TW202506109A - Novel pyrazole derivative and the use thereof - Google Patents

Abstract

The present invention provides a novel pyrazole derivative compound, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as a caspase-3 inhibitor. The novel pyrazole derivative compound of the present invention has been found to exhibit excellent caspase-3 inhibitory activity, which can be used for the prevention or treatment of a disease associated with caspase-3, especially pulmonary arterial hypertension. Thus, the novel pyrazole derivative compounds of the present invention may be useful in the field of medicine and pharmacy for the prevention or treatment of a disease associated with caspase-3.

Description

Novel pyrazole derivatives and their use

Cross-reference to related applications

This application claims the benefit of and priority to KR Patent Application No. 10-2023-0085927 filed on July 3, 2023. The entire disclosure of the application identified in this paragraph is incorporated herein by reference.

The present invention relates to a novel pyrazole derivative compound, and more particularly, to a novel pyrazole derivative compound as a caspase-3 inhibitor.

Apoptosis is an intrinsic cellular behavior that plays an important role in many physiological processes, including biological development, immune system regulation, and tissue formation. Apoptosis occurs to eliminate unnecessary cells, eliminate self cells and damaged cells in immune responses, and eliminate tumor cells. Cells undergoing apoptosis show unique morphological and biochemical changes, such as membrane remodeling, nuclear condensation, DNA fragmentation, and activation of a family of intracellular cysteine degrading enzymes (called apoptotic proteases). The caspase involved in apoptosis can be distinguished based on their substrate specificity; specifically, primary effector caspase including caspase-3 or caspase-7 show preference for substrates containing the four-amino acid recognition sequence DEVD, which is usually present in cytoplasmic or nuclear caspase substrates. Caspase-3 is known to play a key role in the execution of apoptosis, as it is degraded by chromosomal nucleosome fragmentation and promotes the activity of other effector caspase. Activated caspase-3 can also cleave a variety of cellular substrates, such as poly-(ADP-ribose) polymerase (PARP), inhibitor of caspase-activated deoxyribonuclease (ICAD), and α-spectrin, which leads to apoptosis.

Apoptosis protease-3 is a member of the apoptosis protease family, which is a protease that reacts specifically with Cys and Asp amino acid residues and is known to play a role in tissue differentiation, regeneration and neural development (Biotechnol Appl Biochem. 2022 Aug;69(4):1633-1645.). It is a key enzyme for cell apoptosis and is cleaved and converted to an active form through a signaling pathway that induces cell apoptosis. The active form of apoptosis protease-3 recognizes specific proteins in the cell and cleaves them at specific amino acid binding sites, thereby activating other apoptosis proteases. This proteolytic process leads to nuclear collapse, cell membrane damage and degradation of cell cycle regulatory proteins, which is the execution stage of cell death. Abnormal activation of caspase-3 is also associated with a variety of diseases. In cancer cells, abnormal activation of caspase-3 can inhibit cell apoptosis and promote tumor proliferation. On the other hand, lack of caspase-3 activity may be associated with nervous system diseases, where it interferes with the normal progression of cell apoptosis and affects the regulation of cell survival signaling pathways.

Therefore, apoptosis proteinase-3 is considered to play an important role in the biological signaling system. In addition, it is reported that apoptosis, inflammation, and fibrosis lead to hypertensive vascular remodeling, thereby linking apoptosis to microvascular disease ( Hypertensio . 2001; 38[Part 2]: 581-587.), and it is also reported that endothelial cell apoptosis in pulmonary artery hypertension is controlled by the microRNA/programmed cell death 4/apoptosis proteinase-3 axis (Hypertension. 2014; 64: 185-194). Therefore, apoptosis proteinase-3 is considered to be a novel therapeutic strategy for treating apoptosis-related diseases in medical research. Invention Objectives

The problem to be solved by the present invention is to provide a novel structured apoptosis-promoting proteinase-3 inhibitory compound that exhibits excellent inhibitory activity against apoptosis-promoting proteinase-3.

In addition, the problem to be solved by the present invention is to provide a pharmaceutical composition for preventing or treating diseases associated with caspase-3, wherein the pharmaceutical composition comprises a novel structured caspase-3 inhibitory compound.

In addition, the problem to be solved by the present invention is to provide a method for preventing or treating diseases associated with caspase-3 using novel structured caspase-3 inhibitory compounds.

In addition, the problem to be solved by the present invention is to provide a novel structured apoptosis proteinase-3 inhibitory compound for use in preventing or treating diseases related to apoptosis proteinase-3. The problem to be solved by the present invention is not limited to the above-mentioned problem, and those familiar with this technology can clearly understand other technical problems not mentioned from the following description.

To solve the above problems, according to one aspect of the present invention, a pyrazole derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof is provided, wherein: ^R1 is -C(O) ^OR3 or a 5-7 membered heteroaryl ring having 1 to 4 N atoms, L is -N( ^R4 )C(O)-, -N( ^R4 )C(O)O-, -N( ^R4 )C(O) _CH2N ( ^R5 )- or -C(O)N( ^R4 )-, ^R2 is a _C5-12 aryl group having 1 to 2 rings, or a bicyclic fused ring in which a 5-7 membered heterocycloalkyl ring having 1 to 2 N atoms is fused to an aryl ring, ^R2 is substituted or unsubstituted by a single or multiple independent ^R6 , ^Ra and ^Rb are independently _C1-3 alkyl, ^R3 , ^R4 and ^R5 are independently -H or _C1-3 alkyl, ^R6 is C ^R7 is a 5- to 7-membered heterocycloalkyl ring having 1 to 2 _N atoms, R7 is substituted or unsubstituted by ^R8 , ^R8 is a ^C1-3 alkoxy _{C1-3 alkyl} group, m and n are independently integers from 1 to ⁵ , and p is an integer from ₀ to 3.

According to another aspect of the present invention, a pharmaceutical composition for preventing or treating a disease associated with caspase-3 is provided, wherein the pharmaceutical composition comprises a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

According to another aspect of the present invention, a method for preventing or treating a disease associated with caspase-3 is provided, wherein the method uses a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, there is provided a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof for use in preventing or treating a disease associated with caspase-3.

According to another aspect of the present invention, a pharmaceutical composition is provided, which comprises a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

It has been found that the novel pyrazole derivative compounds of the present invention have excellent CPase-3 inhibitory activity and can be used to prevent or treat diseases associated with CPase-3, especially pulmonary arterial hypertension.

Therefore, the novel pyrazole derivative compounds of the present invention can be used in the medical field to prevent or treat diseases related to caspase-3.

The effects of the present invention are not limited to the above effects, but should be understood to include all effects that can be inferred from the invention description or invention composition detailed in the patent application scope.

The present invention provides a pyrazole derivative compound represented by the following formula (I), a hydrate thereof, a solvent thereof or a pharmaceutically acceptable salt thereof, wherein: <Formula (I)> ^R1 is -C(O) ^OR3 or a 5-7 membered heteroaryl ring having 1 to 4 N atoms, L is -N( ^R4 )C(O)-, -N( ^R4 )C(O)O-, -N( ^R4 )C(O) _CH2N ( ^R5 )- or -C(O)N( ^R4 )-, ^R2 is a _C5-12 aryl group having 1 to 2 rings, or a bicyclic fused ring in which a 5-7 membered heterocycloalkyl ring having 1 to 2 N atoms is fused to an aryl ring, ^R2 is substituted or unsubstituted by a single or multiple independent ^R6 , ^Ra and ^Rb are independently _C1-3 alkyl, ^R3 , ^R4 and ^R5 are independently -H or _C1-3 alkyl, ^R6 is C ^R7 is a 5- to 7-membered heterocycloalkyl ring having 1 to 2 _N atoms, R7 is substituted or unsubstituted by ^R8 , ^R8 is a ^C1-3 alkoxy _{C1-3 alkyl} group, m and n are independently integers from 1 to ⁵ , and p is an integer from ₀ to 3.

In one embodiment, R ¹ can be ethoxycarbonyl, hydroxycarbonyl or tetrazolyl.

In one embodiment, L can be -NHC(O)-, -NHC(O)O-, -NHC(O)CH ₂ NH-, or -C(O)NH-.

In one embodiment, R ² can be phenyl, naphthyl, indolinyl, isoindolinyl, dihydroisoquinolinyl or tetrahydroisoquinolinyl.

In one embodiment, ^Ra and ^Rb can independently be methyl or ethyl.

In one embodiment, R ³ , R ⁴ and R ⁵ are independently -H or ethyl.

In one embodiment, R ⁶ can be methoxy, oxo, hydroxy, —C(O)OH, —C(O)C(O)OH, pyrrolidinylsulfonyl or phenyl.

In one embodiment, R ⁸ can be methoxymethyl.

In one embodiment, m may be an integer 1, and n may be an integer 1.

In one embodiment, p can be 0, 1 or 2.

Unless otherwise specified, the following definitions are used in this specification when defining the pyrazole derivative compounds of formula (I).

