RU2816835C1 - Novel pyrazole derivatives - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to novel pyrazole derivatives of chemical formula I, where R, A and B are defined in the claim, stereoisomers or pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing same for preventing, improving clinical course or treating diseases associated with oxidative stress.

EFFECT: novel pyrazole derivatives are disclosed.

9 cl, 8 dwg, 2 tbl, 73 ex

Description

TECHNICAL FIELD

The present invention relates to a new pyrazole derivative with excellent oxidative stress inhibitory activity and, more particularly, to a new pyrazole derivative showing the ability to prevent, ameliorate or treat various diseases due to its excellent oxidative stress inhibitory activity, its optical isomer, its stereoisomer, its a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof, a method for their preparation and a pharmaceutical composition containing them.

BACKGROUND ART

Oxidative stress means a phenomenon in which the production of reactive oxygen species or reactive nitrogen species and the antioxidant defense mechanism are out of balance in biomolecules, cells and tissues in vivo, and the production of reactive oxygen species or reactive nitrogen species becomes relatively excessive, in which case it usually occurs damage to cells and tissues.

Reactive oxygen species (ROS) are free oxygen radicals, the formation of which is due to the chemical properties of oxygen and oxygen-containing compounds, and collectively refer to superoxide anion (O ₂ -), hydrogen peroxide (H ₂ O ₂ ), hydroxyl group (OH), alkoxy group (RO), peroxyl group (ROO), etc.

Because these reactive oxygen species are chemically very unstable and highly reactive, they cause enzyme catalytic reaction, mitochondrial electron transfer, cell signaling system and gene expression, activation of transcription factors and inflammation around, causing widespread oxidative damage in biomolecules, cells, tissues and so on. in vivo, and are involved as a major factor in tissue fibrosis. This oxidative damage causes various diseases in all tissues of the human body. In particular, they are known to be involved in the occurrence of cancer in tissues such as skin, kidney, heart, joint, lung, brain, blood vessel, intestinal tract, eye, etc. and progression of the resulting cancer, and are also known to play an important role in almost all diseases, including cardiovascular diseases, inflammation, fibrotic diseases, diabetes, etc.

Recently, it has become known that the interaction between the tumor microenvironment and cancer cells plays an important role in tumor growth, metastasis, expression of resistance to anticancer agents, in which case cancer associated fibroblast (CAF) has an important effect. Cancer-associated fibroblast is known to be activated by ROS, promoting the disappearance of tumor immunity, thereby affecting cancer malignancy and metastasis. Therefore, cancer-associated fibroblast has recently become a new target for cancer treatment.

It has been reported that in liver tissue from patients experiencing liver fibrosis, increased ROS production by hepatocytes is induced by TGF-β (transforming growth factor beta) stimulation, followed by increased expression of collagen and αSMA (smooth muscle actin alpha), which is important for fibrosis. ROS have been reported to exacerbate pulmonary fibrosis in the lung tissue of patients with idiopathic pulmonary fibrosis.

The brain is a tissue with high metabolic activity and is therefore very vulnerable to oxidative damage. Therefore, many studies have been conducted on the effective removal of ROS for the treatment of various neurodegenerative diseases (Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, ischemic and traumatic brain injury, etc.), but without success. Recently, since ROS has been found to be an important factor in these brain diseases, the possibility of treatment through ROS inhibition has been reported.

Keloid is a type of benign tumor disease in which the connective tissue of the skin proliferates abnormally to form hard lumps and the epidermis becomes thin, shiny and reddish. It has been reported that the onset and exacerbation of keloid is also one of the causes of overexpression of connective tissue growth factor (CTGF) by ROS produced by TGF-β stimulation.

In the case of diabetes, complications such as diabetic nephropathy and diabetic retinopathy may accompany long-term hyperglycemia, and ROS are known to play an important role in the occurrence of complications. In other words, high blood sugar causes an increase in the production of ROS, and in this case, the resulting ROS can cause diabetic nephropathy and diabetic retinopathy through a series of processes including the death of kidney cells and retinal cells.

In addition, keloid disease has been reported to cause retinal fibrosis and macular degeneration and the like when the CTGF gene is overexpressed in the retina.

Therefore, the inventors of the present invention conducted research focusing on the fact that a therapeutic agent against cancer, inflammatory disease, fibrotic disease, neurodegenerative disease, liver disease, skin disease or retinal disease or the like caused by oxidative stress can be developed using molecular mechanism inhibiting the production of oxidative stress, and, as a result, found that the new pyrazole derivative of the present invention has excellent ROS production inhibitory activity, and confirmed that it can be used for the treatment of various diseases associated with oxidative stress, thereby creating real invention.

Prior Art

Patent Document 1: WO 2016-207785

DISCLOSURE OF INVENTION

TECHNICAL PROBLEM

An object of the present invention is to provide a pyrazole compound of chemical formula I, an optical isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

An object of the present invention is to provide a pharmaceutical composition containing a compound of chemical formula I or an isomer thereof, a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

An object of the present invention is to provide a method of controlling the production of ROS using a compound of chemical formula I or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

An object of the present invention is to provide a method of treating diseases associated with oxidative stress by administering to a subject a compound of chemical formula I or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

An object of the present invention is to provide a method for preparing a compound of chemical formula I or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof.

The object of the present invention is to use a compound of chemical formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention, reversal or treatment of diseases associated with oxidative stress.

TECHNICAL SOLUTION

To solve the above objects, one aspect of the present invention may provide a new pyrazole derivative, a compound represented by Chemical Formula I below, or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

Chemical formula I

In the above formula, A, B and R are as defined below.

In one aspect of the present invention there is provided a compound represented by chemical formula I, a solvate, stereoisomer or pharmaceutically acceptable salt thereof, useful for the prevention, reversal or treatment of diseases associated with oxidative stress.

In one aspect of the present invention there is provided a pharmaceutical composition for the treatment of diseases associated with oxidative stress, containing a compound represented by chemical formula I, a solvate, stereoisomer or pharmaceutically acceptable salt thereof as an active ingredient and an acceptable carrier.

The present invention further provides a method for treating diseases associated with oxidative stress, comprising administering to a subject in need of such treatment a compound represented by Chemical Formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof in an effective amount.

Moreover, the present invention provides the use of a compound of chemical formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of diseases associated with oxidative stress.

ADVANTAGE EFFECTS

The new pyrazole derivative and the pharmaceutical composition containing the same pyrazole derivative of the present invention provide excellent effect against diseases associated with oxidative stress.

In addition, the novel pyrazole derivative effectively inhibits oxidative stress and αSMA production in various cells, and in particular has the effect of effectively reversing cancer, inflammatory disease, fibrotic disease, neurodegenerative disease, liver disease, skin disease or retinal disease or the like. caused by oxidative stress.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

FIG. 1 demonstrates the effect of the compounds of the Synthetic Examples in inhibiting ROS production induced by PMA ((phorbol-12-myristate-13-acetate) in LX-2 (liver stellate cells) and NHLF (normal human lung fibroblasts) cells.

FIG. 2 shows the effect of the compound of Synthesis Example 3 in inhibiting ROS production induced by preformed alpha-synuclein fibrils (PFF) in N27 cells.

FIG. 3a and FIG. 3b demonstrates the effect of the compounds from the Synthetic Examples (FIG. 3a: Compounds 1, 23 and 12, FIG. 3b: Compounds 5, 14 and 33) in inhibiting TGF β1-induced αSMA expression in HFF cells (human foreskin fibroblasts).

FIG. 4 shows the effect of the compound of Synthesis Example 1 in inhibiting the expression of αSMA induced by TGF β1 in various cells.

FIG. 5 demonstrates the effect of the compounds from the Synthesis Examples in inhibiting IL6 expression in P.CAF (pancreatic cancer associated fibroblasts) cells.

FIG. 6 shows the effect of the compounds of the Synthesis Examples in inhibiting IL8 expression in P.CAF cells.

FIG. 7 demonstrates the effect of the compounds of the Synthesis Examples in inhibiting collagen gel contraction induced by TGF β1 in HFF cells.

FIG. 8 shows the effect of the compounds of the Synthesis Examples in inhibiting LPS (lipopolysaccharide)-induced IL1β expression in LX2, NHLF, ARPE19 (human retinal pigment epithelial cells) and KEL-Fib (keloid fibroblast) cells.

BEST OPTION FOR IMPLEMENTING THE INVENTION

Hereinafter, the present invention will be described in more detail.

Unless otherwise defined, all technical terms used herein have the meanings commonly understood by those skilled in the art to which the present invention relates. In addition, numerical values disclosed herein include the value “about” unless expressly stated otherwise. All publications and other sources of information referred to in this document are incorporated herein by reference in their entirety.

The definitions of residues in this document are set out below. In addition, if definitions for individual residues are not available, they are used with meanings commonly understood by those skilled in the art.

As used herein, the term "independently" means that when more than one substituent is selected from among several possible substituents, the substituents may be identical or may be different from each other.

As used herein, the term “alkyl” refers to an aliphatic hydrocarbon radical and means a linear or branched monovalent saturated hydrocarbon group. Unless otherwise defined, an alkyl group typically contains 1-10, 1-8, 1-6, 1-4, or 1-3 carbon atoms. An example of an alkyl group includes methyl, ethyl, propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl and t-butyl), pentyl (for example, n-pentyl, isopentyl and neopentyl), n-hexyl , n-heptyl, n-octyl, n-nonyl and n-decyl.

As used herein, the term "alkenyl" refers to an aliphatic hydrocarbon radical containing one or more carbon-carbon double bonds and includes linear and branched hydrocarbon radicals, for example "alkenyl" is vinyl, allyl, but-1-enyl or but-1-enyl. 2-enyl.

As used herein, the term “alkynyl” refers to an aliphatic hydrocarbon radical containing one or more carbon-carbon triple bonds and includes all linear and branched hydrocarbon radicals. For example, "alkynyl" is ethynyl, propynyl or butynyl.

As used herein, the term “haloalkyl” means an alkyl group having one or more halogen substituents. Haloalkyl includes -CF ₃ , -C ₂ F ₅ , -CHF ₂ , -CCl ₃ , -CHCl ₂ and -C ₂ Cl ₅ . Unless otherwise defined, a haloalkyl group typically contains 1-6, 1-5, 1-4, or 1-3 carbon atoms and may optionally be substituted with other substituents.

As used herein, the term "alkoxy" may be a straight chain, a branched chain, or a ring chain. The number of carbon atoms of the alkoxy group is not particularly limited, but the number of carbon atoms is 1-10, 1-8, 1-6, 1-4 or 1-3. Specifically, it may be, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, sec-butoxy, n-pentyloxy, neopentyloxy, isopentyloxy, and the like.

As used herein, the term “hydroxy” or “hydroxyl” means -HO, alone or in combination with another term.

As used herein, the term "amino" means -NH ₂ .

As used herein, the terms "halogen", "halogeno" and "halogenide(s)" mean fluorine, chlorine, bromine and iodine.

As used herein, the term “cycloalkyl” means a non-aromatic carbocyclic ring including cyclic alkyl, alkenyl and alkynyl groups. The cycloalkyl group may contain a monocyclic or polycyclic ring. A polycyclic ring has, for example, 2, 3 or 4 fused rings. Unless otherwise defined, a cycloalkyl group typically contains 3-10 or 3-7 ring carbon atoms. The cycloalkyl group includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexadienyl, cycloheptatrienyl and the like. and may be further substituted with other substituents.

As used herein, the term "aryl" means an aromatic hydrocarbon group having a monocyclic or polycyclic ring, and it may be further substituted with other substituents. As used herein, a polycyclic group means a group in which an aryl group is directly bonded or fused to another cyclic group. As used herein, the other cyclic group may be an aryl group, but it may be another type of cyclic group, such as a cycloalkyl group, a heteroaryl group and the like. The polycyclic group may have, for example, 2, 3 or 4 rings. Unless otherwise defined, an aryl group typically has 5-20, 6-15, 6-12, or 6-10 ring carbon atoms. The aryl group includes, for example, phenyl, naphthyl (for example, naphthyl-1-yl and naphthyl-2-yl), biphenyl, anthracenyl, phenanthrenyl and the like.

As used herein, a “heterocycle” is an aromatic, saturated or partially unsaturated mono-, bi-, di- or polycyclic system containing the stated number of ring atoms and one or more heteroatoms selected from N, O and S. A ring member, in herein a heterocyclic ring, connected to the main molecule through a ring atom (can be C or N). The bicyclic system can be linked by a 1,1-fusion (spiro), a 1,2-fusion (fused), or a 1,>2-fusion (bridged).

As used herein, the term “heteroaryl” means a monovalent aromatic group having one or more heteroatoms selected from N, O and S as ring members. The heteroaryl group includes a monocyclic or polycyclic structure. The polycyclic structure may have, for example, 2, 3 or 4 fused rings. Unless otherwise defined, a heteroaryl group typically contains 3-10, 3-7, or 3-5 ring atoms. A heteroaryl group may contain 1, 2 or 3 heteroatoms. The heteroaryl group includes, for example, furanyl, pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, dihydroisoquinolyl, thienyl, imidazolyl, furanyl, thiazolyl, indolyl, pyryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, furinyl, benzimidazolyl, indolinyl and the like. and may be further substituted with other substituents.

As used herein, “heterocycloalkyl” refers to a monocyclic, bicyclic, tricyclic or polycyclic alkyl having 3-10 carbocycle members containing one or more, for example 1-4, 1-3 or 1-2 heteroatoms selected from N, O and S In addition, the heterocycle of the present invention may also be a fused or cross-linked heterocycloalkyl. An example of a non-aromatic ring can be azetidinyl, oxetanyl, tetrahydro, tetrahydrofuran, pyrrole, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, those trahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrazolopyridinyl , morpholinyl, indolinyl, azethiomorpholinyl, etc.

The addition of a heterocycloalkyl substituent can take place at a carbon atom or at a heteroatom. The heterocycloalkyl group may be optionally substituted with one or more suitable groups by one or more of the above groups. Unless otherwise defined, heterocycloalkyl refers to a 4-12 membered heterocycloalkyl, preferably a 4-10 membered heterocycloalkyl, more preferably a 4-7 membered heterocycloalkyl.

As used herein, the term "arylalkyl" represents an alkyl group substituted with an aryl group. "Aryl" and "alkyl" are as defined above.

As used herein, the term “heteroarylalkyl” represents an alkyl group substituted with a heteroaryl group. "Heteroaryl" and "alkyl" are as defined above.

As used herein, the term “alkylheterocycloalkyl” represents a heterocycloalkyl group substituted with an alkyl group. "Alkyl" and "heterocycloalkyl" are as defined above.

As used herein, the "substituted or unsubstituted amine group" may be selected from the group consisting of a monoalkylamine group, -NH ₂ and a dialkylamine group, and "alkyl" as defined above. A specific example of the substituted or unsubstituted amine group includes, but is not limited to, NH ₂ , methylamine group, dimethylamine group, ethylamine group, diethylamine and the like.

As used herein, "alkylene group" means an alkyl group having two binding sites, that is, a divalent group. The description of the above alkyl group can be applied to such groups except that they are divalent, respectively.

As used herein, the term "substitution" means that a hydrogen atom bonded to a carbon atom of a compound is replaced by another substituent, and the position to be substituted is not limited as long as the position at which the hydrogen atom is substituted, that is, the position where the substituent is located is not limited, and when there are 2 or more substituents, the 2 or more substituents may be identical or different, and 2 or more identical or different substituents may be combined and substituted.

As used herein, the term "substituted alkyl" is a form in which the next substituent is on the C ₁ -C ₁₀ carbon atom of a linear or branched alkyl. Specifically, it is a form in which one or more substituents or the same or different 2 or more substituents are connected and substituted, which is selected from heavy hydrogen, hydrogen, halogen, cyano, nitro, carboxyl, substituted or unsubstituted amine, substituted or unsubstituted C ₅ -C ₂₀ aryl or C ₅ -C ₂₀ heteroaryl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkyl. As an illustrative substituent, trifluoromethyl, halogen, cyano, methoxy, carboxyl, methyl, amino, nitro, dimethylamino, cyclopropyl, substituted imidazole, pyridine, substituted or unsubstituted sulfonyl and the like may be used, but is not limited to them.

As used herein, the term "substituted cycloalkyl" is a form in which one or more substituents, or the same or different 2 or more substituents, are coupled to and substituted with C ₃ -C ₈ cycloalkyl, which are selected from heavy hydrogen, hydrogen, halogen, cyano, nitro , carboxyl, substituted or unsubstituted amine, substituted or unsubstituted C ₅ -C ₂₀ aryl or C ₅ -C ₂₀ heteroaryl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ haloalkyl. As an illustrative substituent, trifluoromethyl, halogen, cyano, methoxy, carboxyl, methyl, amino, nitro, dimethylamino, cyclopropyl, substituted imidazole, substituted or unsubstituted sulfonyl, and the like may be used, but is not limited to.

As used herein, the term "substituted aryl" or "substituted heteroaryl" is a form in which one or more substituents, or the same or different 2 or more substituents, are coupled to and substituted with a C ₅ -C ₂₀ aryl or C ₅ -C ₅₀ heteroaryl, which selected from heavy hydrogen, hydrogen, halogen, cyano, nitro, carboxyl, substituted or unsubstituted amine, substituted or unsubstituted _C5 - _C20 aryl or _C5 - _C20 heteroaryl, _C1 - _C5 alkoxy, _C1 - _C5 haloalkyl , C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ heterocycloalkyl, C ₃ -C ₈ cycloalkyl-C ₁ -C ₁₀ alkyl, C ₅ -C ₂₀ aryl-C ₁ -C ₁₀ alkyl. As an illustrative substituent, trifluoromethyl, halogen, cyano, methoxy, carboxyl, methyl, amino, nitro, dimethylamino, cyclopropyl, substituted imidazole, substituted or unsubstituted sulfonyl, and the like may be used, but is not limited to.

As used herein, a “neighboring” group may mean a substituent substituted at an atom directly bonded to the atom on which the corresponding substituent is located, a substituent sterically proximal to the corresponding substituent, or another substituent located at the atom on which the corresponding substituent is located. For example, two substituents at the ortho position of a benzene ring and two substituents on the same carbon atom of an aliphatic ring can be interpreted as being “adjacent” to each other.

As used in relation to a compound, an "effective dose" is an amount effective to treat or prevent a disease in a subject as described herein.

Compound

To solve the above problem, the present invention provides a compound of chemical formula I below, or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof:

in this formula

A is substituted or unsubstituted 5-20 membered heteroaryl or substituted or unsubstituted C ₅ -C ₂₀ aryl; And

wherein a 5-20 membered heteroaryl or C ₅ -C ₂₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₁₀ alkoxy groups, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted amine, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted 5-20 membered heteroaryl and substituted or unsubstituted 5-20 membered heterocycloalkyl, and R ₁ may be hydrogen, heavy hydrogen, C ₁ - C ₁₀ alkyl; And

two or more than two adjacent groups can be combined with each other to form a substituted or unsubstituted aromatic hydrocarbon ring, where the aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring or a C ₅ -C ₁₀ aryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S; And

R represents hydrogen, heavy hydrogen, cyano, halogen, nitro, haloalkyl, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted 5 -20-membered heteroaryl or -C(=O)R ₂ , wherein R ₂ is C ₃ -C ₈ cycloalkyl, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl or C ₆ -C ₁₀ aryl; And

B represents -NKM, or substituted or unsubstituted 5-20 membered heteroaryl, or substituted or unsubstituted 5-20 membered heterocycloalkyl; And

K and M are each independently hydrogen, heavy hydrogen, cyano, halogen, nitro, haloalkyl, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ aryl-C ₁ -C ₁₀ alkyl, substituted or unsubstituted 5-20 membered heteroaryl or substituted or unsubstituted 5-20 membered heteroaryl-C ₁ -C ₁₀ alkyl;

where C ₁ -C ₁₀ alkyl is unsubstituted or substituted with 1, 2, 3 or 4 types of substituents selected from the group consisting of heavy hydrogen, halogen, hydroxy, cyano, nitro, carboxyl, substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ haloalkyl, substituted or unsubstituted C ₁ -C ₁₀ hydroxyalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkylsulfonyl, C ₅ -C ₂₀ arylsulfonyl, C ₅ -C ₂₀ aryloxy, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted 5-20 membered heteroaryl and substituted or unsubstituted 5-20 membered heterocycloalkyl; And

The C ₃ -C ₈ cycloalkyl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of substituents selected from the group consisting of heavy hydrogen, halogen, cyano, nitro, carboxyl, substituted or unsubstituted amine, substituted or unsubstituted C ₅ -C ₂₀ aryl or 5-20 membered heteroaryl, C ₁ -C ₁₀ alkoxy and C ₁ -C ₁₀ haloalkyl; And

5-20 membered heteroaryl, 5-20 membered heterocycloalkyl or C ₅ -C ₂₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of substituents selected from the group consisting of heavy hydrogen, halogen, cyano, nitro, -C(=O)R', -C(=O)OR', -NH-C(=O)R'', substituted or unsubstituted amino, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ haloalkyl, substituted or unsubstituted C ₁ -C ₁₀ hydroxyalkyl, substituted or unsubstituted C ₁ -C ₁₀ alkylsulfonyl, substituted or unsubstituted C ₅ -C ₂₀ arylsulfonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl-C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted C ₅ -C ₂₀ aryl-C ₁ -C ₁₀ alkyl , substituted or unsubstituted 5-12 membered heterocycloalkyl, substituted or unsubstituted C ₁ -C ₁₀ alkyl-C ₃ -C ₈ cycloalkyl and substituted or unsubstituted C ₁ -C ₁₀ alkyl-5-20 membered heterocycloalkyl, and

wherein R' and R'' are each independently hydrogen, heavy hydrogen, substituted or unsubstituted amine, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ - C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl or substituted or unsubstituted C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl; And

the substituted amino group is substituted with 1 type or 2 types of C ₁ -C ₁₀ alkyl groups; And

The heteroatom of the heterocycloalkyl or heteroaryl ring is one or more types selected from N, S and O.

In one particular aspect

A is unsubstituted or substituted 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl, and the 5-12 membered heteroaryl or C ₆ -C ₁₀ aryl may be substituted with 1, 2, 3 or 4 types of substituents selected from the group consisting of cyano, halogen, C ₁ -C ₆ haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , C ₁ - C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, amino, C ₆ -C ₁₀ aryl, 5-12 membered heteroaryl and 5-12 membered heterocycloalkyl, and R ₁ represents hydrogen, heavy hydrogen or C ₁ -C ₆ alkyl; And

two or more than two adjacent groups can be combined with each other to form a substituted or unsubstituted aromatic hydrocarbon ring, where the aromatic hydrocarbon ring can form a 5-7 membered heteroaryl ring or a C ₆ -C ₉ aryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

In one particular aspect, A may be a 5-10 membered heteroaryl or a C ₆ -C ₉ aryl having 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O and S.

In one particular aspect, A can be pyridinyl, pyrimidinyl, pyrazinyl, triazolyl, thiazolyl, phenyl, or thieno[3,2]pyridine.

