Novel carboxamide derivative compounds and pharmaceutical compositions containing the same

Abstract

The present invention relates to carboxamide derivative compounds represented by chemical formula I, their stereoisomers, pharmaceutically acceptable salts thereof, or their hydrates or solvates, and compositions comprising the same, as well as methods and uses of the same in the prevention or treatment of IRAK-4 or IRAK-1 related diseases. TIFF2026521796000137.tif4664

Description

[Technical Field]

[0001] The present invention relates to novel carboxamide derivative compounds, their stereoisomers, pharmaceutically acceptable salts thereof, or their hydrates or solvates, and pharmaceutical compositions comprising the same. [Background technology]

[0002] The IL-1R / TLR (IL-1 receptor / Toll-like receptor) signaling pathway plays a crucial role in immune and inflammatory responses and has been reported to be involved in the development of various inflammatory and autoimmune diseases, including sepsis, asthma, arteriosclerosis, Alzheimer's disease, rheumatoid arthritis, atopic dermatitis, hidradenitis suppurativa, psoriasis, ulcerative colitis, and systemic lupus erythematosus (Journal of Investigative Dermatology.2019;139(1):146-156 / Annals of the New York Academy of Sciences.2008;1143:21-34 / Journal of Immunology research.2019;1824624 / International Immunopharmacology.2007;7(10):1271-1285). In particular, recent studies have reported that blocking the IL-1R / TLR signaling pathway through IRAK-4 (interleukin-1 receptor-associated kinase 4) inhibition is effective in treating chronic inflammatory skin diseases such as psoriasis and atopic dermatitis (Science Translational Medicine. 2023;15:eabj3289). IL-1R / TLR expression has been reported to be involved in the proliferation of various cancer cells (Oncogene.2008;27(2):218-224). In particular, hyperactivation of IL-1R / TLR signaling due to MyD88 mutations has been reported in ABC DLBCL, a type of diffuse large B-cell lymphoma (DLBCL), and Waldenstrom macroglobulinemia (WM), a lymphocytic malignancy (Nature.2011;470(7332):115-119 / New England journal of medicine.2012;367(9):826-833). More recently, IRAK-4 and IRAK-1 have also been reported to be involved in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (Current Opinion in Hematology.2022;29(1):8-19). When pathogen-associated molecular patterns (PAMPs), commonly expressed in various pathogens, and damage-associated molecular patterns (DAMPs), released in stressed or dying cells, bind to IL-1R / TLR, lower-level signaling mechanisms are activated, leading to an inflammatory response. If such an inflammatory response persists, it can develop into cancer (Nature Immunology. 2011 Jul 19;12(8):715-723). Through the aforementioned reports, research is actively being conducted to either block TLRs themselves, which play a crucial role in the IL-1R / TLR signaling pathway, or to develop substances that suppress IRAKs, which are responsible for lower-level signaling of TLRs. In particular, there is a large amount of research targeting IRAK-4. IRAK exists as a serine / threonine kinase with four subtypes (IRAK-1, IRAK-2, IRAK-M, and IRAK-4). Research primarily focuses on IRAK-4 and IRAK-1, which exhibit kinase function. In particular, IRAK-4, which plays a crucial role in midsome formation in the IL-1R / TLR signaling pathway, is the most extensively studied, although research on IRAK-1 has also become active recently. While no drugs targeting IRAK-4 or IRAK-1 have yet been launched, Phase 1 and Phase 2 clinical trials are underway for various diseases (autoimmune diseases, inflammatory diseases, and hematological cancers). [Overview of the project] [Problems that the invention aims to solve]

[0003] The present invention provides novel carboxamide derivative compounds, their stereoisomers, pharmaceutically acceptable salts thereof, or their hydrates or solvates. The present invention provides a pharmaceutical composition comprising a novel carboxamide derivative compound, its stereoisomer, a pharmaceutically acceptable salt thereof, or its hydrate or solvate. The present invention provides a pharmaceutical composition for the prevention or treatment of IRAK-4 or IRAK-1 related diseases, comprising a novel carboxamide derivative compound, its stereoisomer, a pharmaceutically acceptable salt thereof, or its hydrate or solvate as an active ingredient. The present invention provides a method for preventing or treating IRAK-4 or IRAK-1 related diseases, comprising the step of administering a novel carboxamide derivative compound, its stereoisomer, a pharmaceutically acceptable salt thereof, or its hydrate or solvate to an individual. The present invention provides novel carboxamide derivative compounds, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates for the use of IRAK-4 or IRAK-1 related diseases. The present invention provides the use of novel carboxamide derivative compounds, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates in the manufacture of agents for the prevention or treatment of IRAK-4 or IRAK-1 related diseases. [Means for solving the problem]

[0004] Therefore, the applicant has developed a novel compound with a structure that potently inhibits IRAK-4 or IRAK-1. Activity evaluations against IRAK-4 and IRAK-1 enzymes, as well as changes in inflammatory cytokine secretion, have been conducted, confirming that the compound of the present invention is a highly active substance. The present invention relates to compounds useful for the prevention or treatment of autoimmune diseases, inflammatory diseases, or tumors associated with IRAK (interleukin-1 receptor-related kinase), and more specifically to compounds that inhibit the function of IRAK-4 or IRAK-1, and pharmaceutical compositions and functional food compositions containing the same. The present invention will now be described in more detail. All combinations of the various elements disclosed in this invention fall within the scope of the invention. Furthermore, the scope of the invention is not limited by the specific descriptions described below. The research relating to this invention was conducted with funding from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare of the Republic of Korea, and supported by the Korea Drug Development Fund's National New Drug Development Project (Project ID: RS-2023-00284094). The aforementioned project ID may be used in conjunction with "1711200965". Compounds represented by chemical formula I The present invention provides compounds represented by chemical formula I, their stereoisomers, pharmaceutically acceptable salts thereof, or their hydrates or solvates.

[0005] [ka]

[0006] In the aforementioned chemical formula I, X is phenyl or pyridinyl, One or more of the H atoms in X may be substituted with a 5- to 12-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of halogens, C1-C6 alkyl groups, C(=O)Ra, NH2, NO2, S(=O)2Rb, N, O, and S. The aforementioned Ra and Rb are each independently 3- to 12-membered heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from the group consisting of C1-C6 alkyl, NH2, or N, O, and S within the ring. Y is a 3- to 12-membered heterocycloalkylene containing a single bond, 1 to 3 heteroatoms independently selected from the group consisting of 6- to 14-membered arylenes, N, O, and S, or a 5- to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. L1 is a single bond, C1-C6 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C6 alkylene), C(=O)NH-(C1-C6 alkylene)-C(=O)O, or C(=O)NH-(C1-C6 alkylene)-C(=O)NH. R1 is a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF3, NRcRd, N, O, and S, or a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. The aforementioned Rc and Rd are each independently H or C1-C6 alkyl. Q1 and Q2 are independently either N or N-L2-R2, and Q1 and Q2 cannot be N at the same time. When Q2 is N, the above

[0007] [ka]

[0008] teeth

[0009] [ka]

[0010] And when Q1 is N, the above

[0011] [ka]

[0012] teeth

[0013] [ka]

[0014] And, The aforementioned L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), The aforementioned R2 is a 3- to 12-membered heterocycloalkyl, C1-C6 alkoxy, CONH2, NReRf, SO2Rg, or OH group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring. Re, Rf, and Rg are each independently H or C1-C6 alkyl. In one embodiment, in the chemical formula I, X is phenyl or pyridinyl, One or more H atoms in X may be substituted with a 5- to 12-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of halogens, C(=O)Ra, NH2, NO2, S(=O)2Rb, N, O, and S. The aforementioned Ra and Rb are each independently 3- to 12-membered heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from the group consisting of NH2 or N, O, and S within the ring. Y is a 3- to 12-membered heterocycloalkylene containing a single bond, 1 to 3 heteroatoms independently selected from the group consisting of 6- to 14-membered arylenes, N, O, and S, or a 5- to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. L1 is a single bond, C1-C6 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C6 alkylene), C(=O)NH-(C1-C6 alkylene)-C(=O)O, or C(=O)NH-(C1-C6 alkylene)-C(=O)NH. R1 is a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF3, NRcRd, N, O, and S, or a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. The aforementioned Rc and Rd are each independently a C1-C6 alkyl group. Q1 and Q2 are independently either N or N-L2-R2, and Q1 and Q2 cannot be N at the same time. When Q2 is N, the above

[0015] [ka]

[0016] teeth

[0017] [ka]

[0018] And when Q1 is N, the above

[0019] [ka]

[0020] teeth

[0021] [ka]

[0022] And, The aforementioned L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), The aforementioned R2 is a 3- to 12-membered heterocycloalkyl, C1-C6 alkoxy, CONH2, NReRf, SO2Rg, or OH group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring. Re, Rf, and Rg may each be independently a C1-C6 alkyl group. In one embodiment, in the chemical formula I, X is phenyl or pyridinyl, One or more H atoms in X may be substituted with a 5-membered or 6-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of F, Cl, C(=O)Ra, NH2, NO2, S(=O)2Rb, N, and S. The aforementioned Ra and Rb are each independently 5- to 7-membered heterocycloalkyl groups containing 1 to 3 heteroatoms independently selected from the group consisting of NH2 or N and O within the ring. Y is a 5- to 7-membered heterocycloalkylene containing a single bond, 1 to 3 heteroatoms independently selected from the group consisting of 6- to 12-membered arylenes, N, O, and S, or a 5- or 6-membered heteroarylene containing 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S. L1 consists of a single bond, C1-C4 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C2 alkylene), C(=O)NH-(C1-C5 alkylene)-C(=O)O, or C(=O)NH-(C1-C3 alkylene)-C(=O)NH. R1 is a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of H, F, Cl, C1-C3 alkyl, C1-C3 alkoxy, OH, CF3, NRcRd, N, and O, or a 5- or 6-membered heteroaryl group containing 1 or 2 heteroatoms independently selected from the group consisting of N and O. The aforementioned Rc and Rd are each independently a C1-C3 alkyl group. Q1 and Q2 are independently either N or N-L2-R2, and Q1 and Q2 cannot be N at the same time. When Q2 is N, the above

[0023] [ka]

[0024] teeth

[0025] [ka]

[0026] And when Q1 is N, the above

[0027] [ka]

[0028] teeth

[0029] [ka]

[0030] And, The aforementioned L2 is C1-C6 alkylene or (C1-C3 alkylene)-O-(C1-C3 alkylene), The aforementioned R2 is a 5- to 7-membered heterocycloalkyl, C1-C3 alkoxy, CONH2, NReRf, SO2Rg, or OH group containing 1 to 3 heteroatoms independently selected from the group consisting of N and O within the ring. The Re, Rf, and Rg mentioned above may each be independently a C1-C3 alkyl group. In one embodiment, in the chemical formula I, X is

[0031] [ka]

[0032] And Z1 may be CH or N. In this invention, the term "Cm-Cn" (where m and n are independently integers of 1 or more) means the number of carbon atoms, and for example, "C1-C5 alkyl" means an alkyl group having 1 to 5 carbon atoms. In the present invention, "substitution" or "substituted with ~" is defined as including the implicit condition that such a substitution leads to a stable compound, such as a compound that is not spontaneously deformed by recombination, cyclization, removal, etc., according to the acceptable valency of the substituted atom and the substituted product. In this invention, "single bond" means that adjacent atoms or groups of atoms are directly bonded together. In the present invention, unless otherwise specified, "alkyl" means a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group. Examples of alkyl groups include, but are not limited to, one or more selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl. In the present invention, unless otherwise specified, "alkylene" means a divalent functional group derived from alkyl as defined above. In the present invention, "cycloalkyl" means a monocyclic or polycyclic saturated hydrocarbon ring unless otherwise specified. Examples of cycloalkyl include, but are not limited to, one or more selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, spiropentyl, spirohexyl, spiroheptyl, and spirooctyl. In the present invention, unless otherwise specified, "cycloalkylene" means a divalent functional group derived from a cycloalkyl as defined above. In the present invention, "cycloalkenyl" means a monocyclic or polycyclic unsaturated hydrocarbon ring containing one or more double bonds, unless otherwise specified. Examples of cycloalkenyls include, but are not limited to, one or more selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and others. In the present invention, unless otherwise specified, "cycloalkenylene" means a divalent functional group derived from a cycloalkenyl as defined above. In the present invention, unless otherwise specified, "heterocycloalkyl" means a monocyclic or polycyclic ring in which at least one carbon atom forming the cycloalkyl ring as defined above is substituted with a heteroatom selected from the group consisting of N, O, and S. Examples of heterocycloalkyls include, but are not limited to, one or more selected from oxylanil, dioxolanil, oxetanil, tetrahydrofuranil, tetrahydropyranil, azetidinil, pyrrolidinil, piperidinil, azepanil, morpholinil, piperazinil, thiomorpholinil, tetrahydrothiophenyl, tetrahydrothiopyranil, and others. In the present invention, unless otherwise specified, "heterocycloalkylene" means a divalent functional group derived from a heterocycloalkyl as defined above. In the present invention, unless otherwise specified, "heterocycloalkenyl" means a monocyclic or polycyclic ring in which at least one carbon atom forming the cycloalkenyl ring as defined above is substituted with a heteroatom selected from the group consisting of N, O, and S. Examples of heterocycloalkenyls include, but are not limited to, one or more selected from dihydropyridinyl, dihydropyranyl, dihydrothiopyranyl, etc. In the present invention, unless otherwise specified, "heterocycloalkenylene" means a divalent functional group derived from a heterocycloalkenyl as defined above. In the present invention, "aryl" means a monocyclic or polycyclic aromatic cyclic group having one or more condensed or uncondensed aromatic rings, unless otherwise specified. Examples of aryls include, but are not limited to, one or more selected from phenyl, naphthalenyl, indenyl, and anthracenyl. In this invention, unless otherwise specified, "alylene" means a divalent functional group derived from the aryl as defined above. In the present invention, unless otherwise specified, "heteroaryl" means a monocyclic or polycyclic aromatic heterocyclic group having one or more condensed or uncondensed aromatic rings containing at least one heteroatom selected from the group consisting of N, O, and S within the ring. Examples of heteroaryls include, but are not limited to, one or more selected from pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranil, benzopyrrolyl, furanil, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridadinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzimidazolyl, dihydrobenzothiophenyl, flunyl, indolidinyl, clomenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyridinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazoll, etc. In the present invention, unless otherwise specified, "heteroarylene" means a divalent functional group derived from a heteroaryl as defined above. In the present invention, unless otherwise specified, "halogen" may be F, Cl, Br, or I. Furthermore, unless otherwise defined, terms and abbreviations used herein shall have their original meanings. The present invention provides compounds listed in Table 1 below, their stereoisomers, pharmaceutically acceptable salts thereof, or their hydrates or solvates.

[0033] [Table 1-1]

[0034] [Table 1-2]

[0035] Table 1-3

[0036] Table 1-4

[0037] Table 1-5

[0038] Table 1-6

[0039] Table 1-7

[0040] Table 1-8

[0041] Table 1-9

[0042] Table 1-10

[0043] Table 1-11

[0044] Table 1-12

[0045] Table 1-13

[0046] Table 1-14

[0047] Table 1-15

[0048] Table 1-16

[0049] Table 1-17

[0050] Table 1-18

[0051] Table 1-19

[0052] Table 1-20

[0053] Table 1-21

[0054] Table 1-22

[0055] Table 1-23

[0056] Table 1-24

[0057] Table 1-25

[0058] Table 1-26

[0059] Table 1-27

[0060] Table 1-28

[0061] Table 1-29

[0062] Table 1-30

[0063] Table 1-31

[0064] Table 1-32

[0065] Table 1-33

[0066] Table 1-34

[0067] Table 1-35

[0068] Table 1-36

[0069] Table 1-37

[0070] Table 1-38

[0071] Table 1-39

[0072] Table 1-40

[0073] Table 1-41

[0074] Table 1-42

[0075] Table 1-43

[0076] [Table 1-44]

[0077] Method for producing compounds represented by chemical formula I The present invention provides a method for producing compounds represented by chemical formula I, the compounds listed in Table 1, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates. The compounds represented by chemical formula I of the present invention, the compounds listed in Table 1, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates may be produced, for example, by the method of reaction formula 1 below, but are not limited thereto.

