Novel carboxamide derivative compound and pharmaceutical composition comprising same

Abstract

The present invention relates to: a carboxamide derivative compound represented by chemical formula I; a stereoisomer thereof; a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof; a composition comprising same; a method using same in the prevention or treatment of IRAK-4 or IRAK-1-related diseases; and uses thereof.

Description

[0001]

specification

[0002]

Title of invention

[0003]

Technical Field

[0004]

Background Technology

[0005] The IL-1R / TLR (IL-1 receptor / Toll-like receptor) signaling pathway plays an important role in immune and inflammatory responses, and has been reported to be involved in the development of various inflammatory and autoimmune diseases, such as sepsis, asthma, arteriosclerosis, Alzheimer's disease, rheumatoid arthritis, atopy, hidradenitis suppurativa, psoriasis, rheumatoid arthritis, ulcerative colitis, and lupus (Journal of Investigative Dermatology. 2019; 139(1) : 146-156 / Anna 1 s of the New York Academy of Sciences . 2008; 1143 : 21— 34 / Journal of Immunology research. 2019; 1824624 / Internat ional Immunopharmaco 1 ogy . 2007; 7(10) : 1271-1285) . In particular, it has been recently reported that blocking the IL-1R / TLR signaling pathway through inhibition of IRAK-4 (inter leukin-1 receptor-associated kinase 4) is effective in chronic inflammatory skin diseases such as psoriasis and atopy (Science Translational Medicine. 2023: 15: eabj3289). It has also been reported that IL-1R / TLR expression is involved in the proliferation of various cancer cells (Oncogene. 2008; 27(2): 218-224). In particular, diffuse large B-cell lymphoma

[0006] It has been reported that IL-1R / TLR signaling is overactivated due to MyD88 mutation in ABC DLBCL, a type of diabetic large B-cell 1 lymphoma (DLBCL), and Waldenstrom macroglobulinemi a (WM), a lymphocytic malignancy (Nature . 2011; 470(7332):115-119 / New England journal of medi cine . 2012; 367(9) : 826-833). 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 by various pathogens and damage-associated molecular patterns (DAMPs) released from stressed or dying cells bind to IL-1R / TLR, downstream signaling mechanisms are activated, resulting in an inflammatory response. If this inflammatory response persists, it can lead to cancer (Nature Immunology. 2011 Jul 19; 12(8): 715-723). Based on the above reports, active research is being conducted to develop substances that block TLR itself, which plays an important role in the IL-1R / TLR signaling pathway, or inhibit IRAK, which is responsible for downstream signals of TLR. In particular, many studies are targeting IRAK-4.

[0007] IRAK is a serine / threonine carboxylic acid 0]There are four subtypes of IRAK (IRAK-1, IRAK-2, IRAK-M, IRAK-4). Among these, research is mainly focused on IRAK-4 and IRAK-1, which have kinase function. In particular, research is most focused on IRAK-4, which plays an important role in forming myddosomes in the IL-1R / TLR signaling pathway, and research on IRAK-1 is also actively underway recently. Although there are no drugs released targeting IRAK-4 or IRAK-1, phase 1 and 2 clinical trials are in progress for various diseases (autoimmune diseases, inflammatory diseases, and blood cancers).

[0008]

Detailed Description of the Invention

[0009]

Technical Problem

[0010]

Technical Solution

[0011] <Chemical Formula 1> In the above formula I, o is phenyl or pyridinyl, and at least one of o may be substituted with a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of halogen, C1-C6 alkyl, C(=O)Ra, NH2, NO2, S(=OhRb, N, 0 and S) in the ring, wherein Ra and Rb are each independently a 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of C1-C6 alkyl, NH2 or N, 0 and S in the ring, and S is a single bond, a 6- to 14-membered arylene, a 3- to 12-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, or 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S. A 5- to 12-membered heteroarylene containing 3 heteroatoms in the ring,

[0012] Li is a single bond, C1-C6 alkylene, C(=0), C(=O)NH, C(=O)NH- (Cl- C6 alkylene), C(=O)NH-(C1-C6 alkylene) - C(=0)0 or C(=O)NH-(C1-C6 alkylene) -C(=O)NH,

[0013] Ri is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF3, NRcRd, N, 0 and S in the ring, or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein Rc and Rd are each independently H or C1-C6 alkyl,

[0014] Qi and Q2 are each independently N or N- L2- R2, but Qi and Q2 cannot be N at the same time. The above L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), the above R2 is 3-12 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, C1-C6 alkoxy, CONH2, NReRf, S02Rg or OH, and the above Re, Rf and Rg are each independently H or C1-C6 alkyl. In one embodiment, in the above formula I, phenyl or pyridinyl, and at least one of the above may be substituted with a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from the group consisting of halogen, C(=O)Ra, NH2, NO2, S(=OhRb, N, 0, and , wherein Ra and Rb are each independently NH2 or a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0, and S, and wherein the above formula I is a single bond, a 6- to 14-membered arylene, a 3- to 12-membered heterocycloalkylene group containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0, and S, or a 3- to 12-membered heterocycloalkylene group containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0, and S, within the ring. Heteroarylene of 5 to 12 won,

[0015] Li is a single bond, C1-C6 alkylene, C(=0), C(=O)NH, C(=O)NH- (Cl- C6 alkylene), C(=O)NH-(C1-C6 alkylene) - C(=0)0 or C(=O)NH-(C1-C6 alkylene) -C(=O)NH,

[0016] Ri is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF3, NRcRd, N, 0 and S in the ring, or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein Rc and Rd are each independently C1-C6 alkyl,

[0017] Qi and Q2 are each independently N or N- L2- R2, but Qi and Q2 cannot be N at the same time. The above L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), the above R2 is 3-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, C1-C6 alkoxy, CONH2, NReRf, S02Rg or OH, and the above Re, Rf and Rg can each independently be C1-C6 alkyl. In one embodiment, in the above formula I, is phenyl or pyridinyl, and at least one of X may be substituted with a 5-membered or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from the group consisting of F, Cl, C(=O)Ra, NH2, N02, S(=0)2Rb, N and S within the ring, wherein Ra and Rb are each independently NH2 or a 5-membered to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of N and 0 within the ring, and S is a single bond, a 6-membered to 12-membered arylene, a 5-membered to 7-membered heterocycloalkylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S within the ring, or a 5-membered or It is a 6-membered heteroarylene,

[0018] Li is a single bond, C1-C4 alkylene, C(=0), C(=O)NH, C(=O)NH- (Cl- C2 alkylene), C(=O)NH-(C1-C5 alkylene) - C(=0)0 or C(=O)NH-(C1-C3 alkylene) -C(=O)NH,

[0019] Ri is a 5- to 7-membered heterocycloalkyl 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 0 within the ring, or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from the group consisting of N and 0 within the ring, wherein Rc and Rd are each independently C1-C3 alkyl,

[0020] Qi and Q2 are each independently N or N- L2- R2, but Qi and Q2 cannot be N at the same time. The above L2 is C1-C6 alkylene or (C1-C3 alkylene)-O-(C1-C3 alkylene), and the above R2 is 1 to 1 independently selected from the group consisting of N and 0.

[0021] A 5- to 7-membered heterocycloalkyl having 3 heteroatoms in the ring, C1-C3 alkoxy, CONH2, NReRf, S02Rg or OH, wherein Re, Rf and Rg can each independently be C1-C3 alkyl. In one embodiment, in the above formula I, There is. In the present invention, the term "Cm-Cn" (wherein m and n are each independently an integer greater than or equal to 1) means the number of carbons, for example, 'C1-C5 alkyl' means alkyl having 1 to 5 carbons. In the present invention, "substitution" or "substituted with ~" is defined to include the implicit condition that such substitution depends on the allowable valency of the substituted atom and the substituent, and that the substitution leads to a stable compound, for example, a compound that does not undergo spontaneous transformation by rearrangement, cyclization, elimination, etc. In the present invention, "single bond" means a case where adjacent atoms or groups of atoms are directly bonded to each other. In the present invention, "alkyl" means a linear (or straight-chain) saturated hydrocarbon group or a branched (or side-chain) saturated hydrocarbon group, unless otherwise specified. Examples of alkyl 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 stated, "alkylene" means a divalent functional group derived from alkyl defined as above. In the present invention, unless otherwise stated, "cycloalkyl" means a monocyclic or polycyclic saturated hydrocarbon ring. 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, spiroctyl, and the like. In the present invention, unless otherwise stated, "cycloalkylene" means a divalent functional group derived from cycloalkyl as defined above. In the present invention, unless otherwise stated, "cycloalkenyl" means a monocyclic or polycyclic unsaturated hydrocarbon ring containing one or more double bonds.Examples of cycloalkenyl include, but are not limited to, one or more selected from cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. In the present invention, unless otherwise stated, "cycloalkenylene" means a divalent functional group derived from cycloalkenyl as defined above. In the present invention, unless otherwise stated, "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, 0, and S. Examples of heterocycloalkyl include, but are not limited to, one or more selected from oxiranyl, dioxolanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, etc. In the present invention, unless otherwise stated, "heterocycloalkylene" means a divalent functional group derived from heterocycloalkyl defined as above. In the present invention, unless otherwise stated, "heterocycloalkenyl" means a monocyclic or polycyclic ring in which at least one carbon atom constituting the cycloalkenyl ring defined as above is substituted with a heteroatom selected from the group consisting of N, 0, and . Examples of heterocycloalkenyl include, but are not limited to, one or more selected from dihydropyridinyl, dihydropyranyl, dihydrothiopyranyl, etc. In the present invention, unless otherwise stated, "heterocycloalkenylene" means a divalent functional group derived from heterocycloalkenyl as defined above. In the present invention, unless otherwise stated, "aryl" means a monocyclic or polycyclic aromatic cyclic group having one or more aromatic rings, which are fused or non-fused.Examples of aryl include, but are not limited to, one or more selected from phenyl, naphthalenyl, indenyl, and anthracenyl. In the present invention, unless otherwise specified, "arylene" means a divalent functional group derived from aryl defined as above. In the present invention, unless otherwise specified, "heteroaryl" means a monocyclic or polycyclic aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of N, 0, and S in the ring and having one or more aromatic rings, which are fused or non-fused. Examples of heteroaryl include pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrrolyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, Triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazole, etc. may be mentioned, but are not limited thereto. In the present invention, unless otherwise stated, "heteroarylene" means a divalent functional group derived from heteroaryl defined as above. In the present invention, "halogen" may be F, Cl, Br, or I, unless otherwise stated. In addition, terms and abbreviations used herein have their original meanings unless defined otherwise. The present invention provides a compound described in Table 1 below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0022] [Table 1] Method for producing a compound represented by a chemical formula The present invention provides a method for preparing a compound represented by Chemical Formula I, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The compound of Chemical Formula I of the present invention, the compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may be prepared, for example, according to the method of the following Reaction Scheme 1, but is not limited thereto.

[0023] <Reaction Scheme 1> In the above reaction formula 1, each of Ri, R2, LI, L2, X and Y is the same as defined in the compound item represented by the above chemical formula I.

[0024] [Step 1] Starting from the coupling reaction starting material (compound (0), it is possible to prepare a 1- or 2-substituted indazole derivative (compound (ii)) (see Scheme 1 above). Useful reactions for this purpose include reactions using R2-L2-B (B is chloride, bromide, iodide or 4-methylbenzenesulfonate) and a base, optionally in a solvent. Optionally, when one of R2-L2-B is chloride or bromide, it is also possible to add an alkali metal iodide, such as potassium iodide or sodium iodide. Both organic and inorganic bases can be used as the base, and for example, the inorganic base can be potassium carbonate, cesium carbonate or sodium hydride. In the case of a reactive halide, it is also possible in some cases to use N-cyclohexyl-N-methylcyclohexanamine as the organic base. As the solvent, for example, 1-methylpyrrolidin-2-one, DMF, DMSO or THF can be used.