As used herein, the term "alkyl" refers to a straight or branched chain hydroxyl group, preferably a _C1 - _C10 alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, isopropyl, n -butyl, isobutyl , tert-butyl, n- pentyl, isopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl.

As used herein, the term "cycloalkyl" refers to a partially or fully saturated monocyclic or fused-ring hydrocarbon, preferably a C ₃ -C ₁₀ -cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl.

Unless otherwise defined, as used herein, the term "hydroxy" is defined as -OH, and the term "alkoxy" refers to an alkoxy group, ie, a group in which the hydrogen atom of the hydroxyl group is substituted with 1 to 10 alkyl groups.

As used herein, the term "impurity atom" means N, O or S.

As used herein, the term "heterocycloalkyl" refers to a non-aromatic alkyl ring, which is a non-aromatic carbon ring having one or more heteroatoms such as N, O or S in the ring. The ring may be 5, 6, 7 or 8 membered and/or fused to another ring such as a cycloalkyl or aromatic ring. Examples of such compounds include pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, oxathiolanyl, dithiolanyl, piperidinyl, tetrahydropyranyl, thiopyranyl, piperazinyl, morpholino and dioxanyl.

As used herein, the term "aryl" means an aromatic hydrocarbon, including a polycyclic aromatic ring system in which a carbocyclic aromatic ring or a heteroaromatic ring is fused with one or more other rings, preferably a C ₅ -C ₁₂ aryl, more preferably a C ₅ -C ₁₀ aryl. Examples of aryl include, but are not limited to, phenyl, naphthyl, and tetrahydronaphthyl. In addition, there are also groups in which a heteroaromatic ring is fused with a cycloalkyl or non-aromatic heterocyclic ring, such as indanyl or tetrahydrobenzopyranyl.

The term "heteroaryl" or "aromatic heterocycle" means a 3- to 12-membered, more preferably 5- to 10-membered aromatic hydrocarbon, which forms a monocyclic or condensed ring, has one or more heteroatoms selected from N, O and S as ring atoms, and may be fused with a benzo or C ₃ -C ₈ cycloalkyl group. For example, heteroaryl includes, but is not limited to, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, oxazinyl, triazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, furanyl, benzofuranyl, thienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolyl, isoquinolyl, and the like. Heteroaryl also includes a group in which a heteroaryl ring is fused with a cycloalkyl group or a non-aromatic heterocyclic ring, such as dihydrocyclopentylpyrazinyl.

Representative examples of the pyrazole derivative compounds according to the present invention are as follows: [1] 2-(1-(4-(3-(2,3-dioxoindolyl-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [2] 2-(1-(4-(2-(2,3-dioxoindolyl-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [3] 2-(1-(4-(2-(2,3-dioxoindolyl-5-(pyrrolidin-1-ylsulfonyl)indolyl-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethyl acetate, [4] 2-(2-((2-((4-((4-(carboxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)amino)-2-oxoethyl)amino)-5-(pyrrolidin-1-ylsulfonyl)phenyl)-2-oxoacetic acid, [5] (S)-2-(1-(4-(2-(5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-2,3-dioxoindolyl-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)ethyl acetate, [6] 2-(1-(4-(1,3-dioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester, [7] 2-(3,5-dimethyl-1-(4-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetic acid ethyl ester, [8] 2-(3,5-dimethyl-1-(4-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetic acid ethyl ester, [9] 6-((4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)aminocarbonyl)-1-hydroxy-3-oxoisoindole-1-carboxylic acid, [10] 6-((4-((4-(carboxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)aminocarbonyl)-1-hydroxy-3-oxoisoindole-1-carboxylic acid, [11] 2-(3,5-dimethyl-1-(4-(3-(1,3,4-trioxo-3,4-dihydroisoquinolin-2(1H)-yl)propionamido)benzyl)-1H-pyrazol-4-yl)acetate, [12] 2-(3,5-dimethyl-1-(4-((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)aminomethyl)benzyl)-1H-pyrazol-4-yl)acetic acid, [13] 2-(3,5-dimethyl-1-(4-((((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-1H-pyrazol-4-yl)acetic acid, [14] 2-(1-(4-((((2-methoxynaphthalen-1-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [15] 2-(1-(4-((([1,1'-biphenyl]-4-ylmethoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [16] N-(4-((4-((1H-tetrazolyl-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, and [17] N-(4-((4-((1H-tetrazolyl-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-3-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-yl)propionamide.

The pyrazole derivative compound represented by the above formula (I) according to the present invention can be prepared in the form of a prodrug, a hydrate, a solvent complex and a pharmaceutically acceptable salt and used to enhance in vivo absorption or increase solubility. Therefore, the prodrug, the hydrate, the solvent complex and the pharmaceutically acceptable salt also belong to the scope of the present invention.

The term "prodrug" refers to a substance that is converted into a parent drug in the body . Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they are bioavailable by oral administration, while the parent drug is not. Prodrugs may also have better solubility than the parent drug in pharmaceutical compositions. For example, a prodrug may be an in vivo hydrolyzable ester of a compound according to the present invention and a pharmaceutically acceptable salt thereof. Another example of a prodrug may be a short peptide (polyamino acid), in which the peptide is coupled to an acidic group that is metabolically converted to reveal an active site.

The term "hydrate" refers to a compound of the present invention or a salt thereof having a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "solvent" refers to a solvent in which the compound of the present invention or its salt has a stoichiometric or non-stoichiometric amount bound by non-covalent intermolecular forces. Therefore, preferred solvents include volatile, non-toxic and/or solvents suitable for human administration.

The term "isomer" refers to compounds of the present invention or their salts having the same chemical formula or molecular formula, but different in structure or space. Such isomers include structural isomers, such as tautomeric isomers, and include stereoisomers, such as R or S isomers with asymmetric carbon centers and geometric isomers (trans, cis). All such isomers and mixtures thereof are also included in the scope of the present invention.

The term "pharmaceutically acceptable salt" refers to a salt form of a compound that does not cause severe irritation to an organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. Pharmaceutically acceptable salts include acid addition salts formed by acids having pharmaceutically acceptable anions and forming non-toxic acid addition salts, such as inorganic acids, such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; organic carbonic acids, such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, apple acid, salicylic acid, etc.; sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. For example, pharmaceutically acceptable carboxylates include metal salts or alkali earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; amino acid salts, such as lysine, arginine, guanidine, etc.; organic salts, such as dicyclohexylamine, N-methyl-D-glucamine, trihydroxymethylmethylamine, diethanolamine, choline and triethylamine, etc. The compound of formula I according to the present invention can also be converted into its salt by conventional methods.

The present invention also provides a method for preparing the pyrazole derivative compound represented by the above formula (I).

The preparation of the pyrazole derivative compound represented by formula (I) of the present invention is illustrated by Examples 1 to 17, and the following preparation method does not limit the method for preparing the pyrazole derivative compound represented by formula (I) according to the present invention. It should be understood that the preparation methods of the following Examples 1 to 17 are only illustrative and can be easily modified by those skilled in the art according to specific substituents.

The present invention also provides a pharmaceutical composition for preventing or treating diseases associated with caspase-3, wherein the pharmaceutical composition comprises a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a method for preventing or treating a disease associated with caspase-3, comprising the following steps: administering a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof to a subject in need thereof.

The present invention also provides a use of a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof in the manufacture of a drug for preventing or treating a disease associated with caspase-3.

In one embodiment, the disease associated with caspase-3 may be pulmonary arterial hypertension.

The pyrazole derivative compounds of the present invention were measured for their caspases-3 inhibitory activity and were found to exhibit excellent caspases-3 inhibitory activity.

The present invention also provides a pharmaceutical composition comprising a pyrazole derivative compound represented by the above formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

Additives may include pharmaceutically acceptable carriers or diluents, each of which can be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols; external preparations; suppositories; and sterile injectable solutions according to conventional methods.

Pharmaceutically acceptable carriers include lactose, glucose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like. They also include diluents or formulators such as fillers, expanders, binders, wetting agents, disintegrants and surfactants. Oral solid dosage forms include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like, and may also include lubricants such as magnesium stearate, talc. Oral liquid preparations may include suspensions, oral solutions, emulsions, syrups and the like, and may also include diluents such as water and liquid wax, wetting agents, sweeteners, flavoring agents, preservatives and the like. Parenteral preparations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, creams, lyophilized preparations and suppositories; non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils (such as olive oil) and injectable esters (such as ethyl oleate). The matrix of suppositories can be witepsol, macrogol, Tween 61, cocoa gum, laurin gum, glycerin gelatin, etc.

The dosage of the active ingredient in the pharmaceutical composition of the present invention depends on the patient's disease and weight, the extent of the disease, the formulation of the active ingredient, the route of administration and the duration of administration, and can be appropriately adjusted according to the patient's condition. For example, the active ingredient can be administered at a dosage of 0.0001 to 1000 mg/kg per day, preferably 0.001 to 100 mg/kg, and the dosage can be administered once a day or divided into several doses per day. In addition, the pharmaceutical composition of the present invention may contain 0.001% by weight to 90% by weight of the active ingredient based on the total weight of the composition.

