Heteroaryl derivative compound and use thereof

Abstract

The present invention relates to a heteroaryl derivative compound and use thereof. The heteroaryl derivative of the present invention exhibits excellent inhibitory activity against c-MET kinase and c-MET mutant cells, and thus can be effectively used for the prevention or treatment of c-MET-related diseases.

Description

Heteroaryl derivative compounds and uses thereof

[0001] The present invention relates to heteroaryl derivative compounds and their pharmaceutical uses. Specifically, the present invention relates to heteroaryl derivative compounds having inhibitory activity against c-MET kinase and activity for inhibiting the proliferation of c-MET mutant cells.

[0002] Protein kinases act as molecular switches in signal transduction pathways, requiring smooth cellular regulation of the transition between active and inactive states of target proteins. If this transition is abnormally regulated, it can lead to excessive activation or inactivation of intracellular signaling, leading to uncontrolled cell division and proliferation. In particular, abnormal activation of protein kinase genes, resulting from mutations, amplification, and / or overexpression, plays a crucial role in the development and progression of various tumors and in the pathogenesis of various diseases, including inflammatory diseases, neurodegenerative diseases, and autoimmune diseases.

[0003] c-MET (mesenchymal-epithelial transition factor), which is mainly expressed in epithelial cells, is a protein of the receptor tyrosine kinase (RTK) subfamily that penetrates the plasma membrane of cells and has tyrosine kinase activity in its intracellular domain. It is also called HGFR (hepatocyte growth factor receptor). When its ligand, HGF (hepatocyte growth factor), binds to c-MET, activation is induced through dimerization and phosphorylation, followed by intracellular signaling by downstream molecules.

[0004] c-MET plays a crucial role in regulating tissue homeostasis by regulating a wide range of complex cell signaling pathways, including cell proliferation, motility, migration, and invasion (Organ SL and Tsao MS, 2011, Therapeutic Advances in Medical Oncology 3 (1 Suppl): S7-19). However, c-MET mutations, which cause abnormal regulation through deletion, amplification, and overexpression, can occur alone or as resistance after use of existing treatments, and abnormal c-MET activation is known to be one of the representative mechanisms of tumorigenesis and is related to tumor proliferation, inhibition of apoptosis, angiogenesis, invasion, and metastasis (Bottaro DP et al., 1991, Science 251: 802-804; Day RM et al., 1999, Oncogene 18: 3399-3406). In addition, abnormal activation of c-MET due to mutation and amplification of c-MET has been reported to be related to various cancers such as lung cancer, colon cancer, head and neck cancer, gastric cancer, and breast cancer, and to be associated with increased tumor aggressiveness and poor prognosis (Lefebvre J et al., 2012, FASEB J 26: 1387-1399; Liu X et al., 2010, Trends Mol Med 16: 37-45; Smolen GA et al., 2006, Proc Natl Acad Sci USA 103: 2316-2321; Foveau B et al., 2009, Mol Biol Cell 20: 2495-2507).

[0005] As such, c-MET is highly correlated with tumor progression, metastasis, and prognosis, and is attracting attention as a target for therapeutics. In addition, the number of patients with c-MET mutations that develop resistance to existing treatments is increasing worldwide, and thus, there is a growing demand for the development of novel compounds that can be usefully utilized as treatments for c-MET-related diseases.

[0006] The object of the present invention is to provide a novel structural heteroaryl derivative compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide a method for producing the heteroaryl derivative compound.

[0008] Another object of the present invention is to provide a pharmaceutical use of the heteroaryl derivative compound, and specifically, to provide a pharmaceutical composition for preventing or treating c-MET-related diseases, which comprises the heteroaryl derivative compound as an active ingredient.

[0009] Another object of the present invention is to provide a use for preventing or treating a c-MET-related disease using the compound, or a method for preventing or treating a c-MET-related disease comprising a step of administering the compound.

[0010] In order to achieve the above purpose, the inventors of the present invention completed the present invention by confirming that the heteroaryl derivative compounds represented by the chemical formula 1 mentioned below inhibit the activity of c-MET kinase and inhibit the proliferation of c-MET mutant cells as a result of research efforts.

[0011] This is described in detail below. All combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention is not limited by the specific description below.

[0012] Heteroaryl derivative compounds

[0013] The present invention provides a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] X1 and X2 are each independently CR X or N;

[0018] R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -Halloween;

[0019] L1 and L2 are each independently -H, -C 1-6 Alkyl, or -(4-6 membered heterocycloalkyl), wherein the -C 1-6 One or more H of alkyl is L X , wherein the -(4-6 membered heterocycloalkyl) ring comprises one or more N, O, or S atoms, and one or more H of the -(4-6 membered heterocycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -halo, -C(=O)-C 1-6 may be substituted with alkyl, or -(3-6 membered cycloalkyl);

[0020] L X is -NR a R b , -OH, -OC 1-6 Alkyl, -OP(=O)(OH)2, -halo, -OC(=O)-C 1-6 Alkyl, -(4-6 membered heterocycloalkyl), or -phenyl, wherein the -OC(=O)-C 1-6 At least one H of the alkyl is substituted with -NH2, -OH, or -SH, and the -(4-6 membered heterocycloalkyl) ring contains at least one N, O, or S atom, and at least one H of the -(4-6 membered heterocycloalkyl) or -phenyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -halo, -C(=O)-C 1-6 may be substituted with alkyl, or -(3-6 membered cycloalkyl);

[0021] R1 to R4 are each independently -H or -halo;

[0022] Ring Y is -(8-10 membered heteroaryl) or -(9-14 membered heterohydroaryl), wherein said -(8-10 membered heteroaryl) or -(9-14 membered heterohydroaryl) ring contains one or more N, O, or S atoms, and one or more H of said -(8-10 membered heteroaryl) or -(9-14 membered heterohydroaryl) ring is -C 1-6 Alkyl, -C 1-6 Deuterated alkyl, -C 1-6 Haloalkyl, -NR a R b , -OR c , -halo, or -(3-6 membered cycloalkyl), and at least one -CH2- of the -(9-14 membered heterohydroaryl) ring may be substituted with -C(=O)- or -(3-6 membered cycloalkyl);

[0023] R a and R b are each independently -H or -C 1-6 It is alkyl;

[0024] R c is -H, -C 1-6 Alkyl, -C 1-6 Deuterated alkyl, -C 1-6 Haloalkyl, or -(3-6 membered cycloalkyl).

[0025] According to one specific example of the present invention, the ring Y is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , wherein one or more H of the ring Y are each independently -C 1-6 Alkyl, -C 1-6 Deuterated alkyl, -C 1-6 Haloalkyl, -NR a R b , -OR c , -halo, or -(3-6 membered cycloalkyl), and one or more -CH2- of the ring Y may be substituted with -C(=O)- or -(3-6 membered cycloalkyl), and R a , R b , and R c is as defined above.

[0026] More specifically, the above ring Y is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , wherein one or more H of the ring Y are each independently -C 1-3 Alkyl, -C 1-3 Deuterated alkyl, -C 1-3 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -OC 1-3 Alkyl, -OC 1-3 Deuterated alkyl, -OC 1-3 may be substituted with haloalkyl, -O-(3-4 membered cycloalkyl), -halo, or -(3-4 membered cycloalkyl), and one or more -CH2- of the ring Y may be substituted with -C(=O)- or -(5-6 membered cycloalkyl).

[0027] Here, when the -CH2- of the ring Y is substituted with -(5-6 membered cycloalkyl), the ring Y forms a spiro ring sharing one carbon atom with the -(5-6 membered cycloalkyl). For example, the ring Y is -CH2-, -CH2- are each substituted with -C(=O)- and -(6-membered cycloalkyl). It can have a structure.

[0028] According to one specific example of the present invention, either one of L1 and L2 is -C 1-6 Alkyl, and the other one of L1 and L2 is -H, -C 1-6 alkyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , wherein one or more H of the rings listed above is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -halo, -C(=O)-C 1-6 It may be substituted with alkyl or -(3-6 membered cycloalkyl).

[0029] More specifically, one of L1 and L2 is -CH3, and the other of L1 and L2 is -H, -CH3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , wherein one or more H of the rings listed above is -C 1-3 Alkyl, -C 1-3 Haloalkyl, -halo, -C(=O)-C 1-3 It may be substituted with alkyl or -(3-4 membered cycloalkyl).

[0030] According to one specific embodiment of the present invention, at least one of R1 to R4 may be -halo. For example, (1) either R1 or R2 is -halo, and the others are all -H; (2) either R3 or R4 is -halo, and the others are all -H; (3) each of R1 and R2 is -halo, and R3 and R4 are each -H; (4) each of R1 and R2 is -H, and R3 and R4 are each -halo; (5) each of R1 and R4 is -halo, and R2 and R3 are each -H; (6) each of R1 and R4 is -H, and R2 and R3 are each -halo; (7) each of R1 and R3 is -halo, and R2 and R4 are each -H; (8) each of R1 and R3 is -H, and R2 and R4 are each -halo. However, the present invention is not limited thereto.

[0031] According to another specific embodiment of the present invention, R1 to R4 can all be -H.

[0032] According to one specific example of the present invention, the compound represented by the chemical formula 1 may be selected from the group consisting of compounds listed in Table 1 described below.

[0033] In the present invention, "alkyl" may mean a straight or branched chain acyclic, cyclic or saturated hydrocarbon with a combination thereof, unless otherwise specified. For example, "C 1-6"Alkyl" may mean alkyl having 1 to 6 carbon atoms. Acyclic alkyl may include, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and 2-methylpentyl, for example. As used herein, a residue obtained by removing one hydrogen atom from the "alkyl" is referred to as "alkylene." Cyclic alkyl may be used interchangeably with "cycloalkyl" as used herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, for example.

[0034] In the present invention, "deuterated alkyl" may mean a straight or branched chain alkyl (hydrocarbon) substituted with one or more deuterium (D; Deuterium). For example, "C 1-6 "Deuterated alkyl" may include, but is not limited to, -CDH2, -CD2H, -CD3, etc.

[0035] In the present invention, "alkenyl" and "alkynyl" may mean a straight or branched chain acyclic, cyclic or unsaturated hydrocarbon group combined therewith. For example, "C 2-6 "Alkenyl" may mean an unsaturated hydrocarbon having 2 to 6 carbon atoms with one or more double bonds, and "C 2-6 "Alkynyl" may mean an unsaturated hydrocarbon having 2 to 6 carbon atoms with one or more triple bonds.

[0036] In the present invention, "alkoxy" may mean an alkyl ether group -(R'-OR"), where R' is a single bond and C 1-6 may be selected from the group consisting of alkyl, and R" is C 1-6 It may be alkyl, where alkyl is as defined above. For example, "C 1-6 "Alkoxy" of C 1-6Alkoxy containing alkyl, i.e., -(OC 1-6 alkyl) or -(C 1-6 Alkyl-OC 1-6 Alkoxy may mean, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0037] In the present invention, “halo” may be F, Cl, Br, or I.

[0038] In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having carbon atoms substituted with one or more halo groups as defined herein. Examples of such haloalkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, each independently substituted with one or more halogens, such as F, Cl, Br, or I.

[0039] In the present invention, "hydroxyalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with hydroxy (OH). Examples of such hydroxyalkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl independently substituted with -OH.

[0040] In the present invention, "alkylamino" or "aminoalkyl" may mean -(NR'R"), wherein R' and R" are each independently hydrogen, C 1-6alkyl, and N protecting groups (e.g., Boc), wherein the selected R' and R" may each be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylamino" is amino (-NH2) or C that does not contain alkyl. 1-6 Amino containing alkyl, i.e., -NH(C 1-6 alkyl) or -N(C 1-6 alkyl)2, and may include, but is not limited to, dimethylamino, diethylamino, methylethylamino, methylpropylamino, or ethylpropylamino.

[0041] As used herein, “cyanoalkyl” may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with cyano (CN).

[0042] In the present invention, "alkylsulfonyl" may mean -(R'-S(=O)2-R"), where R' is a single bond and C 1-6 may be selected from the group consisting of alkyl, and R" is hydroxy and C 1-6 It can be selected from the group consisting of alkyl. The selected R' and R" can be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylsulfonyl" is a sulfonic acid group (-S(=O)2OH) or C that does not contain alkyl. 1-6 A sulfonyl group containing an alkyl group, i.e., -S(=O)2-(C 1-6 alkyl) or -(C 1-6 alkyl)-S(=O)2-(C 1-6 alkyl) and may include, but is not limited to, methylsulfonyl, (methylsulfonyl)methyl, (methylsulfonyl)ethyl, ethylsulfonyl, (ethylsulfonyl)methyl, and (ethylsulfonyl)ethyl.

[0043] In the present invention, "alkylcarbonyl" may mean -(R'-C(=O)-R"), where R' is a single bond and C 1-6may be selected from the group consisting of alkyl, and R" is hydrogen and C 1-6 It can be selected from the group consisting of alkyl. The selected R' and R" can be independently substituted or unsubstituted. In addition, "C 0-6 "Alkylcarbonyl" is an aldehyde group (-C(=O)H) or C that does not contain alkyl. 1-6 A ketone group containing alkyl, i.e., -C(=O)-(C 1-6 alkyl) or -(C 1-6 alkyl)-C(=O)-(C 1-6 It can mean alkyl.

[0044] In the present invention, "cycloalkyl" may mean a hydrocarbon ring that does not contain a heteroatom (such as N, O, P, P(=O), S, or S(=O)2) within the ring, and may be saturated or partially unsaturated. If unsaturated, it may be referred to as a cycloalkene. Unless otherwise stated, a cycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring.

[0045] In the present invention, "heterocycloalkyl" may mean a ring containing at least one selected from N, O, P, P(=O), S, and S(=O)2 within the ring, and may be saturated or partially unsaturated. If unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, a heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring, or a fused ring. Additionally, "heterocycloalkyl having 3 to 12 atoms" may mean a heterocycloalkyl having 3 to 12 ring-forming atoms, and as an example, the heterocycloalkyl may be pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, It may include, but is not limited to, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane.

[0046] In the present invention, "heterobicycloalkyl" may mean multiple rings such as a spiro ring, a bridged ring or a fused ring containing at least one selected from N, O, P, P(=O), and S within the ring, and may be saturated or partially unsaturated. If unsaturated, it may be referred to as heterobicycloalkene. Examples of heterobicycloalkyl may include, but are not limited to, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1r,5s)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, or (1r,4r)-2-oxa-5-azabicyclo[2.2.2]octane.

[0047] In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The number of ring-forming carbon atoms of the arene may be 5 to 30, 5 to 20, or 5 to 15. Examples of arenes include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaternary benzene, quincbenzene, sexibenzene, triphenylene, pyrene, benzofluoranthene, chrysene, and the like. In the present specification, a residue obtained by removing one hydrogen atom from the "arene" is referred to as "aryl."

