WO2025003987A1 - Novel carboxamide derivative compound and pharmaceutical composition comprising same - Google Patents

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

【Specification】

【Title of invention】 Novel carboxamide derivative compound and pharmaceutical composition containing the same

【Technical Field】 The present invention relates to a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and a pharmaceutical composition comprising the same.

【Background Technology】

The IL-1R/TLR (IL-1 receptor/Toll-like receptor) signaling pathway plays an important role in immunity and inflammatory responses, and has been reported to be involved in the development of various inflammatory diseases 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 IRAK-4 (inter leukin-1 receptor-associated kinase 4) inhibition is also 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

It has been reported that IL-1R/TLR signaling is hyperactivated due to MyD88 mutation in ABC DLBCL, a type of dif fuse large B-cell 1 lymphoma, 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 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, the downstream signaling pathway is activated, resulting in an inflammatory response. If this inflammatory response continues, 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 the downstream signal of TLR. In particular, many studies are targeting IRAK-4.

IRAK is a serine/threonine ^kinase and has four subtypes (IRAK-1, IRAK-2, IRAK-M, IRAK-4). Among them, studies on IRAK-4 and IRAK-1, which have kinase function, are mainly conducted. In particular, IRAK-4, which plays an important role in forming myddosome in the IL-1R/TLR signaling pathway, There is the most research, 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 phase 2 clinical trials are underway for various diseases (autoimmune diseases, inflammatory diseases, and blood cancers).

【Detailed description of the invention】

【Technical Problem】 The present invention provides a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provides a pharmaceutical composition comprising the novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention provides a pharmaceutical composition comprising the novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient for preventing or treating an IRAK-4 or IRAK-1 related disease. The present invention provides a method for preventing or treating an IRAK-4 or IRAK-1 related disease, comprising a step of administering to a subject a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The present invention relates to a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, IRAK-4. Or provides a use for preventing or treating an IRAK-4 or IRAK-1 related disease. The present invention provides a use of a novel carboxamide derivative compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in the manufacture of a medicament for preventing or treating an IRAK-4 or IRAK-1 related disease.

본 발명은 화학식 I로 표시되는 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 또는 이의 수화물 또는 용매화물을 제공한다. 【Technical Solution】 Accordingly, the applicant of the present invention developed a compound having a new structure that strongly inhibits IRAK-4 or IRAK-1. The activity of IRAK-4 and IRAK-1 enzymes and the change in secretion of inflammatory cytokines were evaluated, and it was confirmed through these that the present compound is an excellent active substance. The present invention relates to a compound useful for the prevention or treatment of autoimmune diseases, inflammatory diseases or tumors related to IRAK (interleukin-1 receptor-associated kinase), and specifically, to a compound that inhibits the function of IRAK-4 or IRAK-1, and a pharmaceutical composition and a health functional food composition containing the same. Hereinafter, the present invention will be described in more detail. All combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, the scope of the present invention should not be considered limited by the following specific description. Research on the present invention was supported by the National New Drug Development Project of the National Drug Development Agency with financial resources from the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare of the Republic of Korea. (This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Wei fare(RS— 2023— 00284094, Republic of Korea)). The above project identification number can be used together as '1711200965'. A compound represented by the chemical formula

The present invention provides a compound represented by chemical formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

상기 화학식 I에서, <Chemical Formula 1>

In the above chemical formula I,

Li is a single bond or C1-C6 alkylene, and the following is thiazolidine,

Ri is a 3-12 membered heterocycloalkyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, 6-14 membered aryl, N, 0 and , a 3-12 membered heterocycloalkenyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and S, or a 3-12 membered heterocycloalkenyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and A 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of (C=0)0-(Cl-C6 alkyl) or NRaRb in the ring, wherein Ra and Rb are each independently H, a 6- to 14-membered aryl or a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and , and at least one of Ri may be substituted with C1-C6 alkyl, C1-C6 alkoxy, OH, NO2, NRaRb, C(=O)-(C1-C6 alkylene)- OH, CF ₃ or halogen, and wherein Ra and Rb are each independently H or C1-C6 alkyl,

상기 L2은 C1-C6 알킬렌 또는 （C1-C6 알킬렌）- O-（C1-C6 알킬렌）이고, 상기 R2는 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1개 내지 3개의 헤테로원자를 고리 내에 포함하는 3원 내지 12원의 헤테로사이클로알킬, NRcRd, S0₂Re, C（=0）NH₂ 또는 OH이고, 상기 Rc, Rd 및 Re는 각각독립적으로 H 또는 C1-C6 알킬이며 , 오는 6원 내지 14원의 아릴렌 또는 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1개 내지 3개의 헤테로원자를 고리 내에 포함하는 5원 내지 12원의 헤테로아릴렌이고, Qi and Q2 are each independently N or N- L『 R2 , but Qi and Q2 cannot be N at the same time.

wherein L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), R2 is a 3-membered to 12-membered heterocycloalkyl, NRcRd, S0 ₂ Re, C(=0)NH ₂ or OH, wherein Rc, Rd and Re are each independently H or C1-C6 alkyl, and a 6-membered to 14-membered arylene or a 5-membered to It is a 12-membered heteroarylene,

L3 is a single bond, C1-C6 alkylene, - NH(C=O)-, - (C=o)-, - C(=O)NH- or - (C=0)0-,

R3 is a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, N, 0 and , NH2, _CF3 or 0H, and at least one of said R3 may be substituted with a 3- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of OH, C(=0)NH2, C(=O)OH, C(=0)0-(Cl-C6 alkyl), C(=O)NH-(C1-C6 alkyl), N, 0 and , or a 5- to 12-membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S, and - CH2 - of said heterocycloalkyl of R ₃ is C=0 can be substituted. In one embodiment, in the chemical formula I,

Li is a single bond or C1-C6 alkylene, and the following is thiazolidine,

Ri is a 3-12 membered heterocycloalkyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, 6-14 membered aryl, N, 0 and , a 3-12 membered heterocycloalkenyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and S, or a 3-12 membered heterocycloalkenyl containing 1 to 3 heteroatoms in the ring independently selected from the group consisting of N, 0 and A 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, OH, NO2, NRaRb,

C(=O)-(C1-C6 alkylene)- OH, CF ₃ or may be substituted with halogen, and Ra and Rb are each independently H or 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.

^Q O 尺2* ¹²斗0

상기 L2은 C1-C6 알킬렌 또는 (C1-C6 알킬렌)- O-(C1-C6 알킬렌)이고, 상기 R2는 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1개 내지 3개의 헤테로원자를 고리 내에 포함하는 3원 내지 12원의 헤테로사이클로알킬, NRcRd, C(=0)NH₂ 또는 OH이고, 상기 Rc 및 Rd는 각각독립적으로 C1-C6 알킬이며 , 오는 6원 내지 14원의 아릴렌 또는 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1개 내지 3개의 헤테로원자를 고리 내에 포함하는 5원 내지 12원의 헤테로아릴렌이고, When Q2 is N, the above ^Q 2 is N, and when Q1 is N, the above

wherein L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), R2 is a 3-membered to 12-membered heterocycloalkyl, NRcRd, C(=0) _NH2 or OH containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, and wherein Rc and Rd are each independently C1-C6 alkyl, a 6-membered to 14-membered arylene or a 5-membered to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring,

L3 is a single bond, C1-C6 alkylene, - (C=0)-, -C(=O)NH- or - (C=0)0-,

R3 is selected from the group consisting of H, halogen, C1-C6 alkyl, N, 0 and A 3-membered ring containing 1 to 3 independently selected heteroatoms

12-membered heterocycloalkyl, NH2, _CF3 or 0H, and at least one of said R3 is OH, C(=0)NH2, C(=O)OH, C(=0)0-(Cl-C6 alkyl),

Independently selected from the group consisting of C(=O)NH-(C1-C6 alkyl), N, 0 and

A 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms in the ring or independently selected from the group consisting of N, 0 and

may be substituted with a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms in the ring. In one embodiment, in the chemical formula I,

Li is a single bond or C1-C2 alkylene, and the following is thiazolidine,

Ri is H, C1-C4 alkyl, C5-C7 cycloalkyl, 6-12 membered aryl, N and

A 5- to 7-membered heterocycloalkyl comprising 1 to 3 heteroatoms independently selected from the group consisting of 0 in the ring, a 5- to 7-membered heterocycloalkenyl comprising 1 or 2 heteroatoms independently selected from the group consisting of N and 0 in the ring, or a 5- or 6-membered heteroaryl comprising 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and , wherein at least one of Ri is C1-C3 alkyl, C1-C3 alkoxy, OH, NO2, NRaRb,

C(=0)-(C2-C4 alkylene)- OH, CF ₃ , F or C1 may be substituted, and Ra and Rb are each independently H or C1-C3 alkyl, Qi and Q2 are each independently N or N-R2, but Qi and Q2 cannot be simultaneously.

^Q O R2* ^L2 >O

상기 L2은 C1-C6 알킬렌 또는 (C1-C2 알킬렌)- O-(C1-C2 알킬렌)이고, 상기 R2는 N 및 0로 이루어진 군으로부터 독립적으로 선택되는 1개 내지 3개의 헤테로원자를 고리 내에 포함하는 4원 내지 7원의 헤테로사이클로알킬, NRcRd, C(=0)NH₂ 또는 OH이고, 상기 Rc 및 Rd는 각각독립적으로 C1-C3 알킬이며 , 오는 6원 내지 12원의 아릴렌 또는 N, 0 및 S로 이루어진 군으로부터 독립적으로 선택되는 1개 내지 3개의 헤테로원자를 고리 내에 포함하는 5원 또는 6원의 헤테로아릴렌이고, When Q2 is N, the above ^Q 2 is N, and when Q1 is N, the above

wherein L2 is C1-C6 alkylene or (C1-C2 alkylene)-O-(C1-C2 alkylene), R2 is a 4- to 7-membered heterocycloalkyl, NRcRd, C(=0) _NH2 or OH containing 1 to 3 heteroatoms independently selected from the group consisting of N and 0 in the ring, Rc and Rd are each independently C1-C3 alkyl, and is a 6- to 12-membered arylene or a 5- or 6-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring,

L3 is a single bond, C1-C2 alkylene, - (C=0)-, -C(=O)NH- or - (C=0)0-,

R3 is a 5- to 7-membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of H, F, Cl, C1-C3 alkyl, N and 0, NH2, _CF3 or 0H, and at least one of said R3 is a 5- to 7-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of OH, C(=0)NH2, C(=O)OH, C(=O)O-(C1-C3 alkyl), C(=O)NH-(C1-C3 alkyl), N and 0. Independently selected from the group consisting of heterocycloalkyl or N and 0

Herein, the term "Cm-Cn" (wherein m and n are each independently an integer of 1 or more) means the number of carbons, for example, "C1-C5 alkyl" means alkyl having 1 to 5 carbons. The term "substituted" or "substituted with ~" as used herein 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 induces a stable compound, for example, a compound that does not naturally undergo rearrangement, cyclization, elimination, etc. The term "single bond" as used herein means a case where adjacent atoms or groups of atoms are directly bonded to each other. The term "alkyl" as used herein means a linear (or straight-chain) saturated hydrocarbon group or a branched (or branched) 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: Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, spiropentyl, spirohepyl, spiroctyl, etc. may be mentioned, but are not limited thereto. 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, and the like. In the present invention, unless otherwise stated, "heterocycloalkylene" is as above. Hereinafter, the term "heterocycloalkenyl" will be understood to mean a divalent functional group derived from heterocycloalkenyl as defined above. In the present invention, unless otherwise stated, "heterocycloalkenyl" means a monocyclic or polycyclic ring in which at least one carbon atom forming the cycloalkenyl ring as defined above is substituted with a heteroatom selected from the group consisting of N, 0, and . Examples of heterocycloalkenyl include, but are not limited to, one or more selected from dihydropyridinyl, dihydropyranyl, dihydrothiopyranyl, and the like. 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 ring group having one or more fused or non-fused aromatic rings. 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 stated, "arylene" means a divalent functional group derived from aryl defined as above. In the present invention, unless otherwise stated, "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 fused or non-fused aromatic rings. Examples of heteroaryl include pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrroleyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, Examples of at least one selected from pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, purinyl, indolizinyl, chloromethyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, bezothiadiazolyl, bezotriazolyl, benzoxadiazole, etc., may be cited, but are not limited thereto. In the present invention, unless otherwise stated, "heteroarylene" means a divalent functional group derived from heteroaryl as defined above. In the present invention, "halogen" may be F, Cl, Br or I unless otherwise stated. In addition, terms and abbreviations used in the present specification 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.

화학식 I로 표시되는 화합물의 제조 방법 본 발명은 화학식 I로 표시되는 화합물, 상기 표 1의 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 또는 이의 수화물 또는 용매화물의 제조 방법을 제공한다. 본 발명의 화학식 I로 표시되는 화합물, 상기 표 1의 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 또는 이의 수화물 또는 용매화물은 예를 들어 하기 반응식 1의 방법에 따라 제조될 수 있으나, 이에 한정하지 않는다. [Table 1]

Method for Preparing a Compound Represented by Chemical Formula I 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 represented by 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 can be prepared, for example, according to the method of the following Reaction Scheme 1, but is not limited thereto.

상기 반응식 1에서 Ri, R₂, RS, LI, L₂, L3, X 및 Y 각각은 상기 화학식<Reaction Formula 1>

In the above reaction formula 1, Ri, R ₂ , RS, LI, L ₂ , L3, X and Y are each represented by the chemical formula

Each is identical to that defined in the compound entry indicated by I.

[Step 1] Coupling reaction starting material (compound (0) to produce 1 or 2-substituted indazole derivatives

(It is possible to prepare compound (ii), compound (vi)) (see the reaction scheme 1 above). Useful reactions for this purpose optionally include reactions using R2-L2-Z (Z is chloride, bromide, iodide or 4-methylbenzenesulfonate) in a solvent and a base. Optionally, when one of R ₂ -L ₂ -Z is chloride or bromide, it is also possible to add an alkali metal iodide, such as potassium iodide or sodium iodide. Both organic bases and inorganic bases can be used as the base, and for example, the inorganic base can be potassium carbonate, cesium carbonate or sodium hydride. Reactivity In the case of halides, it is also possible in some cases to use N-cyclohexyl-N-methylcyclohexanamine as an organic base. As the solvent, for example, 1-methylpyrrolidin-2-one, DMF, DMSO or THF can be used.

[Step 2.5] A step of preparing the compound (iii) or compound (vii) by stirring for 0.5 to 24 hours under heating conditions using a palladium catalyst or a nickel catalyst for the coupling reaction of a condensate and a coupling reaction in a pressure tube or a general reactor in a solvent which is inert to the coupling reaction and a base; and an equal amount or excess 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). Specifically, the compound (iii) or compound (vii) can be prepared by stirring at 20 to 120°C for 0.5 to 24 hours. The solvent is not particularly limited as long as it is inert to the reaction, and may include, but is not limited to, methanol, ethanol, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, water, N,N-dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene or mixtures 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 [1,1'-bis(diphenylphosphino)ferrocene]nickel dichloride or bis(triphenylphosphine)nickel dichloride. As the base, both organic and inorganic bases can be used, 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.

[Step 3.6] Reduction reaction is a step of preparing the compound (iv) or compound (vii i) by stirring the compound (iii) or compound (vii) in a solvent with palladium/charcoal and hydrogen gas for 3 to 96 hours under cooling or heating. Specifically, the compound (iv) or compound (vii i) 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.

[Step 4.7] A step for producing the compound (v) or compound (ix) by stirring the compound (iv) or compound (vii i) in an inert solvent for 1 to 24 hours using an equivalent amount or an excess of the corresponding -Li-X-Ri substituted aromatic carboxylic acid and a condensing agent under cooling or heating. Specifically, the compound (v) or compound (ix) can be produced 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 may include N,N-dimethylformamide, dimethylacetamide, dichloromethane, 1,2-dichloroethane, Chloroform, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile or a mixture thereof can be used. As the condensing agent, pentafluorophenyl trifluoroacetate, dicyclocarbodiimide (DCC), 亡_{ethyl_3_} ( _{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 additive, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt),

본 발명은 상기 화학식 I로표시되는 화합물, 상기 표 1의 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 또는 이의 수화물 또는 용매화 물을 유효성분으로포함하는 약학적 조성물을 제공한다. 본 발명은 상기 화학식 I로표시되는 화합물, 상기 표 1의 화합물, 이의 입체 이성질체, 이의 약학적으로 허용 가능한 염, 또는 이의 수화물 또는 용매화 물을 포함하는 건강기능식품조성물을 제공한다. 본 발명에서 "입체 이성질체"는 부분입체 이성질체 (diastereomer) 및 광 학이성질체 (optical isomer)를 포함하는 것으로, 광학 이성질체는 거울상 이성질 체 (enantiomer)뿐만 아니라 거울상 이성질체의 혼합물 및 라세미체까지 모두 포 함한다. 본 발명에서 "약학적으로 허용 가능한"은 생리학적으로 허용되고 개체에 게 투여될 때, 통상적으로 위장 장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 것을 의미할수 있다. 본 발명의 약학적으로 허용 가능한 염은 당업계 통상의 기술자에게 공지 된 통상적인 방법에 의해 제조될 수 있다. 본 발명의 "수화물"은 화학식 I로 표시되는 화합물, 상기 표 1의 화합 물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염과 물이 비공유적 분자간 힘으로 결합되어 있는 것으로, 화학양론적 또는 비화학양론적 양의 물을 포함하는 것일 수 있다. 구체적으로 상기 수화물은 활성성분 1몰을 기준으로 물 을 약 0.25몰 내지 약 10몰의 비율로 포함할 수 있으며, 보다 구체적으로는 약 0.5몰, 약 1몰, 약 1.5몰, 약 2몰, 약 2.5몰, 약 3몰, 약 5몰 등으로 포함할 수 있다. 본 발명의 "용매화물"은 화학식 I로표시되는 화합물, 상기 표 1의 화합 물, 이의 입체 이성질체 또는 이의 약학적으로 허용 가능한 염과, 물이 아닌 용 매가 비공유적 분자간 힘으로 결합되어 있는 것으로, 화학양론적 또는 비화학양 론적 양의 용매를 포함하는 것일 수 있다. 구체적으로 상기 용매화물은 활성성분 1몰을 기준으로 용매분자를 약 0.25몰 내지 약 10몰 비율로 포함할 수 있으며, 보다 구체적으로는 약 0.5몰, 약 1몰, 약 1.5몰, 약 2몰, 약 2.5몰, 약 3몰, 약1-Hydroxy-7-azabenzotriazole (HOAt), etc. can be used. As the base, an organic base such as triethylamine or diisopropylethylamine; or an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide or sodium hydroxide can be used. A composition comprising a compound represented by chemical formula I, a method of using a compound represented by chemical formula I, and a use of a compound represented by chemical formula I

The present invention provides a pharmaceutical composition comprising 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 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 the above 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 enantiomers. It includes not only enantiomers but also mixtures of mirror image isomers and racemates. In the present invention, "pharmaceutically acceptable" may mean physiologically acceptable and, when administered to a subject, does not typically cause allergic reactions such as gastrointestinal disorders, dizziness or similar reactions. The pharmaceutically acceptable salt of the present invention can be prepared by conventional methods 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 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 Chemical Formula I, a compound of Table 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a solvent other than water are bound by non-covalent intermolecular forces, and may contain a stoichiometric or non-stoichiometric amount of 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 about 0.5 mol, about 1 mol, about 1.5 mol, about 2 mol, about 2.5 mol, about 3 mol, about

It can be included in 5 moles, etc. The compound represented by the above chemical 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 can 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 an autoimmune disease, an inflammatory disease, or a tumor. The pharmaceutical composition of the present invention may further comprise one or more pharmaceutically acceptable carriers in addition to the compound represented by the above chemical formula I, the compound of 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 or more 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 relates to a compound represented by the above chemical formula I, a compound of the above Table 1, and a pharmaceutically acceptable carrier comprising: A method for preventing or treating an IRAK-4 or IRAK-1 related disease is provided, comprising administering to a subject a stereoisomer, 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 chemical formula I, 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. "Prevention" in the present invention 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 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. 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 the above 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, 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 prevention or treatment of an IRAK-4 or IRAK-1 related disease. The present invention provides a compound represented by the chemical formula I, a compound of the above Table 1, 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 an IRAK-4 or IRAK-1 related disease. Provides a use of water, or a pharmaceutical composition comprising the same.

【Effect of the invention】 The compound represented by chemical formula I of the present invention, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof exhibits an inhibitory effect on IRAK-4 or IRAK-1, and can be usefully used for the prevention or treatment of diseases related to IRAK-4 or IRAK-1 activity.

【Mode for Carrying Out the Invention】 Hereinafter, the present invention will be described in more detail. Any examples provided herein, or the use of exemplary language, are merely intended to better illustrate the present invention and do not limit the scope of the claimed invention.

＜Example＞ The compound represented by the chemical formula I of the present invention, the compound of the above Table 1 can be prepared by the method described below. Unless otherwise described, the starting materials are commercially available or can be prepared by a known method. Example 1. N-(1-(3 -hydroxy-3 -methylbutyl)-6-(thiophene-3 -yl)-1H-indazol-5-yl)-2-(pyridin-3 -yl)thiazole-4-carboxamide

[Step 1] Synthesis of 4-(6-bromo-5-nitro-1H-indazol-1-yl)-2-methylbutan-2-ol

6-Bromo-5-nitro-2H-indazole (2 g, 8.26 mmol) was added to dimethylformamide (20 mL) and stirred at room temperature. While stirring at room temperature, potassium carbonate (4.57 g, 33.05 mmol) and potassium iodide (0.14 g, 0.83 mmol) were added, and 4-bromo-2-methyl-2-butanol (1.97 ml, 16.5 mmol) was added dropwise. The reaction temperature was raised to 100°C and stirred for 5 hours. Upon completion of the reaction, the internal temperature was cooled to room temperature, diluted with ethyl acetate (40 mL), and washed with purified water (40 mL). Then, magnesium sulfate was added, filtered, concentrated, purified by MPLC (combiFlash NEXTGEN 300+), and concentrated to obtain the title compound (1.2 g). P— NMR (DMSO-d ⁶ ) 1.07(s, 6H) , 1.89(t, 2H) , 4.48(m, 3H) , 8.25(s, 1H), 8.28(s, 1H), 8.55(s, 1H)

［Step 2］ Synthesis of 2-methyl-4-(5-nitro-6-(thiophene-3-yl)-1H-indazol-1-yl)butan-2-ol To the compound of ［Step 1］ (1.1 g, 3.35 mmol) was added 1,4-dioxane and purified water in a 10:1 ratio (llmL) and stirred at room temperature. Sodium carbonate (1.78 g, 16.8 mmol) and tetrakis(triphenylphosphine)palladium (0.19 g, 0.17 mmol) were added and stirred. 4, 4, 5, 5-tetramethyl-2-(thiophene-3-yl)-1,3, 2-dioxaborolane (1.06 g, 5.03 mmol) was added and stirred. The reactor was heated to 100°C and stirred for 8 hours. After stirring, cooled to room temperature when the reaction was complete, ethyl acetate (22 mL) was added, and washed with sodium bicarbonate aqueous solution (22 mL). Afterwards, magnesium sulfate was added, filtered, concentrated, purified by MPLC (combiFlash NEXTGEN 300+), and concentrated to obtain the title compound (0.42 g). P— NMR (DMSO-d ⁶ ) 1.07 (s, 6H) , 1.89 (t, 2H) , 4.48 (s, 1H) , 4.51 (m, 2H), 7.13 (s, 1H), 7.63 (m, 2H) , 8.25 (s, 1H) , 8.28 (s, 1H) , 8.55 (s, 1H)

6H) , 1.96(t, 2H) , 4.36(m, 2H) , 4.43(s, 2H),［Step 3］ Synthesis of 4-(5-amino-6-(thiophene-3-yl)-1H-indazol-1-yl)-2-methylbutan-2-ol To the compound of ［Step 2］ (0.54 g, 1.63 mmol) was added ethyl acetate (5.4 mL). The mixture was hydrogenated with 0.11 g (0.2 w/w) of palladium on activated carbon under standard hydrogen pressure at 25°C for more than 3 hours. The reaction mixture was filtered through Celite, the filter was washed with ethyl acetate (5.4 mL), and the filtrate was concentrated. The title compound (0.45 g) was obtained.

6H) , 1.96(t, 2H) , 4.36(m, 2H) , 4.43(s, 2H),

4.45(s, 1H), 6.77(s, 1H), 7.30(m, 2H), 7.34(m, 1H), 7.62(m, 1H), 7.94(s, 1H) ［Step 4］ Synthesis of N-(1-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-1H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 1) Dimethylformamide (1.5 mL) was added to the compound (0.15 g, 0.5 mmol) of the above ［Step 3］ and stirred. DIPEA (0.35 ml, 1.99 mmol), HATU (0.38 g, l.Ommol) were added and stirred. 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.1 g, 0.5 mmol) was added and stirred at room temperature for more than 6 hours. After the reaction was completed, the mixture was washed with purified water (1.5 ml), magnesium sulfate was added, and filtered. The residue was concentrated and purified by MPLC (combi Fl ash NEXTGEN 300+), concentrated and dried to obtain the title compound (0.12 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 1.90(t, 2H) , 4.47(t, 2H) , 4.49(s, 1H), 7.42(m, 1H), 7.48(m, 1H) , 7.67(m, 1H) , 7.79(m, 1H) , 7.86(m, 1H) , 7.86(m, 1H) , 8.08(s, 1H), 8.23(m, 1H) , 8.50(s, 1H) , 8.71(m, 1H) , 9.10(d, 1H) , 9.90(s, 1H)

LC-MS (ESI, m/z) = 490.1 (M+H+) Example 2. N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), dimethylformamide (20 mL), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol) and 4-bromo-2-methyl-2-butanol (1.97 ml,

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),After the reaction was carried out in the same manner using 16.5 mmol), the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.925 g).

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),

8.13(s, 1H), 8.59(s, 1H) , 8.75(s, 1H) ［Step 2］ Synthesis of 2-methyl-4-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)butan-2-ol Example 1 ［Step 2］ Under the same conditions as above, the compound of [Step 1] (0.9 g, 2.74 mmol), sodium carbonate (1.45 g, 13.7 mmol), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol) and 4, 4, The reaction was performed in the same manner using 5, 5 -tetramethyl- 2-(thiophene- 3 -yl)- 1,3, 2 -dioxaborolane (0.86 g, 4.11 mmol) followed by MPLC (combiFlash NEXTGEN 300+) ) was purified and concentrated 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)

［Step 3］ Synthesis of 4-(5-amino-6-(thiophene-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.4 g, 1.22 mmol) was hydrogenated with 0.08 g (0.2 w/w) of palladium on activated carbon. The residue was purified by MPLC (combiFlash NEXTGEN 300+) and 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)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 2) Under the same conditions as in ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.36 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.08 g, 0.36 mmol), HATU (0.28 g,

After the reaction was carried out in the same manner using DI PEA (0.73 mmol) and DI PEA (0.25 mL, 1.46 mmol). The title compound (0.09 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02(t, 2H) , 4.44(s, 1H) , 4.46(t, 2H), 7.38(m, 1H), 7.58(m, 2H) , 7.78(m, 1H) , 7.81(m, 1H) , 8.22(m, 1H) , 8.42(s, 1H) , 8.49(s, 1H), 8.51(s, 1H) , 8.63(s, 1H) , 9.08(s, 1H) , 9.81(s, 1H)

LC-MS (ESI, m/z) = 490.1 (M+H+) Example 3. N-(6-(furan-3-yl)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[Step 1] Synthesis of 1-(6-bromo-5-nitro-1H-indazol-2-yl)-2-methylpropan-2-ol Under the same conditions as in [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol), and 1-bromo-2-methylpropanol (1.65 ml, 16.5 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.92 g). P- NMR (DMSO-d ⁶ ) 1.09(s, 6H) , 4.34(s, 2H) , 4.69(s, 1H) , 8.25(s, 1H), 8.29(s, 1H), 8.55(s, 1H)

[Step 2] 1- (6-(furan- 3 -yl)- 5 -nitro- 1H-indazol- 2 -yl)- 2 -methylpropane- 2- Under the same conditions as in [Step 2] of Synthetic Example 1 of All, the compound of [Step 1] (0.9 g, 2.88 mmol), sodium carbonate (1.52 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.14 mmol), and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.84 g, 4.31 mmol) 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 (0.5 g). P— NMR (DMSO-d ⁶ ) 1.08(s, 6H) , 4.37(s, 2H) , 4.87(s, 1H) , 6.55(s, 1H), 7.69(s, 1H), 7.71(s, 1H) , 8.25(s, 1H) , 8.29(s, 1H) , 8.55(s, 1H)

［Step 3］ Synthesis of 1-(5-amino-6-(furan-3-yl)-1H-indazol-1-yl)-2-methylpropan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.66 mmol) was hydrogenated with 0.1 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.35 g). P— NMR (DMSO-d ⁶ ) 1.05(s, 6H) , 4.19(s, 2H) , 4.50(s, 2H) , 4.80(s, 1H), 5.96(s, 2H), 6.82(s, 1H) , 6.83(s, 1H) , 7.25(s, 1H) , 7.29(s, 1H) , 7.55(s, 1H)

6H) , 4.32(t, 2H) , 4.72(s, 1H) , 6.95(s, 1H),［Step 4］ Synthesis of N-(6-(furan-3-yl)-1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 3) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.41 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.09 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), and DI PEA (0.28 mL, 1.62 mmol) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.08 g). Obtained.