The pharmaceutical composition of the present invention can be administered to mammals, such as rats, mice, livestock and humans, by various routes, such as oral, transdermal, intraperitoneal, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intraventricular injection.

Hereinafter, the present disclosure is described in more detail by using preparation examples, examples and experimental examples. However, the following examples and experimental examples are intended to illustrate the present invention, and the scope of the present invention is not limited thereto.

Preparation Example 1. Ethyl 2-(1-(4- aminobenzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

Step 1: ethyl 2-(3,5-dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)acetate

Ethyl 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetate (67.8 g, 372 mmol) was dissolved in acetonitrile (750 mL) and 4-nitrobenzyl bromide (64.3 g, 298 mmol) and potassium carbonate (46.3 g, 335 mmol) were added at room temperature. The reaction mixture was stirred at 40°C for 16 hours. After cooling to room temperature, the precipitate was removed with a filter. The filtrate was concentrated under reduced pressure, ethyl acetate (1.00 L) was added and washed with water (2.00 L) and brine (1.00 L). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and diethyl ether/hexane (200 mL/500 mL) was added. The mixture was stirred at room temperature for 1 h and filtered to give ethyl 2-(3,5-dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)acetate (91.3 g, 77%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 5.31 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.36 (s, 2H), 2.23 (s, 3H), 2.12 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H). Step 2: Ethyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate

Ethyl 2-(3,5-dimethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)acetate (91.3 g, 288 mmol) obtained in step 1 was dissolved in methanol (800 mL), and palladium carbon (18.3 g, 20 wt%) was added. The reaction mixture was stirred under hydrogen for 24 h. The reaction mixture was filtered through diatomaceous earth. The filtrate was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and diethyl ether/hexane (200 mL/800 mL) was added. The mixture was stirred at room temperature for 30 min and filtered to obtain the target compound ethyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (65.2 g, 79%).

¹ H NMR (400 MHz, CD ₃ OD) δ 6.84 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 5.08 (s, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.38 (s, 2H), 2.16 (s, 3H), 2.12 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).

Preparation Example 2. Ethyl 2-(1-(4-(3-chloropropionamido ) benzyl ) -3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

To an ice-cold mixture of ethyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (200 mg, 0.696 mmol) and potassium carbonate (443 mg, 3.2 mmol) in dichloromethane (2.3 mL) was added 3-chloropropanoyl chloride (100 μL, 1.044 mmol) dropwise and stirred at room temperature for 17 hours. The reaction mixture was concentrated, and the residue was diluted with water and dichloromethane, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the target compound ethyl 2-(1-(4-(3-chloropropionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (256 mg, 97%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.85 (s, 1H), 7.38 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 5.16 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.86 (t, J = 6.4 Hz, 2H), 3.34 (s, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).

Preparation Example 3. Ethyl 2-(1-(4-(2- chloroacetamido ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

To an ice-cold mixture of ethyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (200 mg, 0.696 mmol) and potassium carbonate (443 mg, 3.2 mmol) in dichloromethane (5 mL) was added chloroacetyl chloride (84 μL, 1.044 mmol) dropwise and stirred at room temperature for 6 hours. The reaction mixture was concentrated, and the residue was diluted with water and dichloromethane, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the target compound ethyl 2-(1-(4-(2-chloroacetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (204 mg, 80%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.06 (d, J = 8.5 Hz, 2H), 5.13 (s, 2H), 4.23 (s, 2H), 4.04 (d, J = 7.1 Hz, 2H), 2.09 (s, 3H), 2.04 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H).

Preparation Example 4. 1,3- Dihydroxy -1,2,3,4- tetrahydroisoquinoline- 6- carboxylic acid

Step 1: Methyl 4-cyano-3-(cyanomethyl)benzoate

Methyl cyanoacetate (4.9 mL, 55.81 mmol) was slowly added to a DMSO suspension (17 mL) of ice-cold sodium hydroxide (60%, 2.23 g, 55.81 mmol) and stirred at room temperature for 30 min. A DMSO solution (27 mL) of methyl 4-cyano-3-fluorobenzoate (5 g, 27.9 mmol) was added to the reaction mixture, followed by stirring at 90° C. for 12 hours. A small amount of aqueous hydrochloric acid solution (2 M) was added to the reaction solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give methyl 4-cyano-3-(1-cyano-2-methoxy-2-oxoethyl)benzoate, which was dissolved in DMSO-H ₂ O (9:1, 30 mL) and stirred at 120° C. for 16 hr. The reaction mixture was diluted with EtOAc and brine and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (Hx:EtOAc=98:2 to 90:10) to give the target compound methyl 4-cyano-3-(cyanomethyl)benzoate (3.5 g, 63%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 0.8 Hz, 1H), 8.14 (dd, J = 8.0, 1.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 4.05 (s, 2H), 3.99 (s, 3H).

Step 2: 1,3-dihydroxy-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

A solution of methyl 4-cyano-3-(cyanomethyl)benzoate (3.5 g, 17.48 mmol) obtained in step 1 in concentrated hydrochloric acid (80 mL) was stirred at 110°C for 15 hours. After slowly cooling to room temperature, the solid precipitated in the reaction solution was filtered under reduced pressure. The solid was washed with EtOAc, water, MeOH, _Et2O and dried to obtain the target compound 1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (3.58 g, 100%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 11.43 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 8.02-7.89 (m, 2H), 4.11 (s, 2H).

Preparation Example 5. 4-((4-(2- ethoxy - 2- oxoethyl )-3,5 -dimethyl -1H -pyrazol -1- yl ) methyl ) benzoic acid

Step 1: 4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoic acid tributyl ester

To a mixture of ethyl 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetate (5.370 mmol) in CH ₃ CN (5.5 mL) was added tert-butyl 4-bromomethylbenzoate (1.31 g, 4.833 mmol) and potassium carbonate (668 mg, 4.833 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and brine and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CH ₂ Cl ₂ :EtOAc=95:5 to 90:10) to give the target compound 4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoic acid tributyl ester (1.4 g, 70%) as a yellow liquid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.77 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 4.73 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.19 (s, 3H), 2.06 (s, 3H), 1.46 (s, 9H), 1.11 (t, J = 7.1 Hz, 3H). Step 2: 4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoic acid

To a solution of tributyl 4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoate (1.38 g, 3.71 mmol) obtained in step 1 in dichloromethane (2 mL) was added trifluoroacetic acid (7.5 mL) and the mixture was stirred at room temperature for 7 hrs. The reaction mixture was concentrated under reduced pressure, _Et2O was added and stirred at room temperature for 30 min. The solid in the mixture was filtered under reduced pressure and dried to give the target compound 4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoic acid (978 mg, 83%) as a white solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.83 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 3.98 (q, J = 7.1 Hz, 2H), 3.16 (s, 3H), 2.06 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H).

Preparation Example 6. (1,3- Bis (( tributyldiphenylsilyl )oxy ) isoquinolin- 6- yl ) methanol

Step 1: tert-butyldiphenylsilyl 1,3-bis((tert-butyldiphenylsilyl)oxy)isoquinoline-6-carboxylate

To a mixture of 1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (300 mg, 1.46 mmol) and imidazole (402 mg, 5.84 mmol) in dichloromethane (12 ml) was added tributyldiphenylsilyl chloride (1.14 mL, 4.38 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered, the filtrate was diluted with dichloromethane and water, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (Hx:EtOAc=97:3) to give the target compound tert-butyldiphenylsilyl 1,3-bis((tert-butyldiphenylsilyl)oxy)isoquinoline-6-carboxylate (850 mg, 63%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.96 (dd, J = 8.6, 1.6 Hz, 1H), 7.75-7.68 (m, 8H), 7.51 (dd, J = 8.0, 1.2 Hz, 4H), 7.42-7.37 (m, 2H), 7.37-7.31 (m, 7H), 7.28 (dt, J = 14.6, 4.2 Hz, 5H), 7.23-7.16 (m, 5H), 1.17 (d, J = 3.6 Hz, 18H), 0.90 (s, 9H).

Step 2: (1,3-Bis((tert-butyldiphenylsilyl)oxy)isoquinolin-6-yl)methanol

To a mixture of tert-butyldiphenylsilyl 1,3-bis((tert-butyldiphenylsilyl)oxy)isoquinoline-6-carboxylate (850 mg, 0.923 mmol) obtained in step 1 in THF (10 mL) was added lithium aluminum hydroxide (15 mg, 3.69 mmol) in several small portions and stirred at room temperature for 4 hours. EtOAc and a saturated aqueous solution of potassium sodium tartrate were added to the reaction mixture and stirred at room temperature until the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc, the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Hx:EtOAc=80:20) to give the target compound ((1,3-bis((tributyldiphenylsilyl)oxy)isoquinolin-6-yl)methanol (137 mg, 22%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.26 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.1, 1.3 Hz, 4H), 7.55 (dd, J = 8.0, 1.3 Hz, 4H), 7.40-7.27 (m, 10H), 7.23 (t, J = 7.4 Hz, 4H), 6.25 (s, 1H), 4.76 (d, J = 5.7 Hz, 2H), 1.19 (s, 9H), 0.91 (s, 9H). MS (ESI) m/z 668 [M+H] ⁺ .