[0025] [Step 2] A step of preparing the compound (iii) by stirring for 0.5 to 24 hours under heating conditions using a condensate and a coupling reaction using a palladium catalyst or a nickel catalyst; and an equal or excess amount of a boronic acid, a boronic acid pinacol ester (in the case of Suzuki-Miyaura coupling), an organotin reagent (in the case of Stille coupling), or an alkene compound (in the case of Heck reaction) in a pressure tube or a general reactor in a solvent inert to the coupling reaction, in the presence of a base. Specifically, the compound (iii) can be prepared by stirring for 0.5 to 24 hours at 20 to 120°C. The solvent is not particularly limited as long as it is inert to the reaction, but may include methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene, or a mixture thereof. The palladium catalyst may include tetrakis(triphenylphosphine)palladium, [i,r-bis(diphenylphosphino)ferrocene]dichloropalladium, tris(dibenzylideneacetone)dipalladium, palladium acetate, acetylacetonepalladium, or bis(triphenylphosphine)palladium dichloride. The nickel catalyst may include [i,r-bis(diphenylphosphino)ferrocene]nickel dichloride or bis(triphenylphosphine)nickel dichloride. Both organic and inorganic bases can be used as the base, and examples thereof include organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.di-7-undecene (DBU) or 1,5-diazabicyclo[4.3.di-5-nonene (DBN); or inorganic bases such as potassium bicarbonate, sodium bicarbonate, potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium phosphate or sodium phosphate.

[0026] [Step 3] Reduction reaction is a step of preparing the compound (iv) by stirring the compound (iii) in a solvent with palladium / charcoal and hydrogen gas for 3 to 96 hours under cooling or heating. Specifically, the compound (iv) can be prepared by stirring at room temperature (10 to 25 °C) to 60 °C for 0.5 to 48 hours. The solvent is not particularly limited as long as it does not inhibit the reaction, but methanol, ethanol, tetrahydrofuran, ethyl acetate, dichloromethane, or a mixture thereof can be used.

[0027] [Step 4] Amidation reaction is a step of preparing the compound 1C by stirring the compound (iv) in an inert solvent for 1 to 24 hours under cooling or heating using an equal or excess amount of the corresponding X-substituted aromatic carboxylic acid and a condensing agent. Specifically, the compound (v) can be prepared by stirring at room temperature to 120°C for 1 to 8 hours. The solvent is not particularly limited as long as it is inert to the reaction, but N,N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, or a mixture thereof can be used. As the above condensing agent, pentafluorophenyl trifluoroacetate, dicyclocarbodiimide (DCC), 3-ethyl (3-dimethylaminopropyl) carbodiimide (EDCI), 1,1'-carbonyldiimidazole, etc. can be used. In addition, an additive or base can be used in the reaction. As the above additive, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt),

[0028] 1-Hydroxy-7-azabenzotriazole (HOAt) etc. can be used. As the base, organic bases such as triethylamine and diisopropylethylamine; or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide can be used. A composition including a compound represented by chemical formula I, a method using a compound represented by chemical formula I and a use of a compound represented by chemical formula The present invention provides a pharmaceutical composition comprising a compound represented by the above chemical formula I, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient. The present invention provides a health functional food composition comprising a compound represented by the above chemical formula I, a compound of 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. "Pharmaceutically acceptable" in the present invention may mean that it is physiologically tolerable and does not typically cause an allergic reaction such as gastrointestinal disorder or dizziness or a similar reaction when administered to a subject. The pharmaceutically acceptable salt of the present invention can be prepared by a conventional method known to those skilled in the art. The "hydrate" of the present invention is a compound represented by Chemical Formula I, a compound of Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and water are bound by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of water. Specifically, the hydrate may contain water in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, and more specifically, may contain water in a ratio of 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 "solvate" of the present invention is a compound represented by the chemical formula I, a compound of Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a solvent other than water, which are bound by non-covalent intermolecular forces, and may include 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, and more specifically, may contain them in a ratio of 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 the above formula I, the compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutical composition comprising 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, "IRAK-4 or IRAK-1 related diseases" may be autoimmune diseases, inflammatory diseases, or tumors. The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by the above chemical formula I, the compound of the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. At this time, the pharmaceutically acceptable carrier is one commonly used in the art at the time of formulation, and may be at least one selected from lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. In addition, the pharmaceutical composition of the present invention may additionally include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, or a preservative in addition to the above components.The present invention provides a method for preventing or treating an IRAK-4 or IRAK-1 related disease, comprising administering to a subject a compound represented by the above chemical formula I, a compound of the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same. The method for preventing or treating an IRAK-4 or IRAK-1 related disease of the present invention may comprise administering a therapeutically effective amount of a compound represented by the above chemical formula I, a compound of the above Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same. In the present invention, "prevention" means any act of inhibiting or delaying the onset of an IRAK-4 or IRAK-1 related disease by administering a compound represented by the above chemical formula I of the present invention, a compound of the above Table 1, 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 an IRAK-4 or IRAK-1 related disease by administering a compound represented by the chemical formula I of the present invention, a compound of Table 1, 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 chemical formula I of the present invention, a compound of Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same, for the prevention or treatment of an IRAK-4 or IRAK-1 related disease.The present invention provides the use of a compound represented by the above formula I, a compound of the above table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for preventing or treating a disease associated with IRAK-4 or IRAK-1.

[0029]

Effect of the invention

[0030]

Mode for Embodiment of the Invention

[0031] <Example> The compound represented by the chemical formula I of the present invention and the compound in Table 1 above can be prepared by the method described below. Unless otherwise stated, the starting materials are commercially available or can be prepared by a known method. Example 1. N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)isophthalamide

[0032] [Step 1] Preparation of 2-(6-bromo-5-nitro-2H-indazol-2-yl)-N,N-dimethylethan-1-amine

[0033] 6-Bromo-5-nitro-2H-indazole (5 g, 20.66 mmole) was added potassium carbonate (11.42 g, 82.64 mmole), potassium iodide (0.5 g, 3.01 mmole), 2-chloro- N, N-dimethylethan-1-amine hydrochloride (2.98 g, 20.66 mmole) and dimethylformamide (50 mL) and stirred at 80°C for 17 h. After completion of the reaction, ethyl acetate (50 mL) was added and washed with purified water (50 mL). Anhydrous magnesium sulfate was added and filtered. After concentration under reduced pressure, the residue was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.88 g). P— 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)

[0034] [Step 2] Preparation of N,N-dimethyl-2-(5-nitro-6-(thiophen-3-yl)-2H-indazol-2-yl)ethan-1-amine The compound obtained in [Step 1] (0.4 g, 1.277 mmole) was added with sodium carbonate (677 mg, 6.39 mmole), tetrakis(triphenylphosphine)palladium (74 mg,

[0035] 0.06 mmole), thiophene-3-boronic acid pinacol ester (402 mg, 1,916 mmole), 1,4-dioxane (10 mL) and purified water (1 mL) were added and stirred at 100°C for 17 hours. After completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (30 mL) was added, washed with purified water (30 mL), anhydrous magnesium sulfate was added and filtered. After concentration under reduced pressure, the residue was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.46 g). P— 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)

[0036] [Step 3] Preparation of 2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-amine Palladium on activated carbon (50 mg, 0.2 w / w) and methanol (20 mL) were added to the compound obtained in the above [Step 2] (250 mg, 0.79 mmole), and hydrogenation was performed under standard hydrogen pressure at room temperature for 3 hours. After completion of the reaction, the reaction solution was filtered through celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the title compound (230 mg). P— 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)

[0037] [Step 4] Preparation of N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)isophthalamide (Compound 1) Dimethylformamide (ImL) was added dropwise to the compound (104 mg, 0.363 mmole) obtained in the above [Step 3], and DIPEA (0.247 mL, 1.452 mmole) and HATU (207 mg, 0.545 mmole) were added and stirred for 30 minutes. Then, 3-carbamoylbenzoic acid (60 mg, 0.363 mmole) was added and stirred at room temperature for 17 hours. After completion of the reaction, ethyl acetate (30 mL) was added, the mixture was washed with purified water (30 mL), and anhydrous magnesium sulfate was added and filtered. After concentration under reduced pressure, the residue was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (70 mg). P— NMR (DMSO-d6 ) 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)

[0038] LC-MS (ESI, m / z) = 434.7 (M+H + ) Example 2. N-(2-(3-Hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-5-nitro nicotinamide

[0039] 0丄스广N.

[0040] HN-」 『4OH

[0041] O 2N 、히스

[0042] [Step 1] Preparation of 4-(5-Nitro-1H-indazol-6-yl)morpholine

[0043] Morpholine (21.6 mL, 247.92 mmol) was added to 6-bromo-5-nitro-1H-indazole (5 g, 20.66 mmol), and the mixture was stirred at 140 °C for 23 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (5.14 g). 1H-NMR (DMSO-d 6 ) 2.94 (t, 4H), 3.68 (t, 4H), 7.22 (s 1H), 8.16 (s, 1H), 8.35 (s, 1H)

[0044] [Step 2] Synthesis of 2-methyl-4-(6-morpholino-5-nitro-2H-indazol-2-yl)butan-2-ol Under the same conditions as [Step 1] of Example 1, 4-bromo-2-methylbutan-2-ol (1.89 mL, 15.5 mmole), potassium carbonate (5.7 g, 41.32 mmole), potassium iodide (257 mg, 1.55 mmole), and dimethylformamide (lOmL) were added to the compound obtained in [Step 1], and stirred at 90°C for 4 hours. After completion of the reaction, ethyl acetate (50 mL) was added, the mixture was washed with purified water (50 mL), and anhydrous magnesium sulfate was added and filtered. After concentration under reduced pressure, the product was purified by MPLC (combi Flash NEXTGEN 300+) to obtain the title compound (1.46 g). 6H) , 1.99(m, 2H) , 2.89(t, 4H) , 3.66(t, 4H),

[0045] 4.47(m, 2H), 4.48(s, 1H) , 7.32(s, 1H) , 8.31(s, 1H) , 8.57(s, 1H)

[0046] [Step 3] Preparation of 4-(5-amino-6-morpholino-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound (900 mg, 2.692 mmole) obtained in [Step 2] was dissolved in ethyl acetate (9 mL) and hydrogenated by adding palladium on activated carbon (180 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (820 mg). 6H) , 1.95(m, 2H) , 2.75(t, 4H) , 3.48(t, 4H),

[0047] 4.35(m, 2H), 4.36(s, 1H) , 4.50(s, 2H) , 7.29(s, 1H) , 7.75(s, 1H) , 8.05(s, 1H)

[0048] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-5-nitronicotinamide (Compound 2) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] (0.1 g, 0.3285 mmole), 5-nitronicotinic acid (0.07 g, 0.299 mmole), dimethylformamide (5 mL), DIPEMO. 284 mL, 1.314 mmole) and HATU (0.24 g, 0.4928 mmole) were used, and the reaction was carried out in the same manner. After adding purified water, the resulting solid was filtered and dried, and then ethyl acetate was added and filtered to obtain the title compound (12 mg). P- 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)

[0049] LC-MS (ESI, m / z) = 455.4 (M+H + ) Example 3. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide

[0050] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 3) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] of Example 2 (0.1 g, 0.3285 mmole), 3-nitrobenzoic acid (0.07 g, 0.299 mmole), dimethylformamide (5 mL), HATU (0.24 g, 0.4928 mmole), and DIPEA (0.284 mL, 1.314 mmole) were used. After the reaction was carried out in the same manner, purified water was added, the resulting solid was filtered, dried, and methanol was added and filtered to obtain the title compound (53 mg). P— 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) ,

[0051] 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-indazol-5-yl)-3-nitrobenzamide

[0052] [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,

[0053] The reaction was carried out in the same manner using potassium carbonate (6.85 g, 49.6 mmole), potassium iodide (0.21 g, 1,81 mmole), 4-bromo-2-methylbutan-2-ol (2.27 mL, 18.6 mmole) and dimethylformamide (30 mL), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.91 g). P— 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)