[0048] In the present invention, "heteroarene" may be a ring containing at least one of O, N, P, Si, and S as a heteroatom. The number of ring-forming atoms of the heteroarene may be 3 or more and 30 or less, 3 or more and 20 or less, or 3 or more and 15 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a two-ring or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, pyridin-2-one, pyridin-3-one, pyridin-4-one, bipyridine, triazine, acridyl, pyridazine, pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or Examples thereof include, but are not limited to, pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, thiadiazole, benzothiazole, tetrazole, phenothiazine, dibenzosilole, and dibenzofuran. In the present specification, a residue obtained by removing one hydrogen atom from the above-mentioned "heteroarene" is referred to as "heteroaryl."

[0049] In the present invention, “hydroarene” or “hydroaryl” is an aromatic hydrocarbon ring in which at least one double bond is saturated.

[0050] In the present invention, "heterohydroarene" may mean a multi-ring (bi- to tetra-ring) containing 1 to 5 heteroatoms selected from N, O, and S as ring-forming atoms, and at least one of the multi-rings may be a saturated or partially unsaturated ring, and at least another may have an aromatic ring. In the present specification, a residue obtained by removing one hydrogen atom from the "heterohydroarene" is referred to as a "heterohydroaryl."

[0051] In the present invention, the "ring" may be a single ring or a multi-ring. The multi-ring may be a spiro ring, a bridged ring, or a fused ring.

[0052] In the present invention, "stereoisomer" means a compound having the same chemical formula or molecular formula but sterically different. In the present specification, stereoisomers include optical isomers, enantiomers, diastereomers, cis / trans isomers, rotamers, and atropisomers, and each of these isomers, racemates, and mixtures thereof are also included in the scope of the present invention. For example, the compound represented by Chemical Formula 1 of the present invention may include the stereoisomers of Chemical Formula 1 because the stereochemical structure is not specified. Unless otherwise stated, a solid bond ( ) is a wedge-shaped solid line combination representing the absolute arrangement of the stereocenter. ) and wedge-shaped dotted line combination ( ) may be included.

[0053] The compound represented by Chemical Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt." Accordingly, the category of the compound of the present invention includes a pharmaceutically acceptable salt of the compound represented by Chemical Formula 1. The term "pharmaceutically acceptable salt" of the present invention means any organic or inorganic acid addition salt of the compound, which has a relatively non-toxic and harmless effective effect in a patient at a concentration, and wherein the side effects caused by the salt do not reduce the beneficial effects of the compound represented by Chemical Formula 1.

[0054] In particular, the pharmaceutically acceptable salt may be an acid addition salt formed by a free acid. Here, the acid addition salt may be obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc.; non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc.; organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc.

[0055] Such pharmaceutically acceptable salts may include sulfate, sulfite, nitrate, phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, benzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, glycolate, malate, tartrate, mandelate, and the like.

[0056] The above acid addition salt can be prepared by a conventional method, for example, by dissolving the derivative of chemical formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., adding an organic acid or inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0057] In addition, the pharmaceutically acceptable salt may be a salt or metal salt obtained using a base. As an example of a metal salt, an alkali metal or alkaline earth metal salt can be obtained by dissolving a compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. As an alkali metal salt, sodium, potassium, or calcium salts may be pharmaceutically suitable. In addition, a corresponding salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate), and can be prepared through a salt preparation method known in the art.

[0058] Uses of heteroaryl derivative compounds

[0059] The present invention provides a use of a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0060] [Chemical Formula 1]

[0061]

[0062] The above chemical formula 1 is as defined above.

[0063] The compound represented by Chemical Formula 1 of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof can inhibit the activity of c-MET kinase. Accordingly, the present invention provides a c-MET inhibitor comprising the compound represented by Chemical Formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0064] According to one specific example of the present invention, the heteroaryl derivative represented by the above chemical formula 1 exhibits excellent inhibitory activity against c-MET kinase and has proliferation inhibitory activity against c-MET mutant cells, and thus can be used to prevent or treat diseases related to c-MET, particularly cancer. The c-MET mutation may be, for example, Y1230H, Y1230C, D1228V, D1228H, D1228N, G1090, V1092, G1163R, D1010H, L1195F, F1200I, c-MET amplification, c-MET overexpression, or exon 14 skipping, but is not limited thereto.

[0065] In the present invention, the cancer includes all cancers that can exhibit therapeutic or preventive efficacy due to inhibition of c-MET activity, and may be solid cancer or blood cancer, and includes not only primary cancer but also metastatic cancer.

[0066] As a specific example, the solid tumor may be one or more from the group consisting of, but is not limited to, Uterine Cancer, Ovarian Cancer, Gastrointestinal Tract Cancer, Brain and Nervous System Tumor, Genitourinary Cancer, Head and Neck Cancer, Skin Cancer, Breast Cancer, Bone and Soft Tissue Tumor, Lung and Thoracic Cancer, Endocrine Tumors, and Other Solid Tumors.

[0067] The above uterine cancer may be cervical cancer, endometrial cancer, or uterine carcinosarcoma.

[0068] The above ovarian cancer may be ovarian epithelial cancer or ovarian germ cell tumor.

[0069] The above gastrointestinal tract cancers include Pseudomyxoma Peritonei, Intrahepatic Cholangiocarcinoma, Hepatoblastoma, Liver Cancer, Colon Cancer, Gallbladder Cancer, Bile Duct Cancer, Colorectal Cancer, Ampulla of Vater Cancer, Peritoneal Cancer, Small Intestine Cancer, Esophageal Cancer, Duodenal Cancer, Gastric Cancer, Gastroesophageal Junction Cancer, Gastric Carcinoid Tumor, Gastric Stromal Tumor, Gastrointestinal Stromal Tumor, Rectal Cancer. It could be Rectal Neuroendocrine Tumor, Pancreatic Cancer, or Anal Cancer.

[0070] The above brain and central nervous system tumor may be glioblastoma, brain cancer, pituitary adenoma, retinoblastoma, astrocytoma, meningioma, glioma, pediatric brain cancer, glioma, spinal cord tumor, or vestibular schwannoma.

[0071] The above genitourinary cancer may be bladder cancer, testicular cancer, vulvar cancer, penile cancer, ureteral cancer, urethral cancer, prostate cancer, vaginal cancer, renal pelvis cancer, kidney cancer, or Wilms' tumor.

[0072] The above head and neck cancer may be oral cancer, lip cancer, paranasal sinus cancer, tongue cancer, pharyngeal cancer, tonsil cancer, laryngeal cancer, salivary gland cancer, or eye cancer.

[0073] The above skin cancer may be basal cell carcinoma, malignant melanoma, choroidal melanoma, or mycosis fungoides.

[0074] The breast cancer may be triple-negative breast cancer (TNBC), male breast cancer, or Paget's disease of the nipple.

[0075] The above bone and soft tissue tumor may be a malignant soft tissue tumor, a malignant bone tumor, a sarcoma, or a rhabdomyosarcoma.

[0076] The above lung cancer and thoracic cancer may be non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma, lung adenocarcinoma, pulmonary squamous cell carcinoma, malignant mesothelioma, pleural cancer, mediastinal tumor, or thymic cancer.

[0077] The above endocrine tumors may be thyroid cancer, parathyroid cancer, or adrenal cancer.

[0078] The above other solid tumors may be cardiac tumor, cancer of unknown primary, metastatic bone cancer, metastatic brain cancer, or gestational trophoblastic disease.

[0079] As a specific example, Hematologic Cancer may be Myelodysplastic Syndrome, Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Multiple Myeloma, Chronic Myeloid Leukemia, Chronic Lymphocytic Leukemia, Pediatric Lymphoma, Pediatric Leukemia, Malignant Lymphoma, Mastocytosis, Gastric Lymphoma, or Kaposi's Sarcoma.

[0080] According to one specific example of the present invention, the present invention provides a pharmaceutical composition for the prevention or treatment of a c-MET-related disease, comprising a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. Specifically, the c-MET-related disease may be cancer. The type of cancer is as mentioned above.

[0081] The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by the chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0082] The pharmaceutical composition of the present invention can be used for clinical administration and can be prepared so that it can be administered in various oral and parenteral dosage forms.

[0083] In addition, according to one specific embodiment of the present invention, the present invention provides the use of the compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a c-MET-related disease. Specifically, the c-MET-related disease may be cancer. The type of cancer is as mentioned above.

[0084] In addition, according to one specific embodiment of the present invention, the present invention provides the use of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a drug for the prevention or treatment of cancer. The type of cancer is as mentioned above.

[0085] In addition, according to one specific example of the present invention, the present invention provides a method for preventing or treating a c-MET-related disease, comprising administering a therapeutically effective amount of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal including a human. Specifically, the c-MET-related disease may be cancer. The type of cancer is as mentioned above.

[0086] In addition, according to one specific example of the present invention, the present invention provides a method for preventing or treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The type of cancer is as mentioned above.

[0087] In addition, according to one specific example of the present invention, the present invention provides a method for inhibiting c-MET, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by the above chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0088] The term "therapeutically effective amount" used in the present invention refers to the amount of the compound represented by the above chemical formula 1 that is effective in preventing or treating a c-MET-related disease. Specifically, a "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, type of disease, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with commercially available therapeutic agents. And it can be administered singly or in multiple doses. It is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects by taking all of the above factors into consideration, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the effective ingredient of the pharmaceutical composition of the present invention has excellent safety, it can be used in amounts exceeding the determined dosage.

[0089] As used herein, “prevention” means any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the compound, and “treatment” means any action that improves or beneficially changes the symptoms of the disease by administering the compound.

[0090] In addition, according to one specific embodiment of the present invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the present invention provides a pharmaceutical composition comprising a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable additive.

[0091] Examples of additives used in the above pharmaceutical composition may include sweeteners, binders, solvents, solubilizers, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, flavoring agents, and the like. For example, the additives may include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavoring, and the like.

[0092] The pharmaceutical composition may be formulated in various formulations for oral administration (e.g., suspension, pills, powder, capsules, syrup or emulsion) or parenteral administration (e.g., intramuscular, intravenous or subcutaneous injection).

[0093] For example, the pharmaceutical composition may be formulated as a preparation for oral administration, and the additives used in this case may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. Specifically, solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations may be formulated by mixing at least one excipient, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may be used. In addition, liquid preparations for oral administration may include suspensions, emulsions, syrups, etc., and may include various excipients such as wetting agents, sweeteners, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin.

[0094] Additionally, preparations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include withepsol, macrogol, Tween 61, cacao butter, laurin, and glycerogelatin. Meanwhile, injections may include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0095] Additionally, it can be manufactured as a compound preparation with other active ingredients to have a synergistic effect of the active ingredients.

[0096] The matters mentioned in the uses, compositions, and treatment methods of the present invention apply equally unless they are inconsistent with each other.

[0097] The heteroaryl derivative compound of the present invention exhibits excellent inhibitory activity against c-MET kinase and c-MET mutant cells, and thus can be usefully used for the prevention or treatment of c-MET-related diseases.

[0098] Hereinafter, the present invention will be described in detail through examples and experimental examples. However, the following examples and experimental examples are merely illustrative of the present invention and the scope of the present invention is not limited thereto.

[0099] <Analysis and purification conditions>

[0100] The compounds synthesized in the manufacturing examples and examples of the present invention were purified or subjected to structural analysis under the following conditions.

[0101] 1. LC-MS, Prep-HPLC, MPLC

[0102] Analytical LC-MS (Liquid Chromatography-Mass Spectrometry)

[0103] A Waters-manufactured UPLC system (ACQUITY UPLC PDA Detector) equipped with a Waters-manufactured mass QDa Detector was used. Waters-manufactured ACQUITY UPLC ® A BEH C18 (1.7 μm, 2.1 Х 50 mm) column was used, and the column temperature was 30 °C.

[0104] Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.

[0105] Gradient condition (10-100% B for 3 min, flow rate = 0.6 mL / min)

[0106] Preparative Preparative-Liquid chromatography UV spectrometry (Prep-HPLC)

[0107] The ACCQPrep HP150 equipment manufactured by Teledyne was used. The XTERRA from Waters ® Prep RP18 OBD TM (10 ㎛, 30 Х 300 mm) column was used, and the column temperature was set to room temperature.

[0108] Gradient condition (10-100% B for 120 min, flow rate = 42 mL / min)

[0109] Medium pressure liquid chromatography (MPLC) for purification

[0110] Medium-pressure liquid chromatography was performed using a CombiFlash Rf +UV from Teledyne ISCO.

[0111] 2. NMR interpretation

[0112] NMR analysis was performed using an NMR AVANCE NEO 400 MHz manufactured by Bruker, and data are expressed in ppm (parts per million(δ)).

[0113] The commercially available reagents used were used without further purification. In the present invention, room temperature or ambient temperature refers to a temperature of about 5 to 40°C, for example, 10 to 30°C, or in another example, 20 to 27°C, but is not strictly limited to the above range. Concentration under reduced pressure or solvent distillation was performed using a rotary evaporator.