In one particular aspect, A may be substituted with 1 type, 2 types, 3 types, or 4 types of C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, F, Cl, Br, I, cyano, amino, nitro, - C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , 5-12 membered heterocycloalkyl, and R _a can be hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl.

In one particular aspect, A may be substituted with 1 type, 2 types, 3 types, or 4 types of methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, F, Cl, Br, I, cyano, amino, nitro , -C(=O)OH, -C(=O)CH ₃ , -NH-C(=O)CH ₃ , morpholino or piperidine

In one particular aspect, R is hydrogen, heavy hydrogen, cyano, halogen, nitro, unsubstituted or substituted with C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, 5-12-membered heteroaryl, -C(=O)R ₂ , and R ₂ represents C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, or C ₆ -C ₁₀ aryl.

In one particular aspect, R ₂ can be cyclopropyl, methyl, ethyl, propyl, ethenyl, propenyl or phenyl.

In one particular aspect, R can be hydrogen, heavy hydrogen, cyano, halogen, nitro, methyl, ethyl, propyl, butyl, cyclopropyl methyl, CF ₃ , -C(=O)-cyclopropyl, -C(=O)- ethenyl or benzoyl.

In one particular aspect, B is -NKM or 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl, and wherein the 5-12 membered heteroaryl or 5-12 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3 or 4 types of heavy hydrogen, halogen, cyano, nitro, -NR ₃ R ₄ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, -C(=O)R ₅ , - SO ₂ -R ₆ , and

wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryl can be unsubstituted or substituted with 1, 2, 3 or 4 types of hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryloxy, or unsubstituted or substituted C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylcarbonyl 4-12 membered heterocycloalkyl, and

R ₃ and R ₄ are each independently hydrogen, heavy hydrogen, -C(=O)-R _a , C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, and C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl is unsubstituted or substituted with 1, 2, 3 or 4 types of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryloxy, and wherein R _a is hydrogen , heavy hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

R ₅ represents -OR _b , -NR _c R _d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, and C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl may be unsubstituted or substituted with 1, 2, 3 or 4 types of mono-C ₁ -C ₆ alkylamine or di-C ₁ -C ₆ alkylamine, and wherein R _b , R _c and R _d are each independently hydrogen, heavy hydrogen, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, and

R ₆ is C ₁ -C ₆ alkyl, unsubstituted or substituted with 1, 2, 3 or 4 types of C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, and

K and M are each independently hydrogen, heavy hydrogen, cyano, halogen, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl-, 5-12-membered heteroaryl, 5-12-membered heteroaryl-C ₁ -C ₆ alkyl, and C ₁ -C ₆ alkyl , C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl or 5-12 membered heteroaryl may be substituted with 1, 2, 3 or 4 types of cyano, halogen, C ₁ -C ₆ alkyl , C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, C ₆ -C ₁₀ arylsulfonyl, -NR ₇ R ₈ , -C(=O)R ₉ , 5-12 membered heterocyclyl, hydroxy, nitro, C ₆ -C ₁₀ aryl, and at the same time, 5-12 membered heterocyclyl or C ₆ -C ₁₀ aryl may be unsubstituted or substituted with C ₁ -C ₆ alkyl, and

R ₉ is -OR _e , -NR _e R _f , unsubstituted or substituted with 1, 2, 3 or 4 types of -NR _e R _f C ₂ -C ₆ alkenyl or C ₆ -C ₁₀ aryl, and wherein R _e and R _f is each independently hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, or C ₁ -C ₆ alkyl.

In one particular aspect, B may be a 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl having 1-3 types of heteroatoms selected from the group consisting of N, O and S, and these may be substituted with the above substituents or may be unsubstituted.

In one particular aspect, B may be pyrrolidine, piperazine, dihydroisoquinoline, morpholine or piperidine, and they may be substituted with the above substituents or may be unsubstituted.

In one particular aspect, the compound of Chemical Formula I may be a compound of Chemical Formula I-1 as set forth below:

Chemical formula I-1

in this formula

the definition of K, M and R is the same as for chemical formula I; And

D is CR ₁₀ , N, O or S, or E is CR ₁₁ , N, O or S, or F is CR ₁₂ , N, O or S, or G is CR ₁₃ , N, O or S , or J is CR ₁₄ , N, O or S, but N, O and S are present in an amount of one or more; And

R ₁₀ -R ₁₄ are the same or different and, each independently, can be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, haloalkyl, nitro, -C(=O)R ₁ , -C(= O)OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted amine, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted 5-12 membered heteroaryl and substituted or unsubstituted 5-12 membered heterocycloalkyl, and R ₁ may be hydrogen, heavy hydrogen, C ₁ -C ₁₀ alkyl; And

two or more than two adjacent groups can be combined with each other to form a substituted or unsubstituted aromatic hydrocarbon ring, where the aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring or a C ₆ -C ₁₀ aryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S.

In one particular aspect, the compound of Chemical Formula I may be a compound of Chemical Formula I-2 as set forth below:

Chemical formula I-2

in this formula

the definition of R is the same as for chemical formula I; And

D is CR ₁₀ , N, O or S, or E is CR ₁₁ , N, O or S, or F is CR ₁₂ , N, O or S, or G is CR ₁₃ , N, O or S , or J is CR ₁₄ , N, O or S, but N, O and S are present in an amount of one or more; And

R ₁₀ -R ₁₄ are the same or different and, each independently, can be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, haloalkyl, nitro, -C(=O)R ₁ , -C(=O )OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₁₀ alkoxy, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl, substituted or unsubstituted amine, substituted or unsubstituted C ₅ -C ₂₀ aryl, substituted or unsubstituted 5-12 membered heteroaryl and substituted or unsubstituted 5-12 membered heterocycloalkyl, and R ₁ may be hydrogen, heavy hydrogen, C ₁ -C ₁₀ alkyl; And

two or more than two adjacent groups can be combined with each other to form a substituted or unsubstituted aromatic hydrocarbon ring, where the aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring or a C ₆ -C ₁₀ aryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S, and

n is an integer 0, 1 or 2; And

L represents CH ₂ , NH or O; And

may be unsubstituted or may be substituted by 1, 2, 3 or 4

types of heavy hydrogen, halogen, cyano, nitro, -NR ₃ R ₄ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, -C(=O)R ₅ , -SO ₂ -R ₆ , and wherein when the substituent is 2 types or more, two or more than two adjacent groups can be combined with each other to form a substituted or unsubstituted 5-20 membered heteroaryl or a substituted or unsubstituted 5-20 membered heterocycloalkyl with And

wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of hydroxy, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, C ₆ -C ₁₀ aryloxy or unsubstituted or substituted C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylcarbonyl 4-12 membered heterocycloalkyl, and

R ₃ and R ₄ are each independently hydrogen, heavy hydrogen, -C(=O)-R _a , C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, and C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryloxy, and wherein R _a is hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And

R ₅ represents -OR _b , -NR _c R _d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, and C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of mono-C ₁ -C ₆ alkylamine or di-C ₁ -C ₆ alkylamine, and R _b , R _c and R _d are each independently hydrogen, heavy hydrogen, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, and

R ₆ is C ₁ -C ₆ alkyl, unsubstituted or substituted with 1, 2, 3 or 4 types of C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl.

In one particular aspect, when L is in is substituted, then L represents CH ₂ or NH, and among them, one type or 2 types of H may be substituted with the above substituents.

In one particular aspect, the compound of Chemical Formula I may be a compound of Chemical Formula I-3, set forth below:

Chemical formula I-3

in this formula

the definition of K, M, R, D, E, F and G is the same as for chemical formula I-1.

In one particular aspect, the compound of Chemical Formula I may be a compound of Chemical Formula I-4, set forth below

Chemical formula I-4

in this formula

the definition of L, n, R, D, E, F and G is the same as for chemical formula I-2.

In one aspect, the compounds of Chemical Formula I of the present invention may be one or more compounds selected from the group consisting of, but not limited to, the following compounds 1-161:

1) 5-(benzylmethylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

2) 5-(benzylcyclopropylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

3) 4-{[(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)methylamino]methyl}benzonitrile;

4) 5-[(4-fluorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

5) 5-[(2,4-difluorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

6) 5-[(2-chlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

7) 5-[(3-chlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

8) 5-[methyl-(4-trifluoromethylbenzyl)amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol;

9) 5-[methyl-(3-methylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

10) 5-[methyl-(3-trifluoromethylbenzyl)-amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol;

11) 5-[methyl-(2-trifluoromethylbenzyl)-amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol;

12) 5-[(4-methanesulfonylbenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

13) 5-[(3-methoxybenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

14) 5-piperidin-1-yl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

15) 5-morpholino-4-yl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

16) 5-(4-methylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

17) 5-(4-(2-(2-hydroxymethoxy)ethyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3- ol;

18) 5-(3,4-dihydro-1H-isoquinolin-2-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

19) 5-[(4-chlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

20) 5-(benzylethylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

21) 5-(benzylpropylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

22) 5-(benzylbutylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

23) 5-[methyl(3-methylsulfonylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

24) 5-[methyl-(4-methylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

25) 3-{[(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)methylamino]methyl}benzonitrile;

26) 5-[(2-methoxybenzyl)-methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

27) 5-[(3-fluorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

28) 5-[(4-methoxybenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

29) 5-[methyl-(2-methylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

30) 5-[(2,4-dichlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

31) 5-[(3,4-dichlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

32) 5-(3,4-difluorophenylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

33) 5-[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3- ol;

34) 5-(((3-(hydroxymethyl)-5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)-2-(pyridine -2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

35) 5-{[(3-(hydroxymethyl)-5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl]methylamino}-2-(pyridin-2- yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

36) 5-{methyl[3-methyl-5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]methylamino}-2-(pyridin-2-yl)-4 ,5,6,7-tetrahydro-2H-indazol-3-ol;

37) 5-{methyl[5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]methylamino}-2-(pyridin-2-yl)-4,5,6 ,7-tetrahydro-2H-indazol-3-ol;

38) cyclopropyl[4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2-indazol-5-yl)piperazin-1-yl]methanone;

39) 5-(benzylmethylamino)-2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

40) 5-(benzylmethylamino)-2-(5-chloropyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

41) 5-(benzylmethylamino)-2-(6-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

42) 5-(benzylmethylamino)-2-(6-methylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

43) 5-(benzylmethylamino)-2-(3-fluoropyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

44) 6-(5-(benzylmethylamino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinonitrile;

45) 5-(benzylmethylamino)-2-(6-methyl-4-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

46) 5-(benzylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

47) 2-(pyridin-2-yl)-5-[(pyridin-2-ylmethyl)amino]-4,5,6,7-tetrahydro-2H-indazol-3-ol;

48) 5-[methyl(pyridin-2-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

49) 5-[methyl(pyridin-4-ylmethyl)amino]-2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

50) 2-(5-chloropyridin-2-yl)-5-[methyl(pyridin-4-ylmethyl)amino]-4,5,6,7-tetrahydro-2H-indazol-3-ol;

51) 5-[methyl(pyridin-4-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

52) 2-(4-bromophenyl)-5-[methyl(pyridin-4-ylmethyl)amino]-4,5,6,7,-tetrahydro-2H-indazol-3-ol;

53) 5-(benzylmethylamino)-2-(thieno[3,2-c]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

54) 2-(6-aminopyridin-2-yl)-5-(benzylmethylamino)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

55) 5-phenylamino-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

56) 5-[(2,5-dimethylphenyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

57) 5-[(4-nitrophenyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

58) 5-[(4-methoxyphenyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

59) 5-(phenylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

60) 2-(pyridin-2-yl)-5-(quinolin-3-ylamino)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

61) 5-[methyl(naphthalene-2-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

62) 5-[(isoquinolin-3-ylmethyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

63) 5-[methyl(quinolin-6-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

64) 5-[(isoquinolin-3-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

65) 5-[methyl(pyridin-2-ylmethyl)amino]-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-ol;

66) 5-[ethyl(pyridin-4-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

67) 5-[(3-dimethylaminobenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

68) 5-[(4-dimethylaminobenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-2-ol;

69) 5-[(3-dimethylaminobenzyl)methylamino)]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

70) 5-[(4-dimethylamino)benzylmethylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

71) 5-[(2-dimethylamino)benzylmethylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

72) 5-(benzylmethylamino)-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-ol;

73) 4-[(5-benzylmethylamino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl]benzoic acid;

74) 5-(benzylmethylamino)-2-(4-bromophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

75) 5-(benzylmethylamino)-2-(2-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

76) 5-(benzylmethylamino)-2-(2-methoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

77) 2-(2-chlorophenyl)-5-[(3-dimethylaminobenzyl)methylamino]-4,5,6,7-tetrahydro-2H-indazol-3-ol;

78) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)benzoic acid;

79) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)benzamide;

80) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)-N-methylbenzamide ;

81) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)-N,N -dimethylbenzamide;

82) 5-(4-methylpiperazin-1-yl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

83) 2-(6-chloropyridin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

84) 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol ;

85) 5-(4-methylpiperazin-1-yl)-2-(thieno[3,2-c]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

86) 2-(3-fluoropyridin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

87) 2-(pyridin-2-yl)-5-(4-(pyridin-2-ylmethyl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

88) 5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

89) 1-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)but-2- en-1-one;

90) 2-(pyridin-2-yl)-5-(4-(quinolin-6-ylmethyl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

91) 5-(4-ethylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

92) 5-(phenylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

93) 5-(phenethylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

94) 2-(4-chlorophenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

95) 5-(4-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

96) 2-(pyridin-2-yl)-5-(pyrrolidin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

97) 1-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)prop-2- en-1-one;

98) (E)-4-(dimethylamino)-1-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl) piperazin-1-yl)but-2-en-1-one;

99) (E)-4-(dimethylamino)-N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-N- methylbut-2-enamide;

100) 5-(4-propylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

101) 2-(4-bromophenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

102) 2-(4-fluorophenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

103) 4-(3-hydroxy-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzonitrile;

104) 5-(4-phenethylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

105) 5-(4-benzylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

106) 5-(4-(cyclohexylmethyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

107) 5-(4-(3-phenylpropyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

108) 5-(4-methylpiperazin-1-yl)-2-(pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

109) 5-(piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

110) 5-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

111) 5-(4-(phenylsulfonyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

112) 2-(pyridin-2-yl)-5-(4-tosylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

113) 4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-N-phenylpiperazin-1-carboxamide;

114) benzyl 4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazine-1-carboxylate;

115) 2-(1-methyl-1H-pyrrol-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

116) 5-(4-methylpiperazin-1-yl)-2-(thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

117) 5-(4-methylpiperazin-1-yl)-2-(oxazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

118) 2-(1-methyl-1H-pyrazol-5-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

119) 2-(1-methyl-1H-imidazol-5-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

120) 2-(1-methyl-1H-imidazol-5-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

121) 5-(benzyl(methyl)amino)-2-(pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

122) 5-(benzyl(methyl)amino)-2-(1-methyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

123) 5-(benzyl(methyl)amino)-2-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

124) 5-(benzyl(methyl)amino)-2-(1-methyl-1H-imidazol-5-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

125) 5-(benzyl(methyl)amino)-2-(oxazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

126) 2-(pyridin-2-yl)-5-(4-(para-tolyl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

127) 5-(4-(4-hydroxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

128) 5-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

129) 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

130) 1-(4-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)phenyl )ethan-1-one;

131) 5-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

132) 5-(4-(4-phenoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

133) 5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

134) 5-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol- 3-ol;

135) 5-(4-((1-benzylpiperidin-4-yl)methyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol- 3-ol;

136) 1-(4-((4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl) methyl)piperidin-1-yl)ethan-1-one;

137) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)benzamide;

138) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-2-phenylacetamide;

139) 1-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-3-phenylurea;

140) 1-benzyl-3-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)urea;

141) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)benzenesulfonamide;

142) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-4-methylbenzenesulfonamide;

143) benzyl-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)carbamate;

144) 2-(5-fluoro-4-morpholinopyrimidin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

145) N-benzyl-3-methoxy-N-methyl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-amine;

146) N-benzyl-3-(cyclopropylmethoxy)-N-methyl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-amine;

147) 5-(benzyl(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ylcyclopropanecarboxylate;

148) 5-(benzyl(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-yl acrylate;

149) 5-(benzyl(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ylbenzoate;

150) 2-(5-(benzyl(methyl)amino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)pyrimidine-5-carboxylic acid;

151) methyl 2-(5-(benzyl(methyl)amino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinate;

152) N-(6-(5-(benzyl(methyl)amino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)pyridin-2-yl)acetamide;

153) 5-(benzyl(methyl)amino)-2-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3- ol;

154) 5-(4-methylpiperazin-1-yl)-2-(pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

155) 2-(5-chloropyridazin-3-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

156) 2-(pyridin-2-yl)-5-(4-(pyrimidin-2-yl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

157) 5-(benzyl(methyl)amino)-2-(5-nitropyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

158) 5-((4-hydroxybenzyl)(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

159) 5-(methyl(4-nitrobenzyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol;

160) 5-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; And

161) 2,2,2-trifluoro-N-(1-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)pyrrolidin- 3-yl)acetamide.

Unless specifically stated otherwise, the chemical formulas or names given in this specification and claims refer to tautomers and all stereoscopic, optical and geometric isomers (e.g., enantiomers, diastereomers, E/Z isomers, etc.) and their racemates, as well as mixtures of enantiomers in varying proportions, mixtures of diastereomers or mixtures of any of the above forms in which isomers and enantiomers exist, and their pharmaceutically acceptable salts and solvates, such as hydrates, including, for example, solvates and hydrates of the free compound or solvates and hydrates salts of the corresponding compound.

In one embodiment, a compound of the present invention may be present in the form of a pharmaceutically acceptable salt. Salt means a salt commonly used in the medical field to which the present invention relates, and a useful acid addition salt formed by a pharmaceutically acceptable free acid is used. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic acid addition salt of a compound whose inherent side effects do not reduce the beneficial efficacy of the compound of the present invention at an effective concentration and which is relatively non-toxic and harmless for the patient.

An acid addition salt is prepared in a conventional manner, for example by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of the compound and the acid or alcohol (eg glycol monoethyl ether) in water can be heated and the mixture can then be evaporated to dryness, or the precipitated salt can be filtered under vacuum.

Further, as the free acid, organic acid and inorganic acid can be used, and as the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used, and as the organic acid, used methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid , galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., but not limited to them.

In addition, a pharmaceutically acceptable metal salt can be formed using a base. An alkali metal salt or an alkaline earth metal salt is prepared, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering off the undissolved salt of the compound, and then evaporating and drying the filtrate. Further, the metal salt is a pharmaceutically acceptable salt of sodium, potassium or calcium, but is not limited to them. In addition, the corresponding silver salt can be prepared by reacting an alkali metal salt or an alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

A pharmaceutically acceptable salt of a compound of the present invention, unless otherwise specified, includes salts formed by acidic or basic groups which may be present in the compounds described in Chemical Formula I above. For example, as a pharmaceutically acceptable salt, sodium, calcium and potassium salts formed by hydroxy groups can be used, and other pharmaceutically acceptable salt formed by an amino group includes hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate salts, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate), etc., and they can be prepared by a salt preparation method known in the art.

As the salt of the compound described by Chemical Formula I above, any pharmaceutically acceptable salt which is a salt of the compound described by Chemical Formula I above exhibiting pharmacological activity equal to that of the compound described in Table 1 can be used in the present invention. , without limitation.

In addition, the compound of the present invention may also exist in the form of its stereoisomer. Stereoisomer includes all stereoisomers such as enantiomers and diastereomers. The compound may be a stereoisomerically pure form or a mixture of one or more stereoisomers, for example a racemic mixture. The separation of specific stereoisomers can be accomplished by one of the conventional methods known in the art. Some examples of the compounds of the present invention may have a higher inhibitory effect on oxidative stress in the form of a particular stereoisomer. In this case, when using a specific stereoisomer, the dosage may be reduced. Accordingly, a specific stereoisomer with a high inhibitory effect on oxidative stress, such as an enantiomer or a diastereomer, can be isolated and thereby effectively treat diseases associated with oxidative stress.

The compound of the present invention may be in the form of a solvate thereof. "Solvate" means a complex or aggregate of one or more dissolved molecules, that is, a compound of chemical formula I or a pharmaceutically acceptable salt thereof, and one or more solvent molecules. The solvate may be, for example, a complex or aggregate formed by molecules of various solvents such as water, methanol, ethanol, isopropanol or acetate or the like.

Solvates in which water is the solvent molecule are called hydrates. The hydrate includes a composition containing a stoichiometric amount of water, as well as a composition containing a varying amount of water.

The compound of the present invention may also exist in the form of its tautomer.

The term "tautomer" or "tautomeric form" means changing constitutional isomers of different energies that are capable of interconversion through low energy barriers. Some non-limiting examples of protic tautomers (also known as proton tautomers) include proton transfer interconversions such as keto-enol and imine-enamine isomerization. Valence tautomers involve interconversion through the rearrangement of some bonding electrons.

The compound of the present invention may also be in the form of an isotopic variant thereof.

The term "isotopic variant" means a compound in which at least one atom has the same number of atoms for any compound, but is replaced by another atom having an atomic mass different from the atomic mass normally and commonly found in nature.

The solvate, stereoisomer, tautomer and isotopic variant of a compound of chemical formula I above can be prepared from this compound using a method known in the art.

In the production method of the present invention, as the reagents used in the above reaction formulas, commercially available compounds can be purchased and used as is, or they can be synthesized by performing one or more reactions known in the art as is, or by appropriate their changes. For example, they can be synthesized by performing one or more reactions in a sequential order, taking into account, but not limited to, the presence, type and/or position of the reactive functional group and/or heteroelement included in the structure.

In one embodiment, the compounds of the Synthetic Examples of the present invention exhibit an inhibitory effect on ROS production of 30%, 50%, 70% or more compared to the control group when treated with ROS produced by PMA in HL-60 cells (human leukemia cells), and also exhibit concentration-independent inhibitory ability and, therefore, the compounds of the present invention can be used for the prevention or treatment of diseases associated with oxidative stress.

The differentiation of fibroblasts into myofibroblasts has been reported to generate cancer-associated fibroblasts (CAFs) or to induce fibrosis in various tissues. By treating HFF-1 cells (human foreskin fibroblasts) in which fibrosis was induced by treatment with TGF-β1 with the compounds of the Synthesis Examples of the present invention, the effect of inhibiting the expression of αSMA, an indicator of fibrosis, was shown. Thus, the compounds of the present invention can be used to prevent or treat diseases associated with fibrosis and can be used to treat cancer through the regulation of cancer-associated fibroblasts, an important indicator of tumor microenvironment interactions.

When ROS levels increase in neuronal cells, lipid oxidation is induced and is known to be an important factor in neuronal cell death. Co-treatment of N27 cells (rat dopaminergic neuronal cells) with the ROS-inducing MPP+ (1-methyl-4-phenylpyridinium) and the compounds from the Synthetic Examples was effective in inhibiting ROS production. Accordingly, the compounds of the present invention can be used to prevent or treat diseases associated with the death of neuronal cells due to oxidative stress.