6H) , 4.32(t, 2H) , 4.72(s, 1H) , 6.95(s, 1H),

7.83(m, 1H), 7.89(m, 1H) , 8.04(m, 1H) , 8.08(m, 1H) , 8.25(m, 2H) , 8.28(m, 1H) , 8.69(s, 1H), 8.93 (m, 2H), 10.14(s, 1H)

LC-MS (ESI, m/z) = 460.1 (M+H+) Example 4. N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[Step 1] Synthesis of 1-(6-bromo-5-nitro-2H-indazole-2-yl)-2-methylpropan-2-ol Under the same conditions as [Step 1] of Example 1, 6-bromo-5-nitro-2H-indazole

(2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol) and 1-bromo-2-methylpropanol (1.65 ml, 16.5 mmol) were used in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.90 g). p- NMR (DMSO-d ⁶ ) 1.08 (s, 6H) , 4.37 (s, 2H) , 4.89 (s, 1H) , 8.15 (s, 1H) , 8.61 (s, 1H) , 8.63 (s, 1H)

[Step 2] Synthesis of 1- (6-(furan-3-yl)-5-nitro-2H-indazol-2-yl)-2-methylpropan-2-ol Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] (0.5 g,

The reaction was carried out in the same manner using sodium carbonate (0.85 g, 7.99 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol) and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.47 g, 2.4 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.45 g). P— NMR (DMSO-d ⁶ ) 1.08(s, 6H) , 4.37(s, 2H) , 4.87(s, 1H) , 6.55(s, 1H), 7.71-7.72(m, 2H) , 8.15(s, 1H) , 8.61(s, 1H) , 8.63(s, 1H)

［Step 3］ Synthesis of 1-(5-amino-6-(furan-3-yl)-2H-indazol-2-yl)-2-methylpropan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.45 g, 1.66 mmol) was hydrogenated with 0.09 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.32 g). P— NMR (DMSO-d ⁶ ) 1.04(s, 6H) , 4.19(s, 2H) , 4.49(s, 2H) , 4.75(s, 1H), 5.74(s, 1H), 6.72-6.73(m, 2H) , 7.05(s, 1H) , 7.10(s, 1H) , 7.44(s, 1H)

［Step 4］ Synthesis of N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 4) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.41 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.09 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), and DI PEA (0.28 mL, 1.62 mmol) were used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.08 g). Obtained. P- NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 4.32 (t, 2H) , 4.85 (s, 1H) , 6.94 (s, 1H) , 7.69 (s, 1H) , 7.90 (m, 3H) , 8.06 (s, 1H) , 8.32 (s, 1H) , 8.44 (s, 1H) , 8.57 (s, 1H) , 8.77 (m, 2H) , 9.99 (s, 1H)

LC-MS (ESI, m/z) = 460.1 (M+H+) Example 5. N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 2-(6-bromo-5-nitro-2H-indazol-2-yl)-N,N-dimethylethane-1-amine Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol), and 2-chloro-N,N-dimethylethane-1-amine hydrochloride (2.38 g, 16.5 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.93 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)

［Step 2］ 2- (6- (furan- 3 -yl)- 5 - nitro- 2H-indazol- 2 -yl)- N, N- dimethyl ethane-

Synthesis of 1-amines Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] (0.9 g,

The reaction was carried out in the same manner using sodium carbonate (2.87 mmol), sodium hydroxide (1.52 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.14 mmol) and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.84 g, 4.31 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.73 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)

［Step 3］ Synthesis of 2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.2 g, 0.74 mmol) was hydrogenated with 0.04 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.13 g). 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), 7.61(s, 1H), 7.64(s, 1H) , 7.66(s, 1H) , 7.95(s, 1H) , 7.99(s, 1H)

［Step 4］ Synthesis of N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 5) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.41 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), and DI PEA (0.28 mL, 1.63 mmol) were used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). Obtained. P- NMR (DMSO-d ⁶ ) 2.17 (s, 6H) , 2.79 (m, 2H) , 4.49 (t, 2H) , 6.93 (s, 1H), 7.67 (s, 1H), 7.90 (m, 2H) , 7.92 (m, 1H) , 8.06 (s, 1H) , 8.40 (s, 1H) , 8.42 (s, 1H) , 8.57 (s, 1H), 8.77 (m, 2H) , 9.99 (s, 1H)

LC-MS (ESI, m/z) = 459.1 (M+H+) Example 6. N-(1-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 2-(6-bromo-5-nitro-1H-indazol-1-yl)-N,N-dimethylethane-1-amine Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol), and 2-chloro-N,N-dimethylethane-1-amine hydrochloride (2.38 g, 16.5 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.91 g). P— NMR (DMSO-d ⁶ ) 2.12(s, 6H) , 2.77(t, 2H) , 4.55(t, 2H) , 8.25(s, 1H), 8.29(s, 1H), 8.55(s, 1H)

［Step 2］ 2- (6- (furan- 3 -yl)- 5 - nitro- 1H- indazol- 1-yl)- N, N- dimethyl ethane- Under the same conditions as in [Step 2] of Example 1 of Synthesis of 1-Amine, the compound of [Step 1] (0.9 g, 2.87 mmol), sodium carbonate (1.52 g, 14.4 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.14 mmol), and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.84 g, 4.31 mmol) were used to carry out the reaction in the same manner.

The title compound (0.75 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 2.12 (s, 6H) , 2.77 (t, 2H) , 4.55 (t, 2H) , 6.55 (s, 1H), 7.69 (s, 1H), 7.71 (s, 1H) , 8.25 (s, 1H) , 8.29 (s, 1H) , 8.55 (s, 1H)

［Step 3］ Synthesis of 1-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-1H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.2 g, 0.74 mmol) was hydrogenated with 0.04 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.12 g). P— NMR (DMSO-d ⁶ ) 2.08(s, 6H) , 2.60(t, 2H) , 4.37(t, 2H) , 4.49(s, 2H), 6.43(s, 1H), 7.66(s, 1H) , 7.69(s, 1H) , 7.72(s, 1H) , 7.74(s, 1H) , 8.02(s, 1H)

［Step 4］ Synthesis of N-(1-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 6) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.41 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), and DI PEA (0.28 mL, 1.63 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.06 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P- NMR (DMSO-d ⁶ ) 2.17 (s, 6H) , 2.73 (m, 2H) , 4.50 (m, 2H) , 6.98 (s, 1H), 7.81 (s, 1H), 7.93 (m, 3H) , 8.07 (m, 2H) , 8.36 (s, 1H) , 8.58 (s, 1H) , 8.77 (m, 2H) , 10.1 (s, 1H)

LC-MS (ESI, m/z) = 459.1 (M+H+) Example 7. N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[Step 4] Synthesis of N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 7) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] of Example 4 (0.11 g, 0.41 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.09 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), and DI PEA (0.28 mL, 1.62 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.08 g) was obtained. P- NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 4.32 (m, 2H) , 4.84 (s, 1H) , 6.94 (s, 1H) , 7.60 (m, 1H) , 7.69 (s, 1H) , 7.86 (s, 1H) , 8.08 (s, 1H) , 8.32 (m, 2H) , 8.44 (s, 1H) , 8.50 (s, 1H) , 8.70 (m, 1H) , 9.17 (s, 1H) , 9.99 (s, 1H) LC-MS (ESI, m/z) = 460.1 (M+H+) Example 8. N-(2-(2-(dimethylamino)ethyl)-6-(1H-pyrazol-3-yl)-2H-indazole-

5-yl)-2-(pyridine-4-yl)thiazole-4-carboxamide

［Step 2］ N,N-Dimethyl- 2- (5 -nitro- 6- (1- (tetrahydro- 2H-pyran- 2 -yl)-

Synthesis of 1H-pyrazol-5-yl)-2H-indazol-2-yl)ethan-1-amine Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] of Example 5

The reaction was carried out in the same manner using sodium carbonate (0.51 g, 4.79 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol) and 3-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-1H-pyrazole (0.4 g, 1.44 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.31 g). P— NMR (DMSO-d ⁶ ) 2.21(s, 6H) , 2.78(m, 2H) , 4.55(t, 2H) , 6.97(d, 1H), 7.92 (d, 1H), 8.60(s, 1H) , 8.77(s, 1H) , 9.01(s, 1H) , 12.4(s, 1H)

[Step 3] Synthesis of 2-(2-(dimethylamino)ethyl)-6-(1H-pyrazol-5-yl)-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.3 g, 0.78 mmol) was hydrogenated with 0.06 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.13 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 2.12 (s, 6H) , 2.78 (t, 2H) , 4.49 (s, 2H) , 4.55 (t, 2H), 6.53 (d, 1H), 7.52 (d, 1H) , 8.15 (s, 1H) , 8.61 (s, 1H) , 8.63 (s, 1H) , 11.6 (s, 1H)

［Step 4］ Synthesis of N-(2-(2-(dimethylamino)ethyl)-6-(1H-pyrazol-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 8) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.41 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.41 mmol), HATU (0.31 g, 0.81 mmol), and DI PEA (0.28 mL, 1.63 mmol) were used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 2.23 (s, 6H) , 2.80 (m, 2H) , 4.56 (t, 2H) , 6.99 (d, 1H), 8.00 (m, 2H), 8.02 (s, 1H) , 8.08 (m, 2H) , 8.61 (s, 1H) , 8.79 (m, 3H) , 9.03 (s, 1H) , 12.4 (s, 1H)

LC-MS (ESI, m/z) = 459.1 (M+H+) Example 9. N-(2-(2-(1,3 ■dioxolane- 2 -yl)ethyl)- 6-(furan- 3 -yl)- 2H -indazole- 5 -yl)- 2-(pyridin- 4 -yl)thiazole- 4 -carboxamide

[Step 1] 2-(2-(1,3-dioxolane-2-yl)ethyl)-6-bromo-5-nitro-2H- Under the same conditions as in [Step 1] of Synthetic Example 1 of Indazole, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol), and 2-(2-bromoethyl)-1,3-dioxolane (3.0 g, 16.5 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.02 g). P— NMR (DMSO-d ⁶ ) 2.29(t, 2H) , 3.79(m, 2H) , 3.91(m, 2H) , 4.54(m, 2H), 4.81(m, 1H), 8.15(s, 1H) , 8.61(s, 1H) , 8.63(s, 1H)

［Step 2］ Synthesis of 2-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-5-nitro-2H-indazole Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ (1.0 g, 2.92 mmol), sodium carbonate (1.55 g, 14.6 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol), and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.85 g, 4.38 mmol) was 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 (0.79 g). P— NMR (DMSO-d ⁶ ) 2.27(t, 2H) , 3.75(m, 2H) , 3.83(m, 2H) , 4.49(m, 2H), 4.80(m, 1H), 6.55(s, 1H) , 7.71-7.72 (m, 2H) , 8.18 (s, 1H) , 8.64 (s, 1H) , 8.69 (s, 1H)

2H) , 3.61(m, 2H) , 3.74(m, 2H) , 4.35(m, 2H),[Step 3] Synthesis of 2-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.5 g, 1.52 mmol) was hydrogenated with 0.1 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.32 g).

2H) , 3.61(m, 2H) , 3.74(m, 2H) , 4.35(m, 2H),

4.52(s, 2H), 4.61(m, 1H) , 6.49(s, 1H) , 7.50- 7.51(m, 2H) , 7.82(s, 1H) , 8.31(s, 1H), 8.35(s, 1H)

［Step 4］ Synthesis of N-(2-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 9) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.37 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.37 mmol), HATU (0.28 g, 0.73 mmol), and DI PEA (0.26 mL, 1.47 mmol) was reacted in the same manner, and then purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.08 g) was obtained. P— NMR (DMSO-d ⁶ ) 2.25(t, 2H) , 3.77(m, 2H) , 3.89(m, 2H) , 4.50(m, 2H), 4.83(m, 1H), 6.93(s, 1H) , 7.67(s, 1H) , 7.89(m, 1H) , 7.93(m, 1H) , 8.06(s, 1H) , 8.41(s, 1H), 8.43(s, 1H) , 8.58(s, 1H) , 8.77- 8.78(m, 3H) , 9.98(s, 1H) LC-MS (ESI, m/z) = 488.1 (M+H+) Example 10. N-(1-(2-(1,3 ■dioxolane-2 -yl)ethyl)-6-(furan-3 -yl)-1H-indazol-5 -yl)-2-(pyridin-4 -yl)thiazole-4 -carboxamide

［Step 1］ Synthesis of 1-(2-(1,3-dioxolane-2-yl)ethyl)-6-bromo-5-nitro-1H-indazole Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.05 mmol), potassium iodide (0.14 g, 0.83 mmol), and 2-(2-bromoethyl)-1,3-dioxolane (3.0 g, 16.5 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.23 g). P- NMR (DMSO-d ⁶ ) 2.14(m, 2H) , 3.75(t, 2H) , 3.88(m, 2H) , 4.48(m, 2H), 4.81(m, 1H), 8.13(s, 1H) , 8.58(s, 1H) , 8.75(s, 1H)

［Step 2］ Synthesis of 1-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-5-nitro-1H-indazole Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ (1.0 g, 2.92 mmol), sodium carbonate (1.55 g, 14.6 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol), and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.85 g, 4.38 mmol) was used. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.71 g). P- NMR (DMSO-d ⁶ ) 2.14(m, 2H) , 3.75(t, 2H) , 3.88(m, 2H) , 4.48(m, 2H), 4.81(m, 1H), 6.98(s, 1H) , 7.75(s, 1H) , 7.91(s, 1H) , 8.13(s, 1H) , 8.58(s, 1H) , 8.75(s, 1H)

［Step 3］ Synthesis of 1-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-1H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.52 mmol) was hydrogenated with 0.1 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.3 g). P- NMR (DMSO-d ⁶ ) 2.09(m, 2H) , 3.70(m, 2H) , 3.83(m, 2H) , 4.43(m, 2H), 4.49(s, 2H), 4.76(m, 1H) , 6.93(s, 1H) , 7.69(s, 1H) , 7.86(s, 1H) , 8.07(s, 1H) , 8.53(s, 1H), 8.68(s, 1H)

［Step 4］ Synthesis of N-(1-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 10) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.37 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.37 mmol), HATU (0.28 g, 0.73 mmol), and DI PEA (0.26 mL, 1.47 mmol) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.07 g) was obtained. P- NMR (DMSO-d ⁶ ) 2.14 (m, 2H) , 3.75 (t, 2H) , 3.88 (m, 2H) , 4.48 (m, 2H), 4.81 (m, 1H), 6.98 (s, 1H) , 7.75 (s, 1H) , 7.92 (s, 1H) , 8.09 (m, 1H) , 8.13 (s, 1H), 8.38 (m, 2H), 8.58 (s, 1H) , 8.75 (s, 1H) , 8.77 (m, 2H) , 10.07 (s, 1H)

LC-MS (ESI, m/z) = 488.1 (M+H+) Example 11. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl) Thiazole-4-carboxamide

[Step 1] Synthesis of 4-(6-bromo-5-nitro-2H-indazole-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 1] of Example 1, 6-bromo-5-nitro-1H-indazole

(3 g, 12.4 mmol), potassium carbonate (6.85 g, 49.6 mmol), potassium iodide (0.21 g, 1.24 mmol) and 4-bromo-2-methylbutan-2-ol (2.96 mL, 24.8 mmol) were used in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give 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)

［Step 2］ Synthesis 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 of ［Step 1］ (1.9 g, 5.79 mmol), sodium carbonate (3.07 g, 28.9 mmol), tetrakis(triphenylphosphine)palladium (0.33 g, 0.29 mmol), and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (1.69 g, 8.69 mmol) was reacted in the same manner. The resultant product was purified by MPLC (combiFlash NEXTGEN 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)

［Step 3］ Synthesis of 4-(5-amino-6-(furan-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (1.5 g, 4.76 mmol) was hydrogenated with 0.3 g (0.2 w/w) of palladium on activated carbon. 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)

［Step 4］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 11) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.39 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) were used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.08 g). Obtained.

1H-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), 7.89(m, 2H) , 7.90(s, 1H) , 8.06(s, 1H) , 8.40(s, 1H) , 8.43(s, 1H), 8.50(s, 1H), 8.77(m, 2H) , 9.98(s, 1H)

LC-MS (ESI, m/z) = 474.1 (M+H+) Example 12. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl) Thiazole-4-carboxamide

[Step 4] Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 12) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] of Example 11 (0.11 g, 0.39 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.08 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was reacted in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.08 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.02 (t, 2H) , 4.46— 4.47 (m, 3H) , 6.92 (s, 1H) , 7.60 (m, 1H) , 7.66 (s, 1H) , 7.86 (s, 1H) , 8.07 (s, 1H) , 8.31 (m, 1H) , 8.40 (s, 1H) , 8.43 (s, 1H) , 8.50 (s, 1H) , 8.71 (m, 1H) , 9.17 (s, 1H) , 9.98 (s, 1H)

［단계 1］ 4- (6 -브로모- 5 -니트로- 1H-인다졸- 1-일)- 2 -메틸부탄- 2 -올의 합성 실시예 1의 ［단계 1］과 동일 조건에서 , 6 -브로모- 5 -니트로- 1H-인다졸 (2g, 8.26mmol), 탄산 칼륨 (4.57g, 33.1mmol), 요오드화 칼륨 (0.14g, 0.83mmol) 및 4 -브로모- 2 -메틸부탄- 2 -올 (1.97mL, 16.5mmol)을 사용하여 동일한 방법으로 반응 후 MPLC(combiFlash NEXTGEN 300+)로 정제하고 농축하여 표제 화합물 (1.27g)을수득하였다. 피— NMR (DMSO-d⁶) 1.12(s, 6H) , 1.90(m, 2H) , 4.46— 4.49(m, 3H) , 8.06(s, 1H), 8.11(s, 1H), 8.56(s, 1H) LC-MS (ESI, m/z) = 474.1 (M+H+) Example 13. N-(6-(furan-3-yl)-1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 4-(6-bromo-5-nitro-1H-indazol-1-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-1H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.1 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-bromo-2-methylbutan-2-ol (1.97 mL, 16.5 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.27 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 1.90(m, 2H) , 4.46— 4.49(m, 3H) , 8.06(s, 1H), 8.11(s, 1H), 8.56(s, 1H)

2H) , 4.46— 4.49(m, 3H) , 6.97(s,［Step 2］ Synthesis of 4-(6-(furan-3-yl)-5-nitro-1H-indazol-1-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ (1.0 g, 3.05 mmol), sodium carbonate (1.61 g, 15.2 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol), and 4,4,5,5-tetramethyl-2-(furan-3-yl)-1,3,2-dioxaborolane (0.89 g, 4.57 mmol) was 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 (0.75 g). Blood— NMR (DMSO-d ⁶ ) 1.13(s,

2H) , 4.46— 4.49(m, 3H) , 6.97(s,

1H), 7.70(s, 1H), 7.93(s, 1H) , 8.07(s, 1H) , 8.12(s, 1H) , 8.59(s, 1H)

[Step 3] Synthesis of 4-(5-amino-6-(furan-3-yl)-1H-indazol-1-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 1, the compound of [Step 2] (0.7 g, 2.45 mmol) was hydrogenated with 0.14 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through celite, and the filtrate was concentrated to give the title compound (1.04 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) , 7.93 (s, 1H) , 8.01 (s, 1H) , 8.22 (s, 1H)

2H) , 4.46— 4.49(m, 3H) , 6.98(s,［Step 4］ Synthesis of N-(6-(furan-3-yl)-1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 13) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.39 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.09 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.09 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 1.13(s,

2H) , 4.46— 4.49(m, 3H) , 6.98(s,

1H), 7.71(s, 1H), 7.92(m, 3H) , 8.06(s, 1H) , 8.11(s, 1H) , 8.39(s, 1H) , 8.58(s, 1H), 8.77(m, 2H) ), 10.06(s, 1H)

LC-MS (ESI, m/z) = 474.1 (M+H+) Example 14. N-(6-(furan-3-yl)-1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(6-(furan-3-yl)-1-(3-hydroxy-3-methylbutyl)-1H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 14) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 13 (0.11 g, 0.39 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.09 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.08 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 1.92 (t, 2H) , 4.46— 4.49 (m, 3H) , 6.97 (s, 1H) , 7.70 (m, 1H) , 7.90 (s, 1H) , 7.92 (s, 1H) , 8.06 (s, 1H) , 8.12 (s, 1H) , 8.32 (m, 1H) , 8.39 (s, 1H) , 8.50 (s, 1H) , 8.70 (m, 1H) , 9.19 (s, 1H) , 10.05 (s, 1H)

LC-MS (ESI, m/z) = 474.1 (M+H+) Example 15. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(thiophene- 3 -yl)- 2H -indazole-

5-yl)-2-(pyridine-4-yl)thiazole-4-carboxamide

6H) , 2.03(t, 2H) , 4.46- 4.49(m, 3H) , 7.40(m,[Step 4] N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(thiophene- 3 -yl)- 2H -indazole- 5- Synthesis of 2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 15) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] of Example 2 (0.11 g, 0.36 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.08 g, 0.36 mmol), HATU (0.28 g, 0.73 mmol), and DI PEA (0.25 mL, 1.46 mmol) was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g).

6H) , 2.03(t, 2H) , 4.46- 4.49(m, 3H) , 7.40(m,

1H), 7.59(s, 1H), 7.80-7.82(m, 3H) , 8.42(s, 1H) , 8.56(s, 1H) , 8.63(s, 1H) , 8.75(s, 1H), 8.76(s , 1H) , 9.80(s, 1H)

LC-MS (ESI, m/z) = 490.1 (M+H+) Example 16. N-(1-(3 -hydroxy- 3 -methylbutyl)- 6-(thiophene- 3 -yl)- 1H-indazol- 5 -yl)- 2-(pyridin- 4 -yl)thiazole- 4 -carboxamide

［Step 4］ Synthesis of N-(1-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 16) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 1 (0.15 g, 0.5 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.1 g, 0.5 mmol), HATU (0.38 g, l.Ommol) and DI PEA (0.35 mL, 1.99 mmol) was reacted in the same manner, and purified by MPLC (COMBI FLASH NEXTGEN 300+) to obtain the title compound. (0.09g) Obtained. Blood— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 1.90 (t, 2H) , 4.45— 4.48 (m, 3H) , 7.42 (m, 1H), 7.67 (s, 1H), 7.84 (m, 4H) , 8.09 (s, 1H) , 8.57 (s, 1H) , 8.62 (s, 1H) , 8.75 (m, 2H), 9.89 (s, 1H)

LC-MS (ESI, m/z) = 490.1 (M+H+) Example 17. N-(1-(2-(dimethylamino)ethyl)-6-(thiophene-3 -yl)-1H-indazol-5-yl)-2-(pyridin-3 -yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 2-(6-bromo-5-nitro-1H-indazol-1-yl)-N,N-dimethylethane-1-amine Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 2-chloro-N,N-dimethylethane-1-amine (1.78 g, 16.53 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.16 g). P— NMR (DMSO-d ⁶ ) 2.14(s, 6H) , 2.69(m, 2H) , 4.48(m, 2H) , 8.08(s, 1H), 8.49(s, 1H), 8.59(s, 1H)

［Step 2］ N,N-Dimethyl-2-(5-nitro-6-(thiophene-3-yl)-1H-indazole-1- (1) Ethane-1-amine Synthesis Example 1 Under the same conditions as in [Step 2], the compound of [Step 1] (0.5 g, 1.60 mmol), sodium carbonate (0.75 g, 7.04 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 4,4,5,5-tetramethyl-2-(thiophene-3-yl)-1,3,2-dioxaborolane (0.50 g, 2.40 mmol) 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 (0.5 g). P— NMR (DMSO-d ⁶ ) 2.14(s, 6H) , 2.69(m, 2H) , 4.48(m, 2H) , 7.74(s, 1H), 7.78(m, 1H), 7.84(m, 1H) , 8.08(s, 1H) , 8.49(s, 1H) , 8.59(s, 1H)

［Step 3］ Synthesis of 1-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-1H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.58 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P— NMR (DMSO-d ⁶ ) 2.14(s, 6H) , 2.69(m, 2H) , 4.48(m, 2H) , 7.41(s, 2H), 7.74(s, 1H), 7.78(m, 1H) , 7.84(m, 1H) , 8.08(s, 1H) , 8.49(s, 1H) , 8.59(s, 1H)

［Step 4］ Synthesis of N-(1-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-1H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 17) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.40 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.29 g, 1.40 mmol), HATU (1.06 g, 2.79 mmol), and DI PEA (0.97 mL, 5.59 mmol) were used in the same manner to obtain the title compound (0.3 g). The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated. Obtained. Blood— NMR (DMSO-d ⁶ ) 2.14 (s, 6H) , 2.69 (m, 2H) , 4.48 (m, 2H) , 7.41 (s, 1H), 7.59 (m, 1H), 7.75 (s, 1H) , 7.79 (m, 1H) , 7.84 (m, 1H) , 8.08 (s, 1H) , 8.26 (m, 1H) , 8.49 (s, 1H), 8.60 (s, 1H) , 8.69 (m, 1H) , 9.11 (s, 1H) , 9.91 (s, 1H)

LC-MS (ESI, m/z) = 475.3 (M+H+) Example 18. N-(1-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(1-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-1H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 18) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 17 (0.4 g, 1.40 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.29 g, 1.40 mmol), HATU (1.06 g, 2.79 mmol), and DI PEA (0.97 mL, 5.59 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.3 g) was obtained. P— NMR (DMSO-d ⁶ ) 2.14 (s, 6H) , 2.69 (m, 2H) , 4.48 (t, 2H) , 7.42 (m, 1H), 7.75 (m, 1H), 7.83 (m, 4H) , 8.09 (s, 1H) , 8.56 (s, 1H) , 8.60 (s, 1H) , 8.75 (m, 2H) ,

9.90(s, 1H) LC-MS (ESI, m/z) = 475.3 (M+H+) Example 19. N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3 -yl)-2H-indazol-5-yl)-2-(pyridin-3 -yl)thiazole-4-carboxamide

［Step 2］ Synthesis of N,N-dimethyl-2-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)ethan-1-amine Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 5 (0.5 g, 1.60 mmol), sodium carbonate (0.75 g, 7.04 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 4,4,5,5-tetramethyl-2-(thiophene-3-yl)-1,3,2-dioxaborolane (0.50 g, 2.40 mmol) was reacted in the same manner, and purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. Compound (0.5 g) was obtained. P- NMR (DMSO-d ⁶ ) 2.46 (s, 6H) , 3.60 (m, 2H) , 4.80 (m, 2H) , 7.62 (s, 1H), 7.81 (m, 1H), 7.82 (m, 1H) , 8.49 (s, 1H) , 8.51 (s, 1H) , 8.68 (s, 1H)

[Step 3] Synthesis of 2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-amine Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.5 g, 1.58 mmol) was hydrogenated with palladium on activated carbon (0.10 g, 0.093 mmol). The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). Obtained. P- NMR (DMSO-d ⁶ ) 2.46 (s, 6H) , 3.60 (m, 2H) , 4.80 (m, 2H) , 7.38 (s, 2H), 7.62 (s, 1H), 7.81 (m, 1H) , 7.82 (m, 1H) , 8.49 (s, 1H) , 8.51 (s, 1H) , 8.68 (s, 1H)

［Step 4］ Synthesis of N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 19) Under the same conditions as ［Step 4］ of Example 1, the compound obtained in ［Step 3］ (0.4 g, 1.40 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.29 g, 1.40 mmol), HATU (1.06 g, 2.79 mmol), and DI PEA (0.97 mL, 5.59 mmol) were used in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.3 g). P-NMR (DMSO-d ⁶ ) 2.46(s, 6H) , 3.60(m, 2H) , 4.80(m, 2H) , 7.38(s, 1H), 7.58(m, 1H), 7.63(m, 1H) , 7.82(m, 2H) , 8.22(m, 1H) , 8.50(m, 2H) , 8.70(m, 2H) , 9.09(s, 1H), 9.84(s, 1H)