Preparation Example 7. Ethyl 2-(1-(4-( azidocarbonyl ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

To a mixture of 4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoic acid (500 mg, 1.58 mmol) obtained in Preparation Example 5 and triethylamine (0.28 mL, 2.05 mmol) in THF (5 mL) was added diphenylphosphatyl azide (0.44 mL, 2.05 mmol) and stirred at room temperature for 15 hours and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hx: EtOAc = 1: 1) to give the target compound ethyl 2-(1-(4-(azidocarbonyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (475 mg, 88%) as a white solid. MS (ESI) m/z 364 [M+Na] ⁺

Preparation Example 8. 4-((3,5 -diethyl- 4-((1- trityl- 1H -tetrazol -5- yl ) methyl )-1H -pyrazol -1- yl ) methyl ) aniline

Step 1: 2-(3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)acetonitrile

To a MeOH solution of (4-nitrobenzyl)hydrazine (2.77 g, 16.57 mmol) was slowly added a MeOH solution of 4-oxo-3-propanoylhexanenitrile (2.5 mL 14.91 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and EtOAc, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CHCl ₃ :EtOAc=98:2 to 95:5) to give the target compound 2-(3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)acetonitrile (2.6 g, 58%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.16 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 5.33 (s, 2H), 3.46 (s, 2H), 2.61 (dd, J = 26.4, 7.6 Hz, 4H), 1.27 (t, J = 7.6 Hz, 3H), 1.07 (t, J = 7.7 Hz, 3H). MS (ESI) m/z 321 [M+Na] ⁺

Step 2: 5-((3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)methyl)-1H-tetrazolyl

To a solution of 2-(3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)acetonitrile (2.5 g, 8.38 mmol) obtained in step 1 in ⁱ PrOH-H ₂ O (1:1, 30 mL) was added sodium azide (1.81 g, 27.9 mmol) and zinc bromide (6.28 g, 27.9 mmol) and stirred at 100° C. for 25 hours. The reaction was slowly cooled to room temperature and the precipitated solid was filtered off. The solid was dissolved in MeOH, 6 M aqueous hydrochloric acid solution was added and stirred at room temperature for 1 hour.

The mixture was extracted with _CH2Cl2 :MeOH (9:1), the organic layer was dried _{over MgSO4} , filtered and concentrated under reduced pressure to give the target compound 5-((3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)methyl)-1H-tetrazole (2.46 g, 72%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 5.41 (s, 2H), 4.03 (s, 2H), 2.59 (q, J = 7.5 Hz, 2H), 2.45 (t, J = 7.5 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). MS (ESI) m/z 364 [M+Na] ⁺ Step 3: 5-((3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)methyl)-1-trityl-1H-tetrazolyl

To a DCM solution of 5-((3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)methyl)-1H-tetrazole (380 mg, 1.11 mmol) obtained in step 2, trityl chloride (372 mg, 1.33 mmol), triethylamine (279 μL, 2.0 mmol) and DMAP (5 mg, 0.04 mmol) were added and stirred at room temperature for 3 hours. The reaction mixture was diluted with water and DCM, and the aqueous layer was extracted with DCM. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CHCl ₃ :MeOH=98:2 to 95:5) to give the target compound 5-((3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)methyl)-1-trityl-1H-tetrazole (430 mg, 66%) as a pale yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.13 (d, J = 8.8 Hz, 2H), 7.39 - 7.31 (m, 9H), 7.23 (d, J = 8.7 Hz, 2H), 6.99 (dd, J = 7.8, 1.8 Hz, 6H), 5.38 (s, 2H), 4.00 (s, 2H), 2.54 (d, J = 7.6 Hz, 2H), 2.43 (t, J = 7.6 Hz, 2H), 1.02 (t, J = 7.6 Hz, 3H), 0.82 (t, J = 7.5 Hz, 3H). MS (ESI) m/z 606 [M+Na] ⁺

Step 4: 4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)aniline

To a solution of 5-((3,5-diethyl-1-(4-nitrobenzyl)-1H-pyrazol-4-yl)methyl)-1-trityl-1H-tetrazole (430 mg, 0.737 mmol) obtained in step 3 in MeOH (7 mL) was added Pd/C (10%, 75 mg), and stirred at room temperature for 3 hours under a hydrogen stream. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the target compound 4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)aniline (400 mg, 98%) as a pale yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.82 (d, J = 8.2 Hz, 2H), 6.48 (dd, J = 8.7, 2.1 Hz, 2H), 4.98 (s, 2H), 3.89 (s, 2H), 2.54 (d, J = 7.8 Hz, 2H), 2.44 (dd, J = 15.6, 7.8 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H), 0.84 (t, J = 7.3 Hz, 3H). MS (ESI) m/z 334 [M+Na] ⁺

Preparation Example 9. 3-(4- cyano -3-( cyanomethyl ) phenyl ) propionic acid

Step 1: 4-Bromo-2-(cyanomethyl)benzonitrile

To an ice-cold suspension of sodium hydride (60%, 200 mg, 5.00 mmol) in DMSO (1.5 mL) was added dropwise methyl 2-cyanoacetate (0.44 mL, 5.00 mmol) and stirred at room temperature for 30 min. To this reaction mixture was added a DMSO solution (2.5 mL) of 4-bromo-2-fluorobenzonitrile (500 mg, 2.50 mmol), followed by stirring at 90° C. for 5 hours. A small amount of aqueous hydrochloric acid solution (2 M) was added to the reaction solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered, and concentrated under reduced pressure to give 2-(5-bromo-2-cyanophenyl)-2-cyanoacetate, which was dissolved in DMSO-H ₂ O (9:1, 3 mL) and stirred at 120° C. for 6 h. The reaction mixture was diluted with EtOAc and brine, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (Hx:EtOAc=98:2 to 95:5) to give the target compound 4-bromo-2-(cyanomethyl)benzonitrile (895 mg, 81%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.89 (dd, J = 5.0, 3.2 Hz, 2H), 7.82 (dd, J = 8.3, 1.9 Hz, 1H), 4.28 (s, 2H).

Step 2: Ethyl 3-(4-cyano-3-(cyanomethyl)phenyl)propionate

To a solution of 4-bromo-2-(cyanomethyl)benzonitrile (2.0 g, 9.05 mmol) obtained in step 1 in DMF (36 ml) were added tetra-n-butylammonium bromide (2.9 g, 9.05 mmol), tributylamine (4.3 mL, 18.1 mmol), palladium (II) acetate (61 mg, 0.27 mmol) and acrolein diethyl acetal (4.1 mL, 27.14 mmol), and stirred at 100° C. for 5 hours. Aqueous hydrochloric acid solution (1 M) was added to the reaction solution, which was then diluted with Et ₂ O and water and the aqueous layer was extracted with Et ₂ O. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (Hx:EtOAc=90:10 to 80:20) to give the target compound ethyl 3-(4-cyano-3-(cyanomethyl)phenyl)propanoate (1.2 g, 50%) as an orange liquid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.83 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 4.24 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.95 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 7.4 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H). MS (ESI) m/z 265 [M+Na] ⁺

Step 3: 3-(4-cyano-3-(cyanomethyl)phenyl)propionic acid

To a solution of ethyl 3-(4-cyano-3-(cyanomethyl)phenyl)propanoate (1.0 g, 4.13 mmol) obtained in step 2 in THF (10 mL) was added water (2 mL) and lithium hydroxide (198 mg, 8.26 mmol) and stirred at room temperature for 3 h, then concentrated under reduced pressure. The residue was acidified with aqueous hydrochloric acid (1 M) and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the target compound 3-(4-cyano-3-(cyanomethyl)phenyl)propanoic acid (890 mg, 100%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 7.83 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 4.24 (s, 2H), 2.92 (t, J = 7.4 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H). MS (ESI) m/z 237 [M+Na] ⁺

Example 1. 2-(1-(4-(3-(2,3- dioxindolin- 1- yl ) propionamido ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetic acid

Step 1: 2-(1-(4-(3-(2,3-dioxindolin-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate

To an ice-cold suspension of sodium hydroxide (60%, 12 mg, 0.289 mmol) in DMF (1 mL) were added isatin (36 mg, 0.241 mmol), ethyl 2-(1-(4-(3-chloropropionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (100 mg, 0.265 mmol) obtained in Preparation Example 2 and a catalytic amount of potassium iodide, and the reaction was stirred at 120° C. for 20 hours. Aqueous ammonium chloride solution was added to the reaction mixture and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CHCl ₃ :EtOAc=90:10 to 75:25, followed by CHCl 3 :EtOAc:MeOH=60:40:2) to give the target compound ethyl 2-(1-(4-(3-(2,3-dioxoindolyl-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (25 mg, 21%) as an orange solid. MS (ESI) m/z 511 [M+Na] ⁺

Step 2: 2-(1-(4-(3-(2,3-dioxindolin-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid

To a THF solution (0.5 mL) of ethyl 2-(1-(4-(3-(2,3-dioxoindolin-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (25 mg, 0.051 mmol) obtained in step 1 was added water (0.25 mL) and lithium hydroxide (3 mg, 0.13 mmol). The reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was acidified with aqueous hydrochloric acid solution (1.0 M) and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CHCl ₃ :MeOH=6:1) to give the target compound 2-(1-(1-(4-(3-(2,3-dioxoindolin-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (10 mg, 42%) as an orange solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.63-7.36 (m, 4H), 7.16 (d, J = 8.2 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 5.16 (s, 2H), 4.09 (t, J = 6.8 Hz, 2H), 3.21 (s, 2H), 2.74 (t, J = 6.9 Hz, 2H), 2.18 (s, 3H), 2.13 (s, 3H).