[0054] [Step 2] Preparation of 4-(6-(furan-3-yl)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] (1.9 g, 5.79 mmole), sodium carbonate (3.07 g, 28.9 mmole), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmole), 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (1.69 g, 8.69 mmole), 1,4-dioxane (20 mL) and purified water (2 mL) were used, and the reaction was carried out in the same manner. MPLC(combiFlash NEXTGEN

[0055] 300+) and concentrated to obtain the title compound (1.5 g). P— 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)

[0056] [Step 3] Preparation of 4-(5-amino-6-(furan-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 1, the compound obtained in [Step 2] (1.5 g, 4.76 mmole) was hydrogenated by adding palladium on activated carbon (0.3 g, 0.2 w / w). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (1.06 g). P- 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)

[0057] [Step 4] Preparation of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 4) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] (87 mg, 0.305 mmole), 3-nitrobenzoic acid (42 mg, 0.254 mmole), dimethylformamide (ImL), HATU (145 mg, 0.381 mmole) and DIPEA (0.173 mL, 1.016 mmole) were used, and the reaction was carried out in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (15 mg). P- 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)

[0058] LC-MS (ESI, m / z) = 435.4 (M+H + ) Example 5. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)- 5 ■Nitronicotinamide

[0059] [Step 4] Preparation of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-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 mmole), 5-nitronicotinic acid (43 mg, 0.254 mmole), dimethylformamide (ImL), HATU (145 mg, 0.381 mmole), and DIPEA (0.173 mL, 1.016 mmole) were reacted in the same manner, and the resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (15 mg). Blood— 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)

[0060] LC-MS (ESI, m / z) = 436.4 (M+H + ) Example 6. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)isophthalamide

[0061] [Step 4] Preparation of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-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 mmole), 3-carbamoylbenzoic acid (42 mg, 0.254 mmole), dimethylformamide (ImL), HATU (145 mg, 0.381 mmole), and DIPEA (0.173 mL, 1.016 mmole) were reacted in the same manner, and the resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (29 mg). P- 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)

[0062] LC-MS (ESI, m / z) = 433.5 (M+H + ) Example 7. N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-5 ■Nitronicotinamide

[0063] [Step 2] Preparation of 2-methyl-4-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)butan-2-ol Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] of Example 4 (0.9 g, 2.74 mmole), sodium carbonate (1.45 g, 13,7 mmole), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmole), 4,4,5,5-tetramethyl-2-(thiophene-3-yl)-1,3,2-dioxaborolane (0.86 g, 4.11 mmole), 1,4-dioxane (10 mL) and purified water (1 mL) were reacted in the same manner, followed by MPLC (combiFlash) The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.44 g). P- 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)

[0064] [Step 3] Preparation of 4-(5-amino-6-(thiophene-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 1, the compound obtained in [Step 2] (0.4 g, 1.22 mmole) was hydrogenated by adding palladium on activated carbon (0.08 g, 0.2 w / w). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.33 g). P- 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)

[0065] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-5-nitronicotinamide (Compound 7) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] (0.113 g, 0.375 mmole), 5-nitronicotinic acid (52.5 mg, 0.3125 mmole), dimethylformamide (ImL), HATU (0.178 g, 0.469 mmole) and DIPEA (0.213 mL,

[0066] 1.25 mmole) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (47 mg). P- 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)

[0067] LC-MS (ESI, m / z) = 452.5 (M+H + ) Example 8. N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-3-nitrobenzamide

[0068] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-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 mmole), 3-nitrobenzoic acid (52 mg, 0.3125 mmole), dimethylformamide (ImL), HATU (0.178 g, 0.469 mmole), and DIPEA (0.213 mL, 1.25 mmole) were reacted in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (47 mg). P- 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)

[0069] LC-MS (ESI, m / z) = 451.5 (M+H + ) Example 9. N-(6-morpholino-2-(2-(piperidin-1-yl)ethyl)-2H-indazol-5-yl)-3-nitrobenzamide

[0070] [Step 1] Preparation of 6-bromo-5-nitro-2-(2-(piperidin-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 mmole), potassium carbonate (17.3 g, 125.18 mmole), potassium iodide (0.5 g, 3.012 mmole), 1-(2-chloroethyl)piperidine (5.7 g, 31 mmole) and dimethylformamide (50 mL) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.83 g). P— NMR (DMSO-d6 ) 1.35(m, 4H) , 1.78(m, 2H) , 3.47(m, 2H) ,

[0071] 3.66(m, 2H) , 4.80(m, 2H) , 7.25(s , 1H) , 8.29(s , 1H) , 8.42(s , 1H)

[0072] [Step 2] Preparation of 4-(5-nitro-2-(2-(piperidin-1-yl)ethyl)-2H-indazol-6-yl)morpholine Under the same conditions as [Step 1] of Example 2, morpholine (5 mL) was added to the compound (lOOmg, 0.283mmole) obtained in [Step 1], and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (30 mg) was obtained. P— NMR (DMSO-d 6 ) 1.35(m, 4H) , 1.78(m, 2H) , 2.91(m, 4H) ,

[0073] 3.47(m, 2H) , 3.66(m, 2H) , 3.79(m, 4H) , 4.80(m, 2H) , 7.87(m, 1H) , 8.56(m, 1H) ,

[0074] 8.71 (m, 1H) [Step 3] Preparation of 6-morpholino-2-(2-(piperidin-1-yl)ethyl)-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (30 mg, 0.091 mmole) obtained in [Step 2] was dissolved in ethyl acetate (5 mL) and hydrogenated by adding palladium on activated carbon (3 mg, 0.03 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (27 mg). P- NMR (DMSO-d 6 ) 1.35(m, 4H) , 1.78(m, 2H) , 2.81(m, 4H) ,

[0075] 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)

[0076] [Step 4] Preparation of N-(6-morpholino-2-(2-(piperidin-1-yl)ethyl)-2H-indazol-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 mmole), 3-nitrobenzoic acid (13 mg, 0.09 mmole), dimethylformamide (0.06 mL), HATU (44 mg, 0.123 mmole), and DIPEA (0.06 mL, 0.328 mmole) were used, and the reaction was carried out in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (8 mg). P- NMR (DMSO-d 6 ) 1.36(m, 4H) , 1.79(m, 2H) , 2.91(m, 4H) ,

[0077] 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)

[0078] LC-MS (ESI, m / z) = 479.5 (M+H + ) Example 10. N-(2-(2-(dimethylamino)ethyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide

[0079] [Step 2] Preparation of N,N-dimethyl-2-(6-morpholino-5-nitro-2H-indazol-2-yl)ethan-1-amine Under the same conditions as [Step 1] of Example 2, morpholine (5 mL) was added to the compound (500 mg, 1.6 mmole) obtained in [Step 1] of Example 1, and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (135 mg) was obtained. P- 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)

[0080] [Step 3] Preparation of 2-(2-(dimethylamino)ethyl)-6-morpholino-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (135 mg, 0.467 mmole) obtained in [Step 2] was dissolved in ethyl acetate (5 mL) and hydrogenated by adding palladium on activated carbon (14 mg, 0.03 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (122 mg). P- 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)

[0081] [Step 4] Preparation of N-(2-(2-(dimethylamino)ethyl)-6-morpholino-2H-indazol-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 mmole), 3-nitrobenzoic acid (32 mg, 0.232 mmole), dimethylformamide (5 mL), HA TUC10 mg, 0.316 mmole) and DIPEA (0.13 mL, 0.843 mmole) were reacted in the same manner, and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (8 mg). P- 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)

[0082] LC-MS (ESI, m / z) = 439.5 (M+H + ) Example 11. N-(2-(2-methoxyethyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide

[0083] [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 mmole), potassium carbonate (11.42 g, 82.64 mmole), potassium iodide (0.5 g, 3.012 mmole), 2-chloroethyl methyl ester (5.7 g, 31 mmole) and dimethylformamide (50 mL) were used. The reaction was carried out in the same manner, and the resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (2.09 g). P- NMR (DMSO-d 6 ) 3.13(s, 3H), 3.75(m, 2H), 4.51(m, 2H), 7.35(s, 1H),

[0084] 8.30(s, 1H), 8.42(s, 1H) [Step 2] Preparation of 4-(2-(2-methoxyethyl)-5-nitro-2H-indazol-6-yl)morpholine Under the same conditions as [Step 1] of Example 2, morpholine (10 mL) was added to the compound (800 mg, 2.67 mmole) obtained in [Step 1], and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (180 mg) was obtained. P— 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)

[0085] [Step 3] Preparation of 2-(2-methoxyethyl)-6-morpholino-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (180 mg, 0.588 mmole) obtained in [Step 2] was dissolved in ethyl acetate (20 mL) and hydrogenated by adding palladium on activated carbon (36 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (162 mg). P— 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)

[0086] [Step 4] Preparation of N-(2-(2-methoxyethyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 11) 3-nitrobenzoic acid (90 mg, 0.539 mmole), dimethylformamide (5 mL), EDC-HC1 (310 mg, 1.572 mmole), and HOBt-H2O (218 mg, 1.613 mmole) were added to the compound obtained in [Step 3], and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, ethyl acetate (40 mL) was added, and the mixture was washed with purified water (40 mL). Anhydrous magnesium sulfate was added, filtered, concentrated under reduced pressure, and purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (54 mg). P— NMR (DMSO-d 6 ) 2.90(m, 4H) , 3.20(s, 3H) , 3.78(m, 6H) , 4.51(m, 2H),

[0087] 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)

[0088] LC-MS (ESI, m / z) = 426.4 (M+H + ) Example 12. N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-3-(thiazol-2-yl)benzamide

[0089] [Step 4] Preparation of N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-3-(thiazol-2-yl)benzamide (Compound 12) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] of Example 1 (104 mg, 0.363 mmole), 3-(1,3-thiazol-2-yl)benzoic acid (70 mg, 0.363 mmole), dimethylformamide (ImL), HATU (207 mg, 0.545 mmole) and DIPEA (0.247 mL, 1.452 mmole) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound. (89 mg) was obtained. P- 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)

[0090] LC-MS (ESI, m / z) = 474.5 (M+H + ) Example 13. N-(2-(2-(methylsulfonyl)ethyl)-6-morsolino-2H-indazol-5-yl)-

[0091] 3-nitrobenzamide

[0092] [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, 2-bromoethyl methyl sulfone (5.8 g, 31 mmole), potassium carbonate (5.7 g, 41.32 mmole), potassium iodide (257 mg, 1.55 mmole) and dimethylformamide (50 mL) were added to 6-bromo-5-nitro-2H-indazole, and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (1.5 g) was obtained. P- 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)

[0093] [Step 2] Preparation of 4-(2-(2-(methylsulfonyl)ethyl)-5-nitro-2H-indazol-6-yl)morpholine Under the same conditions as [Step 1] of Example 2, morpholine (10 mL) was added to the compound (1.5 g, 4.31 mmole) obtained in [Step 1], and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (594 mg) was obtained. P— 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)

[0094] [Step 3] Preparation of 2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (594 mg, 1.83 mmole) obtained in [Step 2] was dissolved in ethyl acetate (lOOmL) and hydrogenated by adding palladium on activated carbon (109 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (544 mg). P- 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)

[0095] [Step 4] Preparation of N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 13) Under the same conditions as in [Step 4] of Example 11, the compound (136 mg, 0.42 mmole) obtained in [Step 3] was reacted in the same manner using 3-nitrobenzoic acid (64 mg, 0.383 mmole), dimethylformamide (lOmL), EDC-HCl (0.22 g, 1.15 mmole) and HOBt-H2O (0.155 g, 1.15 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (44 mg). P- 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)

[0096] LC-MS (ESI, m / z) = 474.5 (M+H +) Example 14. N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-yl)-

[0097] 3-(morpholinosulfonyl)benzamide

[0098] [Step 4] Preparation of N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-yl)-3-(morpholinosulfonyl)benzamide (Compound 14) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] of Example 13 (136 mg, 0.42 mmole), 3-(morpholinosulfonyl)benzoic acid (136 mg, 0.462 mmole), dimethylformamide (10 mL), HATU (217 mg, 0.63 mmole) and DIPEA (0.2 mL, 1.68 mmole) were reacted in the same manner, and the resulting product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (26 mg). Obtained. Blood— 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)

