RU2788147C2 - Compounds having inhibitory activity relatively to pde9a and their pharmaceutical use - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions relates to the field of pharmaceutical chemistry and includes a compound of the formula 1 or its pharmaceutically acceptable salt and a pharmaceutical composition based on them. In the formula 1, A is phenyl, linear or branched C_1-5 alkyl unsubstituted or substituted with one or two halogen atoms, 3-6-element cycloalkyl unsubstituted or substituted with one or two halogen atoms, or 3-6-element heterocycloalkyl containing nitrogen, oxygen, or sulfur as a heteroatom, each of R¹ and R² is independently -H, a halogen atom, -NO₂, -CF₃, phenyl, linear or branched C_1-5 alkyl unsubstituted or substituted with one or two halogen atoms, or a linear or branched C_1-5 alkoxy group unsubstituted or substituted with one or two halogen atoms.

EFFECT: compound of the formula 1, having inhibitory activity relatively to PDE9A.

8 cl, 2 tbl, 56 ex

Description

Technical field

This application claims priority on the basis of Korean Application No. 10-2018-0156031 filed on December 6, 2018, and the entire contents of the description and drawings of said application are incorporated herein by reference.

The present invention relates to a group of compounds having a specific structure and excellent PDE9A inhibitory activity. The present invention also relates to pharmaceutical compositions containing such compounds. The present invention relates to a method that can be used to treat diseases associated with PDE9A, using these compounds. Thus, the present invention relates to the medical use of the compounds according to the present invention for the treatment or prevention of diseases associated with PDE9A.

State of the art

Phosphodiesterase 9A (PDE9A) is mainly expressed in the brain, in particular in the neocortex, cerebellum and hippocampus; it is known to be associated with the regulation of cGMP concentration, ie. signals associated with glutamate and involved in the mechanisms of memory and learning. Thus, inhibition of phosphodiesterase 9A is known to be useful in the treatment of Alzheimer's disease, CNS disorders or cognitive disorders caused by various neurodegenerative processes. Therefore, it is considered a useful pharmacological target for the treatment or alleviation of cognitive disorders, for example, dementia with degeneration of the frontal lobe, including dementia with Lewy bodies, Pick's syndrome, Parkinson's disease and Alzheimer's disease with learning and memory problems.

In addition, in addition to cranial nerve disease, phosphodiesterase 9A overexpression has recently been found in patients with cardiac disease, especially in patients with cardiac output-sparing heart failure; in addition, overexpression of phosphodiesterase 9A was observed in animal models inducing pathological conditions of the heart. In addition, the effects of improving cardiac function and alleviating myocardial hypertrophy due to inhibition of phosphodiesterase 9A have been reported; thus, it has recently attracted attention as a pharmacological target that can be used in patients with cardiovascular diseases, especially cardiac output-sparing heart failure.

Description

Technical task

Accordingly, the object to be solved by the present invention is to provide a compound having a PDE9A inhibitory activity, a pharmaceutical composition containing said compound as an active ingredient, and a medical use for the treatment or prevention of PDE9A related diseases.

Yet another object to be solved by the present invention is to provide a method for treating or alleviating diseases associated with PDE9A, characterized in that it inhibits the activity of PDE9A, and comprises administering a compound of the present invention to a patient in need of treatment, improvement or prevention of diseases associated with PDE9A.

Technical solution

In order to solve the above problem, in one embodiment, the present invention provides a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof,

[Chemical formula 1]

while in the chemical formula 1

A is phenyl, unsubstituted or substituted with one or more halogen atoms, linear or branched C _1-5 alkyl, unsubstituted or substituted with one or more halogen atoms, 3-6 membered cycloalkyl, unsubstituted or substituted with one or more halogen atoms, or 3 -6-membered heterocycloalkyl, unsubstituted or substituted with one or more halogen atoms,

each of R ¹ and R ² independently represents -H, a halogen atom, -NO ₂ , -CF ₃ , phenyl, unsubstituted or substituted with one or more halogen atoms, C _1-5 linear or branched alkyl, unsubstituted or substituted with one or more halogen atoms, or a C _1-5 linear or branched alkoxy group, unsubstituted or substituted with one or more halogen atoms.

In this document, the terms "halogen" and "halo" mean fluorine, chlorine, bromine or iodine.