[0078] [ka]

[0079] In the above reaction equation 1, R1, R2, L1, L2, X, and Y are the same as those defined in the compound item represented by chemical formula I. [Step 1] Coupling reaction It is possible to produce 1 or 2-substituted indazole derivatives (compound (ii)) from a starting material (compound (i)) (see reaction formula 1 above). Reactions useful for this purpose optionally involve the use of R2-L2-B (where B is a chloride, bromide, iodide, or 4-methylbenzenesulfonate) and a base in a solvent. Optionally, if B in R2-L2-B is a chloride or bromide, it is also possible to add an alkali metal iodide, such as potassium iodide or sodium iodide. The base can be either an organic or inorganic base; for example, the inorganic base may be potassium carbonate, cesium carbonate, or sodium hydride. In the case of reactive halides, it is also possible to use N-cyclohexyl-N-methylcyclohexaneamine as the organic base in some cases. The solvent may be, for example, 1-methylpyrrolidine-2-one, DMF, DMSO, or THF. [Step 2] Coupling reaction The step involves producing compound (iii) by carrying out a coupling reaction with the condensate in a reaction-inert solvent, in the presence of a base, in a pressure reactor (pressure tube) or a general reactor, using a palladium catalyst or nickel catalyst; and an equal or excess amount of boronic acid, pinacol boronic acid ester (in the case of the Suzuki-Miyaura coupling), organotin reagent (in the case of the Stille coupling), or alkene compound (in the case of the Heck reaction), while stirring under heating conditions for 0.5 to 24 hours. Specifically, compound (iii) can be produced by stirring at 20 to 120°C for 0.5 to 24 hours. The aforementioned solvent is not particularly limited as long as it is inert to this reaction, but methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, or mixtures thereof may be used. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, acetylacetone palladium, or bis(triphenylphosphine)palladium dichloride may be used. As the nickel catalyst, [1,1'-bis(diphenylphosphine)ferrocene]nickel dichloride or bis(triphenylphosphine)nickel dichloride may be used. The aforementioned base can be either an organic or inorganic base. For example, an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), or 1,5-diazabicyclo[4.3.0]-5-nonene (DBN) may be used; or an inorganic base such as potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate, or sodium phosphate may be used. [Step 3] Reduction reaction The step involves stirring compound (iii) with palladium / charcoal and hydrogen gas as a solvent for 3 to 96 hours under cooling or heating to produce compound (iv). Specifically, compound (iv) can be produced by stirring at room temperature (10 to 25°C) to 60°C for 0.5 to 48 hours. The aforementioned solvent is not particularly limited as long as it does not inhibit the reaction, but methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, or mixtures thereof may be used. [Step 4] Amidation reaction The step involves preparing compound 1C by stirring compound (iv) in a reaction-inert solvent with an equal or excess amount of the corresponding X-substituted aromatic carboxylic acid and a condensing agent for 1 to 24 hours under cooling or heating. Specifically, compound (v) can be prepared by stirring at room temperature to 120°C for 1 to 8 hours. The aforementioned solvent is not particularly limited as long as it is inert to this reaction, but may be N,N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or mixtures thereof. The condensing agent may be pentafluorophenyl trifluoroacetate, dicyclocarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 1,1'-carbonyldiimidazole, etc. Furthermore, additives or bases may be used in the reaction. Examples of such additives include N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), and 1-hydroxy-7-azabenzotriazole (HOAt). Examples of such bases include organic bases such as triethylamine and diisopropylethylamine; or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, or sodium hydroxide. Compositions containing compounds represented by chemical formula I, methods utilizing compounds represented by chemical formula I, and uses of compounds represented by chemical formula I The present invention provides a pharmaceutical composition containing as an active ingredient a compound represented by the chemical formula I, a compound listed in Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provides a health functional food composition comprising a compound represented by the chemical formula I, a compound listed in Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. In the present invention, "stereoisomer" includes diastereomers and optical isomers, and optical isomers include not only enantiomers but also mixtures of enantiomers and racemates. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and, when administered to an individual, does not typically cause gastrointestinal disorders, dizziness, or other allergic or similar reactions. The pharmaceutically acceptable salts of the present invention can be produced by conventional methods known to the commonly skilled in the art. The "hydrate" of the present invention is a compound represented by chemical formula I, one of the compounds listed in Table 1, one of its stereoisomers, or a pharmaceutically acceptable salt thereof, bonded to water by non-covalent intermolecular forces, and may contain stoichiometric or non-stoichiometric amounts of water. Specifically, the hydrate may contain water in a ratio of about 0.25 moles to about 10 moles based on 1 mole of the active ingredient, and more specifically, it may contain about 0.5 moles, about 1 mole, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, etc. The "solvate" of the present invention is a compound represented by Chemical Formula I, the compound of Table 1, its stereoisomer or its pharmaceutically acceptable salt, which is bonded to a solvent other than water by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of the solvent. Specifically, the solvate may contain solvent molecules in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient. More specifically, it may contain about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about 5 mol, etc. The compound represented by Chemical Formula I, the compound of Table 1, its stereoisomer, its pharmaceutically acceptable salt, or its hydrate or solvate, and a pharmaceutical composition containing the same as an active ingredient exhibit IRAK-4 and / or IRAK-1 inhibitory activity, and may be used for the prevention, treatment or improvement of IRAK-4 or IRAK-1 related diseases. In the present invention, the "IRAK-4 or IRAK-1 related disease" may be an autoimmune disease, an inflammatory disease or a tumor. The pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable carriers in addition to the compound represented by Chemical Formula I, the compound of Table 1, its stereoisomer, its pharmaceutically acceptable salt, or its hydrate or solvate. Here, the pharmaceutically acceptable carrier is one commonly used in the art during formulation, and may be one or more selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, alginic acid, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil, etc., but is not limited thereto. In addition, the pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent or a preservative, etc. in addition to the above components. The present invention provides a method for preventing or treating IRAK-4 or IRAK-1 related diseases, which comprises administering to an individual a compound represented by the above chemical formula I, a compound of Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition containing the same. The method for preventing or treating IRAK-4 or IRAK-1 related diseases of the present invention may include administering a compound represented by the above chemical formula I, a compound of Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition containing the same, in a therapeutically effective amount. In the present invention, "prevention" means any act of suppressing or delaying the onset of IRAK-4 or IRAK-1 related diseases by administering a compound represented by the chemical formula I of the present invention, a compound of Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. In the present invention, "treatment" means any act of improving or beneficially changing the symptoms of IRAK-4 or IRAK-1 related diseases by administering a compound represented by the chemical formula I of the present invention, a compound of Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provides the use of a compound represented by the above chemical formula I, a compound of Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition containing the same, for preventing or treating IRAK-4 or IRAK-1 related diseases. The present invention provides the use of a compound represented by the above chemical formula I, a compound of Table 1 above, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition containing the same, for the manufacture of a medicament for preventing or treating IRAK-4 or IRAK-1 related diseases.

Advantages of the Invention

[0080] The compound represented by chemical formula I of the present invention, its stereoisomer, its pharmaceutically acceptable salt, or its hydrate or solvate exerts an inhibitory effect on IRAK-4 or IRAK-1 and can be usefully used for the prevention or treatment of diseases associated with IRAK-4 or IRAK-1 activity. [Modes for carrying out the invention]

[0081] The present invention will be described in further detail below. All examples or use of illustrative terms provided herein are merely intended to better illustrate the present invention and are not intended to limit the scope of the claimed invention. <Examples> The compounds represented by chemical formula I of the present invention and the compounds listed in Table 1 can be produced by the methods described below. Unless otherwise specified, the starting materials may be purchased or produced by known methods. Example 1. N-(2-(2-(dimethylamino)ethyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)isophthalamide

[0082] [ka]

[0083] [Step 1] Preparation of 2-(6-bromo-5-nitro-2H-indazole-2-yl)-N,N-dimethylethane-1-amine 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmol) was mixed with potassium carbonate (11.42 g, 82.64 mmol), potassium iodide (0.5 g, 3.01 mmol), 2-chloro-N,N-dimethylethane-1-amine hydrochloride (2.98 g, 20.66 mmol), and dimethylformamide (50 mL), and the mixture was stirred at 80°C for 17 hours. After the reaction was complete, ethyl acetate (50 mL) was added, the mixture was washed with purified water (50 mL), anhydrous magnesium sulfate was added, and the mixture was filtered. After concentration under reduced pressure, the mixture was purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.88 g). 1 H-NMR (DMSO-d 6) 2.12(s, 6H), 2.77(t, 2H), 4.55(t, 2H), 8.15(s, 1H), 8.61(s, 1H), 8.63(s, 1H) [Step 2] Preparation of N,N-dimethyl-2-(5-nitro-6-(thiophen-3-yl)-2H-indazole-2-yl)ethane-1-amine To the compound obtained in [Step 1] (0.4 g, 1.277 mmol), sodium carbonate (677 mg, 6.39 mmol), tetrakis(triphenylphosphine)palladium (74 mg, 0.06 mmol), thiophene-3-boronic acid pinacol ester (402 mg, 1.916 mmol), 1,4-dioxane (10 mL), and purified water (1 mL) were added, and the mixture was stirred at 100 °C for 17 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, ethyl acetate (30 mL) was added, followed by washing with purified water (30 mL), and then filtered after adding anhydrous magnesium sulfate. After concentration under reduced pressure, the mixture was purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.46 g). 1 H-NMR (DMSO-d 6 ) 2.12(s, 6H), 2.77(t, 2H), 4.55(t, 2H), 6.55(s, 1H), 7.71-7.72(m, 2H), 8.15(s, 1H), 8.61(s, 1H), 8.63(s, 1H) [Step 3] Preparation of 2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazole-5-amine The compound obtained in [Step 2] (250 mg, 0.79 mmol) was mixed with palladium (50 mg, 0.2 w / w) on activated carbon and methanol (20 mL), and hydrogenated at room temperature under standard hydrogen pressure for 3 hours. After the reaction was complete, the reaction mixture was filtered using Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound (230 mg). 1 H-NMR (DMSO-d 6) 2.08 (s, 6H), 2.61 (t, 2H), 4.38 (t, 2H), 4.50 (s, 2H), 6.41 (s, 1H), 7.63 (s, 1H), 7.64 (s, 1H), 7.66 (s, 1H), 7.95 (s, 1H), 7.99 (s, 1H) [Step 4] Production of N-(2-(2-(dimethylamino)ethyl)-6-(thiophen-3-yl)-2H-indazol-5-yl)isophthalamide (Compound 1) Dimethylformamide (1 mL) was added dropwise to the compound (104 mg, 0.363 mmol) obtained in [Step 3], DIPEA (0.247 mL, 1.452 mmol) and HATU (207 mg, 0.545 mmol) were added, and the mixture was stirred for 30 minutes. Then, 3-carbamoylbenzoic acid (60 mg, 0.363 mmol) was added, and the mixture was stirred at room temperature for 17 hours. After the reaction was completed, ethyl acetate (30 mL) was added, washed with purified water (30 mL), anhydrous magnesium sulfate was added, and the mixture was filtered. After concentration under reduced pressure, it was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (70 mg). 1 H-NMR (DMSO-d 6 ) 2.16 (d, 6H), 2.77 (t, 2H), 4.50 (t, 2H), 7.29 (m, 1H), 7.42 (s, 1H), 7.49 (m, 1H), 7.51 (m, 1H), 7.58 (s, 1H), 7.65 (s, 1H), 7.75 (s, 1H), 7.95 (m, 1H), 7.98 (m, 1H), 8.01 (m, 1H), 9.33 (s, 1H), 9.38 (s, 1H), 9.89 (s, 1H) LC-MS (ESI, m / z) = 434.7 (M+H + ). Example 2. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-5-nitronicotinamide

[0084]

Chemical Structure

[0085] [Step 1] Preparation of 4-(5-nitro-1H-indazole-6-yl)morpholine 6-bromo-5-nitro-1H-indazole (5 g, 20.66 mmol) was mixed with morpholine (21.6 mL, 247.92 mmol) and stirred at 140°C for 23 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure and purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (5.14 g). 1 H-NMR (DMSO-d 6 ) 2.94(t, 4H), 3.68(t, 4H), 7.22(s 1H), 8.16(s, 1H), 8.35(s, 1H) [Step 2] Synthesis of 2-methyl-4-(6-morpholino-5-nitro-2H-indazole-2-yl)butan-2-ol Under the same conditions as in Step 1 of Example 1, 4-bromo-2-methylbutan-2-ol (1.89 mL, 15.5 mmol), potassium carbonate (5.7 g, 41.32 mmol), potassium iodide (257 mg, 1.55 mmol), and dimethylformamide (10 mL) were added to the compound obtained in Step 1 (2.57 g, 10.33 mmol) and the mixture was stirred at 90°C for 4 hours. After the reaction was complete, ethyl acetate (50 mL) was added, the mixture was washed with purified water (50 mL), anhydrous magnesium sulfate was added, and the mixture was filtered. After concentration under reduced pressure, the mixture was purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.46 g). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 1.99(m, 2H), 2.89(t, 4H), 3.66(t, 4H), 4.47(m, 2H), 4.48(s, 1H), 7.32(s, 1H), 8.31(s, 1H), 8.57(s, 1H) [Step 3] Production of 4-(5-amino-6-morpholino-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (900 mg, 2.692 mmol) was dissolved in ethyl acetate (9 mL), palladium on activated carbon (180 mg, 0.2 w / w) was added, and hydrogenated. The reaction solution was filtered using celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (820 mg). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 1.95(m, 2H), 2.75(t, 4H), 3.48(t, 4H), 4.35(m, 2H), 4.36(s, 1H), 4.50(s, 2H), 7.29(s, 1H), 7.75(s, 1H), 8.05(s, 1H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-5-nicotinamide (Compound 2) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.1 g, 0.3285 mmol), 5-nicotinic acid (0.07 g, 0.299 mmol), dimethylformamide (5 mL), DIPEA (0.284 mL, 1.314 mmol) and HATU (0.24 g, 0.4928 mmol) were reacted in the same manner, then purified water was added, the resulting solid was filtered and dried, and then ethyl acetate was added and filtered to obtain the title compound (12 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.00(t, 2H), 2.89(m, 4H), 3.75(m, 4H), 4.41(m, 2H), 4.48(s, 1H), 7.36(s, 1H), 8.26(s, 1H), 8.32(s, 1H), 8.95(s, 1H), 9.44(s, 1H), 9.53(s, 1H), 10.11(s, 1H) LC-MS (ESI, m / z) = 455.4 (M+H + ). Example 3. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0086] [ka]

[0087] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 3) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] of Example 2 (0.1 g, 0.3285 mmol), 3-nitrobenzoic acid (0.07 g, 0.299 mmol), dimethylformamide (5 mL), HATU (0.24 g, 0.4928 mmol), and DIPEA (0.284 mL, 1.314 mmol) were reacted in the same manner. After adding purified water, the resulting solid was filtered, dried, and then filtered again with methanol to obtain the title compound (53 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.00(t, 2H), 2.90(m, 4H), 3.78(m, 4H), 4.41(t, 2H), 4.47(s, 1H), 7.39(s, 1H), 7.86(m, 1H), 8.31(s, 1H), 8.35(m, 2H), 8.37(m, 1H), 8.70(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 454.4 (M+H + ). Example 4. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0088] [ka]

[0089] [Step 1] Preparation of 4-(6-bromo-5-nitro-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (3 g, 12.4 mmol), potassium carbonate (6.85 g, 49.6 mmol), potassium iodide (0.21 g, 1.81 mmol), 4-bromo-2-methylbutan-2-ol (2.27 mL, 18.6 mmol), and dimethylformamide (30 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.91 g). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02(m, 2H), 4.46-4.49(m, 3H), 8.10(s, 1H), 8.42(s, 1H), 8.49(s, 1H) [Step 2] Preparation of 4-(6-(furan-3-yl)-5-nitro-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 (1.9 g, 5.79 mmol), sodium carbonate (3.07 g, 28.9 mmol), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol), 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (1.69 g, 8.69 mmol), 1,4-dioxane (20 mL), and purified water (2 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.5 g). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02(m, 2H), 4.46-4.49(m, 3H), 6.93(s, 1H), 7.66(s, 1H), 7.79(s, 1H), 8.11(s, 1H), 8.43(s, 1H), 8.50(s, 1H) [Step 3] Production of 4-(5-amino-6-(furan-3-yl)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, palladium (0.3 g, 0.2 w / w) on activated carbon was added to the compound obtained in [Step 2] (1.5 g, 4.76 mmol) and hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (1.06 g). 1 H-NMR (DMSO-d 6 ) 1.09(s, 6H), 1.94(m, 2H), 4.32-4.35(m, 3H), 4.52(s, 2H), 6.72(s, 1H), 7.46(s, 1H), 7.58(s, 1H), 7.91(s, 1H), 8.22(s, 1H), 8.33(s, 1H) [Step 4] Preparation of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 4) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (87 mg, 0.305 mmol), 3-nitrobenzoic acid (42 mg, 0.254 mmol), dimethylformamide (1 mL), HATU (145 mg, 0.381 mmol), and DIPEA (0.173 mL, 1.016 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (15 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.04(t, 2H), 4.49(m, 3H), 6.79(s, 1H), 7.65(s, 1H), 7.71(m, 1H), 7.74(s, 1H), 7.81(t, 1H), 7.84(s, 1H), 8.34(d, 1H), 8.40(s, 2H), 8.73(s, 1H), 10.28(s, 1H) LC-MS (ESI, m / z) = 435.4 (M+H + ). Example 5. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-5-nitronicotinamide

[0090] [ka]

