg of adult patient body weight, preferably from 1 mg / day to 10 mg / day, and may be administered at regular intervals, in divided doses several times a day, preferably 2 to 3 times a day, as determined by a physician or pharmacist.

[0161] On the other hand, the present invention provides a method for treating protein kinase-mediated diseases, particularly RON-mediated diseases, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula 1 above or a pharmaceutically acceptable salt thereof.

[0162] On the other hand, the present invention provides a method for inhibiting RON receptor activity, the method comprising administering to a subject a therapeutically effective amount of a compound of formula 1 above or a pharmaceutically acceptable salt thereof.

[0163] In this specification, the term "therapeuticly effective amount" refers to the amount by which each formulation, in the course of treatment with the formulation itself, achieves the goal of reducing the severity and frequency of disease attacks, while avoiding adverse reactions commonly associated with other therapies. For example, effective oncology agents exhibit effects such as prolonging patient survival, inhibiting the proliferation of tumor-associated cells, or causing tumor regression.

[0164] In the following text, exemplary compounds of the present invention can be prepared according to the methods described below, but the compounds of the present invention are not limited to the preparation methods described.

[0165] Preparation Example 1. 4-(4-amino-2-fluorophenoxy)-3-chloropyridine-2-amine

[0166]

[0167] In the following text, the compound of Preparation Example 1 was prepared according to reaction scheme 1 described below.

[0168] Reaction scheme 1.

[0169]

[0170] Step 1) N-(3-chloropyridin-2-yl)-1,1-diphenylmethylene

[0171]

[0172] 2,3-Dichloropyridine (21 g, 142 mmol) was dissolved in methyl tert-butyl ether (MTBE), and then Pd(OAc)₂ (318 mg, 1.42 mmol), rac-BINAP (1.4 g, 2.13 mmol), Cs₂CO₃ (0.9 g, 2.84 mmol), and benzophenone imine (26 g, 142 mmol) were added. The reaction mixture was refluxed and stirred at 70 °C for 12 hours. The reaction mixture was cooled to room temperature, and the resulting solid was filtered through diatomaceous earth to concentrate the solvent. The residue was purified by column chromatography to give the title compound (20 g, yield: 48%).

[0173] MS m / z: 293 [M+H]

[0174] Step 2) N-(3-chloropyridin-2-yl)-1,1-diphenylmethylene

[0175]

[0176] The compound N-(3-chloropyridin-2-yl)-1,1-diphenylmethyleneimine (20 g, 68.3 mmol) obtained in step 1 above was dissolved in THF (100 mL), and triisopropyl borate (19.3 g, 102 mmol) was added, followed by cooling 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, water (100 mL) was added, followed by sodium percarbonate (16 g, 102 mmol), and the mixture was stirred further at room temperature for 3 hours. A saturated aqueous solution of NaHCO3 (50 mL) was slowly added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was concentrated and used in step 3 below without further purification.

[0177] MS m / z: 309 [M+H]

[0178] Step 3) N-(3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl-1,1-diphenylmethylimine)

[0179]

[0180] The compound N-(3-chloropyridin-2-yl)-1,1-diphenylmethyleneimine (20 g, 65 mmol) 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 give the title compound (21 g, yield: 72%).

[0181] MS m / z: 448 [M+H]

[0182] Step 4) 4-((3-chloro-2-(diphenylmethylene)amino)pyridin-4-yl)oxy-3-fluoroaniline

[0183]

[0184] The compound N-(3-chloro-4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl-1,1-diphenylmethyleneimine (20 g, 44.6 mmol) obtained in step 3 above was dissolved in isopropanol, and ammonium sulfide (30.4 mL, 446 mmol) was added. The mixture was then stirred at room temperature for 1 hour. The reaction mixture was then stirred again at 70 °C for 3 hours. After the reaction was complete, water was added, and the reaction mixture was cooled to room temperature. The resulting solid was obtained by filtration, and butyl acetate was added to it. The solid was heated and dissolved at 80 °C, and heptane was added. The reaction mixture was then cooled to room temperature. After the reaction mixture was cooled to room temperature, the resulting solid was filtered and dried to give the title compound (14 g, 75%).

[0185] MS m / z: 418 [M+H]

[0186] Step 5) 4-(4-amino-2-fluorophenoxy)-3-chloropyridine-2-amine

[0187]

[0188] The compound 4-((3-chloro-2-(diphenylmethylene)amino)pyridin-4-yl)oxy-3-fluoroaniline (14 g, 33 mmol) obtained in step 4 above was dissolved in THF, and 1 M HCl (14 ml) was added. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then saturated NaHCO3 was added. The reaction mixture was extracted three times with ethyl acetate. The organic solution was washed with brine and concentrated. The residue was purified by column chromatography to give the title compound (7.1 g, yield: 84%).