[0099] LC-MS (ESI, m / z) = 578.7 (M+H + ) Example 15. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-4-sulfamoylbenzamide

[0100] [Step 4] N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-

[0101] 4 - Sulfamoylbenzamide (Compound 15) Preparation Under the same conditions as [Step 4] of Example 11, 3 -sulfamoylbenzoic acid (10 mg, 0.547 mmole), dimethylformamide (5 mL), EDC-HCl (315 mg, 1.641 mmole) and HOBt -H2O (222 mg, 1.642 mmole) were added to the compound obtained in [Step 3] of Example 2 (0.199 g, 0.654 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+) and concentration, the title compound (106 mg) was obtained. P— 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)

[0102] LC-MS (ESI, m / z) = 488.6 (M+H + ) Example 16. N-(7-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-nitrobenzamide

[0103] [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 mmole), dimethylformamide (20 mL), potassium carbonate (4.56 g, 27.30 mmole), potassium iodide (0.14 g, 0.83 mmole) and 4-bromo-2-methylbutan-2-ol were used. The reaction was carried out in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P— 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)

[0104] [Step 2] Preparation of 4-(7-(furan-3-yl)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] (0.5 g, 1,52 mmole), sodium carbonate (0.81 g, 7.62 mmole), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmole) and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.44 g, 2.29 mmole) were reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound. (0.5 g) was obtained. P— 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)

[0105] [Step 3] Preparation of 4-(5-amino-7-(furan-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 1, the compound (0.5 g, 1.59 nmole) obtained in [Step 2] was hydrogenated by adding palladium on activated carbon (0.10 g, 0.2 w / w) and ethyl acetate (10 mL). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.44 g). P— 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)

[0106] [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 [Step 3] (0.173 g, 0.61 mmole), 3-nitrobenzoic acid (0.085 g, 0.51 mmole), HATU (0.777 g, 2.04 mmole), and DIPEA (0.35 mL, 2.04 mmole) were used, and the reaction was carried out in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (85 mg). 6H) , 1.42(m, 2H) , 1.81(d, 2H) , 2.02(t, 2H),

[0107] 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)

[0108] LC-MS (ESI, m / z) = 435.4 (M+H + ) Example 17. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazol-5-yl)-3-sulfamoylbenzamide

[0109] [step 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 mmole), potassium carbonate (2.23 g, 16.12 nmole), potassium iodide (100 mg, 0.6 mmole) and dimethylformamide (20 mL) were added to the compound (lg, 4.03 mmole) obtained in [Step 1] of Example 2, and the reaction was performed in the same manner.

[0110] The title compound (430 mg) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P- 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)

[0111] [Step 3] Preparation of 2-(2-(5-amino-6-morpholino-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in [Step 3] of Example 1, the compound (430 mg, 1.23 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL) and hydrogenated by adding palladium on activated carbon (65 mg, 0.15 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (393 mg). P- 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)

[0112] [Step 4] Preparation of N-(2-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazol-5-yl)-3-sulfamoylbenzamide (Compound 17) Under the same conditions as in [Step 4] of Example 11, the compound (98 mg, 0.31 mmole) obtained in [Step 3] was reacted in the same manner using 3-sulfamoylbenzoic acid (94 mg, 0.465 mmole), dimethylformamide (5 mL), EDC-HCl (178 mg, 0.93 mmole), and HOBt-H2O (126 mg, 0.93 mmole), and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (67 mg). P- 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)

[0113] LC-MS (ESI, m / z) = 503.5 (M+H + ) Example 18. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazol-5-yl)isophthalamide

[0114] [Step 4] Preparation of N-(2-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-morpholino-2H-indazol-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 mmole), 3-carbamoylbenzoic acid (65 mg, 0.39 mmole), dimethylformamide (lOmL), HATU (0.268 g, 0.71 mmole), and DIPEA (0.27 mL, 1.56 mmole) were reacted in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (29 mg). Pi-1 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)

[0115] LC-MS (ESI, m / z) = 467.5 (M+H + ) Example 19. N-(6-morpholino-2-(2-morpholinoethyl)-2H-indazol-5-yl)-3-nitrobenzamide

[0116] [Step 1] Preparation of 4-(2-(6-bromo-5-nitro-2H-indazol-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 mmole), potassium carbonate (11.42 g, 82.64 mmole), potassium iodide (0.5 g, 3.012 mmole), 4-(2-chloroethyl)morpholine hydrochloride (5.77 g, 31 mmole) and dimethylformamide (50 mL) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.5 g). P— 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)

[0117] [Step 2] Preparation of 4-(2-(6-morpholino-5-nitro-2H-indazol-2-yl)ethyl)morpholine Under the same conditions as [Step 1] of Example 2, morpholine (10 mL) was added to the compound (lg, 2.82 mmole) obtained in [Step 1], and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (1.15 g) was obtained. P- 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)

[0118] [Step 3] Preparation of 6-morpholino-2-(2-morpholinoethyl)-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (520 mg, 1.44 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL) and hydrogenated by adding palladium on activated carbon (78 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (476 mg). P— 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)

[0119] [Step 4] Preparation of N-(6-morpholino-2-(2-morpholinoethyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 19) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] (238 mg, 0.72 mmole), 3-nitrobenzoic acid (120 mg, 0.72 mmole), dimethylformamide (10 mL), HATUCl.lg, 2.88 mmole) and DIPEA (0.49 mL, 2.88 mmole) were reacted in the same manner, and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (38 mg). P— 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)

[0120] LC-MS (ESI, m / z) = 481.5 (M+H+ ) Example 20. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide

[0121] [Step 4] Preparation of 6-bromo- N- (2- (3-hydroxy- 3-methylbutyl)- 6-morpholino- 2H- indazol- 5 -yl) picolinamide

[0122] 6-Bromopicolinic acid (382 mg, 1.892 mmole) was added EDC-HC1 (453 mg, 2.366 mmole), H0Bt-H20 (320 mg, 2.366 mmole) and dichloromethane (20 mL) and stirred at room temperature for 2 hours. Thereafter, the compound obtained in [Step 3] of Example 2 (480 mg, 1.577 mmole) was added and stirred at room temperature for 3 hours. After completion of the reaction, dichloromethane (40 mL) was added and washed with purified water (40 mL). Anhydrous magnesium sulfate was added, filtered, concentrated under reduced pressure and purified by 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). P- 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)

[0123] [Step 5] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(1H-pyrazol-4-yl)picolinamide (Compound 20) To the compound (lOOmg, 0.2mmole) obtained in the above [Step 4], 4-pyrazole boronic acid pinacol ester (50mg, 0.26mmole), (1,1'-bis(diphenylphosphino)ferrocine)dichloropalladium-dichloromethane (l:l) (8mg, 0.013mmole), potassium carbonate (83mg, 0.6mmole), 1,4-dioxane (lmL) and purified water (0.2mL) were added and the mixture was stirred at 100°C for 23 hours. It was stirred. After the reaction was completed, the reaction solution was concentrated, ethyl acetate (50 mL) was added, and washed with purified water (50 mL). After that, anhydrous magnesium sulfate was added, filtered, concentrated under reduced pressure, and purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (18 mg) as a light brown solid. P— 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)

[0124] LC-MS (ESI, m / z) = 476.1 (M+H + ) Example 21. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(1H-pyrazol-5-yl)benzamide

[0125] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(1H-pyrazol-5-yl)benzamide (Compound 21) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (40 mg, 0.132 mmole), 6-(1H-pyrazol-5-yl)picolinic acid (30 mg, 0.159 mmole), EDC-HCl (38 mg, 0.198 mmole), HOBt-H2O (27 mg, 0.198 mmole) and dichloromethane (6 mL) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated. The title compound (10 mg) was obtained. P— 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)

[0126] LC-MS (ESI, m / z) = 476.1 (M+H + ) Example 22. 2-Fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3 ■Nitrobenzamide

[0127] [Step 4] Preparation of 2-fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 22) Under the same conditions as [Step 4] of Example 11, 2-fluoro-3-nitrobenzoic acid (90 mg, 0.542 mmole), dimethylformamide (5 mL), EDC-HCl (207 mg, 1.08 mmole), and HOBt-H2O (146 mg, 1.08 mmole) were added to the compound obtained in [Step 3] of Example 2 (0.11 g, 0.36 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the product was concentrated to obtain the title compound (77 mg). Blood— 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)

[0128] LC-MS (ESI, m / z) = 472.5 (M+H + ) Example 23. 4 -Amino- N- (2- (3 -hydroxy- 3 -methylbutyl)- 6 -morpholino- 2H -indazol- 5 -yl)- 3 ■Nitrobenzamide [Step 4] Preparation of 4-amino-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 23) Under the same conditions as [Step 4] of Example 11, 4-amino-3-nitrobenzoic acid (99 mg, 0.542 mmole), dimethylformamide (5 mL), EDC-HCl (207 mg, 1.08 mmole), and HOBt-H2O (146 mg, 1.08 mmole) were added to the compound obtained in [Step 3] of Example 2 (0.11 g, 0.36 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the product was concentrated to obtain the title compound (23 mg). 6H) , 1.98(t, 2H) , 2.88(m, 4H) , 3.81(m, 4H),

[0129] 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)

[0130] LC-MS (ESI, m / z) = 469.5 (M+H + ) Example 24. 3-Fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-5-nitrobenzamide

[0131] [Step 4] Preparation of 3-fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-5-nitrobenzamide (Compound 24) Under the same conditions as [Step 4] of Example 11, 3-fluoro-5-nitrobenzoic acid (lOOmg, 0.542mmole), dimethylformamide (5mL), EDC-HCl (207mg, 1.08mmole), and HOBt-H2O (146mg, 1.08mmole) were added to the compound obtained in [Step 3] of Example 2 (0.11g, 0.36mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the product was concentrated to obtain the title compound (23mg). P- NMR (DMSO-d 6 ) 1.12(s, 6H) , 2H) , 2.89(m, 4H) , 3.76(m, 4H),

[0132] 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)

[0133] LC-MS (ESI, m / z) = 472.5 (M+H + ) Example 25. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)isophthalamide

[0134] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)isophthalamide (Compound 25) Under the same conditions as in [Step 4] of Example 11, 3-carbamoylbenzoic acid (154 mg, 0.93 mmole), dimethylformamide (5 mL), EDC-HCl (357 mg, 1.86 mmole), and HOBt-H2O (251 mg, 1.86 mmole) were added to the compound obtained in [Step 3] of Example 2 (0.189 g, 0.62 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the product was concentrated to obtain the title compound (74 mg). P- NMR (DMSO-d 6 ) 1.12(d, 6H) , 2.00(t, 2H) , 2.88(m, 4H) , 3.76(m, 4H),

[0135] 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)

[0136] LC-MS (ESI, m / z) = 452.5 (M+H + ) Example 26. 4 —Fluoro— N— (2— (3 —hydroxy— 3 —methylbutyl) 1 6 —Morsolino- 2H~ indazol- 5 -yl)- 3 ■Nitrobenzamide

[0137] [Step 4] Preparation of 4-fluoro-N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 26) Under the same conditions as [Step 4] of Example 11, 4-fluoro-3-nitrobenzoic acid (lOOmg, 0.542mmole), dimethylformamide (5mL), EDC-HCl (207mg, 1.08mmole), and HOBt-H2O (146mg, 1.08mmole) were added to the compound obtained in [Step 3] of Example 2 (0.11g, 0.36mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the product was concentrated to obtain the title compound (7mg). P- 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)

[0138] LC-MS (ESI, m / z) = 472.5 (M+H + ) Example 27. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-(thiazol-2-yl)benzamide

[0139] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-3-(thiazol-2-yl)benzamide (Compound 27) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.086 g, 0.283 mmole) was added 3-(1,3-thiazol-2-yl)benzoic acid (0.076 g, 0.37 mmole), dichloromethane (8 mL), EDC-HCl (0.081 g, 0.425 mmole) and HOBt^20 (0.057 g,