[0091] [Step 4] Preparation of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-5-nitronicotinamide (compound 5) Under the same conditions as in Step 4 of Example 1, the compound obtained in Step 3 of Example 4 (87 mg, 0.305 mmol), 5-nitronicotinic acid (43 mg, 0.254 mmol), dimethylformamide (1 mL), HATU (145 mg, 0.381 mmol), and DIPEA (0.173 mL, 1.016 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (15 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02(t, 2H), 4.48(m, 3H), 6.81(m, 1H), 7.66(m, 1H), 7.71(m, 1H), 7.77(m, 1H), 7.88(m, 1H), 8.41(s, 1H), 8.97(s, 1H), 9.41(s, 1H), 9.50(s, 1H), 10.43(s, 1H) LC-MS (ESI, m / z) = 436.4 (M+H + ). Example 6. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl) isophthalamide

[0092] [ka]

[0093] [Step 4] Preparation of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)isophthalamide (compound 6) Under the same conditions as in Step 4 of Example 1, the compound obtained in Step 3 of Example 4 (87 mg, 0.305 mmol), 3-carbamoylbenzoic acid (42 mg, 0.254 mmol), dimethylformamide (1 mL), HATU (145 mg, 0.381 mmol), and DIPEA (0.173 mL, 1.016 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (29 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02(m, 2H), 4.48(m, 3H), 6.80(s, 1H), 7.44(m, 1H), 7.56(m, 1H), 7.64(s, 1H), 7.70(m, 2H), 7.83(s, 1H), 8.02(m, 3H), 8.39(m, 2H), 9.97(s, 1H) LC-MS (ESI, m / z) = 433.5 (M+H + ). Example 7. N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-5-nitronicotinamide

[0094] [ka]

[0095] [Step 2] Production of 2-methyl-4-(5-nitro-6-(thiophen-3-yl)-2H-indazole-2-yl)butan-2-ol Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (0.9 g, 2.74 mmol), sodium carbonate (1.45 g, 13.7 mmol), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane (0.86 g, 4.11 mmol), 1,4-dioxane (10 mL), and purified water (1 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.44 g). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.04(t, 2H), 4.50(s, 1H), 4.53(m, 2H), 7.08(s, 1H), 7.58(s, 2H), 8.13(s, 1H), 8.59(s, 1H), 8.75(s, 1H). [Step 3] Production of 4-(5-amino-6-(thiophen-3-yl)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, palladium (0.08 g, 0.2 w / w) on activated carbon was added to the compound obtained in [Step 2] (0.4 g, 1.22 mmol) and hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.33 g). 1 H-NMR (DMSO-d 6 ) 1.09(s, 6H), 1.85(t, 2H), 3.88(s, 2H), 4.40(s, 1H), 4.50(m, 2H), 6.94(s, 1H), 7.34(m, 2H), 7.66(m, 2H), 7.70(s, 1H). [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-5-nitronicotinamide (compound 7) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.113 g, 0.375 mmol), 5-nitronicotinic acid (52.5 mg, 0.3125 mmol), dimethylformamide (1 mL), HATU (0.178 g, 0.469 mmol), and DIPEA (0.213 mL, 1.25 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (47 mg). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.03(t, 2H), 4.50(m, 3H), 7.30(m, 1H), 7.52(m, 1H), 7.60(s, 1H), 7.67(s, 1H), 7.80(s, 1H), 8.43(s, 1H), 8.87(s, 1H), 9.30(s, 1H), 9.48(s, 1H), 10.38(s, 1H) LC-MS (ESI, m / z) = 452.5 (M+H + ). Example 8. N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-3-nitrobenzamide

[0096] [ka]

[0097] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 8) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] of Example 7 (0.113 g, 0.375 mmol), 3-nitrobenzoic acid (52 mg, 0.3125 mmol), dimethylformamide (1 mL), HATU (0.178 g, 0.469 mmol), and DIPEA (0.213 mL, 1.25 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (47 mg). 1H-NMR (DMSO-d 6 ) 1.23(s, 6H), 2.02(t, 2H), 4.49(m, 3H), 7.38(m, 1H), 7.64(m, 2H), 7.80(m, 2H), 8.02(m, 3H), 8.74(m, 2H), 10.20(s, 1H) LC-MS (ESI, m / z) = 451.5 (M+H + ). Example 9. N-(6-morpholino-2-(2-(piperidine-1-yl)ethyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0098] [ka]

[0099] [Step 1] Preparation of 6-bromo-5-nitro-2-(2-(piperidine-1-yl)ethyl)-2H-indazole Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmol), potassium carbonate (17.3 g, 125.18 mmol), potassium iodide (0.5 g, 3.012 mmol), 1-(2-chloroethyl)piperidine (5.7 g, 31 mmol), and dimethylformamide (50 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.83 g). 1 H-NMR (DMSO-d 6 ) 1.35(m, 2H), 1.61(m, 4H), 1.78(m, 2H), 3.47(m, 2H), 3.66(m, 2H), 4.80(m, 2H), 7.25(s, 1H), 8.29(s, 1H), 8.42(s, 1H) [Step 2] Preparation of 4-(5-nitro-2-(2-(piperidine-1-yl)ethyl)-2H-indazole-6-yl)morpholine Under the same conditions as in Step 1 of Example 2, morpholine (5 mL) was added to the compound obtained in Step 1 (100 mg, 0.283 mmol), and the reaction was carried out in the same manner. After purification using MPLC (combiFlash NEXTGEN 300+), the title compound (30 mg) was obtained. 1 H-NMR (DMSO-d 6 ) 1.35(m, 2H), 1.61(m, 4H), 1.78(m, 2H), 2.91(m, 4H), 3.47(m, 2H), 3.66(m, 2H), 3.79(m, 4H), 4.80(m, 2H), 7.87(m, 1H), 8.56(m, 1H), 8.71(m, 1H) [Step 3] Preparation of 6-morpholino-2-(2-(piperidine-1-yl)ethyl)-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (30 mg, 0.091 mmol) was dissolved in ethyl acetate (5 mL), palladium on activated carbon (3 mg, 0.03 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (27 mg). 1 H-NMR (DMSO-d 6 ) 1.35(m, 2H), 1.61(m, 4H), 1.78(m, 2H), 2.81(m, 4H), 3.37(m, 2H), 3.46(m, 2H), 3.59(m, 4H), 4.49(m, 2H), 4.51(s, 2H), 7.57(m, 1H), 8.36(m, 1H), 8.51(m, 1H) [Step 4] Preparation of N-(6-morpholino-2-(2-(piperidine-1-yl)ethyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 9) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (27 mg, 0.082 mmol), 3-nitrobenzoic acid (13 mg, 0.09 mmol), dimethylformamide (0.06 mL), HATU (44 mg, 0.123 mmol), and DIPEA (0.06 mL, 0.328 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (8 mg). 1 H-NMR (DMSO-d 6 ) 1.36(m, 2H), 1.61(m, 4H), 1.79(m, 2H), 2.91(m, 4H), 3.47(m, 2H), 3.66(m, 2H), 3.79(m, 4H), 4.80(m, 2H), 7.41(m, 1H), 7.87(m, 1H), 8.40(m, 3H), 8.71(m, 1H), 9.08(m, 1H), 10.03(s, 1H) LC-MS (ESI, m / z) = 479.5 (M+H + ). Example 10. N-(2-(2-(dimethylamino)ethyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0100] [ka]

[0101] [Step 2] Preparation of N,N-dimethyl-2-(6-morpholino-5-nitro-2H-indazole-2-yl)ethane-1-amine Under the same conditions as in Step 1 of Example 2, morpholine (5 mL) was added to the compound obtained in Step 1 of Example 1 (500 mg, 1.6 mmol), and the reaction was carried out in the same manner. After purification using MPLC (combiFlash NEXTGEN 300+), the title compound (135 mg) was obtained. 1 H-NMR (DMSO-d 6) 2.78(s, 6H), 2.92(m, 4H), 3.63(m, 2H), 3.78(m, 4H), 4.77(m, 2H), 7.32(s, 1H), 8.34(s, 1H), 8.59(s, 1H) [Step 3] Preparation of 2-(2-(dimethylamino)ethyl)-6-morpholino-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (135 mg, 0.467 mmol) was dissolved in ethyl acetate (5 mL), palladium on activated carbon (14 mg, 0.03 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (122 mg). 1 H-NMR (DMSO-d 6 ) 2.69(s, 6H), 2.85(m, 4H), 3.59(m, 2H), 3.70(m, 4H), 4.47(m, 2H), 4.51(s, 2H), 7.30(s, 1H), 7.75(s, 1H), 8.05(s, 1H) [Step 4] Preparation of N-(2-(2-(dimethylamino)ethyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 10) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (61 mg, 0.21 mmol), 3-nitrobenzoic acid (32 mg, 0.232 mmol), dimethylformamide (5 mL), HATU (110 mg, 0.316 mmol), and DIPEA (0.13 mL, 0.843 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (8 mg). 1 H-NMR (DMSO-d 6) 2.75(s, 6H), 2.90(m, 4H), 3.62(m, 2H), 3.78(m, 4H), 4.77(m, 2H), 7.40(m, 1H), 7.86(m, 1H), 8.38(m, 3H), 8.70(m, 1H), 9.23(m, 1H), 10.02(s, 1H) LC-MS (ESI, m / z) = 439.5 (M+H + ). Example 11. N-(2-(2-methoxyethyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0102] [ka]

[0103] [Step 1] Preparation of 6-bromo-2-(2-methoxyethyl)-5-nitro-2H-indazole Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmol), potassium carbonate (11.42 g, 82.64 mmol), potassium iodide (0.5 g, 3.012 mmol), 2-chloroethylmethyl ester (5.7 g, 31 mmol), and dimethylformamide (50 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (2.09 g). 1 H-NMR (DMSO-d 6 ) 3.13(s, 3H), 3.75(m, 2H), 4.51(m, 2H), 7.35(s, 1H), 8.30(s, 1H), 8.42(s, 1H) [Step 2] Preparation of 4-(2-(2-methoxyethyl)-5-nitro-2H-indazole-6-yl)morpholine Under the same conditions as in Step 1 of Example 2, morpholine (10 mL) was added to the compound obtained in Step 1 (800 mg, 2.67 mmol), and the reaction was carried out in the same manner. After purification with MPLC (combiFlash NEXTGEN 300+), the title compound (180 mg) was obtained. 1 H-NMR (DMSO-d 6 ) 2.81(m, 4H), 3.11(s, 3H), 3.59(m, 4H), 3.72(m, 2H), 4.51(m, 2H), 7.37(s, 1H), 8.32(s, 1H), 8.42(s, 1H) [Step 3] Preparation of 2-(2-methoxyethyl)-6-morpholino-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (180 mg, 0.588 mmol) was dissolved in ethyl acetate (20 mL), palladium on activated carbon (36 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (162 mg). 1 H-NMR (DMSO-d 6 ) 2.90(m, 4H), 3.20(s, 3H), 3.78(m, 6H), 4.51(m, 2H), 7.17(s, 1H), 8.12(s, 1H), 8.20(s, 1H) [Step 4] Preparation of N-(2-(2-methoxyethyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 11) To the compound obtained in [Step 3] (0.162 g, 0.586 mmol), 3-nitrobenzoic acid (90 mg, 0.539 mmol), dimethylformamide (5 mL), EDC·HCl (310 mg, 1.572 mmol), and HOBt·H2O (218 mg, 1.613 mmol) were added and the mixture was stirred at room temperature for 17 hours. After the reaction was complete, ethyl acetate (40 mL) was added and the mixture was washed with purified water (40 mL). Anhydrous magnesium sulfate was added and the mixture was filtered, concentrated under reduced pressure, and purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (54 mg). 1 H-NMR (DMSO-d 6) 2.90(m, 4H), 3.20(s, 3H), 3.78(m, 6H), 4.51(m, 2H), 7.40(s, 1H), 7.87(m, 1H), 8.28(s, 1H), 8.35(m, 2H), 8.43(m, 1H), 8.70(m, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 426.4 (M+H + ) Example 12. N-(2-(2-(dimethylamino)ethyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-3-(thiazole-2-yl)benzamide

[0104] [ka]

[0105] [Step 4] Preparation of N-(2-(2-(dimethylamino)ethyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-3-(thiazole-2-yl)benzamide (compound 12) Under the same conditions as in Step 4 of Example 1, the compound obtained in Step 3 of Example 1 (104 mg, 0.363 mmol), 3-(1,3-thiazole-2-yl)benzoic acid (70 mg, 0.363 mmol), dimethylformamide (1 mL), HATU (207 mg, 0.545 mmol), and DIPEA (0.247 mL, 1.452 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (89 mg). 1 H-NMR (DMSO-d 6 ) 2.26(s, 6H), 2.92(m, 2H), 4.56(m, 2H), 7.32(m, 1H), 7.53(m, 1H), 7.61(m, 2H), 7.66(m, 1H), 7.82(m, 2H), 7.90(m, 1H), 7.94(m, 1H), 8.09(m, 1H), 8.35(s, 1H), 8.41(s, 1H), 10.03(s, 1H) LC-MS (ESI, m / z) = 474.5 (M+H + ). Example 13. N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0106] [ka]

[0107] [Step 1] Preparation of 6-bromo-2-(2-(methylsulfonyl)ethyl)-5-nitro-2H-indazole Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmol) was mixed with 2-bromoethylmethylsulfone (5.8 g, 31 mmol), potassium carbonate (5.7 g, 41.32 mmol), potassium iodide (257 mg, 1.55 mmol), and dimethylformamide (50 mL). The reaction was carried out in the same manner, and then purified with MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.5 g). 1 H-NMR (DMSO-d 6 ) 2.90(s, 3H), 3.73(t, 2H), 4.76(t, 2H), 7.70(s, 1H), 8.42(s, 1H), 8.56(s, 1H) [Step 2] Preparation of 4-(2-(2-(methylsulfonyl)ethyl)-5-nitro-2H-indazole-6-yl)morpholine Under the same conditions as in Step 1 of Example 2, morpholine (10 mL) was added to the compound obtained in Step 1 (1.5 g, 4.31 mmol), and the reaction was carried out in the same manner. After purification using MPLC (combiFlash NEXTGEN 300+), the title compound (594 mg) was obtained. 1 H-NMR (DMSO-d 6 ) 2.86(s, 3H), 2.94(m, 4H), 3.59(m, 4H), 3.76(t, 2H), 4.78(t, 2H), 7.72(s, 1H), 8.31(s, 1H), 8.57(s, 1H) [Step 3] Preparation of 2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (594 mg, 1.83 mmol) was dissolved in ethyl acetate (100 mL), palladium on activated carbon (109 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (544 mg). 1 H-NMR (DMSO-d 6 ) 2.82(s, 3H), 2.84(m, 4H), 3.43(m, 4H), 3.63(t, 2H), 4.30(s, 2H), 4.60(t, 2H), 7.52(s, 1H), 8.11(s, 1H), 8.27(s, 1H) [Step 4] Preparation of N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 13) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (136 mg, 0.42 mmol) was reacted in the same manner with 3-nitrobenzoic acid (64 mg, 0.383 mmol), dimethylformamide (10 mL), EDC·HCl (0.22 g, 1.15 mmol), and HOBt·H2O (0.155 g, 1.15 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (44 mg). 1 H-NMR (DMSO-d 6 ) 2.87(s, 3H), 2.94(m, 4H), 3.59(m, 4H), 3.75(t, 2H), 4.78(t, 2H), 6.99(d, 1H), 7.63(d, 1H), 7.71(m, 1H), 8.40(m, 3H), 8.78(s, 1H), 10.14(s, 1H) LC-MS (ESI, m / z) = 474.5 (M+H + ). Example 14. N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-yl)-3-(morpholinosulfonyl)benzamide

[0108] [ka]

[0109] [Step 4] Preparation of N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-yl)-3-(morpholinosulfonyl)benzamide (Compound 14) Under the same conditions as in Step 4 of Example 1, the compound obtained in Step 3 of Example 13 (136 mg, 0.42 mmol), 3-(morpholinosulfonyl)benzoic acid (136 mg, 0.462 mmol), dimethylformamide (10 mL), HATU (217 mg, 0.63 mmol), and DIPEA (0.2 mL, 1.68 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (26 mg). 1 H-NMR (DMSO-d 6 ) 2.87(s, 3H), 2.89(m, 8H), 3.62(m, 4H), 3.78(m, 4H), 3.82(m, 2H), 4.80(m, 2H), 7.41(1H), 7.87(m, 1H), 7.94(m, 1H), 8.22(m, 1H), 8.26(m, 1H), 8.40(m, 2H), 9.97(s, 1H) LC-MS (ESI, m / z) = 578.7 (M+H + ). Example 15. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-4-sulfamoylbenzamide

[0110] [ka]

[0111] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-4-sulfamoylbenzamide (Compound 15) Under the same conditions as in [Step 4] of Example 11, 3-sulfamoylbenzoic acid (110 mg, 0.547 mmol), dimethylformamide (5 mL), EDC·HCl (315 mg, 1.641 mmol) and HOBt·H2O (222 mg, 1.642 mmol) were added to the compound (0.199 g, 0.654 mmol) obtained in [Step 3] of Example 2, and after reacting in the same manner, it was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (106 mg). 1 H-NMR (DMSO-d 6 ) 1.12 (d, 6H), 2.00 (t, 2H), 2.88 (m, 4H), 3.77 (m, 4H), 4.41 (m, 2H), 4.47 (s, 1H), 7.42 (s, 1H), 7.48 (s, 2H), 7.78 (t, 1H), 8.02 (d, 1H), 8.12 (d, 1H), 8.31 (s, 1H), 8.37 (s, 1H), 8.41 (s, 1H), 9.88 (s, 1H) LC-MS (ESI, m / z) = 488.6 (M+H + ). Example 16. N-(7-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0112]