LC-MS (ESI, m/z) = 475.3 (M+H+) Example 20. N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3 -yl)-2H-indazol-5-yl)-2-(pyridin-4 -yl)thiazole-4 -carboxamide

[Step 4] Synthesis of N-(2-(2-(dimethylamino)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 20) Under the same conditions as in [Step 4] of Example 1, the compound obtained in [Step 3] of Example 19 (0.4 g, 1.40 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.29 g, 1.40 mmol), HATU (1.06 g, 2.79 mmol) and DI PEA (0.97 mL, 5.59 mmol) were reacted in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.3 g). P- NMR (DMSO-d ⁶ ) 2.16(s, 6H) , 2.77(m, 2H) , 4.49(m, 2H) , 7.40(m, 1H), 7.59(m, 1H), 7.82(m, 4H) , 8.41(m, 1H) , 8.56(m, 1H) , 8.63(s, 1H) , 8.76(m, 2H) 9.80(s, 1H)

LC-MS (ESI, m/z) = 475.3 (M+H+) Example 21. N-(6-(furan- 3 -yl)- 2- (2 -morpholinoethyl)- 2H -indazol- 5 -yl)- 2-

(Pyridine-3-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 4-(2-(6-bromo-5-nitro-2H-indazol-2-yl)ethyl)morpholine Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-(2-chloroethyl)morpholine hydrochloride (3.08 g, 16.53 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.16 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.51(m, 4H) , 4.53(2H), 7.67(s, 1H), 7.86(s, 1H) , 8.50(s, 1H)

［Step 2］ Synthesis of 4-(2-(6-(furan-3-yl)-5-nitro-2H-indazol-2-yl)ethyl)morpholine Under the same conditions as in ［Step 2］ of Example 1, the compound of ［Step 1］ (0.5 g, 1.41 mmol), sodium carbonate (0.75 g, 7.04 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.08 mmol), and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.41 g, 2.11 mmol) were used. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P-NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.51(m, 4H) , 4.53(2H), 7.67(s, 1H), 7.86(s, 1H) , 8.07(s, 1H) , 8.31(d, 1H) , 8.50(s, 1H) , 8.70(d, 1H)

［Step 3］ Synthesis of 6-(furan-3-yl)-2-(2-morpholinoethyl)-2H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.46 mmol) was hydrogenated with palladium on activated carbon (0.10 g, 0.093 mmol). The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.51(m, 4H) , 4.53(2H), 6.93(s, 2H), 7.67(s, 1H) , 7.86(s, 1H) , 8.07(s, 1H) , 8.31(d, 1H) , 8.50(s, 1H) , 8.70(d, 1H)

[Step 4] Synthesis of N-(6-(furan-3-yl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 21) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] (0.4 g, 1.28 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.26 g, 1.28 mmol), HATU (0.97 g,

The reaction was performed in the same manner using 2.56 mmol) and DI PEA (0.89 mL, 5.12 mmol), and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). P-NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.51(m, 4H) , 4.53(2H), 6.93(s, 1H), 7.60(m, 1H) , 7.67(s, 1H) , 7.86(s, 1H) , 8.07(s, 1H) , 8.32(m, 1H) , 8.42(m, 2H), 8.50(s, 1H) , 8.70(m, 1H) , 9.17(s, 1H) , 9.99(s, 1H)

LC-MS (ESI, m/z) = 501.2 (M+H+) Example 22. N-(6-(furan-3-yl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(6-(furan-3-yl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 22) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 21 (0.4 g, 1.28 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.26 g, 1.28 mmol), HATU (0.97 g, 2.56 mmol), and DI PEA (0.89 mL, 5.12 mmol) was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). P- NMR (DMSO-d ⁶ ) 2.45(m, 4H) , 2.84(m, 2H) , 3.51(m, 4H) , 4.53(m, 2H), 6.93(s, 1H), 7.67(s, 1H) , 7.90(m, 2H) , 7.93(s, 1H) , 8.06(s, 1H) , 8.42(m, 2H) ,

8.57(s, 1H), 8.77(m, 2H) , 9.99(s, 1H)

LC-MS (ESI, m/z) = 501.3 (M+H+) Example 23. N-(2-(2-morpholinoethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-

2-(pyridin-3-yl)thiazole-4-carboxamide

[Step 1] Synthesis 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

(2 g, 8.26 mmol), dimethylformamide 20 mL, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-(2-chloroethyl)morpholine hydrochloride (3.08 g, 16.53 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.16 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.52(m, 4H) , 4.54(m, 2H), 7.60(s, 1H), 8.49(s, 1H) , 8.63(s, 1H)

[Step 2] Synthesis of 4-(2-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)ethyl)morpholine Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] (0.5 g, 1.41 mmol), sodium carbonate (0.75 g, 7.04 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.07 mmol) and 4, 4, 5, 5-tetramethyl-2-(thiophene-3-yl)-1,3, 2-dioxaborolane (0.44 g, 2.11 mmol) were used in the same manner, and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.52(m, 4H) , 4.54(m, 2H), 7.60(s, 1H), 7.78(m, 1H) , 7.81(m, 1H) , 8.43(s, 1H) , 8.49(s, 1H) , 8.63(s, 1H)

［Step 3］ Synthesis of 2-(2-morpholinoethyl)-6-(thiophene-3-yl)-2H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.40 mmol) was hydrogenated with palladium on activated carbon (0.10 g, 0.093 mmol). The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.52(m, 4H) , 4.54(m, 2H), 7.39(s, 2H), 7.60(s, 1H) , 7.78(m, 1H) , 7.81(m, 1H) , 8.43(s, 1H) , 8.49(s, 1H) , 8.63(s, 1H)

［Step 4］ Synthesis of N-(2-(2-morpholinoethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 23) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.22 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.25 g, 1.22 mmol), HATU (0.93 g, 2.44 mmol), and DI PEA (0.85 mL, 4.87 mmol) was used in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.3 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.52(m, 4H) , 4.54(m, 2H), 7.38(m, 1H), 7.58(m, 2H) , 7.78(m, 1H) , 7.81(m, 1H) , 8.23(m, 1H) , 8.43(s, 1H) ,

8.49(s, 1H), 8.64(s, 1H) , 8.70(m, 1H) , 9.09(s, 1H) , 9.82(s, 1H)

LC-MS (ESI, m/z) = 517.4 (M+H+) Example 24. N-(2-(2-morpholinoethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-

2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(2-(2-morpholinoethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 24) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 23 (0.4 g, 1.22 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.25 g, 1.22 mmol), HATU (0.93 g, 2.44 mmol), and DI PEA (0.85 mL, 4.87 mmol) was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). P- NMR (DMSO-d ⁶ ) 2.46(m, 4H) , 2.84(m, 2H) , 3.52(m, 4H) , 4.54(m, 2H), 7.39(m, 1H), 7.60(m, 1H) , 7.81(m, 1H) , 7.83(m, 2H) , 8.06(m, 1H) , 8.43(m, 1H) , 8.56(m, 1H), 8.64(s, 1H) , 8.76(m, 2H) , 9.82(s, 1H)

LC-MS (ESI, m/z) = 518.0 (M+H+) Example 25. N-(2-(2-(1,3 -dioxolane- 2 -yl)ethyl)- 6-(furan- 3 -yl)- 2H- Indazole-5-yl)-2-(pyridine-3-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(2-(2-(1,3-dioxolan-2-yl)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 25) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 9 (0.11 g, 0.37 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.08 g, 0.37 mmol), HATU (0.28 g, 0.73 mmol), and DI PEA (0.26 mL, 1.47 mmol) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.08 g) was obtained. P- NMR (DMSO-d ⁶ ) 2.24(m, 2H) , 3.76(m, 2H) , 3.89(m, 2H) , 4.50(m, 2H), 4.82(m, 1H), 6.93(s, 1H) , 7.60(m, 1H) , 7.67(s, 1H) , 7.87(s, 1H) , 8.08(s, 1H) , 8.31(m, 1H), 8.41(m, 2H) , 8.50(s, 1H) , 8.70(s, 1H) , 9.17(s, 1H) , 9.99(s, 1H) LC-MS (ESI, m/z) = 488.1 (M+H+) Example 26. N-(2-(3 -Hydroxy- 3 -methylbutyl)- 6-(pyridin- 4 -yl)- 2H -indazole-

5-yl)-2-(pyridine-4-yl)thiazole-4-carboxamide

[Step 1] 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutane-2-ol Under the same conditions as in [Step 1] of Synthetic Example 1, 6-bromo-5-nitro-1H-indazole

(lg, 4.13 mmol), potassium carbonate (2.28 g, 16.5 mmol), potassium iodide (0.07 g, 0.41 mmol) and 4-bromo-2-methylbutan-2-ol (0.99 mL, 8.27 mmol) were used in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.62 g). p- NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.04 (m, 2H) , 4.50 (m, 3H) , 8.10 (s, 1H), 8.29 (s, 1H), 8.57 (s, 1H)

［Step 2］ Synthesis of 2-methyl-4-(5-nitro-6-(pyridin-4-yl)-2H-indazol-2-yl)butan-2-ol Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ (0.6 g, 1.83 mmol), sodium carbonate (0.97 g, 9.14 mmol), tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol), and 4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.69 g, 2.74 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.42 g). P- NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.04(m, 2H) , 4.50(m, 3H) , 8.10(s, 1H), 8.15(m, 2H), 8.29(s, 1H) , 8.57(s, 1H) , 8.65(m, 2H)

[Step 3] Synthesis of 4-(5-amino-6-(pyridin-4-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.4 g, 1.35 mmol) was hydrogenated with 0.08 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to give the title compound (0.31 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 2.01 (m, 2H) , 4.42 (m, 3H) , 4.54 (s, 2H), 8.02 (s, 1H), 8.06 (m, 2H) , 8.19 (s, 1H) , 8.43 (s, 1H) , 8.50 (m, 2H)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(pyridin-4-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 26) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.2 g, 0.67 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.15 g, 0.67 mmol), HATU (0.51 g, 1.35 mmol), and DI PEA (0.47 mL, 2.70 mmol) were used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.18 g). Obtained. P- NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.04 (m, 2H) , 4.50 (m, 3H) , 7.78 (s, 1H), 8.11 (s, 1H), 8.15 (m, 2H) , 8.30 (s, 1H) , 8.47 (m, 2H) , 8.59 (s, 1H) , 8.65 (m, 2H) , 8.73 (m, 2H), 9.83 (s, 1H)

LC-MS (ESI, m/z) = 485.1 (M+H+) Example 27. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(pyridin- 3 -yl)- 2H -indazol- 5 -yl)- 2-(pyridin- 4 -yl)thiazole- 4 -carboxamide

[Step 2] Synthesis of 2-methyl-4-(5-nitro-6-(pyridin-3-yl)-2H-indazol-2-yl)butan-2-ol Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] of Example 26 (0.6 g, 1.83 mmol), sodium carbonate (0.97 g, 9.14 mmol), tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol), and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-3-yl)pyridine (0.69 g, 2.74 mmol) was reacted in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.41 g). P- NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.04(m, 2H) , 4.50(m, 3H) , 8.02(s, 1H), 8.08(d, 1H), 8.11(s, 1H), 8.12(d, 1H) , 8.15(m, 1H) , 8.29(s, 1H) , 8.57(s, 1H)

1H) , 8.19(s, 1H) ,［Step 3］ Synthesis of 4-(5-amino-6-(pyridin-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.4 g, 1.35 mmol) was hydrogenated with 0.08 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.30 g). P— NMR (DMSO-d ⁶ ) 1.09(s, 6H) , 2.01(m, 2H) , 4.42(m, 3H) , 4.56(s, 2H), 7.87(s, 1H), 7.91(d, 1H) , 8.01(s, 1H) , 8.03(d, 1H) ,

1H) , 8.19(s, 1H) ,

8.27(s, 1H)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(pyridin-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 27) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.15 g, 0.51 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.11 g, 0.51 mmol), HATU (0.38 g, l.Olmmol), and DI PEA (0.35 mL, 2.02 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.15 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P- NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.04 (m, 2H) , 4.50 (m, 3H) , 7.63 (s, 1H) , 7.78 (m, 2H) , 8.01 (s, 1H) , 8.06 (d, 1H) , 8.13 (d, 1H) , 8.17 (m, 1H) , 8.30 (s, 1H) , 8.47 (m, 2H) , 8.65 (m, 2H) , 8.73 (m, 2H) , 9.83 (s, 1H)

LC-MS (ESI, m/z) = 485.1 (M+H+) Example 28. N-(2-(3-Hydroxy-3-methylbutyl)-6-(pyridin-3-yl)-2H-indazole boron sulfate 1-paraffinic acid)thiazole tri-4-carboxamide

[Step 4] Synthesis of N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(pyridin- 3 -yl)- 2H -indazol- 5-yl)- 2-(pyridin- 3 -yl)thiazole- 4-carboxamide (Compound 28) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] of Example 27 (0.15 g, 0.51 mmol), 2-(pyridin- 3 -yl)thiazole- 4-carboxylic acid (0.11 g, 0.51 mmol), HATU (0.38 g, l.Olmmol) and DI PEA (0.35 mL, 2.02 mmol) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.15 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.06 (t, 2H) , 4.50 (m, 3H) , 7.61 (s, 1H), 7.97 (m, 1H), 8.03 (m, 2H) , 8.16 (m, 1H) , 8.37 (s, 1H) , 8.42 (s, 1H) , 8.47 (s, 1H), 8.65 (m, 1H), 8.69 (m, 1H) , 8.73 (s, 1H) , 9.03 (m, 1H) , 9.75 (s, 1H) LC-MS (ESI, m/z) = 485.1 (M+H+) Example 29. N-(2-(3-hydroxy- 3 ■methylbutyl)- 6-(4-hydroxyphenyl)- 2H- indazol- 5 -yl)- 2-(pyridin- 4 -yl)thiazole- 4 -carboxamide

[Step 2] Synthesis of 4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)phenol Under the same conditions as [Step 2] of Example 1, the compound of [Step 1] of Example 26

(0.6 g, 1.83 mmol), sodium carbonate (0.97 g, 9.14 mmol), tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol), and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.60 g, 2.74 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.51 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02(t, 2H) , 4.47(m, 2H) , 4.49(s, 1H), 6.97(m, 2H), 7.38(m, 2H) , 8.13(s, 1H) , 8.42(m, 2H) , 8.45(s, 1H) , 8.65(m, 2H) , 8.68(s, 1H)

[Step 3] Synthesis of 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)phenol Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.5 g, 1.46 mmol) was hydrogenated with 0.1 g (0.2 w/w) of palladium on activated carbon. The reaction mixture The residue was filtered through celite and concentrated to obtain the title compound (0.36 g). P— NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 2.00 (t, 2H) , 4.35 (m, 2H) , 4.40 (s, 1H), 4.54 (s, 2H), 6.67 (m, 2H) , 7.18 (m, 2H) , 8.04 (s, 1H) , 8.22 (m, 2H) , 8.26 (s, 1H) , 8.45 (m, 2H) , 8.51 (s, 1H) , 8.53 (s, 1H)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxyphenyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 29) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.15 g, 0.48 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.11 g, 0.48 mmol), HATU (0.37 g, 0.96 mmol), and DI PEA (0.34 mL, 1.93 mmol) was used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.12 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.02 (t, 2H) , 4.47 (m, 2H) , 4.49 (s, 1H), 7.43 (s, 1H), 8.14 (s, 1H) , 8.39 (m, 2H) , 8.42 (m, 2H) , 8.45 (s, 1H) , 8.62 (m, 2H) , 8.68 (m, 3H), 9.63 (s, 1H) , 9.77 (s, 1H)

LC-MS (ESI, m/z) = 500.1 (M+H+) Example 30. N-(2-(3-hydroxy-3 ■methylbutyl)-6-(4-hydroxyphenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[Step 4] N-(2-(3-hydroxy-3-methylbutyl)-6-(4-hydroxyphenyl)-2H-indazole- Synthesis of 5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 30) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] of Example 29 (0.15 g, 0.48 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.11 g, 0.48 mmol), HATU (0.37 g, 0.96 mmol), and DI PEA (0.34 mL, 1.93 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.12 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 4.47(m, 2H) , 4.49(s, 1H), 7.44(s, 1H), 7.64(m, 1H) , 7.66(m, 1H) , 8.24(s, 1H) , 8.41(m, 2H) , 8.53(s, 1H) , 8.61(m, 2H), 8.73(m, 3H) , 9.63(m, 1H) , 9.86(s, 1H)

LC-MS (ESI, m/z) = 500.1 (M+H+) Example 31. Methyl 3-(2-(3 -hydroxy-3 -methylbutyl)-5-(2-(pyridin-3 -yl)thiazole-4 -carboxamido)-2H-indazol-6 -yl)benzoate

［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-1H-indazole (2 g, 8.26 mmol), potassium carbonate (4.57 g, 33.1 mmol), potassium iodide (0.14 g, 0.83 mmol) and 4-bromo-2-methylbutan-2-ol (1.97 mL, 16.53 mmol) were used, and the reaction was performed in the same manner. The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (1.27 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.04 (m, 2H) , 3.88 (s, 3H) , 4.50 (m, 3H), 8.40 (s, 1H), 8.51 (s, 1H), 8.65 (s, 1H)

［Step 2］ Synthesis of methyl 3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzoate Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ (1.2 g, 3.66 mmol), sodium carbonate (1.94 g, 18.3 mmol), tetrakis(triphenylphosphine)palladium (0.21 g, 0.18 mmol), and methyl 3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.44 g, 5.48 mmol) was used. 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) , 2.04(m, 2H) , 3.88(s, 3H) , 4.50(m, 3H), 7.43(m, 1H), 7.65(s, 1H) , 8.01(d, 1H) , 8.40(s, 1H) , 8.46(s, 1H) , 8.51(s, 1H) , 8.65(s, 1H)

［Step 3］ Synthesis of methyl 3-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)benzoate Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.9 g, 2.35 mmol) was hydrogenated with 0.18 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.51 g). P— NMR (DMSO-d ⁶ ) 1.09(s, 6H) , 2.00(m, 2H) , 3.74(s, 3H) , 4.43(m, 3H), 4.54(s, 2H), 7.23(m, 1H) , 7.49(s, 1H) , 7.90(d, 1H) , 8.21(s, 1H) , 8.31(s, 1H) ,

8.42(s, 1H), 8.48(s, 1H) [Step 4] Synthesis of methyl 3-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-3-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)benzoate (Compound 31) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] (0.15 g, 0.42 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.09 g, 0.42 mmol), HATU (0.32 g, 0.85 mmol), and DI PEA (0.30 mL, 1.70 mmol) was used, and the reaction was performed in the same manner. The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.13 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.04 (m, 2H) , 3.88 (s, 3H) , 4.50 (m, 3H), 7.41 (m, 1H), 7.58 (s, 1H) , 7.63 (s, 1H) , 7.68 (s, 1H) , 8.01 (d, 1H) , 8.09 (d, 2H) , 8.44 (s, 1H), 8.46 (s, 1H) , 8.54 (s, 1H) , 8.67 (d, 1H) , 8.71 (s, 1H) , 9.63 (s, 1H) LC-MS (ESI, m/z) = 542.1 (M+H+) Example 32. N-(6-(3-aminophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 2］ Synthesis of 4-(6-(3-aminophenyl)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 11 (0.3 g, 0.91 mmol), sodium carbonate (0.48 g, 4.57 mmol), tetrakis(triphenylphosphine)palladium (0.05 g, 0.05 mmol) and 3-(4, 4,5,5- The reaction was performed in the same manner using tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.30 g, 1.37 mmol), and the resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.22 g). P— NMR (DMSO-d ⁶ ) 1.14(s, 6H) , 2.05(m, 2H) , 4.50(m, 3H) , 5.99(s, 2H), 7.55(m, 1H), 7.74(s, 1H) , 7.92(s, 1H) , 7.97(m, 1H) , 8.18(s, 1H) , 8.47(s, 1H) , 8.49(s, 1H), 8.75(m, 2H)

2.01(m, 2H) , 4.45(m, 3H) , 4.54 (s, 2H) ,［Step 3］ Synthesis of 4-(5-amino-6-(3-aminophenyl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.20 g, 0.59 mmol) was hydrogenated with 0.04 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.12 g).

2.01(m, 2H) , 4.45(m, 3H) , 4.54 (s, 2H) ,

5.88(s, 2H), 7.42(m, 1H) , 7.68(s, 1H) , 7.86(s, 1H) , 7.91(m, 1H) , 8.08(s, 1H) , 8.27(s, 1H), 8.29 (s, 1H), 8.75(m, 2H)

［Step 4］ Synthesis of N-(6-(3 -aminophenyl)-2-(3 -hydroxy-3 -methylbutyl)-2H -indazol-5-yl)-2-(pyridin-3 -yl)thiazole-4-carboxamide (Compound 32) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.1 g, 0.32 mmol), 2-(pyridin-3 -yl)thiazole-4-carboxylic acid (0.07 g, 0.32 mmol), HATU (0.24 g, 0.64 mmol), and DI PEA (0.22 mL, 1.29 mmol) was used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.09 g). P— NMR (DMSO-d ⁶ ) 1.14(s, 6H) , 2.05(m, 2H) , 4.50(m, 3H) , 7.53(m, 1H), 7.62(m, 1H), 7.76(m, 2H) , 7.91(s, 1H) , 7.96(m, 1H) , 8.18(s, 1H) , 8.47(s, 1H) ,

8.49(s, 1H), 8.71(m, 1H) , 8.75(m, 2H) , 9.75(s, 1H)

LC-MS (ESI, m/z) = 499.1 (M+H+) Example 33. 2- (2-Aminopyridine- 4 -yl)- N- (6-(furan- 3 -yl)- 2- (2 -hydroxy-

2 ■Methylpropyl)-2H-indazole-5-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-bromo-N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 4 (0.44 g, 1.62 mmol), 2-bromothiazole-4-carboxylic acid (0.36 g, 1.62 mmol), HATU (1.23 g, 3.24 mmol), and DI PEA (1.13 mL, 6.49 mmol) was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.59 g). P- NMR (DMSO-d ⁶ ) 1.09(s, 6H) , 4.32(m, 2H) , 4.84(s, 1H) , 6.98(s, 1H), 7.61(s, 1H), 7.97(s, 1H) , 8.16(m, 1H) , 8.41(s, 1H) , 8.74(s, 1H) , 9.03(s, 1H) , 9.75(s, 1H)

[Step 5] Synthesis of 2-(2-aminopyridin-4-yl)-N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 33) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] (0.12 g, The reaction was carried out in the same manner using sodium carbonate (0.14 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, O.Olmmol) and 4-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)pyridin- 2 -amine (0.09 g, 0.39 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g). P— NMR (DMSO-d ⁶ ) 1.09(s, 6H) , 4.32(m, 2H) , 4.85(s, 1H) , 7.02 (s, 1H) , 7.61(s, 1H), 7.97(m, 1H) , 8.16(m, 1H) , 8.37(s, 1H) , 8.42(s, 1H) , 8.47(s, 1H) , 8.65(m, 1H), 8.69(m, 1H) , 8.73(s, 1H) , 9.03(m, 1H) , 9.75(s, 1H)

LC-MS (ESI, m/z) = 475.1 (M+H+) Example 34. 2-Hydroxypropane- 2 -yl 4- (4- ((6-(furan- 3 -yl)- 2- (2-hydroxy -2 -methylpropyl )-2H-indazol- 5 -yl)carbamoyl)thiazole- 2 -yl )-3,6-dihydropyridine- 1 (2H)-carboxylate

［Step 5］ Synthesis of 2-hydroxypropane-2-yl 4-(4-((6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)carbamoyl)thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Compound 34) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 33 (0.12 g, 0.26 mmol), sodium carbonate (0.14 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, O.Olmmol) and 2-hydroxypropane-2-yl 4-(4, 4,5, 5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)- The reaction was performed in the same manner using carboxylate (0.12 g, 0.39 mmol), purified by MPLC (combiFlash NEXTGEN 300+), and concentrated to obtain the title compound (0.05 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 1.42(s, 9H) , 2.84— 2.86(m, 2H) , 3.42— 3.44(m, 2H), 3.56- 3.58(m, 2H) , 4.32(m, 2H) , 4.84(s, 1H) , 6.29(t, 1H) , 7.02(s, 1H), 7.61(s, 1H), 7.97(s, 1H) , 8.16(s, 1H) , 8.27(s, 1H) , 8.41(s, 1H) , 8.74(s, 1H), 9.77(s, 1H)

LC-MS (ESI, m/z) = 564.1 (M+H+) Example 35. N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-2-(thiophene-2-yl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-2-(thiophene-2-yl)thiazole-4-carboxamide (Compound 35) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 33 (0.12 g, 0.26 mmol), sodium carbonate (0.14 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, O.Olmmol), and 4,4,5,5-tetramethyl-2-(thiophene-2-yl)-1,3,2-dioxaborolane (0.08 g, 0.39 mmol) was used. After reaction in the same manner, the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.05 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 4.47(m, 2H) , 4.49(s, 1H) , 6.99(m, 2H), 7.31(m, 2H), 7.44(s, 1H) , 7.66(m, 2H) , 8.40(s, 1H) , 8.53(s, 1H) , 8.73(s, 1H) , 9.86(s, 1H)

LC-MS (ESI, m/z) = 465.1 (M+H+) Example 36. N-(6-(2-Aminopyridin-4-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 2］ Synthesis of 4-(6-(2-aminopyridin-4-yl)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 11 (0.3 g, 0.91 mmol), sodium carbonate (0.48 g, 4.57 mmol), tetrakis(triphenylphosphine)palladium (0.05 g, 0.05 mmol), and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.30 g, 1.37 mmol) was 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. (0.22 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.14 (s, 6H) , 2.05 (m, 2H) , 4.50 (m, 3H) , 7.55 (m, 1H), 7.74 (s, 1H), 7.92 (s, 1H) , 8.18 (s, 1H) , 8.47 (s, 1H) , 8.49 (s, 1H) , 8.75 (m, 2H)

2.01(m, 2H) , 4.45(m, 3H) , 4.54 (s, 2H) ,[Step 3] Synthesis of 4-(5-amino-6-(2-aminopyridin-4-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.20 g, 0.59 mmol) was hydrogenated with 0.04 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.12 g).