[0140] 0.425 mmole) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (47 mg). P— 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-indazol-5-yl)-3-nitrobenzamide

[0141] [Step 2] Preparation of 2-methyl-4-(6-morpholino-5-nitro-1H-indazol-1-yl)butan-2-ol Under the same conditions as [Step 1] of Example 1, 4-bromo-2-methylbutan-2-ol (1.89 mL, 15.5 mmole), potassium carbonate (5.7 g, 41.32 mmole), potassium iodide (257 mg, 1.55 mmole) and dimethylformamide (10 mL) were added to the compound obtained in [Step 1] of Example 2 (2.57 g, 10.33 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+) and concentration, the title compound (1.8 g) was obtained. P- 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)

[0142] [Step 3] Preparation of 4-(5-amino-6-morpholino-1H-indazol-1-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound (lOOmg, 0.3mmole) obtained in [Step 2] was dissolved in ethyl acetate (10mL) and hydrogenated by adding palladium on activated carbon (20mg, 0.2w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (91mg). 6H) , 1.95(m, 2H) , 2.75(t, 4H) , 3.48(t, 4H),

[0143] 4.35(m, 2H), 4.36(s, 1H) , 4.50(s, 2H) , 7.41(s, 1H) , 7.75(s, 1H) , 8.05(s, 1H)

[0144] [Step 4] Preparation of N-(1-(3-hydroxy-3-methylbutyl)-6-morpholino-1H-indazol-5-yl)-3-nitrobenzamide (Compound 28) Under the same conditions as in [Step 4] of Example 11, the compound of [Step 3] (91 mg, 0.3 mmole) was reacted in the same manner using 3-nitrobenzoic acid (50 mg, 0.3 mmole), dimethylformamide (10 mL), EDC-HCl (173 mg, 0.9 mmole), and HOBt-H2O (122 mg, 0.9 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (84 mg). P— 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)

[0145] LC-MS (ESI, m / z) = 456.5 (M+H + ) . Example 29. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2H-indazol-5-yl)-3-sulfamoylbenzamide

[0146] [Step 1] Preparation of 2-(1-(5-nitro-1H-indazol-6-yl)piperidin-4-yl)propan-2-ol

[0147] 6-Bromo-5-nitro-1H-indazole (4 g, 16.53 mmole) was added 2-piperidin-4-ylpropan-2-ol (9.47 g, 66.11 mmole) and DMSO (15 mL) and stirred at 120°C for 3 days. After completion of the reaction, ethyl acetate (150 mL) was added, washed with purified water (150 mL), anhydrous magnesium sulfate was added, and filtered. After concentration under reduced pressure, the title compound (2.82 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+). P- 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)

[0148] [Step 2] Preparation of 4-(6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 2] of Example 2, the compound obtained in [Step 1] (2.8 g, 9.2 mmole), 4-bromo-2-methylbutan-2-ol (1.68 mL, 13.8 mmole), potassium carbonate (5.09 g, 36.8 mmole), potassium iodide (0.28 g, 1.69 mmole), and dimethylformamide (56 mL) were used in the same manner, and the reaction was followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.9 g). P- NMR (DMSO-d 6 ) 1.06(s, 6H) , 1.35(m, 1H) , 1.42(m, 2H),

[0149] 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)

[0150] [Step 3] Preparation of 4-(5-amino-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 2, the compound (900 mg, 2.3 mmole) obtained in [Step 2] was dissolved in ethyl acetate (45 mL) and hydrogenated by adding palladium on activated carbon (200 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (320 mg). P- NMR (DMSO-d 6 ) 1.06(s, 6H) , 1.35(m, 1H) , 1.42(m, 2H),

[0151] 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)

[0152] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2H-indazol-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 mmole), 3-sulfamoylbenzoic acid (54.2 mg, 0.266 mmole), EDC-HC1 (64 mg,

[0153] The reaction was carried out in the same manner using HOBt-H20 (46 mg, 0.333 mmole) and dichloromethane (5 mL), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (18 mg). P- NMR (DMSO-d 6 ) 1.06(s, 6H) , 1.35(m, 1H) , 1.43(m, 2H),

[0154] 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)

[0155] LC-MS (ESI, m / z) = 544.7 (M+H + ) Example 30. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2H-indazol-5-yl)-3 Nitrobenzamide

[0156] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 30) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] of Example 29 (80 mg, 0.222 mmole), 3-nitrobenzoic acid (44.4 mg, 0.266 mmole), EDC-HCl (64 mg, 0.333 mmole), HOBt-H2O (46 mg, 0.333 mmole) and dichloromethane (5 mL) were reacted in the same manner, and then the product was purified by MPLC (combiFlash NEXTGEN 300+). The title compound (28 mg) was obtained by purification and concentration. P— 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)

[0157] LC-MS (ESI, m / z) = 510.6 (M+H + ) Example 31. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidin-1-yl)-2H-indazol-5-yl)-3-sulfamoylbenzamide

[0158] [Step 2] Preparation of 1-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)piperidin-4-ol Under the same conditions as [Step 1] of Example 29, 4-hydroxypiperidine (9.247 g, 91,4 mmole) and DMS0 (5 mL) were added to the compound (3 g, 9.142 mmole) obtained in [Step 1] of Example 4, and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (0.33 g) was obtained. P- 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)

[0159] [Step 3] Preparation of 1-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)piperidin-4-ol Under the same conditions as in [Step 3] of Example 2, the compound (330 mg, 0.947 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL) and hydrogenated by adding palladium on activated carbon (66 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (302 mg). P- 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)

[0160] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidin-1-yl)-2H-indazol-5-yl)-3-sulfamoylbenzamide (Compound 31) Under the same conditions as in [Step 4] of Example 11, the compound obtained in [Step 3] (lOOmg, 0.314mmole), 3-sulfamoylbenzoic acid (95mg, 0.471mmole), EDC-HC1 (181mg, 0.942mmole), HOBt-H20 (127mg, 0.942mmole) and dimethylformamide (5mL) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (21 mg) was obtained. P- 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)

[0161] LC-MS (ESI, m / z) = 502.6 (M+H + ) Example 32. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidin-1-yl)-2H-indazol-5-yl)-3 ■Nitrobenzamide

[0162] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxypiperidin-1-yl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 32) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] of Example 31 (lOOmg, 0.314mmole), 3-nitrobenzoic acid (79mg, 0.471mmole), EDC-HCl (181mg, 0.942mmole), HOBt-H2O (127mg, 0.942mmole) and dimethylformamide (5mL) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (28 mg) was obtained. P- 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)

[0163] LC-MS (ESI, m / z) = 468.5 (M+H + ) Example 33. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6 ■Thiomorpholino- 2H-indazole-

[0164] 5-day) Isophthalamide

[0165] [Step 2] Preparation of 2-methyl-4-(5-nitro-6-thiomorpholino-2H-indazol-2-yl)butan-2-ol To the compound (2 g, 6.09 mmole) obtained in [Step 1] of Example 4, thiomorpholine (10 mL), DIPEA (3.1 mL, 18.28 mmole) and DMSO (lOmL) were added and stirred at 100°C for 7 days. After completion of the reaction, ethyl acetate (50 mL) was added and washed with purified water (50 mL), anhydrous magnesium sulfate was added and filtered. After concentration under reduced pressure, the residue was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (670 mg). P— 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)

[0166] [Step 3] Preparation of 4-(5-amino-6-thiomorpholino-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound (670 mg, 1.91 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL) and hydrogenated with palladium on activated carbon (lOl mg, 0.15 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (613 mg). P— 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-indazol-5-yl)isophthalamide (Compound 33) Under the same conditions as in [Step 4] of Example 11, the compound (0.150 g, 3-Carbamoylbenzoic acid (65 mg, 0.394 mmole), dimethylformamide (5 mL), EDC-HCl (227 mg, 1.18 mmole) and HOBt-H2O (158 mg, 1.169 mmole) were used in the same manner, and the reaction was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (20 mg). P— 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)

[0167] LC-MS (ESI, m / z) = 468.6 (M+H + ) Example 34. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-3-nitrobenzamide

[0168] [Step 2] Preparation of 4-(2-(6-(4-fluorophenyl)-5-nitro-2H-indazol-2-yl)ethyl)morpholine Under the same conditions as [Step 2] of Example 1, the compound (1.0 g, 2.82 mmole) obtained in [Step 1] of Example 19 was reacted in the same manner using sodium carbonate (1.49 g, 14.8 mmole), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmole), and (4-fluorophenyl)boronic acid (0.59 g, 4.22 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.86 g). P— 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-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (0.8 g, 2.16 mmole) obtained in [Step 2] was added with ethyl acetate (80 mL) and palladium on activated carbon. (0.16 g, 0.2 w / w) was added and hydrogenated. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain the title compound (0.61 g). P— 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)

[0169] [Step 4] Preparation of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 34) Under the same conditions as in [Step 4] of Example 1, the compound (0.2 g, 0.59 mmole) obtained in [Step 3] was reacted in the same manner using 3-nitrobenzoic acid (99 mg, 0.59 mmole), dimethylformamide (2 mL), HATU (0.45 g, 1.18 mmole), and DIPEA (0.41 mL, 2.35 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.2 g). P— 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)

[0170] LC-MS (ESI, m / z) = 490.5 (M+H + ) Example 35. N-(2-(3-hydroxy-3 ■methylbutyl)-6-(3-(morpholine-4-carbonyl)phenyl)-2H-indazol-5 -yl)-3 ■nitrobenzamide

[0171] [Step 1] Preparation of 3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-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 mmole), sodium carbonate (1.94 g, 18.3 mmole), tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmole) and 3-carboxyphenylboronic acid pinacol ester (1.44 g, 5.48 mmole) were used, and the reaction was carried out in the same manner. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.01 g). P— 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)

[0172] [Step 2] Preparation of (3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)phenyl)(morpholino)methanone Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 1] (0.5 g, 1.66 mmole), morpholine (0.14 g, 1.66 mmole), EDC-HCl (0.48 g, 2.49 mmole), HOBt^20 (0.34 g, 2.49 mmole) and dichloromethane (2 mL) were used, and the reaction was carried out in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (120 mg). P— 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)

[0173] [Step 3] Preparation of (3-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)phenyl)(morpholino)methanone Under the same conditions as [Step 3] of Example 1, the compound (0.5 g, 1.14 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL), and then palladium on activated carbon (0.02 g, 0.2 w / w) was added to hydrogenate. After the reaction, the mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.1 g). P— 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)

[0174] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(3-(morpholine-4-carbonyl)phenyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 35) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] (0.4 g, 0.98 mmole), 3-nitrobenzoic acid (0.16 g, 0.98 mmole), dimethylformamide (10 mL), HATU (0.74 g, 1.96 mmole) and DIPEA (0.68 mL, 3.92 mmole) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.4 g) was obtained. P— 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)

[0175] LC-MS (ESI, m / z) = 558.1 (M+H + ) Example 36. N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(thiophene-3-yl)picolinamide

[0176] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-morpholino-2H-indazol-5-yl)-6-(thiophene-3-yl)picolinamide (Compound 36) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] of Example 2 (0.086 g, 0.283 mmole) was reacted in the same manner using 6-(thiophene-3-yl)picolinic acid (76 mg, 0.37 mmole), dichloromethane (8 mL), EDC-HCl (0.081 g, 0.425 mmole) and HOBt^20 (0.057 g, 0.425 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated. The title compound (48 mg) was obtained. P— 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)

[0177] LC-MS (ESI, m / z) = 492.1 (M+H + ) Example 37. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-morpholinophenyl)-2H-indazol-5-yl)-3 ■Nitrobenzamide

[0178] [Step 2] Preparation of 2-methyl-4-(6-(4-morpholinophenyl)-5-nitro-2H-indazol-2-yl)butan-2-ol Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] of Example 4 (0.5 g, 1,52 mmole), sodium carbonate (0.81 g, 7.61 mmole), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmole), 4-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.66 g, 2.29 mmole), 1,4-dioxane (20 mL) and purified water (2 mL) were used to prepare the compound. The title compound (0.5 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— 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)

[0179] [Step 3] Preparation of 4-(5-amino-6-(4-morpholinophenyl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound (0.5 g, 1.22 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL), palladium on activated carbon (0.10 g, 0.093 mmole) was added, and hydrogenation was performed. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.36 g). P— 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)

[0180] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-morpholinophenyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 37) Under the same conditions as [Step 4] of Example 1, the compound (0.4 g, 1.05 mmole) obtained in [Step 3] was reacted in the same manner using 3-nitrobenzoic acid (0.18 g, 1.05 mmole), dimethylformamide (5 mL), HATU (0.80 g, 2.10 mmole), and DIPEA (0.73 mL, 4.21 mmole), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (30 mg). P— 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)

[0181] LC-MS (ESI, m / z) = 530.4 (M+H + ) Example 38. N-(6-(dimethylamino)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-nitrobenzamide

[0182] [Step 1] Preparation of N,N-dimethyl-5-nitro-1H-indazol-6-amine

[0183] 6-Bromo-5-nitro-1H-indazole (5g, 20.66mmole) was added dimethylformamide (20mL) and potassium iodide (500mg, 3.012mmole).