Chemical Structure

[0113] [Step 1] Preparation of 4-(7-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 1] of Example 1, 7-bromo-5-nitro-1H-indazole (2 g, 8.26 mmol), dimethylformamide (20 mL), potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol) and 4-bromo-2-methylbutan-2-ol were reacted in the same manner, and after purification by MPLC (combiFlash NEXTGEN 300+) and concentration, the title compound (0.5 g) was obtained. 1H-NMR (DMSO-d 6 ) 1.14(s, 6H), 2.07(t, 2H), 4.49(s, 1H), 4.51(t, 2H), 8.21(s, 1H), 8.42(s, 1H), 8.51(s, 1H) [Step 2] Preparation of 4-(7-(furan-3-yl)-5-nitro-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.62 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.44 g, 2.29 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.5 g). 1 H-NMR (DMSO-d 6 ) 1.14(s, 6H), 2.07(t, 2H), 4.49(s, 1H), 4.51(t, 2H), 7.21(d, 1H), 8.06(d, 1H), 8.21(s, 1H), 8.42(s, 1H), 8.51(s, 1H), 8.58(s, 1H) [Step 3] Production of 4-(5-amino-7-(furan-3-yl)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (0.5 g, 1.59 mmol) was hydrogenated with palladium (0.10 g, 0.2 w / w) on activated carbon and ethyl acetate (10 mL). The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.44 g). 1 H-NMR (DMSO-d 6) 1.14 (s, 6H), 2.07 (t, 2H), 4.49 (s, 1H), 4.51 (t, 2H), 7.11 (s, 2H), 7.21 (d, 1H), 8.06 (d, 1H), 8.21 (s, 1H), 8.42 (s, 1H), 8.51 (s, 1H), 8.58 (s, 1H) [Step 4] Preparation of N-(7-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 16) Under the same conditions as in [Step 4] of Example 1, the compound obtained in the above [Step 3] (0.173 g, 0.61 mmol), 3-nitrobenzoic acid (0.085 g, 0.51 mmol), HATU (0.777 g, 2.04 mmol) and DIPEA (0.35 mL, 2.04 mmol) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (85 mg). 1 H-NMR (DMSO-d 6 ) 1.11 (s, 6H), 1.42 (m, 2H), 1.81 (d, 2H), 2.02 (t, 2H), 2.32 (m, 1H), 2.99 (t, 2H), 3.77 (d, 2H), 4.43 (t, 2H), 4.47 (s, 1H), 6.82 (s, 1H), 7.48 (s, 1H), 7.57 (s, 1H), 7.85 (s, 1H), 7.99 (s, 1H), 8.36 (s, 1H), 8.56 (s, 1H), 9.63 (s, 1H) LC-MS (ESI, m / z) = 435.4 (M+H + ). Example 17. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0114]

Chemical Structure

[0115] [Step 2] Preparation of 2-(2-(6-morpholino-5-nitro-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in Step 1 of Example 1, 2-(2-chloroethoxy)acetamide (0.83 g, 6.05 mmol), potassium carbonate (2.23 g, 16.12 mmol), potassium iodide (100 mg, 0.6 mmol), and dimethylformamide (20 mL) were added to the compound obtained in Step 1 of Example 2 (1 g, 4.03 mmol) and reacted in the same manner. After purification and concentration using MPLC (combiFlash NEXTGEN 300+), the title compound (430 mg) was obtained. 1 H-NMR (DMSO-d 6 ) 2.93(m, 4H), 3.75(m, 6H), 3.93(t, 2H), 4.56(t, 2H), 7.32(s, 1H), 8.31(s, 1H), 8.56(s, 1H) [Step 3] Preparation of 2-(2-(5-amino-6-morpholino-2H-indazole-2-yl)ethoxy)acetamide Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (430 mg, 1.23 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (65 mg, 0.15 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (393 mg). 1 H-NMR (DMSO-d 6 ) 2.86(m, 4H), 3.63(m, 6H), 3.79(t, 2H), 4.43(t, 2H), 4.49(s, 2H), 7.29(s, 1H), 7.63(s, 1H), 8.05(s, 1H) [Step 4] Preparation of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 17) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (98 mg, 0.31 mmol) was reacted in the same manner with 3-sulfamoylbenzoic acid (94 mg, 0.465 mmol), dimethylformamide (5 mL), EDC·HCl (178 mg, 0.93 mmol), and HOBt·H2O (126 mg, 0.93 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (67 mg). 1 H-NMR (DMSO-d 6 ) 2.91(m, 4H), 3.76-3.78(m, 6H), 3.93(t, 2H), 4.56(t, 2H), 7.19-7.23(m, 2H), 7.42(s, 1H), 7.48(s, 2H), 7.78(t, 1H), 8.02(d, 1H), 8.14(d, 1H), 8.36(s, 1H), 8.37(s, 1H), 8.43(s, 1H), 9.89(s, 1H) LC-MS (ESI, m / z) = 503.5 (M+H + ). Example 18. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazole-5-yl)isophthalamide

[0116] [ka]

[0117] [Step 4] Preparation of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazole-5-yl)isophthalamide (Compound 18) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] of Example 17 (150 mg, 0.47 mmol), 3-carbamoylbenzoic acid (65 mg, 0.39 mmol), dimethylformamide (10 mL), HATU (0.268 g, 0.71 mmol), and DIPEA (0.27 mL, 1.56 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (29 mg). 1 H-NMR (DMSO-d 6 ) 2.90(br. s, 4H), 3.76(s, 2H), 3.78(br. s, 4H), 3.91(t, 2H), 4.56(t, 2H), 7.20(d, 2H), 7.40(s, 1H), 7.87(t, 1H), 8.19(d, 2H), 8.36(s, 3H), 8.42(d, 1H), 8.71(s, 1H), 10.00(s, 1H) LC-MS (ESI, m / z) = 467.5 (M+H + ). Example 19. N-(6-morpholino-2-(2-morpholinoethyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0118] [ka]

[0119] [Step 1] Preparation of 4-(2-(6-bromo-5-nitro-2H-indazole-2-yl)ethyl)morpholine Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmol), potassium carbonate (11.42 g, 82.64 mmol), potassium iodide (0.5 g, 3.012 mmol), 4-(2-chloroethyl)morpholine hydrochloride (5.77 g, 31 mmol), and dimethylformamide (50 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.5 g). 1 H-NMR (DMSO-d 6 ) 2.83(t, 2H), 3.48(t, 4H), 3.78(m, 4H), 4.53(t, 2H), 7.22(s, 1H), 8.16(s, 1H), 8.36(s, 1H) [Step 2] Preparation of 4-(2-(6-morpholino-5-nitro-2H-indazole-2-yl)ethyl)morpholine Under the same conditions as in Step 1 of Example 2, morpholine (10 mL) was added to the compound obtained in Step 1 (1 g, 2.82 mmol) and reacted in the same manner. The compound was then purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.15 g). 1 H-NMR (DMSO-d 6 ) 2.43(m, 4H), 2.83(t, 2H), 2.90(m, 4H), 3.48(t, 4H), 3.78(m, 4H), 4.53(t, 2H), 7.26(s, 1H), 8.31(s, 1H), 8.54(s, 1H) [Step 3] Preparation of 6-morpholino-2-(2-morpholinoethyl)-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (520 mg, 1.44 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (78 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (476 mg). 1 H-NMR (DMSO-d 6 ) 2.41(m, 4H), 2.76(t, 2H), 2.80(m, 4H), 3.41(t, 4H), 3.62(m, 4H), 4.50(t, 2H), 4.53(s, 2H), 7.15(s, 1H), 8.16(s, 1H), 8.39(s, 1H) [Step 4] Preparation of N-(6-morpholino-2-(2-morpholinoethyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 19) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (238 mg, 0.72 mmol), 3-nitrobenzoic acid (120 mg, 0.72 mmol), dimethylformamide (10 mL), HATU (1.1 g, 2.88 mmol), and DIPEA (0.49 mL, 2.88 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (38 mg). 1 H-NMR (DMSO-d 6 ) 2.41(m, 4H), 2.83(t, 2H), 2.90(m, 4H), 3.51(t, 4H), 3.78(m, 4H), 4.53(t, 2H), 7.39(s, 1H), 7.86(m, 1H), 8.31(s, 1H), 8.35(m, 2H), 8.37(m, 1H), 8.70(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 481.5 (M+H + ). Example 20. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-6-(1H-pyrazole-4-yl)picolinamide

[0120] [ka]

[0121] [Step 4] Preparation of 6-bromo-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)picolinamide 6-bromopicolinic acid (382 mg, 1.892 mmol) was mixed with EDC·HCl (453 mg, 2.366 mmol), HOBt·H2O (320 mg, 2.366 mmol), and dichloromethane (20 mL), and the mixture was stirred at room temperature for 2 hours. Then, the compound obtained in [Step 3] of Example 2 (480 mg, 1.577 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, dichloromethane (40 mL) was added, and the mixture was washed with purified water (40 mL). Anhydrous magnesium sulfate was added, the mixture was filtered, concentrated under reduced pressure, and purified using MPLC (combiFlash NEXTGEN 300+). The separated compound was concentrated, ethyl acetate (3 mL) was added, and the resulting solid was filtered to obtain the title compound (610 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.99(m, 2H), 2.90(t, 4H), 3.93(t, 4H), 4.41(m, 2H), 4.48(s, 1H), 7.43(s, 1H), 7.92(d, 1H), 8.01(t, 1H), 8.17(d, 1H), 8.31(s, 1H), 8.68(s, 1H), 11.03(s, 1H) [Step 5] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-6-(1H-pyrazole-4-yl)picolinamide (Compound 20) To the compound obtained in [Step 4] (100 mg, 0.2 mmol), 4-pyrazoleboronic acid pinacol ester (50 mg, 0.26 mmol), (1,1'-bis(diphenylphosphino)ferrosine)dichloropalladium-dichloromethane (1:1) (8 mg, 0.013 mmol), potassium carbonate (83 mg, 0.6 mmol), 1,4-dioxane (1 mL), and purified water (0.2 mL) were added and stirred at 100°C for 23 hours. After the reaction was complete, the reaction mixture was concentrated, ethyl acetate (50 mL) was added, and washed with purified water (50 mL). Then, anhydrous magnesium sulfate was added, filtered, and concentrated under reduced pressure, and purified with MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (18 mg) as a light brown solid. 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.00(m, 2H), 2.90(t, 4H), 3.79(t, 4H), 4.42(m, 2H), 4.48(s, 1H), 7.39(s, 1H), 7.94(m, 1H), 7.97(m, 1H), 9.30(s, 1H), 8.31(s, 1H), 8.50(s, 1H), 8.67(s, 1H), 10.94(s, 1H) LC-MS (ESI, m / z) = 476.1 (M+H + ). Example 21. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-6-(1H-pyrazole-5-yl)benzamide

[0122] [ka]

[0123] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-6-(1H-pyrazole-5-yl)benzamide (Compound 21) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (40 mg, 0.132 mmol), 6-(1H-pyrazole-5-yl)picolinic acid (30 mg, 0.159 mmol), EDC·HCl (38 mg, 0.198 mmol), HOBt·H2O (27 mg, 0.198 mmol), and dichloromethane (6 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (10 mg). 1 H-NMR (DMSO-d 6) 1.12(s, 6H), 2.00(m, 2H), 2.89(s, 4H), 3.83(s, 4H), 4.42(m, 2H), 4.48(s, 1H), 7.10(s, 1H), 7.39(s, 1H), 7.94(s, 1H), 8.09(s, 1H), 8.17(m, 1H), 8.31(s, 1H), 8.69(s, 1H), 11.00(s, 1H) LC-MS (ESI, m / z) = 476.1 (M+H + ). Example 22. 2-Fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0124] [ka]

[0125] [Step 4] Preparation of 2-fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (Compound 22) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.11 g, 0.36 mmol) was mixed with 2-fluoro-3-nitrobenzoic acid (90 mg, 0.542 mmol), dimethylformamide (5 mL), EDC·HCl (207 mg, 1.08 mmol), and HOBt·H2O (146 mg, 1.08 mmol). The mixture was reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (77 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.99(t, 2H), 2.88(m, 4H), 3.77(m, 4H), 4.42(t, 2H), 4.44(s, 1H), 7.43(s, 1H), 7.59(t, 1H), 8.23(t, 1H), 8.29-8.32(m, 2H), 8.53(s, 1H), 10.03(s, 1H) LC-MS (ESI, m / z) = 472.5 (M+H + ). Example 23. 4-amino-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0126] [ka]

[0127] [Step 4] Preparation of 4-amino-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (Compound 23) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.11 g, 0.36 mmol) was mixed with 4-amino-3-nitrobenzoic acid (99 mg, 0.542 mmol), dimethylformamide (5 mL), EDC·HCl (207 mg, 1.08 mmol), and HOBt·H2O (146 mg, 1.08 mmol). The mixture was reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (23 mg). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 1.98(t, 2H), 2.88(m, 4H), 3.81(m, 4H), 4.40(t, 2H), 4.47(s, 1H), 7.11(d, 1H), 7.40(s, 1H), 7.87(s, 2H), 7.92(d, 1H), 8.28(s, 1H), 8.39(s, 1H), 8.59(s, 1H), 9.69(s, 1H) LC-MS (ESI, m / z) = 469.5 (M+H + ). Example 24. 3-Fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-5-nitrobenzamide

[0128] [ka]

[0129] [Step 4] Preparation of 3-fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-5-nitrobenzamide (Compound 24) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.11 g, 0.36 mmol) was mixed with 3-fluoro-5-nitrobenzoic acid (100 mg, 0.542 mmol), dimethylformamide (5 mL), EDC·HCl (207 mg, 1.08 mmol), and HOBt·H2O (146 mg, 1.08 mmol). The mixture was reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (23 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.91(t, 2H), 2.89(m, 4H), 3.76(m, 4H), 4.41(t, 2H), 4.48(s, 1H), 7.38(s, 1H), 8.22(d, 1H), 8.26(s, 1H), 8.32(s, 1H), 8.36(d, 1H), 8.57(s, 1H), 10.04(s, 1H) LC-MS (ESI, m / z) = 472.5 (M+H + ). Example 25. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)isophthalamide

[0130] [ka]

[0131] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)isophthalamide (Compound 25) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.189 g, 0.62 mmol) was mixed with 3-carbamoylbenzoic acid (154 mg, 0.93 mmol), dimethylformamide (5 mL), EDC·HCl (357 mg, 1.86 mmol), and HOBt·H2O (251 mg, 1.86 mmol). The mixture was reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (74 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.00(t, 2H), 2.88(m, 4H), 3.76(m, 4H), 4.41(t, 2H), 4.47(s, 1H), 7.40(s, 1H), 7.87(t, 1H), 8.19(d, 2H), 8.31(s, 1H), 8.33(m, 2H), 8.41(d, 1H), 8.69(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 452.5 (M+H + ). Example 26. 4-Fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0132] [ka]

[0133] [Step 4] Preparation of 4-fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 26) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.11 g, 0.36 mmol) was mixed with 4-fluoro-3-nitrobenzoic acid (100 mg, 0.542 mmol), dimethylformamide (5 mL), EDC·HCl (207 mg, 1.08 mmol), and HOBt·H2O (146 mg, 1.08 mmol). The mixture was reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (7 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.99(t, 2H), 2.88(m, 4H), 3.76(m, 4H), 4.43(t, 2H), 4.47(s, 1H), 7.38(s, 1H), 7.79(t, 1H), 8.29(s, 1H), 8.31(s, 1H), 8.34(d, 1H), 8.65(d, 1H), 9.95(s, 1H) LC-MS (ESI, m / z) = 472.5 (M+H + ). Example 27. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-(thiazole-2-yl)benzamide

[0134] [ka]

[0135] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-3-(thiazole-2-yl)benzamide (compound 27) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.086 g, 0.283 mmol) was reacted in the same manner with 3-(1,3-thiazole-2-yl)benzoic acid (0.076 g, 0.37 mmol), dichloromethane (8 mL), EDC·HCl (0.081 g, 0.425 mmol), and HOBt·H2O (0.057 g, 0.425 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (47 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.00(m, 2H), 2.91(t, 4H), 3.82(t, 4H), 4.42(m, 2H), 4.48(s, 1H), 7.43(s, 1H), 7.70(t, 1H), 7.86(d, 1H), 7.97(d, 1H), 8.03(d, 1H), 8.16(d, 1H), 8.31(s, 1H), 8.45(s, 1H), 8.51(s, 1H), 9.94(s, 1H) LC-MS (ESI, m / z) = 492.1 (M+H + ). Example 28. N-(1-(3-hydroxy-3-methylbutyl)-6-morpholino-1H-indazole-5-yl)-3-nitrobenzamide