The production of extracellular matrix such as collagen type I and the like by CTGF (connective tissue growth factor) from keloid fibroblasts is one of the causes of cutaneous fibrotic diseases. When fibrosis was induced by treatment with the compounds of the Synthesis Examples and then treatment with TGF-β1 (transforming growth factor beta 1) of KEL-FIB cells (keloid fibroblasts), the expression of the CTGF gene and type I collagen gene was effectively inhibited. Therefore, the compounds of the present invention can be used for the prevention or treatment of cutaneous keloid diseases.

Pharmaceutical composition and medical use

The compound of the present invention, its optical isomer, its stereoisomer, its solvate, its isotopic variant, its tautomer or its pharmaceutically acceptable salt may be suitable for the prevention, amelioration or treatment of various diseases caused by oxidative stress due to its biological characteristics.

The pharmaceutical composition of the present invention can be used for the treatment of diseases associated with oxidative stress. The disease may be cancer, inflammatory disease, fibrotic disease, neurodegenerative disease, neurological disease, liver disease, skin disease, mitochondrial disorder, aging, chronic alcoholism, stem cell dysfunction, lameness, metabolic syndrome, Down syndrome, infertility, overproduction of lipid peroxides in tissue, muscle disease, accumulation of lipid peroxides in cell membranes, chronic fatigue or retinal disease.

The cancer may be selected from the group consisting of liver cancer, hepatocellular carcinoma, gastrointestinal malignancy, gastric cancer, intracranial meningioma associated with neurofibroma, pancreatic cancer, leukemia, myeloproliferative/myelodysplastic disease, dermatofibrosarcoma, breast cancer, lung cancer, thyroid cancer, colorectal cancer, prostate cancer, breast cancer, ovarian cancer, brain tumor, head and neck cancer, glioblastoma, etc. In addition, the cancer may be a secondary cancer that has metastasized to another organ from different types of cancer.

The metabolic syndrome may be obesity, diabetes, high blood pressure, hyperlipidemia, arteriosclerosis, peripheral vascular disease, ischemic perfusion, myocardial infarction or stroke, or the like.

The inflammatory disease may be rheumatoid arthritis, osteoarthritis, pneumonia, hepatitis, inflammatory colorectal disease, intestinal enteritis, glomerulonephritis, gastritis, vasculitis, pancreatitis, peritonitis, bronchitis, cardiomyositis, encephalitis, inflammation due to post-ischemic reperfusion injury, inflammation resulting from tissue and organ transplant rejection, various inflammations occurring on the skin such as burns, allergic contact dermatitis, etc., inflammation resulting from multiple organ disorders, diabetic inflammation including diabetic nephropathy, infectious inflammation caused by viral or bacterial infection, or an autoimmune disease such as atopic disease, lupus, psoriasis, atherosclerosis, and the like.

The fibrotic disease may be metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced liver fibrosis or cirrhosis, NASH-induced liver fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, infectious agent-induced liver fibrosis or cirrhosis, liver fibrosis or cirrhosis caused by a parasitic infection, liver fibrosis or cirrhosis caused by a bacterial infection, liver fibrosis or cirrhosis caused by a viral infection, liver fibrosis or cirrhosis caused by HBV (hepatitis B virus) infection liver fibrosis or cirrhosis caused by HCV (hepatitis C virus) infection fibrosis or cirrhosis liver caused by HIV (human immunodeficiency virus) infection liver fibrosis or cirrhosis caused by both HCV and HIV infection liver fibrosis or cirrhosis caused by radiation or chemotherapy fibrosis or cirrhosis, bile duct fibrosis, liver fibrosis or cirrhosis caused by chronic cholestatic disease, fibrosis of the digestive tract of any etiology, fibrosis caused by Crohn's disease, fibrosis caused by ulcerative colitis, fibrosis of the small intestine, fibrosis of the colon, gastric fibrosis, pulmonary fibrosis, skin fibrosis, epidermal fibrosis, endothelial fibrosis, skin fibrosis caused by scleroderma /systemic sclerosis, chronic obstructive pulmonary disease (COPD), asthma, emphysema, smoker's lung, tuberculosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF) followed by pulmonary fibrosis, cardiac fibrosis, renal fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue fibrosis tissues, myelofibrosis, joint fibrosis, tendon fibrosis, chondrofibrosis, pancreatic fibrosis, uterine fibrosis, nervous system fibrosis, testicular fibrosis, ovarian fibrosis, adrenal fibrosis, arterial fibrosis, venofibrosis, ocular fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis , progressive giant fibrosis, which is a complication of pneumoconiosis, proliferative fibrosis, neoplastic fibrosis, peripheral graft fibrosis, asbestosis, articular fibrosis or adhesive capsulitis.

The neurodegenerative disease may be Alzheimer's disease (including mild or early Alzheimer's disease, mild-moderate Alzheimer's disease, moderate-intermediate Alzheimer's disease, moderate-severe Alzheimer's disease, moderately severe Alzheimer's disease, severe Alzheimer's disease and Alzheimer's disease with Lewy bodies), Parkinson's disease (including Parkinson's disease chemically induced by exposure to environmental agents such as pesticides, insecticides or herbicides and/or metals such as manganese, aluminum, cadmium, copper or zinc, SNCA gene-associated Parkinson's disease, sporadic or idiopathic Parkinson's disease or Parkinson- or LRRK2-associated Parkinson's disease), autosomal dominant Parkinson's disease, diffuse Lewy body disease (DLBD) (also known as dementia with Lewy bodies (DLB)), true autonomic ataxia, dysphagia with Lewy bodies, random LBD, genetic LBD (eg, alpha-synuclein gene mutation, PARK3 and PARK4), multiple system atrophy (including olivopontocerebellar atrophy, striatonigral degeneration, Shy-Dredger syndrome (MSA)), complex Alzheimer's disease and Parkinson's disease and/or MSA, Huntington's disease, synuclein disease, a disorder or condition characterized by the presence of Lewy bodies, multiple sclerosis, amyotrophic lateral sclerosis (ALS), dementia (including vascular dementia, dementia with Lewy bodies, Parkinson's dementia and frontotemporal dementia), psychosis (including anxiety due to neurodegenerative disease or associated with dopamine therapy, e.g., Parkinson's psychosis, Alzheimer's psychosis, psychosis in dementia with Lewy bodies (but not limited to), dyskinesia (including anxiety due to or associated with dopamine therapy), anxiety (including anxiety due to or associated with a neurodegenerative disease). with dopamine therapy), a condition associated with dopamine therapy (including myodystonia, myoclonus, or tremor), synuclein disease, disease associated with abnormal α-synuclein expression, ischemic cerebral disease, Creutzfeldt-Jakob disease, Machado-Joseph disease, or spino - cerebellar ataxia, or Pick's disease.

The liver disease may be metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, infectious agent-induced liver disease, inflammatory liver disease, immune system dysfunction-mediated liver disease or dyslipidemia.

The skin disease may be a keloid disease, psoriasis or leukoplakia, and the retinal disease may be retinal fibrosis, macular degeneration, diabetic retinopathy, diabetic macular degeneration, retinopathy of prematurity, retinal injury associated with ischemic reperfusion, retinitis pigmentosa, cataracts or neovascular glaucoma.

Mitochondrial disorder may be genetic mitochondrial disorder, Alpers disease, Barth syndrome, chronic progressive extrinsic ocular palsy (CPEO), long-chain acyl-CoA dehydrogenase deficiency (LCAD), MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), hereditary optic Leber's neuropathy (LHON), Leigh's disease, Leigh's syndrome, Luft's disease, Pearson's syndrome, neuropathy, ataxia and retinitis pigmentosa (NARP), Co-Q10 deficiency, MERRF syndrome (MERRF - myoclonic epilepsy with broken red fibers)), mitochondrial wasting syndrome DNA (MDS), lethal infantile cardiomyopathy (LIC), mitochondrial neurogastrointestinal encephalomyopathy, beta-oxidation defect, Friedreich's Ataxia FA, Kearns-Sayre syndrome (KSS) or lactic acidosis.

The neurological disorder may be bipolar disorder, developmental disorder, autism, Asperger's syndrome, Rett's disorder, visual impairment, optical neuropathy, attention disorder hyperactivity disorder (ADHD), epilepsy, mood disorder, Tourette's syndrome or schizophrenia or the like. The muscle disease may be a myopathy, muscular dystrophy, cardiomyopathy, encephalomyopathy or spinal muscular atrophy or the like.

In another aspect of the present invention, there is provided a pharmaceutical composition comprising a therapeutically effective dose of a compound of chemical formula I as defined above, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, and a pharmaceutically acceptable carrier.

In the composition of the present invention, the compound or a pharmaceutically acceptable salt or solvate or stereoisomer thereof is as described above.

In the composition of the present invention, a "pharmaceutically acceptable carrier" is a substance, usually an inert substance, used in combination with an active ingredient to facilitate the use of the active ingredient. The carrier includes a conventional pharmaceutically acceptable excipient, additive or diluent. The carrier may contain one or more selected, for example, from the following: filler, binder, disintegrant, buffer, preservative, antioxidant, glidant, flavoring agent, thickener, coloring agent, emulsifier, suspending agent, stabilizer, pH-regulating agent and isotonic agent .

As the diluent, sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salt, clay, polyethylene glycol, anhydrous calcium phosphate or a mixture thereof or the like can be used; and starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, fructose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose, hydroxypropylcellulose, natural gum can be used as a binder , synthetic gum gelatin or a mixture thereof or the like.

As the disintegrant, starch or modified starch such as sodium gluconic acid modified starch, corn starch, potato starch, pregelatinized starch or the like can be used; clay such as bentonite, montmorillonite or vigum or the like; cellulose such as microcrystalline cellulose, hydroxypropyl cellulose or carboxyl methyl cellulose or the like; algins such as sodium alginate or alginate or the like; cross-linked celluloses such as croscarmellose or the like; gums such as guar gum, xanthan gum or the like; cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone) or the like; effervescent agents such as sodium bicarbonate, citrate or the like. or mixtures thereof.

As the lubricant, talc, stearate, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl monolaurate, glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide or mixtures thereof or the like can be used.

As the pH adjusting agent, acidifying agents such as acetate, ascorbic acid, sodium ascorbate, sodium esteric acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citrate), and alkalizing agents such as such as precipitated calcium carbonate, ammonia water, meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate and tribasic calcium phosphate and the like.

Dibutylated hydroxytoluene, butylated hydroxyanisole, tocopheryl acetate, tocopherol, propyl gallate, sodium bisulfite, sodium pyrosulfite, etc. can be used as an antioxidant. In the preceding category of the present invention, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid esters such as polysorbate, sodium docusate, poloxamer or the like can be used as the solubilizer.

In addition, an enteric polymer, a water-insoluble polymer, a hydrophobic compound and a hydrophilic polymer may be included in the composition to obtain a sustained release agent.

Enteric polymer refers to a polymer that is insoluble or stable under acidic conditions at pH less than 5 and dissolves or degrades under specific conditions of pH 5 or greater and, for example, includes enteric cellulose derivatives such as hypromellose acetate succinate, hypromellose phthalate (hydroxypropyl methylcellulose phthalate) , hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose succinate acetate, cellulose acetate malate, cellulose phthalate benzoate, cellulose phthalate propionate, methylcellulose phthalate, carboxymethylethylcellulose phthalate and ethylhydroxyethylcellulose, methylhydroxyethylcellulose; enteric acrylate copolymers such as styrene-acrylate copolymer, acrylate-methyl acrylate copolymer, acrylate-methyl methacrylate copolymer (eg, aryl-is), butyl acrylate-styrene-acrylate copolymer, and methyl acrylate-methacrylate-octyl acrylate copolymer; enteric polymethacrylate copolymers such as poly(methacrylate-methyl methacrylate) copolymer (eg Eudragit L, Eudragit S, Evonik, Germany), poly(methacrylate ethyl acrylate) copolymer (eg Eudragit L100-55); enteric maleic acid copolymers such as anhydrous vinyl acetate-maleic acid anhydride copolymer, styrene-maleic acid copolymer, styrene-maleic acid-monoesterol copolymer, vinyl methyl ether-maleic acid anhydride copolymer, ethylene-maleic acid anhydride copolymer, vinyl butyl ether-maleic acid copolymer einic acid anhydride, acrylonitrile-methylacrylate-maleic acid copolymer anhydride and butyl acrylate-styrene-maleic acid copolymer anhydride; and enteric polyvinyl derivatives such as polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinyl butylate phthalate and polyvinyl acetate phthalate.

Water-insoluble polymer refers to a pharmaceutically acceptable drug release controlling polymer that is insoluble in water. For example, the water-insoluble polymer includes polyvinyl acetate (e.g., Kollicoat SR30D), water-insoluble polymethacrylate copolymer [e.g., poly(ethyl acrylate-methyl methacrylate) copolymer (e.g., Eudragit NE30D, poly(ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer (e.g., Eudragit RSPO ) etc.), methylcellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate, etc.

A hydrophobic compound refers to a pharmaceutically acceptable substance that controls the release of a drug that is insoluble in water. For example, it includes fatty acid and fatty acid esters such as glyceryl palmitostearate, glyceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl monooleate and stearate; fatty alcohols such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; wax such as carnauba wax, cera and microcrystalline wax; and minerals such as talc, precipitated calcium carbonate, calcium hydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and veegum and the like.

Hydrophilic polymer refers to a pharmaceutically acceptable polymeric substance that controls the release of a drug that is soluble in water. For example, it includes saccharides such as dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin; cellulose derivatives such as hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose and sodium carboxymethylcellulose; gums such as guar gum, locust bean gum, tragacanth, carrageenan, gum arabic, acacia gum, gellan gum and xanthan gum; proteins such as gelatin, casein and zein; polyvinyl derivatives such as polyvinyl alcohol, polyvinylpyrrolidone and polyvinylacetal diethylaminoacetate; hydrophilic polymethacrylate copolymers such as poly(butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate) copolymer (e.g. Eudragit E100, Evonik, Germany), poly(ethyl acrylate-methyl methacrylate-triethylaminoethyl-methacrylate chloride) copolymer (e.g. Eudragit RL, RS , Evonik, Germany); polyethylene derivatives such as polyethylene glycol and polyethylene oxide; carbomer, etc.

In addition, as various additives selected from coloring agents and flavoring agents, the composition of the present invention can be prepared by selecting and using a pharmaceutically acceptable additive.

In the present invention, the range of additives is not limited to the use of the above additives, and a composition containing a dose in the usual range can be prepared by selecting the above additive.

The pharmaceutical composition of the present invention can be used as prepared in the form of an oral composition such as powder, granule, tablet, capsule, suspension, emulsion, syrup and aerosol, and an external preparation, suppository or sterile injection solution.

The composition of the present invention can be administered orally or parenterally, including intravenous, intraperitoneal, subcutaneous, intrarectal and topical administration.

In another aspect of the present invention, there is provided a method of treating a disease in a subject, comprising administering to the subject a therapeutically effective dose of a compound of chemical formula I or a pharmaceutically acceptable salt, or solvate, or stereoisomer thereof.

In the method, those skilled in the art can appropriately select the route of administration according to the condition of the patient. Administration may be oral or parenteral. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intracranial and local administration.

In the method, the dose may be varied differently depending on various factors such as the condition of the patient, the route of administration, the judgment of the family physician and the like. The effective dose can be estimated from a dose-response curve obtained from an in vitro experiment or testing in an animal model. The proportion and concentration of the compound of the present invention present in the composition to be administered may be determined depending on the chemical properties, route of administration, therapeutic dose and the like. The dosage may be administered to a subject at an effective dose of from about 1 μg/kg to about 1 g/kg/day or from about 0.1 mg/kg to about 500 mg/kg/day. The dosage may be adjusted depending on the subject's age, body weight, sensitivity or symptoms.

Moreover, a pharmaceutical composition containing a compound of the present invention or a stereoisomer thereof, a solvate thereof, an isotopic variant thereof, a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient can be used in a method of preventing or treating a disease selected from the group consisting of cancer ; inflammatory diseases selected from rheumatoid arthritis, osteoarthritis, pneumonia, hepatitis, inflammatory colorectal disease, intestinal enteritis, glomerulonephritis, gastritis, vasculitis, pancreatitis, peritonitis, bronchitis, cardiomyositis, encephalitis, allergic contact dermatitis, diabetic inflammation, infectious inflammation and autoimmune disease; fibrotic diseases selected from hepatic fibrosis, cirrhosis, small intestinal fibrosis, colonic fibrosis, gastric fibrosis, pulmonary fibrosis, skin fibrosis, epidermal fibrosis, dermal sclerosis/systemic sclerosis, cardiac fibrosis and renal fibrosis; neurodegenerative diseases selected from Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Alzheimer's disease, multiple sclerosis, ischemic and traumatic brain injury; neurological diseases selected from bipolar disorder, developmental disorder, autistic disorder, Asperger's syndrome, Rett syndrome, visual impairment, optical neuropathy, attention deficit hyperactivity disorder (ADHD), epilepsy, mood disorder, Tourette's syndrome and schizophrenia; liver diseases; skin diseases; mitochondrial disorders selected from genetic mitochondrial disorder, Alpers disease, Barth syndrome, progressive extrinsic ocular palsy (CPEO), long-chain acyl-CoA dehydrogenase deficiency (LCAD), MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes), hereditary optic neuropathy Leber's disease (LHON), Leigh's disease, Leigh's syndrome, Luft's disease, Pearson's syndrome, neuropathy, ataxia and retinitis pigmentosa (NARP), Co-Q10 deficiency, MERRF syndrome (MERRF), mitochondrial DNA depletion syndrome (MDS), lethal infantile cardiomyopathy ( LIC), mitochondrial neurogastrointestinal encephalomyopathy, beta-oxidation defect, Friedreich's Ataxia FA, Kearns-Sayre syndrome (KSS), or lactic acidosis; aging; chronic alcoholism; stem cell dysfunction; lameness; metabolic syndromes selected from obesity, diabetes, high blood pressure, hyperlipidemia, arteriosclerosis, peripheral vascular disease, ischemic perfusion, myocardial infarction and stroke; Down syndrome; infertility; overproduction of lipid peroxides in tissue; muscle diseases selected from myopathy, muscular dystrophy, myocardiopathy, encephalomyopathy and back muscle atrophy; accumulation of lipid peroxides in cell membranes; chronic fatigue; and retinal diseases selected from retinal fibrosis, macular degeneration, diabetic retinopathy, cataracts and neovascular glaucoma, comprising administering it to a subject in need thereof.

PRINCIPLE OF THE INVENTION

Examples

Hereinafter, the present invention will be described in more detail with the help of examples. These examples are intended to more specifically illustrate the present invention, and those skilled in the art will appreciate that the scope of the present invention is not limited to these examples.

Supporting Example: Preparation of Intermediates 1-3

Intermediate 1: Preparation of methyl 8-oxo-1,4-dioxaspiro[4,5]decane-7-carboxylate

4-Dioxaspiro[4.5]decan-8-one (10.0 g, 64 mmol) was dissolved in 250 ml of tetrahydrofuran and then sodium hydride (1.84 g, 77 mmol, 1.2 eq.) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then dimethyl carbonate (11.5 g, 128 mmol, 2 eq.) was added. After stirring at room temperature for 12 hours, 200 ml of saturated aqueous ammonium chloride solution was added to the reaction mixture. The reaction mixture was extracted with ethyl acetate (100 ml×3) and salt water and dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 18/1) to give the title compound (6.94 g, 56%) as a colorless oil.

^1H NMR (400 MHz, CDCl ₃ ): δ 12.19 (s, 1H), 4.04 (s, 4H), 3.79 (s, 3H), 2.60-2.50 (m, 4H), 2.30-2.05 (m, 1H) , 1.88 (t, J=4.8 Hz, 2H).

4-Dioxaspiro[4.5]decan-8-one (15.0 g, 96.04 mmol) was dissolved in 250 ml of anhydrous tetrahydrofuran and then sodium hydride (9.22 g, 192.08 mmol, 2 eq.) was added at room temperature temperature. The reaction mixture was refluxed at 50°C for 30 minutes and then dimethyl carbonate (17.3 g, 192.08 mmol, 2 eq.) was added. The reaction mixture was refluxed for 4 hours, then cooled to room temperature and then neutralized at 0°C with 2M aqueous hydrochloric acid. The reaction mixture was extracted with ethyl acetate (100 ml×3) and salt water, dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to give the title compound as a white solid (18.10 g, 88%).

Intermediate 2: Preparation of 2'-(pyridin-2-yl)-2,'4,'6,'7'-tetrahydrospiro[[1,3]dioxolan-2,5'-indazol]-3'-ol

Methyl 8-oxo-1,4-dioxaspiro[4,5]decane-7-carboxylate (2.0 g, 10.3 mmol) was dissolved in 20 ml ethanol and then 2-hydrazinylpyridine (1.1 g, 10 .3 mmol, 1.0 eq.). The reaction mixture was refluxed for 12 hours and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (1.5 g, 54%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.56 (s, 1H), 8.41 (t, J=4.8 Hz, 2H), 7.88 (t, J=8.0 Hz, 1H), 7.19 (t, J=6.0 Hz, 1H), 3.95-3.90 (m, 4H), 2.60-2.52 (m, 2H), 2.38-2.33 (m, 2H), 1.89-1.84 (m, 2H).

Methyl 8-oxo-1,4-dioxaspiro[4,5]decane-7-carboxylate (18.1 g, 84.53 mmol) was dissolved in 120 ml ethanol and then 2-hydrazinylpyridine (9.22 g, 84 .53 mmol, 1.0 eq.). The reaction mixture was refluxed at 100°C for 4 hours and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (16.39 g, 71%).

Intermediate 3: Preparation of 3-hydroxy-2-pyridin-2-yl-2,4,6,7-tetrahydroindazol-5-one

2'-(Pyridin-2-yl)-2',4',6',7'-tetrahydrospiro[[1,3]dioxolan-2,5'-indazol]-3'-ol (5.0 g, 18.3 mmol, 1.0 eq.) was dissolved in 40 ml of dichloromethane and then trifluoroacetate (80 ml) was added. The reaction mixture was refluxed at 50°C for 12 hours and then concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane and then adjusted to pH 6 using sodium bicarbonate. The reaction mixture was extracted with dichloromethane and water, then dried using sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane/methanol = 20/1) to give the title compound as a brown solid (2.3 g, 54.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.48-8.40 (m, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.00-7.90 (m, 1H), 7.25-7.22 ( m, 1H), 3.09 (s, 2H), 2.93 (t, J=6.8 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H). MS (mass spectrometry): Calc: 229.2; MC: Found: 230.2 ([M+H] ⁺ ).