[0189] MS m / z: 254 [M+H]

[0190] Preparation Example 2. 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0191]

[0192] In the following text, the compound of Preparation Example 2 was prepared according to reaction scheme 2 described below.

[0193] Reaction scheme 2.

[0194]

[0195] Step 1) Ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-ketobutyrate

[0196]

[0197] Ethyl 4,4,4-trifluoro-3-ketobutyrate (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%).

[0198] MS m / z: 241 [M+H]

[0199] Step 2) Ethyl 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate

[0200]

[0201] The compound ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-ketobutyrate (0.5 g, 2.1 mmol) obtained in step 1 above and (2-fluorophenyl)hydrazine (0.263 g, 2.1 mmol) were dissolved in 7 mL of ethanol. The reaction mixture was then stirred at 70 °C for 4 hours and extracted with ethyl acetate and water. The residue was purified by column chromatography to give the title compound (0.38 g, yield: 60%).

[0202] MS m / z: 303 [M+H]

[0203] Step 3) 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid

[0204]

[0205] The compound ethyl 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (0.38 g, 1.3 mmol) obtained in step 2 above was dissolved in 4 ml of ethanol, and then 2 ml of 6N sodium hydroxide solution was added at room temperature, followed by stirring for 1 hour. Ice water was added to the reaction product, and the resulting solid was filtered to give the title compound (0.18 g, yield: 52%).

[0206] MS m / z: 275 [M+H]

[0207] Example 1. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0208]

[0209] In the following text, the compound of Example 1 was prepared according to reaction scheme 3 described below.

[0210] Reaction scheme 3.

[0211]

[0212] The compound 4-(4-amino-2-fluorophenoxy)-3-chloropyridin-2-amine (50 mg, 0.20 mmol) obtained in Preparative Example 1 was dissolved in 3 mL of THF, and then 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid (61 mg, 0.24 mmol), HATU (114 mg, 0.3 mmol), and DIPEA (52 μl, 0.3 mmol) were added. The mixture was then 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 preparative HPLC (0.1% formic acid aqueous solution / acetonitrile) to give the title compound (72 mg, yield: 74%).

[0213] 1 MS m / z:492[M+H]

[0214] Example 2. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0215]

[0216] In a manner similar to that of Example 1, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (4 mg, yield: 36%).

[0217] 1 H NMR (400MHz, DMSO-d6) δ8.16(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]

[0218] Example 3. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-pyrazole-4-carboxamide

[0219]

[0220] In a manner similar to that of Example 1, 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (7 mg, yield: 50%).

[0221] 1 H NMR (400MHz, DMSO-d6) δ10.14(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]

[0222] Example 4. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide

[0223]

[0224] In a manner similar to that of Example 1, 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (11 mg, yield: 60%).

[0225] 1 H NMR(400MHz,DMSO-d6)δ10.14(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]

[0226] Example 5. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-ethyl-1-phenyl-1H-pyrazole-4-carboxamide

[0227]

[0228] In a manner similar to that of Example 1, 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (8 mg, yield: 55%).

[0229] 1 H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.32(s,1H),7.97(d,1H),7.78(d,1H),7.62(m,4 H),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]

[0230] Example 6. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxamide

[0231]

[0232] In a manner similar to that of Example 1, 5-(difluoromethyl)-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (51 mg, yield: 68%).

[0233] 1H NMR (400MHz, DMSO-d6) δ10.55(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]

[0234] Example 7. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide

[0235]

[0236] In a manner similar to that of Example 1, 1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (51 mg, yield: 77%).

[0237] 1 H NMR(400MHz,DMSO-d6)δ10.26(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]

[0238] 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

[0239]

[0240] In a manner similar to that of Example 1, 1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (46 mg, yield: 58%).

[0241] 1H NMR(400MHz,DMSO-d6)δ10.77(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(d,1H),4.43(m,1H),3.99(m,1H),3.91(m,1H),3.70(m,1H),3.35(m,1H),2.20(m,2H),1.81(m,2H); MS m / z:500[M+H]

[0242] Example 9. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide

[0243]

[0244] In a manner similar to that of Example 1, 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (54 mg, yield: 83%).

[0245] 1 H NMR(400MHz,DMSO-d6)δ10.41(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]

[0246] Example 10. 5-Amino-N-(4-(((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide

[0247]

[0248] In a manner similar to that of Example 1, 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (29 mg, yield: 42%).

[0249] 1H NMR(400MHz,DMSO-d6)δ9.85(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]

[0250] Example 11. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0251]

[0252] In a manner similar to that of Example 1, 1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (40 mg, yield: 50%).

[0253] 1 H NMR (400MHz, DMSO-d6) δ10.83(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]

[0254] Example 12. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0255]

[0256] In a manner similar to that of Example 1, 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid obtained in Preparation Example 2 was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (20 mg, yield: 33%).