2.01(m, 2H) , 4.45(m, 3H) , 4.54 (s, 2H) ,

7.42(m, 1H), 7.68(s, 1H) , 7.86(s, 1H) , 8.08(s, 1H) , 8.27(s, 1H) , 8.29(s, lH),8.75(m, 2H)

［Step 4］ Synthesis of N-(6-(2-aminopyridin-4-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 36) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.1 g, 0.32 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.07 g, 0.32 mmol), HATU (0.24 g, 0.64 mmol), and DI PEA (0.22 mL, 1.29 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.08 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.04 (m, 2H) , 4.49 (m, 3H) , 5.91 (s, 2H), 6.23 (m, 2H), 6.59 (m, 1H) , 7.50 (s, 1H) , 7.79 (m, 2H) , 8.06 (s, 1H) , 8.45 (s, 1H) , 8.55 (s, 1H), 8.75 (m, 2H) , 9.67 (s, 1H)

LC-MS (ESI, m/z) = 500.1 (M+H+) Example 37. N-(2-(3-hydroxy-3-methylbutyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

1H) , 6.58(s, 1H) , 7.61(m, 1H) , 8.25(m, 1H) , 8.46(s,［Step 2］ Synthesis of 2-methyl-4-(5-nitro-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-indazol-2-yl)butan-2-ol Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 11 (0.6 g, 1.83 mmol), sodium carbonate (0.97 g, 9.14 mmol), tetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)- The same method was used to obtain the title compound (0.45 g) using 1H-pyrazole (0.76 g, 2.74 mmol), which was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated. P— NMR (DMSO-d ⁶ ) 1.14 (s, 6H) , 1.37— 1.47 (m, 6H) , 2.05 (m, 2H) , 3.78 (m, 2H), 4.51 (m, 3H),

1H) , 6.58(s, 1H) , 7.61(m, 1H) , 8.25(m, 1H) , 8.46(s,

1H), 8.56(s, 1H)

［Step 3］ Synthesis of 4-(5-amino-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 3］ of Example 1, the compound of ［Step 2］ (0.45 g, 1.13 mmol) was hydrogenated with 0.09 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain the title compound (0.30 g). p- NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 1.31- 1.43 (m, 6H) , 1.99 (m, 2H) , 3.65 (m,

2H), 4.40(m, 3H) , 4.58 (s, 2H) , 5.01(m, 1H) , 6.50(s, 1H) , 7.52(m, 1H) , 8.16(m, 1H), 8.36(s, 1H), 8.42(s, 1H)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 37) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.2 g, 0.54 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.12 g, 0.54 mmol), HATU (0.41 g, 1.08 mmol), and DI PEA (0.38 mL, 2.17 mmol) was used, and the reaction was performed in the same manner, followed by MPLC (combiFlash) The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.14 g). P— NMR (DMSO-d ⁶ ) 1.14(s, 6H) , 1.37— 1.47(m, 6H) , 2.04(m, 2H) , 3.78(m, 2H), 4.50(m, 3H) , 5.09(m, 1H) , 6.57(s, 1H) , 7.59(m, 1H) , 7.67(s, 1H) , 7.72(s, 1H), 8.12 (s, 1H), 8.24(m, 1H) , 8.45(s, 1H) , 8.49(s, 1H) , 8.55(s, 1H) , 8.71(s, 1H), 9.64(s, 1H)

LC/MS (ESI, m/z) = 558.1 (M+H+) Example 38. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide

[Step 4] Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide (Compound 38) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] of Example 11

(0.11 g, 0.39 mmol), 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.08 g,

The reaction was carried out in the same manner using HATU (0.29 g, 0.77 mmol) and DI PEA (0.27 mL, 1.54 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.11 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.01(t, 2H) , 4.48(m, 3H) , 6.83(s, 1H), 7.67(s, 1H), 7.74(s, 1H) , 7.94(s, 1H) , 8.16(s, 1H) , 8.40(s, 1H) , 8.76(s, 1H) , 9.90(s, 1H)

LC-MS (ESI, m/z) = 465.1 (M+H+) Example 39. 2- (2-Fluoropyridin- 4 -yl)- N- (2- (3 -hydroxy- 3 -methylbutyl)-

6-(thiophene-3-yl)-2H-indazole-5-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-bromo-N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazole—5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 2 (0.5 g, 1.66 mmol), 2-bromothiazole-4-carboxylic acid (0.37 g, 1.66 mmol), HATU (1.26 g, 3.32 mmol), and DI PEA (1.16 mL, 6.64 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.62 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02(t, 2H) , 4.44(s, 1H) , 4.46(t, 2H), 7.38(m, 1H), 7.58(m, 2H) , 7.61(m, 1H) , 8.22(m, 1H) , 8.51(s, 1H) , 8.63(m, 1H) , 9.81(s, 1H)

［Step 5］ Synthesis of 2-(2-fluoropyridin-4-yl)-N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 39) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ (0.2 g, 0.41 mmol), sodium carbonate (0.22 g, 2.03 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol), and 2-fluoro-4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.61 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.15 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. Blood— NMR (DMSO-d ⁶ ) 1.12 (brs, 6H) , 2.02 (m, 2H) , 4.49 (m, 3H) , 7.39 (m, 1H), 7.60 (m, 1H), 7.63 (m, 1H) , 7.80 (m, 3H) , 8.42 (m, 2H) , 8.60 (m, 2H) , 9.82 (s, 1H) LC-MS (ESI, m/z) = 508.1 (M+H+) Example 40. N- (2- (3 -Hydroxy- 3 -methylbutyl)- 6- (thiophene- 3 -yl)- 2H-Indazole Boal, the three immortals, the three deities, the three parasites, the three halves of Tiwazol, the three forests, and the three carbosaman

1H) , 9.38(m, 1H) , 9.69(m, 1H) , 11.63(s, 1H) [Step 5] Synthesis of N-(2-(3 -hydroxy-3 -methylbutyl)-6-(thiophene-3 -yl)-2H-indazol-5-yl)-2-(6 -hydroxypyridin-3 -yl)thiazole-4-carboxamide (Compound 40) Under the same conditions as in [Step 2] of Example 1, the compound of [Step 4] of Example 39 (0.2 g, 0.41 mmol), sodium carbonate (0.22 g, 2.03 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol) and 5-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)pyridin- 2 -ol (0.13 g, 0.61 mmol) was used, and the reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated in the same manner to obtain the title compound (0.14 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.01(m, 2H) , 4.45(m, 2H) , 4.48(s, 1H), 7.31(m, 1H), 7.54(m, 1H) , 7.57(m, 1H) , 7.67(m, 1H) , 7.70(m, 1H) , 8.40(m, 2H) , 8.64(m,

1H) , 9.38(m, 1H) , 9.69(m, 1H) , 11.63(s, 1H)

LC-MS (ESI, m/z) = 506.1 (M+H+) Example 41. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide

［Step 4］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide (Compound 41) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (0.11 g, 0.39 mmol), 2-phenylthiazole-4-carboxylic acid (0.09 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was used, and the reaction was performed in the same manner. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.10 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.01 (m, 2H) , 4.47 (m, 3H) , 6.92 (m, 1H), 7.54 (m, 3H), 7.65 (s, 1H) , 7.92 (m, 1H) , 7.95 (m, 2H) , 8.07 (m, 1H) , 8.41 (m, 2H) , 8.50 (m, 1H), 9.95 (s, 1H)

LC-MS (ESI, m/z) = 473.1 (M+H+) Example 42. 2- (4-fluorophenyl)- N- (2- (3-hydroxy- 3 -methylbutyl)- 6-

(thiophene-3-yl)-2H-indazole-5-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-(4-fluorophenyl)-N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 42) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 2 (0.11 g, 0.36 mmol), 2-(4-fluorophenyl)thiazole-4-carboxylic acid (0.08 g, 0.36 mmol), HATU (0.28 g, 0.73 mmol), and DI PEA (0.25 mL, 1.46 mmol) was used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.01(m, 2H) , 4.46(m, 3H) , 7.38(m, 3H), 7.57(m, 1H), 7.79(s, 1H) , 7.82(m, 1H) , 7.92(m, 2H) , 8.41(m, 2H) , 8.66(m, 1H) , 9.77(s, 1H)

LC-MS (ESI, m/z) = 507.1 (M+H+) Example 43. N-(2-(3 -hydroxy-3 -methylbutyl)-6-(3-(methylcarbamoyl)phenyl)-

2H-indazole-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(3-(methylcarbamoyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 43) The compound of ［Step 4］ of Example 31 (0.12 g, 0.22 mmol) and N-methylamine in methanol (10 ml) were used, followed by reaction at 120°C for more than 6 hours, and then concentration. Thereafter, the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H), 2.04(t, 2H), 2.68(d, 3H), 4.48— 4.51(m, 3H), 7.51-7.54(m, 1H), 7.57(s, 1H), 7.61(t , 1H) , 7.68(d, 1H) , 8.01(m, 1H) , 8.08(m, 2H) , 8.43(s , 1H) , 8.45(s , 1H) , 8.48(m, 1H) , 8.60(s , 1H) , 8.92(d, 1H) , 9.61(s , 1H)

LC-MS (ESI, m/z) = 541.1 (M+H+) Example 44. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(3-(methylcarbamoyl)phenyl)-

2H-indazole-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of methyl 3-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-4-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)benzoate Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 31 (0.15 g, 0.42 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.09 g, 0.42 mmol), HATU (0.32 g, 0.85 mmol), and DI PEA (0.30 mL, 1.70 mmol) was reacted in the same manner. The mixture 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) , 2.04(t, 2H) , 3.85(s, 3H) , 4.48- 4.51(m, 3H), 7.51-7.54(m, 1H) , 7.57(s, 1H) , 7.61(t, 1H) , 7.68(d, 1H) , 8.01(m, 1H) , 8.08(m, 2H), 8.43(s, 1H) , 8.45(s, 1H) , 8.48(m, 1H) , 8.60(s, 1H) , 8.92(d, 1H) , 9.61(s, 1H)

［Step 5］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(3-(methylcarbamoyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 44) The compound of ［Step 4］ (0.12 g, 0.22 mmol) and N-methylamine in methanol (10 ml) were used, followed by reaction at 120°C for more than 6 hours, and then concentration. Afterwards, purification was performed by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.07 g). P- NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 2.68(d, 3H) , 4.48- 4.50(m, 3H), 7.52-7.54(m, 1H) , 7.59(s, 1H) , 7.62(t, 1H) , 7.69(d, 1H) , 8.03(m, 1H) , 8.09(m, 2H), 8.45(s, 1H) , 8.46(s, 1H) , 8.49(m, 1H) , 8.62(s, 1H) , 8.90(d, 1H) ,

9.63 (s, 1H)

LC-MS (ESI, m/z) = 541.1 (M+H+) Example 45. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(3-(methylcarbamoyl)phenyl)-

2H-indazole-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide

[Step 4] Methyl 3-(2-(3 -hydroxy-3 -methylbutyl)-5-(2 -

Synthesis of (trifluoromethyl)thiazole-4-carboxamido)-2H-indazol-6-yl)benzoate Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] of Example 31

(0.15 g, 0.42 mmol 1 ), 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.08 g,

The reaction was carried out in the same manner using HATU (0.32 g, 0.85 mmol) and DI PEA (0.30 mL, 1.70 mmol), and the residue 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) , 2.04 (m, 2H) , 3.88 (s, 3H) , 4.50 (m, 3H),

7.58(s, 1H), 7.63(s, 1H) , 7.68(s, 1H) , 8.01(d, 1H) , 8.44(s, 1H) , 8.46(s, 1H) ,

8.54(s, 1H), 8.67(d, 1H) , 9.63(s, 1H)

[Step 5] N-(2-(3-hydroxy-3-methylbutyl)-6-(3-(methylcarbamoyl)phenyl)-

Synthesis of 2H-indazole-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide (Compound 45) The compound of the above ［Step 4］ (0.12 g, 0.23 mmol) and N-methylamine in methanol (10 ml) were reacted at 120°C for more than 6 hours, and then concentrated. Thereafter, the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(m, 2H) , 2.69(d, 3H) , 4.50(m, 3H), 7.59(s, 1H), 7.64(s, 1H) , 7.69(s, 1H) , 8.03(d, 1H) , 8.46(s, 1H) , 8.47(s, 1H) , 8.55(s, 1H), 8.68(d, 1H) , 9.64(s, 1H)

LC-MS (ESI, m/z) = 532.1 (M+H+) Example 46. 2-(4-fluorophenyl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-(4-fluorophenyl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 46) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (0.11 g, 0.39 mmol), 2-(4-fluorophenyl)thiazole-4-carboxylic acid (0.09 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was used in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.11 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02(m, 2H) , 4.48(m, 3H) , 6.94(m, 1H), 7.54(m, 2H), 7.67(s, 1H) , 7.93(m, 1H) , 7.96(m, 2H) , 8.06(m, 1H) , 8.39(m, 2H) ,

8.51(m, 1H), 9.97(s, 1H)

LC-MS (ESI, m/z) = 491.1 (M+H+) Example 47, 2— (3—fluorophenyl)— N— (6— (furan— 3 —yl)— 2— (3—hydroxy- 3~ methylbutyl)-2H-indazol- 5 -yl)thiazole- 4 -carboxamide

6H) , 2.01(t, 2H) , 4.49(m, 3H) , 6.93(s, 1H),［Step 4］ Synthesis of 2-bromo-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (1.0 g, 3.5 mmol), 2-bromothiazole-4-carboxylic acid (0.79 g, 3.5 mmol), HATU (2.67 g, 7.01 mmol), and DI PEA (2.44 mL, 14.02 mmol) was used in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.03 g).

6H) , 2.01(t, 2H) , 4.49(m, 3H) , 6.93(s, 1H),

7.56(s, 1H), 7.68(s, 1H) , 7.92(s, 1H) , 8.18(s, 1H) , 8.42(s, 1H) , 8.78(s, 1H) , 9.92(s, 1H)

[Step 5] Synthesis of 2-(3-fluorophenyl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 47) Under the same conditions as in [Step 2] of Example 1, the compound of [Step 4] (0.1 g, The reaction was carried out in the same manner using sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 2-(3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.07 g, 0.32 mmol).

The title compound (0.08 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 4.51(m, 3H) , 6.91(s, 1H), 7.62-7.63(m, 2H) , 7.98(s, 1H) , 8.20(s, 1H) , 8.39(s, 1H) , 8.40(d, 1H) , 8.46(s, 1H), 8.52 (d, 1H), 8.55-8.56(m, 1H) , 8.58(s, 1H) , 9.96(s, 1H) LC-MS (ESI, m/z) = 491.1 (M+H+) Example 48. N- (6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide (Compound 48) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (0.09 g, 0.32 mmol) was used. After reaction in the same manner, the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.05(t, 2H) , 4.53(m, 3H) , 6.71(s, 1H), 7.65-7.67(m, 2H) , 7.90(s, 1H) , 8.11(s, 1H) , 8.30(s, 1H) , 8.38(d, 1H) , 8.39(s, 1H), 8.42 (d, 1H), 8.50-8.51(m, 1H) , 8.52(s, 1H) , 9.45(s, 1H)

LC-MS (ESI, m/z) = 541.1 (M+H+) Example 49. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(4-(trifluoromethyl)phenyl)thiazole-4-carboxamide (Compound 49) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (0.09 g, 0.32 mmol) was used, and the reaction was carried out in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.07 g). P— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.05 (t, 2H) , 4.53 (m, 3H) , 6.71 (s, 1H) , 7.65-7.67 (m, 2H) , 7.92 (s, 1H) , 8.13 (s, 1H) , 8.41 (s, 1H) , 8.48 (d, 2H) , 8.52 (d, 2H), 8.54(s, 1H), 9.48(s, 1H)

LC-MS (ESI, m/z) = 541.1 (M+H+) Example 50. 2-Ethyl- N- (6-(furan- 3 -yl)- 2- (3 -hydroxy- 3 -methylbutyl)- 2H- indazol- 5 -yl) thiazole- 4 -carboxamide

3H) , 2.01(t, 2H) , 2.46— 2.47(m,［Step 4］ Synthesis of 2-ethyl- N- (6-(furan-3-yl)- 2- (3-hydroxy- 3-methylbutyl)- 2H- indazol- 5 -yl) thiazole- 4-carboxamide (Compound 50) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (0.11 g, 0.39 mmol), 2-ethylthiazole- 4-carboxylic acid (0.07 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g).

3H) , 2.01(t, 2H) , 2.46— 2.47(m,

2H), 4.49(m, 3H) , 6.92(s, 1H) , 7.57(s, 1H) , 7.69(s, 1H) , 7.91(s, 1H) , 8.16(s, 1H), 8.40(s, 1H) ), 8.76(s, 1H), 9.94(s, 1H)

LC-MS (ESI, m/z) = 439.1 (M+H+) Example 51. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-methylthiazole-4-carboxamide

6H) , 2.01(t, 2H) , 2.79(s, 3H) , 4.49(m, 3H),［Step 4］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-methylthiazole-4-carboxamide (Compound 51) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (0.11 g, 0.39 mmol), 2-methylthiazole-4-carboxylic acid (0.06 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.09 g).

6H) , 2.01(t, 2H) , 2.79(s, 3H) , 4.49(m, 3H),

6.93(s, 1H), 7.56(s, 1H) , 7.68(s, 1H) , 7.92(s, 1H) , 8.18(s, 1H) , 8.42(s, 1H) , 8.78(s, 1H), 9.92 (s, 1H)

LC-MS (ESI, m/z) = 411.1 (M+H+) Example 52. 2-Cyclohexyl- N-(6-(furan- 3 -yl)- 2-(3 -hydroxy- 3 -methylbutyl)-

2H-indazole-5-yl)thiazole-4-carboxamide

[Step 4] 2 -Cyclohexyl- N-(6-(furan-3-yl)- 2-(3-hydroxy- 3-methylbutyl)-

6H) , 1.45- 1.48(m, 2H) , 1.51-1.53 (m,2H),Synthesis of 2H-indazole-5-yl)thiazole-4-carboxamide (compound 52) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] of Example 11 (0.11 g, 0.39 mmol), 2-cyclohexylthiazole-4-carboxylic acid (0.08 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol) and DI PEA (0.27 mL, 1.54 mmol) 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 (0.07 g). P- NMR

6H) , 1.45- 1.48(m, 2H) , 1.51-1.53 (m,2H),

1.84-1.86(m, 4H), 2.01(t, 2H) , 2.73(m, 1H) , 4.49(m, 3H) , 6.93(s, 1H) , 7.56(s, 1H), 7.68(s, 1H) , 7.92(s, 1H) , 8.18(s, 1H) , 8.42(s, 1H) , 8.78(s, 1H) , 9.92(s, 1H)

LC-MS (ESI, m/z) = 479.1 (M+H+) Example 53. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-nitrophenyl)thiazole-4-carboxamide

[Step 5] Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-nitrophenyl)thiazole-4-carboxamide (Compound 53) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 47 was prepared.

(0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4, 4, 5, 5 -tetramethyl-2- The same method was followed using (3-nitrophenyl)-1,3,2-dioxaborolane (0.08 g, 0.32 mmol), after which the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.10 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 4.51(m, 3H) , 6.91(s, 1H), 7.62-7.63(m, 2H) , 7.99(s, 1H) , 8.27(s, 1H) , 8.42(s, 1H) , 8.48(d, 1H) , 8.50(s, 1H), 8.54 (d, 1H), 8.59-8.60(m, 1H) , 8.62(s, 1H) , 10.5(s, 1H)

LC-MS (ESI, m/z) = 518.1 (M+H+) Example 54. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(thiophene-2-yl)thiazole-4-carboxamide

6H) , 2.01(t, 2H) , 4.49(m, 3H) , 6.99(m, 2H), 7.59(m, 2H), 7.72— 7.73(m, 2H) , 7.91(s, 1H) , 8.16(s, 1H) , 8.40(s, 1H) , 8.68(s, 1H), 9.67(s, 1H) ［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(thiophene-2-yl)thiazole-4-carboxamide (Compound 54) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4,4,5,5-tetramethyl-2-(thiophene-2-yl)-1,3,2-dioxaborolane (0.07 g, 0.32 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.09 g) was obtained by purification and concentration using MPLC (combiFlash NEXTGEN 300+).

6H) , 2.01(t, 2H) , 4.49(m, 3H) , 6.99(m, 2H), 7.59(m, 2H), 7.72— 7.73(m, 2H) , 7.91(s, 1H) , 8.16(s, 1H) , 8.40(s, 1H) , 8.68(s, 1H), 9.67(s, 1H)

LC-MS (ESI, m/z) = 479.1 (M+H+) Example 55. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-methoxyphenyl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-methoxyphenyl)thiazole-4-carboxamide (Compound 55) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.07 g, 0.32 mmol) was used, and the reaction was performed in the same manner using MPLC (combiFlash The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.09 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 3.82(s, 3H) , 4.51(m, 3H), 6.93(s, 1H), 7.63-7.64(m, 2H) , 7.97(s, 1H) , 8.25(s, 1H) , 8.41(s, 1H) , 8.46(d, 1H), 8.49(s, 1H), 8.53 (d, 1H) , 8.56- 8.58(m, 1H) , 8.12(s, 1H) , 9.46(s, 1H) LC-MS (ESI, m/z) = 503.1 (M+H+) Example 56. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)—2-(oxazol-4-yl)thiazole-4-carboxamide

6H) , 2.01(t, 2H) , 4.49(m, 3H) , 6.99(m, 2H),［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(oxazol-4-yl)thiazole-4-carboxamide (Compound 56) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (0.06 g, 0.32 mmol) was used, and the reaction was performed in the same manner, followed by MPLC (combiFlash) The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.05 g).

6H) , 2.01(t, 2H) , 4.49(m, 3H) , 6.99(m, 2H),

7.59(m, 1H), 7.72-7.75(m, 2H) , 7.90(s, 1H) , 8.15(s, 1H) , 8.38(s, 1H) , 8.66(s, 1H), 9.62(s, 1H)

LC-MS (ESI, m/z) = 464.1 (M+H+) Example 57. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)thiazole-4-carboxamide

6H) , 1.98(t, 2H) , 2.85(s, 3H) , 4.48(m, 3H),［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(6-methylpyridin-3-yl)thiazole-4-carboxamide (Compound 57) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.07 g, 0.32 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.09 g) was obtained by purification and concentration using MPLC (combiFlash NEXTGEN 300+).

6H) , 1.98(t, 2H) , 2.85(s, 3H) , 4.48(m, 3H),

6.90(s, 1H), 7.60-7.62(m, 2H) , 7.96(s, 1H) , 8.22(s, 1H) , 8.24(s, 1H) , 8.41(s, 1H), 8.43(d, 1H) , 8.48(s, 1H) , 8.53(s, 1H) , 9.82(s, 1H)

LC-MS (ESI, m/z) = 488.1 (M+H+) Example 58. 2-(6-fluoropyridine-3-yl)-N-(6-(furan-3-yl)-2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 5］ 2-(6-fluoropyridine-3-yl)-N-(6-(furan-3-yl)-2-(2-hydroxy- Synthesis of 2-methylpropyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 58) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 33 (0.12 g, 0.26 mmol), sodium carbonate (0.14 g, 1.30 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, O.Olmmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.09 g, 0.39 mmol) was used. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.09 g). P- NMR (DMSO-d ⁶ ) 1.14(s, 6H) , 4.46- 4.49(m, 3H) , 7.20-7.21 (d, 2H) , 7.40(d, 1H), 7.56(s, 1H) , 8.03(s, 1H) , 8.25(s, 1H) , 8.40(s, 1H) , 8.50(s, 1H) , 8.70(s, 1H), 9.06(s, 1H) , 10.2(s, 1H)

LC-MS (ESI, m/z) = 478.1 (M+H+) Example 59. 2- (4-fluorophenyl)- N- (2- (3-hydroxy- 3-methylbutyl)- 6~ (3~

(morpholine-4-carbonyl)phenyl)-2H-indazole-5-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzoic acid The compound of ［Step 2］ of Example 31 (0.3 g, 0.78 mmol), tetrahydrofuran (6 mL), and 2N sodium hydroxide aqueous solution (6 mL) were added and stirred at room temperature for 3 hours or more. After completion of the reaction, a 2N hydrochloric acid aqueous solution was added to adjust the pH to 5-6. After concentration, filtering, washing with purified water and drying, the title compound (0.26 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.05 (t, 2H) , 4.50 (s, 1H) , 4.50 (t, 2H), 7.36 (s, 1H), 7.54 (s, 1H) , 8.04 (s, 1H) , 8.12 (m, 1H) , 8.34 (s, 1H) , 8.44 (s, 1H), 8.52 (s, 1H)

［Step 2］ Synthesis of (3-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)phenyl)(morpholino)methanone The compound of ［Step 1］ (0.2 g, 0.46 mmol), methylene chloride (2 mL), morpholine (0.04 g, 0.46 mmol), H0Bt-H ₂ 0 (0.09 g, 0.69 mmol), and EDC-HC1 (0.13 g, 0.669 mmol) were added and stirred at room temperature for more than 6 hours. Purified water (2 mL) was added, dried over magnesium sulfate, and concentrated. Then, the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.12 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.05(t, 2H) , 3.10— 3.25(m, 4H) , 3.58(m, 4H), 4.49- 4.51(m, 3H) , 7.37(s, 1H), 7.56(s, 1H) , 8.05 (s, 1H) , 8.14(m, 1H) , 8.30(s, 1H), 8.45(s, 1H) , 8.53(s, 1H)

［Step 3］ Synthesis of (3-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)phenyl)(morpholino)methanone Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.12 g, 0.27 mmol) was hydrogenated with 0.02 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through celite, and the filtrate was concentrated to obtain the title compound (0.1 g). P— NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 2.01 (t, 2H) , 3.01— 3.06 (m, 4H) , 3.41 (m, 4H), 4.32- 4.34(m, 3H) , 4.54(s, 2H) , 7.27(m, 2H) , 7.41(s, 1H) , 7.91(s, 1H) , 8.01(m, 1H), 8.23(s, 1H) , 8.30(s, 1H) , 8.41(s, 1H) , 9.42(s,lH)

［Step 4］ 2-(4-fluorophenyl)-N-(2-(3-hydroxy-3-methylbutyl)-6-(3-

Synthesis of (morpholine-4-carbonyl)phenyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 59) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] (0.1 g, 0.24 mmol), 2-(4-fluorophenyl)thiazole-4-carboxylic acid (0.05 g, 0.24 mmol), HATU (0.19 g, 0.49 mmol), and DI PEA (0.17 mL, 0.98 mmol) was used, and the reaction was performed in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.05(t, 2H) , 3.10— 3.25(m, 4H) , 3.58(m, 4H), 4.49(s, 1H), 4.50(t, 2H) , 7.37(m, 2H) , 7.46(s, 1H) , 7.54(s, 1H) , 7.61(m, 2H), 7.75(m, 2H) , 8.04 (s, 1H) , 8.12(m, 1H) , 8.34(s, 1H) , 8.44(s, 1H) , 8.52(s, 1H); 9.53(s,lH)

[단계 5] 3-（2-（3 -히드록시- 3 -메틸부틸）- 5-（2-（피리딘- 3 -일）티아졸- 4- 카르복사마이도) -2H-인다졸- 6 -일)벤조산의 합성 실시예 31의 ［단계 4］의 화합물 (0.5g, 0.95mmol), 테트라히드로퓨란 (lOmL) 및 2N-수산화나트륨수용액 (10mL)을 투입하고 실온에서 3시간 이상 교반하였다. 반응 종결 후 2N-염산수용액을 투입하여 pH를 4- 5으로 조절하고 농축한 뒤 여과하고, 정제수로 세척 후 건조하여 표제 화합물 (0.41g)을 수득하였다. 피- NMR (DMSO-d⁶) 1.13(s, 6H) , 2.02- 2.04(m, 3H) , 3.37- 3.38(m, 2H) , 7.53-7.55(m, 1H) , 7.57- 7.60(m, 2H) , 7.70(d, 1H) , 8.03(d, 1H) , 8.05(d, 1H) , 8.07(s, 1H), 8.43(s, 1H) , 8.45(s, 1H) , 8.53(t, 1H) , 8.62(s, 1H) , 8.71(d, 1H) , 8.95(s, 1H), 9.68(s, 1H) LC/MS (ESI, m/z) = 614.1 (M+H+) Example 60. N-(2-(3-hydroxy-3-methylbutyl)-6-(3-((2-hydroxyethyl)carbamoyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[Step 5] Synthesis of 3-(2-(3 -hydroxy-3 -methylbutyl)-5-(2-(pyridin-3 -yl)thiazole-4-carboxamido)-2H-indazol-6 -yl)benzoic acid The compound of [Step 4] of Example 31 (0.5 g, 0.95 mmol), tetrahydrofuran (lOmL) and 2N sodium hydroxide aqueous solution (10 mL) were added and stirred at room temperature for 3 hours or more. After completion of the reaction, a 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 (0.41 g). P- NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02- 2.04(m, 3H) , 3.37- 3.38(m, 2H) , 7.53-7.55(m, 1H) , 7.57- 7.60(m, 2H) , 7.70(d, 1H) , 8.03(d, 1H) , 8.05(d, 1H) , 8.07(s, 1H), 8.43(s, 1H) , 8.45(s, 1H) , 8.53(t, 1H) , 8.62(s, 1H) , 8.71(d, 1H) , 8.95(s, 1H); 9.68(s, 1H)

6H) , 2.02- 2.05(m, 3H) , 3.36- 3.38(m, 2H) ,［Step 6］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(3-((2-hydroxyethyl)carbamoyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 60) The compound of ［Step 1］ (0.2 g, 0.38 mmol), methylene chloride (2 mL), aminoethanol (0.2 mL, 0.38 mmol), HOBt- _H20 (0.08 g, 0.57 mmol), and EDC-HC1 (0.11 g, 0.57 mmol) were added and stirred at room temperature for more than 6 hours. Purified water (2 mL) was added, dried over magnesium sulfate, and concentrated. Afterwards, it was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.14 g). P- NMR

6H) , 2.02- 2.05(m, 3H) , 3.36- 3.38(m, 2H) ,

4.48- 4.51(m, 4H) , 4.64(t, 1H) , 7.52- 7.54(m, 1H) , 7.58- 7.61(m, 2H) , 7.69(d, 1H), 8.01(d, 1H), 8.03( d, 1H), 8.05(s, 1H) , 8.44(s, 1H) , 8.46(s, 1H) , 8.51(t, 1H), 8.60(s, 1H), 8.69(d, 1H) , 8.93(s, 1H) , 9.67(s, 1H)

틸부틸)- 6- (3-((2- 모르폴리노에틸）카르바모일）페닐） -2H-인다졸- 5 -일）- 2-（피리딘- 3 -일）티아졸- 4- 카르복사마이드 (화합물 61)의 합성 실시예 60의 ［단계 5］의 화합물 (0.2g, 0.38mmol), 염화 메틸렌 (2mL) , 4- (2 -아미노에틸)모르폴린 (0.05g, 0.38mmol), HOBt - H₂0 (0.08g, 0.57mmol) 및 EDC - HC1 (0.11g, 0.57mmol)을 투입하고 실온에서 6시간 이상 교반하였다. 정제수 (2ml)를 투입하고, 황산마그네슘으로 건조 후 농축하였다. 이후 MPLC(combiFlash NEXTGEN 300+)로 정제하고 농축하여 표제 화합물 (0.16g)을 수득하였다.