2'-(Pyridin-2-yl)-2',4',6',7'-tetrahydrospiro[[1,3]dioxolan-2,5'-indazol]-3'-ol (12.99 g, 47.56 mmol) was dissolved in 120 ml of dichloromethane and then trifluoroacetate (240 ml) was added. The reaction mixture was refluxed at 60°C for 12 hours and then concentrated under reduced pressure. The reaction mixture was recrystallized from diethyl ether to give the title compound as a light brown solid (10.88 g, 99%).

Synthesis examples

Synthesis example 1. Preparation of methyl 8-oxo-1,4-dioxaspiro[4,5]decane-7-carboxylate

4-Dioxaspiro[4.5]decan-8-one (10.0 g, 64 mmol) was dissolved in 250 ml tetrahydrofuran and then sodium hydride (1.84 g, 77 mmol, 1.2 eq.) was added at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then dimethyl carbonate (11.5 g, 128 mmol, 2 eq.) was added. After stirring at room temperature for 12 hours, 200 ml of saturated aqueous ammonium chloride solution was added to terminate the reaction. The reaction mixture was extracted with ethyl acetate (100 ml×3) and salt water, dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 18/1) to give the title compound as a colorless oil (6.94 g, 56%).

^1H NMR (400 MHz, CDCl ₃ ): δ 12.19 (s, 1H), 4.04 (s, 4H), 3.79 (s, 3H), 2.60-2.50 (m, 4H), 2.30-2.05 (m, 1H) , 1.88 (t, J=4.8 Hz, 2H).

4-Dioxaspiro[4.5]decan-8-one (15.0 g, 96.04 mmol) was dissolved in 250 ml of anhydrous tetrahydrofuran and then sodium hydride (9.22 g, 192.08 mmol, 2 eq.) was added at room temperature temperature. The reaction mixture was refluxed at 50°C for 30 minutes and then dimethyl carbonate (17.3 g, 192.08 mmol, 2 eq.) was added. The reaction mixture was refluxed for 4 hours, then cooled to room temperature and then neutralized at 0°C with 2M aqueous hydrochloric acid. The reaction mixture was extracted with ethyl acetate (100 ml×3) and salt water, dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1) to give the title compound as a white solid (18.10 g, 88%).

Synthesis example 2. Preparation of 2'-(pyridin-2-yl)-2',4',6',7'-tetrahydrospiro[[1,3]dioxolan-2,5'-indazol]-3'-ol

Methyl 8-oxo-1,4-dioxaspiro[4,5]decane-7-carboxylate (2.0 g, 10.3 mmol) was dissolved in 20 ml ethanol and then 2-hydrazinylpyridine (1.1 g, 10 .3 mmol, 1.0 eq.). The reaction mixture was refluxed for 12 hours and then concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (1.5 g, 54%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.56 (s, 1H), 8.41 (t, J=4.8 Hz, 2H), 7.88 (t, J=8.0 Hz, 1H), 7.19 (t, J=6.0 Hz, 1H), 3.95-3.90 (m, 4H), 2.60-2.52 (m, 2H), 2.38-2.33 (m, 2H), 1.89-1.84 (m, 2H).

Methyl 8-oxo-1,4-dioxaspiro[4,5]decane-7-carboxylate (18.1 g, 84.53 mmol) was dissolved in 120 ml ethanol and then 2-hydrazinylpyridine (9.22 g, 84 .53 mmol, 1.0 eq.). The reaction mixture was refluxed at 100°C for 4 hours. The residue was recrystallized from ethyl acetate to give the title compound as a yellow solid (16.39 g, 71%).

Synthesis Example 3: Preparation of 3-hydroxy-2-pyridin-2-yl-2,4,6,7-tetrahydroindazol-5-one

2'-(Pyridin-2-yl)-2',4',6',7'-tetrahydrospiro[[1,3]dioxolan-2,5'-indazol]-3'-ol (5.0 g, 18.3 mmol, 1.0 eq.) was dissolved in 40 ml of dichloromethane and then trifluoroacetate (80 ml) was added. The reaction mixture was refluxed at 50°C for 12 hours and then concentrated under reduced pressure. The reaction mixture was diluted with dichloromethane and then adjusted to pH 6 using dichloromethane and water. The reaction mixture was extracted with dichloromethane and water, then dried using sodium sulfate and filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane/methanol = 20/1) to give the title compound as a yellow solid (2.3 g, 54.9%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.48-8.40 (m, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.00-7.90 (m, 1H), 7.25-7.22 ( m, 1H), 3.09 (s, 2H), 2.93 (t, J=6.8 Hz, 2H), 2.62 (t, J=6.8 Hz, 2H). MC: Calculated: 229.2; MC: Found: 230.2 ([M+H] ⁺ ).

2'-(Pyridin-2-yl)-2',4',6',7'-tetrahydrospiro[[1,3]dioxolan-2,5'-indazol]-3'-ol (12.99 g, 47.56 mmol) was dissolved in 120 ml of dichloromethane and then trifluoroacetate (240 ml) was added. The reaction mixture was recrystallized from diethyl ether to give the title compound as a light brown solid (10.88 g, 99%).

Synthesis Example 4: Preparation of 5-(benzylpropylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 21)

3-Hydroxy-2-pyridin-2-yl-2,4,6,7-tetrahydroindazol-5-one (500 mg, 2.18 mmol, 1.0 eq.) was dissolved in 30 ml dichloromethane and then under a stream of nitrogen tert-butyldimethylsilyl chloride (494 mg, 3.27 mmol, 1.5 eq) and triethylamine (0.6 mL, 4.36 mmol, 2.0 eq) were added slowly. The reaction mixture was stirred at room temperature for 12 hours and then extracted with water and salt water. The organic layer was dried using anhydrous sodium sulfate, and then the mixture was used in the next step without further purification.

To the resulting compound was added N-benzylpropan-1-amine (649 mg, 4.36 mmol, 2.0 eq.), sodium triacetoxyborohydride (1.39 g, 6.54 mmol, 3.0 eq. ) and acetate (4 drops), and then the mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the reaction mixture to adjust the pH to about 8, and then it was extracted with dichloromethane (30 ml x 3). The organic layer was dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was first purified through a silica gel column (solvent: dichloromethane/methanol = 20/1) to give Mixture 6 (400 mg). The initially purified mixture was purified secondarily by separation high performance liquid chromatography to obtain the title compound as a yellow solid (104 mg, 13.1%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.40 (s, 1H), 8.15-8.11 (m, 1H), 8.08-8.01 (m, 1H), 7.56-7.53 (m, 2H), 7.41 (s , 3H), 7.34 (t, J=6.4 Hz, 1H), 4.58-4.51 (m, 1H), 4.38-4.31 (m, 1H), 3.72-3.68 (m, 1H), 3.25-3.18 (m , 1H), 3.15-2.83 (m, 3H), 2.80-2.70 (m, 2H), 2.50-2.42 (m, 1H), 2.20-2.08 (m, 1H), 1.75-1.60 (m, 1H), 1.60 -1.57 (m, 1H), 0.90-0.81 (m, 3H). MS: Calculated: 362.2; MS: Found: 363.3 ([M+H] ⁺ ).

Synthesis Example 5: Preparation of 5-(benzylethylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 20)

Based on the preparation method of Compound 21, the title compound was obtained as a yellow solid (120 mg, 15.8%).

^1H NMR (400 MHz, CD ₃ OD): δ 9.55-9.40 (m, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.40-8.30 (br, 1H), 7.92 (t, J =8.0 Hz, 1H), 7.60-7.45 (m, 4H), 7.23 (t, J=6.8 Hz, 1H), 4.68 (t, J=13.6 Hz, 1H), 4.50-4.44 ( m, 1H), 3.90-3.86 (m, 1H), 3.47-3.37 (m, 2H), 3.20-3.02 (m, 2H), 2.95-2.90 (m, 2H), 2.60-2.50 (m, 1H), 2.35-2.25 (m, 1H), 1.47-1.37 (m, 3H). MC: Calculated: 347.5; MC: Found: 349.2 ([M+H] ⁺ ).

Synthesis Example 6: Preparation of 5-(benzylbutylamino)-2-pyrizin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 22)

Based on the preparation method of Compound 21, the title compound was obtained as a yellow solid (100 mg, 12.1%).

^1H NMR (400 MHz, CD ₃ OD): δ 9.55-9.40 (m, 1H), 8.42 (d, J=4.0 Hz, 1H), 8.40-8.30 (br, 1H), 7.92 (t, J =8.0 Hz, 1H), 7.60-7.45 (m, 5H), 7.23 (t, J=6.8 Hz, 1H), 4.61-4.50 (m, 1H), 4.40-4.35 (m, 1H), 3.66-3.50 (m, 2H), 3.30-3.15 (m, 2H), 3.10-2.90 (m, 1H), 2.80-2.55 (m, 4H), 2.45-2.30 (m, 1H), 2.15-1.80 (m , 1H), 1.75-1.60 (m, 1H), 1.60-1.40 (m, 1H), 1.35-1.22 (m, 3H). MS: Calculated: 376.2; MS: Found: 377.2 ([M+H] ⁺ ).

Synthesis Example 7: Preparation of 5-[(2-methoxybenzyl)-methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 26)

3-Hydroxy-2-pyridin-2-yl-2,4,6,7-tetrahydroindazol-5-one (500 mg, 2.18 mmol, 1.0 eq.) was dissolved in 30 ml of dichloromethane and then 1- (2-methoxyphenyl)-N-methylmethanamine (658 mg, 4.36 mmol, 2.0 eq.), sodium triacetoxyborohydride (1.39 g, 6.54 mmol, 3.0 eq.) and 4 drops of acetate. The reaction mixture was stirred at room temperature for 12 hours. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the reaction mixture, and then it was extracted with dichloromethane (50 ml x 2). After washing the organic layer with salt water, it was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by separation high performance liquid chromatography to give the title compound as a yellow solid (200 mg, 34.0%). Compounds 39-60, 64-68, 72-76, 78-81, 121-125, 146-153 and 157-159 were prepared by the above method.

¹ H NMR (400 MHz, CD ₃ OD): δ 8.56 (d, J=5.2 Hz, 1H), 8.30-8.22 (m, 2H), 7.59-7.52 (m, 3H), 7.19 (d, J =8.4 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 4.78 (dd, J ₁ =12.8 Hz, J ₂ =19.2 Hz, 1H), 4.20 (dd, J ₁ =12.8 Hz, J ₂ =27.6 Hz, 1H), 4.00 (s, 3H), 3.90-3.85 (m, 1H), 3.15-3.08 (m, 2H), 3.00-2.85 (m, 5H) , 2.60-2.50 (m, 1H), 2.40-2.10 (m, 1H). MC: Calculated: 364.2; MC: Found: 365.3 ([M+H] ⁺ ).

Synthesis Example 8. Preparation of 5-(benzylmethylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 1)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (200 mg, 27.4%)

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 10.8-10.50 (br, 1H), 8.45-8.38 (m, 2H), 7.88 (t, J=11.2 Hz, 1H), 7.40-7.15 ( m, 6H), 3.63 (q, J ₁ =18.4 Hz, J ₂ =34.4 Hz, 2H), 2.80-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.52-2.50 ( m, 1H), 2.48-2.30 (m, 1H), 2.31-2.25 (m, 1H), 2.16 (s, 3H), 2.05-1.85 (m, 1H), 1.71-1.65 (m, 1H). MS: Calculated: 334.2; MS: Found: 335.2 ([M+H] ⁺ ).

Synthesis Example 9. Preparation of 5-(benzylcyclopropylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 2)

Based on the preparation method of Compound 26, the title compound was obtained as a yellow solid (94 mg, 11.9%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.39 (s, 1H), 8.42-8.37 (m, 2H), 7.92-7.85 (m, 1H), 7.31-7.15 (m, 6H), 3.82 ( s, 2H), 2.80-2.70 (m, 1H), 2.60-2.52 (m, 1H), 2.50-2.35 (m, 2H), 2.13-2.00 (m, 2H), 1.77-1.72 (m, 1H), 0.48-0.43 (m, 2H), 0.30-0.26 (m, 2H). MS: Calculated: 360.2; MS: Found: 361.0 ([M+H] ⁺ ).

Synthesis Example 10. Preparation of 4-{[(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)methylamino]methyl}benzonitrile (Compound 3)

Based on the preparation method of Compound 26, the title compound was obtained as a yellow solid (103 mg, 16.4%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 8.40 (s, 1H), 7.96-7.60 (m, 4H), 7.60-7.55 (m, 2H), 7.22-7.18 (m, 0.5H), 6.95 -6.90 (m, 0.5H), 3.80-3.62 (m, 2H), 2.90-2.75 (m, 1H), 2.75-2.60 (m, 2H), 2.50-2.22 (m, 2H), 2.21-2.04 (m , 3H), 2.05-1.92 (m, 1H), 1.75-1.62 (m, 1H). MC: Calculated: 359.4; MS: Found: 360.2 ([M+H] ⁺ ).

Synthesis Example 11. Preparation of 5-[(4-fluorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 4)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (189 mg, 30.8%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 8.40-8.33 (m, 2H), 7.90-7.83 (m, 1H), 7.40-7.30 (m, 2H), 7.22-7.10 (m, 3H), 3.58 (q, J ₁ =13.6 Hz, J ₂ =30.0 Hz, 2H), 2.75-2.60 (m, 2H), 2.50-2.22 (m, 1H), 2.21-2.04 (m, 1H), 2.15 (s, 3H), 2.03-1.96 (m, 1H), 1.68-1.52 (m, 1H). MS: Calculated: 352.2; MS: Found: 353.1 ([M+H] ⁺ ).

Synthesis Example 12: Preparation of 5-[(2,4-difluorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 5)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (150 mg, 23.3%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.60-11.45 (br, 1H), 8.50-8.36 (m, 2H), 7.96-7.92 (m, 1H), 7.46 (q, J ₁ =11, 2 Hz, J ₂ =20.4 Hz, 2H), 7.22-7.16 (m, 2H), 7.10-7.05 (m, 1H), 3.63 (q, J ₁ =9.6 Hz, J ₂ =28.0 Hz, 2H), 2.75-2.60 (m, 2H), 2.60-2.50 (m, 1H), 2.50-2.42 (m, 1H), 2.42-2.20 (m, 1H), 2.20 (s, 3H), 2.03- 1.96 (m, 1H), 1.72-1.68 (m, 1H). MC: Calculated: 370.2; MC: Found: 371.1 ([M+H] ⁺ )

Synthesis Example 13: Preparation of 5-[(2-chlorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 6)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (270 mg, 42.0%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.60-11.45 (br, 1H), 8.50-8.38 (m, 2H), 7.92-7.90 (m, 1H), 7.53 (d, J=7.2 Hz, 1H), 7.42 (d, J=7.6 Hz, 1H), 7.40-7.35 (m, 1H), 7.35-7.30 (m, 1H), 7.20-7.17 (m, 1H), 3.76-3.68 ( m, 2H), 2.85-2.70 (m, 2H), 2.65-2.55 (m, 1H), 2.55-2.50 (m, 1H), 2.42-2.20 (m, 2H), 2.20 (s, 3H), 2.03- 1.96 (m, 1H), 1.72-1.68 (m, 1H). MC: Calculated: 368.9; MC: Found: 369.1 ([M+H] ⁺ )

Synthesis Example 14: Preparation of 5-[(3-chlorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 7)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (150 mg, 23.4%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.50-11.42 (br, 1H), 8.50-8.38 (m, 2H), 7.90-7.80 (m, 1H), 7.40-7.23 (m, 4H), 7.30-7.23 (m, 1H), 3.65 (q, J ₁ =14.0 Hz, J ₂ =32.0 Hz, 2H), 2.85-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.55-2.50 (m, 1H), 2.42-2.20 (m, 1H), 2.20 (s, 3H), 2.03-1.96 (m, 1H), 1.68-1.60 (m, 1H). MC: Calculated: 368.1; MC: Found: 369.1 ([M+H] ⁺ )

Synthesis Example 15: Preparation of 5-[methyl-(4-trifluoromethylbenzyl)amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 8)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (304 mg, 43.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ11.43 (s, 1H), 8.44-8.38 (m, 2H), 7.92-7.90 (m, 1H) 7.67 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.0 Hz, 2H), 7.17 (t, J=5.6 Hz, 1H), 3.70 (q, J ₁ =14.4 Hz, J ₂ =31.2 Hz , 2H), 2.85-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.55-2.50 (m, 1H), 2.42-2.30 (m, 1H), 2.30-2.20 (m, 1H), 2.20 (s, 3H), 2.03-1.96 (m, 1H), 1.72-1.68 (m, 1H). MC: Calculated: 402.4; MC: Found: 403.1 ([M+H] ⁺ )

Synthesis Example 16. Preparation of 5-[methyl-(3-methylbenzyl)amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 9)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (103 mg, 17.0%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.43 (s, 1H), 8.44-8.38 (m, 2H), 7.92-7.90 (m, 1H), 7.21-7.04 (m, 4H), 7.04- 7.02 (m, 1H), 3.60-3.48 (m, 2H), 2.80-2.72 (m, 1H), 2.70-2.66 (m, 1H), 2.48-2.40 (m, 1H), 2.29 (s, 3H), 2.20-2.16 (m, 1H), 2.19 (s, 3H), 2.03-1.96 (m, 2H), 1.70-1.62 (m, 1H). MS: Calculated: 348.4; MS: Found: 349.2 ([M+H] ⁺ )

Synthesis Example 17. Preparation of 5-[methyl-(3-trifluoromethylbenzyl)-amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 10)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (292 mg, 57.5%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.43 (s, 1H), 8.44-8.38 (m, 2H), 7.92-7.90 (m, 1H), 7.71-7.52 (m, 4H), 7.19- 7.16 (m, 1H), 3.70 (q, J ₁ =12.0 Hz, J ₂ =30.4 Hz, 2H), 2.85-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.55- 2.50 (m, 1H), 2.45-2.20 (m, 2H), 2.20 (s, 3H), 2.03-1.96 (m, 1H), 1.73-1.68 (m, 1H). MS: Calculated: 402.4; MS: Found: 403.2 ([M+H] ⁺ )

Synthesis Example 18. Preparation of 5-[methyl-(2-trifluoromethylbenzyl)-amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 11)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (117 mg, 16.7%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.52-11.47 (br, 1H), 8.50-8.38 (m, 2H), 7.89-7.83 (m, 2H), 7.70-7.65 (m, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.18 (br, 1H), 3.80 (q, J ₁ =10.0 Hz, J ₂ =25.0 Hz, 2H), 2.86-2.70 (m, 1H), 2.65-2.55 (m, 1H), 2.53-2.50 (m, 1H), 2.42-2.31 (m, 1H), 2.29-2.20 (m, 1H), 2.20 (s, 3H), 2.05-1.96 ( m, 1H), 1.72-1.68 (m, 1H). MS: Calculated: 402.4; MS: Found: 403.1 ([M+H] ⁺ )

Synthesis Example 19. Preparation of 5-[(4-methanesulfonylbenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 12)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (100 mg, 11.1%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.45 (s, 1H), 8.44-8.38 (m, 2H), 7.89 (d, J=8.0 Hz, 3H), 7.60 (d, J= 8.0 Hz, 2H), 7.19-7.16 (m, 1H), 3.72 (q, J ₁ =14.8 Hz, J ₂ =31.2 Hz, 2H), 3.19 (s, 3H), 2.84-2.80 (m, 1H), 2.65-2.55 (m, 1H), 2.55-2.50 (m, 1H), 2.42-2.32 (m, 1H), 2.28-2.20 (m, 1H), 2.20 (s, 3H), 2.05 -1.98 (m, 1H), 1.72-1.68 (m, 1H). MS: Calculated: 412.1; MS: Found: 413.1 ([M+H] ⁺ )

Synthesis Example 20: Preparation of 5-[(3-methanesulfonylbenzyl)methylamino]-2-1-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 23)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (50 mg, 5.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.51-8.30 (m, 2H), 7.95-7.85 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.25-7.15 (m, 1H), 3.76 (dd, J ₁ =14.0 Hz, J ₂ =31, 6 Hz, 2H), 3.21 (s, 3H), 2.90-2.80 (m, 1H), 2.70-2.60 (m, 1H), 2.60-2.50 (m, 1H), 2.50-2.40 (m, 1H), 2.30 -2.15 (m, 4H), 2.10-2.00 (m, 1H), 1.70-1.60 (m, 1H). MC: Calculated: 412.5; MC: Found: 413.1 ([M+H] ⁺ ).

Synthesis Example 21. Preparation of 5-[methyl-(4-methylbenzyl)amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 24)

Based on the preparation method of Compound 26, the title compound was obtained as a bright yellow solid (50 mg, 5.5%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.51-8.50 (m, 1H), 8.35-8.20 (m, 2H), 7.65-7.47 (m, 3H), 7.34 (d, J=8.0 Hz , 2H), 4.63 (t, J=13.2 Hz, 1H), 4.34 (t, J=13.6 Hz, 1H), 3.90-3.70 (m, 1H), 3.20-3.00 (m, 2H), 3.00-2.75 (m, 5H), 2.65-2.52 (m, 1H), 2.41 (s, 3H), 2.25-2.10 (m, 1H). MS: Calculated: 348.2; MS: Found: 349.2 ([M+H] ⁺ ).

Synthesis Example 22. Preparation of 5-[(3-methoxybenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 13)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (105 mg, 13.2%).