[0184] The mixture was stirred at 120°C for 3 days. After completion of the reaction, ethyl acetate (200 mL) was added, washed with purified water (200 mL), anhydrous magnesium sulfate was added, and filtered. After concentration under reduced pressure, the mixture was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (2.12 g) as an orange solid. P- NMR (DMSO-d 6 ) 2.74(s, 6H), 7.20(s 1H), 8.14(s, 1H), 8.32(s, 1H)

[0185] [Step 2] Preparation of 4-(6-(dimethylamino)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol To the compound obtained in [Step 1] (2.12 g, 10.28 mmole), 4-bromo-2-methylbutan-2-ol (1.874 mL, 15.42 mmole), potassium carbonate (5.68 g, 41.12 mmole), potassium iodide (212 mg, 1.277 mmole), and dimethylformamide (20 mL) were added, and the mixture was stirred at 90°C for 5 hours. After completion of the reaction, ethyl acetate (50 mL) was added, the mixture was washed with purified water (50 mL), and anhydrous magnesium sulfate was added and filtered. After concentration under reduced pressure, the product was purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.3 g) as an orange solid. 6H) , 1.99(m, 2H) , 2.67(s , 6H) , 4.47(t , 2H) ,

[0186] 4.48(s , 1H) , 7.30(s , 1H) , 8.29(s , 1H) , 8.54(s , 1H)

[0187] [Step 3] Preparation of 4-(5-amino-6-(dimethylamino)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 2, the compound (lOOmg, 0.342mmole) obtained in [Step 2] was added with palladium on activated carbon (20mg, 10w / w), dichloromethane (20mL), and ethyl acetate (20mL), and hydrogenation was performed using the same method. The reaction solution was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain the title compound (90mg). 6H) , 1.95(m, 2H) , 2.54(s, 6H) , 4.35(m, 2H),

[0188] 4.36(s, 1H), 4.40(s, 2H) , 7.29(s, 1H) , 7.75(s, 1H) , 8.05(s, 1H)

[0189] [Step 4] Preparation of N-(6-(dimethylamino)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 38) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] (90 mg, 0.342 mmole), 3-nitrobenzoic acid (68.6 mg, 0.41 mmole), EDC-HC1 (98 mg, 0.513 mmole), HOBt-H2O (69 mg, 0.513 mmole) and dichloromethane (5 mL) were used in the same manner, and then dichloromethane (20 mL) was added and washed with purified water (20 mL). Anhydrous magnesium sulfate was added, 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). P— 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)

[0190] LC-MS (ESI, m / z) = 412.3 (M+H + ) Example 39. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(morpholinomethyl)phenyl)-2H-indazol-5-yl)-3-sulfamoylbenzamide

[0191] [Step 2] Preparation of 2-methyl-4-(5-nitro-6-(4-(trifluoromethyl)phenyl)-2H-indazol-2-yl)butan-2-ol Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] of Example 4 (1.0 g, 3.05 mmole), sodium carbonate (1.61 g, 15.24 mmole), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmole), 4-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)morpholine (1.39, 4.57 mmole), 1,4-dioxane (10 mL) and purified water (1 mL) were reacted in the same manner. The title compound (1.10 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d 6 ) 1.12(s, 6H) , 2.02(t, 2H) , 3.61(br. s, 4H) , 3.50(t,

[0192] 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)

[0193] [Step 3] Preparation of 4-(5-amino-6-(4-(trifluoromethyl)phenyl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound (1.0 g, 2.36 mmole) obtained in [Step 2] was dissolved in ethyl acetate (20 mL) and hydrogenated by adding palladium on activated carbon (0.2 g, 0.2 w / w). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.72 g). P— 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)

[0194] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(morpholinomethyl)phenyl)-2H-indazol-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 mmole), 3-sulfamoylbenzoic acid (0.06 g, 0.28 mmole), HATU (0.21 g, 0.56 mmole) and DIPEA (0.19 mL, 1.12 mmole) were used, and the reaction was carried out in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.13 g). P— 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)

[0195] LC-MS (ESI, m / z) = 578.1 (M+H + ) Example 40. N-(2-(3-hydroxy-3-methylbutyl)-6-thiomorpholino-2H-indazole-boal)sangenitrobenzamide

[0196] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-thiomorpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 40) Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] of Example 33 (0.150 g, 0.468 mmole) was reacted in the same manner using 3-nitrobenzoic acid (65 mg, 0.389 mmole), dimethylformamide (5 mL), EDC-HCl (224 mg, 1.17 mmole), and HOBt-H2O (158 mg, 1.169 mmole), and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (14 mg). P- 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)

[0197] 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-indazol-5-yl)-3 Nitrobenzamide

[0198] [Step 2] Preparation of methyl (4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzoyl)glycinate Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] of Example 4 (1.9 g, 5.79 mmole), sodium carbonate (3.07 g, 28.9 mmole), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmole), (4-((2-methoxy-2-oxoethyl)carbamoyl)phenyl)boronic acid (2.06 g, 8.68 mmole), 1,4-dioxane (20 mL) and purified water (2 mL) were reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated. The title compound (1.84 g) was obtained. P- 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)

[0199] [Step 3] Preparation of methyl (4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)benzoyl)glycinate Under the same conditions as [Step 3] of Example 1, the compound (1.5 g, 3.41 mmole) obtained in [Step 2] was hydrogenated by adding palladium on activated carbon (0.3 g, 0.2 w / w) and ethyl acetate (20 mL). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (1.92 g). 6H) , 2.01- 2.03(m, 2H) , 3.62(s, 3H) , 4.35(d,

[0200] 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)

[0201] [Step 4] Preparation of methyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(3-nitrobenzamido)-2H-indazol-6-yl)benzoyl)glycinate Under the same conditions as [Step 4] of Example 11, the compound obtained in [Step 3] (1.5 g, 3.65 mmole) was reacted in the same manner using 3-nitrobenzoic acid (0.67 g, 3.65 mmole), dichloromethane (15 mL), EDC-HCl (1.05 g, 5.48 mmole), and HOBt^20 (0.74 g, 5.48 mmole), and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.60 g). 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)

[0202] [Step 5] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2-(methylamino)-2-oxoethyl)carbamoyl)phenyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 41) To the compound (0.1 g, 0.17 mmole) obtained in the above [Step 4], 40% N-methylamine in methanol solution (10 ml) was added, stirred at 120 °C for 6 hours, concentrated, and purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.25 g). P- 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)

[0203] 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-indazol-5 -yl)-3 -sulfamoylbenzamide

[0204] [Step 2] Preparation of methyl 4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-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 mmole), sodium carbonate (3.07 g, 28.9 mmole), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmole) and methyl 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.28 g, 8.68 mmole) were reacted in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound. (1.61 g) was obtained. P— 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)

[0205] [Step 3] Preparation of methyl 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)benzoate Under the same conditions as in [Step 3] of Example 2, the compound (1.5 g, 3.91 mmole) obtained in [Step 2] was dissolved in ethyl acetate (30 mL) and hydrogenated with palladium on activated carbon (0.3 g, 0.2 w / w). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (1.18 g). P— 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)

[0206] [Step 4] Preparation of methyl 4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)benzoate Under the same conditions as [Step 4] of Example 11, 3-sulfamoyl benzoic acid (0.68 g, 3.11 mmole), dichloromethane (llmL), EDC-HCl (0.90 g, 4.67 mmole), and HOBt^20 (0.63 g, 4.67 mmole) were added to the compound obtained in [Step 3] (1.1 g, 3.11 mmole), and the reaction was carried out under the same conditions. After purification by MPLC (combiFlash NEXTGEN 300+), concentration, and drying, the title compound (1.2 g) was obtained. Blood— 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)

[0207] [Step 5] Preparation of 4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamide)-2H-indazol-6-yl)benzoic acid Tetrahydrofuran (22 mL) and 2N sodium hydroxide aqueous solution (11 mL) were added to the compound obtained in the above [Step 4] (1.1 g, 2.05 mmole), and stirred at room temperature for more than 3 hours. After completion of the reaction, 2N hydrochloric acid aqueous solution was added to adjust the pH to 4-5, concentrated, filtered, washed with purified water, and dried to obtain the title compound (0.81 g). p- 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)

[0208] [Step 6] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2,2,2-trifluoroethyl)carbamoyl)phenyl)-2H-indazol-5-yl)-3-sulfamoylbenzamide (Compound 42) Under the same conditions as [Step 4] of Example 11, 2,2,2-trifluoroethane-1-amine (0.04 g, 0.40 mmole), dichloromethane (2 mL), EDC-HCl (0.12 g, 0.61 mmole), and HOBt^20 (0.08 g, 0.61 mmole) were added to the compound obtained in [Step 5], and the reaction was performed in the same manner, followed by MPLC (combiFlash NEXTGEN 300+). The title compound (0.16 g) was obtained by purification, concentration, and drying. P— 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)

[0209] 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-indazol-5-yl)-3-nitrobenzamide

[0210] [Step 5] Preparation of 4-(2-(3-hydroxy-3-methylbutyl)-5-(3-nitrobenzamido)-2H-indazol-6-yl)benzoic acid The compound obtained in [Step 4] of Example 41 (0.5 g, Immole), tetrahydrofuran (10 mL) and 2N sodium hydroxide aqueous solution (5 mL) were added and stirred at room temperature for 3 hours. After completion of the reaction, 2N hydrochloric acid aqueous solution was added to adjust the pH to 4-5, concentrated, filtered, washed with purified water and dried to obtain the title compound (0.3 g). P- 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)

[0211] [Step 6] Preparation of N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 43) Under the same conditions as [Step 4] of Example 11, the compound (0.3 g, 0.42 mmole) obtained in [Step 5] was added with glycinamide hydrochloride (0.06 g, 0.51 mmole), dichloromethane (3 ml), EDC - HC1 (0.15 g, 0.76 mmole), and H0Bt-H20 (0.1 g, 0.76 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the product was concentrated to obtain the title compound. (0.2 g) was obtained. P- 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)

[0212] LC-MS (ESI, m / z) = 545.6 (M+H + ) Example 44. N- (2- (3 -hydroxy- 3 -methylbutyl)- 6- (4-

[0213] (Methoxycarbamoyl)phenyl)-2H-indazole-5-yl)-3-sulfamoylbenzamide

[0214] [Step 4] Preparation of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(methoxycarbamoyl)phenyl)-2H-indazol-5-yl)-3-sulfamoylbenzamide (Compound 44) ​​Under the same conditions as [Step 4] of Example 11, hydroxyamine-0-sulfonic acid (0.05 g, 0.40 mmole), dichloromethane (2 mL), EDC-HCl (0.12 g, 0.61 mmole) and HOBt^20 (0.08 g, 0.61 mmole) were added to the compound obtained in [Step 5] of Example 42, and the reaction was carried out in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. The residue was dried to obtain the title compound (0.12 g). P— 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)