2.43(m, 2H) , 2.70(br. s, 4H) , 2.71-LC-MS (ESI, m/z) = 571.1 (M+H+) Example 61. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(3-((2-morpholinoethyl)carbamoyl)phenyl)- 2H-indazol- 5 -yl)- 2-(pyridin- 3 -yl)thiazole- 4-carboxamide

Synthesis of ethyl butyl)-6-(3-((2-morpholinoethyl)carbamoyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 61) The compound of [Step 5] of Example 60 (0.2 g, 0.38 mmol), methylene chloride (2 mL), 4-(2-aminoethyl)morpholine (0.05 g, 0.38 mmol), HOBt - H ₂ 0 (0.08 g, 0.57 mmol), and EDC - HC1 (0.11 g, 0.57 mmol) were added and stirred at room temperature for more than 6 hours. Purified water (2 mL) was added, dried over magnesium sulfate, and concentrated. Afterwards, it was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated. The title compound (0.16 g) was obtained.

2.43(m, 2H) , 2.70(br. s, 4H) , 2.71-

2.76(m, 4H), 3.50- 3.51(m, 4H), 4.50- 4.53(m, 3H), 7.52- 7.54(m, 1H), 7.58- 7.61(m, 2H), 7.69(d, 1H), 8.01(d, 1H) , 8.03(d, 1H) , 8.05(s, 1H) , 8.44(s, 1H) , 8.46(s, 1H), 8.51(t, 1H), 8.60(s, 1H) , 8.69(d, 1H) ) , 8.93(s, 1H) , 9.67(s, 1H) LC-MS (ESI, m/z) = 640.1 (M+H+) Example 62. 2-(6-Fluoropyridin-3-yl)-N-(2-(3-hydroxy-3-methylbutyl )-

6-(thiophene-3-yl)-2H-indazole-5-yl)thiazole-4-carboxamide

1H) , 9.38(m, 1H) , 9.69(m, 1H) , 11.63(s, 1H) ［Step 5］ Synthesis of 2-(6-fluoropyridin-3-yl)-N-(2-(3-hydroxy-3-methylbutyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 62) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 39 (0.2 g, 0.41 mmol), sodium carbonate (0.22 g, 2.03 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.61 mmol) was used. After the reaction in the same manner, the title compound (0.15 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.01 (m, 2H) , 4.45 (m, 2H) , 4.48 (s, 1H), 7.31 (m, 1H), 7.54 (m, 1H) , 7.57 (m, 1H) , 7.67 (m, 1H) , 7.70 (m, 1H) , 8.40 (m, 1H) , 8.64 (m,

1H) , 9.38(m, 1H) , 9.69(m, 1H) , 11.63(s, 1H)

LC-MS (ESI, m/z) = 508.1 (M+H+) Example 63. N-(6-(2-Aminopyridin-4-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(6-(2-aminopyridin-4-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-bromothiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 36 (0.12 g, 0.39 mmol), 2-bromothiazole-4-carboxylic acid (0.09 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.12 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.05(m, 2H) , 4.48(m, 3H) , 5.93(s, 2H), 6.23(s, 1H), 6.57(s, 1H) , 7.51(s, 1H) , 7.78(m, 1H) , 8.06(s, 1H) , 8.45(s, 1H) , 8.55(s, 1H), 9.67(s, 1H)

［Step 5］ Synthesis of N-(6-(2-aminopyridin-4-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide (Compound 63) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ (0.11 g, 0.22 mmol), sodium carbonate (0.12 g, l.lOmmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.07 g, 0.33 mmol) was used in the same manner as in ［Step 2］ of Example 1. after

The title compound (0.05 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.05(m, 2H) , 4.48(m, 3H) , 5.93(s, 2H), 6.23(m, 2H), 6.59(m, 1H) , 7.51(s, 1H) , 7.79(m, 2H) , 8.06(s, 1H) , 8.45(s, 1H) , 8.55(s, 1H), 8.61(s, 1H) , 9.67(s, 1H)

LC-MS (ESI, m/z) = 518.1 (M+H+) Example 64. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(2-aminopyridin-4-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 2-(2-(6-bromo-5-nitro-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-1H-indazole (3 g, 12.4 mmol), potassium carbonate (6.85 g, 49.6 mmol), potassium iodide (0.21 g, 1.24 mmol), and 2-(2-chloroethoxy)acetamide (2.56 g, 18.6 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (2.4 g). P— NMR (DMSO-d ⁶ ) 3.76(s, 2H) , 3.92(t, 2H) , 4.68(t, 2H) , 7.20(d, 2H), 8.14(s, 1H), 8.61(s, 1H), 8.78(s, 1H)

[Step 2] Synthesis of 2-(2-(6-(2-aminopyridin-4-yl)-5-nitro-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] (2.0 g, 5.83 mmol), sodium carbonate (3.09 g, 29.1 mmol), tetrakis(triphenylphosphine)palladium

(0.34 g, 0.29 mmol) and 4-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)pyridin- 2 -amine (1.92 g, 8.74 mmol) were used in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.58 g). P— NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.90(t, 2H) , 4.70(t, 2H) , 5.99(s, 2H), 6.37(s, 1H), 6.42(d, 1H) , 7.16— 7.21(m, 2H) , 7.62(s, 1H) , 8.15(s, 1H) , 8.60(d, 1H), 8.80(s, 1H)

［Step 3］ Synthesis of 2-(2-(5-amino-6-(2-aminopyridin-4-yl)-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (1.0 g, 2.81 mmol) was hydrogenated with 0.4 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.57 g). P— NMR (DMSO-d ⁶ ) 3.71(s, 2H) , 3.82(t, 2H) , 4.59 (s, 2H) , 4.64(t, 2H) , 5.91(s, 2H), 6.32(s, 1H) , 6.37(d, 1H) , 7.12(d, 2H) , 7.58(s, 1H) , 8.10(s, 1H) , 8.54(d, 1H), 8.74(s, 1H)

［Step 4］ Synthesis of N-(2-(2-(2-amino-2—oxoethoxy)ethyl)-6-(2-aminopyridin-4-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 64) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.2 g, 0.61 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.14 g, 0.61 mmol), HATU (0.47 g, 1.23 mmol), and DI PEA (0.43 mL, 2.45 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.18g) Obtained. P- NMR (DMSO-d ⁶ ) 3.78 (s, 2H) , 3.93 (t, 2H) , 4.62 (t, 2H) , 6.16 (s, 2H) , 6.56 (s, 1H) , 6.62 (d, 1H) , 7.23 (br. S, 2H) , 7.51 (s, 1H) , 7.57- 7.59 (m, 1H) , 8.02 (d, 1H) , 8.19 (d, 1H) , 8.47 (d, 2H) , 8.62 (s, 1H) , 8.68 (d, 1H) , 9.06 (s, 1H) , 9.72 (s, 1H)

LC-MS (ESI, m/z) = 515.0 (M+H+) Example 65. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(2-aminopyridin-4-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

[Step 4] Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(2-aminopyridin-4-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 65) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] (0.2 g, 0.61 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.14 g, 0.61 mmol), HATU (0.47 g, 1.23 mmol), and DI PEA (0.43 mL, 2.45 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.18 g) was obtained. P— NMR (DMSO-d ⁶ ) 3.77 (s, 6H) , 3.93 (t, 2H) , 4.62 (t, 2H) , 6.23 (s, 2H), 6.57 (s, 1H), 6.59 (s, 1H) , 7.23 (s, 2H) , 7.51 (s, 1H) , 7.77 (s, 2H) , 8.05 (s, 1H) , 8.49(s, 1H), 8.54(s, 1H) , 8.67(s, 1H) , 8.74(s, 2H) , 9.70(s, 1H)

LC-MS (ESI, m/z) = 515.0 (M+H+) Example 66. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-

2H-Indazole-5-yl)-2-(2-aminopyridin-4-yl)thiazole-4-carboxamide

［Step 2］ Synthesis of 2-(2-(6-(4-fluorophenyl)-5-nitro-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 64 (1.0 g, 2.91 mmol), sodium carbonate (1.54 g, 14.6 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol), and (4-fluorophenyl)boronic acid (0.61 g, 4.37 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.79 g). P— NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.94(t, 2H) , 4.63(t, 2H) , 7.22— 7.24(d, 2H), 7.37(d, 2H), 7.53(d, 2H) , 8.05(s, 1H) , 8.44(s, 1H) , 8.63(s, 1H)

[Step 3] Synthesis of 2-(2-(5-amino-6-(4-fluorophenyl)-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.6 g, 1.67 mmol) was hydrogenated with 0.12 g (0.2 w/w) of palladium on activated carbon. Reaction The mixture was filtered through celite, and the filtrate was concentrated to give the title compound (0.34 g). P— NMR (DMSO-d ⁶ ) 3.69 (s, 2H) , 3.84 (t, 2H) , 4.56 (s, 2H) , 4.58 (t, 2H), 7.13-7.14 (d, 2H), 7.29 (d, 2H) , 7.48 (d, 2H) , 7.98 (s, 1H) , 8.36 (s, 1H) , 8.58 (s, 1H)

［Step 4］ Synthesis of N-(2-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-bromothiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.3 g, 0.91 mmol), 2-bromothiazole-4-carboxylic acid (0.20 g, 0.91 mmol), HATU (0.69 g, 1.83 mmol), and DI PEA (0.64 mL, 3.65 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.34 g). P- NMR (DMSO-d ⁶ ) 3.78(s, 2H) , 3.93(t, 2H) , 4.63(t, 2H) , 6.70(d, 1H), 6.80(s, 1H), 6.70(d, 2H) , 7.19- 7.22(d, 2H) , 7.53- 7.56(s, 1H) , 8.00(s, 1H), 8.44(s, 1H), 8.59(s, 1H) , 9.52(s, 1H)

［Step 5］ Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-(2-aminopyridin-4-yl)thiazole-4-carboxamide (Compound 66) Under the same conditions as in ［Step 2］ of Example 1, the compound of ［Step 4］ (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.06 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-

2 - After the reaction using amine (0.07 g, 0.32 mmol), MPLC (combiFlash) was performed in the same manner. The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.06 g). P- NMR (DMSO-d ⁶ ) 3.78(s, 2H) , 3.93(t, 2H) , 4.63(t, 2H) , 6.19(s, 2H), 6.70(d, 1H), 6.80(s, 1H) , 6.70(d, 2H) , 7.19- 7.22(d, 2H) , 7.40(s, 2H) , 7.53- 7.56(m, 2H), 8.00(d, 1H) , 8.44(s, 1H) , 8.48(s, 1H) , 8.59(s, 1H) , 9.52(s, 1H)

LC-MS (ESI, m/z) = 532.0 (M+H+) Example 67. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-(3-aminophenyl)thiazole-4-carboxamide

［Step 5］ N-(2-(2-(2 -amino- 2 -oxoethoxy)ethyl)- 6-(4 -fluorophenyl)-

Synthesis of 2H-indazole-5-yl)-2-(3-aminophenyl)thiazole-4-carboxamide (compound 67) Under the same conditions as in [Step 2] of Example 1, the compound of [Step 4] of Example 66 was prepared.

(0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.06 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 3-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)aniline (0.07 g, 0.32 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.06 g). P— NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.94(t, 2H) , 4.63(t, 2H) , 6.20(s, 2H), 6.70(d, 1H), 6.83(d, 1H) , 6.96(t, 1H) , 7.10(t, 1H) , 7.20- 7.23(m, 2H) , 7.38- 7.41(m, 2H), 7.51(s, 1H) , 7.55- 7.56(m, 2H) , 8.03(s, 1H) , 8.48(s, 1H) , 8.66(s, 1H), 9.51(s, 1H)

LC-MS (ESI, m/z) = 531.0 (M+H+) Example 68. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-

2H-Indazole-5-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide

[Step 4] N-(2-(2-(2-amino-2—oxoethoxy)ethyl)-6-(4-fluorophenyl)-

Synthesis of 2H-indazol-5-yl)-2-(3-fluorophenyl)thiazole-4-carboxamide (Compound 68) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] of Example 66 (0.11 g, 0.34 mmol), 2-(3-fluorophenyl)thiazole-4-carboxylic acid (0.07 g, 0.34 mmol), HATU (0.25 g, 0.67 mmol), and DI PEA (0.23 mL, 1.34 mmol) was used in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.10 g). P- NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.94(t, 2H) , 4.63(t, 2H) , 7.22- 7.24(d, 2H), 7.37(d, 2H), 7.52- 7.53(m, 3 H) , 7.54- 7.59(m, 3H) , 8.05(s, 1H) , 8.43(s, 1H), 8.48(s, 1H), 8.63(s, 1H) , 9.56(s, 1H)

LC-MS (ESI, m/z) = 534.0 (M+H+) Example 69. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-(3-hydroxyphenyl)thiazole-4-carboxamide

［Step 5］ N-(2-(2-(2 -amino- 2 -oxoethoxy)ethyl)- 6-(4 -fluorophenyl)-

Synthesis of 2H-indazole-5-yl)-2-(3-hydroxyphenyl)thiazole-4-carboxamide (compound 69) Under the same conditions as in [Step 2] of Example 1, the compound of [Step 4] of Example 66

(0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.06 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 3-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenol (0.07 g, 0.32 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.05 g). P— NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.94(t, 2H) , 4.63(t, 2H) , 6.99(d, 1H), 7.08(d, 1H), 7.18(s, 1H) , 7.21- 7.25(m, 2H) , 7.38(s, 1H) , 7.50(s, 1H) , 7.56- 7.58(m, 2H), 8.03(s, 1H) , 8.48(s, 1H) , 8.62(s, 1H) , 9.54(s, 1H) , 9.59(s, 1H) LC-MS (ESI, m/z) = 532.0 (M+H+) Example 70. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide

［Step 5］ N-(2-(2-(2 -amino- 2 -oxoethoxy)ethyl)- 6-(4 -fluorophenyl)- Synthesis of 2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide (Compound 70) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 66 (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.06 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.07 g, 0.32 mmol) was used. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). P- NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.94(t, 2H) , 4.63(t, 2H) , 7.22- 7.24(m, 2H), 7.32-7.34(m, 2H) , 7.52- 7.53(m, 1H) , 7.53- 7.54(m, 1H) , 7.55- 7.57(m, 1H) , 8.29(s, 1H), 8.45(s, 1H) , 8.46(s, 1H) , 8.49(s, 1H) , 8.53(s, 1H) , 8.67(s, 1H) , 9.60(s, 1H)

LC-MS (ESI, m/z) = 535.0 (M+H+) Example 71. N-(2-(2-(2 -amino- 2 -oxoethoxy)ethyl)- 6-(4 -fluorophenyl)-

2H-indazole-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[Step 4] N-(2-(2-(2 -amino- 2 -oxoethoxy)ethyl)- 6-(4 -fluorophenyl)-

Synthesis of 2H-indazole-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (compound 71) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] of Example 66 (0.11 g, 0.34 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.07 g, 0.34 mmol), HATU (0.25 g, 0.67 mmol) and DI PEA (0.23 mL, 1.34 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.12 g). P— NMR (DMSO-d ⁶ ) 3.78(s, 2H) , 3.94(t, 2H) , 4.63(t, 2H) , 7.19— 7.23(d, 2H), 7.37(d, 2H), 7.50- 7.53(m, 2H) , 7.56- 7.59(m, 2H) , 8.08(s, 1H) , 8.46(s, 1H), 8.49(s, 1H), 8.59(s, 1H) , 8.70(d, 1H) , 9.59(s, 1H)

LC-MS (ESI, m/z) = 517.0 (M+H+) Example 72. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(4-fluorophenyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 72) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 66 (0.11 g, 0.34 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.07 g, 0.34 mmol), HATU (0.25 g, 0.67 mmol), and DI PEA (0.23 mL, 1.34 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.11 g) was obtained. P— NMR (DMSO-d ⁶ ) 3.78 (s, 2H) , 3.93 (t, 2H) , 4.62 (t, 2H) , 7.20-7.24 (d, 2H), 7.40 (t, 2H), 7.54 (s, 1H), 7.57-7.59 (m, 2H), 7.67 (d, 2H), 8.49

(s, 1H), 8.53 (s, 1H), 8.60 (s, 1H), 8.70 (d, 2H), 9.57 (s, 1H)

LC-MS (ESI, m/z) = 517.0 (M+H+) Example 73. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide

［Step 2］ Synthesis of 2-(2-(6-(furan-3-yl)-5-nitro-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 64 (1.0 g, 2.91 mmol), sodium carbonate (1.54 g, 14.6 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol), and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.85 g, 4.37 mmol) were used, and the reaction was performed in the same manner. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.76 g) was obtained. P— NMR (DMSO-d ⁶ ) 3.77 (s, 2H) , 3.94 (t, 2H) , 4.61 (t, 2H) , 6.83 (s, 1H), 7.20-7.23 (d, 2H), 7.74 (s, 1H) , 7.95 (s, 1H) , 8.10 (s, 1H) , 8.49 (s, 1H) , 8.76 (s, 1H)

[Step 3] Synthesis of 2-(2-(5-amino-6-(furan-3-yl)-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.5 g, 1.51 mmol) was hydrogenated with 0.25 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.37 g). P— NMR (DMSO-d ⁶ ) 3.71(s, 2H) , 3.88(t, 2H) , 4.54(s, 2H) , 4.54(t, 2H), 6.76(s, 1H), 7.13-7.17(d, 2H) , 7.68(s, 1H) , 7.87(s, 1H) , 8.12(s, 1H) , 8.38(s, 1H), 8.70(s, 1H)

［Step 4］ Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide (Compound 73) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.37 mmol), 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.08 g, 0.37 mmol), HATU (0.28 g, 0.73 mmol), and DI PEA (0.26 mL, 1.47 mmol) was used in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.08 g). P- NMR (DMSO-d ⁶ ) 3.78(s, 2H) , 3.93(t, 2H) , 4.62(t, 2H) , 6.83(s, 1H), 7.20-7.23(d, 2H), 7.68(s, 1H) , 7.74(s, 1H) , 7.95(s, 1H) , 8.10(s, 1H) , 8.49(s, 1H), 8.76(s, 1H), 9.57(s, 1H)

LC-MS (ESI, m/z) = 480.0 (M+H+) Example 74. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide

［Step 2］ Synthesis of 2-(2-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 64 (1.1 g, 3.18 mmol), sodium carbonate (1.68 g, 15.9 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.16 mmol), and 4,4,5,5-tetramethyl-2-(thiophene-3-yl)-1,3,2-dioxaborolane (1.0 g, 4.76 mmol) was reacted in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.84 g) was obtained. P— NMR (DMSO-d ⁶ ) 3.77 (s, 2H) , 3.93 (t, 2H) , 4.61 (t, 2H) , 7.20— 7.21 (d, 2H), 7.38 (d, 1H), 7.78- 7.81 (m, 2H), 8.47 (s, 1H) , 8.64 (s, 1H) , 8.78 (s, 1H)

［Step 3］ Synthesis of 2-(2-(5-amino-6-(thiophene-3-yl)-2H-indazol-2-yl)ethoxy)acetamide Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.8 g, 2.31 mmol) was hydrogenated with 0.4 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.43 g). P— NMR (DMSO-d ⁶ ) 3.71(s, 2H) , 3.87(t, 2H) , 4.56 s, 2H) , 4.55(t, 2H) , 7.13-7.14(d, 2H), 7.32(d, 1H) , 7.72- 7.73(m, 2H) , 8.41(s, 1H) , 8.58(s, 1H) , 8.72(s, 1H)

［Step 4］ N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(thiophene-3-yl)-2H- Synthesis of indazole-5-yl)-2-bromothiazole-4-carboxamide Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] (0.2 g, 0.63 mmol), 2-bromothiazole-4-carboxylic acid (0.13 g, 0.63 mmol), HATU (0.48 g, 1.26 mmol), and DI PEA (0.44 mL, 2.53 mmol) was used, and the reaction was performed in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.21 g). P— NMR (DMSO-d ⁶ ) 3.77(s, 2H) , 3.93(t, 2H) , 4.61(t, 2H) , 7.20— 7.21(d, 2H), 7.38(d, 1H), 7.60(s, 1H) , 7.78- 7.81(m, 2H) , 8.47(s, 1H) , 8.64(s, 1H) , 8.78(s, 1H), 9.81(s, 1H)

［Step 5］ Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide (Compound 74) Under the same conditions as ［Step 2］ of Example 1, using the compound of ［Step 4］ (0.2 g, 0.39 mmol), sodium carbonate (0.21 g, 1.97 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, 0.02 mmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.59 mmol). After reaction in the same manner, the title compound (0.10 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 3.77 (s, 2H) , 3.93 (t, 2H) , 4.61 (t, 2H) , 7.20— 7.21 (d, 2H), 7.38 (d, 1H), 7.42 (d, 1H) , 7.60 (s, 1H) , 7.78- 7.81 (m, 2H) , 8.41- 8.42 (m, 1H), 8.47 (d, 2H), 8.64 (s, 1H) , 8.78 (s, 1H) , 9.81 (s, 1H)

LC-MS (ESI, m/z) = 523.0 (M+H+) Example 75. N-(2-(2-(2 -amino-2 -oxoethoxy)ethyl)-6-(thiophene-3 -yl)-2H-indazol-5 -yl)-2-( Pyridine-3-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 75) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 74 (0.1 g, 0.32 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.07 g, 0.63 mmol), HATU (0.24 g, 0.63 mmol), and DI PEA (0.22 mL, 1.26 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.12 g) was obtained. P— NMR (DMSO-d ⁶ ) 3.78(s, 2H) , 3.93(t, 2H) , 4.62(t, 2H) , 7.24(d, 2H), 7.36-7.39(m, 1H) , 7.56- 7.60(m, 2H) , 7.76- 7.79(m, 1H) , 7.80- 7.82(m, 1H) , 8.22- 8.24(m, 1H), 8.46(s, 1H) , 8.48(s, 1H) , 8.65(s, 1H) , 8.79(dd, 1H) , 9.08(d, 1H), 9.82(s, 1H)

LC-MS (ESI, m/z) = 505.0 (M+H+) Example 76. N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(2-(2-(2-amino-2-oxoethoxy)ethyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 76) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 74 (0.1 g, 0.32 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.07 g, 0.63 mmol), HATU (0.24 g, 0.63 mmol), and DI PEA (0.22 mL, 1.26 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.11 g) was obtained. P— NMR (DMSO-d ⁶ ) 3.77 (s, 2H) , 3.93 (t, 2H) , 4.61 (t, 2H) , 7.22 (d, 2H), 7.39 (s, 1H), 7.60 (s, 1H) , 7.81- 7.84 (m, 2H) , 8.47 (s, 1H) , 8.56 (d, 2H) , 8.64 (s, 1H), 8.75 (s, 1H), 8.76 (d, 2H) , 9.81 (s, 1H)

LC-MS (ESI, m/z) = 505.0 (M+H+) Example 77. N-(2-(2-(dimethylamino)ethyl)- 6-(6 -fluoropyridin- 3 -yl)-

2H-indazole-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide

[Step 2] Synthesis of 2-(6-(6-fluoropyridine-3-yl)-5-nitro-2H-indazol-2-yl)-N,N-dimethylethan-1-amine Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] of Example 5 (0.5 g, 1.6 mmol), sodium carbonate (0.85 g, 7.98 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.53 g, 2.39 mmol) was 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 (0.42 g). P— NMR (DMSO-d ⁶ ) 2.83(s, 6H) , 3.72(t, 2H) , 4.87(t, 2H) , 7.17— 7.19(m, 1H), 8.02-8.04(m, 3H) , 8.27(s, 1H), 8.55(s, 1H) , 8.64(s, 1H)

［Step 3］ Synthesis of 2-(2-(dimethylamino)ethyl)-6-(6-fluoropyridin-3-yl)-2H-indazol-5-amine Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.4 g, 1.21 mmol) was hydrogenated with 0.08 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.23 g). P— NMR (DMSO-d ⁶ ) 2.77(s, 6H) , 3.66(t, 2H) , 4.56(s, 2H) , 4.81(t, 2H), 7.11-7.12(m, 1H), 7.96-7.98(m, 3H), 8.21(s, 1H) , 8.49(s, 1H) , 8.58(s, 1H)

［Step 4］ Synthesis of N-(2-(2-(dimethylamino)ethyl)-6-(6-fluoropyridin-3-yl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide (Compound 77) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.2 g, 0.67 mmol), 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.13 g, 0.67 mmol), HATU (0.41 g, 1.08 mmol), and DI PEA (0.38 mL, 2.17 mmol) were used in the same manner, and the resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound.