^1H NMR (400 MHz, CDCl ₃ ) 5 8.24 (br, 1H), 7.82 (m, 2H), 7.26-7.22 (m, 1H), 7.14-7.02 (m, 1H), 7.00-6.90 (m, 2H ), 6.80-6.75 (m, 1H), 3.85-3.80 (m, 3H), 3.65 (s, 2H), 2.95-2.78 (m, 2H), 2.65-2.52 (m, 2H), 2.50-2.40 (m , 1H), 2.32-2.28 (m, 3H), 2.27-2.16 (m, 1H), 1.72-1.58 (m, 1H). MS: Calculated: 364.2; MS: Found: 365.1 ([M+H] ⁺ )

Synthesis Example 23: Preparation of 5-piperidin-1-yl-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 14)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (70 mg, 10.7%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 9.74 (br, 1H), 8.42 (d, J=4.4 Hz, 1H), 8.35 (d, J=8.0 Hz, 1H), 7.92 (t, J=8.4 Hz, 1H), 7.23 (t, J=6.8 Hz, 1H), 3.60-3.40 (m, 3H), 3.12-3.02 (m, 2H), 2.75-2.60 (m , 3H), 2.55-2.48 (m, 1H), 2.30-2.27 (m, 1H), 1.90-1.70 (m, 6H), 1.50-1.42 (m, 1H). MC: Calculated: 298.2; MC: Found: 299.2 ([M+H] ⁺ )

Synthesis Example 24: Preparation of 5-morpholin-4-yl-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 15)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (80 mg, 11.3%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.65-11. 47 (br, 1H), 8.39-8.33 (m, 2H), 7.89 (t, J=7.2 Hz, 1H), 7.18 (t, J=5.6 Hz, 1H), 3.59-3.53 (m, 4H), 2.60-2.55 (m, 2H), 2.55-2.45 (m, 4H), 2.45-2.40 (m, 1H), 2.20-2.05 (m, 1H), 2.01-1.98 (m, 1H), 1.62- 1.50 (m, 1H). MS: Calculated: 300.4; MS: Found: 301.2 ([M+H] ⁺ )

Synthesis Example 25: Preparation of 5-(4-methylpiperazin-1-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 16)

Based on the preparation method of Compound 26, the title compound was obtained as a gray solid (195 mg, 28.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.42 (d, J=4.4 Hz, 1H), 8.35 (d, J=8.4 Hz, 1H), 7.91 (t, J=7, 6 Hz, 1H), 7.22 (t, J=5.6 Hz, 1H), 3.70-3.20 (br, 9H), 2.88 (s, 3H), 2.74-2.51 (m, 3H), 2.42-2.37 (m , 1H), 2.26-2.23 (m, 1H), 1.82-1.72 (m, 1H). MS: Calculated: 313.4; MS: Found: 314.2 ([M+H] ⁺ )

Synthesis Example 26. Preparation of 5-(3,4-dihydro-1H-isoquinolin-2-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 18)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (120 mg, 16.0%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.47 (s, 1H), 8.44-8.38 (m, 2H), 7.91-7.88 (m, 1H), 7.19-7.16 (m, 1H), 7.10- 7.04 (m, 4H), 3.76 (s, 2H), 2.91-2.50 (m, 7H), 2.50-2.40 (m, 1H), 2.40-2.25 (m, 1H), 2.20-2.02 (m, 1H), 1.78-1.70 (m, 1H). MS: Calculated: 346.2; MS: Found: 347.2 ([M+H] ⁺ )

Synthesis Example 27. Preparation of 3-{[(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)methylamino]methyl}benzonitrile hydrochloride (Compound 25)

Based on the preparation method of Compound 26, the title compound was obtained as a yellow solid (104 mg, 13.3%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.5 (d, J=6.0 Hz, 1H), 8.40-8.32 (m, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.16-8.10 (m, 1H), 8.08-8.00 (m, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.66-7.56 ( m, 1H), 4.80-4.75 (m, 1H), 4.62-4.45 (m, 1H), 4.00-3.80 (m, 1H), 3.25-3.00 (m, 2H), 3.00-2.80 (m, 5H), 2.70-2.60 (m, 1H), 2.30-2.15 (m, 1H). MS: Calculated: 359.1, MS: Found: 360.1 ([M+H] ⁺ ).

Synthesis Example 28. Preparation of 5-[(4-chlorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 19)

Based on the preparation method of Compound 26, the title compound was obtained as a brown solid (144 mg, 22.5%).

^1H NMR (400 MHz, DMSO- _d6 ): δ 11.42 (s, 1H), 8.44-8.38 (m, 2H), 7.87 (m, 1H), 7.39-7.33 (m, 4H), 7.19-7.16 ( m, 1H), 3.72 (q, J ₁ =13.6 Hz, J ₂ =30.4 Hz, 2H), 2.83-2.80 (m, 1H), 2.65-2.55 (m, 1H), 2.55-2.50 ( m, 1H), 2.42-2.32 (m, 1H), 2.28-2.20 (m, 1H), 2.16 (s, 3H), 2.05-1.98 (m, 1H), 1.72-1.68 (m, 1H). MC: Calculated: 368.1; MC: Found: 369.1 ([M+H] ⁺ )

Synthesis Example 29. Preparation of 5-[(3-fluorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 27)

Based on the preparation method of Compound 26, the title compound was obtained as a yellow solid (95 mg, 12.3%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.44 (d, J=5.6 Hz, 1H), 8.25-8.15 (m, 1H), 8.15-8.10 (m, 1H), 7.50-7.45 (m , 2H), 7.39 (d, J=8.4 Hz, 2H), 7.25-7.10 (m, 1H), 4.65-4.55 (m, 1H), 4.40-4.28 (m, 1H), 3.80-3.65 (m , 1H), 3.10-2.90 (m, 2H), 2.85-2.65 (m, 5H), 2.50-2.40 (m, 1H), 2.15-2.00 (m, 1H). MS: Calculated: 352.2; MS: Found: 353.1 ([M+H] ⁺ ).

Synthesis Example 30. Preparation of 5-[(4-methoxybenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 28)

Based on the preparation method of Compound 26, the title compound was obtained as a yellow oil (80 mg, 10.7%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.44 (d, J=5.2 Hz, 1H), 8.30-8.20 (m, 1H), 8.15-8.05 (m, 1H), 7.55-7.40 (m , 3H), 6.94 (d, J=8.4 Hz, 2H), 4.50 (t, J=12.8 Hz, 1H), 4.22 (t, J=14.0 Hz, 1H), 3.76-3.64 ( m, 4H), 3.10-2.93 (m, 2H), 2.92-2.70 (m, 5H), 2.50-2.42 (m, 1H), 2.10-2.00 (m, 1H). MS: Calculated: 364.2; MS: Found: 365.2 ([M+H] ⁺ ).

Synthesis Example 31. Preparation of 5-[methyl-(2-methylbenzyl)amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 29)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (300 mg, 39.5%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.43 (d, J=5.2 Hz, 1H), 8.20-8.10 (m, 2H), 7.50-7.37 (m, 2H), 7.35-7.20 (m , 3H), 4.68 (dd, J ₁ =13.6 Hz, J ₂ =23.6 Hz, 1H), 4.21 (dd, J ₁ =13.2 Hz, J ₂ =32.8 Hz, 1H), 3.90-3.73 (m, 1H), 3.10-2.85 (m, 2H), 2.84-2.65 (m, 5H), 2.51-2.45 (m, 1H), 2.43 (s, 3H), 2.30-2.00 (m, 1H ). MS: Calculated: 348.2; MS: Found: 349.2 ([M+H] ⁺ ).

Synthesis Example 32. Preparation of 5-[(2,4-dichlorobenzyl)methylamino]-2-1 shridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 30)

Based on the preparation method of Compound 26, the title compound was obtained as a white solid (127 mg, 13.3%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.42 (d, J=5.2 Hz, 1H), 8.20-8.07 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H), 7.49-7.35 (m, 2H), 4.78-4.68 (m, 1H), 4.50-4.30 (m, 1H), 3.90-3.70 (m, 1H), 3.10-2.90 (m, 2H), 2.90-2.65 (m, 5H), 2.55-2.45 (m, 1H), 2.30-2.05 (m, 1H). MS: Calculated: 402.1; MS: Found: 403.1 ([M+H] ⁺ ).

Synthesis Example 33. Preparation of 5-[(3,4-dichlorobenzyl)methylamino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol hydrochloride (Compound 31)

Based on the preparation method of Compound 26, the title compound was obtained as a yellow solid (144 mg, 16.4%).

¹ H NMR (400 MHz, CD ₃ OD): δ 8.54 (d, J=5.2 Hz, 1H), 8.30-8.20 (m, 2H), 7.93 (d, J=1.6 Hz, 1H), 7.75-7.60 (m, 2H), 7.58-7.50 (m, 1H), 4.75-4.60 (m, 1H), 4.50-4.35 (m, 1H), 3.95-3.76 (m, 1H), 3.20-3.00 (m , 2H), 3.00-2.77 (m, 5H), 2.62-2.55 (m, 1H), 2.23-2.15 (m, 1H). MS: Calculated: 402.1; MS: Found: 403.1 ([M+H] ⁺ ).

Synthesis Example 34. Preparation of 5-(methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazole -3-ol (Compound 33)

1) Preparation of N-methyl-5,6,7,8-tetrahydroquinoline-8-amine

6,7-Dihydroquinolin-8(5H)-one (2.0 g, 13.59 mmol) was dissolved in 40 ml of dichloroethane and then methylamine (3.39 ml, 27.18 mmol, 2.0 eq) was added and 7 drops of acetate. The reaction mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (5.7 g, 27.18 mmol, 2.0 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours and then a 10% aqueous ammonium chloride solution was added to adjust the pH to approximately 8.0. The reaction mixture was extracted with dichloromethane (60 ml×2), then the organic layer was dried using anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (1.98 g, 90.0%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.33 (d, J=4.1 Hz, 1H), 7.25-7.32 (m, 1H), 7.01 (q, J=4.1 Hz, 1H), 3.66 (m, 1H), 2.73-2.78 (m, 1H), 2.66-2.70 (m, 1H), 2.49 (s, 3H), 2.07-2.11 (hl, 1H), 1.91-1.96 (m, 1H), 1.66 -1.76 (m, 2H).

2) Preparation of 5-(methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3 -ola

3-Hydroxy-2-(pyridin-2-yl)-2,4,6,7-tetrahydro-5H-indazol-5-one (0.03 g, 0.13 mmol) was dissolved in 8 ml of dichloroethane and then added N-methyl-3,6,7,8-tetrahydroquinoline-8-amine (0.02 g, 0.13 mmol, 1.0 eq.) and 2 drops of acetate. The reaction mixture was stirred at room temperature for 1 hour and then sodium cyanoborohydride (0.01 g, 0.16 mmol, 1.2 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours, and then 10% aqueous ammonium chloride was added to adjust the pH to about 8.0. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane/methanol = 5/1+0.1% triethylamine) to give the title compound as a brown solid (0.05 g, 11.0%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.50-8.44 (m, 1H), 8.23-8.17 (m, 1H), 7.90-7.70 (m, 2H), 7.33 (d, J=7.4 Hz, 1H), 7.10-6.97 (m, 2H), 4.20-4.12 (m, 1H), 3.15-2.95 (m, 1H), 2.85-2.77 (m, 3H), 2.71-2.65 (m, 1H), 2.60- 2.42 (m, 2H), 2.29 (s, 3H), 2.27-2.20 (m, 1H), 2.05-1.95 (m, 2H), 1.83-1.67 (m, 3H). MC: Calculated: 375.2; MC: Found: 376.1 ([M+H] ⁺ ).

Synthesis example 35. Preparation of cyclopropyl(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)methanone ( Connection 38)

3-Hydroxy-2-(pyridin-2-yl)-2,4,6,7-tetrahydro-5H-indazol-5-one (2.5 g, 10.9 mmol) was dissolved in 100 ml dichloromethane/dichloroethane (1/1) and then added cyclopropyl(piperazin-1-yl)methanone hydrochloride (3.1 g, 16.4 mmol, 1.5 eq), diisopropylethylamine (2.8 ml, 16.4 mmol, 1. 5 eq.), acetate (1.0 ml, 16.4 mmol, 1.5 eq.). The reaction mixture was stirred at room temperature for 3 hours and then sodium triacetoxyborohydride (4.6 g, 21.8 mmol, 2.0 eq.) was added. The reaction mixture was stirred at room temperature for 48 hours, and then 2 M aqueous sodium hydroxide solution was added to adjust the pH to about 8.0. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was first purified by silica gel column chromatography (dichloromethane/methanol = 5/1) and then recrystallized from diethyl ether to give the title compound as a light brown solid (2.8 g, 70.0%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.23 (d, J=5.5 Hz, 1H), 7.82 (t, J=3.4 Hz, 2H), 7.10 (q, J=4.1 Hz , 1H), 3.74-3.61 (m, 4H), 2.91-2.81 (m, 1H), 2.81-2.52 (m, 8H), 2.44-2.35 (m, 1H), 2.15-2.07 (m, 1H), 1.76 -1.70 (m, 1H), 1.04-0.95 (m, 2H), 0.79-0.70 (m, 2H). MC: Calculated: 367.2; MS: Found: 368.1 ([M+H] ⁺ ).

Synthesis example 36. Preparation of 5-((4-(dimethylamino)benzyl)(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol ( Connection 70)

3-Hydroxy-2-(pyridin-2-yl)-2,4,6,7-tetrahydro-5H-indazol-5-one (0.70 g, 3.04 mmol) was dissolved in 40 ml dichloromethane/dichloroethane (1/1) and then added N,N-dimethyl-4-((methylamino)methyl)aniline (0.50 g, 3.04 mmol, 1.0 eq.) and acetate (0.19 ml, 3. 04 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (0.64 g, 3.04 mmol, 1.0 eq.) was added. The reaction mixture was stirred at room temperature for 18 hours, and then 2 M aqueous sodium hydroxide was added to adjust the pH to about 8.0. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to give the title compound as a black solid (0.094 g, 8.0%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.42-8.34 (m, 1H), 8.25 (d, J=8.8 Hz, 1H), 7.90-7.79 (m, 1H), 7.27 (d, J =9.0 Hz, 2H), 7.18 (dd, J=8.0, 5.4 Hz, 1H), 6.77 (d, J=9.1 Hz, 2H), 4.11 (dd, J=23.9, 13.5 Hz, 2H), 3.55-3.37 (m, 1H), 2.93 (s, 6H), 2.87-2.72 (m, 2H), 2.63 (s, 3H), 2.58-2.47 (m, 2H), 2.34-2.25 ( m, 1H), 2.02-1.92 (m, 1H). MS: Calculated: 377.2; MS: Found: 378.3 ([M+H] ⁺ ).

Synthesis Example 37: Preparation of 2-pyridin-2-yl-5-pyrrolidin-1-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 96)

3-Hydroxy-2-(pyridin-2-yl)-2,4,6,7-tetrahydro-5H-indazol-5-one (0.30 g, 1.30 mmol) was dissolved in 10 ml dichloromethane and then added pyrrolidine (0.32 ml, 3.91 mmol, 3.0 eq.) and acetate (0.16 ml, 2.61 mmol, 2.0 eq.). The reaction mixture was stirred at room temperature for 12 hours and then sodium triacetoxyborohydride (0.35 g, 1.65 mmol, 1.3 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours, and then a 10% aqueous sodium hydrogen carbonate solution was added to adjust the pH to about 8.0. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to give the title compound as a brown gel (0.085 g, 23.0%). Compounds 17, 160 and 161 were obtained using the method described above.

^1H NMR (600 MHz, CDCl ₃ ): δ 10.45 (brs, 1H), 8.23 (s, 1H), 7.98-7.75 (m, 2H), 7.21-7.05 (m, 1H), 3.51-3.20 (m, 5H), 3.00-2.80 (m, 2H), 2.77-2.59 (m, 2H), 2.45-2.30 (m, 1H), 2.15-2.00 (m, 5H). MC: Calculated: 284.2; MC: Found: 285.4 ([M+H] ⁺ ).

Synthesis Example 38. Preparation of 5-(4-methoxybenzylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 88)

Based on the preparation method of Compound 96, the title compound was obtained as a dark gray solid (0.30 g, 39.3%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.23 (d, J=4.8 Hz, 1H), 7.93-7.85 (m, 1H), 7.83-7.77 (m, 1H), 7.36 (d, J= 8.6 Hz, 2H), 7.09 (dd, J=7.5, 5.3 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 3.93 (dd, J=50.4, 13.1 Hz , 2H), 3.06 (ddd, J=12.3, 5.1, 2.6 Hz, 1H), 2.90 (dd, J=14.7, 5.0 Hz, 1H), 2.78 (ddd, J=16.7, 4.9, 3, 9 Hz, 1H), 2.58 (ddd, J=16.8, 11.1, 5.7 Hz, 1H), 2.50 (dd, J=14.6, 9.6 Hz, 1H), 2.26-2.14 (m, 1H), 1.91-1.81 (m, 1H). MC: Calculated: 350.2; MC: Found: 351.3 ([M+H] ⁺ ).

Synthesis Example 39. Preparation of 5-phenethylamino-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 93)

Based on the preparation method of Compound 96, the title compound was obtained as a dark gray solid (0.30 g, 39.3%).

¹ H NMR (600 MHz, DMSO-d ₆ ): δ 8.44-8.23 (m, 2H), 7.85 (t, J=7.1 Hz, 1H), 7.27-7.23 (m, 2H), 7.21-7.18 ( m, 2H), 7.15-7.12 (m, 2H), 2.90-2.75 (m, 3H), 2.72-2.65 (m, 2H), 2.60-2.50 (m, 1H), 2.48-2.35 (m, 2H), 1.95-1.89 (m, 2H), 1.56-1.44 (m, 1H). MC: Calculated: 334.2; MC: Found: 335.3 ([M+H] ⁺ ).

Synthesis Example 40: Preparation of 5-phenylamino-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 92)

Based on the preparation method of Compound 96, the title compound was obtained as a brown solid (0.21 g, 53.2%).

¹ H NMR (600 MHz, CDCl ₃ OD): δ 8.27-8.21 (m, 1H), 7.87-7.79 (m, 2H), 7.20-7.13 (m, 2H), 7.13-7.03 (m, 1H), 6.74 -6.66 (m, 1H), 6.66-6.58 (m, 2H), 3.90-3.73 (m, 1H), 2.95 (ddd, J=16.0, 9.0, 4.5 Hz, 1H), 2.85-2.69 (m, 2H), 2.45-2.33 (m, 1H), 2.23-2.07 (m, 1H), 1.95-1.79 (m, 1H). MC: Calculated: 306.2; MC: Found: 307.3 ([M+H] ⁺ ).

Synthesis Example 41: Preparation of 5-(3,4-difluorophenylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 32)

Based on the preparation method of Compound 96, the title compound was obtained as a dark gray solid (0.22 g, 74.2%).

¹ H NMR (600 MHz, DMSO-d ₆ ): δ 11.50 (s, 1H), 8.39 (d, J=8.4 Hz, 1H), 8.36 (d, J=4.0 Hz, 1H), 7.84 (t, J=7.2 Hz, 1H), 7.14 (dd, J=6.9, 5.2 Hz, 1H), 7.06 (q, J=9.7 Hz, 1H), 6.58 (ddd, J=13.7 , 6.8, 2.4 Hz, 1H), 6.37 (d, J=9.1 Hz, 1H), 5.80 (d, J=8.1 Hz, 1H), 3.62-3.50 (m, 1H), 2.64- 2.55 (m, 2H), 2.51 (dd, J=15.1, 5.1 Hz, 1H), 2.06-2.00 (m, 1H), 2.00-1.93 (m, 1H), 1.64-1.53 (m, 1H). MS: Calculated: 342.1; MS: Found: 343.2 ([M+H] ⁺ ).

Synthesis Example 42. Preparation of 5-(4-ethylpiperazin-1-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 91)

Based on the preparation method of Compound 96, the title compound was obtained as a brown gel (0.20 g, 47.0%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.28-8.00 (m, 1H), 7.95-7.80 (m, 1H), 7.80-7.65 (m, 1H), 7.10-6.95 (m, 1H), 2.85- 2.50 (m, 12H), 2.35-2.25 (m, 1H), 2.15-2.05 (m, 1H), 2.05-1.95 (m, 2H), 1.70-1.55 (m, 1H), 1.50-1.15 (m, 3H ). MS: Calculated: 327.2; MS: Found: 328.4 ([M+H] ⁺ ).

Synthesis Example 43: Preparation of 5-(4-propylpiperazin-1-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 100)

3-Hydroxy-2-(pyridin-2-yl)-2,4,6,7-tetrahydro-5H-indazol-5-one (0.25 g, 1.09 mmol) was dissolved in 14 ml dichloromethane/dichloroethane (1/1) and then 1-propylpiperazine dihydrobromide (0.41 g, 1.42 mmol, 1.3 eq) and diisopropylethylamine (0.50 ml, 2.84 mmol, 2.6 eq) were added. The reaction mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (0.30 g, 1.42 mmol, 1.3 eq.) was added. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to give the title compound as a brown solid (0.11 g, 29.0%). Compounds 127 and 128 were also obtained by the method described above.

^1H NMR (600 MHz, CDCl ₃ OD): δ 8.28-8.16 (m, 1H), 8.00-7.58 (m, 2H), 7.17-6.97 (m, 1H), 3.05-2.87 (m, 8H), 2.85 -2.75 (m, 2H), 2.71 (dd, J=14.5, 4.7 Hz, 1H), 2.68-2.57 (m, 3H), 2.39 (dd, J=14.3, 10.8 Hz, 1H), 2.21 -2.12 (m, 1H), 1.75-1.65 (m, 3H), 0.93 (t, J=7.4 Hz, 3H). MS: Calculated: 341.2; MS: Found: 342.4 ([M+H] ⁺ ).

Synthesis Example 44: Preparation of 5-(4-1-cylohexylmethylpiperazin-1-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 106)

Based on the preparation method of Compound 100, the title compound was obtained as a brown solid (0.14 g, 33.1%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.45-8.20 (m, 2H), 7.87 (dd, J=12.7, 5.3 Hz, 1H), 7.19 (dd, J=7.1, 5.3 Hz , 1H), 3.55-3.35 (m, 1H), 3.09-2.53 (m, 10H), 2.40-2.25 (m, 1H), 2.25-2.07 (m, 1H), 1.92-1.61 (m, 8H), 1.37 -1.28 (m, 4H), 1.26-1.19 (m, 1H), 1.10-0.90 (m, 2H). MS: Calculated: 395.3; MS: Found: 396.3 ([M+H] ⁺ ).

Synthesis Example 45: Preparation of 5-(4-benzylpiperazin-1-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 105)

Based on the preparation method of Compound 100, the title compound was obtained as a brown solid (0.20 g, 47.1%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.22 (d, J=5.1 Hz, 1H), 7.90-7.70 (m, 2H), 7.39-7.27 (m, 5H), 7.11 (dd, J= 7.5, 5.4 Hz, 1H), 3.75 (brs, 2H), 3.31-2.75 (m, JH), 2.74-2.61 (m, 2H), 2.60-2.42 (m, 1H), 2.41-2.24 (m, 1H), 1.89-1.67 (m, 1H). MS: Calculated: 389.2; MS: Found: 390.3 ([M+H] ⁺ ).

Synthesis Example 46: Preparation of 5-(4-phenethylpiperazin-1-yl)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 104)

Based on the preparation method of Compound 100, the title compound was obtained as a brown solid (0.18 g, 40.9%).

^1H NMR (600 MHz, CDCl ₃ ): δ 10.24 (brs, 1H), 8.24-8.11 (m, 1H), 8.04-7.81 (m, 1H), 7.81-7.69 (m, 1H), 7.27-7.22 ( m, 2H), 7.18-7.14 (m, 3H), 7.07-7.02 (m, 1H), 3.70 (ddd, J=6.6, 4.2, 2.5 Hz, 1H), 2.88-2.64 (m, 12H), 2.63-2.52 (m, 2H), 2.36 (dd, J=14.3, 10.7 Hz, 1H), 2.19-2.10 (m, 1H), 1.84-1.76 (m, 1H), 1.68 (ddd, J=23.9 , 12.2, 5.2 Hz, 1H). MS: Calculated: 403.2; MS: Found: 404.3 ([M+H] ⁺ ).

Synthesis Example 47. Preparation of 5-[4-(3-phenylpropyl)-piperazin-1-yl]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol. (Connection 107)

Based on the preparation method of Compound 100, the title compound was obtained as a brown solid (0.11 g, 24.2%).