[0215] LC-MS (ESI, m / z) = 552.0 (M+H + ) Example 45. N-(2-(2-hydroxy-2 ■methylpropyl)-6-thiomorpholino-2H-indazol-5 -yl)- 3 ■nitrobenzamide

[0216] [Step 1] Preparation of 4-(5-nitro-1H-indazol-6-yl)thiomorpholine Under the same conditions as in [Step 2] of Example 33, 6-bromo-5-nitro-1H-indazole (2.9 g, 12 mmole) was added thiomorpholine (20 mL), DIPEA (6.2 mL, 36.56 mmole) and DMSO (20 mL), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the title compound (1.34 g) was obtained. P— NMR (DMSO-d 6 ) 2.57(t, 4H) , 3.37(t, 4H) , 7.20(s 1H) , 8.12(s, 1H) , 8.30(s, 1H)

[0217] [Step 2] Preparation of 2-methyl-1-(5-nitro-6-thiomorpholino-2H-indazol-2-yl)propan-2-ol Under the same conditions as [Step 1] of Example 1, the compound obtained in [Step 1] (lg, 3.78 mmole), potassium carbonate (2.1 g, 15.12 mmole), potassium iodide (0.1 g, 0.6 mmole), 1-chloro-2-methyl-2-propanol (0.5 mL, 5.67 mmole) and dimethylformamide (50 mL) were used, and the reaction was carried out in the same manner. After the reaction, the title compound (0.32 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— 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)

[0218] [Step 3] Preparation of 1-(5-amino-6-thiomorpholino-2H-indazol-2-yl)-2-methylpropan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound (320 mg, 0.95 mmole) obtained in [Step 2] was dissolved in ethyl acetate (20 mL) and hydrogenated with palladium on activated carbon (64 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (291 mg). P— 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)

[0219] [[Step 4]] Preparation of N-(2-(2-hydroxy-2-methylpropyl)-6-thiomorpholino-2H-indazol-5-yl)-3-nitrobenzamide (Compound 45) Under the same conditions as in [[Step 4]] of Example 11, to the compound (97 mg, 0.317 mmol) obtained in [[Step 3]] above, 3-nitrobenzoic acid (43 mg, 0.257 mmol), dimethylformamide (10 mL), EDC-HCl (165 mg, 0.95 mmol) and HOBt (116 μL, 0.95 mmol) were used and reacted in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+) and concentration, the title compound (20 mg) was obtained. 1H-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)

[0220] LC-MS (ESI, m / z) = 456.5 (M+H + ) Example 46. N-(6-(4-carbamoylphenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-sulfamoylbenzamide

[0221] [[Step 6]] Preparation of N-(6-(4-carbamoylphenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-3-sulfamoylbenzamide (Compound 46) To the compound (0.2 g, 0.40 mmol) obtained in [[Step 5]] of Example 42, 7N ammonia in methanol solution (20 mL) was added, and the mixture was stirred at 120 °C for at least 24 hours. After completion of the reaction, the mixture was cooled and concentrated, and then purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (0.08 g). 1H-NMR (DMSO-d6 ) 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)

[0222] LC-MS (ESI, m / z) = 522.0 (M+H+) Example 47. Ethyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)benzoyl)-D-valinate

[0223] [Step 6] Preparation of ethyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)benzoyl)-D-valinate (Compound 47) In Example 42, the compound (0.2 g, 0.40 mmole) obtained in [Step 5] was added L-valine ethyl ester hydrochloride (0.02 g, 0.40 mmole), dichloromethane (2 mL), EDC-HCl (0.12 g, 0.61 mmole), and HOBt^20 (0.08 g, 0.61 mmole), and the reaction was continued in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+), concentrated, and dried to obtain the title compound (0.11 g). P- 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)

[0224] LC-MS (ESI, m / z) = 650.0 (M+H+) Example 48. Methyl 3-(5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)nicotinamido)propanoate

[0225] [Step 2] Preparation of methyl 5-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)nicotinate Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] of Example 4 (0.5 g, 1,52 mmole), sodium carbonate (0.81 g, 7.61 mmole), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmole), 4-methyl 5-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.60 g, 2.29 mmole), 1,4-dioxane (10 mL) and purified water (1 mL) were reacted in the same manner. The title compound (0.5 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— 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,

[0226] 1H) [Step 3] Preparation of methyl 5-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)nicotinate Under the same conditions as [Step 3] of Example 1, the compound (0.5 g, 1.30 mmole) obtained in [Step 2] was dissolved in ethyl acetate (10 mL) and hydrogenated by adding palladium on activated carbon (0.10 g, 0.093 mmole). The title compound (0.4 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+). P- 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)

[0227] [Step 4] Preparation of methyl 5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-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 mmole), 3-sulfamoylbenzoic acid (0.23 g, 1.13 mmole), dimethylformamide (20 mL), HATU (0.86 g, 2.26 mmole), and DIPEA (0.79 mL, 4.51 mmole) were used, and the reaction was carried out in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (210 mg). P— 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)

[0228] [Step 5] Preparation of 5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)nicotinic acid The compound obtained in the above [Step 4] (0.5 g, 0.93 mmole) was dissolved in tetrahydrofuran (5 mL), methanol (2.5 mL) and purified water (2.5 mL), potassium hydroxide (0.21 g, 3.74 mmole) was added and stirred at 60°C for 3 hours. After completion of the reaction, it was cooled to room temperature and concentrated under reduced pressure. Distilled water (lOmL) was added and washed with ethyl acetate (10 mL), and the pH of the aqueous layer was adjusted to 4 using 1 N hydrochloric acid, and the precipitated solid was filtered and dried to obtain the title compound (0.4 g). P— 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)

[0229] [Step 6] Preparation of methyl 3-(5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)nicotinamido)propanoate (Compound 48) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 5] (0.4 g, 0.76 mmole) was added with methyl 3-aminopropanoate hydrochloride (0.11 g, 0.76 mmole), dimethylformamide (10 mL), HATU (0.58 g, 1.53 mmole), and

[0230] DIPEA (0.53 mL, 3.06 mmole) was added and the reaction was carried out in the same manner. The title compound (0.4 g) was obtained by purification using MPLC (combiFlash NEXTGEN 300+). P— 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) ,

[0231] 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-

[0232] 3 ■Methylbutyl)-2H-indazol-5-yl)isophthalamide

[0233] [Step 2] Preparation of N-(furan-3-ylmethyl)-4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzamide Under the same conditions as [Step 2] of Example 1, the compound obtained in [Step 1] of Example 4 (1.0 g, 3.05 mmole), sodium carbonate (1.61 g, 15.24 mmole), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmole), and N-(furan-3-ylmethyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)benzamide (1.5 g, 4.57 mmole) were used in the same manner as in [Step 2] of Example 1. After purification by MPLC (combiFlash NEXTGEN 300+) and concentration, the title compound (1.18 g) was obtained. P— 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)

[0234] [Step 3] Preparation of 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)-N-(furan-3-ylmethyl)benzamide Under the same conditions as [Step 3] of Example 1, the compound (1.0 g, 2.23 mmole) obtained in [Step 2] was hydrogenated by adding palladium on activated carbon (0.2 g, 0.2 w / w) and ethyl acetate (20 mL). The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.77 g). P- 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)

[0235] [Step 4] Preparation of N-(6-(4-((furan-3-ylmethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)isophthalamide (Compound 49) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] (0.20 g, 0.48 mmole) was reacted in the same manner using 3-carbamoylbenzoic acid (0.08 g, 0.48 mmole), dimethylformamide (2 mL), HATU (0.36 g, 0.96 mmole), and DIPEA (0.33 mL, 1.91 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.2 g) was obtained. P— 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)

[0236] LC-MS (ESI, m / z) = 566.1 (M+H + ) Example 50. N-(2-(2-hydroxy-2-methylpropyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)~3"nitrobenzamide

[0237] [Step 1] Preparation of 1-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylpropan-2-ol

[0238] 6-Bromo-5-nitro-2H-indazole (2 g, 8.26 mmole) was added dimethylformamide (20 mL), potassium carbonate (4.56 g, 27.30 mmole), potassium iodide (0.14 g, 0.83 mmole), and 1-chloro-2-methylpropan-2-ol (1.312 g, 12.39 mmole) and stirred at 100°C for 5 h. After the reaction, ethyl acetate (50 mL) was added and washed with purified water. After drying over magnesium sulfate and filtering, the filtrate was concentrated and purified by MPLC (combiFlash NEXTGEN 300+) to obtain the title compound (1.16 g).

[0239] ^-NMRCDMSO-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)

[0240] [Step 2] Preparation of 2-methyl-1-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)propan-2-ol Under the same conditions as [Step 2] of Example 1, sodium carbonate (1.72 g, 16.23 mmole), tetrakis(triphenylphosphine)palladium (0.19 g, 0.16 mmole), 4,4,5,5-tetramethyl-2-(thiophene-3-yl)-1,3,2-dioxoborane (1.02 g, 4.875 mmole), 1,4-dioxane (15 mL) and purified water (1.5 mL) were added to the compound obtained in [Step 1], and the reaction was carried out in the same manner, followed by MPLC (combiFlash) The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.79 g).

[0241] ^-NMRCDMSO-d6 ) 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)

[0242] [Step 3] Preparation of 1-(5-amino-6-(thiophene-3-yl)-2H-indazol-2-yl)-2-methylpropan-2-ol Under the same conditions as [Step 3] of Example 2, the compound (0.36 g, 2 mmole) obtained in [Step 2] was dissolved in ethyl acetate (5 mL), and then palladium on activated carbon (0.128 g, 0.1 mmole) was added to hydrogenate. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.26 g). P- 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)

[0243] [Step 4] Preparation of N-(2-(2-hydroxy-2-methylpropyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-3-nitrobenzamide (Compound 50) Under the same conditions as [Step 4] of Example 1, 3-nitrobenzoic acid (0.23 g, 1.39 mmole), dimethylformamide (10 mL), HATU (1.06 g, 2.78 mmole), and DIPEA (0.97 mL, 5.57 mmole) were added to the compound obtained in [Step 3] (0.4 g, 1.39 mmole), and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the mixture was concentrated, and the title compound (0.3 g) was obtained. P- 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)

[0244] LC-MS (ESI, m / z) = 437.2 (M+H + ) Example 51. (R)-5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)-N-(1-(methylamino)-1-oxopropan-2-yl)nicotinamide

[0245] [Step 7] Preparation of (R)-5-(2-(3-hydroxy-3-methylbutyl)-5-(3-sulfamoylbenzamido)-2H-indazol-6-yl)-N-(1-(methylamino)-1-oxopropan-2-yl)nicotinamide (Compound 51) Under the same conditions as [Step 4] of Example 11, (R)-2-amino-N-methylpropanamide (0.13g, 0.94mmole), dichloromethane (5mL), EDC-HCl (0.27g, 1.41mmole), and HOBt^20 (0.19g, 1.41mmole) were added to the compound (0.5g, 0.94mmole) obtained in [Step 6] of Example 48, and the reaction was carried out in the same manner. The title compound (0.41 g) was obtained after purification by MPLC (combiFlash NEXTGEN 300+), concentration and drying. P— 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)

[0246] LC-MS (ESI, m / z) = 608.0 (M+H + ) Example 52. N-(1-(2-(methylsulfonyl)ethyl)-6-morpholino-1H-indazol-5-yl)-3-nitrobenzamide

[0247] [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, 2-bromoethyl methyl sulfone (5.8 g, 31 mmole), potassium carbonate (5.7 g, 41.32 mmole), potassium iodide (257 mg, 1.55 mmole) and dimethylformamide (50 mL) were added to 6-bromo-5-nitro-2H-indazole (5 g, 20.66 mmole), and the mixture was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (3.5 g). P— 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)