Example 2. 2-(1-(4-(2-(2,3- dioxindolin- 1- yl ) acetamido ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetic acid

Isatin (10 mg, 0.07 mmol) and ethyl 2-(1-(4-(2-chloroacetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (29 mg, 0.08 mmol) obtained in Preparation Example 3 were treated according to the method of Example 1 to obtain the target compound 2-(1-(1-(4-(2-(2,3-dioxoindolyl-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (12 mg, 35%) as an orange solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.96 (s, 1H), 7.59 (t, J = 6.7 Hz, 2H), 7.26 (d, J = 2.4 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 2H), 5.07 (s, 2H), 4.48 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 3.32 (s, 2H), 2.13 (d, J = 5.8 Hz, 6H), 1.23 (d, J = 7.1 Hz, 3H).

Example 3. Ethyl 2-(1-(4-(2-(2,3- dioxo -5-( pyrrolidin- 1- ylsulfonyl ) indolyl- 1- yl ) acetamido ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

5-(Pyrrolidin-1-ylsulfonyl)indoline-2,3-dione (400 mg, 1.427 mmol) and ethyl 2-(1-(4-(2-chloroacetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (519 mg, 1.427 mmol) obtained in Preparation Example 3 were treated according to the method of Step 1 in Example 1 to obtain the target compound ethyl 2-(1-(4-(2-(2,3-dioxo-5-(pyrrolidin-1-ylsulfonyl)indoline-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (287 mg, 33%) as a yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 9.05 (s, 1H), 8.07-7.98 (m, 2H), 7.27 (s, 1H), 7.24 (s, 1H), 7.10 (d, J = 8.3 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 5.14 (s, 2H), 4.52 (s, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.35 (s, 2H), 3.23 (t, J = 6.7 Hz, 4H), 2.18 (s, 3H), 2.15 (s, 3H), 1.84 - 1.78 (m, 4H), 1.25 (dd, J = 9.2, 5.0 Hz, 3H). MS (ESI) m/z 630 [M+Na] ⁺

Example 4. 2-(2-((2-((4-((4-( carboxymethyl )-3,5 -dimethyl -1H -pyrazol -1- yl ) methyl ) phenyl ) amino )-2 - oxoethyl ) amino )-5-( pyrrolidin -1- ylsulfonyl)phenyl )-2 -oxoacetic acid

Ethyl 2-(1-(4-(2-(2,3-dioxo-5-(pyrrolidin-1-ylsulfonyl)indolin-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (100 mg, 0.165 mmol) obtained in Example 3 was treated according to the method of Step 2 of Example 1 to give the target compound 2-(2-((2-((4-((4-(carboxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)amino)-2-oxoethyl)amino)-5-(pyrrolidin-1-ylsulfonyl)phenyl)-2-oxoacetic acid (12 mg, 12%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H), 10.30 (s, 1H), 9.31 (t, J = 5.2 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 9.1, 2.1 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 9.2 Hz, 1H), 5.13 (s, 2H), 4.29 (d, J = 5.2 Hz, 2H), 3.26 (s, 2H), 3.09 (t, J = 6.6 Hz, 4H), 2.09 (s, 3H), 2.05 (s, 3H), 1.68 (dd, J = 8.1, 5.3 Hz, 4H).

Example 5. (S)-ethyl 2-(1-(4-(2-(5-((2-( methoxymethyl ) pyrrolidin -1- yl ) sulfonyl )-2,3 -dioxindolyl- 1- yl ) acetamido ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

(S)-5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)indoline-2,3-dione (100 mg, 0.308 mmol) and ethyl 2-(1-(4-(2-chloroacetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (112 mg, 0.308 mmol) obtained in Preparation Example 3 were treated according to the procedure of Example 1 to obtain the target compound (S)-ethyl 2-(1-(4-(2-(5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-2,3-dioxoindoline-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (150 mg, 61%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.81 (s, 1H), 8.18-7.95 (m, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.2 Hz, 2H), 5.14 (s, 2H), 4.53 (s, 2H), 4.34 (d, J = 7.0 Hz, 1H), 4.13 (dt, J = 9.8, 5.8 Hz, 2H), 4.00-3.92 (m, 1H), 3.86 (dd, J = 9.2, 6.1 Hz, 1H), 3.79-3.64 (m, 2H), 3.57 (dd, J = 9.4, 3.8 Hz, 1H), 3.45 - 3.40 (m, 1H), 3.35 (d, J = 4.5 Hz, 3H), 3.11 (d, J = 8.0 Hz, 1H), 2.19 (s, 3H), 2.14 (s, 3H), 1.84 (d, J = 1.7 Hz, 2H), 1.68 (s, 2H), 1.26 (d, J = 3.5 Hz, 3H). MS (ESI) m/z 674 [M+Na] ⁺

Example 6. Ethyl 2-(1-(4-(1,3- dioxo- 1,2,3,4- tetrahydroisoquinoline- 6 -carboxamido ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetate

To a pyridine (5 mL) solution of 1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (500 mg, 2.437 mmol) obtained in Preparation Example 4 and ethyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (700 mg, 2.437 mmol) obtained in Preparation Example 1 was slowly added N,N-diisopropylethylamine (0.42 mL, 2.437 mmol) and then slowly added phosphorus oxychloride (0.23 mL, 2.437 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction mixture was ice-cooled, water was slowly added dropwise to the mixture over 2 hours and the precipitated solid was filtered under reduced pressure. The solid was washed with water and _Et2O , and then dried to obtain the target compound ethyl 2-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (269 mg, 23%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 11.43 (s, 2H), 10.45 (s, 1H), 7.94 (t, J = 9.5 Hz, 3H), 7.71 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 5.16 (s, 2H), 4.11 (s, 4H), 4.04 (q, J = 7.1 Hz, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H).

Example 7. 2-(3,5 -dimethyl -1-(4-(1,3,4- trioxy -1,2,3,4- tetrahydroisoquinoline- 6 -carboxamido ) benzyl )-1H -pyrazol -4- yl ) acetic acid

Step 1: 2-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid

To a THF solution (1 mL) of ethyl 2-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (20 mg, 0.042 mmol) obtained in Example 6, water (1 mL) and lithium hydroxide (10 mg, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was acidified with citric acid, and the solid was filtered off under reduced pressure. The solid was dried to give 2-(1-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (3 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 11.43 (s, 1H), 10.45 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 8.01-7.82 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 5.16 (s, 2H), 4.11 (s, 2H), 3.26 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H). MS (ESI) m/z 445 [MH] ^-

In the above purification process, the residual solid after filtration was collected and concentrated with MeOH, EtOAc and CHCl ₃ to give 2-(3,5-dimethyl-1-(4-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetic acid (about 2 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 10.69 (s, 1H), 8.61-7.86 (m, 3H), 7.74 (d, J = 8.5 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 5.17 (s, 2H), 3.26 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H). MS (ESI) m/z 459 [MH] ^-

Step 2: 2-(3,5-dimethyl-1-(4-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetic acid

2-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (3 mg) obtained in step 1 was dissolved in DMSO-d ₆ (0.75 mL) and left at room temperature. The progress of the reaction was checked by ¹ H NMR measurement. After completion of the oxidation, DMSO was evaporated under reduced pressure to give the target compound 2-(3,5-dimethyl-1-(4-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetic acid (3 mg, 100%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 10.69 (s, 1H), 8.67-7.88 (m, 3H), 7.74 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 3.26 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H).