^1H NMR (600 MHz, CD ₃ OD): δ 8.36 (ddd, J=5.0, 1.9, 0.9 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.83 (ddd, J =8.4, 7.4, 1.9 Hz, 1H), 7.28-7.22 (m, 2H), 7.21-7.12 (m, 4H), 3.05-2.78 (m, 8H), 2.75 (ddd, J=16.1, 5.3, 3.2 Hz, 3H), 2.67-2.55 (m, 4H), 2.31-2.23 (m, 1H), 2.13 (ddtdd, J =8.1, 5.4,2.7, 1.3, 0.6 Hz, 1H), 1.96- 1.88 (m, 3H), 1.76-1.66 (m, 1H). MS: Calculated: 417.3; MS: Found: 418.3 ([M+H] ⁺ ).

Synthesis example 48. Preparation of 5-((2-(dimethylamino)benzyl)(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol ( Connection 71)

5-(Methylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (0.20 g, 0.82 mmol) was dissolved in 15 ml of dichloroethane and then 2-(dimethylamino)benzaldehyde (0.18 g, 1.23 mmol, 1.5 eq) and 2 drops of acetate were added. The reaction mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (0.35 g, 1.63 mmol, 2.0 eq.) was added. The reaction mixture was stirred at room temperature for 16 hours and then a 2 M aqueous sodium hydroxide solution was added. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to give the title compound as a light brown solid (0.09 g, 29%). Compounds 69 and 77 were also obtained by the method described above.

¹ H NMR (600 MHz, CD ₃ OD): δ 8.38-8.35 (m, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.86-7.81 (m, 1H), 7.44-7.37 (m , 2H), 7.34 (d, J=7.4 Hz, 1H), 7.20-7.14 (m, 2H), 4.31 (s, 2H), 3.38 (tdd, J=5.2, 4.5, 2.7 Hz, 1H ), 2.83 (ddd, J=16.8, 5.3, 2.5 Hz, 1H), 2.80-2.74 (m, 1H), 2.71 (s, 6H), 2.69-2.64 (m, 1H), 2.65 (s, 3H ) 2.61 (dd, J=13.8, 11.1 Hz, 1H), 2.29 (ddd, J=7.0, 5.2, 2.7 Hz, 1H), 2.02 (qd, J=11.9, 5.5 Hz, 1H) . MS: Calculated: 377.2; MS: Found: 378.3 ([M+H] ⁺ ).

Synthesis Example 49. Preparation of 5-(methylquinolin-6-ylmethylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 63)

5-Methylamino-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (0.25 g, 1.02 mmol) was dissolved in 20 ml of dichloromethane/dichloroethane (1 /1) and then quinoline-6-carboxaldehyde (0.24 g, 1.5 mmol, 1.5 eq.) and acetate (0.06 ml, 1.0 mmol, 1 eq.) were added. The reaction mixture was stirred at room temperature for 1 hour and then sodium triacetoxyborohydride (0.09 g, 1.5 mmol, 1.5 eq.) was added. The reaction mixture was stirred at room temperature for 12 hours, and then a 10% aqueous sodium hydroxide solution was added to adjust the pH to about 8.0. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1+0.1% triethylamine) to give the title compound as a brown solid (0.058 g, 14.7%). Compound 61 was also obtained using the method described above.

¹ H NMR (600 MHz, DMSO-d ₆ ): δ 11.42 (brs, 1H), 8.81 (dd, J=4.2, 1.8 Hz, 1H), 8.42-8.33 (m, 2H), 8.30 (d, J=7.7 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.84 (s, 2H), 7.72 (dd, J=8.6, 1.7 Hz, 1H), 7.46 (dt , J=4.1, 3.0 Hz, 1H), 7.10-7.20 (m, 1H), 3.78 (dd, J=43.2, 13.9 Hz, 2H), 2.84 (ddd, J=10.8, 5.0, 2, 7 Hz, 1H), 2.72-2.61 (m, 1H), 2.57-2.47 (m, 1H), 2.40 (tddd, J=7.9, 6.7,3.5, 2.1 Hz, 1H), 2.30-2.14 (m, lH), 2.19(s, 3H), 2.09-1.99 (m, 1H), 1.70 (qd, J=12.0, 5.4 Hz, 1H). MC: Calculated: 385.2; MC: Found: 386.2 ([M+H] ⁺ ).

Synthesis Example 50: Preparation of 5-(isoquinolin-3-ylmethyl-methylamino)-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 62)

Based on the preparation method of Compound 63, the title compound was obtained as a brown solid (0.02 g, 6.1%).

^1H NMR (600 MHz, DMSO-d ₆ ): δ 11.45 (brs, 1H), 9.21 (s, 1H), 8.47-8.31 (m, 2H), 8.05 (d, J=8.2 Hz, 1H) , 7.92 (d, J=8.2 Hz, 1H), 7.89-7.79 (m, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.58 (t, J=7.4 Hz, 1H ), 7.10-7.20 (m, 1H), 3.88 (dd, J=41.3, 14.7 Hz, 2H), 2.93-2.81 (m, 1H), 2.71-2.59 (m, 1H), 2.56-2.36 (m , 2H), 2.27 (s, 3H), 2.25-2.14 (m, 1H), 2.09-1.99 (m, 1H), 1.75-1.64 (m, 1H). MC: Calculated: 385.2; MC: Found: 386.2 ([M+H] ⁺ ).

Synthesis Example 51. Preparation of 5-(methyl((5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)amino)-2-(pyridin-2-yl) -4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 37)

5-(Methylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (0.13 g, 0.55 mmol) was dissolved in 6 ml of dichloromethane mixture /dichloroethane (1/1) and then added 5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-2-carbaldehyde (0.20 g, 0.82 mmol, 1.5 eq. ) and 3 drops of acetate. The reaction mixture was stirred at 45°C for 16 hours and then sodium cyanoborohydride (0.07 g, 1.09 mmol, 2.0 eq.) was added. The reaction mixture was stirred at 45°C for 24 hours and then a 2 M aqueous sodium hydroxide solution was added. The reaction mixture was extracted with dichloromethane (20 ml×2), and then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: dichloromethane/methanol = 5/1) to give the title compound as a light brown solid (0.059 g, 15%). Compounds 35 and 36 were also obtained by the method described above.

¹ H NMR (600 MHz, CD ₃ OD): δ 8.39-8.33 (m, 1H), 8.27 (d, J=8.8 Hz, 1H), 7.88-7.78 (m, 1H), 7.67 (s, 1H ), 7.28 (ddd, J=31.9, 16.9, 6.7 Hz, 2H), 7.15 (dd, J=8.1, 5.3 Hz, 1H), 6.52-6.40 (m, 1H), 3.94 (dd, J =26.0, 14.0 Hz, 2H), 3.24-3.01 (m, 4H), 3.02-2.93 (m, 1H), 2.82-2.56 (m, 7H), 2.43 (s, 3H), 2.37 (s, 3H ), 2.41-2.35 (m, 1H), 2.26-2.19 (m, 1H), 1.80 (qd, J=11.9, 5.4 Hz, 1H). MS: Calculated: 472.2; MS: Found: 473.4 ([M+H] ⁺ ).

Synthesis Example 52. Preparation of 5-{methyl-[6-(4-methyl-piperazin-1-yl)-pyrimidin-4-ylmethyl]-amino}-2-pyridin-2-yl-4,5,6,7 -tetrahydro-2H-indazol-3-ol (Compound 34)

Based on the preparation method of Compound 37, the title compound was obtained as a brown solid (0.03 g, 12.7%).

^1H NMR (600 MHz, CD ₃ OD): δ 8.40-8.32 (m, 2H), 8.27 (d, J=8.4 Hz, 1H), 7.87-7.79 (m, 1H), 7.16 (dd, J =7.2, 5.0 Hz, 1H), 6.87 (s, 1H), 3.76-3.54 (m, 6H), 2.94-2.87 (m, 1H), 2.80-2.70 (m, 1H), 2.65-2.53 (m , 2H), 2.53-2.42 (m, 5H), 2.35 (s, 3H), 2.29 (s, 3H), 2.15-2.08 (m, 1H), 1.81 (dtd, J=22.2, 11.0, 5.4 Hz , 1H). MS: Calculated: 434.3; MS: Found: 435.5([M+H] ⁺ ).

Synthesis Example 53. Preparation of 1-[4-(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-piperazin-1-yl]-2 -butyn-1-one (Compound 89)

1) Preparation of tert-butyl-4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-carboxylate

3-Hydroxy-2-pyridin-2-yl-2,4,6,7-tetrahydroindazol-5-one (1.55 g, 6.78 mmol, 1.0 eq.) was dissolved in 80 ml of dichloromethane/dichloroethane (1/1) and then tert-butylpiperazine-1-carboxylate (3.65 g, 16.97 mmol, 2.5 eq) and acetate (0.4 mL, 6.77 mmol, 1.5 eq) were added under a stream of nitrogen. 0 eq.). The reaction mixture was stirred at room temperature for 2 hours, then sodium triacetoxyborohydride (4.31 g, 20.3 mmol, 3.0 eq.) was added at 0° C. and then stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate (20 ml) was added to the reaction mixture to adjust the pH to about 7, and then it was extracted with dichloromethane (30 ml x 3). The organic layer was dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column (solvent: dichloromethane/methanol = 10/1) to give the title compound as a yellow solid (1.59 g, 58.8%). Compound 109 was also obtained using the method described above.

^1H NMR (600 MHz, CDCl ₃ ) δ 8.23 (dt, J=5.0, 1.2 Hz, 1H), 7.81 (dd, J=11.0, 4.4 Hz, 2H), 7.09 (dd, J=8.3 , 5.1 Hz, 1H), 3.49 (brt, 4H), 2.88-2.78 (m, 2H), 2.73-2.61 (m, 6H), 2.42-2.31 (m, 1H), 2.15 (dd, J=8.4 , 5.1 Hz, 1H), 1.77-1.64 (m, 1H), 1.46 (s, 9H).

2) Preparation of 5-(piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol dihydrochloride

tert-Butyl-4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazine-1-carboxylate (1.59 g, 3.98 mmol, 1.0 eq.) was dissolved in 30 ml of methanol and then 10 ml of 4.6 N was added under a stream of nitrogen. isopropanol solution of hydrochloric acid. The reaction mixture was stirred at room temperature for 1 day and concentrated under reduced pressure. The residue was recrystallized from ethyl alcohol and diethyl ether to give the title compound as a yellow solid (1.31 g, 87.8%).

¹ H NMR (600 MHz, CD ₃ OD) δ 8.51-8.44 (m, 1H), 8.26 (dd, J=8.5, 0.8 Hz, 1H), 8.17-8.11 (m, 1H), 7.47-7.35 ( m, 1H), 4.01-3.61 (m, 9H), 3.08 (dd, J=14.2, 5.1 Hz, 1H), 3.01 (ddd, J=17.4, 5.4, 2.3 Hz, 1H), 2.89 ( ddd, J=17.4, 11.6, 5.7 Hz, 1H), 2.78-2.70 (m, 1H), 2.61-2.53 (m, 1H), 2.13 (qd, J=12.1, 5.5 Hz, 1H).

3) Preparation of 1-[4-(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-piperazin-1-yl]-2-butine -1-she

To 2-butenoic acid 2,5-dioxopyrrolidin-1-yl ester (0.12 g, 0.65 mmol) was added 5-(piperazin-1-yl)-2-(pyridin-2-yl)-4.5 ,6,7-tetrahydro-2H-indazol-3-ol dihydrochloride (0.24 g, 0.65 mmol, 1.0 eq.) dissolved in 5 ml acetonitrile, followed by N,N-diisopropylethylamine (0.6 ml, 3.25 mmol, 5.0 eq.). The reaction mixture was stirred at room temperature for 1 day, and then it was extracted with water and salt water. The reaction mixture was extracted with dichloromethane (20 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1) to give the title compound as a green solid (0.25 g, 92.6%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.22 (d, J=3.3 Hz, 1H), 7.80 (s, 2H), 7.08 (s, 1H), 3.74 (dd, J=10.3, 5, 8 Hz, 2H), 3.70-3.58 (m, 2H), 2.89-2.69 (m, 2H), 2.69-2.51 (m, 6H), 2.40-2.27 (m, 1H), 2.07 (d, J=10, 4 Hz, 1H), 2.01-1.92 (m, 3H), 1.69 (dt, J=11.4, 7.0 Hz, 1H). MC: Calculated: 365.2; MC: Found: 367.2 ([M+H] ⁺ ).

Synthesis example 57a. Preparation of 1-[4-(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-piperazin-1-yl]-propenone (Compound 97)

5-(Piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol dihydrochloride (0.038 g, 0.10 mmol) was dissolved in 3 ml of dichloromethane and then triethylamine (0.04 ml, 0.30 mmol, 3.0 eq.) was added. The reaction mixture was stirred at 0°C for 10 minutes. Acryl chloride (0.01 mL, 0.10 mmol, 1.0 eq.) was added and stirred at 0° C. for 30 minutes, and then aqueous sodium hydrogen carbonate was used for neutralization. The reaction mixture was extracted with dichloromethane (10 ml×2), then the organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1 + 1% ammonia water) to give the title compound as a brown solid (19 mg, 53.7%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.23 (s, 1H), 7.82 (s, 2H), 7.10 (s, 1H), 6.64-6.48 (m, 1H), 6.28 (dd, J=16.8, 1.6 Hz, 1H), 5.76-5.59 (m, 1H), 3.85-3.40 (m, 4H), 2.95-2.50 (m, 7H), 2.44-2.28 (m, 1H), 2.09 (s, 1H) , 1.84-1.61 (m, 1H), 0.86 (dd, J=17.6, 10.5 Hz, 1H). MC: Calculated: 353.2; MS: Found: 354.3([M+H] ⁺ ).

Synthesis example 57b. Synthesis reaction of amide, carbonate, urea and sulfonamide derivatives

5-(Piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol dihydrochloride (0.038 g, 0.10 mmol) was dissolved in mixed a solution of 5 ml of acetonitrile and 1 ml of water and a saturated solution of NaHCO ₃ (200 μl) was added. To synthesize each derivative, one of carboxyl chloride, chloroformate, isocyanate, and sulfonyl chloride was added at room temperature. The reaction solution was stirred at room temperature for 1 hour, and the completion of the reaction was confirmed by LC-MS (liquid chromatography/mass spectrometry), and then 50 ml of ethyl acetate was added and diluted and washed with a mixed solution of saturated salt water and NaHCO ₃ . The product was isolated and purified by TLC (thin layer chromatography) for purification and the yield was in the range of 10-70%. In addition, data are described for the compounds of the Synthetic Examples prepared according to the general synthetic method and the synthetic method using specific substances. Compounds 110-114 were obtained using the method described above.

Synthesis Example 54. Preparation of 4-dimethylamino-1-[4-(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-piperazin-1- yl]-2-buten-1-one (Compound 98)

5-(Piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol dihydrochloride (0.37 g, 1.00 mmol) was dissolved in 15 ml of dichloromethane and then added (E)-4-(dimethylamino)-2-butenoic acid hydrochloride (0.20 g, 1.20 mmol, 1.2 eq.), hydroxybenzotriazole (0.18 g, 1.30 mmol, 1.3 eq.) and N,N-diisopropylethylamine (1.74 mL, 10.0 mmol, 10.0 eq.). The reaction mixture was stirred at 0°C for 10 minutes, then 1,3-diisopropylcarbodiimide (0.19 ml, 1.20 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature for 8 hours. Sodium hydrogen carbonate solution was used to neutralize the reaction mixture, and then the mixture was extracted with dichloromethane (10 ml x 2). The organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol = 5/1+0.1% ammonia water) to give the title compound as a brown solid (0.27 g, 65.8%). Compound 99 was also obtained by the method described above.

^1H NMR (600 MHz, CDCl ₃ ): δ 8.25 (d, J=5.0 Hz, 1H), 7.83 (dt, J=14.3, 7.8 Hz, 2H), 7.13-7.07 (m, 1H) , 6.84 (dt, J=15.2, 6.3 Hz, 1H), 6.50-6.43 (m, 1H), 3.70 (d, J=0.9 Hz, 2H), 3.52 (s, 2H), 3.30-3.22 (m, 2H), 2.84 (d, J=16.5 Hz, 1H), 2.77-2.69 (m, 1H), 2.69-2.60 (m, 4H), 2.57 (s, 2H), 2.41-2.33 (m , 7H), 2.11-2.04 (m, 1H), 1.70 (qd, J=12.1, 5.3 Hz, 1H). MC: Calculated:410.2; MC: Found: 411.3([M+H] ⁺ ).

Synthesis Example 55. Preparation of 5-(4-methylpiperazin-1-yl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol ( Connection 82)

Methyl 5-(4-methylpiperazin-1-yl)-2-oxocyclohexane-1-carboxylate (0.19 g, 0.75 mmol) was dissolved in 15 ml ethanol and then 5 drops of acetate and 2-hydrazinyl-5- (trifluoromethyl)pyridine (0.13 g, 0.75 mmol, 1.0 eq.). The reaction mixture was stirred at room temperature for 1 hour and at 100°C for 4 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/diethyl ether to give the title compound as a light brown solid (0.092 g, 32%). Compounds 115-120, 132, 137-145 and 154-156 were also prepared by the method described above.

¹ H NMR (600 MHz, CD ₃ OD): δ 8.69 (s, 1H), 8.57 (d, J=8.5 Hz, 1H), 8.15 (dd, J=8.9, 2.4 Hz, 1H), 3.55-2.86 (m, 8H), 2.84 (s, 3H), 2.76 (dd, J=5.1, 3.3 Hz, 1H), 2.70-2.61 (m, 2H), 2.59-2.51 (m, 1H), 2.31 (dd, J=14.5, 10.1 Hz, 1H), 2.16-2.09 (m, 1H), 1.80 (qd, J=11.2, 5.5 Hz, 1H). MS: Calculated: 381.2; MS: Found: 382.3 ([M+H] ⁺ ).

Synthesis Example 56. Preparation of 2-(6-chloro-pyridin-2-yl)-5-(4-methyl-piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Connection 83)

Based on the preparation method of Compound 82, the title compound was obtained as a bright gray solid (0.11 g, 59.8%).

¹ H NMR (600 MHz, D ₂ O): δ 7.91 (d, J=8.2 Hz, 1H), 7.80 (t, J=7.9 Hz, 1H), 7.23 (d, J=7.9 Hz, 1H), 3.82-3.30 (m, 8H), 2.97-2.87 (m, 1H), 2.93 (s, 3H), 2.84-2.75 (m, 2H), 2.74-2.65 (m, 1H), 2.48- 2.40 (m, 1H), 2.33 (dd, J=8.4, 3.3 Hz, 1H), 1.93 (qd, J=11.9, 5.6 Hz, 1H). MS: Calculated: 347.1; MS: Found: 348.2 ([M+H] ⁺ ).

Synthesis Example 57. Preparation of 5-(4-methyl-piperazin-1-yl)-2-(6-methyl-4-trifluoromethyl-pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazole -3-ola (Compound 84)

Based on the preparation method of Compound 82, the title compound was obtained as a gray solid (0.12 g, 73.8%).

^1H NMR (600 MHz, CD ₃ OD): δ 8.41 (s, 1H), 7.73 (s, 1H), 4.16-3.59 (m, 9H), 3.30 (s, 3H), 3.33-3.24 (m, 2H ), 3.19 (ddd, J=18.6, 10.1, 3.7 Hz, 1H), 2.84 (s, 3H), 2.91-2.77 (m, 1H), 2.74-2.67 (m, 1H), 2.30 (qd, J =12.0, 5.6 Hz, 1H). MS: Calculated: 395.2; MS: Found: 396.3 ([M+H] ⁺ ).

Synthesis Example 58. Preparation of 5-(4-methyl-piperazin-1-yl)-2-thieno[3,2-c]pyridin-4-yl-4,5,6,7-tetrahydro-2H-indazol-3 -ola (Compound 85)

Based on the preparation method of Compound 82, the title compound was obtained as a gray solid (0.11 g, 43.0%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.22 (d, J=5.6 Hz, 1H), 8.03 (d, J=5.3 Hz, 1H), 7.90 (d, J=5.6 Hz, 1H), 7.74 (d, J=5.7 Hz, 1H), 3.22-2.86 (m, 9H), 2.81 (ddd, J=16.9, 5.0, 3.2 Hz, 1H), 2.76 (s, 3H), 2.73-2.62 (m, 2H), 2.42-2.34 (m, 1H), 2.19-2.12 (m, 1H), 1.79 (qd, J=11.6, 5.4 Hz, 1H). MS: Calculated: 369.1; MS: Found: 370.2 ([M+H] ⁺ ).

Synthesis example 59. Preparation of 2-(3-fluoro-pyridin-2-yl)-5-(4-methyl-piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Connection 86)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.41 g, 86.3%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.34 (d, J=4.6 Hz, 1H), 7.81-7.76 (m, 1H), 7.51-7.43 (m, 1H), 3.00-2.69 (m , 9H), 2.68-2.59 (m, 2H), 2.52 (s, 3H), 2.32 (dd, J=14.8, 10.7 Hz, 1H), 2.20-2.13 (m, 1H), 1.83-1.70 (m , 1H), 0.92-0.79 (m, 1H). MS: Calculated: 331.2; MS: Found: 332.3 ([M+H] ⁺ ).

Synthesis Example 60. Preparation of 2-pyridin-2-yl-5-(4-pyridin-2-ylmethyl-piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 87)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.064 g, 23.6%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.47 (d, J=4.4 Hz, 1H), 8.36 (d, J=4.6 Hz, 1H), 8.26 (d, J=8.4 Hz, 1H), 7.87-7.77 (m, 2H), 7.52 (d, J=7.8 Hz, 1H), 7.31 (dd, J=7.3, 5.2 Hz, 1H), 7.16 (dd, J= 7.1, 5.1 Hz, 1H), 3.69 (s, 2H), 2.90-2.69 (m, 6H), 2.69-2.50 (m, 6H), 2.34-2.23 (m, 1H), 2.22-2.14 (m, 1H), 1.76-1.64 (m, 1H). MS: Calculated: 390.2; MS: Found: 391.3 ([M+H] ⁺ ).

Synthesis Example 61. Preparation of 2-pyridin-2-yl-5-(4-quinolin-6-ylmethylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 90)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.064 g, 23.6%).

^1H NMR (600 MHz, DMSO- _d6 ): δ 11.40 (s, 1H), 8.83 (dd, J=4.2, 1.8 Hz, 1H), 8.38 (d, J=8.5 Hz, 1H) , 8.36-8.34 (m, 1H), 8.31 (d, J=8.2 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.83 (d, J=10.9 Hz, 2H ), 7.69 (dd, J=8.6, 1.6 Hz, 1H), 7.47 (dd, J=8.3, 4.1 Hz, 1H), 7.17-7.11 (m, 1H), 3.62 (s, 2H), 2.67-2.23 (m, 12H), 2.14-2.01 (m, 1H), 2.00-1.90 (m, 1H), 1.60-1.45 (m, 1H). MC: Calculated: 440.2; MC: Found: 441.4 ([M+H] ⁺ ).