[0248] [Step 2] Preparation of 4-(2-(2-(methylsulfonyl)ethyl)-5-nitro-2H-indazol-6-yl)morpholine Under the same conditions as [Step 1] of Example 2, morpholine (10 mL) was added to the compound (3.5 g, lOmmole) obtained in [Step 1], and the reaction was carried out in the same manner. After purification by MPLC (combiFlash NEXTGEN 300+), the mixture was concentrated to obtain the title compound (1.3 g). P— 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)

[0249] [Step 3] Preparation of 2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound (1.3 g, 4 mmole) obtained in [Step 2] was dissolved in ethyl acetate (lOOmL) and hydrogenated by adding palladium on activated carbon (109 mg, 0.2 w / w). The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.15 g). P- 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)

[0250] [Step 4] Preparation of N-(1-(2-(methylsulfonyl)ethyl)-6-morpholino-1H-indazol-5-yl)-3-nitrobenzamide (Compound 52) Under the same conditions as in [Step 4] of Example 11, the compound (136 mg, 0.42 mmole) obtained in [Step 3] was reacted in the same manner using 3-nitrobenzoic acid (64 mg, 0.383 mmole), dimethylformamide (lOmL), EDC-HCl (0.22 g, 1.15 mmole), and HOBt-H2O (0.155 g, 1.15 mmole), and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (44 mg). P- 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)

[0251] LC-MS (ESI, m / z) = 474.5 (M+H + ) Example 53. N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-yl)-

[0252] 3-sulfamoylbenzamide

[0253] [Step 4] Preparation of N-(2-(2-(methylsulfonyl)ethyl)-6-morpholino-2H-indazol-5-yl)-3-sulfamoylbenzamide (Compound 53) Under the same conditions as [Step 4] of Example 1, the compound obtained in [Step 3] of Example 13 (136 mg, 0.42 mmole), 3-sulfamoylbenzoic acid (93 mg, 0.462 mmole), dimethylformamide (10 mL), HATU (217 mg, 0.63 mmole), and DIPEA (0.2 mL, 1.68 mmole) were reacted in the same manner, and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (10 mg). P— 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)

[0254] LC-MS (ESI, m / z) = 508.6 (M+H + )

[0255] <Experimental Example>Evaluation of physiological efficacy Experimental Example 1. IRAK4 enzyme activity inhibition experiment An experiment on the inhibition of IRAK4 enzyme activity of the present compound was conducted.

[0256] Using the IRAK4 enzyme kit (purchased from Promega, product number: V2621), a mixture of 0. lug / uL of the enzyme substrate myelin basic protein MBP (Myelin in Basic Protein) and 1.25 mM ATP was diluted with reaction buffer (40 mM Tris-HCl, pH 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 uM DTT) according to the instructions, and 2 uL was dispensed into a 384-well white plate. Then, the test compound was gradient diluted from ImM, and 1 uL was added to the 384-well plate. After that, the IRAK4 enzyme was diluted with reaction buffer to a final concentration of 5 ng / uL, and 2 uL / well was dispensed into the 384-well white plate, and the reaction was performed at 37°C for 60 minutes. After the reaction was completed, 5uL of ADP-Glo ​​reaction reagent was added using the ADP-Glo™ enzyme test kit (purchased from Promega, product number: V9102), and the reaction was performed at 37°C for 40 minutes. Then, 10uL of enzyme color development reagent was added again, and the luminescence signal was measured using an absorbance measurement device (THECA"}, Microplate Reader). The activity inhibition rate was calculated from the measured value, and the 50% inhibition concentration (IC50 value) was analyzed through nonlinear regression analysis based on the % inhibition at each concentration of the test compound, and is shown in Table 2.

[0257] [Table 2]

[0258] As can be seen in Table 2 above, the compound of the present invention exhibits excellent IRAK4 inhibitory activity. Experimental Example 2. IRAKI Enzyme Activity Inhibition Experiment The IRAKI enzyme activity inhibition experiment of the compound of the present invention was conducted.

[0259] Using the IRAKI enzyme kit (purchased from Promega, product number: VA7477), 0. lug / uL of the enzyme substrate protein AKT (protein kinase B) and 1.25 mM ATP mixture were diluted with reaction buffer (40 mM Tr-is-HCl, pH 7.5; 20 mM MgCl2; 0.1 mg / mL BSA; 50 μM DTT) according to the instructions, and 2 μL was dispensed into a 384-well white plate. Then, the test compound was diluted gradiently from ImM, and luL was added to the 384-well white plate. After that, the IRAKI enzyme was diluted with reaction buffer to a final concentration of 5 ng / uL, and 2 μL / well was dispensed into the 384-well white plate, and the reaction was performed at 37°C for 60 minutes. After the reaction, 5uL of ADP-Glo ​​reaction reagent was added using the ADP-G 1 oTM enzyme test kit (purchased from Promega, product number: V9102), and the reaction was performed at 37°C for 40 minutes. Then, 10uL of enzyme color development reagent was added again, and the luminescence signal was measured using an absorbance measurement device (THECA"}, Microplate Reader). The activity inhibition rate was calculated from the measured value, and the 50% inhibition concentration (IC50 value) was analyzed through nonlinear regression analysis based on the % inhibition at each concentration of the test compound, and is shown in Table 3.

[0260] [Table 3] As can be confirmed in Table 3 above, the compound of the present invention exhibits excellent IRAKI inhibitory activity. Experimental Example 3: Cell-based inflammatory cytokine secretion inhibition experiment An inflammatory cytokine secretion inhibition experiment of the present compound was conducted. 1.0 X 10 PBMC (LONZA, peripheral blood mononuclear cells) isolated from human whole blood was 5Cells were seeded into 96-well plates at a density of 10 cells / well and stabilized for 20 hours. Afterwards, test compounds diluted at four different concentrations in RPMI (Roswel 1 Park Memor i al Inst i tute) medium were added and reacted for 1 hour. LPS (Lipopolysaccharide) was treated to a final concentration of 1g / mL and reacted for another hour. hTNF- a, an inflammatory cytokine, was measured by enzyme-linked immunosorbent assay (ELISA) using an ELISA kit from Goma Biotech. Cell supernatant, standard drugs, and antibodies were added to the ELISA plate, and after a total of 4 hours of reaction, the plate was washed, streptavidin-HRP was reacted for 30 minutes, and the plate was washed again. Afterwards, TMB substrate was added and reacted in the dark. When sufficient color development was achieved, the reaction was stopped by adding stop solution. hTNF- a was measured by measuring the absorbance at 450 nM using an absorbance measuring device (BioTeK Microplate Reader). The activity inhibition rate was calculated from the measured absorbance value, and the % inhibition at each concentration of the test compound was calculated. The 50% inhibition concentration (IC50 value) was analyzed through nonlinear regression analysis, and is shown in Table 4.

[0261] [Table 4]

[0262] As can be seen in Table 4 above, the compound of the present invention exhibits an excellent inflammatory cytokine secretion inhibitory effect. While the present invention has been described in detail, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereby. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims

【Scope of Claims】 【 Claim 11 A compound represented by the formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: <화학식 1> In the above formula I, phenyl or pyridinyl is present, and at least one of the above five may be substituted with a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of halogen, C1-C6 alkyl, C(=O)Ra, NH2, N02, S(=OhRb, N, 0 and S) in the ring, wherein Ra and Rb are each independently a 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of C1-C6 alkyl, NH2 or N, 0 and S in the ring, and 1 to 3 heteroatoms independently selected from the group consisting of a single bond, a 6- to 14-membered arylene, N, 0 and S in the ring, or a 3- to 12-membered heterocycloalkylene having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S. A 5- to 12-membered heteroarylene containing 3 heteroatoms in the ring, Li is a single bond, C1-C6 alkylene, C(=0), C(=O)NH, C(=O)NH- (Cl- C6 alkylene), C(=O)NH-(C1-C6 alkylene) - C(=0)0 or C(=O)NH-(C1-C6 alkylene) -C(=O)NH, Ri is H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF3, NRcRd, N, 0 and A 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of S in the ring or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein Rc and Rd are each independently H or C1-C6 alkyl, Qi and Q2 are each independently N or N- L『 R2 , but Qi and Q2 cannot be N at the same time, R2' L2 ' N [in] When Q2 is N, the above N and when Q1 is N, / note Q 1: J N 0 N Q2 is - -, wherein L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), wherein R2 is a 3- to 12-membered heterocycloalkyl, C1-C6 alkoxy, CONH2, NReRf, S02Rg or OH containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, and wherein Re, Rf and Rg are each independently H or C1-C6 alkyl. 【

2. In claim 1, in the chemical formula I, The following is phenyl or pyridinyl, and at least one of the above five may be substituted with a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of halogen, C(=O)Ra, NH2, NO2, S(=OhRb, N, 0 and , wherein Ra and Rb are each independently NH2 or a 3- to 12-membered heterocycloalkyl group containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and S, and the following is a single bond, a 6- to 14-membered arylene, a 3- to 12-membered heterocycloalkylene containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and S, or a 5- to 12-membered heteroaryl group containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and S. It is a heteroarylene, Li is a single bond, C1-C6 alkylene, C(=0), C(=O)NH, C(=O)NH- (Cl- C6 alkylene), C(=O)NH-(C1-C6 alkylene) - C(=0)0 or C(=O)NH-(C1-C6 alkylene) -C(=O)NH, Ri is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, C1-C6 alkoxy, OH, CF3, NRcRd, N, 0 and S in the ring, or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, wherein Rc and Rd are each independently C1-C6 alkyl, Qi and Q2 are each independently N or N- L2- R2, but Qi and Q2 cannot be N at the same time. 114 Company Z N 0 Qi ：、J r A compound represented by formula I, wherein Q2 is R2— L2, wherein L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), wherein R2 is a 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S, C1-C6 alkoxy, CONH2, NReRf, S02Rg or OH, wherein Re, Rf and Rg are each independently C1-C6 alkyl, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 【

3. In claim 1, in the chemical formula I, phenyl or pyridinyl is present, and at least one H of X may be substituted with a 5-membered or 6-membered heteroaryl group containing 1 to 3 heteroatoms independently selected from the group consisting of F, Cl, C(=O)Ra, NH2, Nt》, S(=0)2Rb, N and S in the ring, and Ra and Rb are each independently a 5-membered to 7-membered heterocycloalkyl group containing 1 to 3 heteroatoms independently selected from the group consisting of NH2 or N and 0 in the ring, and S is a single bond, a 6-membered to 12-membered arylene, N, 0 and S in the ring. A 5- to 7-membered heterocycloalkylene containing 1 to 3 independently selected heteroatoms within the ring, or a 5- or 6-membered heteroarylene containing 1 or 2 independently selected heteroatoms within the ring from the group consisting of N, 0, and Li is a single bond, C1-C4 alkylene, C(=0), C(=O)NH, C(=O)NH- (Cl- C2 alkylene), C(=O)NH-(C1-C5 alkylene) - C(=0)0 or C(=O)NH-(C1-C3 alkylene) -C(=O)NH, Ri is a 5- to 7-membered heterocycloalkyl 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 0 within the ring, or a 5- or 6-membered heteroaryl containing 1 or 2 heteroatoms independently selected from the group consisting of N and 0 within the ring, wherein Rc and Rd are each independently C1-C3 alkyl, Qi and Q2 are each independently N or N- L『 R2 , but Qi and Q2 cannot be N at the same time, The above L2 is C1-C6 alkylene or (C1-C3 alkylene)- O-(C1-C3 alkylene), and the above R2 is 1 to 1 independently selected from the group consisting of N and 0. 5 to 7-membered heterocycloalkyl containing 3 heteroatoms in the ring, C1-C3 alkoxy, CONH2, NReRf, S02Rg or OH, 116 A compound represented by the formula I, wherein Re, Rf and Rg are each independently C1-C3 alkyl, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

4. A compound described in the table below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof: 117 【

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. A pharmaceutical composition according to claim 5, wherein the pharmaceutical composition is for the prevention or treatment of a disease related to IRAK-4 or IRAK-1. 【

7. A 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 administering to a subject 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. 【Claims 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 a medicament for the prevention or treatment of a disease associated with IRAK-4 or IRAK-1. 122

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