[0114] Manufacturing Examples 1 to 24: Manufacturing of intermediate compounds of the present invention

[0115] Manufacturing Example 1. Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3,5-difluoroaniline

[0116] [Reaction Formula 1]

[0117]

[0118] [Step 1] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline

[0119] 4-Chloro-6,7-dimethoxyquinoline (3.0 g, 13.4 mmol) and 2,6-difluoro-4-nitrophenol (3.9 g, 22.0 mmol) were dissolved in N-methyl-2-pyrrolidone (NMP, 26 mL), and N,N-diisopropylethylamine (DIPEA, 5.8 mL, 33.0 mmol) was added. The reaction mixture was stirred at 140 °C for 15 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with 1 N aqueous sodium hydroxide solution, the separated organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (2.3 g, 6.3 mmol, 47% yield) as a yellow solid. MS (ESI): m / z = 363 [M+H] +

[0120] [Step 2] Preparation of 4-((6,7-dimethoxyquinolin-4-yl)oxy)-3,5-difluoroaniline

[0121] 4-(2,6-Difluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (4.0 g, 11.0 mmol) and iron (1.8 g, 33.1 mmol) obtained in Step 1 were dissolved in ethanol (49.7 mL) and water (5.5 mL), and hydrochloric acid (0.5 mL, 6.6 mmol) was added. The reaction mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was filtered through Celite and washed with methanol. The obtained filtrate was concentrated to obtain the target compound (3.5 g, 10.5 mmol, 95% yield) as a brown solid, which was used in the next step without further purification. MS (ESI): m / z = 333 [M+H] +

[0122] Manufacturing Example 2. Manufacturing of 3,5-difluoro-4-((7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)oxy)aniline

[0123] [Reaction Formula 2]

[0124]

[0125] [Step 1] Preparation of 4-chloro-7-methoxyquinolin-6-ol

[0126] 4-Chloro-6,7-dimethoxyquinoline (5.0 g, 22.4 mmol) was dissolved in sulfuric acid (43.8 g, 447 mmol), and L-methionine (6.7 g, 44.7 mmol) was added at room temperature. The reaction mixture was stirred at 120 °C for 5 h. After confirming the completion of the reaction using LC-MS, ice and aqueous ammonia solution were added to the reaction mixture to adjust the pH to 8. Then, dichloromethane / methanol (9:1) was added to extract the organic matter. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (hexane / ethyl acetate) to obtain the target compound (3.50 g, 16.7 mmol, 75% yield) as a white solid. MS (ESI): m / z = 210 [M+H] +

[0127] [Step 2] Preparation of 6-(benzyloxy)-4-chloro-7-methoxyquinoline

[0128] 4-Chloro-7-methoxyquinolin-6-ol (3.5 g, 16.7 mmol) and potassium carbonate (6.9 g, 50.1 mmol) obtained in Step 1 were dissolved in N,N-dimethylformamide (DMF, 33 mL), and benzyl bromide (3.14 g, 18.4 mmol) was added at room temperature. The reaction mixture was stirred at 45 °C for 3 h. After confirming the completion of the reaction using LC-MS, water was added to the reaction mixture to precipitate a solid. The target compound (3.3 g, 11.0 mmol, 66% yield) as a brown solid obtained by filtration was used in the next reaction without further purification. MS (ESI): m / z = 300 [M+H] +

[0129] [Step 3] Preparation of 6-(benzyloxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline

[0130] 6-(Benzyloxy)-4-chloro-7-methoxyquinoline (3.3 g, 11.0 mmol) and 2,6-difluoro-4-nitrophenol (3.9 g, 22.0 mmol) obtained in Step 2 were dissolved in NMP (26 mL), and then DIPEA (5.8 mL, 33.0 mmol) was added. The reaction mixture was stirred at 140 °C for 15 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with 1 N aqueous sodium hydroxide solution, the remaining organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (3.5 g, 8.0 mmol, 73% yield) as a white solid. MS (ESI): m / z = 439 [M+H] +

[0131] [Step 4] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinolin-6-ol

[0132] 6-(Benzyloxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (3.5 g, 8.0 mmol) obtained in the above step 3 was dissolved in trifluoroacetic acid (TFA, 16 mL) and stirred at 80°C for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture to extract the organic matter. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (2.5 g, 7.2 mmol, 90% yield) as a yellow solid was used in the next reaction without further purification. MS (ESI): m / z = 349 [M+H] +

[0133] [Step 5] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-6-(2-methoxyethoxy)quinoline

[0134] 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinolin-6-ol (2.5 g, 7.2 mmol) and 2-methoxyethanol-1-ol (1.6 g, 21.6 mmol) obtained in Step 4 were dissolved in toluene (15.0 mL), and nitrogen was substituted at room temperature. Then, (cyanomethylene)tributylphosphoraine (CMBP, 1.7 g, 14.4 mmol) was added to the mixture, and the mixture was stirred at 100 °C for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate and a saturated aqueous sodium bicarbonate solution were added to the reaction mixture to extract organic substances. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (hexane / ethyl acetate), obtaining the target compound (1.80 g, 4.6 mmol, 64% yield) as a white solid. MS (ESI): m / z = 407 [M+H] +

[0135] [Step 6] Preparation of 3,5-difluoro-4-((7-methoxy-6-(2-methoxyethoxy)quinolin-4-yl)oxy)aniline

[0136] 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-6-(2-methoxyethoxy)quinoline (1.80 g, 4.6 mmol) and iron (0.77 g, 13.8 mmol) obtained in Step 5 were dissolved in ethanol (18.0 mL) and water (1.8 mL), and hydrochloric acid (0.1 g, 2.5 mmol) was added. The reaction mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was filtered through Celite and washed with methanol. The obtained filtrate was concentrated to obtain the target compound (1.70 g, 4.4 mmol, 90% yield) as a brown solid, which was used in the next step without further purification.

[0137] Manufacturing Example 3. Manufacturing of 3,5-difluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)aniline

[0138] [Reaction Formula 3]

[0139]

[0140] [Step 1] Preparation of 7-(benzyloxy)-4-chloro-6-methoxyquinoline

[0141] 4-Chloro-6-methoxyquinolin-7-ol (10.0 g, 47.7 mmol) was dissolved in DMF (95.0 mL), potassium carbonate (33.0 g, 239 mmol) and benzyl bromide (6.24 mL, 52.5 mmol) were added at room temperature, and the mixture was stirred at 45 °C for 12 h. After confirming the completion of the reaction using LC-MS, the temperature of the reaction mixture was lowered to room temperature, distilled water was added, and the yellow solid compound produced was filtered. The target compound (13.6 g, 45.2 mmol, 95% yield) as a yellow solid was used in the next reaction without further purification. MS (ESI): m / z = 300 [M+H]+

[0142] [Step 2] Preparation of 7-(benzyloxy)-4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinoline

[0143] 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (13.5 g, 45.0 mmol) obtained in Step 1 was dissolved in NMP (113.0 mL), 2,6-difluoro-4-nitrophenol (11.8 g, 67.6 mmol) and DIPEA (23.6 mL, 135 mmol) were added, and the mixture was stirred at 140 °C for 12 h. After confirming the completion of the reaction using LC-MS, 1 N aqueous sodium hydroxide solution was added, and the organic matter was extracted with ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. Then, it was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (19.1 g, 43.6 mmol, 97% yield) as a yellow solid. MS (ESI): m / z = 439 [M+H] +

[0144] [Step 3] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol

[0145] 7-(Benzyloxy)-4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinoline (19.0 g, 43.3 mmol) obtained in the above step 2 was dissolved in TFA (87 mL) and stirred at 80°C for 2 h. After confirming the completion of the reaction using LC-MS, the organic matter was extracted with dichloromethane. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (5.1 g, 14.6 mmol, 34% yield) as a concentrated white solid was used in the next reaction without further purification. MS (ESI): m / z = 349 [M+H] +

[0146] [Step 4] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline

[0147] 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol (0.50 g, 1.44 mmol) obtained in the above step 3 was dissolved in toluene (2.87 mL), and 2-methoxyethanol-1-ol (0.34 mL, 4.31 mmol) and CMBP (1.13 mL, 4.31 mmol) were added, and the mixture was stirred at 80 °C for 2 h. After confirming the completion of the reaction using LC-MS, the organic matter was extracted with dichloromethane. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (0.51 g, 1.26 mmol, 87% yield) as a concentrated white solid was used in the next reaction without further purification. MS (ESI): m / z = 407 [M+H] +

[0148] [Step 5] Preparation of 3,5-difluoro-4-((6-methoxy-7-(2-methoxyethoxy)quinolin-4-yl)oxy)aniline

[0149] 4-(2,6-Difluoro-4-nitrophenoxy)-6-methoxy-7-(2-methoxyethoxy)quinoline (0.51 g, 1.26 mmol) obtained in the above step 4 was dissolved in ethanol (5.5 mL) and water (0.5 mL), and then iron (0.21 g, 3.77 mmol) and hydrochloric acid (0.062 mL, 0.75 mmol) were added, and the mixture was stirred at 80 °C for 2 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered using Celite and washed with methanol. The collected filtrate was concentrated after removing the remaining water using sodium sulfate. The target compound (0.38 g, 1.01 mmol, 80% yield) as a concentrated yellow solid was used in the next reaction without further purification. MS (ESI): m / z = 377 [M+H] +

[0150] Manufacturing Example 4. Preparation of 3,5-difluoro-4-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinolin-4-yl)oxy)aniline

[0151] [Reaction Formula 4]

[0152]

[0153] [Step 1] Preparation of tert-butyl 4-(((4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate

[0154] 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-ol (1.00 g, 2.87 mmol), tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (1.04 g, 3.73 mmol) and potassium carbonate (0.79 g, 5.74 mmol) obtained in step 3 of the above manufacturing example 3 were dissolved in DMF (28.7 mL). The mixture was stirred at 80°C for 2 hours. After confirming the completion of the reaction using LC-MS, the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. Then, it was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (0.94 g, 1.72 mmol, 60% yield) as a yellow solid. MS (ESI): m / z = 546 [M+H] +

[0155] [Step 2] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-(piperidin-4-ylmethoxy)quinoline

[0156] tert-Butyl 4-(((4-(2,6-difluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yl)oxy)methyl)piperidine-1-carboxylate (0.94 g, 1.72 mmol) obtained in the above step 1 was dissolved in dichloromethane (8.6 mL), TFA (6.6 mL, 86.0 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated, and the organic matter was extracted by adding ethyl acetate and saturated aqueous sodium bicarbonate solution. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (0.77 g, 1.72 mmol, 100% yield) as a concentrated yellow solid was used in the next reaction without further purification. MS (ESI): m / z = 446 [M+H] +

[0157] [Step 3] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinoline

[0158] 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-(piperidin-4-ylmethoxy)quinoline (0.77 g, 1.72 mmol) obtained in step 2 above was dissolved in dichloromethane (3.45 mL), and acetic acid (0.01 mL, 0.17 mmol), formaldehyde (0.64 mL, 8.61 mmol), and sodium triacetoxyborohydride (STAB, 0.73 g, 3.44 mmol) were added, and the mixture was stirred at room temperature for 30 min. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated, and the organic matter was extracted by adding ethyl acetate and a saturated aqueous sodium bicarbonate solution. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. Afterwards, it was purified using MPLC (hexane / ethyl acetate) and the target compound (0.34 g, 0.74 mmol, 43% yield) was obtained as a yellow solid. MS (ESI): m / z = 460 [M+H] +

[0159] [Step 4] Preparation of 3,5-difluoro-4-((6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinolin-4-yl)oxy)aniline

[0160] 4-(2,6-difluoro-4-nitrophenoxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinoline (0.34 g, 0.74 mmol) obtained in the above step 3 was dissolved in ethanol (3.2 mL) and water (0.4 mL), and then iron (0.12 g, 2.20 mmol) and hydrochloric acid (0.04 mL, 0.44 mmol) were added, and the mixture was stirred at 80 °C for 2 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered using Celite and washed with methanol. The collected filtrate was concentrated after removing the remaining water using sodium sulfate. The target compound (0.31 g, 0.72 mmol, 98% yield) as a concentrated yellow solid was used in the next reaction without further purification. MS (ESI): m / z = 430 [M+H]+

[0161] Manufacturing Example 5. Preparation of 6-methoxy-1-tosyl-1H-indazole-5-carboxylic acid

[0162] [Reaction Formula 5]

[0163]

[0164] [Step 1] Preparation of methyl 6-methoxy-1H-indazole-5-carboxylate

[0165] 6-Methoxy-1H-indazole-5-carboxylic acid (2.0 g, 10.4 mmol) was dissolved in methanol (34.7 mL), and sulfuric acid (1.99 mL, 37.5 mmol) was added at room temperature. The reaction mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, dichloromethane was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. After concentration, the target compound (2.0 g, 9.7 mmol, 93% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 207 [M+H] +

[0166] [Step 2] Preparation of methyl 6-methoxy-1-tosyl-1H-indazole-5-carboxylate

[0167] Methyl 6-methoxy-1H-indazole-5-carboxylate (2.0 g, 9.7 mmol) and potassium tert-butoxide (1.5 g, 13.5 mmol) obtained in Step 1 were dissolved in tetrahydrofuran (THF, 19 mL), and then p-toluenesulfonyl chloride (p-TsCl, 2.22 g, 11.6 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (1.4 g, 3.9 mmol, 40% yield) as a white solid. MS (ESI): m / z = 361 [M+H] +

[0168] [Step 3] Preparation of 6-methoxy-1-tosyl-1H-indazole-5-carboxylic acid

[0169] Methyl 6-methoxy-1-tosyl-1H-indazole-5-carboxylate (1.4 g, 3.9 mmol) obtained in the above step 2 was dissolved in THF (17 mL) and water (2 mL), and then lithium hydroxide (0.18 g, 7.7 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 3 h. After confirming the completion of the reaction using LC-MS, ice water was added. Then, hydrochloric acid was added to the reaction mixture to adjust the pH to 3. The precipitated solid was filtered, and the target compound (0.85 g, 2.4 mmol, 63% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 347 [M+H] +

[0170] Manufacturing Example 6. Preparation of 4-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[0171] [Reaction Formula 6]

[0172]

[0173] [Step 1] Preparation of methyl 4-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate

[0174] Ethyl 4-chloro-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (500 mg, 2.1 mmol) was dissolved in methanol (4 mL), and sodium methoxide (255 mg, 4.2 mmol) was added at room temperature. The reaction mixture was stirred at 50 °C for 2 h. After confirming the completion of the reaction using LC-MS, dichloromethane was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. After concentration, the target compound (460 mg, 2.1 mmol, 99% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 222 [M+H] +

[0175] [Step 2] Preparation of 4-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid

[0176] Methyl 4-methoxy-1-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (460 mg, 2.1 mmol) obtained in the above step 1 was dissolved in THF:methanol:water (2:1:0.5) (10 mL), and 1 N aqueous sodium hydroxide solution (6.2 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, 1 N aqueous hydrochloric acid solution was added to the reaction mixture to adjust the pH to 2. The reaction mixture was concentrated by adding silica gel, and then purified using MPLC (dichloromethane / methanol) to obtain the target compound (362 mg, 1.75 mmol, 84% yield) as a white solid. MS (ESI): m / z = 208 [M+H] +

[0177] Manufacturing Example 7. Preparation of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid

[0178] [Reaction Formula 7]

[0179]

[0180] [Step 1] Preparation of methyl 6-methoxy-2-methyl-2H-indazole-5-carboxylate

[0181] Methyl 6-methoxy-1H-indazole-5-carboxylate (2.0 g, 9.7 mmol) and trimethyloxonium tetrafluoroborate (2.2 g, 14.6 mmol) obtained in step 1 of the above Preparation Example 5 were dissolved in ethyl acetate (97 mL), and the reaction mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate), and the target compound (1.8 g, 9.7 mmol, 84% yield) was obtained as a white solid. MS (ESI): m / z = 221 [M+H] +

[0182] [Step 2] Preparation of 6-methoxy-2-methyl-2H-indazole-5-carboxylic acid

[0183] Methyl 6-methoxy-2-methyl-2H-indazole-5-carboxylate (1.8 g, 9.7 mmol) obtained in the above step 1 was dissolved in THF (17 mL) and water (2 mL), and lithium hydroxide (0.18 g, 7.7 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 3 h. After confirming the completion of the reaction using LC-MS, ice water was added. Saturated hydrochloric acid was then added to the reaction mixture to adjust the pH to 3. The precipitated solid was filtered, and the target compound (1.5 g, 7.4 mmol, 91% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 207 [M+H] +