[0136] [ka]

[0137] [Step 2] Production of 2-methyl-4-(6-morpholino-5-nitro-1H-indazole-1-yl)butan-2-ol Under the same conditions as in Step 1 of Example 1, 4-bromo-2-methylbutan-2-ol (1.89 mL, 15.5 mmol), potassium carbonate (5.7 g, 41.32 mmol), potassium iodide (257 mg, 1.55 mmol), and dimethylformamide (10 mL) were added to the compound obtained in Step 1 of Example 2 and reacted in the same manner. After purification and concentration using MPLC (combiFlash NEXTGEN 300+), the title compound (1.8 g) was obtained. 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.99(m, 2H), 2.89(t, 4H), 3.66(t, 4H), 4.47(m, 2H), 4.48(s, 1H), 7.57(s, 1H), 7.86(s, 1H), 8.17(s, 1H) [Step 3] Production of 4-(5-amino-6-morpholino-1H-indazole-1-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (100 mg, 0.3 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (20 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (91 mg). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 1.95(m, 2H), 2.75(t, 4H), 3.48(t, 4H), 4.35(m, 2H), 4.36(s, 1H), 4.50(s, 2H), 7.41(s, 1H), 7.75(s, 1H), 8.05(s, 1H) [Step 4] Preparation of N-(1-(3-hydroxy-3-methylbutyl)-6-morpholino-1H-indazole-5-yl)-3-nitrobenzamide (compound 28) Under the same conditions as in [Step 4] of Example 11, the compound from [Step 3] (91 mg, 0.3 mmol) was reacted in the same manner with 3-nitrobenzoic acid (50 mg, 0.3 mmol), dimethylformamide (10 mL), EDC·HCl (173 mg, 0.9 mmol), and HOBt·H2O (122 mg, 0.9 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (84 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 1.90(t, 2H), 2.80(m, 4H), 3.69(m, 4H), 4.39(t, 2H), 4.42(s, 1H), 7.35(s, 1H), 7.70(m, 1H), 8.20(s, 1H), 8.24(m, 2H), 8.29(m, 1H), 8.60(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 456.5 (M+H + ). Example 29. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0138] [ka]

[0139] [Step 1] Preparation of 2-(1-(5-nitro-1H-indazole-6-yl)piperidine-4-yl)propan-2-ol 6-bromo-5-nitro-1H-indazole (4 g, 16.53 mmol) was mixed with 2-piperidine-4-ylpropan-2-ol (9.47 g, 66.11 mmol) and DMSO (15 mL), and the mixture was stirred at 120°C for 3 days. After the reaction was complete, ethyl acetate (150 mL) was added, the mixture was washed with purified water (150 mL), anhydrous magnesium sulfate was added, and the mixture was filtered. After concentration under reduced pressure, the mixture was purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (2.82 g). 1 H-NMR (DMSO-d 6) 1.06(s, 6H), 1.35(m, 1H), 1.80(m, 2H), 1.97(m, 2H), 2.64(m, 2H), 3.07(d, 2H), 4.11(s, 1H), 7.32(s, 1H), 8.31(s, 1H), 8.55(s, 1H) [Step 2] Preparation of 4-(6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-5-nitro-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in Step 2 of Example 2, the compound obtained in Step 1 (2.8 g, 9.2 mmol), 4-bromo-2-methylbutan-2-ol (1.68 mL, 13.8 mmol), potassium carbonate (5.09 g, 36.8 mmol), potassium iodide (0.28 g, 1.69 mmol), and dimethylformamide (56 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.9 g). 1 H-NMR (DMSO-d 6 ) 1.06(s, 6H), 1.11(s, 6H), 1.35(m, 1H), 1.42(m, 2H), 1.80(m, 2H), 1.97(m, 2H), 2.64(m, 2H), 3.07(d, 2H), 4.11(s, 1H), 4.40(t, 2H), 4.47(s, 1H), 7.29(s, 1H), 8.25(s, 1H), 8.56(s, 1H) [Step 3] Preparation of 4-(5-amino-6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 2, the compound obtained in [Step 2] (900 mg, 2.3 mmol) was dissolved in ethyl acetate (45 mL), palladium on activated carbon (200 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (320 mg). 1 H-NMR (DMSO-d6 ) 1.06(s, 6H), 1.11(s, 6H), 1.35(m, 1H), 1.42(m, 2H), 1.80(m, 2H), 1.97(m, 2H), 2.64(m, 2H), 3.07(d, 2H), 4.11(s, 1H), 4.40(t, 2H), 4.47(s, 1H), 7.29(s, 1H), 7.75(s, 1H), 8.06(s, 1H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 29) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (80 mg, 0.222 mmol), 3-sulfamoylbenzoic acid (54.2 mg, 0.266 mmol), EDC·HCl (64 mg, 0.333 mmol), HOBt·H2O (46 mg, 0.333 mmol), and dichloromethane (5 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (18 mg). 1 H-NMR (DMSO-d 6 ) 1.06(s, 6H), 1.11(s, 6H), 1.35(m, 1H), 1.43(m, 2H), 1.80(m, 2H), 1.99(m, 2H), 2.62-2.67(m, 2H), 3.07(d, 2H), 4.11(s, 1H), 4.41(t, 2H), 4.47(s, 1H), 7.36(s, 1H), 7.46(s, 2H), 7.74(t, 1H), 8.02(d, 1H), 8.12(d, 1H), 8.29(s, 1H), 8.36(s, 1H), 8.44(s, 1H), 9.81(s, 1H) LC-MS (ESI, m / z) = 544.7 (M+H + ). Example 30. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2H-indazole-5-yl)-3-nitrobenzamide

[0140] [ka]

[0141] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidine-1-yl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 30) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 29 (80 mg, 0.222 mmol), 3-nitrobenzoic acid (44.4 mg, 0.266 mmol), EDC·HCl (64 mg, 0.333 mmol), HOBt·H2O (46 mg, 0.333 mmol), and dichloromethane (5 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (28 mg). 1 H-NMR (DMSO-d 6 ) 1.05(s, 6H), 1.12(s, 6H), 1.34-1.37(m, 1H), 1.44-1.46(m, 2H), 1.78-1.81(m, 2H), 1.97-2.00(m, 2H), 2.64(t, 2H), 3.09-3.11(m, 2H), 4.11(s, 1H), 4.41(t, 2H), 4.47(s, 1H), 7.35(s, 1H), 7.83(t, 1H), 8.29(s, 1H), 8.36(d, 1H), 8.39(s, 1H), 8.42(m, 1H), 8.67(s, 1H), 9.94 (s, 1H) LC-MS (ESI, m / z) = 510.6 (M+H + ). Example 31. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidine-1-yl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0142] [ka]

[0143] [Step 2] Preparation of 1-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)piperidine-4-ol Under the same conditions as in Step 1 of Example 29, 4-hydroxypiperidine (9.247 g, 91.4 mmol) and DMSO (5 mL) were added to the compound obtained in Step 1 of Example 4 (3 g, 9.142 mmol) and reacted in the same manner. After purification with MPLC (combiFlash NEXTGEN 300+), the title compound (0.33 g) was obtained. 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.51-1.55(m, 2H), 1.82-1.85(m, 2H), 2.10(t, 2H), 2.65-2.67(m, 2H), 3.23-3.25(m, 2H), 3.52-3.54(m, 1H), 4.40(m, 2H), 4.51(s, 1H), 7.30(s, 1H), 8.30(s, 1H), 8.57(s, 1H) [Step 3] Preparation of 1-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-yl)piperidine-4-ol Under the same conditions as in [Step 3] of Example 2, the compound obtained in [Step 2] (330 mg, 0.947 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (66 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (302 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.40-1.42(m, 2H), 1.68-1.69(m, 2H), 1.89(t, 2H), 2.48-2.53(m, 2H), 3.05-3.08(m, 2H), 3.40-3.44(m, 1H), 4.20(m, 2H), 4.31(s, 1H), 4.44(s, 2H), 7.28(s, 1H), 7.69(s, 1H), 8.02(s, 1H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidine-1-yl)-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 31) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (100 mg, 0.314 mmol), 3-sulfamoylbenzoic acid (95 mg, 0.471 mmol), EDC·HCl (181 mg, 0.942 mmol), HOBt·H2O (127 mg, 0.942 mmol), and dimethylformamide (5 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (21 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.50-1.52(m, 2H), 1.79-1.81(m, 2H), 2.00(t, 2H), 2.60-2.62(m, 2H), 3.20-3.23(m, 2H), 3.52-3.54(m, 1H), 4.43(m, 3H), 7.36(s, 1H), 7.47(s, 2H), 7.74(t, 1H), 8.04(d, 1H), 8.15(d, 1H), 8.21(s, 1H), 8.30(s, 1H), 8.35(s, 1H), 9.79(s, 1H) LC-MS (ESI, m / z) = 502.6 (M+H + ). Example 32. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidine-1-yl)-2H-indazole-5-yl)-3-nitrobenzamide

[0144] [ka]

[0145] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidine-1-yl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 32) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 31 (100 mg, 0.314 mmol), 3-nitrobenzoic acid (79 mg, 0.471 mmol), EDC·HCl (181 mg, 0.942 mmol), HOBt·H2O (127 mg, 0.942 mmol), and dimethylformamide (5 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (28 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.46-1.52(m, 2H), 1.78-1.82(m, 2H), 2.00(t, 2H), 2.60-2.62(m, 2H), 3.19-3.22(m, 2H), 3.51-3.54(m, 1H), 4.41(m, 2H), 4.48(s, 1H), 7.35(s, 1H), 7.83(t, 1H), 8.29(s, 1H), 8.36(d, 1H), 8.38(s, 1H), 8.41(m, 1H), 8.62(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 468.5 (M+H + ). Example 33. N-(2-(3-hydroxy-3-methylbutyl)-6-thiomorpholino-2H-indazole-5-yl)isophthalamide

[0146] [ka]

[0147] [Step 2] Production of 2-methyl-4-(5-nitro-6-thiomorpholino-2H-indazole-2-yl)butan-2-ol The compound obtained in [Step 1] of Example 4 (2 g, 6.09 mmol) was mixed with thiomorpholine (10 mL), DIPEA (3.1 mL, 18.28 mmol), and DMSO (10 mL), and stirred at 100°C for 7 days. After the reaction was complete, ethyl acetate (50 mL) was added, washed with purified water (50 mL), and filtered with anhydrous magnesium sulfate. After concentration under reduced pressure, the mixture was purified with MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (670 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.00(t, 2H), 2.59(m, 4H), 3.41(m, 4H), 4.41(t, 2H), 4.47(s, 1H), 7.32(s, 1H), 8.31(s, 1H), 8.57(s, 1H) [Step 3] Production of 4-(5-amino-6-thiomorpholino-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (670 mg, 1.91 mmol) was dissolved in ethyl acetate (10 mL) and hydrogenated with palladium (101 mg, 0.15 w / w) on activated carbon. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (613 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.00(t, 2H), 2.41(m, 4H), 3.29(m, 4H), 4.29(t, 2H), 4.40(s, 1H), 4.52(s, 2H), 7.29(s, 1H), 7.75(s, 1H), 8.05(s, 1H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-thiomorpholino-2H-indazole-5-yl)isophthalamide (compound 33) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (0.150 g, 0.468 mmol) was reacted in the same manner with 3-carbamoylbenzoic acid (65 mg, 0.394 mmol), dimethylformamide (5 mL), EDC·HCl (227 mg, 1.18 mmol), and HOBt·H2O (158 mg, 1.169 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (20 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.00(t, 2H), 2.59(m, 4H), 3.41(m, 4H), 4.41(t, 2H), 4.47(s, 1H), 7.40(s, 1H), 7.87(t, 1H), 8.19(d, 2H), 8.35(m, 3H), 8.41(d, 1H), 8.69(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 468.6 (M+H + ). Example 34. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0148] [ka]

[0149] [Step 2] Preparation of 4-(2-(6-(4-fluorophenyl)-5-nitro-2H-indazole-2-yl)ethyl)morpholine Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 19 (1.0 g, 2.82 mmol) was reacted with sodium carbonate (1.49 g, 14.8 mmol), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol), and (4-fluorophenyl)boronic acid (0.59 g, 4.22 mmol) in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.86 g). 1H-NMR (DMSO-d 6 ) 2.40-2.41(br. s, 4H), 2.84(t, 2H), 3.50-3.51(m, 4H), 4.53(t, 2H), 7.39(t, 2H), 7.67(d, 2H), 8.44(s, 1H), 8.52(s, 1H), 8.57(s, 1H) [Step 3] Preparation of 6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (0.8 g, 2.16 mmol) was hydrogenated with ethyl acetate (80 mL) and palladium on activated carbon (0.16 g, 0.2 w / w). The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.61 g). 1 H-NMR (DMSO-d 6 ) 2.35-2.36(br. s, 4H), 2.84(t, 2H), 3.45-3.46(m, 4H), 4.51(s, 2H), 4.53(t, 2H), 7.34(t, 2H), 7.63(d, 2H), 8.40(s, 1H), 8.48(s, 1H), 8.52(s, 1H) [Step 4] Preparation of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 34) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.2 g, 0.59 mmol) was reacted in the same manner with 3-nitrobenzoic acid (99 mg, 0.59 mmol), dimethylformamide (2 mL), HATU (0.45 g, 1.18 mmol), and DIPEA (0.41 mL, 2.35 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.2 g). 1 H-NMR (DMSO-d 6) 2.41(br. S, 4H), 2.83(t, 2H), 3.51(t, 4H), 4.53(t, 2H), 7.32(t, 2H), 7.52(s, 1H), 7.58(t, 2H), 7.78(t, 1H), 8.17(d, 1H), 8.37(d, 1H), 8.43(s, 1H), 8.47(s, 1H), 8.49(s, 1H), 9.63(s, 1H) LC-MS (ESI, m / z) = 490.5 (M+H + ). Example 35. N-(2-(3-hydroxy-3-methylbutyl)-6-(3-(morpholine-4-carbonyl)phenyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0150] [ka]

[0151] [Step 1] Preparation of 3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)benzoic acid Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (1.2 g, 3.66 mmol), sodium carbonate (1.94 g, 18.3 mmol), tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmol), and 3-carboxyphenylboronic acid pinacol ester (1.44 g, 5.48 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.01 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.06(t, 2H), 4.50(s, 1H), 4.51(t, 2H), 7.43(m, 2H), 8.15(s, 2H), 8.27(s, 1H), 8.44(s, 1H), 10.27(s, 1H) [Step 2] Production of (3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)phenyl)(morpholino)methanone Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 1] (0.5 g, 1.66 mmol), morpholine (0.14 g, 1.66 mmol), EDC·HCl (0.48 g, 2.49 mmol), HOBt·H2O (0.34 g, 2.49 mmol), and dichloromethane (2 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (120 mg). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.06(t, 2H), 3.13(t, 4H), 3.59(t, 4H), 4.50(s, 1H), 4.51(t, 2H), 7.43(m, 2H), 8.15(s, 2H), 8.27(s, 1H), 8.44(s, 1H), 10.27(s, 1H) [Step 3] Production of (3-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-yl)phenyl)(morpholino)methanone Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (0.5 g, 1.14 mmol) was dissolved in ethyl acetate (10 mL), and then palladium (0.02 g, 0.2 w / w) on activated carbon was added and hydrogenated. After the reaction, the mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.1 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.06(t, 2H), 3.13(t, 4H), 3.59(t, 4H), 4.50(s, 1H), 4.51(t, 2H), 7.18(s, 2H), 7.44(m, 2H), 8.14(s, 2H), 8.29(s, 1H), 8.44(s, 1H), 10.27(s, 1H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(3-(morpholine-4-carbonyl)phenyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 35) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.4 g, 0.98 mmol), 3-nitrobenzoic acid (0.16 g, 0.98 mmol), dimethylformamide (10 mL), HATU (0.74 g, 1.96 mmol), and DIPEA (0.68 mL, 3.92 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.4 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.06(t, 2H), 3.13(t, 4H), 3.59(t, 4H), 4.50(s, 1H), 4.51(t, 2H), 7.18(s, 1H), 7.44(m, 2H), 7.58(m, 3H), 8.14(s, 2H), 8.29(s, 1H), 8.44(s, 1H), 8.59(s, 1H), 10.27(s, 1H) LC-MS (ESI, m / z) = 558.1 (M+H + ). Example 36. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-6-(thiophen-3-yl)picolinamide

[0152] [ka]

[0153] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazole-5-yl)-6-(thiophen-3-yl)picolinamide (compound 36) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.086 g, 0.283 mmol) was reacted in the same manner with 6-(thiophen-3-yl)picolinic acid (76 mg, 0.37 mmol), dichloromethane (8 mL), EDC·HCl (0.081 g, 0.425 mmol), and HOBt·H2O (0.057 g, 0.425 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (48 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.99(m, 2H), 2.89(t, 4H), 3.76(t, 4H), 4.43(m, 2H), 4.48(s, 1H), 7.40(s, 1H), 7.75(dd, 1H), 7.99(dd, 1H), 8.10(m, 3H), 8.32(s, 1H), 8.39(dd, 1H), 8.69(s, 1H), 11.00(s, 1H) LC-MS (ESI, m / z) = 492.1 (M+H + ). Example 37. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-morpholinophenyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0154] [ka]