Synthesis Example 62. Preparation of 2-(4-chlorophenyl)-5-(4-methyl-piperazin-1-yl)-4,5,6,7-tetrahydride-2H-indazol-3-ol hydrochloride (Compound 94)

Based on the preparation method of Compound 82, the title compound was obtained as a beige solid (0.048 g, 39.8%).

^1H NMR (600 MHz, DMSO-d ₆ ): δ 12.47-11.52 (brd, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.45 (d, J=8.9 Hz, 2H) , 3.79-3.24 (m, 10H), 2.80 (s, 3H), 2.75-2.65 (m, 1H), 2.60-2.55 (m, 1H), 2.47-2.40 (m, 1H), 2.38-2.21 (m, 1H), 1.90-1. 75 (m, 1H). MC: Calculated: 382.1 (free base: 346.2); MC: Found: 347.3 ([M+H] ⁺ ).

Synthesis Example 63. Preparation of 5-(4-methyl-piperazin-1-yl)-2-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 95)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.072 g, 68.8%).

¹ H NMR (600 MHz, CD ₃ OD): δ 7.97 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H), 3.00-2.61 (m, 8H), 2.77-2.66 (m, 4H), 2.55 (s, 3H), 2.41-2.11 (m, 2H), 1.75-1.65 (m, 1H). MS: Calculated: 380.2; MC: Found: 381.2 ([M+H] ⁺ ).

Synthesis Example 64: Preparation of 2-(4-bromophenyl)-5-(4-methyl-piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 101)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.005 g, 6%).

¹ H NMR (600 MHz, CD ₃ OD): δ 7.65 (d, J=8.9 Hz, 2H), 7.50 (d, J=8.9 Hz, 2H), 2.89-2.46 (m, 11 Hz) , 2.34 (s, 3H), 2.2-2.30 (m, 1H), 2.19-2.11 (m, 1H), 2.05-1.95 (m, 1H), 1.67 (qd, J=11.8, 5.4 Hz, 1H) . MS: Calculated: 390.1; MS: Found: 391.2 ([M+H] ⁺ ).

Synthesis Example 65. Preparation of 2-(4-methyl-piperazin-1-yl)-2-(4-trifluoromethylphenyl)-4,5,6,7-tetrahydro-2H indazol-3-ol (Compound 102)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.10 g, 55.8%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.53 (dd, J=9.1, 4.8 Hz, 2H), 8.06-8.00 (m, 2H), 3.76-3.61 (m, 4H), 3.61-3.42 (m, 8H), 3.26 (s, 3H), 3.19-3.13 (m, 1H), 3.08-3.02 (m, 1H), 2.59 (ddd, J=24.0, 11.5, 5.4 Hz, 1H). MS: Calculated: 330.2; MS: Found: 331.4 ([M+H] ⁺ ).

Synthesis Example 66. Preparation of 4-[3-hydroxy-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-indazol-2-yl]-benzonitrile (Compound 103)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.035 g, 17.6%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.04 (d, J=8.9 Hz, 2H), 7.68 (d, J=8.9 Hz, 2H), 2.78-3.00 (m, 5H), 2.77-2.66 (m, 4H), 2.66-2.52 (m, 3H), 2.44 (s, 3H), 2.34-2.22 (m, 1H), 2.11-2.17 (m, 1H), 1.69 (ddd, J=24.0 , 11.8, 5.3 Hz, 1H). MS: Calculated: 337.2; MS: Found: 338.2 ([M+H] ⁺ ).

Synthesis Example 67. Preparation of 5-(4-methylpiperazin-1-yl)-2-pyrimidin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 108)

Based on the preparation method of Compound 82, the title compound was obtained as a brown solid (0.10 g, 40.5%).

¹ H NMR (600 MHz, CD ₃ OD): δ 8.71 (d, J=4.9 Hz, 2H), 7.23 (t, J=4.9 Hz, 1H), 2.79-2.68 (m, 6H), 2.67-2.52 (m, 5H), 2.36 (s, 3H), 2.34-2.23 (m, 2H), 2.18-2.11 (m, 1H), 1.68 (ddd, J=23.9, 11.8, 5.3 Hz, 1H ). MS: Calculated: 314.2; MS: Found: 315.3 ([M+H] ⁺ ).

Synthesis Example 68. Preparation of 2-pyridin-2-yl-5-(4-para-tolylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 126)

Based on the preparation method of Compound 96, the title compound was obtained as a beige solid (0.14 g, 32.9%).

¹ H NMR (600 MHz, CDCl3): 5 8.40-8.34 (m, 1H), 8.32-8.26 (m, 1H), 7.85 (ddd, J=8.6, 7.4, 1.9 Hz, 1H), 7.17 (ddd , J=7.3, 5.0, 0.8 Hz, 1H), 7.04 (d, J=8.3 Hz, 2H), 6.87 (d, J=8.6 Hz, 2H), 3.16 (t, J=5 ,0 Hz, 4H), 2.94-2.73 (m, 6H), 2.70-2.59 (m, 2H), 2.32 (dd, J=13.9, 10.9 Hz, 1H), 2.27-2.22 (m, 1H), 2.22 (s, 3H), 1.75 (qd, J=11.8, 5.4 Hz, 1H). MS: Calculated: 389.2; MS: Found: 390.3 ([M+H] ⁺ ).

Synthesis Example 69. Preparation of 5-[4-(4-methoxyphenyl)-piperazin-1-yl]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 129)

Based on the preparation method of Compound 96, the title compound was obtained as a brown solid (0.10 g, 23.7%).

^1H NMR (600 MHz, CDCl ₃ ): δ 8.28-8.19 (m, 1H), 7.90-7.70 (m, 2H), 7.10 (ddd, J=8.4, 4.3, 3.2 Hz, 1H), 6.91 ( d, J=9.1 Hz, 2H), 6.83 (d, J=9.1 Hz, 2H), 3.76 (s, 3H), 3.20-3.10 (m, 4H), 3.01-2.72 (m, 7H) , 2.73-2.60 (m, 1H), 2.52-2.36 (m, 1H), 2.32-2.19 (m, 1H), 1.76 (qd, J=12.2, 5.1 Hz, 1H). MS: Calculated: 405.2; MS: Found: 406.3 ([M+H] ⁺ ).

Synthesis Example 70. Preparation of 1-{4-[4-(3-hydroxy-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-5-yl)-piperazin-1-yl ]-phenyl}-ethanone (Compound 130)

Based on the preparation method of Compound 96, the title compound was obtained as a gray solid (0.14 g, 30.1%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.30-8.22 (m, 1H), 7.89-7.75 (m, 4H), 7.12-7.05 (m, 1H), 6.91-6.80 (m, 2H), 3.40- 3.30 (m, 4H), 2.92-2.59 (m, 8H), 2.50 (s, 3H), 2.45-2.33 (m, 1H), 2.19-2.07 (m, 1H), 1.80-1.65 (m, 1H). MS: Calculated: 417.2; MS: Found: 418.3 ([M+H] ⁺ ).

Synthesis Example 71. Preparation of 5-[4-(4-methanesulfonylphenyl)-piperazin-1-yl]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol (Compound 131)

Based on the preparation method of Compound 96, the title compound was obtained as a light gray solid (0.09 g, 18.1%).

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.25-8.20 (m, 1H), 7.86-7.79 (m, 2H), 7.76 (d, J=9.0 Hz, 2H), 7.11 (ddd, J= 6.8, 5.2, 2.0 Hz, 1H), 6.93 (d, J=9.0 Hz, 2H), 3.43-3.27 (m, 4H), 3.00 (s, 3H), 2.91-2.83 (m, 1H) , 2.82-2.75 (m, 6H), 2.70-2.59 (m, 1H), 2.47-2.37 (m, 1H), 2.19-2.10 (m, 1H), 1.74 (dddd, J=12.6, 7.1, 3.3, 0 .7 Hz, 1H). MS: Calculated: 453.2; MS: Found: 454.2 ([M+H] ⁺ ).

Synthesis Example 72. Preparation of 5-[4-(1-benzylpiperidin-4-ylmethyl)-piperazin-1-yl]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3 -ola (Compound 135)

5-(Piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol dihydrochloride (0.70 g, 1.88 mmol) was dissolved in 30 ml of a mixture of dichloromethane/dichloroethane (1/1) and then 1-benzylpiperidine-4-carbaldehyde (0.35 ml, 1.88 mmol, 1.0 eq.) and triethylamine (0.77 ml, 5.64 mmol, 3.0 eq.). The reaction mixture was stirred at room temperature for 2 hours after adding sodium triacetoxyborohydride (0.79 g, 3.76 mmol, 2.0 eq.) at 0°C. Saturated aqueous sodium hydrogen carbonate (20 ml) was added to the reaction mixture to adjust the pH to about 7, and then the mixture was extracted with dichloromethane (30 ml x 3). The organic layer was dried using anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column (solvent: chloroform/methanol = 5/1 + 1% ammonia water) to give the title compound as a brown solid (0.65 g, 70.3%). Compounds 133, 134 and 136 were also obtained by the method described above.

¹ H NMR (600 MHz, CDCl ₃ ): δ 8.26-8.19 (m, 1H), 7.90-7.80 (m, 2H), 7.27-7.17 (m, 5H), 7.10-7.00 (m, 1H), 3.51 ( s, 2H), 2.96-2.80 (m, 2H), 2.80-2.27 (m, 11H), 2.17 (d, J=7.1 Hz, 2H), 2.00-1.90 (m, 3H), 1.75-1.64 ( m, 2H), 1.55-1.40 (m, 1H), 1.34-1.16 (m, 5H). MS: Calculated: 486.3; MS: Found: 487.4 ([M+H] ⁺ ).

Synthesis example 73. Preparation of 5-{4-[2-(2-hydroxyethoxy)-ethyl]-piperazin-1-yl}-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazole -3-ol (Compound 17)

Based on the preparation method of Compound 96, the title compound was obtained as a yellow solid (0.15 g, 29.5%).

^1H NMR (600 MHz, CDCl3): 5 8.25-8.19 (m, 1H), 7.99-7.73 (m, 2H), 7.11-7.02 (m, 1H), 3.76-3.50 (m, 6H), 2.89-2.55 (m, 14H), 2.39-2.30 (m, 1H), 2.16-2.09 (m, 1H), 1.72-1.60 (m, 1H). MS: Calculated: 387.2; MS: Found: 388.3 ([M+H] ⁺ ).

The structures, MS results, and IUPAC names of the resulting compounds 1-161 from the Synthetic Examples are presented in Table 1 below.

Example 1: Analysis of changes in ROS production induced by PMA treatment in HL-60 cells differentiated into neutrophil cells by DMSO treatment

To confirm the effect of the compounds of the Synthesis Examples on the production of ROS from fibroblasts and specific substrate cells, the production of ROS was induced by stimulation with PMA (phorbol 12-myristate 13-acetate), TGF-β1, palmitate or high-concentration glucose or the like. in HL-60 cells differentiated into neutrophil cells by treatment with DMSO (dimethyl sulfoxide), in NHLF cells (normal human lung fibroblasts, Lonza), LX-2 (human liver stellate cells, Sigma), ARPE19 (human retinal pigment epithelial cells, ATCC (American Type Culture Collection) and KEL-FIB (Keloid Fibroblasts, ATCC), and under these conditions the inhibitory effect of the compounds of the Synthetic Examples on ROS production was determined.

HL-60 cells (human leukemia cells, ATCC) were suspended in medium containing 1.25% DMSO (RPMI + 10% FBS (fetal bovine serum)) and cultured in 5% CO ₂ , 37°C for 6 days , thereby inducing differentiation into neutrophil cells. HL-60 cells differentiated into neutrophil cells were aliquoted at a concentration of 2×10 ⁴ cells per well onto a 96-well plate, and the cells were treated with the compounds of the Synthetic Examples at a concentration of 0.5 mM for 30 minutes. Then, 200 nM PM A was added to each well containing cells and drug to induce ROS production, and such ROS production was measured by determining the luminescence level of each well using 100 μM L-012.

NHLF (normal human lung fibroblasts, Lonza), LX-2 (human liver stellate cells, Sigma), ARPE19 (human retinal pigment epithelial cells, ATCC), KEL-FIB (keloid fibroblasts, ATCC) cells were suspended in a culture medium containing 10% FBS, and aliquoted onto a 96-well plate and then cultured under 5% CO ₂ , 37°C for 24 hours. After pretreatment with compounds from the Synthesis Examples at concentrations of 10, 20, 30, 40, 60 and 80 μM for 30 minutes to 1 hour, each well containing cells and drug was treated with ROS stimulus. After further culture for 48 hours, the level of ROS production was confirmed using L-012 or DCF-DA (2',7'-dichlorofluorescein diacetate).

As a result of the experiment, the compounds from the Synthesis Examples inhibited ROS stimulus-stimulated ROS production in all cells: NHLF, LX-2, ARPE19, KEL-FIB. Specifically, Table 2 presents the results that showed that ROS production induced by PMA was inhibited by treatment with the compounds of Synthesis Examples at 0.5 μM in neutrophil-differentiated HL-60 cells. FIG. 1 shows the result that ROS production induced by PMA is inhibited completely when LX-2 and NHLF cells are treated with Compound 1 and Compound 17 of the Synthesis Examples.

Accordingly, the compounds of the Synthetic Examples were confirmed to effectively inhibit the production of ROS when treated with differentiated HL-60 cells or various fibroblasts or specific substrate cells in which ROS production was induced.

Example 2: Analysis of changes in αSMA expression induced by TGF-β1

It has been reported that cancer associated fibroblast (CAF) is formed, or fibrosis of various tissues is caused when fibroblast differentiates into myofibroblast.

To confirm whether the compounds of the Synthetic Examples of the present invention affect the differentiation of fibroblasts into myofibroblasts, it is necessary to determine the inhibitory effect of the compounds of the Synthetic Examples on the increase in the expression of αSMA (biomarker for confirming differentiation into myofibroblasts) induced by TGF-β1 on HFF-1 cells ( human foreskin fibroblast, ATCC), NHLF (normal human lung fibroblast, Lonza), LX-2 (human liver stellate cell, Sigma), ARPE19 (human retinal pigment epithelial cell, ATCC) and KEL-FIB (keloid fibroblast, ATCC ).

Each cell type was suspended in DMEM containing 10% FBS, and aliquots of 1 x 10 ⁴ to 1.5 x 10 ⁵ cells per well were added to a 4-well slide chamber (Nunc ) and treated with compounds from Synthesis Examples and TGF-β1 (TGF β1 and TGF-β both have the same meaning) to prepare cells to confirm αSMA expression. Confirmation of the expression of αSMA in the prepared cells was carried out by immunocytochemistry as follows. Cells were fixed with 4% paraformaldehyde for 10 minutes and permeabilized using 0.1% Triton x-100, followed by primary antibody treatment (anti-αSMA Ab, 1:200, at 4°C for 16 hours) and secondary antibody (A1exa-594 conjugated Ab, 1:800, at room temperature for 1 hour) against αSMA were performed in order, and then the expression level of αSMA was determined using a fluorescence microscope.

FIG. 3 shows the effect of treatment with various compounds from the Synthesis Examples at 10, 20 and 40 μM after inducing αSMA expression by treating HFF cells with TGF-β1 (10 ng/ml). Compound 1, Compound 23, Compound 12, Compound 5, Compound 14 and Compound 33 of the Synthesis Examples all showed an αSMA expression inhibition effect of 35%-70%, although there was a difference in the degree.

In addition, also in LX-2, NHLF, ARPE19, KEL-FIB cells, it was confirmed that the increase in αSMA expression induced by TGF-β1 (10 ng/ml) was significantly inhibited by treatment with 10 μM Compound 1 of the Synthesis Examples, which can confirm FIG. 4.

Example 3 TGF-β1-Induced Gel Contraction Change Assay

To confirm the effect of the compounds from the Synthesis Examples on the differentiation of fibroblasts into myofibroblasts, the inhibitory effect of the compounds from the Synthesis Examples on the gel shrinkage phenomenon induced by the interaction of human foreskin fibroblasts (HFF-1, ATCC) and collagen was determined.

A mixed solution of HFF-1 cells and collagen (bovine collagen type I), prepared at a concentration of 3×10 ⁶ cells/ml, was aliquoted into a 24-well plate, respectively, and then cultured under 5% CO ₂ , 37°C for 1 hours to induce gel polymerization. Then, after releasing the gel attached to the plate, medium containing TGF-β1 and the compounds from the Synthesis Examples was added to each well using a spoon. After culturing for 72 hours, the compounds of the Synthesis Examples were treated at 10, 20, 30, 40, 60 and 80 μM to measure the gel size, and the degree of gel shrinkage due to drug treatment was confirmed.

As a result of the experiment, as confirmed in FIG. 7, it was determined that gel contraction induced by TGF-β1 (10 ng/ml) was effectively inhibited by treatment with Compound 1, Compound 5, Compound 12, Compound 13, Compound 14, Compound 16, Compound 23, Compound 33, Compound 38, Compound 63 and Compound 62 from Synthesis Examples.

Example 4: Analysis of changes in ROS production on dopaminergic neuronal cells

To confirm the effect of the compounds of the Synthesis Examples on ROS production in dopaminergic neuronal cells, ROS production was induced by stimulation with preformed alpha-synuclein fibrils (PFF) in N27 cells (rat dopaminergic neuronal cells, Sigma), and under these conditions the inhibitory effects of the compounds from Examples of synthesis for the production of ROS.

N27 cells were cultured in RPMI medium containing 10% FBS, 1 μM angiotensin II, and the resulting cells were aliquoted at a concentration of 4×10 ³ cells per well applied to a 6-well plate. The ROS production stimulator PFF (preformed fibrils) and compounds from the Synthetic Examples were added to the cells. After treatment with the compounds of the Synthesis Examples for 24 hours, the fluorescence of each well was measured using CellROX-Deep Red reagent, thereby determining the extent of ROS production.

As a result of the experiment, as confirmed in FIG. 2, it was determined that PFF-induced ROS production was effectively inhibited by treatment with 0.001 μM of Compound 12, Compound 16, Compound 32, and Compound 82 of the Synthetic Examples.

Example 5 Analysis of Changes in IL-1β Expression Induced by LPS

To confirm the effect of the compounds of the Synthesis Examples of the present invention on the inflammatory response in human fibroblasts, it was determined whether the compounds of the Synthesis Examples inhibited the expression of IL-1β increased by LPS (lipopolysaccharide) treatment in fibroblasts from various tissues.

After inoculating 2×10 ⁵ cells in a 6-well plate and then culturing them for 24 hours, they were further cultured in serum-free culture solution for 16 hours, and then pretreated with Compound 1 of the Synthesis Examples for 20 minutes according to each condition. , and the inflammatory response was induced by LPS (1 μg/ml) for 6 hours. IL-1β expression was confirmed using RT-PCR (real-time polymerase chain reaction). Total RNA was isolated from cells using the RNeasy mini kit (Qiagen), and for isolated RNA, 2 μg of cDNA was synthesized using the PrimeScript™ II 1st Strand cDNA Synthesis Kit (TaKaRa), and then PCR was performed using AccuPower® PCR PreMix (Bioneer) for gene amplification. The nucleotide sequences for the target primers are as follows: IL-1β (forward: 5'-CCACAGACCTTCCAGGAGAATG-3' (SEQ ID NO: 1), reverse: 5'-GTGCAGTTCAGTGATCGTACAGG-3' (SEQ ID NO: 2)); GAPDH (forward: 5'-GTGGCTGGCTCAGAAAAAGG-3' (SEQ ID NO: 3), reverse: 5'-GGTGGTCCAGGGGTCTTACT-3' (SEQ ID NO: 4)); β-actin (forward: 5'-CACCATTGGCAATGAGCGGTTC-3' (S EQ ID NO: 5), reverse: 5'-AGGTCTTTGCGGATGTCCACGT-3' (SEQ ID NO: 6)). The PCR product was confirmed by electrophoresis in a 1.5% agarose gel.

As a result of the experiment, as confirmed in FIG. 8, treatment with 10 μM Compound 1 of the Synthesis Examples was determined to effectively inhibit LPS-induced IL-1β in a concentration-dependent manner.

Example 6 Analysis of Changes in IL-6 and IL8 Expression in Cancer-Associated Fibroblasts

To confirm the effect of the compounds of the Synthesis Examples of the present invention on the inflammatory response in cancer-associated fibroblasts, it was determined whether the compounds of the Synthesis Examples inhibited the expression of IL6 and IL8 in pancreatic cancer-associated fibroblasts (P.CAF).

After inoculation of 1.5×10 ⁵ cells in a 6-well plate and subsequent cultivation in complete medium for 48 hours, P.CAF was treated with compounds from the Synthesis Examples at 10, 20, 30, 40, 60 and 80 μM for 48 hours according to each condition, and then the expression of IL-6 and IL-8 was confirmed by performing ELISA (enzyme-linked immunosorbent assay) using a Quantkine ELISA kit (R&D systems) as follows.

100 μl of the culture solution treated with the compounds of the Synthesis Examples for 48 hours was added to a microassay plate containing 100 μl of assay diluent and left to stand at room temperature for 2 hours, and then the contents were removed, then washed 400 µl wash buffer 4 times. 200 μl of human IL-6 or IL-8 conjugate was added and left to stand at room temperature for 2 hours, and then the contents were removed and then washed with 400 μl of wash buffer 4 times. 200 µl of substrate solution was added and left to stand at room temperature for 20 minutes and left to stand at room temperature for 20 minutes and then 50 µl of stop solution was added and absorbance at 450 nm was measured within 30 minutes to confirm the level expression of IL-6 and IL-8.

As a result of the experiment, as confirmed in FIG. 5 and FIG. 6, it was determined that IL-6 and IL-8 expressed in P.CAF were effectively inhibited by treatment with Compound 1, Compound 5, Compounds 12-16, Compound 23, Compound 33, Compound 38, Compound 63 and Compound 62 of the Examples synthesis.

Example 7. Confirmation of the effect of treatment of brain damage

To test the effect of preventing or treating a disease or disorder in the brain of the compounds of the Synthesis Examples, it was evaluated using a mouse model of Parkinson's disease by injecting preformed alpha-synuclein fibrils (PFF).

C57Bl/6 mice were used and all mice were maintained under standard conditions. The experiment was carried out by dividing the experimental animals into a normal control group of animals that were orally administered distilled water (negative control), a group of animals in which Parkinson's disease was induced by injection of preformed alpha-synuclein fibrils (PFF) (vehicle control), and an experimental group of animals. with Parkinson's disease-induced injection of preformed fibrils (PFF), which were orally administered 25 mg/kg of Compound 16 from Synthesis Examples daily (Synthesis Example), 8 animals in each group. Animals of the normal control group were administered saline, and the compound of the Synthesis Examples was orally administered once daily for 7 weeks, and then a behavioral change experiment and a histopathological experiment were performed.

Behavioral change was analyzed using the Rota-rod test, the pole test, and the hindlimb grip test, and the average of 3 experiments per animal was measured.