[0257] 1H NMR(400MHz,MeOD-d4)δ10.86(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]

[0258] Example 13. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-benzyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0259]

[0260] In a manner similar to that of Example 1, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (38 mg, yield: 48%).

[0261] 1 H NMR(400MHz,DMSO-d6)δ10.70(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]

[0262] Example 14. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazol-4-carboxamide

[0263]

[0264] In a manner similar to that of Example 1, 2,5-dimethyl-1-phenyl-1H-imidazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (21 mg, yield: 30%).

[0265] 1H NMR (400MHz, DMSO-d6) δ10.18(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]

[0266] Example 15. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0267]

[0268] In a manner similar to that of Example 1, 1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (51 mg, yield: 51%).

[0269] 1 H NMR (400MHz, DMSO-d6) δ10.83(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]

[0270] Example 16. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0271]

[0272] In a manner similar to that of Example 1, 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (58 mg, yield: 56%).

[0273] 1H NMR(400MHz,DMSO-d6)δ10.77(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]

[0274] Example 17. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0275]

[0276] In a manner similar to that of Example 1, 1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (69 mg, yield: 74%).

[0277] 1 H NMR (400MHz, DMSO-d6) δ10.81(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]

[0278] Example 18. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-chloro-1-phenyl-1H-pyrazole-4-carboxamide

[0279]

[0280] In a manner similar to that of Example 1, 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (18 mg, yield: 20%).

[0281] 1 H NMR (400MHz, DMSO-d6) δ10.40(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]

[0282] Example 19. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1,5-diphenyl-1H-pyrazole-4-carboxamide

[0283]

[0284] In a manner similar to that of Example 1, 1,5-diphenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (27 mg, yield: 34%).

[0285] 1 H NMR(400MHz,DMSO-d6)δ10.22(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]

[0286] Example 20. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-fluoro-1-phenyl-1H-pyrazole-4-carboxamide

[0287]

[0288] In a manner similar to that of Example 1, 5-fluoro-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (3.0 mg, yield: 3%).

[0289] 1 H NMR(400MHz,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]

[0290] Example 21. N-(4-((2-acrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0291]

[0292] In the following text, the compound of Example 21 was prepared according to reaction scheme 4 described below.

[0293] Reaction scheme 4.

[0294]

[0295] The compound N-(4-(((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide (100 mg, 0.20 mmol) from 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 min, diluted with DCM, and washed with brine. The organic layer was concentrated, and the residue was then purified by preparative HPLC (0.1% formic acid aqueous solution / acetonitrile) to give the title compound (23 mg, yield: 21%).

[0296] 1 H NMR(400MHz,DMSO-d6)δ10.82(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]

[0297] Example 22. N-(4-((2-(N-acrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0298]

[0299] The title compound (9 mg, yield: 8%) was obtained as a byproduct of Example 21.

[0300] 1 MS m / z:600[M+H]

[0301] Example 23. N-(4-((3-chloro-2-(cyclopropanecarbamoyl)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide)

[0302]

[0303] In the following text, the compound of Example 23 was prepared according to reaction scheme 5 described below.

[0304] Reaction scheme 5.

[0305]

[0306] The compound N-(4-(((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide (40 mg, 0.08 mmol) from Example 1 was dissolved in pyridine, and cyclopropane carbonyl chloride (9 μl, 0.09 mmol) was slowly added to it 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 then purified by preparative HPLC (0.1% formic acid aqueous solution / acetonitrile) to give the title compound (16 mg, yield: 34%).

[0307] 1 H NMR(400MHz,DMSO-d6)δ10.78(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]

[0308] Example 24. N-(4-((2-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0309]

[0310] In the following text, the compound of Example 24 was prepared according to reaction scheme 6 described below.

[0311] Reaction scheme 6.

[0312]

[0313] Step 1) 4-((2-chloropyridin-4-yl)oxy-3-fluoroaniline

[0314]

[0315] 4-Amino-2-fluorophenol (400 mg, 3.15 mmol) was dissolved in DMF, and then NaH (140 mg, 3.46 mmol) was added, followed by stirring at room temperature for 30 minutes. 2-Chloro-4-nitropyridine (500 mg, 3.15 mmol) was added, and the mixture was 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%).

[0316] MS m / z: 239 [M+H]

[0317] Step 2) N-(4-((2-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0318]

[0319] In a manner similar to that of Example 1, the title compound (180 mg, yield: 90%) was obtained by using the compound 4-((2-chloropyridin-4-yl)oxy-3-fluoroaniline (100 mg, 0.42 mmol) obtained in step 1 above and 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid (130 mg, 0.50 mmol).

[0320] 1 H NMR(400MHz,MeOH-d4)δ8.28(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]

[0321] Example 25. N-(4-((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0322]

[0323] In the following text, the compound of Example 25 was prepared according to reaction scheme 7 described below.

[0324] Reaction scheme 7.