Example 8. 2-(3,5 -dimethyl -1-(4-(1,3,4- trioxy -1,2,3,4- tetrahydroisoquinoline- 6 -carboxamido ) benzyl )-1H -pyrazol -4- yl ) acetic acid ethyl ester

Ethyl 2-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (6 mg, 0.012 mmol) obtained in Example 6 was treated according to the method of Step 2 of Example 7 to obtain the target compound, ethyl 2-(3,5-dimethyl-1-(4-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetate (6 mg, 100%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.09 (s, 1H), 10.69 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.42 (dd, J = 8.1, 1.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 5.18 (s, 2H), 4.04 (d, J = 7.1 Hz, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H).

Example 9. 6-((4-((4-(2- ethoxy - 2- oxoethyl )-3,5 -dimethyl -1H -pyrazol -1- yl ) methyl ) phenyl ) aminocarbonyl )-1- hydroxy -3 -oxoisoindoline -1- carboxylic acid

To a THF solution (1.5 mL) of ethyl 2-(3,5-dimethyl-1-(4-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetate (50 mg, 0.102 mmol) obtained in Example 8 were added water (0.5 mL) and lithium hydroxide (6 mg, 0.255 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was acidified with aqueous hydrochloric acid solution (1 M) and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CHCl 3 : MeOH) to give the target compound 6-((4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)aminocarbonyl)-1-hydroxy-3-oxoisoindoline-1-carboxylic acid (3 mg, 6%) as an orange solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 8.75 (s, 1H), 7.98 (dd, J = 7.8, 1.4 Hz, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.09 (t, J = 8.1 Hz, 2H), 6.66 (s, 1H), 5.16 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 3.37 (d, J = 3.6 Hz, 2H), 2.11 (s, 3H), 2.05 (d, J = 2.2 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H). MS (ESI) m/z 505 [MH]-

Example 10. 6-((4-((4-( Carboxymethyl )-3,5 -dimethyl -1H -pyrazol -1- yl ) methyl ) phenyl ) aminoformyl )-1- hydroxy - 3-oxoisoindoline - 1- carboxylic acid

To a THF solution (1 mL) of ethyl 2-(3,5-dimethyl-1-(4-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetate (31 mg, 0.063 mmol) obtained in Example 8 were added water (0.3 mL) and lithium hydroxide (4 mg, 0.159 mmol). The reaction mixture was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was acidified with 1 M hydrochloric acid solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CHCl 3 : MeOH) to give the target compound 6-((4-((4-(carboxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)aminocarbonyl)-1-hydroxy-3-oxoisoindoline-1-carboxylic acid (3 mg, 9%) as an orange solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 8.75 (s, 1H), 7.97 (dd, J = 7.8, 1.5 Hz, 1H), 7.87 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 7.8 Hz, 1H), 7.08 (d, J = 8.6 Hz, 2H), 6.68 (s, 1H), 5.10 (s, 2H), 2.88 (s, 2H), 2.08 (s, 3H), 2.05 (s, 3H).

Example 11. 2-(3,5 -dimethyl -1-(4-(3-(1,3,4- trioxy -3,4 -dihydroisoquinolin -2(1H) -yl ) propionamido ) benzyl )-1H -pyrazol -4- yl ) acetate

To a mixture of 3-(1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)propanoic acid (50 mg, 0.214 mmol) in THF (0.2 mL) were added a solution of EDCI (49 mg, 0.257 mmol) and DMAP (31 mg, 0.257 mmol) in DMF (0.4 mL) and ethyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (56 mg, 0.193 mmol) obtained in Preparation Example 1 was added and the reaction mixture was stirred at room temperature for 45 hours. The reaction mixture was concentrated under reduced pressure, the residue was added to 1 M hydrochloric acid solution and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (Et ₂ O:CHCl ₃ :EtOAc=1:1:1) to give the target compound ethyl 2-(3,5-dimethyl-1-(4-(3-(1,3,4-trioxy-3,4-dihydroisoquinolin-2(1H)-yl)propanamido)benzyl)-1H-pyrazol-4-yl)acetate (5 mg, 5%) as an orange solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.34 (d, J = 7.2 Hz, 1H), 8.20 (dd, J = 7.6, 1.0 Hz, 1H), 7.87 (dddd, J = 15.1, 8.7, 7.5, 1.2 Hz, 3H), 7.38 (d, J = 8.3 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 5.15 (s, 2H), 4.44 (t, J = 7.3 Hz, 2H), 4.10 (d, J = 7.1 Hz, 2H), 3.33 (s, 2H), 2.76 (t, J = 7.3 Hz, 2H), 2.21 (s, 3H), 2.11 (s, 3H), 1.22 (d, J = 7.1 Hz, 3H). MS (ESI) m/z 539 [M+Na] ⁺

Example 12. 2-(3,5 -dimethyl -1-(4-((1,3,4- trioxy -1,2,3,4- tetrahydroisoquinolin- 6 -yl ) aminocarbonyl ) benzyl ) -1H -pyrazol -4- yl ) acetic acid Step 1: 4-(4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamido)-2-(2-methoxy-2-oxoethyl)benzoic acid methyl ester

4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzoic acid (345 mg, 1.09 mmol) and methyl 4-amino-2-(2-methoxy-2-oxoethyl)benzoate (243 mg, 1.09 mmol) obtained in Preparation Example 5 were treated according to the method of Example 11 to obtain the target compound 4-(4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamido)-2-(2-methoxy-2-oxoethyl)benzoate (399 mg, 70%) to obtain the target compound.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.49 (s, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.85-7.81 (m, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 5.29 (s, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.97 (s, 2H), 3.77 (s, 3H), 3.60 (s, 3H), 3.37 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H), 1.17 (t, J = 7.1 Hz, 3H).

Step 2: 2-(1-(4-((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate

To a solution of methyl 4-(4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamido)-2-(2-methoxy-2-oxoethyl)benzoate (300 mg, 0.575 mmol) obtained in step 1 in MeOH was added aqueous potassium hydroxide solution (322 mg, 5.75 mmol), stirred at room temperature for 48 hours and concentrated under reduced pressure. The residue was acidified by adding aqueous hydrochloric acid (6 M) and concentrated under reduced pressure to give compound 2-(carboxymethyl)-4-(4-((4-(2-methoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamido)benzoic acid as a yellow solid.

Then a suspension of 2-(carboxymethyl)-4-(4-((4-(2-methoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)benzamido)benzoic acid in AcOH (1.2 mL) was stirred at 100° C. until dissolved, followed by addition of urea (80 mg, 1.33 mmol) and stirring at 120° C. for 5 hours. The reaction mixture was cooled to room temperature, water was added and stirred for 30 min, and the precipitated solid was filtered and dried to give the target compound 2-(1-(4-((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)aminocarbonyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (200 mg, 75%) as an ivory solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.19 (s, 1H), 10.54 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.93-7.84 (m, 3H), 7.79 (dd, J = 8.6, 1.7 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 5.29 (s, 2H), 4.03 (s, 2H), 3.59 (s, 3H), 3.40 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H).

Step 3: 2-(1-(4-((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid

Methyl 2-(1-(4-((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (30 mg, 0.065 mmol) obtained in Step 2 was treated according to the method of Step 2 of Example 1 to give the target compound 2-(1-(4-((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (3 mg, 11%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.13 (s, 1H), 11.19 (s, 1H), 10.54 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.92-7.85 (m, 3H), 7.79 (dd, J = 8.7, 1.7 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 5.29 (s, 2H), 4.03 (s, 2H), 3.28 (s, 2H), 2.11 (s, 3H), 2.06 (s, 3H).

Step 4: 2-(3,5-dimethyl-1-(4-((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-1H-pyrazol-4-yl)acetic acid, 2-(1-(4-((1,3-dioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)carbamoyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (3 mg) was treated according to the method of step 2 of Example 7 to obtain the target compound 2-(3,5-dimethyl-1-(4-((1,3,4-trihydroxy-1,2,3,4-tetrahydroisoquinolin-6-yl)aminomethyl)benzyl)-1H-pyrazol-4-yl)acetic acid (3 mg, 100%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.86 (s, 1H), 10.77 (s, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.30-8.25 (m, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 5.30 (s, 2H), 3.28 (s, 2H), 2.09 (d, J = 17.1 Hz, 6H).