[0155] [Step 2] Production of 2-methyl-4-(6-(4-morpholinophenyl)-5-nitro-2H-indazole-2-yl)butan-2-ol Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.61 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.66 g, 2.29 mmol), 1,4-dioxane (20 mL), and purified water (2 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.5 g). 1 H-NMR (DMSO-d 6) 1.13(s, 6H), 2.03(t, 2H), 3.07(t, 4H), 3.68(t, 4H), 4.48(t, 2H), 4.50(s, 1H), 6.91(d, 2H), 7.32(d, 2H), 7.48(s, 1H), 7.75(s, 1H), 8.39(s, 1H) [Step 3] Preparation of 4-(5-amino-6-(4-morpholinophenyl)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (0.5 g, 1.22 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (0.10 g, 0.093 mmol) was added, and the mixture was hydrogenated. The mixture was purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.36 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.03(t, 2H), 3.07(t, 4H), 3.68(t, 4H), 4.48(t, 2H), 4.50(s, 1H), 6.91(d, 2H), 7.32(d, 2H), 7.48(s, 1H), 7.75(s, 1H), 8.39(s, 1H), 8.51(s, 2H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-morpholinophenyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 37) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.4 g, 1.05 mmol) was reacted in the same manner with 3-nitrobenzoic acid (0.18 g, 1.05 mmol), dimethylformamide (5 mL), HATU (0.80 g, 2.10 mmol), and DIPEA (0.73 mL, 4.21 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (30 mg). 1 H-NMR (DMSO-d 6) 1.13(s, 6H), 2.03(t, 2H), 3.07(t, 4H), 3.68(t, 4H), 4.48(t, 2H), 4.50(s, 1H), 6.91(d, 2H), 7.32(d, 2H), 7.48(s, 1H), 7.75(s, 1H), 8.33(t, 2H), 8.39(s, 1H), 8.51(s, 2H), 10.07(s, 1H) LC-MS (ESI, m / z) = 530.4 (M+H + ). Example 38. N-(6-(dimethylamino)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0156] [ka]

[0157] [Step 1] Preparation of N,N-dimethyl-5-nitro-1H-indazole-6-amine 6-bromo-5-nitro-1H-indazole (5 g, 20.66 mmol) was mixed with dimethylformamide (20 mL) and potassium iodide (500 mg, 3.012 mmol) and stirred at 120°C for 3 days. After the reaction was complete, ethyl acetate (200 mL) was added, washed with purified water (200 mL), and filtered after adding anhydrous magnesium sulfate. After concentration under reduced pressure, the mixture was purified with MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (2.12 g) as an orange solid. 1 H-NMR (DMSO-d 6 ) 2.74(s, 6H), 7.20(s 1H), 8.14(s, 1H), 8.32(s, 1H) [Step 2] Preparation of 4-(6-(dimethylamino)-5-nitro-2H-indazole-2-yl)-2-methylbutan-2-ol To the compound obtained in [Step 1] (2.12 g, 10.28 mmol), 4-bromo-2-methylbutan-2-ol (1.874 mL, 15.42 mmol), potassium carbonate (5.68 g, 41.12 mmol), potassium iodide (212 mg, 1.277 mmol), and dimethylformamide (20 mL) were added, and the mixture was stirred at 90°C for 5 hours. After the reaction was complete, ethyl acetate (50 mL) was added, the mixture was washed with purified water (50 mL), anhydrous magnesium sulfate was added, and the mixture was filtered. After concentration under reduced pressure, the mixture was purified with MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.3 g) as an orange solid. 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 1.99(m, 2H), 2.67(s, 6H), 4.47(t, 2H), 4.48(s, 1H), 7.30(s, 1H), 8.29(s, 1H), 8.54(s, 1H) [Step 3] Production of 4-(5-amino-6-(dimethylamino)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 2, the compound obtained in [Step 2] (100 mg, 0.342 mmol) was added to palladium on activated carbon (20 mg, 10 w / w), dichloromethane (20 mL), and ethyl acetate (20 mL), and hydrogenated in the same manner. The reaction mixture was filtered using Celite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the title compound (90 mg). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 1.95(m, 2H), 2.54(s, 6H), 4.35(m, 2H), 4.36(s, 1H), 4.40(s, 2H), 7.29(s, 1H), 7.75(s, 1H), 8.05(s, 1H) [Step 4] Preparation of N-(6-(dimethylamino)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 38) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (90 mg, 0.342 mmol), 3-nitrobenzoic acid (68.6 mg, 0.41 mmol), EDC·HCl (98 mg, 0.513 mmol), HOBt·H2O (69 mg, 0.513 mmol), and dichloromethane (5 mL) were reacted in the same manner. Then, dichloromethane (20 mL) was added and the mixture was washed with purified water (20 mL). Anhydrous magnesium sulfate was added, the mixture was filtered and concentrated under reduced pressure, then methanol (1.5 mL) was added, and the resulting solid was filtered to obtain the title compound (47 mg). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 1.98(t, 2H), 2.67(s, 6H), 4.41(m, 2H), 4.48(s, 1H), 7.27(s, 1H), 7.83(t, 1H), 8.17(s, 1H), 8.27(s, 1H), 8.35(d, 1H), 8.41(d, 1H), 8.70(s, 1H), 9.91(s, 1H) LC-MS (ESI, m / z) = 412.3 (M+H + ). Example 39. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(morpholinomethyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0158] [ka]

[0159] [Step 2] Production of 2-methyl-4-(5-nitro-6-(4-(trifluoromethyl)phenyl)-2H-indazole-2-yl)butan-2-ol Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (1.0 g, 3.05 mmol), sodium carbonate (1.61 g, 15.24 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)morpholine (1.39, 4.57 mmol), 1,4-dioxane (10 mL), and purified water (1 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.10 g). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02(t, 2H), 3.61(br. s, 4H), 3.50(t, 4H), 3.61(s, 2H), 4.48-5.10(m, 3H), 7.49-7.50(d, 2H), 8.12(dt, 1H), 8.44(d, 2H), 8.46(s, 1H), 8.66(s, 1H) [Step 3] Preparation of 4-(5-amino-6-(4-(trifluoromethyl)phenyl)-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (1.0 g, 2.36 mmol) was dissolved in ethyl acetate (20 mL), palladium on activated carbon (0.2 g, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.72 g). 1 H-NMR (DMSO-d 6 ) 1.06(s, 6H), 1.96(t, 2H), 3.55(br. s, 4H), 3.44(t, 4H), 3.55(s, 2H), 4.42-5.04(m, 3H), 4.56(s, 2H), 7.43-7.54(d, 2H), 8.06(dt, 1H), 8.38(d, 2H), 8.40(s, 1H), 8.61(s, 1H) [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(morpholinomethyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 39) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.11 g, 0.28 mmol), 3-sulfamoylbenzoic acid (0.06 g, 0.28 mmol), HATU (0.21 g, 0.56 mmol), and DIPEA (0.19 mL, 1.12 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.13 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.05(t, 2H), 2.28(br. s, 4H), 3.48(br. s, 4H), 3.62(s, 2H), 4.47-4.51(m, 3H), 7.13(d, 2H), 7.28(d, 2H), 7.40(br. s, 2H), 7.49(s, 1H), 7.61(t, 1H), 7.72(s, 1H), 7.91(d, 2H), 8.20(s, 1H), 8.40(s, 1H), 9.97(s, 1H) LC-MS (ESI, m / z) = 578.1 (M+H + ). Example 40. N-(2-(3-hydroxy-3-methylbutyl)-6-thiomorpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0160] [ka]

[0161] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-thiomorpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 40) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] of Example 33 (0.150 g, 0.468 mmol) was reacted in the same manner with 3-nitrobenzoic acid (65 mg, 0.389 mmol), dimethylformamide (5 mL), EDC·HCl (224 mg, 1.17 mmol), and HOBt·H2O (158 mg, 1.169 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (14 mg). 1 H-NMR (DMSO-d 6 ) 1.12(d, 6H), 2.00(t, 2H), 2.59(m, 4H), 3.42(m, 4H), 4.41(t, 2H), 4.47(s, 1H), 7.20(s, 1H), 7.76(m, 1H), 8.33(s, 1H), 8.35(m, 2H), 8.37(m, 1H), 8.74(s, 1H), 10.05(s, 1H) LC-MS (ESI, m / z) = 470.6 (M+H + ). Example 41. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2-(methylamino)-2-oxoethyl)carbamoyl)phenyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0162] [ka]

[0163] [Step 2] Preparation of Methyl (4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)benzoyl)glycinate Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (1.9 g, 5.79 mmol), sodium carbonate (3.07 g, 28.9 mmol), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol), (4-((2-methoxy-2-oxoethyl)carbamoyl)phenyl)boronic acid (2.06 g, 8.68 mmol), 1,4-dioxane (20 mL), and purified water (2 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.84 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.03-2.05(m, 2H), 3.64(s, 3H), 4.38(d, 2H), 4.53-4.57(m, 3H), 7.45(s, 1H), 7.56(s, 1H), 7.88(d, 2H), 7.99(s, 1H), 8.62(s, 1H), 8.78(s, 1H), 9.00(t, 1H) [Step 3] Preparation of Methyl (4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-yl)benzoyl) Glycinate Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (1.5 g, 3.41 mmol) was hydrogenated with palladium (0.3 g, 0.2 w / w) on activated carbon and ethyl acetate (20 mL). The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (1.92 g). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 2.01-2.03(m, 2H), 3.62(s, 3H), 4.35(d, 2H), 4.45(s, 2H), 4.51-4.55(m, 3H), 7.42(s, 1H), 7.45(s, 1H), 7.85(d, 2H), 7.96(s, 1H), 8.58(s, 1H), 8.74(s, 1H), 8.96(t, 1H) [Step 4] Preparation of Methyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(3-nitrobenzamide)-2H-indazole-6-yl)benzoyl)glycinate Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (1.5 g, 3.65 mmol) was reacted in the same manner with 3-nitrobenzoic acid (0.67 g, 3.65 mmol), dichloromethane (15 mL), EDC·HCl (1.05 g, 5.48 mmol), and HOBt·H2O (0.74 g, 5.48 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.60 g). 1 H-NMR (DMSO-d 6 ) 1.11(s, 6H), 2.03(t, 2H), 3.88(d, 2H), 4.49-4.50(m, 3H), 7.52(d, 2H), 7.75(m, 2H), 7.81(d, 2H), 8.18(d, 1H), 8.35(d, 1H), 8.48(s, 1H), 8.51(s, 1H), 8.60(t, 1H), 10.01(s, 1H) [Step 5] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2-(methylamino)-2-oxoethyl)carbamoyl)phenyl)-2H-indazole-5-yl)-3-nitrobenzamide (Compound 41) The compound obtained in [Step 4] (0.1 g, 0.17 mmol) was mixed with 10 ml of a 40% N-methylamine in methanol solution, stirred at 120°C for 6 hours, then concentrated and purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.25 g). 1 H-NMR (DMSO-d 6) 1.13(s, 6H), 2.03-2.05(m, 2H), 2.64(d, 3H), 4.38(d, 2H), 4.53-4.57(m, 3H), 7.45(s, 1H), 7.59(s, 1H), 7.73-7.74(m, 2H), 7.82(d, 2H), 7.99(d, 1H), 8.62(d, 1H), 8.57-8.58(m, 2H), 8.78(s, 1H), 9.01(t, 1H), 9.79(s, 1H) LC-MS (ESI, m / z) = 559.0 (M+H + ). Example 42. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0164] [ka]

[0165] [Step 2] Preparation of methyl 4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)benzoate Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (1.9 g, 5.79 mmol), sodium carbonate (3.07 g, 28.9 mmol), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol), and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.28 g, 8.68 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.61 g). 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02-2.04(m, 2H), 3.84(s, 3H), 4.53-4.55(m, 2H), 4.62(s, 1H), 7.46(s, 1H), 7.48(s, 1H), 7.66(s, 1H), 7.97(s, 1H), 7.98(s, 1H), 8.62(s, 1H), 8.75(s, 1H) [Step 3] Preparation of methyl 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-yl)benzoate Under the same conditions as in [Step 3] of Example 2, the compound obtained in [Step 2] (1.5 g, 3.91 mmol) was dissolved in ethyl acetate (30 mL) and hydrogenated with palladium (0.3 g, 0.2 w / w) on activated carbon. The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (1.18 g). 1 H-NMR (DMSO-d 6 ) 1.07(s, 6H), 1.97-1.99(m, 2H), 3.79(s, 3H), 4.48-4.52(m, 4H), 4.57(s, 1H), 7.41(s, 1H), 7.42(d, 1H), 7.62(s, 1H), 7.91(t, 1H), 7.92(s, 1H), 8.56(s, 1H), 8.69(s, 1H) [Step 4] Preparation of methyl 4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)benzoate Under the same conditions as in [Step 4] of Example 11, 3.11 mL of 3-sulfamoylbenzoic acid (0.68 g, 3.11 mmol), dichloromethane (11 mL), EDC·HCl (0.90 g, 4.67 mmol), and HOBt·H2O (0.63 g, 4.67 mmol) were added to the compound obtained in [Step 3] (1.1 g, 3.11 mmol) and reacted under the same conditions. After purification and concentration using MPLC (combiFlash NEXTGEN 300+), the mixture was dried to obtain the title compound (1.2 g). 1 H-NMR (DMSO-d 6) 1.12(s, 6H), 2.02-2.04(m, 2H), 3.84(s, 3H), 4.53-4.55(m, 2H), 4.62(s, 1H), 7.46(s, 1H), 7.48(d, 1H), 7.66(s, 1H), 7.72(t, 1H), 7.82(d, 2H), 7.87(d, 1H), 7.91(s, 1H), 7.97(d, 1H), 7.98(s, 1H), 8.37(s, 1H), 8.62(s, 1H), 8.75(s, 1H) [Step 5] Preparation of 4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)benzoic acid To the compound obtained in [Step 4] (1.1 g, 2.05 mmol), tetrahydrofuran (22 mL) and 2N sodium hydroxide aqueous solution (11 mL) were added and the mixture was stirred at room temperature for at least 3 hours. After the reaction was completed, 2N hydrochloric acid aqueous solution was added to adjust the pH to 4-5, and the mixture was concentrated. After filtration, washing with purified water, and drying, the title compound (0.81 g) was obtained. 1 H-NMR (DMSO-d 6 ) 1.12(s, 6H), 2.02-2.04(m, 2H), 4.53-4.55(m, 2H), 4.62(s, 1H), 7.46(s, 1H), 7.48(d, 1H), 7.66(s, 1H), 7.72(t, 1H), 7.82(d, 2H), 7.87(d, 1H), 7.91(s, 1H), 7.97(d, 1H), 7.98(s, 1H), 8.37(s, 1H), 8.62(s, 1H), 8.75(s, 1H), 10.2(s, 1H) [Step 6] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 42) Under the same conditions as in [Step 4] of Example 11, 2,2,2-trifluoroethane-1-amine (0.04g, 0.40mmole), dichloromethane (2mL), EDC·HCl (0.12g, 0.61mmole), and HOBt·H2O (0.08g, 0.61mmole) were added to the compound obtained in [Step 5] (0.2g, 0.40mmole) and reacted in the same manner. After purification and concentration using MPLC (combiFlash NEXTGEN 300+), the mixture was dried to obtain the title compound (0.16g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.04-2.05(m, 2H), 3.26(s, 2H), 4.01-4.04(m, 2H), 4.50-4.53(m, 3H), 7.40(s, 1H), 7.56(d, 1H), 7.59(s, 1H), 7.62(t, 1H), 7.72(s, 1H), 7.82(d, 2H), 7.91(t, 2H), 8.21(s, 1H), 8.44(s, 1H), 9.00(t, 1H), 10.20(s, 1H) LC-MS (ESI, m / z) = 604.0 (M+H + ). Example 43. N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide

[0166] [ka]

[0167] [Step 5] Preparation of 4-(2-(3-hydroxy-3-methylbutyl)-5-(3-nitrobenzamide)-2H-indazole-6-yl)benzoic acid The compound obtained in [Step 4] of Example 41 (0.5 g, 1 mmol), tetrahydrofuran (10 mL), and 2N sodium hydroxide aqueous solution (5 mL) were added and stirred at room temperature for 3 hours. After the reaction was complete, 2N hydrochloric acid aqueous solution was added to adjust the pH to 4-5, and the mixture was concentrated. After filtration, washing with purified water, and drying, the title compound (0.3 g) was obtained. 1H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.03(m, 2H), 4.50-4.53(m, 3H), 6.97(s, 1H), 7.32(s, 1H), 7.56(d, 2H), 7.59(s, 1H), 7.83(d, 2H), 8.16(d, 1H), 8.36(d, 1H), 8.45(s, 1H), 8.59(m, 2H), 10.29(s, 1H), 12.1(s, 1H) [Step 6] Preparation of N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 43) Under the same conditions as in [Step 4] of Example 11, glycinamide hydrochloride (0.06 g, 0.51 mmol), dichloromethane (3 ml), EDC·HCl (0.15 g, 0.76 mmol), and HOBt·H2O (0.1 g, 0.76 mmol) were added to the compound obtained in [Step 5] (0.3 g, 0.42 mmol) and reacted in the same manner. After that, the mixture was purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.2 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.04-2.06(m, 2H), 3.75(d, 2H), 4.50-4.53(m, 3H), 6.97(s, 1H), 7.30(s, 1H), 7.54(d, 2H), 7.59(s, 1H), 7.74(d, 2H), 7.82(d, 2H), 8.16(d, 1H), 8.36(d, 1H), 8.45(s, 1H), 8.56-8.58(m, 2H), 10.29(s, 1H) LC-MS (ESI, m / z) = 545.6 (M+H + ). Example 44. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(methoxycarbamoyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0168] [ka]