[0325]

[0326] The compound N-(4-((2-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide (100 mg, 0.21 mmol) from Example 24 was dissolved in 1,4-dioxane. In an alkane, tert-butyl carbamate (74 mg, 0.63 mmol), Cs₂CO₃ (137 mg, 0.42 mmol), xantphos (12 mg, 0.02 mmol), and Pd₂dba₃ (20 mg, 0.02 mmol) were added, and the reaction mixture was purged with nitrogen for 10 min. The reaction mixture was stirred at 100 °C for 12 h. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC (0.1% formic acid aqueous solution / acetonitrile) to give the title compound (10 mg, yield: 11%).

[0327] 1 H NMR(400MHz,MeOH-d4)δ8.06(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]

[0328] Example 26. N-(4-((2-cyclopropanecarbamate)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0329]

[0330] In a manner similar to that of Example 23, N-(4-(((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide (Example 25) was used instead of the compound N-(4-(((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide according to Example 23 to obtain the title compound (2 mg, yield: 23%).

[0331] 1H NMR(400MHz,MeOH-d4)δ8.16(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]

[0332] Example 27. N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0333]

[0334] In the following text, the compound of Example 27 was prepared according to reaction scheme 8 described below.

[0335] Reaction scheme 8.

[0336]

[0337] Step 1) 4-(4-amino-2-fluorophenoxy)-3-nitropyridine-2-amine

[0338]

[0339] 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-nitropyridine-2-amine (2 g, 11.5 mmol) were added. The mixture was then 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%).

[0340] MS m / z: 265 [M+H]

[0341] Step 2) N-(4-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0342]

[0343] In a manner similar to that of Example 1, the title compound (120 mg, yield: 63%) was obtained by using the compound 4-(4-amino-2-fluorophenoxy)-3-nitropyridine-2-amine (100 mg, 0.38 mmol) obtained in step 1 above and 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid (116 mg, 0.45 mmol).

[0344] MS m / z: 502 [M+H]

[0345] Step 3) N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0346]

[0347] The compound N-(4-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide (120 mg, 0.24 mmol) obtained in step 2 above was dissolved in methanol, and Pd / C (25 mg, 0.24 mmol) was added. The mixture was then stirred in hydrogen for 12 hours. The catalyst was removed through a diatomaceous earth filter, the reaction mixture was concentrated, and the residue was purified by column chromatography to give the title compound (83 mg, yield: 74%).

[0348] 1 H MS m / z:473[M+H]

[0349] Example 28. N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0350]

[0351] In a manner similar to that of Example 27, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 27 to obtain the title compound (90 mg, yield: 80%).

[0352] 1H NMR(400MHz,MeOH-d4)δ8.41(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]

[0353] Example 29. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide

[0354]

[0355] In a manner similar to that of Example 1, 4-(4-amino-2-fluorophenoxy)-3-iodopyridine-2-amine was used instead of 4-(4-amino-2-fluorophenoxy)-3-chloropyridine-2-amine according to Example 1 to obtain the title compound (700 mg, yield: 77%).

[0356] 1 H NMR (400MHz, DMSO-d6) δ10.72(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]

[0357] Example 30. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2-phenylthiazolyl-5-carboxamide

[0358]

[0359] In a manner similar to that of Example 1, 2-phenylthiazol-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (35 mg, yield: 51%).

[0360] 1 H MS m / z:441[M+H]

[0361] Example 31. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-2-phenylthiazolyl-5-carboxamide

[0362]

[0363] In a manner similar to that of Example 1, 4-methyl-2-phenylthiazol-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (24 mg, yield: 34%).

[0364] 1 H MS m / z:455[M+H]

[0365] Example 32. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiazolyl-2-carboxamide

[0366]

[0367] In a manner similar to that of Example 1, 5-phenylthiazol-2-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (30 mg, yield: 35%).

[0368] 1 H NMR(400MHz,DMSO-d6)δ11.16(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]

[0369] Example 33. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiophene-2-carboxamide

[0370]

[0371] In a manner similar to that of Example 1, 5-phenylthiophene-2-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (35 mg, yield: 40%).

[0372] 1 H NMR(400MHz,DMSO-d6)δ10.52(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]

[0373] Example 34. Ethyl (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate

[0374]

[0375] In the following text, the compound of Example 34 was prepared according to reaction scheme 9 described below.

[0376] Reaction scheme 9.

[0377]

[0378] Step 1) (4-((2-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)carbamate tert-butyl ester

[0379]

[0380] 4-(4-amino-2-fluorophenoxy)-3-nitropyridine-2-amine (1.6 g, 4.5 mmol) was dissolved in THF, and then boc-anhydride (1.9 g, 9.0 mmol) was added. The mixture was 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%).