[0184] Manufacturing Example 8. Preparation of 6-methoxy-1-methyl-1H-indazole-5-carboxylic acid

[0185] [Reaction Formula 8]

[0186]

[0187] [Step 1] Preparation of methyl 6-methoxy-1-methyl-1H-indazole-5-carboxylate

[0188] Methyl 6-methoxy-1H-indazole-5-carboxylate (1.0 g, 5.2 mmol) and cesium carbonate (5.1 g, 15.6 mmol) obtained in step 1 of Preparation Example 5 were dissolved in DMF (10 mL), and methyl iodide (4.4 g, 31.2 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (0.75 g, 3.4 mmol, 65% yield) as a white solid. MS (ESI): m / z = 221 [M+H] +

[0189] [Step 2] Preparation of 6-methoxy-1-methyl-1H-indazole-5-carboxylic acid

[0190] Methyl 6-methoxy-1-methyl-1H-indazole-5-carboxylate (0.75 g, 3.4 mmol) obtained in the above step 2 was dissolved in THF (9 mL) and water (1 mL), and lithium hydroxide (0.15 g, 6.8 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 3 h. After confirming the completion of the reaction using LC-MS, ice water was added. Saturated hydrochloric acid was then added to the reaction mixture to adjust the pH to 3. The precipitated solid was filtered, and the target compound (0.65 g, 3.2 mmol, 94% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 207 [M+H] +

[0191] Manufacturing Example 9. Preparation of 6-methoxy-3-methylbenzo[d]isoxazole-5-carboxylic acid

[0192] [Reaction Formula 9]

[0193]

[0194] [Step 1] Preparation of methyl 4-(allyloxy)-2-hydroxybenzoate

[0195] Methyl 2,4-dihydroxybenzoate (1.7 g, 10.1 mmol) and potassium carbonate (1.5 g, 11.2 mmol) were dissolved in acetone (20.2 mL), and then allyl bromide (0.9 mL, 11.2 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the solid was filtered. The solid was then washed with acetone, and the combined organic layer was concentrated. The target compound (2.1 g, 10.1 mmol, 99% yield) obtained after concentration was used in the next step without further purification as a white solid. MS (ESI): m / z = 209 [M+H] +

[0196] [Step 2] Preparation of methyl 4-(allyloxy)-2-methoxybenzoate

[0197] Methyl 4-(allyloxy)-2-hydroxybenzoate (2.1 g, 10.1 mmol) and potassium carbonate (1.5 g, 11.2 mmol) obtained in Step 1 were dissolved in acetone (20.2 mL), and methyl iodide (1.9 mL, 30.3 mmol) was added at room temperature. The reaction mixture was stirred at 70 °C for 24 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (1.5 g, 7.1 mmol, 70% yield) as a white solid. MS (ESI): m / z = 223 [M+H] +

[0198] [Step 3] Preparation of methyl 5-acetyl-4-hydroxy-2-methoxybenzoate

[0199] Methyl 4-(allyloxy)-2-methoxybenzoate (0.5 g, 2.3 mmol) and acetyl chloride (0.26 g, 3.4 mmol) obtained in Step 2 were dissolved in BF3·OEt2 (5.6 mL), and the reaction mixture was stirred at 110°C for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (0.33 g, 1.5 mmol, 65% yield) as a white solid. MS (ESI): m / z = 225 [M+H] +

[0200] [Step 4] Preparation of methyl (Z)-4-hydroxy-5-(1-(hydroxyimino)ethyl)-2-methoxybenzoate

[0201] Methyl 5-acetyl-4-hydroxy-2-methoxybenzoate (0.33 g, 1.5 mmol), pyridine (0.36 mL, 4.4 mmol), and hydroxylamine hydrochloride (0.21 g, 2.9 mmol) obtained in Step 3 were dissolved in ethanol (2.4 mL) and water (0.49 mL), and the reaction mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (0.3 g, 1.3 mmol, 85% yield) as a white solid. MS (ESI): m / z = 240 [M+H] +

[0202] [Step 5] Preparation of methyl 6-methoxy-3-methylbenzo[d]isoxazole-5-carboxylate

[0203] 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 0.5 g, 2.2 mmol) and triphenylphosphine (0.57 g, 2.2 mmol) were dissolved in dichloromethane (3 mL) and stirred at room temperature for 10 minutes. Then, methyl (Z)-4-hydroxy-5-(1-(hydroxyimino)ethyl)-2-methoxybenzoate (0.3 g, 1.3 mmol) obtained in step 4 was added at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound as a white solid (0.16 g, 0.7 mmol, 50% yield). MS (ESI): m / z = 222 [M+H] +

[0204] [Step 6] Preparation of 6-methoxy-3-methylbenzo[d]isoxazole-5-carboxylic acid

[0205] Methyl 6-methoxy-3-methylbenzo[d]isoxazole-5-carboxylate (0.16 g, 0.7 mmol) obtained in the above step 5 was dissolved in THF (9 mL) and water (1 mL), and lithium hydroxide (17.3 mg, 0.7 mmol) was added at room temperature. The reaction mixture was stirred at 40 °C for 3 h. After confirming the completion of the reaction using LC-MS, ice water was added. Saturated hydrochloric acid was then added to the reaction mixture to adjust the pH to 3. The precipitated solid was filtered, and the target compound (0.06 g, 0.3 mmol, 40% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 208 [M+H] +

[0206] Manufacturing Example 10. Preparation of 6-methoxy-2-methylimidazo[1,2-a]pyridine-7-carboxylic acid

[0207] [Reaction Formula 10]

[0208]

[0209] [Step 1] Preparation of methyl 6-bromo-2-methylimidazo[1,2-a]pyridine-7-carboxylate

[0210] Methyl 2-amino-5-bromoisonicotinate (1.5 g, 6.5 mmol) was dissolved in ethanol (3.3 mL), and 1-chloropropan-2-one (0.6 mL, 7.8 mmol) was added at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After confirming the completion of the reaction using LC-MS, dichloromethane was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. After concentration, the target compound (0.5 g, 1.9 mmol, 29% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 269.0 [M+H] +

[0211] [Step 2] Preparation of 6-methoxy-2-methylimidazo[1,2-a]pyridine-7-carboxylic acid

[0212] Methyl 6-bromo-2-methylimidazo[1,2-a]pyridine-7-carboxylate (0.3 g, 1.1 mmol) and cesium carbonate (0.7 g, 2.2 mmol) obtained in Step 1 were dissolved in methanol (3 mL), and CuI (0.2 g, 1.1 mmol) and 1,10-phenanthroline (0.2 g, 1.1 mmol) were added at room temperature. The reaction mixture was stirred at 90 °C for 1 h. After confirming the completion of the reaction using LC-MS, dichloromethane / methanol (4:1) was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (dichloromethane / methanol) to obtain the target compound as a white solid (0.1 g, 0.5 mmol, 44% yield). MS (ESI): m / z = 207 [M+H] +

[0213] Manufacturing Example 11. Preparation of (S)-2-((4-(4-amino-2,6-difluorophenoxy)-7-methoxyquinolin-6-yl)oxy)propan-1-ol

[0214] [Reaction Formula 11]

[0215]

[0216] [Step 1] Preparation of 6-bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline

[0217] 6-Bromo-4-chloro-7-methoxyquinoline (10.0 g, 36.7 mmol) and 2,6-difluoro-4-nitrophenol (12.9 g, 73.4 mmol) were dissolved in NMP (183 mL), and then DIPEA (19.2 mL, 110.0 mmol) was added. The reaction mixture was stirred at 140 °C for 15 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with 1 N aqueous sodium hydroxide solution, the combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound (7.0 g, 17.0 mmol, 46% yield) as a white solid. MS (ESI): m / z = 411.1 [M+H] +

[0218] [Step 2] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinolin-6-ol

[0219] 6-Bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (5.0 g, 12.2 mmol), potassium hydroxide (1.6 g, 24.3 mmol), Pd2(dba)3 (0.7 g, 1.2 mmol), and tBuXPhos (0.5 g, 1.2 mmol) obtained in Step 1 were dissolved in dioxane (49 mL) and water (12 mL), and the reaction mixture was stirred at 100 °C for 1 h. After confirming the completion of the reaction using LC-MS, dichloromethane, methanol, and water were added to the reaction mixture to extract the organic matter. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (dichloromethane / methanol) to obtain the target compound as a white solid (3.3 g, 9.6 mmol, 79% yield). MS (ESI): m / z = 349 [M+H] +

[0220] [Step 3] Preparation of (S)-6-((1-(benzyloxy)propan-2-yl)oxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline

[0221] 4-(2,6-Difluoro-4-nitrophenoxy)-7-methoxyquinolin-6-ol (2.3 g, 6.6 mmol), (R)-1-(benzyloxy)propan-2-ol (3.3 g, 19.8 mmol), and triphenylphosphine (5.2 g, 19.8 mmol) obtained in Step 2 above were dissolved in THF (26 mL), and then diisopropyl azodicarboxylate (DIAD, 3.9 mL, 19.8 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, dichloromethane, methanol, and water were added to the reaction mixture to extract the organic matter. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (hexane / ethyl acetate) to obtain the target compound as a white solid (3.3 g, 6.6 mmol, 100% yield). MS (ESI): m / z = 497 [M+H] +

[0222] [Step 4] Preparation of (S)-4-((6-((1-(benzyloxy)propan-2-yl)oxy)-7-methoxyquinolin-4-yl)oxy)-3,5-difluoroaniline

[0223] (S)-6-((1-(benzyloxy)propan-2-yl)oxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxyquinoline (3.3 g, 6.6 mmol) and iron (1.1 g, 19.8 mmol) obtained in the above step 3 were dissolved in ethanol (30 mL) and water (3 mL), and then hydrogen chloride (0.7 g, 6.6 mmol) was added, and the reaction mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was filtered through Celite and washed with methanol. The collected filtrate was concentrated, and the target compound (2.0 g, 4.3 mmol, 65% yield) obtained as a brown solid was used in the next step without further purification. MS (ESI): m / z = 467 [M+H] +

[0224] [Step 5] Preparation of (S)-2-((4-(4-amino-2,6-difluorophenoxy)-7-methoxyquinolin-6-yl)oxy)propan-1-ol

[0225] (S)-4-((6-((1-(benzyloxy)propan-2-yl)oxy)-7-methoxyquinolin-4-yl)oxy)-3,5-difluoroaniline (1.0 g, 2.1 mmol) obtained in the above step 4 was dissolved in TFA (10 mL) and stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, dichloromethane, methanol, and aqueous sodium hydroxide solution were added to the reaction mixture to extract the organic matter. The obtained organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (dichloromethane / methanol) to obtain the target compound (0.8 g, 2.1 mmol, 93% yield) as a white solid. MS (ESI): m / z = 377 [M+H] +

[0226] Manufacturing Example 12. Preparation of (S)-2-((8-(4-amino-2,6-difluorophenoxy)-3-methoxy-1,5-naphthyridin-2-yl)oxy)propan-1-ol

[0227] [Reaction Formula 12]

[0228]

[0229] [Step 1] Preparation of 5-(((6-bromo-5-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0230] 6-Bromo-5-methoxypyridin-3-amine (175.0 g, 861.9 mmol) was dissolved in ethanol (1.5 L), and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (144.4 g, 775.7 mmol) was added. The mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, methyl tert-butyl ether (MTBE) was added, and the precipitated solid was filtered. The target compound (120.0 g, 336.0 mmol, 39% yield) obtained as a gray solid was used in the next step without further purification.

[0231] [Step 2] Preparation of 6-bromo-7-methoxy-1,5-naphthyridin-4-ol

[0232] 5-(((6-Bromo-5-methoxypyridin-3-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (40.0 g, 112.0 mmol) obtained in the above step 1 was dissolved in diphenyl ether (DPE, 400 mL) and stirred at 200 °C for 10 min. After confirming the completion of the reaction using LC-MS, MTBE was added and the precipitated solid was filtered. The target compound (22.3 g, 87.6 mmol, 78% yield) as a yellow solid was used in the next step without further purification.

[0233] [Step 3] Preparation of 2-bromo-8-chloro-3-methoxy-1,5-naphthyridine

[0234] 6-Bromo-7-methoxy-1,5-naphthyridin-4-ol (33.0 g, 129.4 mmol) and DIPEA (50.2 g, 388.1 mmol, 67.6 mL) obtained in the above step 2 were dissolved in toluene (330 mL), and then phosphoryl chloride (POCl 3, 59.5 g, 388.1 mmol, 36.2 mL) was added and stirred at 100 °C for 1 hour. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution, and the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (27.0 g, 98.7 mmol, 76% yield) as a pink solid. MS (ESI): m / z = 274.9 [M+H] +

[0235] [Step 4] Preparation of 2-bromo-8-(2,6-difluoro-4-nitrophenoxy)-3-methoxy-1,5-naphthyridine

[0236] 2-Bromo-8-chloro-3-methoxy-1,5-naphthyridine (27.0 g, 94.8 mmol) and DIPEA (24.5 g, 189.6 mmol, 33.0 mL) obtained in Step 3 were dissolved in NMP (270 mL), and 2,6-difluoro-4-nitro-phenol (24.9 g, 142.2 mmol) was added, and the mixture was stirred at 120 °C for 12 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (25.5 g, 61.9 mmol, 65% yield) as a green solid. MS (ESI): m / z = 413.8 [M+H] +

[0237] [Step 5] Preparation of 4-((6-bromo-7-methoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline

[0238] 2-Bromo-8-(2,6-difluoro-4-nitrophenoxy)-3-methoxy-1,5-naphthyridine (34.0 g, 82.5 mmol) and ammonium chloride (22.1 g, 412.5 mmol) obtained in Step 4 above were dissolved in ethanol (300 mL) and water (60 mL), and iron (23.0 g, 412.5 mmol) was added, followed by stirring at 80 °C for 1 hour. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound as a yellow solid (20.9 g, 54.7 mmol, 66% yield). MS (ESI): m / z = 383.9 [M+H] +

[0239] [Step 6] Preparation of 8-(4-amino-2,6-difluorophenoxy)-3-methoxy-1,5-naphthyridin-2-ol

[0240] 4-((6-Bromo-7-methoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline (16.0 g, 41.9 mmol), potassium hydroxide (7.1 g, 125.6 mmol), and t-BuXPhos (1.8 g, 4.2 mmol) obtained in Step 5 above were dissolved in dioxane (135 mL) and water (27 mL), and Pd2(dba)3 (3.8 g, 4.2 mmol) was added, and the mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was diluted with water, and the pH was adjusted to 6 by adding hydrochloric acid, and the precipitated solid was filtered. The target compound (13.4 g, 41.9 mmol, 100% yield) obtained as a dark brown solid was washed with MTBE and used in the next step without further purification. MS (ESI): m / z = 320 [M+H] +

[0241] [Step 7] Preparation of (S)-4-((6-((1-(benzyloxy)propan-2-yl)oxy)-7-methoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline

[0242] 8-(4-Amino-2,6-difluorophenoxy)-3-methoxy-1,5-naphthyridin-2-ol (9.0 g, 28.2 mmol), (2R)-1-benzyloxypropan-2-ol (9.4 g, 56.4 mmol), and triphenylphosphine (22.2 g, 84.6 mmol) obtained in Step 6 above were dissolved in THF (90 mL), diethyl azodicarboxylate (DEAD, 14.7 g, 84.6 mmol, 15.4 mL) was added at 0 °C, and the mixture was stirred at 25 °C for 12 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / THF) to obtain the target compound (7.0 g, 15.0 mmol, 53% yield) as a red liquid. MS (ESI): m / z = 468 [M+H] +

[0243] [Step 8] Preparation of (S)-2-((8-(4-amino-2,6-difluorophenoxy)-3-methoxy-1,5-naphthyridin-2-yl)oxy)propan-1-ol

[0244] (S)-4-((6-((1-(benzyloxy)propan-2-yl)oxy)-7-methoxy-1,5-naphthyridin-4-yl)oxy)-3,5-difluoroaniline (14.8 g, 29.4 mmol) obtained in the above step 7 was dissolved in isopropanol (150 mL), Pd / C (6.3 g, 5.9 mmol) was added, and the mixture was stirred at 65°C under hydrogen gas (3.4 atm) for 4 hours. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / THF) to obtain the target compound as a white solid (5.2 g, 13.6 mmol, 46% yield). MS (ESI): m / z = 378 [M+H] +

[0245] Manufacturing Example 13. Preparation of 2,3-dihydrofuro[3,2-c]pyridine-7-carboxylic acid

[0246] [Reaction Formula 13]

[0247]

[0248] [Step 1] Preparation of N-furo[3,2-c]pyridin-4-yl-1,1-diphenyl-methanamine

[0249] 4-Chlorofuro[3,2-c]pyridine (60.0 g, 392.2 mmol), diphenylmethanamine (85.0 g, 469.3 mmol, 1.2 eq), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP, 14.6 g, 23.5 mmol), and Pd2(dba)3 (21.3 g, 23.2 mmol) were dissolved in toluene (580 mL), and sodium tert-butoxide (52.6 g, 547.5 mmol) was added. The mixture was stirred at 80 °C for 3 h. After confirming that the reaction was complete using LC-MS, the reaction mixture was concentrated to obtain the target compound (110.0 g, 368.7 mmol, 94% yield) as a dark brown liquid, which was used in the next step without further purification. MS (ESI): m / z = 299 [M+H] +

[0250] [Step 2] Preparation of furo[3,2-c]pyridin-4-amine

[0251] N-Furo[3,2-c]pyridin-4-yl-1,1-diphenyl-methanamine (110.0 g, 368.7 mmol), NH2OH-HCl (76.9 g, 1106.1 mmol), and sodium acetate (121.0 g, 1474.8 mmol) obtained in Step 1 were dissolved in methanol (1.1 L) and stirred at room temperature for 10 hours. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with saturated aqueous sodium chloride solution, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (dichloromethane / methanol) to obtain the target compound (40.0 g, 298.2 mmol, 81% yield) as a yellow solid. MS (ESI): m / z = 135 [M+H] +

[0252] [Step 3] Preparation of 2,3-dihydrofuro[3,2-c]pyridin-4-amine

[0253] Furo[3,2-c]pyridin-4-amine (40.0 g, 298.2 mmol) obtained in the above step 2 was dissolved in methanol (500 mL), and Pd / C (14.5 g, 13.6 mmol) was added. The mixture was stirred at 50°C for 10 h under hydrogen gas (2 atm). After confirming the completion of the reaction using LC-MS, the reaction mixture was filtered through Celite and concentrated. The concentrated mixture was purified using MPLC (dichloromethane / methanol) to obtain the target compound (8.5 g, 61.8 mmol, 23% yield) as a white solid. MS (ESI): m / z = 137 [M+H] +

[0254] [Step 4] Preparation of 7-bromo-2,3-dihydrofuro[3,2-c]pyridin-4-amine

[0255] 2,3-Dihydrofuro[3,2-c]pyridin-4-amine (11.0 g, 80.0 mmol) obtained in the above step 3 was dissolved in acetonitrile (110 mL), and then a solution of NBS (15.5 g, 87.1 mmol) in acetonitrile (110 mL) was added at -10 °C for 10 minutes, and the mixture was stirred at the same temperature for 1 hour. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. Ethyl acetate was added to the concentrated mixture, and the organic matter was extracted after washing with 0.5 N aqueous sodium hydroxide solution. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (11.5 g, 53.5 mmol, 58% yield) obtained by concentration was used in the next step without further purification. MS (ESI): m / z = 214.8 [M+H] +

[0256] [Step 5] Preparation of 7-bromo-2,3-dihydrofuro[3,2-c]pyridine

[0257] 7-Bromo-2,3-dihydrofuro[3,2-c]pyridin-4-amine (11.5 g, 53.5 mmol) obtained in the above step 4 was dissolved in THF (115 mL), and isopentyl nitrite (23.5 g, 200.5 mmol, 27.0 mL) was slowly added at 0 °C, and the mixture was stirred at 70 °C for 3 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (3.8 g, 19.0 mmol, 36% yield) as a yellow liquid. MS (ESI): m / z = 199.8 [M+H] +

[0258] [Step 6] Preparation of methyl 2,3-dihydrofuro[3,2-c]pyridine-7-carboxylate

[0259] 7-Bromo-2,3-dihydrofuro[3,2-c]pyridine (3.6 g, 18.0 mmol) obtained in step 5 above was dissolved in THF (36 mL) and methanol (36 mL), and then DIPEA (642 mg, 5.0 mmol), 1,3-bis(diphenylphosphino)propane (DPPP, 68 mg, 165 μmol), and Pd(OAc)2 (37 mg, 166 μmol) were added (reaction mixture 1). The reaction mixture 1 was adjusted to a flow rate of 4 mL / min through pump 1 while maintaining the carbon monoxide flow rate of 30 mL / min and the pressure of 3.5 MPa in a fixed bed reactor (inner diameter 12.700 mm (1 / 2"), volume 100 mL, temperature 160 ℃). After reacting under these conditions for 1 hour, the reaction mixture 1 was concentrated and purified using MPLC (petroleum ether / THF), obtaining the target compound (2.0 g, 11.2 mmol, 59% yield) as a brown solid. MS (ESI): m / z = 179.9 [M+H] +

[0260] [Step 7] Preparation of 2,3-dihydrofuro[3,2-c]pyridine-7-carboxylic acid

[0261] Methyl 2,3-dihydrofuro[3,2-c]pyridine-7-carboxylate (2.0 g, 11.2 mmol) obtained in the above step 6 was dissolved in THF (15 mL), methanol (15 mL), and water (15 mL), and then sodium hydroxide (2.2 g, 55.8 mmol) was added and stirred at 60°C for 30 min. After confirming the completion of the reaction using LC-MS, the mixture was adjusted to pH 7 by adding hydrochloric acid and concentrated. The concentrated mixture was purified using prep-HPLC (water (0.1% ammonium bicarbonate) / acetonitrile) to obtain the target compound (755 mg, 4.5 mmol, 41% yield) as a white solid. MS (ESI): m / z = 166 [M+H] +

[0262] Manufacturing Example 14. Preparation of 6-(difluoromethoxy)-2-methyl-2H-indazole-5-carboxylic acid

[0263] [Reaction Formula 14]

[0264]

[0265] [Step 1] Preparation of 5-bromo-6-methoxy-2-methyl-2H-indazole

[0266] 5-Bromo-6-methoxy-1H-indazole (10.0 g, 44.0 mmol) was dissolved in ethyl acetate (100 mL), and trimethyloxonium:tetrafluoroborate (6.5 g, 44.0 mmol) was added. The mixture was stirred at 25°C for 4 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated to remove the remaining water using sodium sulfate, and the target compound (9.3 g, 37.8 mmol, 85% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 241 [M+H] +

[0267] [Step 2] Preparation of 5-bromo-2-methyl-2H-indazol-6-ol

[0268] 5-Bromo-6-methoxy-2-methyl-2H-indazole (9.3 g, 37.8 mmol) obtained in the above step 1 was dissolved in dichloromethane (200 mL), and BBr3 (2 M in DCM, 96.4 mL) was added at 0 °C, and the mixture was stirred at 35 °C for 12 h. After confirming the completion of the reaction using LC-MS, the mixture was diluted with water. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture to adjust the pH to 8, and the precipitated solid was filtered. The target compound (7.3 g, 32.2 mmol, 85% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 226.8 [M+H] +

[0269] [Step 3] Preparation of 5-bromo-6-(difluoromethoxy)-2-methyl-2H-indazole

[0270] 5-Bromo-2-methyl-2H-indazol-6-ol (1.0 g, 4.4 mmol) obtained in Step 2 above and 2N aqueous potassium hydroxide solution (5 mL) were dissolved in acetonitrile (5 mL), and then a solution of 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (2.4 g, 8.8 mmol) diluted in THF (3 mL) was added at 0 °C for 5 min. The reaction mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was diluted with water. Hydrochloric acid was added to the diluted mixture to adjust the pH to 3, and the organic matter was extracted with ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound as a yellow solid (1.4 g, 4.7 mmol, 30% yield). MS (ESI): m / z = 276.8 [M+H] +

[0271] [Step 4] Preparation of methyl 6-(difluoromethoxy)-2-methyl-2H-indazole-5-carboxylate

[0272] 5-Bromo-6-(difluoromethoxy)-2-methyl-2H-indazole (1.4 g, 4.7 mmol) and triethylamine (TEA, 1.4 g, 14.0 mmol, 1.9 mL) obtained in Step 3 were dissolved in methanol (20 mL), and Pd(OAc)2 (417 mg, 1.9 mmol) and 1,1'-bis(diphenylphosphino)ferrocene (DPPF, 1.0 g, 1.9 mmol) were added, and the mixture was stirred at 80 °C under carbon monoxide gas (3.4 atm) for 4 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was diluted with water, and the organic matter was extracted with ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (1.0 g, 4.0 mmol, 86% yield) as a yellow solid. MS (ESI): m / z = 256 [M+H] +

[0273] [Step 5] Preparation of 6-(difluoromethoxy)-2-methyl-2H-indazole-5-carboxylic acid

[0274] Methyl 6-(difluoromethoxy)-2-methyl-2H-indazole-5-carboxylate (300 mg, 765 μmol) obtained in the above step 4 was dissolved in methanol (3 mL), water (3 mL), and THF (3 mL), and then sodium hydroxide (153 mg, 3830 μmol) was added and stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the pH was adjusted to 3 by adding hydrochloric acid, and the organic matter was extracted with water and ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (230 mg, 943 μmol, 70% yield) obtained by concentration was used in the next step without further purification. MS (ESI): m / z = 242.9 [M+H] +

[0275] Manufacturing Example 15. Preparation of (S)-2-((4-(4-amino-2,6-difluorophenoxy)-7-methoxy-5-methylquinolin-6-yl)oxy)propan-1-ol

[0276] [Reaction Formula 15]

[0277]

[0278] [Step 1] Preparation of 4-bromo-3-methoxy-5-methyl-aniline

[0279] 3-Methoxy-5-methyl-aniline (9.0 g, 65.6 mmol) was dissolved in DMF (100 mL), and N-bromosuccinimide (NBS, 11.7 g, 65.6 mmol) was added. The mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (5.2 g, 24.1 mmol, 37% yield) as a brown solid. MS (ESI): m / z = 215.8 [M+H] +

[0280] [Step 2] Preparation of 5-(((4-bromo-3-methoxy-5-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0281] 4-Bromo-3-methoxy-5-methyl-aniline (4.2 g, 19.4 mmol) obtained in Step 1 was dissolved in ethanol (50 mL), and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 17.5 mmol) was added, and the mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, MTBE was added, and the precipitated solid was filtered. The target compound (5.5 g, 10.0 mmol, 51% yield) obtained as a yellow solid was used in the next step without further purification.

[0282] [Step 3] Preparation of 6-bromo-7-methoxy-5-methylquinolin-4-ol

[0283] 5-(((4-Bromo-3-methoxy-5-methylphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.5 g, 14.9 mmol) obtained in the above step 2 was dissolved in DPE (80 mL) and stirred at 180 °C for 10 min. After confirming the completion of the reaction using LC-MS, MTBE was added and the precipitated solid was filtered. The target compound (3.0 g, 9.85 mmol, 66% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 269.9 [M+H] +

[0284] [Step 4] Preparation of 6-bromo-4-chloro-7-methoxy-5-methylquinoline

[0285] 6-Bromo-7-methoxy-5-methylquinolin-4-ol (3.0 g, 11.2 mmol) obtained in the above step 3 was dissolved in POCl3 (12 mL) and stirred at 110°C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, and the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.3 g, 8.0 mmol, 71% yield) as a yellow solid. MS (ESI): m / z = 287.9 ​​[M+H] +

[0286] [Step 5] Preparation of 6-bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-5-methylquinoline

[0287] 6-Bromo-4-chloro-7-methoxy-5-methylquinoline (2.3 g, 8.0 mmol) obtained in the above step 4 was dissolved in NMP (25 mL), and 2,6-difluoro-4-nitro-phenol (1.7 g, 9.6 mmol) and DIPEA (2.0 g, 16.1 mmol) were added, and the mixture was stirred at 100 °C for 14 h. After confirming the completion of the reaction using LC-MS, water was added to the reaction mixture, and the precipitated solid was filtered. The target compound (2.9 g, 6.8 mmol, 85% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 425 [M+H] +

[0288] [Step 6] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-5-methylquinolin-6-ol

[0289] 6-Bromo-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-5-methylquinoline (2.5 g, 5.9 mmol), potassium hydroxide (1.0 g, 17.6 mmol), and tBuXPhos (250 mg, 588 μmol) obtained in Step 5 above were dissolved in dioxane (25 mL) and water (5 mL), and Pd2(dba)3 (538 mg, 588 μmol) was added, and the mixture was stirred at 80 °C for 30 min. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was diluted with water, and the pH was adjusted to 6 by adding a saturated aqueous ammonium chloride solution, and the precipitated solid was filtered. The target compound (1.8 g, 5.0 mmol, 85% yield) obtained as a green solid was washed with MTBE and used in the next step without further purification. MS (ESI): m / z = 363 [M+H] +

[0290] [Step 7] Preparation of (S)-6-((1-(benzyloxy)propan-2-yl)oxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-5-methylquinoline