[0169] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(methoxycarbamoyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 44) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 5] of Example 42 (0.2 g, 0.40 mmol) was mixed with hydroxyamine-O-sulfonic acid (0.05 g, 0.40 mmol), dichloromethane (2 mL), EDC·HCl (0.12 g, 0.61 mmol), and HOBt·H2O (0.08 g, 0.61 mmol). The mixture was reacted in the same manner, then purified and concentrated using MPLC (combiFlash NEXTGEN 300+), and dried to obtain the title compound (0.12 g). 1 H-NMR (DMSO-d 6 ) 1.14(s, 6H), 2.03(t, 2H), 3.61(s, 3H), 4.49-4.50(m, 3H), 7.36-7.40(m, 5H), 7.50-7.53(m, 2H), 7.70(s, 1H), 7.92-7.98(m, 3H), 8.24(s, 1H), 8.40(s, 1H), 9.60(s, 1H), 9.99(s, 1H) LC-MS (ESI, m / z) = 552.0 (M+H + ). Example 45. N-(2-(2-hydroxy-2-methylpropyl)-6-thiomorpholino-2H-indazole-5-yl)-3-nitrobenzamide

[0170] [ka]

[0171] [Step 1] Preparation of 4-(5-nitro-1H-indazole-6-yl)thiomorpholine Under the same conditions as in [Step 2] of Example 33, 6-bromo-5-nitro-1H-indazole (2.9 g, 12 mmol) was mixed with thiomorpholine (20 mL), DIPEA (6.2 mL, 36.56 mmol), and DMSO (20 mL). The reaction was carried out in the same manner, and then purified with MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.34 g). 1 H-NMR (DMSO-d 6 ) 2.57(t, 4H), 3.37(t, 4H), 7.20(s 1H), 8.12(s, 1H), 8.30(s, 1H) [Step 2] Production of 2-methyl-1-(5-nitro-6-thiomorpholino-2H-indazole-2-yl)propan-2-ol Under the same conditions as in [Step 1] of Example 1, the compound obtained in [Step 1] (1 g, 3.78 mmol), potassium carbonate (2.1 g, 15.12 mmol), potassium iodide (0.1 g, 0.6 mmol), 1-chloro-2-methyl-2-propanol (0.5 mL, 5.67 mmol), and dimethylformamide (50 mL) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.32 g). 1 H-NMR (DMSO-d 6 ) 1.08(s, 6H), 2.51(m, 4H), 3.38(m, 4H), 4.23(t, 2H), 4.72(s, 1H), 7.32(s, 1H), 8.30(s, 1H), 8.54(s, 1H) [Step 3] Production of 1-(5-amino-6-thiomorpholino-2H-indazole-2-yl)-2-methylpropane-2-ol Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (320 mg, 0.95 mmol) was dissolved in ethyl acetate (20 mL) and hydrogenated with palladium (64 mg, 0.2 w / w) on activated carbon. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (291 mg). 1 H-NMR (DMSO-d 6 ) 1.08(s, 6H), 2.47(m, 4H), 3.28(m, 4H), 4.19(t, 2H), 4.62(s, 1H), 4.66(s, 2H), 7.29(s, 1H), 7.72(s, 1H), 8.04(s, 1H) [Step 4] Preparation of N-(2-(2-hydroxy-2-methylpropyl)-6-thiomorpholino-2H-indazole-5-yl)-3-nitrobenzamide (compound 45) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (97 mg, 0.317 mmol) was reacted in the same manner with 3-nitrobenzoic acid (43 mg, 0.257 mmol), dimethylformamide (10 mL), EDC·HCl (165 mg, 0.95 mmol), and HOBt·H2O (116 mg, 0.95 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (20 mg). 1 H-NMR (DMSO-d 6 ) 1.10(s, 6H), 2.59(m, 4H), 3.42(m, 4H), 4.31(t, 2H), 4.82(s, 1H), 7.18(s, 1H), 7.73(m, 1H), 8.30(s, 1H), 8.31(m, 2H), 8.37(m, 1H), 8.74(s, 1H), 10.05(s, 1H) LC-MS (ESI, m / z) = 456.5 (M+H + ). Example 46. N-(6-(4-carbamoylphenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0172] [ka]

[0173] [Step 6] Preparation of N-(6-(4-carbamoylphenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 46) The compound obtained in [Step 5] of Example 42 (0.2 g, 0.40 mmol) was mixed with 7N ammonia in methanol solution (20 mL) and stirred at 120°C for more than 24 hours. After the reaction was complete, the mixture was cooled and concentrated, then purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.08 g). 1 H-NMR (DMSO-d 6 ) 1.14(s, 6H), 2.03(t, 2H), 4.50-4.52(m, 3H), 7.29(s, 1H), 7.40(s, 2H), 7.52(d, 2H), 7.58(s, 1H), 7.63(t, 1H), 7.72(s, 1H), 7.81(d, 2H), 7.89(s, 1H), 7.93(d, 2H), 8.21(s, 1H), 8.44(s, 1H), 10.10(s, 1H) LC-MS (ESI, m / z) = 522.0 (M+H+). Example 47. Ethyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)benzoyl)-D-valinate

[0174] [ka]

[0175] [Step 6] Preparation of ethyl(4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)benzoyl)-D-valinate (Compound 47) The compound obtained in [Step 5] of Example 42 (0.2 g, 0.40 mmol) was mixed with L-valine ethyl ester hydrochloride (0.02 g, 0.40 mmol), dichloromethane (2 mL), EDC·HCl (0.12 g, 0.61 mmol), and HOBt·H2O (0.08 g, 0.61 mmol), and reacted in the same manner. After purification using MPLC (combiFlash NEXTGEN 300+), the mixture was concentrated and dried to obtain the title compound (0.11 g). 1 H-NMR (DMSO-d 6) 0.90(d, 3H), 0.93(d, 3H), 1.13-1.15(m, 9H), 2.04-2.05(t, 2H), 2.12-2.16(m, 1H), 4.45-4.49(m, 5H), 4.62-4.64(m, 1H), 7.40(s, 2H), 7.54(d, 2H), 7.58(s, 1H), 7.73(s, 1H), 7.83(d, 2H), 7.90(d, 2H), 7.96(d, 1H), 8.23(s, 1H), 8.44(s, 1H), 8.48(d, 1H), 10.10(s, 1H) LC-MS (ESI, m / z) = 650.0 (M+H+). Example 48. Methyl 3-(5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)nicotinamide)propanoate

[0176] [ka]

[0177] [Step 2] Preparation of methyl 5-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)nicotinate Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.61 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), 4-methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.60 g, 2.29 mmol), 1,4-dioxane (10 mL), and purified water (1 mL) were reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.5 g). 1 H-NMR (DMSO-d 6) 1.14(s, 6H), 2.04(t, 2H), 3,73(s, 3H), 4.50-4.54(m, 3H), 7.72(s, 1H), 8.15(s, 1H), 8.21(d, 1H), 8.37(s, 1H), 8.48(s, 1H), 8.68(d, 1H) [Step 3] Preparation of methyl 5-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-yl)nicotinate Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (0.5 g, 1.30 mmol) was dissolved in ethyl acetate (10 mL), palladium on activated carbon (0.10 g, 0.093 mmol) was added, and the mixture was hydrogenated. The mixture was purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.4 g). 1 H-NMR (DMSO-d 6 ) 1.09(s, 6H), 1.99(t, 2H), 3,68(s, 3H), 4.45-4.50(m, 3H), 4.59(s, 2H), 7.68(s, 1H), 8.10(s, 1H), 8.16(d, 1H), 8.32(s, 1H), 8.42(s, 1H), 8.62(d, 1H) [Step 4] Preparation of Methyl 5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)nicotinate Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.4 g, 1.13 mmol), 3-sulfamoylbenzoic acid (0.23 g, 1.13 mmol), dimethylformamide (20 mL), HATU (0.86 g, 2.26 mmol), and DIPEA (0.79 mL, 4.51 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (210 mg). 1 H-NMR (DMSO-d 6) 1.14(s, 6H), 2.04(t, 2H), 3,73(s, 3H), 4.50-4.54(m, 3H), 7.72(s, 1H), 7.78(t, 1H), 7.82(s, 2H), 8.02(d, 1H), 8.15(s, 1H), 8.34(s, 1H), 8.37(s, 1H), 8.39(s, 1H), 8.48(s, 1H), 8.68(d, 1H), 8.94(s, 1H), 9.94(s, 1H) [Step 5] Preparation of 5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)nicotinic acid The compound obtained in [Step 4] (0.5 g, 0.93 mmol) was dissolved in tetrahydrofuran (5 mL), methanol (2.5 mL), and purified water (2.5 mL), and potassium hydroxide (0.21 g, 3.74 mmol) was added. The mixture was stirred at 60°C for 3 hours. After the reaction was complete, the mixture was cooled to room temperature and concentrated under reduced pressure. Distilled water (10 mL) was added, and the mixture was washed with ethyl acetate (10 mL). The pH of the aqueous layer was adjusted to 4 using 1N hydrochloric acid, and the precipitated solid was filtered and dried to obtain the title compound (0.4 g). 1 H-NMR (DMSO-d 6 ) 1.14(s, 6H), 2.04(t, 2H), 4.50-4.54(m, 3H), 7.72(s, 1H), 7.78(t, 1H), 7.82 (s, 2H), 8.02(d, 1H), 8.15(s, 1H), 8.34(s, 1H), 8.37(s, 1H), 8.39(s, 1H), 8.48(s, 1H), 8.68(d, 1H), 8.94(s, 1H), 9.94(s, 1H), 10.21(s, 1H) [Step 6] Preparation of methyl 3-(5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)nicotinamide)propanoate (Compound 48) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 5] (0.4 g, 0.76 mmol) was mixed with methyl 3-aminopropanoate hydrochloride (0.11 g, 0.76 mmol), dimethylformamide (10 mL), HATU (0.58 g, 1.53 mmol), and DIPEA (0.53 mL, 3.06 mmol) and reacted in the same manner. After purification with MPLC (combiFlash NEXTGEN 300+), the title compound (0.4 g) was obtained. 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.06(t, 2H), 2.64(t, 2H), 2.85(t, 2H), 3.56(s, 3H), 4.50(s, 1H), 4.53(t, 2H), 7.39(d, 2H), 7.70(s, 1H), 7.74(s, 1H), 7.93(d, 2H), 7.97(s, 1H), 8.15(s, 1H), 8.27(s, 1H), 8.46(s, 1H), 8.68(s, 1H), 8.73(d, 1H), 8.82(d, 1H), 10.35(s, 1H) LC-MS (ESI, m / z) = 609.4 (M+H + ). Example 49. N-(6-(4-((furan-3-ylmethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)isophthalamide

[0178] [ka]

[0179] [Step 2] Preparation of N-(furan-3-ylmethyl)-4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazole-6-yl)benzamide Under the same conditions as in Step 2 of Example 1, the compound obtained in Step 1 of Example 4 (1.0 g, 3.05 mmol), sodium carbonate (1.61 g, 15.24 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol), and N-(furan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.5 g, 4.57 mmol) were reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.18 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.03(t, 2H), 4.48-4.53(m, 5H), 6.27(d, 1H), 6.36(d, 1H), 7.23(s, 1H), 8.37(s, 1H), 8.45(s, 1H), 8.71(s, 1H), 9.13 (t, 1H) [Step 3] Preparation of 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazole-6-yl)-N-(furan-3-ylmethyl)benzamide Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (1.0 g, 2.23 mmol) was hydrogenated with palladium (0.2 g, 0.2 w / w) on activated carbon and ethyl acetate (20 mL). The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.77 g). 1 H-NMR (DMSO-d 6 ) 1.07(s, 6H), 1.97(t, 2H), 4.42-4.48(m, 5H), 4.56 (s, 2H), 6.21(d, 1H), 6.30(d, 1H), 7.17(s, 1H), 8.30(s, 1H), 8.38(s, 1H), 8.63(s, 1H), 9.07(t, 1H) [Step 4] Preparation of N-(6-(4-((furan-3-ylmethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole-5-yl)isophthalamide (compound 49) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] (0.20 g, 0.48 mmol) was reacted in the same manner with 3-carbamoylbenzoic acid (0.08 g, 0.48 mmol), dimethylformamide (2 mL), HATU (0.36 g, 0.96 mmol), and DIPEA (0.33 mL, 1.91 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.2 g). 1 H-NMR (DMSO-d 6 ) 1.13(s, 6H), 2.04(m, 2H), 4.41(d, 2H), 4.47-4.50(m, 3H), 5.72(s, 1H), 6.21(d, 1H), 6.34(s, 1H), 7.40(s, 1H), 7.48(t, 1H), 7.52(d, 2H), 7.54(s, 1H), 7.57(s, 1H), 7.72(s, 1H), 7.82-7.88(m, 2H), 7.98(d, 1H), 8.00(s, 1H), 8.27(s, 1H), 8.43(s, 1H), 8.89(t, 1H), 9.96 (s, 1H) LC-MS (ESI, m / z) = 566.1 (M+H + ). Example 50. N-(2-(2-hydroxy-2-methylpropyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-3-nitrobenzamide

[0180] [ka]

[0181] [Step 1] Preparation of 1-(6-bromo-5-nitro-2H-indazole-2-yl)-2-methylpropane-2-ol 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol) was mixed with dimethylformamide (20 mL), potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 1-chloro-2-methylpropan-2-ol (1.312 g, 12.39 mmol), and stirred at 100°C for 5 hours. After the reaction, ethyl acetate (50 mL) was added and the mixture was washed with purified water. After drying over magnesium sulfate and filtering, the filtrate was concentrated and purified using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.16 g). 1 H-NMR (DMSO-d 6 ) 1.09(s, 6H), 4.32(s, 2H), 4.85(s, 1H), 7.81(s, 1H), 7.82(s, 1H), 8.60(s, 1H) [Step 2] Production of 2-methyl-1-(5-nitro-6-(thiophen-3-yl)-2H-indazole-2-yl)propan-2-ol Under the same conditions as in Step 2 of Example 1, sodium carbonate (1.72 g, 16.23 mmol), tetrakis(triphenylphosphine)palladium (0.19 g, 0.16 mmol), 4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxoborane (1.02 g, 4.875 mmol), 1,4-dioxane (15 mL), and purified water (1.5 mL) were added to the compound obtained in Step 1 (1.02 g, 3.25 mmol), and the mixture was reacted in the same manner. After that, the mixture was purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.79 g). 1 H-NMR (DMSO-d 6 ) 1.09(s, 6H), 4.32(s, 2H), 4.85(s, 1H), 7.40(d, 1H), 7.60(s, 1H), 7.81(s, 1H), 7.82(s, 1H), 7.91(s, 1H), 8.60(s, 1H) [Step 3] Production of 1-(5-amino-6-(thiophen-3-yl)-2H-indazole-2-yl)-2-methylpropane-2-ol Under the same conditions as in [Step 3] of Example 2, the compound obtained in [Step 2] (0.36 g, 2 mmol) was dissolved in ethyl acetate (5 mL), and then palladium (0.128 g, 0.11 mmol) on activated carbon was added and hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated to obtain the title compound (0.26 g). 1 H-NMR (DMSO-d 6 ) 1.09(s, 6H), 4.32(s, 2H), 4.80(s, 2H), 4.85(s, 1H), 7.22(s, 1H), 7.40(d, 1H), 7.42(s, 1H), 7.60(s, 1H), 7.81(s, 1H), 7.91(s, 1H) [Step 4] Preparation of N-(2-(2-hydroxy-2-methylpropyl)-6-(thiophen-3-yl)-2H-indazole-5-yl)-3-nitrobenzamide (compound 50) Under the same conditions as in [Step 4] of Example 1, 3-nitrobenzoic acid (0.23 g, 1.39 mmol), dimethylformamide (10 mL), HATU (1.06 g, 2.78 mmol), and DIPEA (0.97 mL, 5.57 mmol) were added to the compound obtained in [Step 3] (0.4 g, 1.39 mmol) and reacted in the same manner. After purification and concentration using MPLC (combiFlash NEXTGEN 300+), the title compound (0.3 g) was obtained. 1 H-NMR (DMSO-d 6 ) 1.10(s, 6H), 4.34(s, 2H), 4.86(s, 1H), 7.29(d, 1H), 7.50(m, 1H), 7.59(s, 1H), 7.67(s, 1H), 7.76-7.79(m, 2H), 8.24(d, 1H), 8.32(s, 1H), 8.37(d, 1H), 8.62(s, 1H) LC-MS (ESI, m / z) = 437.2 (M+H + ). Example 51. (R)-5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)-N-(1-(methylamino)-1-oxopropan-2-yl)nicotinamide