(0.22 g) was obtained. P— NMR (DMSO-d ⁶ ) 2.83(s, 6H) , 3.72(t, 2H) , 4.87(t, 2H) , 7.17— 7.19(m,

1H), 7.67(s, 1H), 8.02-8.04(m, 3H) , 8.27(s, 1H) , 8.55(s, 1H) , 8.64(s, 1H) , 10.0(s, 1H)

LC/MS (ESI, m/z) = 479.1 (M+H+) Example 78. N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(3-hydroxyphenyl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-bromo-N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazole—5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 5 (0.2 g, 0.74 mmol), 2-bromothiazole-4-carboxylic acid (0.15 g, 0.74 mmol), HATU (0.56 g, 1.48 mmol), and DI PEA (0.52 mL, 2.96 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.23 g). P— NMR (DMSO-d ⁶ ) 2.17(s, 6H) , 2.79(m, 2H) , 4.49(t, 2H) , 6.93(s, 1H), 7.67(s, 1H), 7.90(m, 2H) , 8.06(s, 1H) , 8.40(s, 1H) , 8.42(s, 1H) , 8.52(s, 1H) , 9.99(s, 1H)

［Step 5］ N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)-

Synthesis of 2-(3-hydroxyphenyl)thiazole-4-carboxamide (compound 78) Under the same conditions as in [Step 2] of Example 1, the compound of [Step 4] (0.1 g, 0.22 mmol), sodium carbonate (0.12 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 3-(4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)phenol (0.07 g, 0.33 mmol) was 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 (0.06 g). P— NMR (DMSO-d ⁶ ) 2.16(s, 6H) , 2.76 t, 2H) , 4.48 (t, 2H) , 6.92 (m, 2H), 7.31-7.32 (m, 2H) , 7.35-7.37 (m, 1H) , 7.66 (s, 1H) , 7.86 (t, 1H) , 8.04 (s, 1H), 8.39 (s, 2H), 8.45 (s, 1H) , 9.80 (s, 1H) , 9.91 (s, 1H)

LC-MS (ESI, m/z) = 474.1 (M+H+) Example 79. 2-(4-Aminophenyl)-N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 5］ Synthesis of 2-(4-aminophenyl)-N-(2-(2-(dimethylamino)ethyl)-6-(furan-3-yl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 79) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 78 (0.1 g, 0.22 mmol), sodium carbonate (0.12 g, 1.09 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.07 g, 0.33 mmol) was used, and the reaction was performed in the same manner using MPLC (combiFlash NEXTGEN). Purified and concentrated to 300+ The title compound (0.04 g) was obtained. P— NMR (DMSO-d ⁶ ) 2.15 (s, 6H) , 2.47 (t, 2H) , 4.48 (t, 2H) , 5.77 (s, 2H), 6.89 (s, 1H), 7.56-7.58 (m, 1H) , 7.59-7.62 (m, 2H) , 7.63 (s, 1H) , 7.88 (s, 1H), 8.07 (s, 1H), 8.15 (s, 1H) , 8.38 (s, 1H) , 8.53 (s, 1H) , 9.82 (s, 1H)

LC-MS (ESI, m/z) = 473.1 (M+H+) Example 80. N-(2-(2-hydroxy-2 ■methylpropyl)-6-(thiophene-3 -yl)-2H-indazol-5 -yl)-2-(pyridin-4 -yl)thiazole-4 -carboxamide

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

6-Bromo-5-nitro-2H-indazole (2 g, 8.26 mmol) was added to dimethylformamide (20 mL) and stirred at room temperature. While stirring at room temperature, potassium carbonate (4.56 g, 27.30 mmol) and potassium iodide (0.14 g, 0.83 mmol) were added, and 1-chloro-2-methylpropan-2-ol (1.312 g, 12.39 mmol) was added dropwise. The reaction temperature was raised to 100°C and stirred for 5 hours. Upon completion of the reaction, the internal temperature was cooled to room temperature, diluted with 50 mL of ethyl acetate, and washed with purified water. The mixture was dried over magnesium sulfate, filtered under vacuum, and concentrated. The filtrate was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.16 g). P- NMR (DMSO-d ⁶ ) 1.09(s, 6H) , 4.32(s, 2H) , 4.85(s, 1H) , 7.81(s, 1H), 7.82(s, 1H), 8.60(s, 1H)

［Step 2］ Synthesis of 2-methyl-1-(5-nitro-6-(thiophene-3-yl)-2H-indazol-2-yl)propan-2-ol To the compound of ［Step 1］ (1.02 g, 3.25 mmol) was added 15 mL of 1,4-dioxane and purified water in a 10:1 ratio, and stirred at room temperature. Sodium carbonate (1.72 g, 16.23 mmol) and tetrakis(triphenylphosphine)palladium (0.19 g, 0.16 mmol) were added, and stirred. 4, 4, 5, 5-Tetramethyl-2-(thiophene-3-yl)-1,3, 2-dioxoborane was added, and stirred. The reactor was heated to 100°C, stirred for 8 hours, and cooled to room temperature upon completion of the reaction. Ethyl acetate (20 mL) was added, and sodium bicarbonate aqueous solution (20 mL) was added and washed. Magnesium sulfate was then added, filtered, concentrated, and purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.79 g). P- NMR (DMSO-d ⁶ ) 1.09 (s, 6H) , 4.32 (s, 2H) , 4.85 (s, 1H) , 7.40 (d, 1H), 7.60 (s, 1H), 7.81 (s, 1H), 7.82 (s, 1H) , 7.91 (s, 1H) , 8.60 (s, 1H)

［Step 3］ Synthesis of 1-(5-amino-6-(thiophene-3-yl)-2H-indazol-2-yl)-2-methylpropan-2-ol To the compound of ［Step 2］ (0.36 g, 2 mmol) was added ethyl acetate (5 mL). The mixture was hydrogenated with 0.128 g (0.11 mmol) of palladium on activated carbon under standard hydrogen pressure at 25°C for 3 hours. The reaction mixture was filtered through Celite, the filter was washed with methanol, and the filtrate was concentrated. The title compound (0.63 g) was obtained. 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)

［Step 4］Synthesis of N-(2-(2-hydroxy-2-methylpropyl)-6-(thiophene-3-yl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 80)

2-(Pyridin-4-yl)thiazole-4-carboxylic acid (0.1 g, 0.481 mmol) was added to dimethylformamide (2 mL) and stirred. HATU (0.33 g, 0.88 mmol) and DI PEA (0.31 mL, 1.75 mmol) were added and stirred at room temperature for 1 hour. The compound of [Step 3] above (0.126 g, 0.44 mmol) was added and stirred at room temperature for 8 hours. Upon completion of the reaction, purified water (5 mL) was added, and the formed crystals were filtered and dried to obtain the title compound (0.101 g). P- NMR (DMSO-d ⁶ ) 9.81(s,lH), 8.76(d, 2H), 8.75(s, 1H), 8.64(s, 1H), 8.56(s, 1H), 8.33(s, 1H), 7.92(s, 1H), 7.82(m, 3H) , 7.61(s, 1H) , 7.39(d, 1H) , 4.85(s, 1H), 4.32(s, 2H) , 1.09(s, 6H)

LC-MS (ESI, m/z) = 476.2 (M+H+) Example 81. 2-(6-fluoropyridine-3-yl)-N-(6-(3-hydroxyphenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide

[Step 1] Synthesis 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-1H-indazole

(3 g, 12.4 mmol), potassium carbonate (6.85 g, 49.6 mmol), potassium iodide (0.21 g, 1.24 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (3.46 g, 18.6 mmol) were used in the same manner, and the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (2.4 g). p- NMR (DMSO-d ⁶ ) 2.40 (br. s, 4H) , 2.83 (t, 2H) , 3.49 (t, 4H) , 4.61 (t, 2H) , 8.27 (s, 1H) , 8.55 (s, 1H) , 8.64 (s, 1H)

［Step 2］ Synthesis of 3-(2-(2-morpholinoethyl)-5-nitro-2H-indazol-6-yl)phenol Under the same conditions as in ［Step 2］ of Example 1, the compound of ［Step 1］ (1.0 g, 2.82 mmol), sodium carbonate (1.49 g, 14.8 mmol), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol), and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.93 g, 4.22 mmol) was used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.78 g). P- NMR (DMSO-d ⁶ ) 2.40(br. s, 4H) , 2.83(t, 2H) , 3.49(t, 4H) , 4.61(t, 2H), 8.27(s, 1H), 8.39(s, 1H) , 8.42(m, 2H) , 8.51(s, 1H) , 8.55(s, 1H) , 8.64(s, 1H), 9.63(s, 1H)

[Step 3] Synthesis of 3-(5-amino-2-(2-morpholinoethyl)-2H-indazol-6-yl)phenol Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.7 g, 1.90 mmol) was hydrogenated with 0.14 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.65 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 2.34 (br. s, 4H) , 2.76 (t, 2H) , 3.42 (t, 4H) , 4.56 (s, 2H) , 4.55 (t, 2H) , 8.21 (s, 1H) , 8.32 (s, 1H) , 8.36 (m, 2H) , 8.45 (s, 1H) , 8.49 (s, 1H) , 8.58 (s, 1H), 9.57 (s, 1H)

［Step 4］ Synthesis of 2-bromo-N-(6-(3-hydroxyphenyl)-2-(2-morpholinoethyl)-2H-indazole—5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.2 g, 0.38 mmol), 2-bromothiazole-4-carboxylic acid (0.08 g, 0.38 mmol), HATU (0.29 g, 0.76 mmol), and DI PEA (0.26 mL, 1.52 mmol) were used in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.15 g). P- NMR (DMSO-d ⁶ ) 2.40(br. s, 4H) , 2.83(t, 2H) , 3.49(t, 4H) , 4.61(t, 2H), 7.43(s, 1H), 8.27(s, 1H) , 8.39(s, 1H) , 8.42(m, 2H) , 8.51(s, 1H) , 8.55(s, 1H), 8.64(s, 1H), 9.63(s, 1H) , 10.0 (s, 1H)

[Step 5] Synthesis of 2-(6-fluoropyridin-3-yl)-N-(6-(3-hydroxyphenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 81) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] (0.14 g, 0.26 mmol), sodium carbonate (0.14 g, 1.32 mmol), tetrakis(triphenylphosphine)palladium (0.02 g, O.Olmmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.09 g, 0.40 mmol) was used, and the reaction was carried out in the same manner.

The title compound (0.07 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 2.40(br. s, 4H) , 2.83(t, 2H) , 3.49(t, 4H) , 4.61(t,

2H), 7.43(s, 1H), 8.27(s, 1H) , 8.39(s, 1H) , 8.42(m, 2H) , 8.45(s, 1H) , 8.51(s, 1H), 8.55(s, 1H) ), 8.62(m, 2H), 8.64(s, 1H) , 9.63(s, 1H) , 10.0 (s, 1H)

LC-MS (ESI, m/z) = 545.0 (M+H+) Example 82. N-(6-(3-hydroxyphenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(6-(3-hydroxyphenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 82) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 104 (0.1 g, 0.30 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.06 g, 0.30 mmol), HATU (0.22 g, 0.59 mmol), and DI PEA (0.21 mL, 1.18 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.11 g) was obtained. P— NMR (DMSO-d ⁶ ) 2.40 (br. S, 4H), 2.85 (br. S, 2H), 3.54 (br. S,

4H), 9.72 (s, 1H), 9.66 (s, 1H) , 8.98 (s, 1H) , 8.75 (s, 1H) , 8.70 (d, 1H) ,

4.55 (br. S, 2H) , 6.87 (s, 1H) , 6.91 (d, 1H) , 6.99 (d, 1H) , 7.35-7.38 (m,

1H), 7.48 (s, 1H), 7.56-7.58 (m, 1H), 8.11 (d, 1H), 8.44 (s, 1H), 8.47 (s,

1H) LC-MS (ESI, m/z) = 527.0 (M+H+) Example 83. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(4-(morpholinomethyl)phenyl)-

2H-indazole-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

[Step 2] Synthesis of 2-methyl-4-(6-nitro-6-(4-(morpholinomethyl)phenyl)-5-nitro-2H-indazol-2-yl)butan-2-ol Under the same conditions as [Step 2] of Example 1, the compound of [Step 1] of Example 11

(1.0 g, 3.05 mmol), sodium carbonate (1.61 g, 15.24 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol) and 4-(4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)morpholine (1.39, 4.57 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (1.10 g). P 一 NMR (DMSO-d ⁶ ) 1.12(s, 6H), 2.02(t, 2H), 3.61(br. S, 4H), 3.50(t,

4H), 3.61(s, 2H), 4.48-5.10(m, 3H), 7.49- 7.50(d, 2H), 8.12(dt, 1H), 8.44(d,

2H), 8.46(s, 1H), 8.66(s, 1H)

[Step 3] 4-(5-amino-6-(4-(trifluoromethyl)phenyl)-2H-indazol-2-yl)-

2-Methylbutane-2-ol Synthesis Example 1 Under the same conditions as [Step 3], the compound of [Step 2] (1.0 g,

2.36 mmol) was hydrogenated with 0.2 g (0.2 w/w) of palladium on activated carbon. The reaction mixture The residue was filtered through celite and 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)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(morpholinomethyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 83) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.11 g, 0.28 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.06 g, 0.28 mmol), HATU (0.21 g, 0.56 mmol), and DI PEA (0.19 mL, 1.12 mmol) was used in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.12 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.02 (t, 2H) , 3.61 (br. S, 4H) , 3.50 (t, 4H), 3.61 (s, 2H), 4.48-5.10 (m, 3H) , 7.49- 7.50 (d, 4H) , 7.50- 7.52 (m, 1H) , 8.12 (dt, 1H), 8.44 (d, 2H) , 8.46 (s, 1H) , 8.66 (s, 1H) , 8.71 (d, 1H) , 8.90 (s, 1H), 9.61 (s, 1H)

［단계 1］ 4- (6 -브로모- 5 -니트로- 2H-인다졸- 2 -일)- 2 -메틸부탄- 2 -올의 합성 실시예 1의 단계 1과 동일 조건에서 , 6 -브로모- 5 -니트로- 2H-인다졸 (2g, 8.26mmol), 디메틸포름아마이드 20mL, 탄산 칼륨 (4.56g, 27.30mmol), 요오드화 칼륨 (0.14g, 0.83mmol) 및 4 -브로모- 2 -메틸- 2 -부탄올 (2.76g, 16.53mmol)을 사용하여 동일한 방법으로 반응 후 MPLC(combiFlash NEXTGEN 300+)로 정제하고 농축하여 표제 화합물 (0.925g)을수득하였다.

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),LC-MS (ESI, m/z) = 583.0 (M+H+) Example 84. 2-(2-Aminopyridin-4-yl)-N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(trifluoromethyl)phenyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as Step 1 of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-bromo-2-methyl-2-butanol (2.76 g, 16.53 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.925 g).

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),

8.13(s, 1H), 8.59(s, 1H) , 8.75(s, 1H)

［Step 2］ Synthesis 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 of ［Step 1］ (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.61 mmol), tetrakis(triphenylphosphine)palladium (0.088 g, 0.38 mmol), and 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (0.62 g, 2.29 mmol) was reacted in the same manner. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.04(t, 2H) , 4.51(s, 1H) , 4.53(m, 2H), 7.56(d, 2H), 7.69(s, 1H) , 7.76(d, 2H) , 8.66(s, 1H) , 8.79(s, 1H)

[Step 3] Synthesis of 4-(5-amino-6-(4-(trifluoromethyl)phenyl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as [Step 3] of Example 1, the compound of [Step 2] (0.5 g, 1.27 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.4 g). Blood— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.04 (t, 2H) , 4.51 (s, 1H) , 4.53 (m, 2H), 6.84 (s, 2H), 7.56 (d, 2H) , 7.69 (s, 1H) , 7.76 (d, 2H) , 8.66 (s, 1H) , 8.79 (s, 1H) ［Step 4］ 2-Bromo- N- (2- (3 -hydroxy- 3 -methylbutyl)- 6- (4-

(Trifluoromethyl)phenyl)-2H-indazol-5-yl)thiazole-4-carboxamide Synthesis of (Trifluoromethyl)phenyl)-2H-indazol-5-yl)thiazole-4-carboxamide Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] (0.4 g, l.lOmmol), 2-bromothiazole-4-carboxylic acid (0.23 g, l.lOmmol), HATU (0.84 g, 2.20 mmol), and DI PEA (0.77 mL, 4.40 mmol) was 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 (0.5 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 4.48(t, 2H) , 4.51(s, 1H), 6.83(s, 1H), 7.76(d, 2H) , 7.88(d, 2H) , 8.43(s, 1H) , 8.47(s, 1H) , 8.49(s, 1H) , 9.58(s, 1H)

［Step 5］ Synthesis of 2-(2-aminopyridin-4-yl)-N-(2-(3-hydroxy-3-methylbutyl)-6-(4-(trifluoromethyl)phenyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 84) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ (0.5 g, 0.90 mmol), sodium carbonate (0.48 g, 4.52 mmol), tetrakis(triphenylphosphine)palladium (0.05 g, 0.05 mmol) and 4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-

2 - After the reaction using amine (0.3 g, 1.36 mmol) in the same manner, MPLC (combiFlash The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.3 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 4.48(t, 2H) , 4.51(s, 1H), 6.21(s, 2H), 6.67(d, 1H) , 6.83(s, 1H) , 7.58(s, 1H) , 7.76(d, 2H) , 7.88(d, 2H) , 7.92(d, 1H), 8.43(s, 1H) , 8.47(s, 1H) , 8.49(s, 1H) , 9.58(s, 1H)

LC-MS (ESI, m/z) = 567.0 (M+H+) Example 85. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 2］ Synthesis 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 of ［Step 1］ of Example 104 (1.0 g, 2.82 mmol), sodium carbonate (1.49 g, 14.8 mmol), tetrakis(triphenylphosphine)palladium (0.16 g, 0.14 mmol), and (4-fluorophenyl)boronic acid (0.59 g, 4.22 mmol) 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 (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］ 6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-amine Under the same conditions as in [Step 3] of Synthetic Example 1, the compound of [Step 2] (0.8 g,

2.16 mmol) was hydrogenated with 0.16 g (0.2 w/w) of palladium on activated carbon. 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)

［Step 4］ Synthesis of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 85) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.2 g, 0.59 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.12 g, 0.59 mmol), HATU (0.45 g, 1.18 mmol), and DI PEA (0.41 mL, 2.35 mmol) was used in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.22 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), 7.31(t, 2H) , 7.39 t, 2H) , 7.51(s, 1H) , 7.55- 7.56(m, 2H) , 7.79- 7.80(m, 2H), 8.36(s, 1H) , 8.43(s, 1H) , 8.60(s, 1H) , 9.54(s, 1H)

LC-MS (ESI, m/z) = 529.0 (M+H+) Example 86. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 86) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 85 (0.2 g, 0.59 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.12 g, 0.59 mmol), HATU (0.45 g, 1.18 mmol), and DI PEA (0.41 mL, 2.35 mmol) was used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.21 g). P— NMR (DMSO-d ⁶ ) 2.40— 2.41 (br . S, 4H) , 2.84(t, 2H) , 3.50-3 ,51(br . S, 4H), 4.53(t, 2H), 7.32- 7.34(m, 2H) , 7.52- 7.53(m, 1H) , 7.56- 7.57(m, 2H) , 8.09(d, 2H), 8.44(s, 1H) , 8.52(s, 1H) , 8.57(s, 1H) , 8.70(s, 1H) , 8.99(s, 1H) , 9.59(s, 1H)

LC-MS (ESI, m/z) = 529.0 (M+H+) Example 87. 2-(4-fluorophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol- 5 -yl)thiazole- 4-carboxamide

[Step 4] 2-(4-fluorophenyl)- N-(6-(4-fluorophenyl)- 2-(2- Synthesis of morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 87) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] of Example 85 (0.2 g, 0.59 mmol), 2-(4-fluorophenyl)thiazole-4-carboxylic acid (0.14 g, 0.59 mmol), HATU (0.45 g, 1.18 mmol), and DI PEA (0.41 mL, 2.35 mmol) was used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.22 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), 7.31(t, 2H) , 7.39(t, 2H) , 7.51(s, 1H) , 7.55- 7.56(m, 2H) , 7.79- 7.80(m, 2H), 8.36(s, 1H) , 8.43(s, 1H) , 8.60(s, 1H) , 9.54(s, 1H)

LC-MS (ESI, m/z) = 546.0 (M+H+) Example 88. 2-(4-amino-3-fluorophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-bromo-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 85 (1.0 g, 2.94 mmol), 2-bromothiazole-4-carboxylic acid (0.61 g, 2.94 mmol), HATU (2.23 g, 5.88 mmol), and DI PEA (2.05 mL, 11.8 mmol) were used in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (1.12 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 2.47— 2.48 (br . S, 4H) , 2.83 (t, 2H) , 3.50— 3.51 (m, 4H) , 4.52 (t, 2H), 7.38-7.39 (m, 2H) , 7.49 (s, 1H) , 7.55- 7.56 (m, 2H) , 8.18 (s, 1H), 8.42 (s, 1H), 8.68 (s, 1H) , 9.50 (s, 1H)

［Step 5］ Synthesis of 2-(4-amino-3-fluorophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 88) Under the same conditions as in ［Step 2］ of Example 1, the compound of ［Step 4］ (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olnmol), and 2-fluoro-4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.07 g, 0.31 mmol) was used, and the reaction was performed in the same manner using MPLC (combiFlash NEXTGEN). The residue was purified and concentrated to obtain the title compound (0.04 g). P— NMR (DMSO-d ⁶ ) 2.47— 2.48(br . S, 4H) , 2.83(t, 2H) , 3.50— 3.51 (m, 4H) , 4.52(t, 2H), 5.85(s, 2H) , 6.79(t, 1H) , 7.28(d, 1H) , 7.30(d, 1H) , 7.38- 7.39(m, 2H), 7.49(s, 1H), 7.55-7.56(m, 2H), 8.18(s, 1H) , 8.42(s, 1H) , 8.68(s, 1H) , 9.50(s, 1H)

LC-MS (ESI, m/z) = 561.0 (M+H+) Example 89. 2-(3-Aminophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 5］ Synthesis of 2-(3-aminophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 89) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 88 (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.07 g, 0.31 mmol) was used, and the reaction was performed in the same manner, followed by MPLC (combiFlash NEXTGEN 300+). The product was purified and concentrated to obtain the title compound (0.05 g). P- NMR (DMSO-d ⁶ ) 2.40- 2.41(br . S, 4H) , 2.83(t, 2H) , 3.50- 3.52(m, 4H) , 4.53(t, 2H), 5.30(s, 2H) , 6.69(d, 1H) , 6.83(d, 1H) , 6.96(s, 1H) , 7.10(t, 1H) , 7.37-7.40(t, 2H), 7.50(s, 1H) , 7.54- 7.57(m, 2H) , 8.29(s, 1H) , 8.43(s, 1H) , 8.63(s, 1H), 9.51(s, 1H)

LC-MS (ESI, m/z) = 543.0 (M+H+) Example 90. 2-(1,3 ■dimethyl- 1H-pyrazol- 4 -yl)- N- (6- (4 -fluorophenyl)- 2- (2 -morpholinoethyl )-2H-indazol- 5 -yl)thiazole- 4 -carboxamide

［Step 5］ Synthesis of 2-(1,3-dimethyl-1H-pyrazol-4-yl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 90) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 88 (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.07 g, The reaction was carried out in the same manner using 0.31 mmol), purified by MPLC (combiFlash NEXTGEN 300+), and concentrated to obtain the title compound (0.04 g). P— NMR (DMSO-d ⁶ ) 2.09 (s, 3H) , 2.40— 2.41(br . S, 4H) , 2.83(t, 2H) , 3.51-3.52(m, 4H) , 3.78(s, 3H) , 4.52(t, 2H) , 7.34(t, 2H) , 7.47(s, 1H) , 7.50- 7.51(m, 2H), 8.01(s, 1H) , 8.20(s, 1H) , 8.42(s, 1H) , 8.62(s, 1H) , 9.26(s, 1H)

［단계 5］ 2-（3 -플루오로페닐）- N-（6-（4 -플루오로페닐）- 2-（2- 모르폴리노에틸）- 2H-인다졸- 5 -일）티아졸- 4 -카르복사마이드（화합물 91）의 합성 실시예 1의 ［단계 2］와 동일 조건에서 , 실시예 88의 ［단계 4］의 화합물LC-MS (ESI, m/z) = 546.0 (M+H+) Example 91. 2-(3-fluorophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide

[Step 5] Synthesis of 2-(3-fluorophenyl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 91) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 88 was prepared.

(0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 2-(3-fluorophenyl)-

The same method was used with 4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolane (0.07 g, 0.31 mmol), and the resulting product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). P— NMR (DMSO-d ⁶ ) 2.42(br. S, 4H) , 2.83(t, 2H) , 3.52(t, 4H) , 4.53(t, 2H), 7.37(t, 2H), 7.49(s, 1H) , 7.52- 7.57(m, 5H) , 8.20(s, 1H) , 8.43(d, 2H) , 8.61(s, 1H), 9.57(s, 1H)

LC-MS (ESI, m/z) = 546.0 (M+H+) Example 92. 2-(2-Aminopyridin-4-yl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide

[Step 5] Synthesis of 2-(2-aminopyridine-4-yl)-N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 92) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 88 was prepared. (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.07 g, 0.31 mmol) were used in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.06 g). P— NMR (DMSO-d ⁶ ) 2.40(br. s, 4H) , 2.84(t, 2H) , 3.52(t, 4H) , 4.53(t, 2H), 6.20(s, 2H), 6.71(d, 1H) , 6.81(s, 1H) , 7.38(t, 3H) , 7.50(s, 1H) , 7.51- 7.55(m, 2H), 7.99(d, 1H) , 8.43(s, 2H) , 8.57(s, 1H) , 9.52(s, 1H)

LC-MS (ESI, m/z) = 544.0 (M+H+) Example 93. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyrimidin-5-yl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(pyrimidin-5-yl)thiazole-4-carboxamide (Compound 93) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 88 (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.06 g, 0.31 mmol) was used, and the reaction was performed in the same manner, followed by MPLC (combiFlash Purified and concentrated with NEXTGEN 300+ The title compound (0.07 g) was obtained. P— NMR (DMSO-d ⁶ ) 2.40 (br. S, 4H) , 2.84 (t, 2H) , 3.52 (t, 4H) , 4.54 (t, 2H), 7.33 (t, 2H), 7.53 (s, 1H) , 7.55- 7.56 (m, 2H) , 8.44 (s, 1H) , 8.49 (s, 1H) , 8.52 (s, 1H), 9.17 (s, 2H) , 9.29 (s, 1H) , 9.65 (s, 1H)

LC-MS (ESI, m/z) = 530.0 (M+H+) Example 94. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(thiophene-3-yl)thiazole-4-carboxamide

[Step 5] Synthesis of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(thiophene-3-yl)thiazole-4-carboxamide (Compound 94) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 88

(0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 4,4,5,5-tetramethyl-2-(thiophene-3-yl)-1,3,2-dioxaborolane (0.07 g, 0.31 mmol) were used in the same manner. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.08 g). P— NMR (DMSO-d ⁶ ) 2.40(br. s, 4H) , 2.84(t, 2H) , 3.52(t, 4H) , 4.54(t, 2H), 7.20-7.26(m, 4H) , 7.49- 7.52(m, 2H) , 7.53(s, 1H) , 7.85(s, 1H) , 8.27(s,

1H), 8.48(s, 1H), 8.69(s, 1H) , 9.62(s, 1H) LC-MS (ESI, m/z) = 534.0 (M+H+) Example 95. N-(6-(4-fluorophenyl)- 2-(2-morpholinoethyl)- 2H-indazole- 5- 1)-2-(2 -fluoropyridine- 3 -yl)thiazole- 4 -carboxamide

[Step 5] Synthesis of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(2-fluoropyridin-3-yl)thiazole-4-carboxamide (Compound 95) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 88 was prepared.

(0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.07 g, 0.31 mmol) were used. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.07 g). P— NMR (DMSO-d ⁶ ) 2.40(br. S, 4H) , 2.83(t, 2H) , 3.50(t, 4H) , 4.53(t, 2H), 7.22(t, 1H), 7.37(t, 1H) , 7.45- 7.49(m, 1H), 7.51(s, 1H) , 7.52- 7.58(m, 1H), 8.17(s, 1H), 8.24-8.25(m, 1H) , 8.27(s, 1H) , 8.39(s, 1H) , 8.52(s, 1H) , 8.59(s, 1H), 9.58(s, 1H)

LC-MS (ESI, m/z) = 547.0 (M+H+) Example 96. N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(5-methoxypyridin-3-yl )thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(4-fluorophenyl)-2-(2-morpholinoethyl)-2H-indazol-5-yl)-2-(5-methoxypyridin-3-yl)thiazole-4-carboxamide (Compound 96) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 88 (0.11 g, 0.21 mmol), sodium carbonate (0.11 g, 1.04 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 3-methoxy-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.07 g, 0.31 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.07 g) was obtained by purification and concentration using MPLC (combiFlash NEXTGEN 300+). P— NMR (DMSO-d ⁶ ) 2.40(br. S, 4H) , 2.84(t, 2H) , 3.52(t, 4H) , 3.90(s, 3H), 4.53(t, 2H), 7.30(t, 2H) , 7.51(s, 1H) , 7.56(t, 2H) , 7.67(s, 1H) , 8.41(s, 1H), 8.43(s, 1H), 8.45(s, 1H) , 8.48(s, 1H) , 8.59(s, 1H) , 9.62(s, 1H)

LC-MS (ESI, m/z) = 559.0 (M+H+) Example 97. N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-bromo-2-methyl-2-butanol (2.76 g, 16.53 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.925 g).

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),

8.13(s, 1H), 8.59(s, 1H) , 8.75(s, 1H)

［Step 2］ Synthesis of 4-(6-(4-fluorophenyl)-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.61 mmol), tetrakis(triphenylphosphine)palladium (0.088 g, 0.38 mmol), and 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 g, 2.29 mmol) were used. The reaction was carried out in the same manner, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.04(t, 2H) , 4.51(s, 1H) , 4.53(m, 2H), 7.25(d, 2H), 7.68(d, 2H) , 7.69(s, 1H) , 8.66(s, 1H) , 8.79(s, 1H) [Step 3] 4-(5-amino-6-(4-fluorophenyl)-2H-indazol-2-yl)-2-methylbutane-

2- Under the same conditions as in [Step 3] of Synthetic Example 1, the compound of [Step 2] (0.5 g, 1.46 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.04(t, 2H) , 4.51(s, 1H) , 4.53(m, 2H), 6.84(s, 2H), 7.25(d, 2H) , 7.68(d, 2H) , 7.69(s, 1H) , 8.66(s, 1H) , 8.79(s, 1H)

［Step 4］ Synthesis of N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 97) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.28 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.23 g, 1.28 mmol), HATU (0.97 g, 2.55 mmol), and DI PEA (0.89 mL, 5.11 mmol) was used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 4.48(t, 2H) , 4.50(s, 1H), 7.40(t, 2H), 7.56(s, 1H) , 7.57(t, 2H) , 7.68(s, 1H) , 7.69(s, 1H) , 8.44(d, 2H) , 8.58(s, 1H), 8.71(d, 2H) , 9.57(s,lH)

LC-MS (ESI, m/z) = 502.3 (M+H+) Example 98. 2-(2-Aminopyridin-4-yl)-N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 4］ Synthesis of 2-bromo-N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 97 (0.4 g, 1.28 mmol), 2-bromothiazole-4-carboxylic acid (0.27 g, 1.28 mmol), HATU (0.97 g, 2.55 mmol), and DI PEA (0.89 mL, 5.11 mmol) was reacted in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 4.48(t, 2H) , 4.50(s, 1H), 7.40(t, 2H), 7.56(s, 1H) , 7.57(t, 2H) , 7.68(s, 1H) , 7.69(s, 1H) , 8.58(s, 1H) , 9.57(s,lH)

[Step 5] Synthesis of 2-(2-aminopyridin-4-yl)-N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 98) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] (0.5 g, 0.99 mmol), sodium carbonate (0.53 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), and 4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.33 g, 1.49 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.3 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) , 4.47(t, 2H) , 4.50(s, 1H), 6.19(s, 1H), 6.70(d, 1H) , 6.80(s, 1H) , 7.39(t, 1H) , 7.40(t, 2H) , 7.55(s, 1H) , 7.56(t, 2H), 8.00(d, 1H) , 8.43(d, 2H) , 8.56(s, 1H) , 9.52(s, 1H)

LC-MS (ESI, m/z) = 517.0 (M+H+) Example 99. N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(4-fluorophenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide (Compound 99) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 98 (0.5 g, 0.99 mmol), sodium carbonate (0.53 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), and 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (0.41 g, 1.49 mmol) was used. After reaction in the same manner, the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.02 (t, 2H) , 4.47 (t, 2H) , 4.50 (s, 1H), 7.33 (t, 2H), 7.51 (d, 1H) , 7.57 (m, 2H) , 7.72 (t, 1H) , 7.90 (d, 2H) , 8.08 (t, 2H) , 8.44 (s, 1H), 8.47 (s, 2H) , 8.54 (s, 1H) , 9.58 (s, 1H) LC-MS (ESI, m/z) = 570.1 (M+H+) Example 100. N-(2-(3-hydroxy-3-methylbutyl)-6-(4-morpholinophenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-bromo-2-methyl-2-butanol (2.76 g, 16.53 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.925 g).