[0291] 4-(2,6-Difluoro-4-nitrophenoxy)-7-methoxy-5-methylquinolin-6-ol (1.3 g, 3.6 mmol), (2R)-1-benzyloxypropan-2-ol (1.2 g, 7.2 mmol) and triphenylphosphine (2.4 g, 9.0 mmol) obtained in step 6 above were dissolved in THF (15 mL), DEAD (1.6 g, 9.0 mmol, 1.6 mL) was added at 0 °C, and the mixture was stirred at room temperature for 14 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / THF) to obtain the target compound (1.7 g, 2.9 mmol, 49% yield) as a yellow solid. MS (ESI): m / z = 511 [M+H] +

[0292] [Step 8] Preparation of (S)-2-((4-(4-amino-2,6-difluorophenoxy)-7-methoxy-5-methylquinolin-6-yl)oxy)propan-1-ol

[0293] (S)-6-((1-(benzyloxy)propan-2-yl)oxy)-4-(2,6-difluoro-4-nitrophenoxy)-7-methoxy-5-methylquinoline (1.8 g, 3.5 mmol) obtained in the above step 7 was dissolved in isopropanol (50 mL), Pd / C (1.6 g, 1.6 mmol) was added, and the mixture was stirred at 65°C under hydrogen gas (3.4 atm) for 14 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / THF) to obtain the target compound as a white solid (568 mg, 1.4 mmol, 45% yield). MS (ESI): m / z = 391 [M+H] +

[0294] Manufacturing Example 16. Preparation of (S)-2-((4-(4-amino-2,6-difluorophenoxy)-5-fluoro-7-methoxyquinolin-6-yl)oxy)propan-1-ol

[0295] [Reaction Formula 16]

[0296]

[0297] [Step 1] Preparation of 4-bromo-3-fluoro-5-methoxy-aniline

[0298] 3-Fluoro-5-methoxy-aniline (9.0 g, 63.8 mmol) was dissolved in DMF (100 mL), and NBS (11.4 g, 63.8 mmol) was added. The mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (10.5 g, 47.7 mmol, 67% yield) as a yellow solid. MS (ESI): m / z = 221.7 [M+H] +

[0299] [Step 2] Preparation of 5-(((4-bromo-3-fluoro-5-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0300] 4-Bromo-3-fluoro-5-methoxy-aniline (9.5 g, 30.2 mmol) obtained in Step 1 was dissolved in ethanol (90 mL), and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (5.1 g, 27.2 mmol) was added, and the mixture was stirred at 80 °C for 1 h. After confirming the completion of the reaction using LC-MS, MTBE was added, and the precipitated solid was filtered. The target compound (8.8 g, 22.6 mmol, 75% yield) obtained as a yellow solid was used in the next step without further purification.

[0301] [Step 3] Preparation of 6-bromo-5-fluoro-7-methoxyquinolin-4-ol

[0302] 5-(((4-Bromo-3-fluoro-5-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (8.8 g, 23.5 mmol) obtained in the above step 2 was dissolved in DPE (90 mL) and stirred at 180 °C for 10 min. After confirming the completion of the reaction using LC-MS, MTBE was added and the precipitated solid was filtered. The target compound (5.6 g, 15.4 mmol, 65% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 271.9 [M+H] +

[0303] [Step 4] Preparation of 6-bromo-4-chloro-5-fluoro-7-methoxyquinoline

[0304] 6-Bromo-5-fluoro-7-methoxyquinolin-4-ol (3.0 g, 11.0 mmol) obtained in the above step 3 was dissolved in POCl3 (12 mL) and stirred at 110°C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was diluted with ethyl acetate, washed with a saturated aqueous sodium bicarbonate solution, and the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.0 g, 6.0 mmol, 54% yield) as a yellow solid. MS (ESI): m / z = 291.9 [M+H] +

[0305] [Step 5] Preparation of 6-bromo-4-(2,6-difluoro-4-nitrophenoxy)-5-fluoro-7-methoxyquinoline

[0306] 6-Bromo-4-chloro-5-fluoro-7-methoxyquinoline (2.9 g, 10.0 mmol) obtained in the above step 4 was dissolved in NMP (30 mL), and 2,6-difluoro-4-nitro-phenol (2.1 g, 12.0 mmol) and DIPEA (2.6 g, 20.0 mmol) were added, and the mixture was stirred at 100 °C for 14 h. After confirming the completion of the reaction using LC-MS, water was added to the reaction mixture, and the precipitated solid was filtered. The target compound (4.2 g, 9.2 mmol, 92% yield) obtained as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 431.0 [M+H] +

[0307] [Step 6] Preparation of 4-(2,6-difluoro-4-nitrophenoxy)-5-fluoro-7-methoxyquinolin-6-ol

[0308] 6-Bromo-4-(2,6-difluoro-4-nitrophenoxy)-5-fluoro-7-methoxyquinoline (4.2 g, 9.79 mmol, 1 eq), potassium hydroxide (1.7 g, 29.4 mmol), and tBuXPhos (416 mg, 979 μmol) obtained in Step 5 above were dissolved in dioxane (20 mL) and water (4 mL), and Pd2(dba)3 (896 mg, 979 μmol) was added, and the mixture was stirred at 80 °C for 30 min. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was diluted with water, and the pH was adjusted to 6 by adding a saturated aqueous ammonium chloride solution, and the precipitated solid was filtered. The target compound (4.1 g, 9.5 mmol, 78% yield) obtained as a green solid was washed with MTBE and used in the next step without further purification. MS (ESI): m / z = 367 [M+H] +

[0309] [Step 7] Preparation of (S)-6-((1-(benzyloxy)propan-2-yl)oxy)-4-(2,6-difluoro-4-nitrophenoxy)-5-fluoro-7-methoxyquinoline

[0310] 4-(2,6-difluoro-4-nitrophenoxy)-5-fluoro-7-methoxyquinolin-6-ol (2.0 g, 5.5 mmol), (2R)-1-benzyloxypropan-2-ol (1.8 g, 10.9 mmol) and triphenylphosphine (3.6 g, 13.7 mmol) obtained in the above step 6 were dissolved in THF (40 mL), DEAD (2.4 g, 13.7 mmol, 2.5 mL) was added at 0 °C, and the mixture was stirred at room temperature for 14 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / THF) to obtain the target compound as a yellow solid (1.9 g, 3.4 mmol, 62% yield). MS (ESI): m / z = 515 [M+H] +

[0311] [Step 8] Preparation of (S)-2-((4-(4-amino-2,6-difluorophenoxy)-5-fluoro-7-methoxyquinolin-6-yl)oxy)propan-1-ol

[0312] (S)-6-((1-(benzyloxy)propan-2-yl)oxy)-4-(2,6-difluoro-4-nitrophenoxy)-5-fluoro-7-methoxyquinoline (1.8 g, 3.5 mmol) obtained in the above step 7 was dissolved in isopropanol (40 mL), Pd / C (500 mg, 0.5 mmol) was added, and the mixture was stirred at 65°C under hydrogen gas (3.4 atm) for 14 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite, and ethyl acetate was added to the filtrate. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / THF) to obtain the target compound as a white solid (625 mg, 1.6 mmol, 42% yield). MS (ESI): m / z = 395 [M+H] +

[0313] Manufacturing Example 17. Preparation of 7-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0314] [Reaction Formula 17]

[0315]

[0316] [Step 1] Preparation of diethyl 2-(((1-methyl-1H-imidazol-5-yl)amino)methylene)malonate

[0317] To a solution of 1-methyl-5-nitro-imidazole (5.0 g, 39.3 mmol) in ethanol (200 mL) was added Pd / C (2.1 g, 2.0 mmol), and the mixture was stirred at room temperature for 3 h under hydrogen gas (1 atm). Diethyl 2-(ethoxymethylene)propanedioate (10.2 g, 47.2 mmol) was added to the reaction solution, and the mixture was stirred for an additional 16 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite and washed with ethanol. The combined organic layer was concentrated and purified using MPLC (dichloromethane / methanol), obtaining the target compound (7.4 g, 28.8 mmol, 70% yield) as a dark brown solid. MS (ESI): m / z = 268 [M+H] +

[0318] [Step 2] Preparation of ethyl 7-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate

[0319] Diethyl 2-(((1-methyl-1H-imidazol-5-yl)amino)methylene)malonate (6.4 g, 25.1 mmol) obtained in the above step 1 was dissolved in POCl3 (80 mL) and stirred at 100°C for 12 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture to extract the organic matter. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.7 g, 11.3 mmol, 45% yield) as a yellow solid. MS (ESI): m / z = 240 [M+H] +

[0320] [Step 3] Preparation of methyl 7-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate

[0321] Ethyl 7-chloro-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate (2.7 g, 11.3 mmol) obtained in the above step 2 was dissolved in methanol (50 mL), sodium methoxide (5.4 M, 20.1 mL) was added, and the mixture was stirred at room temperature for 12 h. After confirming the completion of the reaction using LC-MS, ethyl acetate and saturated aqueous sodium bicarbonate solution were added to the reaction mixture to extract the organic matter. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.1 g, 9.5 mmol, 87% yield) as a transparent oil. MS (ESI): m / z = 222 [M+H] +

[0322] [Step 4] Preparation of 7-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0323] Methyl 7-methoxy-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylate (2.0 g, 9.1 mmol) obtained in the above step 3 was dissolved in methanol (10 mL) and THF (10 mL), and 4N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. Hydrochloric acid was added to the concentrated reaction mixture to adjust the pH to 5, and the precipitated solid was filtered. The target compound (1.7 g, 8.2 mmol, 91% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 208 [M+H] +

[0324] Manufacturing Example 18. Preparation of 4-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0325] [Reaction Formula 18]

[0326]

[0327] [Step 1] Preparation of 4-bromo-3-fluoro-N-methyl-2-nitroaniline

[0328] 4-Bromo-3-fluoro-2-nitroaniline (5.0 g, 21.3 mmol) was dissolved in DMF (150 mL), and sodium hydride (NaH, 1.0 g, 25.5 mmol, 60% purity) was added at 0 °C. The reaction mixture was stirred at the same temperature for 30 min, then iodomethane (3.0 g, 21.3 mmol) was added, and the mixture was stirred at room temperature for 16 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (3.1 g, 12.5 mmol, 58% yield) as a red solid. MS (ESI): m / z = 251.0 [M+H] +

[0329] [Step 2] Preparation of 4-bromo-3-methoxy-N-methyl-2-nitroaniline

[0330] 4-Bromo-3-fluoro-N-methyl-2-nitroaniline (3.1 g, 12.5 mmol) obtained in Step 1 was dissolved in methanol (50 mL), and then sodium methoxide (5.4 M, 14.9 mL) was added at room temperature. The reaction mixture was stirred at 25 °C for 12 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.6 g, 10.1 mmol, 81% yield) as a red solid. MS (ESI): m / z = 260.9 [M+H] +

[0331] [Step 3] 4-Bromo-3-methoxy-N 1 - Manufacture of methylbenzene-1,2-diamine

[0332] 4-Bromo-3-methoxy-N-methyl-2-nitroaniline (2.6 g, 10.1 mmol) obtained in Step 2 was dissolved in ethanol (100 mL) and water (20 mL), and then iron (7.3 g, 130.2 mmol) and ammonium chloride (7.0 g, 130.2 mmol) were added, and the mixture was stirred at 60°C for 12 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.1 g, 9.1 mmol, 90% yield) as a yellow solid. MS (ESI): m / z = 232.9 [M+H] +

[0333] [Step 4] Preparation of 5-bromo-4-methoxy-1-methyl-1H-benzo[d]imidazole

[0334] 4-Bromo-3-methoxy-N obtained in step 3 above 1 -Methylbenzene-1,2-diamine (2.0 g, 8.7 mmol) was dissolved in diethoxymethoxyethane (17.8 g, 120.2 mmol, 20 mL), and p-toluenesulfonic acid (TsOH, 149.0 mg, 0.9 mmol) was added. The mixture was stirred at 100 °C for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (1.9 g, 7.8 mmol, 90% yield) as a yellow solid. MS (ESI): m / z = 240.9 [M+H] +

[0335] [Step 5] Preparation of methyl 4-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate

[0336] 5-Bromo-4-methoxy-1-methyl-1H-benzo[d]imidazole (1.8 g, 7.5 mmol) obtained in step 4 above was dissolved in THF (20 mL) and methanol (20 mL), and then DIPEA (2.9 g, 22.4 mmol), DPPP (308 mg, 747 μmol), and Pd(OAc)2 (168 mg, 747 μmol) were added (reaction mixture 1). While maintaining the carbon monoxide flow rate of 30 mL / min and the pressure of 3.5 MPa in a fixed bed reactor (inner diameter 3.175 mm (1 / 8"), volume 60 mL, temperature 160 ℃), the reaction mixture 1 was adjusted to a flow rate of 1 mL / min through pump 1, and the THF / methanol (10 V / 10 V) solution was adjusted to a flow rate of 0.1 mL / min through pump 2. After reacting under the conditions for 1 hour, the reaction mixture 1 was concentrated and purified using MPLC (petroleum ether / ethyl acetate), and the target compound (0.6 g, 2.7 mmol, 36% yield) as a white solid was obtained. MS (ESI): m / z = 221 [M+H] +

[0337] [Step 6] Preparation of 4-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylic acid

[0338] Methyl 4-methoxy-1-methyl-1H-benzo[d]imidazole-5-carboxylate (500 mg, 2.3 mmol) obtained in the above step 5 was dissolved in THF (5 mL) and methanol (5 mL), and 4N aqueous sodium hydroxide solution (5 mL) was added. The mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. Hydrochloric acid was added to the concentrated reaction mixture to adjust the pH to 5, and the precipitated solid was filtered. The target compound (450 mg, 2.2 mmol, 96% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 207 [M+H] +

[0339] Manufacturing Example 19. Preparation of 1-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0340] [Reaction Formula 19]

[0341]

[0342] [Step 1] Preparation of methyl 1-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate

[0343] 5-Chloro-1-methyl-1H-imidazo[4,5-b]pyridine (900 mg, 5.4 mmol) was dissolved in THF (10 mL) and methanol (10 mL), and then DIPEA (4.2 g, 32.2 mmol), DPPP (221 mg, 537 μmol), and Pd(OAc)2 (121 mg, 537 μmol) were added (reaction mixture 1). While maintaining the carbon monoxide flow rate of 30 mL / min and the pressure of 3.5 MPa in a fixed bed reactor (inner diameter 3.175 mm (1 / 8"), volume 60 mL, temperature 160 ℃), the reaction mixture 1 was adjusted to a flow rate of 1 mL / min through pump 1, and the THF / methanol (10 V / 10 V) solution was adjusted to a flow rate of 0.1 mL / min through pump 2. After reacting under the conditions for 1 hour, the reaction mixture 1 was filtered and concentrated to obtain the target compound (1.0 g, 5.4 mmol, 100% yield) as a yellow solid. MS (ESI): m / z = 192 [M+H] +