[0381] MS m / z: 365 [M+H]

[0382] Step 2) (4-((2,3-aminopyridin-4-yl)oxy-3-fluorophenyl)carbamate tert-butyl ester

[0383]

[0384] The compound (tert-butyl 4-((2-amino-3-nitropyridin-4-yl)oxy-3-fluorophenyl)carbamate (1.6 g, 4.4 mmol) obtained in step 1 above was dissolved in methanol, and Pd / C (0.46 g, 4.4 mmol) was added to it. The mixture was then stirred in hydrogen for 12 hours. The catalyst was removed through a diatomaceous earth filter, the reaction mixture was concentrated, and the residue was purified by column chromatography to give the title compound (1.3 g, yield: 89%).

[0385] MS m / z: 335 [M+H]

[0386] Step 3) (4-((2-amino-3-((ethoxycarbonyl)amino)pyridin-4-yl)oxy-3-fluorophenyl)carbamate tert-butyl ester

[0387]

[0388] The 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, and pyridine (430 μl, 5.4 mmol) was added. The mixture was then cooled to 0 °C. Ethyl chloroformate (320 mg, 2.9 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 min. The temperature was then raised to room temperature and stirred for 12 h. The reaction mixture was concentrated, diluted with DCM, and washed with Na2CO3, followed by brine. The organic layer was concentrated, and the residue was purified by column chromatography to give the title compound (800 mg, yield: 73%).

[0389] MS m / z: 407 [M+H]

[0390] Step 4) (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)carbamate ethyl ester

[0391]

[0392] The compound obtained in step 3 above, tert-butyl 4-((2-amino-3-((ethoxycarbonyl)amino)pyridin-4-yl)oxy-3-fluorophenyl)carbamate (800 mg, 2.0 mmol), was dissolved in 7 mL of DCM, and 3.5 mL of TFA was added. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed with a saturated aqueous solution of NaHCO3. The organic layer was washed again with brine and concentrated, and the residue was then purified by column chromatography to give the title compound (540 mg, yield: 90%).

[0393] MS m / z: 307 [M+H]

[0394] Step 5) (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate

[0395]

[0396] In a manner similar to that of Example 1, ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)carbamate (500 mg, 1.6 mmol) obtained in step 4 above was used with 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid to give the title compound (500 mg, yield: 56%).

[0397] 1 H NMR(400MHz,DMSO-d6)δ10.85(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]

[0398] Example 35. Ethyl (2-amino-4-(4-(5-ethyl-1-phenyl-1H-pyrazol-4-carboxamido)-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate

[0399]

[0400] In the following text, the compound of Example 35 was prepared according to reaction scheme 10 described below.

[0401] Reaction scheme 10.

[0402]

[0403] Step 1) (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate ethyl ester

[0404]

[0405] 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, followed by stirring for 30 min. 2-Bromopropane (103 μl, 1.1 mmol) was slowly added at 0 °C, followed by stirring at room temperature for 12 h. 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 give the title compound (260 mg, yield: 82%).

[0406] MS m / z: 349 [M+H]

[0407] Step 2) (2-amino-4-(4-(5-ethyl-1-phenyl-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate

[0408]

[0409] In a manner similar to that of Example 1, the title compound (26 mg, yield: 64%) was obtained by using ethyl (2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate (30 mg, 0.086 mmol) obtained in step 1 above and 5-ethyl-1H-pyrazole-4-carboxylic acid.

[0410] 1 H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.32(s,1H),7.94(d,1H),7.74(d,1H),7.62(m,6H),7.19(t,1 H),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); m / z:547[M+H]

[0411] Example 36. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0412]

[0413] In a manner similar to that of Example 1, 1-(2-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (35 mg, yield: 56%).

[0414] 1 H NMR(500MHz,DMSO-d6)δ10.82(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]

[0415] Example 37. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0416]

[0417] In a manner similar to that of Example 1, 1-(2,6-difluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (34 mg, yield: 55%).

[0418] 1 MS m / z:528[M+H]

[0419] Example 38. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-3-phenyl-4-(trifluoromethyl)iso 5-oxazolium-5-carboxamide

[0420]

[0421] In a manner similar to that of Example 1, 3-phenyl-4-(trifluoromethyl)isocyanate was used. The title compound (29 mg, yield: 91%) was obtained by substituting 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 with azole-5-carboxylic acid.

[0422] 1H NMR (500MHz, DMSO-d6) δ11.68(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).

[0423] Example 39. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-3-carboxamide

[0424]

[0425] In a manner similar to that of Example 1, 1-phenyl-1H-pyrazole-3-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (11 mg, yield: 16%).

[0426] 1 H NMR(500MHz,DMSO-d6)δ10.46(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).

[0427] Example 40. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-1,2,3-triazol-4-carboxamide

[0428]

[0429] In a manner similar to that of Example 1, 1-phenyl-1H-1,2,3-triazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (45 mg, yield: 64%).

[0430] 1 H NMR (500MHz, DMSO-d6) δ10.96(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).