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),

8.13(s, 1H), 8.59(s, 1H) , 8.75(s, 1H)

［Step 2］ Synthesis 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 of ［Step 1］ (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.61 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 4-(4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.66 g, 2.29 mmol) was used, and the reaction was carried out 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 ) 1.13 (s, 6H) , 2.03 (t, 2H) , 3.20 (t, 4H) , 3.76 (t, 4H), 4.46 (t, 2H), 4.48 (s, 1H) , 7.11 (d, 2H) , 7.38 (d, 2H) , 7.69 (s, 1H) , 8.66 (s, 1H) , 8.79 (s, 1H)

［Step 3］ Synthesis 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 of ［Step 2］ (0.5 g, 1.22 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 3.20(t, 4H) , 3.76(t, 4H), 4.46(t, 2H), 4.48(s, 1H) , 7.11(d, 2H) , 7.38(d, 2H) , 7.43(s, 1H) , 8.40(s, 1H) , 8.47(s, 1H), 8.70(s, 2H)

［Step 4］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-morpholinophenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 100) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.05 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.22 g, 1.05 mmol), HATU (0.80 g, 2.10 mmol), and DI PEA (0.73 mL, 4.21 mmol) was used, and the reaction was performed in the same manner. The product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). Obtained. Blood— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.03 (t, 2H) , 3.20 (t, 4H) , 3.76 (t, 4H), 4.46(t, 2H), 4.48(s, 1H) , 7.11(d, 2H) , 7.38(d, 2H) , 7.43(s, 1H) , 7.53(m, 1H) , 8.07(d, 1H), 8.40(s, 1H) , 8.47(s, 1H) , 8.70(s, 1H) , 8.71(s, 1H) , 8.97(s, 1H) , 9.69(s,lH)

LC-MS (ESI, m/z) = 570.1 (M+H+) Example 101. N- (2- (3 -hydroxy- 3 -methylbutyl)- 6- (6-

(Trifluoromethyl)pyridin-3-yl)-2H-indazole-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-bromo-2-methyl-2-butanol (2.76 g, 16.53 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.925 g).

6H) , 2.01(t, 2H) , 4.50(s, 1H) , 4.53(m, 2H),

8.13(s, 1H), 8.59(s, 1H) , 8.75(s, 1H)

[Step 2] Synthesis of 2-methyl-4-(5-nitro-6-(6-(trifluoromethyl)pyridin-3-yl)-2H-indazol-2-yl)butan-2-ol Under the same conditions as in [Step 2] of Example 1, the compound of [Step 1] (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.61 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (0.62 g, 2.29 mmol) was 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 (0.5 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.03(t, 2H) , 4.52(s, 1H) , 4.57(t, 2H),

7.78(s, 1H), 7.95(d, 1H) , 8.08(d, 1H) , 8.76(s, 1H) , 8.78(s, 1H) , 8.83(s, 1H)

［Step 3］ Synthesis of 4-(5-amino-6-(6-(trifluoromethyl)pyridin-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.27 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 4.50(s, 1H) , 4.53(t, 2H),7.50(s, 2H), 7.73(s, 1H) , 7.95(d, 1H) , 8.16(s, 1H) , 8.68(d, 1H) , 8.90(s, 1H), 9.12(s, 1H)

［Step 4］ N-(2-(3-hydroxy-3-methylbutyl)-6-(6-

Synthesis of (trifluoromethyl)pyridin-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 101) Under the same conditions as in [Step 4] of Example 1, the compound of [Step 3] (0.4 g, l.lOmmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.23 g, l.lOmmol), HATU (0.83 g, After the reaction was carried out in the same manner using 2.20 mmol) and DI PEA (0.76 mL, 4.40 mmol).

The title compound (0.3 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) , 4.50(s, 1H) , 4.53(t, 2H), 7.50(m, 1H), 7.73(s, 1H) , 7.95(d, 1H) , 8.17(s, 1H) , 8.22(t, 2H) , 8.39(s, 1H) , 8.49(s, 1H), 8.69(d, 1H) , 8.90(s, 1H) , 9.13(s, 1H) , 9.94(s,lH)

LC-MS (ESI, m/z) = 553.4 (M+H+) Example 102. N-(2-(3-amino-3-oxopropyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 3-(6-bromo-5-nitro-2H-indazol-2-yl)propanamide Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 3-chloropropanamide (1.244 g, 11.56 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.925 g). P— NMR (DMSO-d ⁶ ) 2.77(t, 2H) , 4.65(t, 2H) , 6.88(s, 1H) , 7.39(s, 1H), 8.12(s, 1H), 8.60(s, 1H), 8.66(s, 1H)

[Step 2] 3-(6-(furan-3-yl)-5-nitro-2H-indazol-2-yl)propanamide Under the same conditions as in [Step 2] of Synthetic Example 1, the compound of [Step 1] (0.5 g,

The reaction was carried out in the same manner using sodium bicarbonate (0.85 g, 7.98 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol) and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.46 g, 2.40 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 2.77(t, 2H) , 4.65(t, 2H) , 6.54(s, 1H) , 6.88(s, 1H), 7.39(s, 1H), 7.70(s, 2H) , 7.87(s, 1H) , 8.49(s, 1H) , 8.62(s, 1H)

［Step 3］ Synthesis of 3-(5-amino-6-(furan-3-yl)-2H-indazol-2-yl)propanamide Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.67 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P— NMR (DMSO-d ⁶ ) 2.77(t, 2H) , 4.65(t, 2H) , 6.82(d, 1H) , 6.86(s, 1H), 7.39(s, 1H), 7.64(s, 2H) , 7.75(d, 1H) , 7.92(s, 1H) , 8.10(s, 1H) , 8.30(s, 1H) , 8.36(s, 1H)

［Step 4］ Synthesis of N-(2-(3-amino-3-oxopropyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-bromothiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.48 mmol), 2-bromothiazole-4-carboxylic acid (0.31 g, 1.48 mmol), HATU (1.13 g, 2.96 mmol), and DI PEA (1.03 mL, 5.92 mmol) were used, and the reaction was carried out 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 ) 2.77 (t, 2H) , 4.60 (t, 2H) , 6.82 (d, 1H) , 6.86 (s, 1H) , 7.39 (s, 1H) , 7.64 (s, 1H) , 7.75 (d, 1H) , 7.92 (s, 1H) , 8.10 (s, 1H) , 8.30 (s, 1H) , 8.36 (s, 1H) , 9.78 (s, 1H)

［Step 5］ Synthesis of N-(2-(3-amino-3-oxopropyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide (Compound 102) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ (0.5 g, 1.09 mmol), sodium carbonate (0.58 g, 5.43 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.23 g, 1.63 mmol) were used, and the reaction was carried out in the same manner.

The title compound (0.3 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 2.77 (t, 2H) , 4.60 (t, 2H) , 6.88 (s, 2H) , 6.92 (s, 1H), 7.39 (m, 1H), 7.66 (s, 2H) , 7.86 (s, 1H) , 8.06 (s, 1H) , 8.32 (s, 1H) , 8.39 (s, 1H) , 8.49 (s, 1H), 8.86 (s, 1H) , 9.98 (s, 1H)

LC-MS (ESI, m/z) = 477.1 (M+H+) Example 103. N-(2-(4-amino-4-oxobutyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide

［Step 1］ Synthesis of 4-(6-bromo-5-nitro-2H-indazol-2-yl)butanamide Under the same conditions as ［Step 1］ of Example 1, 6-bromo-5-nitro-2H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-chlorobutanamide (1.105 g, 9.09 mmol) were used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.96 g). P— NMR (DMSO-d ⁶ ) 2.00(t, 2H) , 2.08(m, 2H) , 4.47(t, 2H) , 6.73(s, 1H), 7.23(s, 1H), 8.14(s, 1H) , 8.60(s, 1H) , 8.71(s, 1H)

［Step 2］ Synthesis of 4-(6-(furan-3-yl)-5-nitro-2H-indazol-2-yl)butanamide Under the same conditions as in ［Step 2］ of Example 1, the compound of ［Step 1］ (0.5 g, 1.53 mmol), sodium carbonate (0.81 g, 7.64 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.44 g, 2.29 mmol) was reacted in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 2.00(t, 2H) , 2.08(m, 2H) , 4.47(t, 2H) , 6.54(s, 1H), 6.74(s, 1H), 7.23(s, 1H) , 7.70(d, 2H) , 8.14(s, 1H) , 8.49(s, 1H) , 8.67(s, 1H)

[Step 3] Synthesis of 4-(5-amino-6-(furan-3-yl)-2H-indazol-2-yl)butanamide Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (0.5 g, 1.59 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 g). P— NMR (DMSO-d ⁶ ) 2.00(t, 2H) , 2.10(m, 2H) , 4.40(t, 2H) , 6.72(s, 1H), 6.82(s, 1H), 7.24(s, 1H) , 7.67(s, 1H) , 7.74(s, 2H) , 7.92(s,lH), 8.10(s, 1H) , 8.36(d, 1H), 8.51(d, 1H)

［Step 4］ Synthesis of N-(2-(4-amino-4-oxobutyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-bromothiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.41 mmol), 2-bromothiazole-4-carboxylic acid (0.29 g, 1.41 mmol), HATU (1.07 g, 2.81 mmol), and DI PEA (0.98 mL, 5.63 mmol) was used. The reaction was carried out in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 2.00(t, 2H) , 2.10(m, 2H) , 4.40(t, 2H) , 6.73(s, 1H), 6.82(s, 1H), 7.24(s, 1H) , 7.67(s, 1H) , 7.74(s, 1H) , 7.92(s, 1H) , 8.10(s, 1H) , 8.35(d, 1H), 8.51(d, 1H) , 9.97(s, 1H)

[Step 5] Synthesis of N-(2-(4-amino-4-oxobutyl)-6-(furan-3-yl)-2H-indazol-5-yl)-2-(6-fluoropyridin-3-yl)thiazole-4-carboxamide (Compound 103) Under the same conditions as in [Step 2] of Example 1, the compound of [Step 4] (0.5 g, 1.05 mmol), sodium carbonate (0.56 g, 5.27 mmol), tetrakis(triphenylphosphine)palladium

(0.06 g, 0.05 nmol) and 2-fluoro-5-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolane-2- After the reaction was carried out in the same manner using pyridine (0.35 g, 1.58 mmol)

The title compound (0.3 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 2.01(t, 2H) , 2.10(t, 2H) , 4.40(t, 2H) , 6.74(s, 2H), 6.92(s, 1H), 7.24(s, 2H) , 7.70(s, 1H) , 7.86(s, 1H) , 8.06(s, 1H) , 8.32(s, 1H) , 8.39(s, 1H), 8.40(s, 1H) , 8.49(s, 1H) , 8.86(s, 1H) , 9.98(s, 1H)

LC-MS (ESI, m/z) = 491.0 (M+H+) Example 104. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-hydroxyphenyl)thiazole-4-carboxamide

［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(3-hydroxyphenyl)thiazole-4-carboxamide (Compound 104) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 was prepared.

(0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 3-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenol (0.07 g, 0.32 mmol) were used in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.10 g). P— NMR (DMSO-d ⁶ ) 1.12 (s, 6H) , 2.92 (t, 2H) , 4.45— 4.49 (m, 3H) , 6.92- 6.93(m, 1H), 7.32-7.37(m, 3H), 7.65(m, 1H), 7.86(s, 1H), 8.04(s, 1H), 8.21(s,

1H), 8.39(s, 1H), 8.40(s, 1H) , 8.46(s, 1H) , 9.81(s, 1H) , 9.91(s, 1H)

LC-MS (ESI, m/z) = 489.1 (M+H+) Example 105. 2-(4-amino-3-fluorophenyl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide

[Step 5] Synthesis of 2-(4-amino-3-fluorophenyl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 105) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 47 was prepared.

(0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol) and 2-fluoro-4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.07 g, 0.32 mmol) were used. The resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to give the title compound (0.07 g). P— NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.02(t, 2H) , 4.45— 4.48(m, 3H) , 5.84(s, 2H), 6.82(t, 1H), 6.90(s, 1H) , 7.44(d, 1H) , 7.56(d, 1H) , 7.64(s, 1H) , 7.84(t, 1H), 8.07(s, 1H), 8.21(s, 1H) , 8.39(s, 1H) , 8.49(s, 1H) , 9.92(s, 1H)

LC-MS (ESI, m/z) = 506.1 (M+H+) Example 106. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-morpholinothiazole-4- Carboxamide

6H) , 2.01(t, 2H) , 3.25(t, 4H) , 3.70(t, 4H),［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-morpholinothiazole-4-carboxamide (Compound 106) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)morpholine (0.07 g, 0.32 mmol) was used, and the reaction was performed in the same manner using MPLC (combiFlash NEXTGEN). The residue was purified and concentrated to obtain the title compound (0.07 g).

6H) , 2.01(t, 2H) , 3.25(t, 4H) , 3.70(t, 4H),

4.43(t, 2H), 4.47(s, 1H) , 6.81(s, 1H) , 7.55(s, 1H) , 7.57(s, 1H) , 7.84(s, 1H) , 7.98(s, 1H), 8.36 (s, 1H), 8.54(s, 1H) , 9.62(s, 1H)

LC-MS (ESI, m/z) = 482.1 (M+H+) Example 107. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(4-hydroxypiperidin-1-yl)thiazole-4-carboxamide

6H) , 1.44(m, 2H) , 1.79(t, 2H) , 2.02(t, 2H),［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-morpholinothiazole-4-carboxamide (Compound 107) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 1-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-4-ol (0.07 g, 0.32 mmol) was used, and the reaction was performed in the same manner, followed by MPLC (combiFlash) The residue was purified and concentrated using NEXTGEN 300+ to obtain the title compound (0.07 g).

6H) , 1.44(m, 2H) , 1.79(t, 2H) , 2.02(t, 2H),

3.16(t, 2H), 3.61(t, 2H), 3.63(m, 1H) , 4.43(t, 2H) , 4.47(s, 1H) , 4.79(d, 1H) , 6.82(s, 1H), 7.47 (s, 1H) , 7.57(s, 1H) , 7.82(s, 1H) , 7.99(s, 1H) , 8.36(s, 1H) , 8.56(s, 1H), 9.63(s, 1H)

［단계 5］ 2-（4-（디메틸아미노）피페리딘- 1-일）- N-（6-（퓨란- 3 -일）- 2-（3- 히드록시- 3 -메틸부틸） -2H-인다졸- 5 -일）티아졸- 4 -카르복사마이드（화합물 108）의 합성 실시예 1의 ［단계 2］와 동일 조건에서 , 실시예 47의 ［단계 4］의 화합물LC-MS (ESI, m/z) = 496.1 (M+H+) Example 108. 2-(4-(dimethylamino)piperidin-1-yl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide

[Step 5] Synthesis of 2-(4-(dimethylamino)piperidin-1-yl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 108) Under the same conditions as [Step 2] of Example 1, the compound of [Step 4] of Example 47 was prepared.

(0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and N,N-dimethyl-1-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidin-4-amine (0.08 g,

6H) , 1.42(m, 2H) , 1.81(d, 2H) , 2.02(t, 2H),The reaction was carried out in the same manner using 0.32 mmol), purified by MPLC (combiFlash NEXTGEN 300+), and concentrated to obtain the title compound (0.07 g).

6H) , 1.42(m, 2H) , 1.81(d, 2H) , 2.02(t, 2H),

2.32(m, 1H), 2.99(t, 2H) , 3.77(d, 2H) , 4.43(t, 2H) , 4.47(s, 1H) , 6.82(s, 1H) , 7.48(s, 1H), 7.57 (s, 1H), 7.85(s, 1H) , 7.99(s, 1H) , 8.36(s, 1H) , 8.56(s, 1H) , 9.63(s, 1H)

LC-MS (ESI, m/z) = 523.1 (M+H+) Example 109. 2-(2-Aminopyridin-4-yl)-N-(7-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide

[Step 1] Synthesis of 4-(7-bromo-5-nitro-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in [Step 1] of Example 1, 7-bromo-5-nitro-1H-indazole (2 g, 8.26 mmol), 20 mL of dimethylformamide, potassium carbonate (4.56 g, 27.30 mmol), potassium iodide (0.14 g, 0.83 mmol), and 4-bromo-2-methylbutan-2-ol (2.76 g, 16.53 mmol) were used. The reaction was carried out in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (1.16 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)

［Step 2］ Synthesis 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 of ［Step 1］ (0.5 g, 1.52 mmol), sodium carbonate (0.81 g, 7.62 mmol), tetrakis(triphenylphosphine)palladium (0.09 g, 0.08 mmol), and 2-(furan-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.44 g, 2.29 mmol) was used. The reaction was performed in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration 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), 7.21(d, 1H), 8.06(d, 1H) , 8.21(s, 1H) , 8.42(s, 1H) , 8.51(s, 1H) , 8.58(s, 1H)

［Step 3］ Synthesis of 4-(5-amino-7-(furan-3-yl)-2H-indazol-2-yl)-2-methylbutan-2-ol Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.5 g, 1.59 mmol) was hydrogenated with 0.10 g (0.093 mmol) of palladium on activated carbon. The residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.4 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)

［Step 4］ Synthesis of 2-bromo-N-(7-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazole—5-yl)thiazole-4-carboxamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.4 g, 1.40 mmol), 2-bromothiazole-4-carboxylic acid (0.29 g, 1.40 mmol), HATU (1.07 g, 2.80 mmol), and DI PEA (0.98 mL, 5.61 mmol) was used in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration 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), 7.11(s, 1H), 7.21(d, 1H), 8.06(d, 1H) , 8.21(s, 1H) , 8.42(s, 1H) , 8.51(s, 1H) , 8.58(s, 1H), 10.14(s, 1H)

［Step 5］ Synthesis of 2-(2-aminopyridin-4-yl)-N-(7-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 109) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ (0.5 g, 1.05 mmol), sodium carbonate (0.56 g, 5.26 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), and 4-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.35 g, 1.58 mmol) was used in the same manner. After the reaction, the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.3 g). P— NMR (DMSO-d ⁶ ) 1.14 (s, 6H) , 2.07 (t, 2H) , 4.49 (s, 1H) , 4.51 (t, 2H), 6.22 (s, 2H), 7.06 (s, 1H) , 7.11 (s, 1H) , 7.21 (d, 1H) , 7.78 (s, 1H) , 7.82 (s, 1H) , 8.06(d, 1H), 8.21(s, 1H) , 8.42(s, 1H) , 8.51(s, 1H) , 8.58(s, 1H) , 10.14(s, 1H)

LC-MS (ESI, m/z) = 489.1 (M+H+) Example 110. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(1H-pyrazol-5-yl)thiazole-4-carboxamide

6H) , 2.01(t, 2H) , 4.43(t, 2H) , 4.47(s, 1H),［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(1H-pyrazol-5-yl)thiazole-4-carboxamide (Compound 110) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ of Example 47 (0.1 g, 0.21 mmol), sodium carbonate (0.11 g, 1.05 mmol), tetrakis(triphenylphosphine)palladium (0.01 g, O.Olmmol), and 5-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.06 g, 0.32 mmol) was used in the same After reaction, the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g).

6H) , 2.01(t, 2H) , 4.43(t, 2H) , 4.47(s, 1H),

6.82(s, 1H), 7.21(m, 1H) , 7.24(m, 1H) , 7.37(s, 1H) , 7.54(s, 1H) , 7.56(s, 1H) , 7.83(s, 1H), 7.99 (s, 1H), 8.35(s, 1H) , 8.53(s, 1H) , 9.64(s, 1H)

LC-MS (ESI, m/z) = 463.1 (M+H+) Example 111. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(2-(3-hydroxy (Roxyphenyl)thiazole-4-yl)acetamide

［Step 4］ Synthesis of 2-(2-bromothiazol-4-yl)-N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)acetamide Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (0.4 g, 1.40 mmol), 2-(2-bromothiazol-4-yl)acetic acid (0.31 g, 1.40 mmol), HATU (1.07 g, 2.80 mmol), and DI PEA (0.98 mL, 5.61 mmol) was reacted in the same manner. The mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.5 g). P— NMR (DMSO-d ⁶ ) 1.10(s, 6H) , 2.01(t, 2H) , 3.83(s, 2H) , 4.43(t, 2H), 4.47(s, 1H), 6.80(s, 1H) , 6.82(m, 1H) , 7.3(d, 1H) , 7.64(d, 1H) , 7.78(s, 1H) , 7.95(s, 1H), 8.32(s, 1H) , 9.69(s, 1H)

［Step 5］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(2-(3-hydroxyphenyl)thiazol-4-yl)acetamide (Compound 111) Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 4］ (0.5 g, 1.02 mmol), sodium carbonate (0.54 g, 5.11 mmol), tetrakis(triphenylphosphine)palladium (0.06 g, 0.05 mmol), and 3-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.34 g, 1.53 mmol) was used, and the reaction was carried out in the same manner. The title compound (0.3 g) was obtained by purification by MPLC (combiFlash NEXTGEN 300+) and concentration. P— NMR (DMSO-d ⁶ ) 1.10(s, 6H) , 2.01(t, 2H) , 3.83(s, 2H) , 4.43(t, 2H), 4.47(s, 1H), 6.80(s, 1H) , 6.81(m, 1H) , 7.26(t, 1H) , 7.3(d, 2H) , 7.45(s, 1H) , 7.64(d, 2H), 7.78(s, 1H) , 7.96(s, 1H) , 8.32(s, 1H) , 9.42(s, 1H) , 9.69(s, 1H)

LC-MS (ESI, m/z) = 503.4 (M+H+) Example 112. Methyl 5—(2—(3—hydroxy-1-3—methylbutyl)-1-5—(2—(pyridin-3—yl)thiazole-4-carboxamido)-2H-indazole-6-yl)nicotinate

［Step 2］ Synthesis 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 of ［Step 1］ of Example 11 (1.0 g, 3,05 mmol), sodium carbonate (1.61 g, 15.24 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol), and methyl 5-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (1.2 g, 4.57 mmol) was used, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (1.01 g) was obtained. 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, 1H)

[Step 3] Methyl 5- (5 -amino- 2- (3 -hydroxy- 3 -methylbutyl)- 2H -indazole- 6 - 1) Synthesis of nicotinate Under the same conditions as in [Step 3] of Example 1, the compound of [Step 2] (1.0 g, 2.60 mmole) was hydrogenated with 0.2 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.81 g). 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) )

[Step 4] Synthesis of methyl 5-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-3-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)nicotinate (Compound 112) Under the same conditions as [Step 4] of Example 1, the compound of [Step 3] (0.11 g, 0.31 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.06 g, 0.31 mmol), HATU

(0.24 g, 0.62 mmol) and DI PEA (0.22 mL, 1.24 mmol) were used in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.11 g). 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)

LC-MS (ESI, m/z) = 543.0 (M+H+) Example 113. N- (2- (3 -hydroxy- 3 -methylbutyl)- 6- (5 -

(Methylcarbamoyl)pyridin-3-yl)-2H-indazole-5-yl)-2- (pyridin-3-yl)thiazole-4- Carboxamide

［Step 5］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(5-(methylcarbamoyl)pyridin-3-yl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 113) The compound of ［Step 4］ of Example 112 (0.1 g, 0.18 mmole) and N-methylamine in methanol (10 ml) were used, followed by reaction at 120°C for more than 6 hours, and then concentration. Thereafter, the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.07 g). P- NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.05(t, 2H) , 2.70(d, 3H) , 4.50- 4.53(m, 3H), 7.53(t, 1H), 7.69(s, 1H) , 8.18(d, 1H) , 8.27(s, 1H) , 8.36(s, 1H) , 8.38(s, 1H), 8.48(s, 1H), 8.61-8.62(m, 1H) , 8.69(d, 1H) , 8.84(s, 1H) , 9.06(s, 1H) , 9.83(s, 1H)

［단계 4］ 메틸 5- (2- (3 -히드록시- 3 -메틸부틸)- 5- (2-(피리딘- 4- 일)티아졸- 4 -카르복사마이도) -2H-인다졸- 6 -일)니코틴에이트 (화합물 114)의 합성 실시 예 1의 ［단계 4］와 동일 조건에서 , 실시 예 112의 ［단계 3］의 화합물 (0.7g, 1 ,98mmole) , 2-(피리딘- 4 -일)티아졸- 4 -카르복실산 (0.41g, 1 .98mmo 1 ) , HATU (1.50g, 3.95mmol ) 및 DI PEA (1.38mL, 7.90mmol )을 사용하여 동일한 방법으로 반응 후 MPLC(combiFlash NEXTGEN 300+)로 정제하고 농축하여 표제 화합물 (0.75g)을 수득하였다. 피- NMR (DMSO-d⁶) 1.12(s , 6H) , 2.01- 2.04(m, 2H) , 4.40- 4.50(m, 2H) , 4.48(s , 3H) , 4.61(d, 1H) , 7.68(d, 1H) , 7.75(s , 1H) , 8.29(d, 1H) , 8.35(s , 1H) , 8.46(d, 1H) , 8.48(d, 1H) , 8.62(s , 1H) , 8.67(s , 2H) , 8.91(d, 1H) , 9.01(d, 1H) , 9.82(d, 1H) LC-MS (ESI, m/z) = 542.0 (M+H+) Example 114. Methyl 5—(2—(3—hydroxy-1-3—methylbutyl)-1-5—(2—(pyridin-4—yl)thiazole-4-carboxamido)-2H-indazole-6-yl)nicotinate

［Step 4］ Synthesis of methyl 5-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-4-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)nicotinate (Compound 114) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 112 (0.7 g, 1,98 mmol), 2-(pyridin-4-yl)thiazole-4-carboxylic acid (0.41 g, 1.98 mmol), HATU (1.50 g, 3.95 mmol), and DI PEA (1.38 mL, 7.90 mmol) were used in the same manner, followed by MPLC (combiFlash NEXTGEN) The residue was purified and concentrated to obtain the title compound (0.75 g). P- NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.01- 2.04(m, 2H) , 4.40- 4.50(m, 2H) , 4.48(s , 3H) , 4.61(d, 1H) , 7.68(d, 1H) , 7.75(s , 1H) , 8.29(d, 1H) , 8.35(s , 1H) , 8.46(d, 1H) , 8.48(d, 1H) , 8.62(s , 1H) , 8.67(s , 2H) , 8.91(d, 1H) , 9.01(d, 1H) , 9.82(d, 1H)

LC-MS (ESI, m/z) = 543.0 (M+H+) Example 115. N-(6-(5-carbamoylpyridin-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 5-2］N-(6-(5-carbamoylpyridin-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide（compound

115) Synthetic Example 112 [Step 4] Compound (0.1 g, 0.18 mmole) and ammonia in After reaction at 100°C for more than 12 hours using methanol (7N) (10 ml), the mixture was concentrated. Afterwards, it was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.02 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 4.48— 4.51(m, 3H) , 7.38(s, 1H), 7.54-7.57(m, 2H) , 7.61(t, 1H) , 7.69(d, 1H) , 8.02- 7.97(m, 3H) , 8.44(s, 1H), 8.45(s, 1H), 8.62(s, 1H) , 8.68(d, 1H) , 8.93(s, 1H) , 9.60(s, 1H)

LC-MS (ESI, m/z) = 528.0 (M+H+) Example 116. N-(6-(5-(hydrazinecarbothyl)pyridin- 3 -yl)- 2- (3 -hydroxy-

3 ■Methylbutyl)-2H-indazole-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 4-2］ Synthesis of N-(6-(5-(hydrazinecarbothyl)pyridin-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide (Compound 116) The compound of ［Step 4］ of Example 114 (0.1 g, 0.18 mmole), methanol (6 mL), and hydrazine hydrate (4 mL) were used, followed by reaction at 100°C for more than 12 hours, and then concentration. Afterwards, the mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.03 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.05(t, 2H) , 4.50— 4.53(m, 5H) , 7.68(s, 1H), 7.76(d, 1H), 8.30(s, 1H) , 8.31(s, 1H) , 8.47(d, 2H) , 8.72(d, 2H) , 8.84(s,

1H), 9.03(s, 1H), 9.80(s, 1H) , 9.99(s, 1H) , 10.2(s, 1H)

LC-MS (ESI, m/z) = 543.0 (M+H+) Example 117. N-(6-(5-((2-amino-2-oxoethyl)carbamoyl)pyridin-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4-carboxamide

［Step 5］ Synthesis of 5-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-4-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)nicotinic acid Compound of ［Step 4］ of Example 114 (0.7 g, 1.98 mmole), tetrahydrofuran

(7 mL) and 2N sodium hydroxide aqueous solution (7 mL) were added 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 (0.49 g). P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.03 (t, 2H) , 4.50 (s, 1H), 4.53 (t, 2H),

7.72(s, 1H), 7.79(d, 1H), 8.16(s, 1H), 8.44(s, 1H), 8.49(s, 1H), 8.71(s, 3H),

8.72(d, 1H), 8.90(d, 1H) , 9.08(d, 1H) , 9.94(s,lH), 11.37(s, 1H)

［Step 6］ N-(6-(5-((2-amino-2-oxoethyl)carbamoyl)pyridin-3-yl)-2-

(3-Hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-4-yl)thiazole-4- Synthesis of Carboxamide (Compound 117) Under the same conditions as in [Step 2] of Example 82, the compound of [Step 5] (0.1 g, 0.18 mmol), methylene chloride (1 ml), glycinamide hydrochloride (0.02 g, 0.18 mmol), EDC - HC1 (0.05 g, 0.27 mmol), and HOBt - H ₂ 0 (0.04 g, 0.27 mmol) 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 (0.08 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.03(t, 2H) , 3.63(t, 2H) , 4.50(s, 1H), 4.53(t, 2H), 7.70(s, 1H) , 7.77(d, 2H) , 8.01(s, 2H) , 8.28(s, 1H) , 8.47(s, 1H) , 8.49(d, 2H), 8.71(d, 2H) , 8.86(d, 1H) , 9.10(s, 2H) , 9.87(s, 1H)

LC-MS (ESI, m/z) = 585.3 (M+H+) Example 118. 2-(4-Fluorophenyl)-N-(6-(4-((furan-3-ylmethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide

［Step 2］ N-(furan-3-ylmethyl)-4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-

Synthesis of 2H-indazole-6-yl)benzamide Under the same conditions as [Step 2] of Example 1, the compound of [Step 1] of Example 11

(1.0g, 3.05mmo 1 ), Sodium carbonate (1.61g, 15.24mmo 1 ), Tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol) and N-(furan-3-ylmethyl)-4-

6H) , 2.04(t, 2H) , 4.50(s, 1H) , 4.56(t, 2H),The same method was used with (4, 4, 5, 5 -tetramethyl- 1,3, 2 -dioxaborolan- 2 -yl)benzamide (1.5 g, 4.57 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (1.18 g).