[0344] [Step 2] Preparation of 1-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0345] Methyl 1-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (800 mg, 4.2 mmol) obtained in the above step 1 was dissolved in THF (8 mL) and water (8 mL), and lithium hydroxide (200 mg, 8.4 mmol) was added, and the mixture was stirred at room temperature for 12 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated, washed with ethyl acetate, and water was removed. The concentrated reaction mixture was purified using prep-HPLC (water (0.05% hydrochloric acid) / methanol (0.05% hydrochloric acid)) to obtain the target compound (280 mg, 1.3 mmol, 45% yield) as a white solid. MS (ESI): m / z = 178 [M+H] +

[0346] Manufacturing Example 20. Preparation of 3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0347] [Reaction Formula 20]

[0348]

[0349] [Step 1] 6-chloro-N 2 Preparation of -methyl-pyridine-2,3-diamine

[0350] 6-Chloro-N-methyl-3-nitropyridin-2-amine (9.0 g, 48.0 mmol) and ammonium chloride (15.4 g, 287.9 ​​mmol) were dissolved in ethanol (200 mL) and water (20 mL), and iron (16.1 g, 287.9 ​​mmol) was added. The mixture was stirred at 80°C for 5 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (4.8 g, 30.5 mmol, 63% yield) as a brown solid. MS (ESI): m / z = 158 [M+H] +

[0351] [Step 2] Preparation of 5-chloro-3-methyl-3H-imidazo[4,5-b]pyridine

[0352] 6-chloro-N obtained in step 1 above 2 -Methyl-pyridine-2,3-diamine (4.0 g, 25.4 mmol) was dissolved in diethoxymethoxyethane (60 mL), and TsOH (437 mg, 2.5 mmol) was added. The mixture was stirred at 70°C for 2 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (4.2 g, 24.3 mmol, 96% yield) as a brown solid. MS (ESI): m / z = 167.9 [M+H] +

[0353] [Step 3] Preparation of methyl 3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0354] 5-Chloro-3-methyl-3H-imidazo[4,5-b]pyridine (800 mg, 4.6 mmol) obtained in step 2 above was dissolved in THF (8 mL) and methanol (8 mL), and then DIPEA (3.6 g, 27.8 mmol), DPPP (191 mg, 463 μmol), and Pd(OAc)2 (104 mg, 463 μmol) were added (reaction mixture 1). While maintaining the carbon monoxide flow rate of 30 mL / min and the pressure of 3.5 MPa in a fixed bed reactor (inner diameter 3.175 mm (1 / 8"), volume 60 mL, temperature 160 ℃), the reaction mixture 1 was adjusted to a flow rate of 1 mL / min through pump 1, and the THF / methanol (10 V / 10 V) solution was adjusted to a flow rate of 0.1 mL / min through pump 2. After reacting under the conditions for 30 minutes, the reaction mixture 1 was concentrated and purified using MPLC (petroleum ether / ethyl acetate), and the target compound (850 mg, 4.0 mmol, 96% yield) as a yellow solid was obtained. MS (ESI): m / z = 192 [M+H] +

[0355] [Step 4] Preparation of 3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0356] Methyl 3-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg, 1.9 mmol) obtained in the above step 3 was dissolved in THF (4 mL) and methanol (4 mL), and 2N aqueous sodium hydroxide solution (4 mL) was added, followed by stirring at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated, and the precipitated solid was filtered. The target compound (250 mg, 1.3 mmol, 67% yield) as a red solid was used in the next step without further purification. MS (ESI): m / z = 178 [M+H] +

[0357] Manufacturing Example 21. Preparation of 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid

[0358] [Reaction Formula 21]

[0359]

[0360] [Step 1] Preparation of (2,4-dichloro-6-methylpyridin-3-yl)methanol

[0361] Ethyl 2,4-dichloro-6-methylnicotinate (50.0 g, 213.6 mmol) was dissolved in dichloromethane (600 mL), and diisobutylaluminum hydride (DIBAL-H, 1 M, 384 mL) was added at -78 °C for 30 min. The reaction mixture was stirred at the same temperature for 2 h, and the completion of the reaction was confirmed using LC-MS. After adjusting the reaction mixture to 0 °C, a saturated aqueous ammonium chloride solution (300 mL) was added, and a 0.2 N aqueous hydrochloric acid solution (200 mL) was added, and the mixture was extracted with dichloromethane. The combined organic layer was removed with sodium sulfate, and the remaining water was removed and concentrated. The target compound (40.0 g, 208.3 mmol, 97% yield) obtained as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 192 [M+H] +

[0362] [Step 2] Preparation of 2,4-dichloro-6-methylnicotinaldehyde

[0363] (2,4-Dichloro-6-methylpyridin-3-yl)methanol (40.0 g, 208.3 mmol) obtained in the above step 1 was dissolved in dichloroethane (500 mL), and then manganese dioxide (MnO 2,250.0 g, 2.9 mol) was added and stirred at 75 °C for 12 hours. After confirming the completion of the reaction using LC-MS, the reaction mixture was filtered and washed with dichloromethane. The collected organic layer was concentrated after removing the remaining water using sodium sulfate, and the target compound (38.0 g, 200.0 mmol, 96% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 191.9 [M+H] +

[0364] [Step 3] Preparation of 4-chloro-1,6-dimethyl-pyrazolo[4,3-c]pyridine

[0365] 2,4-Dichloro-6-methylnicotinaldehyde (35.0 g, 184.2 mmol) obtained in the above step 2 was dissolved in DMF (1000 mL), and methylhydrazine dichloride (24.1 g, 202.6 mmol) and cesium carbonate (180.0 g, 552.6 mmol) were added, and the mixture was stirred at 120 °C for 12 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was filtered and washed with ethyl acetate. The combined organic layer was concentrated and purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (10.0 g, 55.5 mmol, 30% yield) as a yellow solid. MS (ESI): m / z = 182 [M+H] +

[0366] [Step 4] Preparation of methyl 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylate

[0367] 4-Chloro-1,6-dimethyl-pyrazolo[4,3-c]pyridine (20.5 g, 112.9 mmol) obtained in step 3 above was dissolved in THF (205 mL) and methanol (205 mL), and then DIPEA (43.8 g, 338.6 mmol), DPPP (2.8 g, 6.8 mmol), and Pd(OAc)2 (2.5 g, 11.3 mmol) were added (reaction mixture 1). While maintaining the carbon monoxide flow rate of 30 mL / min and the pressure of 3.5 MPa in a fixed bed reactor (inner diameter 3.175 mm (1 / 8"), volume 60 mL, temperature 160 ℃), the reaction mixture 1 was adjusted to a flow rate of 1 mL / min through pump 1, and the THF / methanol (10 V / 10 V) solution was adjusted to a flow rate of 0.1 mL / min through pump 2. After reacting under the conditions for 1 hour, the reaction mixture 1 was concentrated and purified using MPLC (petroleum ether / ethyl acetate), and the target compound (15.0 g, 73.1 mmol, 65% yield) as a white solid was obtained. MS (ESI): m / z = 206 [M+H] +

[0368] [Step 5] Preparation of 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid

[0369] Methyl 1,6-dimethyl-1H-pyrazolo[4,3-c]pyridine-4-carboxylate (10.0 g, 48.7 mmol) obtained in the above step 4 was dissolved in THF (20 mL) and methanol (120 mL), and 4N aqueous sodium hydroxide solution (30 mL) was added, followed by stirring at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. Hydrochloric acid was added to the concentrated reaction mixture to adjust the pH to 5, and the precipitated solid was filtered. The target compound (1.4 g, 7.3 mmol, 10% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 192 [M+H] +

[0370] Manufacturing Example 22. Preparation of 5-methoxy-1-methyl-1H-indazole-4-carboxylic acid

[0371] [Reaction Formula 22]

[0372]

[0373] [Step 1] Preparation of 4-bromo-5-methoxy-1-methyl-1H-indazole

[0374] 4-Bromo-5-methoxy-1H-indazole (4.0 g, 17.6 mmol) was dissolved in THF (200 mL), and 1 N aqueous potassium tert-butoxide solution (26.4 mL) and methyl iodide (5.0 g, 35.2 mmol, 2.2 mL) were added. The mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (2.8 g, 11.4 mmol, 65% yield) as a white solid. MS (ESI): m / z = 242.9 [M+H] +

[0375] [Step 2] Preparation of methyl 5-methoxy-1-methyl-1H-indazole-4-carboxylate

[0376] 4-Bromo-5-methoxy-1-methyl-1H-indazole (3.5 g, 14.5 mmol) obtained in step 1 above was dissolved in THF (35 mL) and methanol (35 mL), and then DIPEA (9.4 g, 72.6 mmol), DPPP (599 mg, 1450 μmol), and Pd(OAc)2 (326 mg, 1450 μmol) were added (reaction mixture 1). While maintaining the carbon monoxide flow rate of 30 mL / min and the pressure of 3.5 MPa in a fixed bed reactor (inner diameter 3.175 mm (1 / 8"), volume 60 mL, temperature 160 ℃), the reaction mixture 1 was adjusted to a flow rate of 1 mL / min through pump 1, and the THF / methanol (10 V / 10 V) solution was adjusted to a flow rate of 0.1 mL / min through pump 2. After reacting under the conditions for 1 hour, the reaction mixture 1 was concentrated and purified using MPLC (petroleum ether / ethyl acetate), and the target compound (2.4 g, 10.9 mmol, 74% yield) as a white solid was obtained. MS (ESI): m / z = 221 [M+H] +

[0377] [Step 3] Preparation of 5-methoxy-1-methyl-1H-indazole-4-carboxylic acid

[0378] Methyl 5-methoxy-1-methyl-1H-indazole-4-carboxylate (2.4 g, 10.9 mmol) obtained in the above step 2 was dissolved in THF (10 mL) and methanol (30 mL), and 4N aqueous sodium hydroxide solution (10 mL) was added. The mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. Hydrochloric acid was added to the concentrated reaction mixture to adjust the pH to 3, and the precipitated solid was filtered. The target compound (1.7 g, 8.3 mmol, 76% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 207 [M+H] +

[0379] Manufacturing Example 23. Manufacturing of 3,4-dihydro-5-oxa-2a,8-diazaacenaphthylene-6-carboxylic acid

[0380] [Reaction Formula 23]

[0381]

[0382] [Step 1] Preparation of 3-bromo-5-nitro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine

[0383] 2-Tetrahydropyran-2-yloxyethanol (3.7 g, 25.3 mmol) was dissolved in THF (100 mL), and NaH (1.0 g, 25.3 mmol) was added at 0 °C and stirred for 30 min. A solution of 3-bromo-4-chloro-5-nitropyridine (5.0 g, 21.1 mmol) dissolved in THF (10 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was cooled to 0 °C, saturated aqueous ammonium chloride solution (300 mL) was added, and extracted using ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (4.6 g, 13.3 mmol, 52% yield) as a yellow liquid. MS (ESI): m / z = 347 [M+H] +

[0384] [Step 2] Preparation of 6-bromo-7-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1H-pyrrolo[3,2-b]pyridine

[0385] 3-Bromo-5-nitro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine (3.6 g, 10.4 mmol) obtained in Step 1 was dissolved in THF (35 mL), and bromo(vinyl)magnesium (1 M, 31.1 mL) was slowly added at -78 °C. The reaction mixture was adjusted to 0 °C and stirred for 2 hours. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with saturated aqueous ammonium chloride solution, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (1.0 g, 2.6 mmol, 25% yield) as a yellow liquid. MS (ESI): m / z = 341 [M+H] +

[0386] [Step 3] Preparation of 2-((6-bromo-1H-pyrrolo[3,2-b]pyridin-7-yl)oxy)ethan-1-ol

[0387] 6-Bromo-7-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)-1H-pyrrolo[3,2-b]pyridine (1.0 g, 2.6 mmol) obtained in the above step 2 was dissolved in 2 M hydrochloric acid / dioxane (15 mL) and stirred at 25 °C for 1 h. After confirming the completion of the reaction using LC-MS, water was added to the reaction mixture and washed with ethyl acetate. After adjusting the pH to 8 by adding sodium carbonate, the organic matter was extracted with ethyl acetate. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The target compound (640 mg, 2.1 mmol, 82% yield) obtained as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 256.9 [M+H] +

[0388] [Step 4] Preparation of 6-bromo-3,4-dihydro-5-oxa-2a,8-diazaacenaphthylene

[0389] 2-((6-Bromo-1H-pyrrolo[3,2-b]pyridin-7-yl)oxy)ethan-1-ol (630 mg, 2.1 mmol) obtained in the above step 3 was dissolved in THF (300 mL), and triphenylphosphine (1.6 g, 6.3 mmol) and DIAD (1.3 g, 6.3 mmol, 1.2 mL) were added, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate), and the target compound (400 mg, 1.7 mmol, 80% yield) as a yellow liquid was obtained. MS (ESI): m / z = 241.0 [M+H] +

[0390] [Step 5] Preparation of methyl 3,4-dihydro-5-oxa-2a,8-diazaacenaphthylene-6-carboxylate

[0391] 6-Bromo-3,4-dihydro-5-oxa-2a,8-diazaacenaphthylene (400 mg, 1.7 mmol) obtained in the above step 4 was dissolved in THF (4 mL) and methanol (4 mL), and then DIPEA (642 mg, 5.0 mmol), DPPP (68 mg, 165 μmol), and Pd(OAc)2 (37 mg, 166 μmol) were added (reaction mixture 1). While the carbon monoxide flow rate of the fixed bed reactor (inner diameter 3.175 mm (1 / 8"), capacity 60 mL, temperature 160 ℃) was maintained at 30 mL / min and the pressure 3.5 MPa, the reaction mixture 1 was adjusted to a flow rate of 1 mL / min through pump 1, and the THF / methanol (10 V / 10 V) solution was adjusted to a flow rate of 0.1 mL / min through pump 2. After reacting under the conditions for 1 hour, the reaction mixture 1 was concentrated to obtain the target compound (360 mg, 2.7 mmol, 99% yield) as a red liquid. MS (ESI): m / z = 219 [M+H] +

[0392] [Step 6] Preparation of 3,4-dihydro-5-oxa-2a,8-diazaacenaphthylene-6-carboxylic acid

[0393] Methyl 3,4-dihydro-5-oxa-2a,8-diazaacenaphthylene-6-carboxylate (360 mg, 1.7 mmol) obtained in the above step 5 was dissolved in THF (3 mL), methanol (3 mL), and water (3 mL), and then sodium hydroxide (132 mg, 3.3 mmol) was added and stirred at 40 °C for 1 h. After confirming the completion of the reaction using LC-MS, water was added and the mixture was washed with ethyl acetate. Hydrochloric acid was added to the washed aqueous layer to adjust the pH to 3, and the precipitated solid was filtered. The target compound (337 mg, 1.7 mmol, 100% yield) as a yellow solid was used in the next step without further purification. MS (ESI): m / z = 205 [M+H] +