[0431] Example 41. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazol-4-carboxamide

[0432]

[0433] In a manner similar to that of Example 1, 5-methyl-1-phenyl-1H-1,2,3-triazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (50 mg, yield: 68%).

[0434] 1 H NMR (500MHz, DMSO-d6) δ10.89(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).

[0435] Example 42. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-carboxamide

[0436]

[0437] In a manner similar to that of Example 1, 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 1 to obtain the title compound (20 mg, yield: 26%).

[0438] 1 H NMR (500MHz, DMSO-d6) δ10.92(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).

[0439] Example 43. N-(4-((2-amino-3-iodopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0440]

[0441] In a manner similar to that of Example 29, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 29 to obtain the title compound (300 mg, yield: 89%).

[0442] 1 H NMR (500MHz, DMSO-d6) δ10.92(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).

[0443] Example 44. N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0444]

[0445] In a manner similar to that of Example 25, 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 25 to obtain the title compound (5 mg, yield: 13%).

[0446] 1 H NMR(500MHz,DMSO-d6)δ10.83(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).

[0447] Example 45. N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-2-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0448]

[0449] In a manner similar to that of Example 2, 4-(4-amino-3-fluorophenoxy)-3-chloropyridine-2-amine was used instead of 4-(4-amino-2-fluorophenoxy)-3-chloropyridine-2-amine according to Example 2 to obtain the title compound (32 mg, yield: 71%).

[0450] 1H NMR(500MHz,DMSO-d6)δ10.41(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]

[0451] Example 46. N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0452]

[0453] 6-(4-amino-2-fluorophenoxy)-5-chloropyrimidin-4-amine (40 mg, 0.16 mmol) was dissolved in 3 mL of THF, and then 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) were added. 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 preparative HPLC (0.1% formic acid aqueous solution / acetonitrile) to give the title compound (32 mg, yield: 44%).

[0454] 1 H NMR (500MHz, DMSO-d6) δ10.78(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]

[0455] Example 47. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-5-ethyl-1-phenyl-pyrazole-4-carboxamide

[0456]

[0457] In a manner similar to that of Example 46, 5-ethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid according to Example 46 to obtain the title compound (33 mg, yield: 37%).

[0458] 1MS m / z:453[M+H]

[0459] Example 48. N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxamide

[0460]

[0461] In a manner similar to that of Example 46, 3,5-dimethyl-1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (40 mg, yield: 57%).

[0462] 1 H NMR (500MHz, DMSO-d6) δ10.08(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]

[0463] Example 49. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-(p-tolyl)-5-(trifluoromethyl)pyrazole-4-carboxamide

[0464]

[0465] In a similar manner to Example 46, 1-(p-tolyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 (32 mg, yield: 40%).

[0466] 1 H NMR (500MHz, DMSO-d6) δ10.73(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]

[0467] Example 50. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-tetrahydropyran-3-yl-5-(trifluoromethyl)pyrazole-4-carboxamide

[0468]

[0469] In a manner similar to that of Example 46, 1-(tetrahydro-2H-pyran-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (47 mg, yield: 60%).

[0470] 1 H NMR(500MHz,DMSO-d6)δ10.73(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]

[0471] Example 51. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl]-1-cyclohexyl-5-(trifluoromethyl)pyrazole-4-carboxamide

[0472]

[0473] In a manner similar to that of Example 46, 1-cyclohexyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (38 mg, yield: 49%).

[0474] 1 H NMR(500MHz,DMSO-d6)δ10.68(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]

[0475] Example 52. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-(trifluoromethyl)pyrazole-4-carboxamide

[0476]

[0477] In a manner similar to that of Example 46, the compound 1-(2-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid obtained in Preparation Example 2 was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (31 mg, yield: 39%).

[0478] 1 H NMR (500MHz, DMSO-d6) δ10.80(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]

[0479] Example 53. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-pyrazole-3-carboxamide

[0480]

[0481] In a manner similar to that of Example 46, 1-phenyl-1H-pyrazole-3-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (33 mg, yield: 66%).

[0482] 1 H NMR (500MHz, DMSO-d6) δ10.41(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).

[0483] Example 54. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-triazol-4-carboxamide

[0484]

[0485] In a manner similar to that of Example 46, 1-phenyl-1H-1,2,3-triazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (30 mg, yield: 58%).

[0486] 1 H NMR (500MHz, DMSO-d6) δ10.90(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).

[0487] Example 55. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-methyl-1-phenyl-triazol-4-carboxamide

[0488]

[0489] In a manner similar to that of Example 46, 5-methyl-1-phenyl-1H-1,2,3-triazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (45 mg, yield: 87%).

[0490] 1 H NMR (500MHz, DMSO-d6) δ10.83(s,1H),7.97(d,2H),7.64(m,6H),7.66(m,2H),7.32(m,2H),2.59(s,3H).