Example 13. 2-(3,5 -dimethyl -1-(4-((((1,3,4- trioxy -1,2,3,4- tetrahydroisoquinolin - 6 - yl ) methoxy ) carbonyl ) amino ) benzyl )-1H -pyrazol -4- yl ) acetic acid,

Step 1: Ethyl 2-(1-(4-((((1,3-bis((tributyldiphenylsilyl)oxy)isoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate

A mixture of ethyl 2-(1-(4-(azidocarbonyl)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (41 mg, 0.119 mmol) in toluene (2 mL) was added to (1,3-bis((tributyldiphenylsilyl)oxy)isoquinolin-6-yl)methanol (88 mg, 0.131 mmol) obtained in Preparation Example 6 and stirred at 100° C. for 8 hours. To the reaction mixture was added triethylamine, stirred at room temperature for 1 h and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (Hx:EtOAc=80:20) to give the target compound, ethyl 2-(1-(4-((((1,3-bis((tributyldiphenylsilyl)oxy)isoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (89 mg, 76%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.31 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.1, 1.3 Hz, 4H), 7.60-7.56 (m, 4H), 7.42-7.37 (m, 4H), 7.37-7.31 (m, 7H), 7.28 (dt, J = 14.8, 4.1 Hz, 6H), 7.05 (d, J = 8.5 Hz, 2H), 6.80 (s, 1H), 6.30 (s, 1H), 5.27 (s, 2H), 5.19 (s, 2H), 4.15 (dt, J = 10.0, 5.7 Hz, 3H), 3.36 (s, 2H), 2.26 (s, 3H), 2.13 (s, 3H), 2.08 (s, 1H), 1.29 (dd, J = 9.1, 5.2 Hz, 2H), 1.22 (s, 9H), 0.95 (s, 9H). MS (ESI) m/z 981 [M+H] ⁺

Step 2: Ethyl 2-(1-(4-((((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate

To a mixture of ethyl 2-(1-(4-((((1,3-bis((tributyldiphenylsilyl)oxy)isoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (30 mg, 0.031 mmol) obtained in step 1 in THF (1 mL) was added aqueous hydrochloric acid solution (1 M) and stirred at room temperature for 9 hours. THF in the reaction mixture was evaporated under reduced pressure, and the precipitated solid was filtered out and dried to give ethyl 2-(1-(4-((((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (15 mg, 96%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.30 (s, 1H), 9.84 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.44-7.35 (m, 3H), 7.03 (d, J = 8.6 Hz, 2H), 5.21 (s, 2H), 5.10 (s, 2H), 4.03 (q, J = 7.1 Hz, 4H), 2.09 (s, 3H), 2.04 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). MS (ESI) m/z 505 [M+H] ⁺

Step 3: 2-(1-(4-((((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid

Ethyl 2-(1-(4-((((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (12 mg, 0.023 mmol) obtained in Step 2 was treated according to the method of Step 2 of Example 1 to give the target compound 2-(1-(4-((((1,3-dioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (3 mg, 27%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 11.30 (s, 1H), 9.84 (s, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.53-7.30 (m, 4H), 7.04 (d, J = 6.8 Hz, 2H), 5.21 (s, 2H), 5.10 (s, 2H), 4.04 (s, 2H), 3.24 (s, 2H), 2.06 (d, J = 17.8 Hz, 6H). Step 4: 2-(3,5-dimethyl-1-(4-((((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-1H-pyrazol-4-yl)acetic acid

2-(1-(4-((((1,3-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (3 mg) obtained in Step 3 was treated according to the method of Step 2 of Example 7 to obtain the target compound 2-(3,5-dimethyl-1-(4-((((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-1H-pyrazol-4-yl)acetic acid (3 mg, 100%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.21-11.30 (m, 2H), 9.89 (d, J = 13.8 Hz, 1H), 8.40-7.51 (m, 3H), 7.40 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 5.33 (s, 2H), 5.10 (s, 2H), 3.24 (s, 2H), 2.08 (s, 3H), 2.04 (s, 3H).

Example 14. 2-(1-(4-((((2- methoxynaphthalen- 1- yl ) methoxy ) carbonyl ) amino ) benzyl )-3,5 -dimethyl -1H -pyrazol -4- yl ) acetic acid

Triphosgene (0.054 g, 0.183 mmol) was dissolved in THF (0.37 mL), and (2-methoxy-1-naphthyl)methanol (0.034 g, 0.183 mmol) was dissolved in DCM and added slowly dropwise. Triethylamine (0.056 mL, 0.402 mmol) was then diluted in DCM and added slowly. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The mixture was then dissolved in THF (0.37 mL) and methyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (0.050 g, 0.183 mmol) was dissolved in THF and added dropwise. After stirring at 70° C. for 30 min and concentrating under reduced pressure, the obtained residue was purified by silica gel chromatography to give the target compound 2-[1-[[4-[(2-methoxy-1-naphthyl)methoxycarbonylamino]phenyl]methyl]-3,5-dimethyl-pyrazol-4-yl]acetic acid methyl ester (0.034 g).

Then methyl 2-[1-[[4-[(2-methoxy-1-naphthyl)methoxycarbonylamino]phenyl]methyl]-3,5-dimethyl-pyrazol-4-yl]acetate (0.034 g, 0.0697 mmol) was dissolved in methanol (0.35 mL) and 4N NaOH (0.061 mL, 0.244 mmol) was added dropwise. The mixture was stirred at room temperature for 12 h and then neutralized with 1N HCl. After extraction with EtOAc, the organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to give the target compound 2-(1-(4-((((2-methoxynaphthalen-1-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid (31 mg, 35%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.03 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 9.1 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.54 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.39 - 7.29 (m, 3H), 7.01 (d, J = 8.2 Hz, 2H), 6.78 (s, 1H), 5.76 (s, 2H), 5.17 (s, 2H), 3.99 (s, 3H), 3.37 (s, 2H), 2.22 (s, 3H), 2.11 (s, 3H).

Example 15. 2-(1-(4-((([1,1'- biphenyl ]-4 - ylmethoxy )carbonyl) amino ) benzyl ) -3,5 - dimethyl - 1H -pyrazol -4- yl ) acetic acid

Methyl 2-(1-(4-aminobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetate (0.050 g, 0.183 mmol) and biphenyl-4-methanol (0.034 g, 0.183 mmol) were treated according to the method of Example 14 to obtain the target compound (0.032 g, 37%).

¹ H NMR (400 MHz, CDCl3) δ 7.62 - 7.58 (m, 4H), 7.49 - 7.37 (m, 4H), 7.35 - 7.32 (m, 3H), 7.05 (d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 5.24 (s, 2H), 5.21 (s, 2H), 3.38 (s, 2H), 2.24 (s, 3H), 2.13 (s, 3H).

Example 16. N-(4-((4-((1H -tetrazolyl -5- yl ) methyl )-3,5 -diethyl - 1H -pyrazol -1- yl ) methyl ) phenyl )-1,3,4- trioxy -1,2,3,4- tetrahydroisoquinoline -6- carboxamide

Step 1: 4-cyano-3-(cyanomethyl)-N-(4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)phenyl)benzamide

To a solution of 4-cyano-3-(cyanomethyl)benzoic acid (135 mg, 0.722 mmol) in DMF (3 mL) were added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate (412 mg, 1.083 mmol), N,N-diisopropylethylamine (0.38 mL, 2.166 mmol) and 4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)aniline (400 mg, 0.722 mmol) obtained in Preparation Example 8. The reaction mixture was stirred at 90° C. for 2 h and concentrated under reduced pressure. Aqueous hydrochloric acid solution (1 M) was added to the residue and extracted with EtOAc. The organic layer was washed with aqueous NaHCO ₃ solution, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography (CH ₂ Cl ₂ :EtOAc=80:20 to 60:40) to give the target compound 4-cyano-3-(cyanomethyl)-N-(4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)phenyl)benzamide (200 mg, 38%) as a yellow solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 8.14-8.05 (m, 3H), 7.67 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 7.2 Hz, 9H), 7.06 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 1.4 Hz, 3H), 6.98 (d, J = 2.0 Hz, 3H), 5.19 (d, J = 7.0 Hz, 2H), 4.38 (s, 2H), 3.98 (s, 2H), 2.55 (d, J = 7.7 Hz, 2H), 2.44 (d, J = 7.6 Hz, 2H), 1.01 (d, J = 7.6 Hz, 3H), 0.84 (d, J = 7.5 Hz, 3H). MS (ESI) m/z 744 [M+Na] ⁺

Step 2: N-(4-((4-((1H-tetrazolyl-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

A solution of 4-cyano-3-(cyanomethyl)-N-(4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)phenyl)benzamide (45 mg, 0.062 mmol) obtained in step 1 in concentrated hydrochloric acid (0.4 mL) was stirred at 50° C. for 1 hr. After slowly cooling to room temperature, the precipitated solid was removed by filtration and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by C18 reverse phase column chromatography (H ₂ O: MeOH = 4: 6) to obtain the target compound N-(4-((4-((1H-tetrazolyl-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (6 mg, 19%). MS (ESI) m/z 521 [M+Na] ⁺

Step 3: N-(4-((4-((1H-tetrazolyl-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide

N-(4-((4-((1H-tetrazol-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (3 mg) obtained in step 2 was dissolved in DMSO-d ₆ (0.75 mL) and allowed to stand at room temperature. The progress of the reaction was checked by ¹ H NMR measurement. After the oxidation was completed, DMSO was evaporated under reduced pressure to give the target compound N-(4-((4-((1H-tetrazol-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (3 mg, 100%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.08 (s, 1H), 10.69 (s, 1H), 8.59 (d, J = 1.7 Hz, 1H), 8.42 (dd, J = 8.1, 1.8 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.6 Hz, 2H), 5.21 (s, 2H), 3.98 (s, 2H), 2.62-2.55 (m, 2H), 2.46 (t, J = 7.6 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H), 0.86 (t, J = 7.5 Hz, 3H). MS (ESI) m/z 535 [M+Na] ⁺