6H) , 2.04(t, 2H) , 4.50(s, 1H) , 4.56(t, 2H),

6.26(s, 1H), 6.37(s, 1H) , 7.42(d, 2H) , 7.55(s, 1H) , 7.66(s, 1H) , 7.89(s, 1H) , 7.90(s, 1H), 8.61 (s, 1H), 8.77(s, 1H) , 9.02(t, 1H)

［Step 3］ Synthesis of 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)-N-(furan-3-ylmethyl)benzamide Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (1.0 g, 2.23 mmol) was hydrogenated with 0.2 g (0.2 w/w) of palladium on activated carbon. 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(t, 6H) , 1.97(t, 2H) , 4.45(s, 1H) , 4.52(t, 2H), 4.56(s, 2H), 6.21(s, 1H) , 6.30(s, 1H) , 7.36(d, 2H) , 7.50(s, 1H) , 7.61(s, 1H) , 7.83(s, 1H), 7.84(s, 1H) , 8.56(s, 1H) , 8.72(s, 1H) , 8.96(t, 1H)

［Step 4］ Synthesis of 2-(4-fluorophenyl)-N-(6-(4-((furan-3-ylmethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)thiazole-4-carboxamide (Compound 118) Under the same conditions as in ［Step 4］ of Example 1, the compound of ［Step 3］ (0.20 g, 0.48 mmol), 2-(4-fluorophenyl)thiazole-4-carboxylic acid (0.11 g, 0.48 mmol), HATU (0.36 g, 0.96 mmol), and DI PEA (0.33 mL, 1.91 mmol) were used in the same manner, and the resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.20 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), 7.24(m, 3H) , 7.52(s, 1H) , 7.64- 7.65(m, 2H) , 7.67- 7.69(m, 2H), 8.11(d, 2H), 8.37(s, 1H) , 8.45(s, 1H) , 8.71(s, 1H) , 9.13 (t, 1H) , 9.56(s, 1H)

LC-MS (ESI, m/z) = 624.0 (M+H+) Example 119. Methyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-3-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)benzoyl)glycinate

［Step 2］ Synthesis 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 of ［Step 1］ of Example 11 (1.0 g, 3.05 mmol), sodium carbonate (1.61 g, 15.24 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 nmol), and (4-((2-methoxy-2-oxoethyl)carbamoyl)phenyl)boronic acid (1.08 g, 4.57 mmol) were used, and the reaction was performed in the same manner. The resultant was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.86 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.04 (t, 2H) , 3.64 (s, 3H) , 4.05 (t, 2H), 4.48- 4.51(t, 3H), 7.66(d, 2H) , 8.03(d, 2H) , 8.44(s, 1H) , 8.56(s, 1H) , 8.66(s, 1H), 9.06(t, 1H)

［Step 3］ Synthesis of methyl (4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)benzoyl)glycinate Under the same conditions as in ［Step 3］ of Example 1, the compound of ［Step 2］ (0.8 g, 1.82 mmol) was hydrogenated with 0.16 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.63 g). P— NMR (DMSO-d ⁶ ) 1.07(s, 6H) , 1.98(t, 2H) , 3.58(s, 3H) , 3.98(t, 2H), 4.42— 4.48(t, 3H), 4.54(s, 2H) , 7.60(d, 2H) , 7.98(d, 2H) , 8.38(s, 1H) , 8.50(s, 1H), 8.61(s, 1H), 9.01(t, 1H)

［Step 4］ Synthesis of methyl (4-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-3-yl)thiazole-4-carboxamido)-2H-indazol-6-yl)benzoyl)glycinate (Compound 119) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ (0.6 g, 1.46 mmol), 2-(pyridin-3-yl)thiazole-4-carboxylic acid (0.32 g, 1.46 mmol), HATU (1.11 g, 2.92 mmol), and DI PEA (1.02 mL, 5.85 mmol) was reacted in the same manner, and the residue was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (0.60 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.04 (t, 2H) , 3.64 (s, 3H) , 4.05 (t, 2H), 4.48- 4.51 (t, 3H), 7.49- 7.50 (m, 1H) , 7.56 (s, 1H) , 7.66 (d, 2H) , 7.91- 7.92 (m, 1H), 8.03 (d, 2H), 8.44 (s, 1H) , 8.46 (s, 1H) , 8.56 (s, 1H) , 8.66 (d, 1H) , 9.02 (d,

1H), 9.06(t, 1H), 9.69(s, 1H) LC-MS (ESI, m/z) = 599.0 (M+H+) Example 120. N-(2-(3 -hydroxy- 3 -methylbutyl)- 6-(4-((2-(methylamino)- 2-oxoethyl)carbamoyl)phenyl)- 2H-indazol- 5 -yl)- 2-(pyridin- 3 -yl)thiazole- 4-carboxamide

［Step 5-2］ Synthesis of N-(2-(3-hydroxy-3-methylbutyl)-6-(4-((2-(methylamino)-2-oxoethyl)carbamoyl)phenyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 120) Under the same conditions as ［Step 5］ of Example 43, the compound of ［Step 4］ of Example 119 (0.1 g, 0.17 mmol) and N-methylamine in methanol (10 ml) were used, and the reaction was performed at 120°C for more than 6 hours, followed by concentration. Afterwards, the product was purified by MPLC (combi Flash NEXTGEN 300+) and concentrated to obtain the title compound (0.08 g). P— NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 2.60(d, 3H) , 3.86(d, 2H), 4.48- 4.51(m, 3H) , 7.50- 7.51(m, 1H) , 7.55(s, 1H) , 7.65(d, 2H) , 7.83- 7.84(m, 1H), 7.95(d, 1H), 8.05(d, 2H) , 8.45(s, 1H) , 8.57(s, 1H) , 8.65 (d, 1H) , 8.88(t, 1H), 9.00(s, 1H), 9.69(s, 1H)

LC-MS (ESI, m/z) = 598.0 (M+H+) Example 121. (4-(2-(3-hydroxy-3-methylbutyl)-5-(2-(pyridin-3-yl)thiazole-

4-Carboxamido)-2H-indazole-6-yl)benzoyl)glycine

［Step 5］ Synthesis of (4-(2-(3 -hydroxy-3 -methylbutyl)-5-(2-(pyridin-3 -yl)thiazole-4-carboxamido)-2H-indazol-6-yl)benzoyl)glycine (Compound 121) Under the same conditions as ［Step 5］ of Example 60, the compound of ［Step 4］ of Example 119 (0.5 g, 0.84 mmol), tetrahydrofuran (lOmL), and 2N sodium hydroxide aqueous solution (5 mL) were added and stirred at room temperature for 3 hours or more. 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 (0.38 g). P— NMR (DMSO-d ⁶ ) 1.28(s, 6H) , 2.20(t, 2H) , 4.17(s, 2H) , 4.65(t, 2H), 4.81(s, 1H), 7.63(s, 1H) , 7.70(d, 2H) , 8.09(d, 2H) , 8.22— 8.24(m, 1H) , 8.48(s, 1H), 8.52(s, 1H), 8.75(s, 1H) , 8.80(d, 1H) , 8.92(d, 1H) , 9.16(s, 1H) , 9.74(s, 1H), 12.1(s, 1H)

LC-MS (ESI, m/z) = 585.0 (M+H+) Example 122. N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide

［Step 6］ Synthesis of N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(pyridin-3-yl)thiazole-4-carboxamide (Compound 122) Under the same conditions as ［Step 6］ of Example 117, the compound of ［Step 5］ of Example 121 (0.3 g, 0.51 mmol), methylene chloride (3 ml), ammonia in methanol (7N) (1 ml), EDC - HC1 (0.15 g, 0.76 mmol), and HOBt - H ₂ 0 (0.1 g, 0.76 mmol) was used in the same manner, and the resultant product was purified by MPLC (combiFlash NEXTGEN 300+). The product was purified and concentrated to obtain the title compound (0.22 g). P- NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.04(t, 2H) , 3.84(t, 2H) , 4.47- 4.50(m, 3H), 7.11(s, 1H), 7.44(s, 1H) , 7.52- 7.54(m, 1H) , 7.54(s, 1H) , 7.65(d, 2H) , 7.96(d, 1H), 8.06(d, 2H) , 8.45(s, 2H) , 8.60(s, 1H) , 8.64(d, 1H) , 8.83(t, 1H) , 8.96(s, 1H); 9.68(s, 1H)

LC-MS (ESI, m/z) = 584.0 (M+H+) Example 123. N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide

［Step 2］ Synthesis of methyl 4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzoate Under the same conditions as ［Step 2］ of Example 1, the compound of ［Step 1］ of Example 1 (2.0 g, 6.09 mmol), sodium carbonate (3.23 g, 30.47 mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.30 mmol), and methyl 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.40 g, 9.14 mmol) was used, and the product was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound. (1.68 g) was obtained. P— NMR (DMSO-d ⁶ ) 1.13 (s, 6H) , 2.02— 2.05 (m, 2H) , 4.05 (s, 3H) , 4.47— 4.50 (m, 3H), 7.46— 7.47 (m, 2H) , 8.10 (d, 2H) , 8.31 (s, 1H) , 8.45 (s, 1H) , 8.70 (s, 1H)

6H) , 2.01- 2.04(m, 2H) , 4.45- 4.48(m, 3H) , 7.44— 7.45(m, 2H) , 8.08(d, 2H) , 8.28(s, 1H) , 8.42(s, 1H) , 8.68(s, 1H) , 11.9(s,［Step 3］ Synthesis of 4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzoic acid The compound of ［Step 2］ (1.6 g, 4.17 mmol), tetrahydrofuran (16 mL) and 2N sodium hydroxide aqueous solution (8 mL) were added 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 (1.05 g). p- NMR

6H) , 2.01- 2.04(m, 2H) , 4.45- 4.48(m, 3H) , 7.44— 7.45(m, 2H) , 8.08(d, 2H) , 8.28(s, 1H) , 8.42(s, 1H) , 8.68(s, 1H) , 11.9(s,

1H)

［Step 4］ Synthesis of N-(2-amino-2-oxoethyl)-4-(2-(3-hydroxy-3-methylbutyl)-5-nitro-2H-indazol-6-yl)benzamide Under the same conditions as ［Step 6］ of Example 117, the compound of ［Step 3］ (1.0 g, 2.71 mmol), methylene chloride (10 ml), glycinamide hydrochloride (0.3 g, 2.71 mmol), EDC - HC1 (0.78 g, 4.07 mmol), and HOBt - H ₂ 0 (0.55 g, 4.07 mmol) was used. The reaction mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.28 g). P- NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02- 2.05(m, 2H) , 3.87(d, 2H) , 4.47- 4.50(m, 3H), 7.46- 7.47(m, 2H) , 7.65- 7.67(m, 4H) , 8.10(d, 2H) , 8.31(s, 1H), 8.45(s, 1H), 8.70(s, 1H) , 8.80(t, 1H)

［Step 5］ Synthesis of 4-(5-amino-2-(3-hydroxy-3-methylbutyl)-2H-indazol-6-yl)-N-(2-amino-2-oxoethyl)benzamide Under the same conditions as ［Step 3］ of Example 1, the compound of ［Step 4］ (0.25 g, 0.59 mmol) was hydrogenated with 0.05 g (0.2 w/w) of palladium on activated carbon. The reaction mixture was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.19 g). P- NMR (DMSO-d ⁶ ) 1.07(s, 6H) , 1.97- 1.99(m, 2H) , 3.81(d, 2H) , 4.41- 4.43(m, 3H), 4.56(s, 2H) , 7.40- 7.41(m, 2H) , 7.60- 7.62(m, 4H) , 8.05(d, 2H), 8.26(s, 1H), 8.40(s, 1H) , 8.66(s, 1H) , 8.72(t, 1H)

［Step 6］ N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-phenylthiazole-4-carboxamide (compound 123）Under the same conditions as in [Step 4] of Synthetic Example 1, the compound of [Step 5] (0.09 g, 0.23 mmol), 2-phenylthiazole-4-carboxylic acid (0.05 g, 0.23 mmol), HATU (0.17 g, 0.46 mmol), and DI PEA (0.16 mL, 0.91 mmol) was 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 (0.10 g). P- NMR (DMSO-d ⁶ ) 1.13(s, 6H) , 2.02- 2.05(m, 2H) , 3.87(d, 2H) , 4.47- 4.50(m, 3H), 7.05(s, 1H) , 7.38(s, 1H) , 7.46- 7.47(m, 3H) , 7.54(s, 1H) , 7.65- 7.67(m, 4H), 8.10(d, 2H) , 8.31(s, 1H) , 8.45(s, 1H) , 8.70(s, 1H) , 8.80(t, 1H) , 9.62(s, 1H)

LC-MS (ESI, m/z) = 583.1 (M+H+) Example 124. N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide

[Step 6] Synthesis of N-(6-(4-((2-amino-2-oxoethyl)carbamoyl)phenyl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-(trifluoromethyl)thiazole-4-carboxamide (Compound 124) Under the same conditions as [Step 4] of Example 1, the compound of [Step 5] of Example 123

(0.09 g, 0.23 mmol), 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.05 g,

The reaction was carried out in the same manner using HATU (0.17 g, 0.46 mmol) and DI PEA (0.16 mL, 0.91 mmol), and the resulting mixture was purified by MPLC (combiFlash NEXTGEN 300+) and concentrated to obtain the title compound (0.09 g). P- NMR (DMSO-d ⁶ ) 1.12(s, 6H) , 2.02- 2.04(m, 2H) , 3.78(br. s, 2H) , 4.49(br. s, 3H) , 6.99(s, 1H) , 7.31- 7.33(m, 2H) , 7.55- 7.56(m, 2H) , 7.88- 7.89(m, 2H), 8.07(s, 1H), 8.44(d, 1H) , 8.63- 8.64(m, 2H) , 9.88(s, 1H)

LC-MS (ESI, m/z) = 575.1 (M+H+) Example 125. N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-isopropylthiazole-4-carboxamide

6H) , 1.31(d, 6H) , 2.01(t, 2H) , 3.25(q, 1H),［Step 4］ Synthesis of N-(6-(furan-3-yl)-2-(3-hydroxy-3-methylbutyl)-2H-indazol-5-yl)-2-isopropylthiazole-4-carboxamide (Compound 125) Under the same conditions as ［Step 4］ of Example 1, the compound of ［Step 3］ of Example 11 (0.11 g, 0.39 mmol), 2-isopropylthiazole-4-carboxylic acid (0.07 g, 0.39 mmol), HATU (0.29 g, 0.77 mmol), and DI PEA (0.27 mL, 1.54 mmol) was used in the same manner, followed by purification by MPLC (combiFlash NEXTGEN 300+) and concentration to obtain the title compound (0.09 g).

6H) , 1.31(d, 6H) , 2.01(t, 2H) , 3.25(q, 1H),

4.44(t, 2H), 4.48(s, 1H) , 6.82(s, 1H) , 7.61(s, 1H) , 7.82(s, 1H) , 8.00(s, 1H) , 8.24(s, 1H), 8.38 (s, 1H), 8.50(s, 1H) , 9.76(s, 1H)

LC-MS (ESI, m/z) = 439.1 (M+H+)

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

Using the IRAK4 enzyme kit (purchased from Promega, product number: V2621), a mixture of 0. lug/uL enzyme substrate myelin in basic protein (MBP) and 1.25 mM ATP was diluted with reaction buffer (40 mM Tris-HCl, pH 7.5; 20 mM MgCl ₂ ; 0. lmg/mL BSA; 50 uM DTT) according to the instructions, and 2 _y L was dispensed into a 384-well white plate. Then, the test compound was gradient diluted from ImM and 1 u L 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 reacted at 37°C for 60 minutes. After the reaction was completed, 5uL of ADP-Glo reaction reagent was added using the ADP-GloTM 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, which is shown in Table 2. [Table 2]

상기 표 2에서 확인할 수 있듯이, 본 발명의 화합물은 우수한 IRAK4 억제 활성을 나타낸다. 실험예 2. IRAKI효소활성 억제 실험 본원 화합물의 IRAKI 효소 활성 억제 실험을 진행하였다.

As can be confirmed in Table 2 above, the compound of the present invention exhibits excellent IRAK4 inhibitory activity. Experimental Example 2. IRAKI enzyme activity inhibition experiment An IRAKI enzyme activity inhibition experiment of the present compound was conducted.

Using the IRAKI enzyme kit (purchased from Promega, product number: VA7477), a mixture of 0. lug/uL of the enzyme reaction substrate protein AKT (protein kinase B) and 1.25 mM ATP was diluted with reaction buffer (40 mM Tris-HCl, pH 7.5; 20 mM MgCl ₂ ; 0. lmg/mL BSA; 50 uM DTT) according to the instructions, and 2 _y L 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 uL/well was dispensed into the 384-well white plate and reacted at 37°C for 60 minutes. After the reaction was completed, ADP-G 1 oTM enzyme test kit (purchased from Promega, product number: Using V9102), 5uL of ADP-Glo reaction reagent was added, reacted at 37°C for 40 minutes, and 10uL of enzyme chromogenic 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, which is shown in Table 3.

상기 표 3에서 확인할 수 있듯이 , 본 발명의 화합물은 우수한 IRAKI 억제 활성을 나타낸다. 실험예 3. 세포기반 염증성 싸이토카인 분비 억제 실험 본원 화합물의 염증성 싸이토카인 분비 억제 실험을 진행하였다. 사람의 전혈에서 분리한 PBMC(LONZA사, 말초혈액단핵구)를 1.0 X 10⁵ 세포/웰의 밀도로 96웰-플레이트에 분주하고 20시간 동안 세포를 안정화시켰다. 이 후 RPMI (Roswel 1 Park Memor i al Inst i tute) 배지로 4개의 농도별 희석한 시험화합물을 첨가하여 1시간 반응시키고 최종농도 l u g/mL이 되도록 LPS(Lipopolysacchar ide)를 처리한 후 1시간 동안 더 반응시켰다. 염증성 싸이토카인인 hTNF- a는 고마바이오텍사의 ELISA 키트를 사용하여 효소결합 면역흡착 분석법 (Enzyme Linked Immunosorbent Assay)으로 측정하였다. ELISA- 플레이트에 세포 상등액과 표준 약물 및 항체를 넣고 총 4시간 반응 후 플레이트를 세척하고 스트렙타비딘- HRP를 30분 반응시키고 다시 플레이트를 세척하였다. 이후 TMB 기질을 넣고 어두운 곳에서 반응시킨 후 충분히 발색이 되면 정지 용액을 넣어 반응을 정지시켰다. hTNF- a의 측정은 흡광 측정용장비 (BioTeK사 Mi croplate Reader )를 이용하여 450nM에서 흡광도를 측정하였다. 측정한 흡광값으로부터 활성 저해율을 계산하였고 시험 화합물의 농도별 % 저해도를 계산한 후 이를 비선형회귀 분석을 통하여 50% 저해농도（IC50 값）을 분석하여 표 4에 나타내었다. [Table 3]

As can be confirmed in the above Table 3, 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. PBMC (LONZA, peripheral blood mononuclear cells) isolated from human whole blood were dispensed into a 96-well plate at a density of 1.0 X 10 ⁵ cells/well, and the cells were stabilized for 20 hours. After that, test compounds diluted at four concentrations in RPMI (Roswel 1 Park Memor i al Inst i tute) medium were added, reacted for 1 hour, and LPS (Lipopolysaccharide) was treated to a final concentration of 1g/mL, and then reacted for 1 more hour. hTNF- a, an inflammatory cytokine, was measured by enzyme-linked immunosorbent assay 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. After that, TMB substrate was added and the reaction was performed in a dark place. When sufficient color development occurred, the reaction was stopped by adding a stop solution. The measurement of hTNF- a was performed 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 degree by 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.

[Table 4]

상기 표 4에서 확인할 수 있듯이 , 본 발명의 화합물은 우수한 염증성 싸이토카인 분비 억제 효과를 나타낸다. 이상, 본 발명을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 , 이러한 구체적 기술은 단지 바람직한 실시 예일뿐이며 , 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서 , 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.

As can be confirmed from the above Table 4, the compound of the present invention exhibits an excellent inflammatory cytokine secretion inhibitory effect. While the present invention has been described in detail above, it will be apparent to those skilled in the art that such specific description is merely a preferred embodiment and that the scope of the present invention is not limited thereby. Accordingly, the substantial 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: <Chemical Formula 1>

In the above chemical formula I, Li is a single bond or C1-C6 alkylene, and the following is thiazolidine, Ri is H, C1-C6 alkyl, C3-C8 cycloalkyl, 6-14 membered aryl, 3-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and , 3-12 membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S, or 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and , (C=0)0-(Cl-C6 alkyl) or NRaRb, wherein Ra and Rb are each independently H, 6-14 membered aryl or 5-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and . It is a heteroaryl, One or more of the above Ri may be substituted with C1-C6 alkyl, C1-C6 alkoxy, OH, NO2, NRaRb, C(=O)-(C1-C6 alkylene)- OH, CF ₃ or halogen, and the above Ra and Rb are each independently H or 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.

wherein L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), R2 is a 3-membered to 12-membered heterocycloalkyl, NRcRd, S0 ₂ Re, C(=0)NH ₂ or OH containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, and Rc, Rd and Re are each independently H or C1-C6 alkyl, and is a 6-membered to 14-membered arylene or a 5-membered to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, L3 is a single bond, C1-C6 alkylene, - NH(C=O)-, - (C=0)-, - C(=O)NH- or - (C=0)0-, R3 is a 3-membered to 4-membered ring containing 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, N, 0 and 12-membered heterocycloalkyl, NH2, CF3 or 0H, and at least one of said R3 may be substituted with a 3-membered to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms within the ring independently selected from the group consisting of OH, C(=0)NH2, C(=O)OH, C(=0)0-(Cl-C6 alkyl), C(=O)NH-(C1-C6 alkyl), N, 0 and or a 5-membered to 12-membered heteroaryl containing 1 to 3 heteroatoms within the ring independently selected from the group consisting of N, 0 and S, and - CH2 - of said heterocycloalkyl of R ₃ may be substituted with C=0. 【Claim 2】 In claim 1, in the chemical formula I, Li is a single bond or C1-C6 alkylene, and the following is thiazolidine, Ri is H, C1-C6 alkyl, C3-C8 cycloalkyl, 6-14 membered aryl, 3-12 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, 3-12 membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring or 5-12 membered heteroaryl containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and in the ring, and one or more of Ri may be substituted with C1-C6 alkyl, C1-C6 alkoxy, OH, NO2, NRaRb, C(=O)-(C1-C6 alkylene)- OH, CF ₃ or halogen, The above Ra and Rb are each independently H or C1-C6 alkyl, Qi and Q2 are each independently N or N- L2- R2, but Qi and Q2 cannot be simultaneously. ^Q OR ₂ * ^L2 >O When Q2 is N, the above ^Q 2 is N, and when ⑴ is N, the above /〒 N fantasy ^Q O 5 Q2 is 尺2, wherein L2 is C1-C6 alkylene or (C1-C6 alkylene)-O-(C1-C6 alkylene), wherein R2 is a 3-membered to 12-membered heterocycloalkyl, NRcRd, C(=0) _NH2 or OH 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, a 6-membered to 14-membered arylene or a 5-membered to 12-membered heteroarylene containing 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S in the ring, L3 is a single bond, C1-C6 alkylene, - (C=0)-, -C(=O)NH- or - (C=0)0-, R3 is a 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of H, halogen, C1-C6 alkyl, N, 0 and NH ₂ , CF ₃ or OH, and at least one of said R3 is independently selected from the group consisting of OH, C(=0)NH2, C(=O)OH, C(=0)0-(Cl-C6 alkyl), C(=O)NH-(C1-C6 alkyl), N, 0 and 218 A compound represented by formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which may be substituted with a 3- to 12-membered heterocycloalkyl having 1 to 3 heteroatoms in the ring or a 5- to 12-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and S. 【Claim 3】 In claim 1, in the chemical formula I, Li is a single bond or C1-C2 alkylene, and the following is thiazolidine, Ri is a 5- to 7-membered heterocycloalkyl having 1 to 3 heteroatoms independently selected from the group consisting of H, C1-C4 alkyl, C5-C7 cycloalkyl, 6- to 12-membered aryl, N and 0, a 5- to 7-membered heterocycloalkenyl having 1 to 2 heteroatoms independently selected from the group consisting of N and 0, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms independently selected from the group consisting of N, 0 and , wherein one or more of Ri may be substituted with C1-C3 alkyl, C1-C3 alkoxy, OH, NO2, NRaRb, C(=0)-(C2-C4 alkylene)- OH, CF ₃ , F or Cl, wherein Ra and Rb are each independently H or It is C1-C3 alkyl, Qi and Q2 are each independently N or N- L2- R2, but Qi and Q2 are simultaneously N. Cannot be, ^Q O R2』 ² >O When Q2 is N, the above ^Q 2 is N, and when Qi is N, the above ^Q / Yes] 1:、J Q ₂ is 尺2시, wherein L2 is C1-C6 alkylene or (C1-C2 alkylene)-O-(C1-C2 alkylene), and R2 is 1 to 1 independently selected from the group consisting of N and 0. A 4- to 7-membered heterocycloalkyl having 3 heteroatoms in the ring, NRcRd, C(=0) _NH2 or OH, wherein Rc and Rd are each independently C1-C3 alkyl, and a 6- to 12-membered arylene or a 5-membered or It is a 6-membered heteroarylene, L3 is a single bond, C1-C2 alkylene, - (C=0)-, -C(=O)NH- or - (C=0)0-, R3 is a 5-7 membered heterocycloalkyl containing 1 to 2 heteroatoms independently selected from the group consisting of H, F, Cl, C1-C3 alkyl, N and 0, NH2, _CF3 or 0H, and at least one of said R3 is a 5-7 membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from the group consisting of OH, C(=0) _NH2 , C(=O)OH, C(=O)O-(C1-C3 alkyl), C(=O)NH-(C1-C3 alkyl), N and 0, or independently selected from the group consisting of N and 0. 220 A compound represented by formula I, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which may be substituted with a 5- or 6-membered heteroaryl having 1 or 2 heteroatoms in the ring. 【Claim 4】 A compound described in the table below, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:

【Claim 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. 【Claim 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. 【Claim 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. 230 【Claim 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. 【Claim 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. 231