[0491] Example 56. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-methyl-triazol-4-carboxamide

[0492]

[0493] In a manner similar to that of Example 46, 1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (285 mg, yield: 52%).

[0494] 1 H NMR (500MHz, DMSO-d6) δ10.83(s,1H),7.97(d,2H),7.78(m,3H),7.66(m,1H),7.32(m,3H),2.50(s,3H).

[0495] Example 57. N-(4-((6-amino-5-chloro-pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-1H-pyrazole-4-carboxamide

[0496]

[0497] In a manner similar to that of Example 46, 1-phenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (32 mg, yield: 48%).

[0498] 1 H NMR(500MHz,DMSO-d6)δ10.23(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]

[0499] Example 58. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-tert-butyl-5-(trifluoromethyl)pyrazole-4-carboxamide

[0500]

[0501] In a manner similar to that of Example 46, 1-(tert-butyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (53 mg, yield: 72%).

[0502] 1 H NMR (500MHz, DMSO-d6) δ10.74(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]

[0503] Example 59. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1,5-diphenyl-pyrazole-4-carboxamide

[0504]

[0505] In a manner similar to that of Example 46, 1,5-diphenyl-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (39 mg, yield: 50%).

[0506] 1 H NMR (500MHz, DMSO-d6) δ10.20(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]

[0507] Example 60. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(1-methyl-3-piperidinyl)-5-(trifluoromethyl)pyrazole-4-carboxamide

[0508]

[0509] In a manner similar to that of Example 46, 1-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (35 mg, yield: 44%).

[0510] MS m / z: 514 [M+H]

[0511] Example 61. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-4-methyl-2-phenyl-thiazolyl-5-carboxamide

[0512]

[0513] In a manner similar to that of Example 46, 4-methyl-2-phenylthiazol-5-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (22 mg, yield: 30%).

[0514] 1 H NMR (500MHz, DMSO-d6) δ10.50(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]

[0515] Example 62. N-(4-((5-chloro-6-(cyclopropylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide

[0516]

[0517] 6-(4-amino-2-fluorophenoxy)-5-chloro-N-chloropyrimidin-4-amine (40 mg, 0.14 mmol) was dissolved in 3 mL of THF, and then 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (42 mg, 0.16 mmol), HATU (77 mg, 0.24 mmol), and DIPEA (47 μl, 0.27 mmol) were added. 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 preparative HPLC (0.1% formic acid aqueous solution / acetonitrile) to give the title compound (30 mg, yield: 42%).

[0518] 1 H NMR(400MHz,DMSO-d6)δ10.75(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).

[0519] Example 63. N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)imidazol-4-carboxamide

[0520]

[0521] In a manner similar to that of Example 46, 1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxylic acid was used instead of 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid according to Example 46 to obtain the title compound (40 mg, yield: 51%).

[0522] 1 H NMR (500MHz, DMSO-d6) δ10.70(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]

[0523] Experimental Example 1. Evaluation of the inhibitory activity of RON and MET [1-1] Evaluation of the inhibitory activity of RON

[0524] To measure the inhibitory activity of each compound against RON, the IC50 of each compound was measured using time-resolved fluorescence energy transfer (TR-FRET). 50 .

[0525] Specifically, the compound was prepared to a concentration of 1 mM in 100% DMSO and then serially diluted 10 times in a 3-fold manner. The serially diluted compound (2 μL) was added to a 96-well plate containing 48 μL of 1x kinase reaction buffer (50 mM HEPES (pH 7.4), 0.01% Tween-20, 5 mM DTT, 0.5 mM Na3VO4, 2 mM EGTA, 10 mM MgCl2).

[0526] 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 then further diluted to a concentration of 0.4 nM in 1x kinase reaction buffer. As a substrate mixture, a RON-specific substrate mixture (40 μM ULight-labeled Poly GT, 100 nM ATP) was prepared at twice the final reaction concentration.

[0527] Then, 384-well plates were prepared by adding 2.5 μl of each diluted example compound to the corresponding well of the experimental group, and dispensing 2.5 μl of 4% DMSO solution to the high control well and the low control well.

[0528] Next, 2.5 μL of 0.4 nM RON was dispensed into each high control well and experimental well, and 2.5 μL of 1x kinase reaction buffer was added to each low control well. All wells were centrifuged at 1,000 RPM for 40 seconds at room temperature and then incubated at room temperature for 20–30 minutes. Then, 5 μL of substrate mixture (2x) was dispensed into each well, and all wells were centrifuged at 1,000 RPM for 40 seconds at room temperature and then incubated at room temperature for 60 minutes. Then, 5 μL of 30 mM EDTA was added to each well to terminate the reaction, and all wells were incubated again at room temperature for 5 minutes. Then, 5 μL of europium-containing 4x phosphotyrosine antibody (Perkin-Elmer) was added to each well, and all wells were incubated at room temperature for 60 minutes. After incubation, the 384-well plate was read using a Vison plate reader. In this case, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm. The IC50 values ​​for each compound in each example are as follows: 50 The values ​​were derived using the GraphPd Prism7 program.