Example 17. N-(4-((4-((1H -tetrazolyl -5- yl ) methyl )-3,5 -diethyl -1H -pyrazol -1- yl ) methyl ) phenyl )-3-(1,3,4- trioxy- 1,2,3,4- tetrahydroisoquinolin -6 -yl ) propanamide

3-(4-cyano-3-(cyanomethyl)phenyl)propanoic acid (193 mg, 0.903 mmol) obtained in Preparation Example 9 and 4-((3,5-diethyl-4-((1-trityl-1H-tetrazol-5-yl)methyl)-1H-pyrazol-1-yl)methyl)aniline (500 mg, 0.903 mmol) obtained in Preparation Example 8 were treated according to the method of Example 16 to obtain the target compound N-(4-((4-((1H-tetrazol-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-3-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)propanamide (6 mg, 1.2%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.89 (s, 1H), 9.96 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.81 (dd, J = 8.0, 1.7 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.73 (dd, J = 79.5, 1.8 Hz, 1H), 5.14 (s, 2H), 3.99 (s, 2H), 3.08 (t, J = 7.5 Hz, 2H), 2.70 (d, J = 7.5 Hz, 2H), 2.58 - 2.54 (m, 2H), 2.43 (d, J = 7.6 Hz, 2H), 1.04 (t, J = 7.5 Hz, 3H), 0.81 (d, J = 7.6 Hz, 3H).

Experimental example 1. Apoptotic protease -3 Evaluation of inhibitory activity

In order to determine the inhibitory activity of the compounds of the present invention prepared in Examples, the activity of caspase-3 was measured using a substrate to which a fluorescent dye was attached. The fluorescent dye attached to the substrate was released from the substrate by caspase and exhibited fluorescence.

Compounds were dissolved in DMSO and stored at -20°C. Enzymatic reactions were performed in a buffer containing 25 mM HEPES, 10 mM DTT, 0.1% CHAPS (wt/vol) (pH 7.5), and specific enzyme activity was measured using 50 μM of the fluorescent substrate N-acetyl-Asp-Glu-Val-Asp-7-amido-4-trifluoromethylcoumarin (Ac-DEVD-AFC) (Cayman) and 2 ng of recombinant human caspase-3 (R&D System) in the presence of different concentrations of compounds. Kinetics were measured using a CLARIOstar Plus spectrometer (BMG Labtech) in the 400/505 nm (Ex/Em) wavelength band. Based on _IC50 (concentration that reduces activity by 50%), results are labeled A for less than 1 μM, B for 1 μM or above but less than 10 μM, and C for 10 μM or above.

The results are shown in Table 1 below. It was found that each compound inhibited the activity of caspase-3, thus proving that the compound of the present invention is a direct caspase-3 inhibitor. [Table 1] IC ₅₀ (μM) Compound ACCase -3 1 C 2 C 3 B 4 C 5 C 6 A 7 A 8 A 9 C 10 C 11 B 12 A 13 A 14 C 15 C 16 A 17 A

The foregoing description of the present invention is for illustrative purposes only, and it is clear to those skilled in the art that various substitutions and modifications may be made to the invention disclosed herein without departing from the spirit or basic features of the present invention. It should therefore be understood that the above embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention in any way. For example, each component described in a single form may also be implemented in a distributed manner, and similarly, components described in a distributed manner may also be implemented in a combined form.

The scope of the present invention is indicated by the following patent application. The meaning and scope of the patent application and all modifications or changes derived from its equivalents are considered to belong to the scope of the present invention.

without

without

Domestic storage information (please note in the order of storage institution, date, and number) None Foreign storage information (please note in the order of storage country, institution, date, and number) None

Claims (14)

A pyrazole derivative compound represented by the following formula (I), a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein: <Formula (I)> ^R1 is -C(O) ^OR3 or a 5-7 membered heteroaryl ring having 1 to 4 N, L is -N( ^R4 )C(O)-, -N( ^R4 )C(O)O-, -N( ^R4 )C(O) _CH2N ( ^R5 )- or -C(O)N( ^R4 )-, ^R2 is a _C5-12 aryl group having 1 to 2 rings, or a bicyclic fused ring in which a 5-7 membered heterocycloalkyl ring having 1 to 2 N is fused to an aryl ring, ^R2 is substituted or unsubstituted by a single or multiple independent ^R6 , ^Ra and ^Rb are independently _C1-3 alkyl, ^R3 , ^R4 and ^R5 are independently -H or _C1-3 alkyl, ^R6 is C ^R7 is a 5- to 7-membered heterocycloalkyl ring having 1 to 2 _N , R7 is substituted or unsubstituted ^{by R8} , ^R8 is a _C1-3 alkoxy _{C1-3 alkyl} , m and ⁿ are independently an integer from 1 to 5, and p is an integer from 0 to 3. The pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein R ¹ is ethoxycarbonyl, hydroxycarbonyl or tetrazolyl. The pyrazole derivative compound as claimed in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein L is -NHC(O)-, -NHC(O)O-, -NHC(O)CH ₂ NH- or -C(O)NH-. The pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein R ² is phenyl, naphthyl, indolinyl, isoindolinyl, dihydroisoquinolinyl or tetrahydroisoquinolinyl. The pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein ^Ra and ^Rb are independently methyl or ethyl. The pyrazole derivative compound as claimed in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein R ³ , R ⁴ and R ⁵ are independently -H or ethyl. A pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein R ⁶ is methoxy, oxo, hydroxy, -C(O)OH, -C(O)C(O)OH, pyrrolidinylsulfonyl or phenyl. The pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein R ⁸ is methoxymethyl. The pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein m is an integer of 1 and n is an integer of 1. The pyrazole derivative compound as described in claim 1, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2. A pyrazole derivative compound, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as described in claim 1, wherein the pyrazole derivative compound represented by the following formula (I) is selected from the group consisting of: [1] 2-(1-(4-(3-(2,3-dioxoindolyl-1-yl)propionamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [2] 2-(1-(4-(2-(2,3-dioxoindolyl-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [3] 2-(1-(4-(2-(2,3-dioxo-5-(pyrrolidin-1-ylsulfonyl)indol-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester, [4] 2-(2-((2-((4-((4-(carboxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)amino)-2-oxoethyl)amino)-5-(pyrrolidin-1-ylsulfonyl)phenyl)-2-oxoacetic acid ethyl ester, [5] (S)-2-(1-(4-(2-(5-((2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)-2,3-dioxoindolyl-1-yl)acetamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester, [6] 2-(1-(4-(1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester, [7] 2-(3,5-dimethyl-1-(4-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetic acid ethyl ester, [8] 2-(3,5-dimethyl-1-(4-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxamido)benzyl)-1H-pyrazol-4-yl)acetate, [9] 6-((4-((4-(2-ethoxy-2-oxoethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)aminocarbonyl)-1-hydroxy-3-oxoisoindole-1-carboxylic acid, [10] 6-((4-((4-(carboxymethyl)-3,5-dimethyl-1H-pyrazol-1-yl)methyl)phenyl)aminocarbonyl)-1-hydroxy-3-oxoisoindole-1-carboxylic acid, [11] 2-(3,5-dimethyl-1-(4-(3-(1,3,4-trioxy-3,4-dihydroisoquinolin-2(1H)-yl)propionamido)benzyl)-1H-pyrazol-4-yl)acetic acid, [12] 2-(3,5-dimethyl-1-(4-((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)aminomethyl)benzyl)-1H-pyrazol-4-yl)acetic acid, [13] 2-(3,5-dimethyl-1-(4-((((1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)carbonyl)amino)benzyl)-1H-pyrazol-4-yl)acetic acid, [14] 2-(1-(4-((((2-methoxynaphthalen-1-yl)methoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [15] 2-(1-(4-((([1,1'-biphenyl]-4-ylmethoxy)carbonyl)amino)benzyl)-3,5-dimethyl-1H-pyrazol-4-yl)acetic acid, [16] N-(4-((4-((1H-tetrazol-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-1,3,4-trioxy-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, and [17] N-(4-((4-((1H-tetrazolyl-5-yl)methyl)-3,5-diethyl-1H-pyrazol-1-yl)methyl)phenyl)-3-(1,3,4-trioxy-1,2,3,4-tetrahydroisoquinolin-6-yl)propionamide. A pharmaceutical composition for preventing or treating a disease associated with caspase-3, comprising a pyrazole derivative compound as described in any one of claims 1 to 11, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition as described in claim 12, characterized in that the disease associated with caspase-3 is pulmonary arterial hypertension. A pharmaceutical composition comprising the pyrazole derivative compound as described in any one of claims 1 to 11, a hydrate thereof, a solvate thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.