[0394] Manufacturing Example 24. Preparation of 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-9-carboxylic acid

[0395] [Reaction Formula 24]

[0396]

[0397] [Step 1] Preparation of methyl 7-bromo-1H-indole-6-carboxylate

[0398] 7-Bromo-1H-indole-6-carboxylic acid (2.0 g, 8.3 mmol) was dissolved in methanol (30 mL), and then thionyl chloride (SOCl2, 5.0 g, 41.7 mmol) was added at room temperature. The reaction mixture was stirred at 70°C for 1 hour. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. Then, saturated aqueous potassium carbonate solution was added to adjust the pH to 7, and the mixture was extracted several times with ethyl acetate. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (1.5 g, 5.6 mmol, 68% yield) as a white solid. MS (ESI): m / z = 253.9 [M+H] +

[0399] [Step 2] Preparation of methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate

[0400] Methyl 7-bromo-1H-indole-6-carboxylate (2.2 g, 8.7 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6.6 g, 26.0 mmol) obtained in Step 1 were dissolved in dioxane (30 mL), and then potassium acetate (2.6 g, 26.0 mmol) and Pd(dppf)Cl2.CH2Cl2 (707.1 mg, 865.9 μmol) were added. The reaction mixture was stirred at 90 °C for 12 h. After confirming the completion of the reaction using LC-MS, the mixture was filtered through Celite and concentrated. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound as a yellow solid (2.4 g, 7.7 mmol, 88% yield). MS (ESI): m / z = 302 [M+H] +

[0401] [Step 3] Preparation of methyl 7-hydroxy-1H-indole-6-carboxylate

[0402] Methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (2.0 g, 6.4 mmol) obtained in the above step 2 was dissolved in THF (18 mL) and water (6 mL), and then sodium perborate (NaBO3, 1.3 g, 12.8 mmol) was added. The reaction mixture was stirred at 20 °C for 12 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was concentrated. Dichloromethane was added to the concentrated solid and washed several times. The collected filtrate was concentrated to obtain the target compound (1.2 g, 6.4 mmol, 100% yield) as a gray solid, which was used in the next step without further purification. MS (ESI): m / z = 192 [M+H] +

[0403] [Step 4] Preparation of methyl 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-9-carboxylate

[0404] Methyl 7-hydroxy-1H-indole-6-carboxylate (1.5 g, 8.1 mmol) and 1,2-dibromoethane (3.0 g, 16.1 mmol, 1.2 mL) obtained in Step 3 were dissolved in DMF (15 mL), and cesium carbonate (5.3 g, 16.1 mmol) was added. The reaction mixture was stirred at 55 °C for 2 h. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The combined organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (petroleum ether / ethyl acetate) to obtain the target compound (1.2 g, 5.5 mmol, 67% yield) as a yellow oil. MS (ESI): m / z = 218 [M+H] +

[0405] [Step 5] Preparation of 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-9-carboxylic acid

[0406] Methyl 2,3-dihydro-[1,4]oxazino[2,3,4-hi]indole-9-carboxylate (500 mg, 2.3 mmol) obtained in the above step 4 was dissolved in methanol (10 mL) and water (10 mL), and then sodium hydroxide (180 mg, 4.5 mmol) was added. The reaction mixture was stirred at 30 °C for 12 h. After confirming the completion of the reaction using LC-MS, ice water was added. Saturated hydrochloric acid was then added to the reaction mixture to adjust the pH to 3. The precipitated solid was filtered, and the target compound (450 mg, 2.2 mmol, 97% yield) obtained as a white solid was used in the next step without further purification. MS (ESI): m / z = 204 [M+H] +

[0407] Example: Preparation of the compound of the present invention

[0408] Example 1. Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-6-methoxy-1H-indazole-5-carboxamide

[0409] [Reaction Formula 25]

[0410]

[0411] [Step 1] Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-6-methoxy-1-tosyl-1H-indazole-5-carboxamide

[0412] 4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3,5-difluoroaniline (0.057 g, 0.17 mmol) obtained in Preparation Example 1 and 6-methoxy-1-tosyl-1H-indazole-5-carboxylic acid (0.040 g, 0.12 mmol) obtained in Preparation Example 5 were dissolved in DMF (0.23 mL), and then hexafluorophosphate azabenzotriazole tetramethyluronium (HATU, 0.11 g, 0.29 mmol) and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU, 0.087 mL, 0.57 mmol) were added at room temperature. The reaction mixture was stirred at 60 °C for 2 hours. After confirming the completion of the reaction using LC-MS, ethyl acetate was added to the reaction mixture. After washing with water, the organic matter was extracted. The collected organic layer was concentrated after removing the remaining water using sodium sulfate. The concentrated mixture was purified using MPLC (dichloromethane / methanol) to obtain the target compound (0.068 g, 0.1 mmol, 89% yield) as a white solid. MS (ESI): m / z = 661 [M+H] +

[0413] [Step 2] Preparation of N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-6-methoxy-1H-indazole-5-carboxamide

[0414] N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)-6-methoxy-1-tosyl-1H-indazole-5-carboxamide (0.068 g, 0.1 mmol) obtained in Step 1 was dissolved in 1,4-dioxane (0.2 mL), and sodium hydroxide (0.020 g, 0.5 mmol) was added at room temperature. The reaction mixture was stirred at 60 °C for 2 h. After confirming the completion of the reaction using LC-MS, the reaction mixture was purified using prep-HPLC (water (0.1% TFA) / methanol (0.1% TFA)) to obtain the target compound (0.008 g, 0.016 mmol, 15% yield) as a white solid. MS (ESI): m / z = 507 [M+H] +

[0415] <Example 1> to <Example 377>

[0416] The example compounds of the present invention (Examples 2 to 377) were prepared in a similar manner to the above Example 1, and the chemical structural formula, compound name, NMR, and LC-MS analysis results of each example compound are summarized and shown in [Table 1] below.

[0417] [Table 1]

[0418]

[0419] Experimental Example 1. Evaluation of inhibitory activity against c-MET kinase

[0420] In order to evaluate the inhibitory activity of the compound of the present invention against c-MET kinase, the compound of the present invention was reacted with purified human c-MET enzyme and evaluated by the following method.

[0421] The reaction buffer consisted of 200 mM Tris-HCl pH 7.4, 100 mM MgCl2, 0.5 mg / mL BSA, and 0.25 mM DTT, and all test reactions were performed in the reaction buffer. The compounds were diluted by a 12-step serial dilution method from a 10 mM DMSO stock, and the enzyme activity was measured at a final compound concentration of 10 to 0.000169 μM or 1 to 0.0000169 μM. After reacting with the appropriate concentration of c-MET enzyme, purified ATP, and enzyme substrate (Poly(4:1 Glu, Tyr)) at 25°C for 1 hour, the enzyme activity was measured in vitro using ADP-Glo TM It was confirmed using kinase assay (Promega). The enzyme activity reaction solution, ADP-Glo ​​reaction solution, and enzyme activity detection solution were reacted in a 2:2:1 ratio, and the degree of enzyme activity inhibition was measured by luminescence. The degree of enzyme activity inhibition according to the treatment concentration of each compound was calculated based on the fluorescence of enzyme activity for the solvent control group that was not treated with the compound. At this time, the concentration of each compound that inhibits enzyme activity by 50% was IC. 50 (nM) value and was obtained using GraphPad Prism 8.4.3 (GraphPad software Inc., San Diego) software. The results are shown in Table 2 below.

[0422] [Table 2]

[0423]

[0424] Experimental Example 2. Evaluation of cancer cell proliferation inhibition activity

[0425] To evaluate the cancer cell proliferation inhibitory activity of the example compound according to the present invention, EBC-1 cells, a lung cancer cell line with a mutated c-MET gene, and Hs746T cells, a gastric cancer cell line, were used.

[0426] The EBC-1 cell line was cultured in Eagle's minimal essential medium (EMEM) supplemented with 10% fetal bovine serum (FBS). The Hs746T cell line was cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS).

[0427] EBC-1 cell line was seeded in a well plate (white clear bottom 96 well plate, Corning) 24 hours before treatment with the example compound. Hs746T cell line was seeded in a well plate (white clear bottom 96 well plate, Corning) 24 hours before treatment with the example compound. The example compound was diluted in DMSO (3-fold dilution, 11 concentrations in total) and injected in a certain amount (EBC-1: 0.5 μL, Hs746T: 1 μL) so that the final concentration was 0.2 nM to 10 μM or 0.02 nM to 1 μM. Measurement of live cells was performed by treating cells with a reagent (CellTiter-Glo cell viability reagent, Promega) after a certain period of time (EBC-1: 72 hours, Hs746T: 144 hours) after treatment with the example compounds, incubating the cells at room temperature for 10 minutes, and measuring the luminescence intensity using a reader (SynergyNeo, Biotek). Each test was repeated three times.

[0428] The results were calculated as cell growth rate (%) compared to the control group, and graphed using software (GraphPad Prism version 8.0) and GI 50 The values ​​were calculated. The results are summarized in Table 3 below.

[0429] [Table 3]

[0430]

[0431] As shown in Tables 2 and 3 above, it can be confirmed that the exemplary compounds of the present invention exhibit high inhibitory activity against c-MET kinase and excellent proliferation inhibitory activity against c-MET gene mutant cells.

[0432] While the present invention has been described in detail through preferred embodiments and experimental examples, the scope of the present invention is not limited to the specific examples and should be interpreted in accordance with the appended claims. Furthermore, those skilled in the art will appreciate that numerous modifications and variations are possible without departing from the scope of the present invention.

Claims

1. A compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, X1 and X2 are each independently CR X or N; R X is -H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, or -Halloween; L1 and L2 are each independently -H, -C 1-6 Alkyl, or -(4-6 membered heterocycloalkyl), wherein the -C 1-6 One or more H of alkyl is L X , wherein the -(4-6 membered heterocycloalkyl) ring comprises one or more N, O, or S atoms, and one or more H of the -(4-6 membered heterocycloalkyl) ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -halo, -C(=O)-C 1-6 may be substituted with alkyl, or -(3-6 membered cycloalkyl); L X is -NR a R b , -OH, -OC 1-6 Alkyl, -OP(=O)(OH)2, -halo, -OC(=O)-C 1-6 Alkyl, -(4-6 membered heterocycloalkyl), or -phenyl, wherein the -OC(=O)-C 1-6 At least one H of the alkyl is substituted with -NH2, -OH, or -SH, and the -(4-6 membered heterocycloalkyl) ring contains at least one N, O, or S atom, and at least one H of the -(4-6 membered heterocycloalkyl) or -phenyl ring is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -halo, -C(=O)-C 1-6 may be substituted with alkyl, or -(3-6 membered cycloalkyl); R1 to R4 are each independently -H or -halo; Ring Y is -(8-10 membered heteroaryl) or -(9-14 membered heterohydroaryl), wherein said -(8-10 membered heteroaryl) or -(9-14 membered heterohydroaryl) ring contains one or more N, O, or S atoms, and one or more H of said -(8-10 membered heteroaryl) or -(9-14 membered heterohydroaryl) ring is -C 1-6 Alkyl, -C 1-6 Deuterated alkyl, -C 1-6 Haloalkyl, -NR a R b , -OR c , -halo, or -(3-6 membered cycloalkyl), and at least one -CH2- of the -(9-14 membered heterohydroaryl) ring may be substituted with -C(=O)- or -(3-6 membered cycloalkyl); R a and R b are each independently -H or -C 1-6 It is alkyl; R c is -H, -C 1-6 Alkyl, -C 1-6 Deuterated alkyl, -C 1-6 Haloalkyl, or -(3-6 membered cycloalkyl).

2. In paragraph 1, The above ring Y is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And, wherein one or more H of the ring Y are each independently -C 1-6 Alkyl, -C 1-6 Deuterated alkyl, -C 1-6 Haloalkyl, -NR a R b , -OR c , -halo, or -(3-6 membered cycloalkyl), and at least one -CH2- of the ring Y may be substituted with -C(=O)- or -(3-6 membered cycloalkyl). A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, The above ring Y is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And, wherein one or more H of the ring Y are each independently -C 1-3 Alkyl, -C 1-3 Deuterated alkyl, -C 1-3 Haloalkyl, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -OH, -OC 1-3 Alkyl, -OC 1-3 Deuterated alkyl, -OC 1-3 haloalkyl, -O-(3-4 membered cycloalkyl), -halo, or -(3-4 membered cycloalkyl), and one or more -CH2- of the ring Y may be substituted with -C(=O)- or -(5-6 membered cycloalkyl). A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, Either L1 or L2 is -C 1-6 It is alkyl, The remaining one of L1 and L2 is -H, -C 1-6 alkyl, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And, wherein one or more H of the rings listed above is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -halo, -C(=O)-C 1-6 which may be substituted with alkyl, or -(3-6 membered cycloalkyl), A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, Either L1 or L2 is -CH3, The remaining one of L1 and L2 is -H, -CH3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And, wherein one or more H of the rings listed above is -C 1-3 Alkyl, -C 1-3 Haloalkyl, -halo, -C(=O)-C 1-3 which may be substituted with alkyl, or -(3-4 membered cycloalkyl), A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, At least one of R1 to R4 is - Halloween, A compound represented by chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

7. A compound selected from the group consisting of the following compounds, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: .

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

9. A pharmaceutical composition for preventing or treating cancer, containing a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

10. In paragraph 9, A pharmaceutical composition that inhibits c-MET.

11. In paragraph 9, A pharmaceutical composition that inhibits c-MET mutation.

12. In paragraph 9, The above cancers are uterine cancer, endometrial cancer, uterine sarcoma, cervical cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, colorectal cancer (CRC), rectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung squamous cell carcinoma, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphoma, prostate cancer, bladder cancer, testicular cancer, kidney cancer, thyroid cancer, malignant bone cancer, sarcoma, malignant soft tissue cancer, brain cancer, glioblastoma, glioma, head and neck cancer, skin cancer, and malignant melanoma. A pharmaceutical composition comprising at least one selected from the group.

13. Use of a compound according to any one of claims 1 to 7, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment or prevention of a c-MET related disease.

14. A method for treating or preventing a c-MET-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 7, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

15. A method for treating uterine cancer, endometrial cancer, uterine sarcoma, cervical cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, breast cancer, triple-negative breast cancer (TNBC), pancreatic cancer, colorectal cancer (CRC), rectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, liver cancer, lung cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung squamous cell carcinoma, leukemia, acute myeloid leukemia, chronic myeloid leukemia, lymphoma, prostate cancer, bladder cancer, A method for treating or preventing one or more diseases selected from the group consisting of testicular cancer, kidney cancer, thyroid cancer, malignant bone cancer, sarcoma, malignant soft tissue cancer, brain cancer, glioblastoma, glioma, head and neck cancer, skin cancer, and malignant melanoma.

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