After completion of testing, animals were anesthetized and brain tissue from each individual was removed and these tissues were fixed in 4% neutral buffered formalin (10% neutral buffered formalin). After this, the fixed tissues were cut to a certain thickness and embedded in paraffin using the general method of tissue processing to obtain sections of 4-5 μm. Therefore, in order to confirm whether the pathological index of Parkinson's disease improved according to the level of protein aggregation in the striatum, it was first labeled with serine-129 phosphorylated alpha-synuclein, and then stained with Thioflavin-T. to make histopathological conclusions.

As a result of the experiment, as a result of the analysis of behavior changes such as descent time, Rota-rod, pole test and hind limb coupling, etc. in the administration group of Compound 16 of the Synthesis Examples, it was determined that the symptoms of Parinsonian-like behavior were reduced by 50% or more, and the aggregation and accumulation of α-synuclein, an important pathological indicator of Parkinson's disease, was reduced by 50% or more.

In conclusion, the compounds of the Synthesis Examples of the present invention were confirmed to effectively improve Parkinson's disease.

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LIST OF SEQUENCES

<110> APTABIO THERAPEUTICS INC.

<120> NEW PYRAZOLE DERIVATIVES

<130>OPP20220759KR

<150> KR 10-2021-0025694

<151> 2021-02-25

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ccacagacct tccaggagaa tg 22

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<223> GAPDH forward primer

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ggtggtccag gggtcttact 20

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caccattggc aatgagcggt tc 22

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<---

Claims (233)

1. A compound of chemical formula I set forth below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: in this formula A is a 5-10 membered heteroaryl or C ₆ -C ₁₀ aryl, and wherein said 5-10 membered heteroaryl or C ₆ -C ₁₀ aryl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of cyano, halogen, C ₁ -C ₆ haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, amino, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, and where R ₁ represents hydrogen, heavy hydrogen or C ₁ - C ₆ alkyl; R represents hydrogen, heavy hydrogen, cyano, halogen, nitro, C ₁ -C ₆ alkyl, optionally substituted with C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl , 5-10-membered heteroaryl or -C(=O)R ₂ , and R ₂ represents C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₆ -C ₁₀ aryl; And B represents -NKM, or 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl; where the specified 5-10-membered heteroaryl or 5-10-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents from heavy hydrogen, halogen, cyano, nitro, -NR ₃ R ₄ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5-12-membered heteroaryl, -C(=O)R ₅ or -SO ₂ -R ₆ , where the specified C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryl optionally substituted with 1, 2, 3 or 4 substituents from hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, optionally substituted hydroxy, C ₃ -C ₈ cycloalkyl, C ₆ - C ₁₀ aryl, 5-10 membered heteroaryl, C(=O)R', C ₁ -C ₁₀ alkylsulfonyl, C ₆ -C ₁₀ aryloxy or 5-10 membered heterocycloalkyl, possibly substituted with C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylcarbonyl, and R ₃ and R ₄ are each independently hydrogen, heavy hydrogen, -C(=O)-R _a , C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, and said C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl is optionally substituted with 1, 2, 3 or 4 substituents of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryloxy, and where R _a represents hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl, R ₅ is -OR _b , -NR _c R _d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl, and where C ₁ -C ₆ alkyl , C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl is optionally substituted with 1, 2, 3 of 4 substituents from mono-C ₁ -C ₆ alkylamine or di-C ₁ -C ₆ alkylamine, and where R _b , R _c and R _d are each independently hydrogen, heavy hydrogen, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, and R ₆ is C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, optionally substituted with 1, 2, 3 or 4 C ₁ -C ₆ alkyl substituents, K represents hydrogen, heavy hydrogen, cyano, halogen, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C(=O)R', -C(=O) OR', -SO ₂ -R'', C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl-, 5-10-membered heteroaryl or 5-10 -membered heteroaryl-C ₁ -C ₆ alkyl, and wherein said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl or 5-10 membered heteroaryl is optionally substituted 1, 2, 3 or 4 substituents selected from the group consisting of amino, amino substituted with 1 or 2 substituents from C ₁ -C ₁₀ alkyl, cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, C ₆ -C ₁₀ arylsulfonyl, -C(=O)R ₉ , 5-10-membered heterocyclyl, 5-10-membered heterocyclyl , substituted with C ₁ -C ₆ alkyl, hydroxy, nitro, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl substituted with C ₁ -C ₆ alkyl, M represents cyano, halogen, nitro, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C(=O)R', -C(=O)OR', -SO ₂ -R'', C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl-, 5-10-membered heteroaryl or 5-10-membered heteroaryl-C ₁ -C ₆ alkyl, and where said C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl or 5-10 membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of amino, amino substituted with 1 or 2 substituents from C ₁ -C ₁₀ alkyl, cyano, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylsulfonyl, C ₆ -C ₁₀ arylsulfonyl, -C(=O)R ₉ , 5-10-membered heterocyclyl, 5-10-membered heterocyclyl, substituted with C ₁ - With ₆ alkyl, hydroxy, nitro, or C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl substituted with C ₁ -C ₆ alkyl, and R ₉ is -OR _e , -NR _e R _f or C ₂ -C ₆ alkenyl, optionally substituted with 1, 2, 3 or 4 of -NR _e R _f , or C ₆ -C ₁₀ aryl, and where R _e and R _f is each independently hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, where R' and R'' are each independently hydrogen, heavy hydrogen, amino, optionally substituted with 1 or 2 substituents of C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, The heteroatom of the heterocycloalkyl or heteroaryl ring is one or more types selected from N, S and O. 2. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the compound of chemical formula I is a compound of chemical formula I-1 given below: Chemical formula I-1 in this formula the definition of K, M and R is the same as for chemical formula I; And D is CR ₁₀ , N, O or S, or E is CR ₁₁ , N, O or S, or F is CR ₁₂ , N, O or S, or G is CR ₁₃ , N, O or S , or J is CR ₁₄ , N, O or S, but N, O and S are present in an amount of one or more; And R ₁₀ -R ₁₄ are the same or different and, each independently, can be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, C ₁ -C ₆ haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, amino, C ₆ -C ₁₀ aryl , 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, and R ₁ may be hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl, and two or more than two adjacent groups can be combined with each other to form an unsubstituted aromatic hydrocarbon ring, where this aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S, or C ₆ -C ₁₀ aryl ring. 3. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the compound of chemical formula I is a compound of chemical formula I-2 set forth below: Chemical formula I-2 in this formula the definition of R is the same as for chemical formula I, and D is CR ₁₀ , N, O or S, or E is CR ₁₁ , N, O or S, or F is CR ₁₂ , N, O or S, or G is CR ₁₃ , N, O or S , or J is CR ₁₄ , N, O or S, but N, O and S are present in an amount of one or more, and R ₁₀ -R ₁₄ are the same or different and, each independently, can be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, C ₁ -C ₆ haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, amino, C ₆ -C ₁₀ aryl , 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, and R ₁ may be hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl, and two or more than two adjacent groups can be combined with each other to form an unsubstituted aromatic hydrocarbon ring, where this aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S, or a C ₆ -C ₁₀ aryl ring, and n is an integer 0, 1 or 2; And L represents CH ₂ , NH or O; And may be unsubstituted or may be substituted by 1, 2, 3 or 4 types of heavy hydrogen, halogen, cyano, nitro, -NR ₃ R ₄ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -C(=O)R ₅ , -SO ₂ -R ₆ , and wherein when the substituent is 2 types or more, two or more than two adjacent groups may be combined with each other each other to form a 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl with And wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of hydroxy, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, C ₆ -C ₁₀ aryl, 5-10-membered heteroaryl, C(=O)R', C ₁ -C ₁₀ alkylsulfonyl, C ₆ -C ₁₀ aryloxy or unsubstituted or substituted with C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylcarbonyl 5-10 membered heterocycloalkyl, and R ₃ and R ₄ are each independently hydrogen, heavy hydrogen, -C(=O)-R _a , C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, and said C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryloxy, and wherein R _a is hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And R ₅ represents -OR _b , -NR _c R _d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl or C ₃ -C ₈ cycloalkyl, and wherein said C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of mono-C ₁ -C ₆ alkylamine or di-C ₁ -C ₆ alkylamine, and R _b , R _c and R _d are each independently hydrogen, heavy hydrogen, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, and R ₆ is C ₁ -C ₆ alkyl, unsubstituted or substituted with 1, 2, 3 or 4 types of C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl. 4. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the compound of chemical formula I is a compound of chemical formula I-3 set forth below: Chemical formula I-3 in this formula the definition of K, M and R is the same as for chemical formula I; And D is CR ₁₀ , N, O or S, or E is CR ₁₁ , N, O or S, or F is CR ₁₂ , N, O or S, or G is CR ₁₃ , N, O or S , but N, O and S are present in an amount of one or more; And R ₁₀ -R ₁₃ are the same or different and, each independently, can be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, C ₁ -C ₆ haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , C ₁ -C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, amino, C ₆ -C ₁₀ aryl , 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, and R ₁ can be hydrogen, heavy hydrogen, C ₁ -C ₁₀ alkyl; And two or more than two adjacent groups can be combined with each other to form an aromatic hydrocarbon ring, where the aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S, or C ₆ -C ₁₀ aryl ring. 5. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the compound of chemical formula I is a compound of chemical formula I-4 set forth below: Chemical formula I-4 in this formula the definition of R is the same as for chemical formula I; And D is CR ₁₀ , N, O or S, or E is CR ₁₁ , N, O or S, or F is CR ₁₂ , N, O or S, or G is CR ₁₃ , N, O or S , but N, O and S are present in an amount of one or more; And R ₁₀ -R ₁₃ are the same or different and, each independently, can be substituted with 1, 2, 3 or 4 types of substituents consisting of cyano, halogen, C ₁ -C ₆ haloalkyl, nitro, -C(=O)R ₁ , -C(=O)OR ₁ , -NH-C(=O)R ₁ , O-C ₁₀ alkoxy, C ₁ -C ₁₀ alkyl, C ₃ -C ₈ cycloalkyl, amino, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl, and R ₁ can be hydrogen, heavy hydrogen, C ₁ -C ₁₀ alkyl; And two or more than two adjacent groups can be combined with each other to form an aromatic hydrocarbon ring, where the aromatic hydrocarbon ring can form a 5-10 membered heteroaryl ring containing 0, 1, 2 or 3 heteroatoms selected from N, O and S , or a C ₆ -C ₁₀ aryl ring, and n is an integer 0, 1 or 2; And L represents CH ₂ , NH or O; And may be unsubstituted or may be substituted by 1, 2, 3 or 4 types of heavy hydrogen, halogen, cyano, nitro, -NR ₃ R ₄ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, -C(=O)R ₅ , -SO ₂ -R ₆ , and wherein when the substituent is of 2 types or more, two or more than two adjacent groups can be combined with each other to form 5-10- membered heteroaryl or 5-10 membered heterocycloalkyl with , And wherein C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of hydroxy, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, C ₆ -C ₁₀ aryloxy or unsubstituted or substituted C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl or C ₁ -C ₆ alkylcarbonyl 5-10 membered heterocycloalkyl, and R ₃ and R ₄ are each independently hydrogen, heavy hydrogen, -C(=O)-R _a , C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl, and this C ₁ -C ₆ alkyl or C ₆ -C ₁₀ aryl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of halogen, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryloxy, and wherein R _a is hydrogen, heavy hydrogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl; And R ₅ represents -OR _b , -NR _c R _d , C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₃ -C ₈ cycloalkyl, and also C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or C ₂ -C ₆ alkynyl may be unsubstituted or may be substituted with 1, 2, 3 or 4 types of mono-C ₁ -C ₆ alkylamine or di-C ₁ -C ₆ alkylamine, and wherein R _b , R _c and R _d are each independently hydrogen, heavy hydrogen, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ aryl-C ₁ -C ₆ alkyl, and R ₆ is C ₁ -C ₆ alkyl, unsubstituted or substituted with 1, 2, 3 or 4 types of C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl. 6. The compound, its stereoisomer or its pharmaceutically acceptable salt according to claim 1, wherein the compound represented by chemical formula I is selected from compounds 1-161 listed below: 1) 5-(benzylmethylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 2) 5-(benzylcyclopropylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 3) 4-{[(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)methylamino]methyl}benzonitrile; 4) 5-[(4-fluorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 5) 5-[(2,4-difluorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 6) 5-[(2-chlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 7) 5-[(3-chlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 8) 5-[methyl-(4-trifluoromethylbenzyl)amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol; 9) 5-[methyl-(3-methylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 10) 5-[methyl-(3-trifluoromethylbenzyl)-amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol; 11) 5-[methyl-(2-trifluoromethylbenzyl)-amino]-2-pyridin-2-yl-4,5,6,7-tetrahydro-2H-indazol-3-ol; 12) 5-[(4-methanesulfonylbenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 13) 5-[(3-methoxybenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 14) 5-piperidin-1-yl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 15) 5-morpholino-4-yl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 16) 5-(4-methylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 17) 5-(4-(2-(2-hydroxymethoxy)ethyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3- ol; 18) 5-(3,4-dihydro-1H-isoquinolin-2-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 19) 5-[(4-chlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 20) 5-(benzylethylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 21) 5-(benzylpropylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 22) 5-(benzylbutylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 23) 5-[methyl(3-methylsulfonylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 24) 5-[methyl-(4-methylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 25) 3-{[(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)methylamino]methyl}benzonitrile; 26) 5-[(2-methoxybenzyl)-methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 27) 5-[(3-fluorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 28) 5-[(4-methoxybenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 29) 5-[methyl-(2-methylbenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 30) 5-[(2,4-dichlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 31) 5-[(3,4-dichlorobenzyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 32) 5-(3,4-difluorophenylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 33) 5-[methyl(5,6,7,8-tetrahydroquinolin-8-yl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3- ol; 34) 5-(((3-(hydroxymethyl)-5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl)(methyl)amino)-2-(pyridine -2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 35) 5-{[(3-(hydroxymethyl)-5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl)methyl]methylamino}-2-(pyridin-2- yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 36) 5-{methyl[3-methyl-5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]methylamino}-2-(pyridin-2-yl)-4 ,5,6,7-tetrahydro-2H-indazol-3-ol; 37) 5-{methyl[5-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridin-2-yl]methylamino}-2-(pyridin-2-yl)-4,5,6 ,7-tetrahydro-2H-indazol-3-ol; 38) cyclopropyl[4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2-indazol-5-yl)piperazin-1-yl]methanone; 39) 5-(benzylmethylamino)-2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 40) 5-(benzylmethylamino)-2-(5-chloropyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 41) 5-(benzylmethylamino)-2-(6-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-ind azol-3-ol; 42) 5-(benzylmethylamino)-2-(6-methylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 43) 5-(benzylmethylamino)-2-(3-fluoropyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 44) 6-(5-(benzylmethylamino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinonitrile; 45) 5-(benzylmethylamino)-2-(6-methyl-4-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 46) 5-(benzylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 47) 2-(pyridin-2-yl)-5-[(pyridin-2-ylmethyl)amino]-4,5,6,7-tetrahydro-2H-indazol-3-ol; 48) 5-[methyl(pyridin-2-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 49) 5-[methyl(pyridin-4-ylmethyl)amino]-2-(5-trifluoromethylpyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 50) 2-(5-chloropyridin-2-yl)-5-[methyl(pyridin-4-ylmethyl)amino]-4,5,6,7-tetrahydro-2H-indazol-3-ol; 51) 5-[methyl(pyridin-4-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 52) 2-(4-bromophenyl)-5-[methyl(pyridin-4-ylmethyl)amino]-4,5,6,7,-tetrahydro-2H-indazol-3-ol; 53) 5-(benzylmethylamino)-2-(thieno[3,2-c]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 54) 2-(6-aminopyridin-2-yl)-5-(benzylmethylamino)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 55) 5-phenylamino-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 56) 5-[(2,5-dimethylphenyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 57) 5-[(4-nitrophenyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 58) 5-[(4-methoxyphenyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 59) 5-(phenylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 60) 2-(pyridin-2-yl)-5-(quinolin-3-ylamino)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 61) 5-[methyl(naphthalene-2-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 62) 5-[(isoquinolin-3-ylmethyl)methylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 63) 5-[methyl(quinolin-6-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 64) 5-[(isoquinolin-3-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 65) 5-[methyl(pyridin-2-ylmethyl)amino]-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-ol; 66) 5-[ethyl(pyridin-4-ylmethyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 67) 5-[(3-dimethylaminobenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 68) 5-[(4-dimethylaminobenzyl)amino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-2-ol; 69) 5-[(3-dimethylaminobenzyl)methylamino)]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 70) 5-[(4-dimethylamino)benzylmethylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 71) 5-[(2-dimethylamino)benzylmethylamino]-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 72) 5-(benzylmethylamino)-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-ol; 73) 4-[(5-benzylmethylamino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl]benzoic acid; 74) 5-(benzylmethylamino)-2-(4-bromophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 75) 5-(benzylmethylamino)-2-(2-chlorophenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 76) 5-(benzylmethylamino)-2-(2-methoxyphenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 77) 2-(2-chlorophenyl)-5-[(3-dimethylaminobenzyl)methylamino]-4,5,6,7-tetrahydro-2H-indazol-3-ol; 78) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)benzoic acid; 79) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)benzamide; 80) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)-N-methylbenzamide ; 81) 4-(((3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)(methyl)amino)methyl)-N,N -dimethylbenzamide; 82) 5-(4-methylpiperazin-1-yl)-2-(5-(trifluoromethyl)pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 83) 2-(6-chloropyridin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 84) 2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol ; 85) 5-(4-methylpiperazin-1-yl)-2-(thieno[3,2-c]pyridin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 86) 2-(3-fluoropyridin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 87) 2-(pyridin-2-yl)-5-(4-(pyridin-2-ylmethyl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 88) 5-((4-methoxybenzyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 89) 1-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)but-2- en-1-one; 90) 2-(pyridin-2-yl)-5-(4-(quinolin-6-ylmethyl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 91) 5-(4-ethylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 92) 5-(phenylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 93) 5-(phenethylamino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 94) 2-(4-chlorophenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 95) 5-(4-methylpiperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 96) 2-(pyridin-2-yl)-5-(pyrrolidin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 97) 1-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)prop-2- en-1-one; 98) (E)-4-(dimethylamino)-1-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl) piperazin-1-yl)but-2-en-1-one; 99) (E)-4-(dimethylamino)-N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-N- methylbut-2-enamide; 100) 5-(4-propylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 101) 2-(4-bromophenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 102) 2-(4-fluorophenyl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 103) 4-(3-hydroxy-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-2-yl)benzonitrile; 104) 5-(4-phenethylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 105) 5-(4-benzylpiperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 106) 5-(4-(cyclohexylmethyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 107) 5-(4-(3-phenylpropyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 108) 5-(4-methylpiperazin-1-yl)-2-(pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 109) 5-(piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 110) 5-(4-(methylsulfonyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 111) 5-(4-(phenylsulfonyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 112) 2-(pyridin-2-yl)-5-(4-tosylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 113) 4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-N-phenylpiperazin-1-carboxamide; 114) benzyl 4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazine-1-carboxylate; 115) 2-(1-methyl-1H-pyrrol-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 116) 5-(4-methylpiperazin-1-yl)-2-(thiazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 117) 5-(4-methylpiperazin-1-yl)-2-(oxazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 118) 2-(1-methyl-1H-pyrazol-5-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 119) 2-(1-methyl-1H-imidazol-5-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 120) 2-(1-methyl-1H-imidazol-5-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 121) 5-(benzyl(methyl)amino)-2-(pyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 122) 5-(benzyl(methyl)amino)-2-(1-methyl-1H-pyrrol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 123) 5-(benzyl(methyl)amino)-2-(1-methyl-1H-pyrazol-5-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 124) 5-(benzyl(methyl)amino)-2-(1-methyl-1H-imidazol-5-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 125) 5-(benzyl(methyl)amino)-2-(oxazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 126) 2-(pyridin-2-yl)-5-(4-(para-tolyl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 127) 5-(4-(4-hydroxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 128) 5-(4-(3,4-difluorophenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 129) 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 130) 1-(4-(4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl)phenyl )ethan-1-one; 131) 5-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 132) 5-(4-(4-phenoxyphenyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 133) 5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 134) 5-(4-((1-methylpiperidin-4-yl)methyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol- 3-ol; 135) 5-(4-((1-benzylpiperidin-4-yl)methyl)piperazin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol- 3-ol; 136) 1-(4-((4-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)piperazin-1-yl) methyl)piperidin-1-yl)ethan-1-one; 137) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)benzamide; 138) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-2-phenylacetamide; 139) 1-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-3-phenylurea; 140) 1-benzyl-3-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)urea; 141) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)benzenesulfonamide; 142) N-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)-4-methylbenzenesulfonamide; 143) benzyl-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)carbamate; 144) 2-(5-fluoro-4-morpholinopyrimidin-2-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 145) N-benzyl-3-methoxy-N-methyl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-amine; 146) N-benzyl-3-(cyclopropylmethoxy)-N-methyl-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-amine; 147) 5-(benzyl(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ylcyclopropanecarboxylate; 148) 5-(benzyl(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-yl acrylate; 149) 5-(benzyl(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ylbenzoate; 150) 2-(5-(benzyl(methyl)amino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)pyrimidine-5-carboxylic acid; 151) methyl 2-(5-(benzyl(methyl)amino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)nicotinate; 152) N-(6-(5-(benzyl(methyl)amino)-3-hydroxy-4,5,6,7-tetrahydro-2H-indazol-2-yl)pyridin-2-yl)acetamide; 153) 5-(benzyl(methyl)amino)-2-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3- ol; 154) 5-(4-methylpiperazin-1-yl)-2-(pyrimidin-4-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 155) 2-(5-chloropyridazin-3-yl)-5-(4-methylpiperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 156) 2-(pyridin-2-yl)-5-(4-(pyrimidin-2-yl)piperazin-1-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 157) 5-(benzyl(methyl)amino)-2-(5-nitropyrimidin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 158) 5-((4-hydroxybenzyl)(methyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 159) 5-(methyl(4-nitrobenzyl)amino)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol; 160) 5-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol and 161) 2,2,2-trifluoro-N-(1-(3-hydroxy-2-(pyridin-2-yl)-4,5,6,7-tetrahydro-2H-indazol-5-yl)pyrrolidin- 3-yl)acetamide. 7. The compound or its salt according to claim 1, wherein the salt is in the form of a salt formed by one or more types of acids selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid and hydroiodic acid; sodium salt; potassium salt; calcium salt; silver salts; hydrobromide; hydrogen sulfate; hydrogen phosphate; dihydrogen phosphate; succinate; citrate; mesylate or tosylate. 8. Pharmaceutical composition for the prevention, improvement of the course or treatment of diseases associated with oxidative stress, containing a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-7 as an active ingredient and a pharmaceutically acceptable carrier. 9. Pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable carrier is one or more types selected from the group consisting of an excipient, a diluent, a disintegrant, a binder, a glidant, a surfactant, an emulsifier, a suspending agent and a diluent.