[0529] [1-2] Evaluation of the inhibitory activity of MET

[0530] In addition, to measure the inhibition of enzyme activity against cMET, the assay was performed in the same manner as the assay for enzyme activity inhibition against RON.

[0531] Specifically, the compound was prepared to a concentration of 1 mM in 100% DMSO and then diluted 10 times stepwise by a 3-fold dilution. The stepwise diluted compound (2 μL) was added to a 96-well plate containing 48 μL of 1x kinase reaction buffer (50 mM HEPES (pH 7.4), 0.05% BSA, 0.005% Tween-20, 1 mM DTT, 0.5 mM MnCl2, 20 mM MgCl2).

[0532] The cMET protein was diluted to a concentration of 263 nM in cMET storage buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.05% Brij35, 1 mM DTT, 10% glycerol), and then diluted again to a concentration of 2 nM in 1x kinase reaction buffer. As a substrate mixture, a MET-specific substrate mixture (5 μM TK peptide, 10 mM ATP) was prepared at twice the final reaction concentration.

[0533] Then, 384-well plates were prepared by adding 2.5 μl of each diluted example compound to the corresponding well of the experimental group, and dispensing 2.5 μl of 4% DMSO solution to the high control well and the low control well.

[0534] Next, 2.5 μL of 2 nM cMET was dispensed into each high control well and experimental well, and 2.5 μL of 1x kinase reaction buffer was added to each low control well. All wells were centrifuged at 1,000 RPM for 40 seconds at room temperature and then incubated at room temperature for 20–30 minutes. Then, 5 μL of substrate mixture (2x) was dispensed into each well, and all wells were centrifuged at 1,000 RPM for 40 seconds at room temperature and then incubated at room temperature for 60 minutes. Then, 5 μL of 90 mM EDTA was added to each well to terminate the reaction, and all wells were incubated again at room temperature for 5 minutes. Then, 5 μL of europium-containing 4x phosphotyrosine antibody (Perkin-Elmer) was added to each well, and all wells were incubated at room temperature for 60 minutes. After incubation, the 384-well plate was read using a Vison plate reader. In this case, the excitation wavelength was 340 nm, and the emission wavelengths were 620 nm and 665 nm. The IC50 values ​​for each compound in the examples are as follows: 50 The values ​​were derived using the GraphPd Prism7 program.

[0535] The evaluation results of the inhibitory activity of the compounds in the examples against RON or cMET are shown in Table 2 below.

[0536] (A: <50nM, B: 50-500nM, C: 500-5,000nM, D: >5,000nM)

[0537] [Table 2]

[0538]

[0539]

[0540]

Claims

1. A pyridine-derived compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-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)-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)-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-imidazol-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-imidazol-4-carboxamide, N-(4-((2-(N-acrylamido-3-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide, N-(4-((3-chloro-2-(cyclopropanecarbamoyl)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide, N-(4-((2-chloropyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide, N-(4-((2-aminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide, N-(4-((2-cyclopropanecarbamate)pyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-4-carboxamide, N-(4-((2,3-diaminopyridin-4-yl)oxy-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-imidazol-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-imidazol-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-2-phenylthiazolyl-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-4-methyl-2-phenylthiazolyl-5-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiazolyl-2-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-phenylthiophene-2-carboxamide, (2-amino-4-(2-fluoro-4-(1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamido)phenoxy)pyridin-3-yl)carbamate, (2-amino-4-(4-(5-ethyl-1-phenyl-1H-pyrazole-4-carbamate)-2-fluorophenoxy)pyridin-3-yl)(isopropyl)carbamate, 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)iso 5-oxazolium-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-1,2,3-triazol-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-methyl-1-phenyl-1H-1,2,3-triazol-4-carboxamide, N-(4-((2-amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-1-(2-fluorophenyl)-5-methyl-1H-1,2,3-triazol-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-triazol-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-5-methyl-1-phenyl-triazol-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-(2-fluorophenyl)-5-methyl-triazol-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-piperidinyl)-5-(trifluoromethyl)pyrazole-4-carboxamide, N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-4-methyl-2-phenyl-thiazolyl-5-carboxamide, N-(4-((5-chloro-6-(cyclopropylamino)pyrimidin-4-yl)oxy)-3-fluorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxamide, and N-[4-(6-amino-5-chloro-pyrimidin-4-yl)oxy-3-fluorophenyl]-1-phenyl-5-(trifluoromethyl)imidazol-4-carboxamide.

2. A pharmaceutical composition comprising: the compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

3. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of cancer.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of immune-related diseases.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of RON-mediated diseases.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of protein kinase-mediated diseases.

7. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the activity of RON receptors.

Images