[0182] [ka]

[0183] [Step 7] Preparation of (R)-5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazole-6-yl)-N-(1-(methylamino)-1-oxopropan-2-yl)nicotinamide (compound 51) Under the same conditions as in [Step 4] of Example 11, (R)-2-amino-N-methylpropanamide (0.13g, 0.94mmole), dichloromethane (5mL), EDC·HCl (0.27g, 1.41mmole), and HOBt·H2O (0.19g, 1.41mmole) were added to the compound obtained in [Step 6] of Example 48 (0.5g, 0.94mmole) and reacted in the same manner. After purification using MPLC (combiFlash NEXTGEN 300+), the mixture was concentrated and dried to obtain the title compound (0.41g). 1 H-NMR (DMSO-d 6 ) 1.14(s, 6H), 1.15(d, 3H), 2.04(t, 2H), 2.65(d, 3H), 4.50-4.54(m, 3H), 4.62-4.65(m, 1H), 7.72(s, 1H), 7.78(t, 1H), 7.82 (s, 2H), 8.02(d, 1H), 8.15(s, 1H), 8.34(s, 1H), 8.37(s, 1H), 8.39(s, 1H), 8.48(s, 1H), 8.68(d, 1H), 8.94(s, 1H), 9.21(d, 1H), 9.46(m, 1H), 9.94 (s, 1H) LC-MS (ESI, m / z) = 608.0 (M+H + ). Example 52. N-(1-(2-(methylsulfonyl)ethyl)-6-morpholino-1H-indazole-5-yl)-3-nitrobenzamide

[0184] [ka]

[0185] [Step 1] Preparation of 6-bromo-1-(2-(methylsulfonyl)ethyl)-5-nitro-1H-indazole Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmol) was mixed with 2-bromoethylmethylsulfone (5.8 g, 31 mmol), potassium carbonate (5.7 g, 41.32 mmol), potassium iodide (257 mg, 1.55 mmol), and dimethylformamide (50 mL). The mixture was reacted in the same manner, and then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (3.5 g). 1 H-NMR (DMSO-d 6 ) 2.90(s, 3H), 3.73(t, 2H), 4.76(t, 2H), 7.92(s, 1H), 8.12(s, 1H), 8.36(s, 1H) [Step 2] Preparation of 4-(2-(2-(methylsulfonyl)ethyl)-5-nitro-2H-indazole-6-yl)morpholine Under the same conditions as in Step 1 of Example 2, morpholine (10 mL) was added to the compound obtained in Step 1 (3.5 g, 10 mmol) and reacted in the same manner. The mixture was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.3 g). 1 H-NMR (DMSO-d 6 ) 2.86(s, 3H), 2.94(m, 4H), 3.59(m, 4H), 3.76(t, 2H), 4.78(t, 2H), 7.91(s, 1H), 8.09(s, 1H), 8.29(s, 1H) [Step 3] Preparation of 2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-amine Under the same conditions as in [Step 3] of Example 1, the compound obtained in [Step 2] (1.3 g, 4 mmol) was dissolved in ethyl acetate (100 mL), palladium on activated carbon (109 mg, 0.2 w / w) was added, and the mixture was hydrogenated. The reaction mixture was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.15 g). 1 H-NMR (DMSO-d 6 ) 2.82(s, 3H), 2.94(m, 4H), 3.59(m, 4H), 3.63(t, 2H), 4.30(s, 2H), 4.60(t, 2H), 7.72(s, 1H), 8.01(s, 1H), 8.20(s, 1H) [Step 4] Preparation of N-(1-(2-(methylsulfonyl)ethyl)-6-morpholino-1H-indazole-5-yl)-3-nitrobenzamide (compound 52) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (136 mg, 0.42 mmol) was reacted in the same manner with 3-nitrobenzoic acid (64 mg, 0.383 mmol), dimethylformamide (10 mL), EDC·HCl (0.22 g, 1.15 mmol), and HOBt·H2O (0.155 g, 1.15 mmol). The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (44 mg). 1 H-NMR (DMSO-d 6 ) 2.90(s, 3H), 2.95(m, 4H), 3.72(t, 2H), 3.78(m, 4H), 4.79(t, 2H), 7.60(s, 1H), 7.87(t, 1H), 8.07(s, 1H), 8.31(s, 1H), 8.38(d, 1H), 8.43(d, 1H), 8.72(s, 1H), 10.01(s, 1H) LC-MS (ESI, m / z) = 474.5 (M+H + ). Example 53. N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0186] [ka]

[0187] [Step 4] Preparation of N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazole-5-yl)-3-sulfamoylbenzamide (Compound 53) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] of Example 13 (136 mg, 0.42 mmol), 3-sulfamoylbenzoic acid (93 mg, 0.462 mmol), dimethylformamide (10 mL), HATU (217 mg, 0.63 mmol), and DIPEA (0.2 mL, 1.68 mmol) were reacted in the same manner. The reaction was then purified and concentrated using MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (10 mg). 1 H-NMR (DMSO-d 6 ) 2.90(s, 3H), 2.98(m, 4H), 3.73(t, 2H), 3.79(m, 4H), 4.78(t, 2H), 7.59(s, 1H), 7.69(s, 2H), 7.80(t, 1H), 7.99(d, 1H), 8.07(s, 1H), 8.18(m, 1H), 8.33(s, 1H), 8.38(s, 1H), 9.91(s, 1H) LC-MS (ESI, m / z) = 508.6 (M+H + ) <Experimental Example> Evaluation of Physiological Efficacy Experimental Example 1. IRAK4 enzyme activity inhibition experiment We conducted experiments to inhibit the IRAK4 enzyme activity of the compounds of the present invention. Using the IRAK4 enzyme kit (purchased from Promega, product number: V2621), a mixture of 0.1 μg / μL of the enzyme reaction substrate, myelin basic protein (MBP), and 1.25 mM ATP was diluted according to the manual with reaction buffer (40 mM Tris-HCl, pH 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 μM DTT). 2 μL of this mixture was dispensed into a 384-well white plate. The test compound was then gradient diluted from 1 mM, and 1 μL was added to the 384-well plate. Subsequently, the IRAK4 enzyme was diluted with reaction buffer to a final concentration of 5 ng / μL, and 2 μL / well was dispensed into the 384-well white plate. The mixture was then reacted at 37°C for 60 minutes. After the reaction was complete, 5 μL of ADP-Glo ​​reaction reagent was added using the ADP-Glo™ enzyme test kit (purchased from Promega, product number: V9102), and the reaction was allowed to proceed at 37°C for 40 minutes. Then, 10 μL of enzyme colorimetric reagent was added, and the luminescence signal was measured using absorbance measurement equipment (THECAN, Microplate Reader). The inhibition rate was calculated from the measured values, and the 50% inhibition concentration (IC) was determined through nonlinear regression analysis based on the % inhibition rate at different concentrations of the test compound. 50 The values ​​were analyzed and are shown in Table 2.

[0188] [Table 2-1]

[0189] [Table 2-2]

[0190] As can be seen from Table 2 above, the compounds of the present invention exhibit excellent IRAK4 inhibitory activity. Experimental Example 2. Experiment to inhibit IRAK1 enzyme activity We conducted experiments to inhibit the IRAK1 enzyme activity of the compound of the present invention. Using the IRAK1 enzyme kit (purchased from Promega, product number: VA7477), a mixture of 0.1 μg / μL of the enzyme reaction substrate, protein AKT (protein kinase B), and 1.25 mM ATP was diluted according to the manual with reaction buffer (40 mM Tris-HCl, pH 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 μM DTT). 2 μL of this mixture was dispensed into a 384-well white plate. The test compound was then gradient diluted from 1 mM, and 1 μL was added to the 384-well white plate. Subsequently, the IRAK1 enzyme was diluted with reaction buffer to a final concentration of 5 ng / μL, and 2 μL / well was dispensed into the 384-well white plate. The mixture was then reacted at 37°C for 60 minutes. After the reaction was complete, 5 μL of ADP-Glo ​​reaction reagent was added using the ADP-Glo™ enzyme test kit (purchased from Promega, product number: V9102), and the reaction was allowed to proceed at 37°C for 40 minutes. Then, 10 μL of enzyme colorimetric reagent was added, and the luminescence signal was measured using absorbance measurement equipment (THECAN, Microplate Reader). The inhibition rate was calculated from the measured values, and the 50% inhibition concentration (IC) was determined through nonlinear regression analysis based on the % inhibition rate at different concentrations of the test compound. 50 The values ​​were analyzed and are shown in Table 3.

[0191] [Table 3-1]

[0192] [Table 3-2]

[0193] As can be seen from Table 3 above, the compounds of the present invention exhibit excellent IRAK1 inhibitory activity. Experiment Example 3. Cell-based inflammatory cytokine secretion suppression experiment Experiments were conducted to suppress the secretion of inflammatory cytokines using the compounds of the present invention. PBMCs (LONZA, peripheral blood mononuclear cells) isolated from human whole blood were measured in 1.0 × 10⁻¹⁶ units. 5Cells were dispensed into 96-well plates at a cell / well density and stabilized for 20 hours. Then, four different concentrations of the test compound were added in RPMI (Roswell Park Memorial Institute) medium and reacted for 1 hour. After adding LPS (Lipopolysaccharide) to a final concentration of 1 μg / mL, the mixture was reacted for another 1 hour. The inflammatory cytokine hTNF-α was measured using an enzyme-linked immunosorbent assay (ELISA) kit from Komabiotech. Cell supernatant, standard drug, and antibody were added to the ELISA plate and reacted for a total of 4 hours. The plate was then washed, streptavidin-HRP was reacted for 30 minutes, and the plate was washed again. TMB substrate was then added and the reaction was carried out in the dark. Once sufficient color development occurred, the reaction was stopped by adding stop solution. hTNF-α was measured by measuring absorbance at 450 nM using absorbance measurement equipment (BioTeK Microplate Reader). The activity inhibition rate is calculated from the measured absorbance values, and the % inhibition rate for each concentration of the test compound is calculated. This is then analyzed using nonlinear regression to determine the 50% inhibitory concentration (IC). 50 The values ​​were analyzed and are shown in Table 4.

[0194] [Table 4]

[0195] As can be seen from Table 4 above, the compounds of the present invention exhibit excellent inhibitory effects on inflammatory cytokine secretion. Although the present invention has been described in detail above, it will be clear to those with ordinary skill in the art that such specific descriptions are merely preferred embodiments and do not limit the scope of the invention. Therefore, the substantial scope of the invention is defined by the appended claims and their equivalents.

Claims

1. Compounds represented by chemical formula I, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates: 【Chemistry 1】 In the aforementioned chemical formula I, X is phenyl or pyridinyl, One or more of the H in X are halogens, C1-C6 alkyls, C(=O)Ra, and NH. ２ NO ２ , S (=O) ２ It may also be substituted with a 5- to 12-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of Rb, N, O, and S. The aforementioned Ra and Rb are each independently C1-C6 alkyl, NH ２ Alternatively, a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring. Y is a 3- to 12-membered heterocycloalkylene containing a single bond, 1 to 3 heteroatoms independently selected from the group consisting of 6- to 14-membered arylenes, and N, O, and S, or a 5- to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. L １ These are single bonds, C1-C6 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C6 alkylene), C(=O)NH-(C1-C6 alkylene)-C(=O)O or C(=O)NH-(C1-C6 alkylene)-C(=O)NH, R １ H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF ３ , a 3-membered to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of NRcRd, N, O, and S, or a 5-membered to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, The Rc and Rd are each independently H or C1-C6 alkyl. Q １ and Q ２ are each independently N or N−L ２ −R ２ wherein Q １ and Q ２ are not both N at the same time Q ２ When N, the above 【Chemistry 2】 teeth 【Transformation 3】 Q １ When N, the above 【Chemistry 4】 teeth 【Transformation 5】 And, Said L ２ This is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), The aforementioned R ２ This refers to a 3- to 12-membered heterocycloalkyl, C1-C6 alkoxy, or CONH group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring. ２ , NReRf, SO ２ Rg or OH, Re, Rf, and Rg are each independently H or C1-C6 alkyl.

2. In the aforementioned chemical formula I, X is phenyl or pyridinyl, One or more H in X are halogen, C(=O)Ra, NH ２ NO ２ , S (=O) ２ It may also be substituted with a 5- to 12-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from the group consisting of Rb, N, O, and S. The aforementioned Ra and Rb are each independently of NH ２ Alternatively, a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring. Y is a 3- to 12-membered heterocycloalkylene containing a single bond, 1 to 3 heteroatoms independently selected from the group consisting of 6- to 14-membered arylenes, and N, O, and S, or a 5- to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S. L １ These are single bonds, C1-C6 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C6 alkylene), C(=O)NH-(C1-C6 alkylene)-C(=O)O or C(=O)NH-(C1-C6 alkylene)-C(=O)NH, R １ H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF ３ , a 3-membered to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of NRcRd, N, O, and S, or a 5-membered to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S, The Rc and Rd are each independently C1-C6 alkyl groups. Q １ and Q ２ These are, independently, N or N-L ２ -R ２ Q １ and Q ２ It is not possible for both to be N at the same time. Q ２ When N, the above 【Transformation 6】 teeth 【Transformation 7】 Q １ When N, the above 【Transformation 8】 teeth 【Chemistry 9】 And, Said L ２ This is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), The aforementioned R ２ This refers to a 3- to 12-membered heterocycloalkyl, C1-C6 alkoxy, or CONH group containing 1 to 3 heteroatoms independently selected from the group consisting of N, O, and S within the ring. ２ , NReRf, SO ２ Rg or OH, The compound represented by chemical formula I according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein Re, Rf, and Rg are each independently a C1-C6 alkyl group.

3. In the aforementioned chemical formula I, X is phenyl or pyridinyl, One or more H in X are F, Cl, C(=O)Ra, NH ２ NO ２ , S (=O) ２ It may be substituted with a 5-membered or 6-membered heteroaryl containing one to three heteroatoms independently selected from the group consisting of Rb, N, and S within the ring. The aforementioned Ra and Rb are each independently of NH ２ Alternatively, a 5- to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of N and O within the ring. Y is a 5- to 7-membered heterocycloalkylene containing a single bond, 1 to 3 heteroatoms independently selected from the group consisting of 6- to 12-membered arylenes, N, O, and S, or a 5- or 6-membered heteroarylene containing 1 or 2 heteroatoms independently selected from the group consisting of N, O, and S. L １ These are single bonds, C1-C4 alkylene, C(=O), C(=O)NH, C(=O)NH-(C1-C2 alkylene), C(=O)NH-(C1-C5 alkylene)-C(=O)O or C(=O)NH-(C1-C3 alkylene)-C(=O)NH, R １ H, F, Cl, C1-C3 alkyl, C1-C3 alkoxy, OH, CF ３ , a 5- to 7-membered heterocycloalkyl group containing one to three heteroatoms independently selected from the group consisting of NRcRd, N, and O, or a 5- or 6-membered heteroaryl group containing one or two heteroatoms independently selected from the group consisting of N and O, The Rc and Rd are each independently C1-C3 alkyl groups. Q １ and Q ２ These are, independently, N or N-L ２ -R ２ Q １ and Q ２ It is not possible for both to be N at the same time. Q ２ When N, the above 【Chemistry 10】 teeth 【Chemistry 11】 Q １ When N, the above 【Chemistry 12】 teeth 【Chemistry 13】 And, Said L ２ These are C1-C6 alkylene or (C1-C3 alkylene)-O-(C1-C3 alkylene), The aforementioned R ２ This refers to a 5- to 7-membered heterocycloalkyl, C1-C3 alkoxy, or CONH group containing 1 to 3 heteroatoms independently selected from the group consisting of N and O within the ring. ２ , NReRf, SO ２ Rg or OH, The compound represented by chemical formula I according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein Re, Rf, and Rg are each independently a C1-C3 alkyl group.

4. The compounds listed in the table below, their stereoisomers, their pharmaceutically acceptable salts, or their hydrates or solvates: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5

5. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

6. The pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is for the prevention or treatment of IRAK-4 or IRAK-1 related diseases.

7. The pharmaceutical composition according to claim 6, wherein the IRAK-4 or IRAK-1 related disease is an autoimmune disease, an inflammatory disease, or a tumor.

8. A method for preventing or treating an IRAK-4 or IRAK-1 related disease, comprising the step of administering to an individual a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

9. Use of a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the prevention or treatment of IRAK-4 or IRAK-1 related diseases.

10. Use of a compound according to any one of claims 1 to 4, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the manufacture of an agent for the prevention or treatment of IRAK-4 or IRAK-1 related disease.

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