In this document, the term "cycloalkyl" means a monocyclic or polycyclic saturated ring containing carbon and hydrogen atoms and not containing carbon-carbon multiple bonds. Examples of cycloalkyl groups include (C ₃ -C ₆ )-cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl groups. The cycloalkyl group may be unsubstituted or optionally substituted. In one embodiment, the cycloalkyl group is a monocyclic ring or a bicyclic ring.

As used herein, the term "heterocycloalkyl" means a ring in which at least one of the carbon atoms of the cycloalkyl group is independently replaced by nitrogen, oxygen, and sulfur.

As used herein, the term "pharmaceutically acceptable salt(s)" refers to a salt derived from the active compounds of the present invention with relatively non-toxic acids or bases, depending on the specific substituents of those compounds. Where compounds contain a relatively acidic group, base addition salts can be prepared by contacting neutral compounds with a sufficient amount of the desired base and a pure or inert solvent. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, calcium, aluminum, organic amines, magnesium, and the like. If the compounds contain a relatively basic group, acid addition salts can be prepared by bringing the neutral compounds into contact with a sufficient amount of the desired acid and a pure or inert solvent. Suitable pharmaceutically acceptable acid addition salts include salts derived from non-toxic organic acids, including acetic acid, propionic acid, isobutyl acid, oxalic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid , benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like, and non-toxic inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarboxylic acid, phosphoric acid, monohydrophosphoric acid, but not limited to dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydrogen iodide, phosphoric acid, and the like. They also include amino acid salts, eg arginate or analogs thereof, as well as organic acid analogs, eg glucuronic or galacturonic acid. Some specific compounds of the present invention contain both basic and acidic functionalities to convert the compounds into salts with a basic or acid moiety (base or acid addition).

As used herein, the phrase "compound(s) according to the present invention" includes any compound(s) according to the chemical formula 1, as well as its clathrates, hydrates, solvates or polymorphs. Even if the term “compound(s) of the present invention” does not mention a pharmaceutically acceptable salt thereof, the term includes salts of said compound. In one embodiment, the compounds of the present invention include compounds that are stereochemically pure, e.g., substantially free of other stereoisomers (e.g., greater than 85% a.i., greater than 90% a.e., greater than 95% a.e. , greater than 97% ee or greater than 99% ee). Thus, if the compounds according to the chemical formula 1 in accordance with the present invention or their salts are tautomeric isomers and/or stereoisomers (for example, geometric isomers and conformational isomers), such isolated isomers and mixtures thereof are also included in the present invention. Where the compounds of the present invention or their salts contain an asymmetric carbon atom, their active optical isomers and their racemic mixtures are also included in the present invention.

In this document, the term "polymorphic" refers to solid crystalline forms of the compounds described in the present invention, or its complexes. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectroscopic properties. Various physical properties include, but are not limited to, stability (eg, to heat or light), compressibility and density (important in formulation and product manufacture), and dissolution rates (which may affect bioavailability). Differences in stability can lead to changes in reactivity (for example, a difference in oxidation, in which a dosage form consisting of one polymorph fades faster than a dosage form consisting of another) or mechanical properties (for example, tablets crumble during storage, because kinetically more a suitable polymorph changes into a more thermodynamically stable one) or both of the above characteristics (for example, tablets of one polymorph are more prone to breaking at high humidity values). Various physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form solvates or may be more difficult to filter or wash away impurities than another due to, for example, particle shape or particle size distribution.

Used in this application, the term "solvate" means a compound or its salt described in this document, which additionally includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces of intermolecular interaction. Preferred solvents are volatile, non-toxic and acceptable for human consumption in trace amounts.

As used herein, the term "hydrate" means a compound or salt thereof as described herein that further contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

As used herein, the term "clathrate" means a compound or salt thereof in the form of a crystal lattice containing cavities (eg, channels) within which impurity molecules (eg, solvent or water) are present.

In one embodiment according to the present invention, substituent A of chemical formula 1 is preferably phenyl, linear or branched C _1-5 alkyl, unsubstituted or substituted with one or more halogen atoms, or 3- or 6-membered heterocycloalkyl containing an O heteroatom or S unsubstituted or substituted with one or more halogen atoms, where R ¹ and R ² are each independently -H, a halogen atom, -NO ₂ , -CF ₃ , phenyl, linear or branched C _1-5 -alkyl, unsubstituted or substituted with one or more halogen atoms, or a linear or branched C _1-5 alkoxy group, unsubstituted or substituted with one or more halogen atoms.

In one embodiment according to the present invention, substituent A of chemical formula 1 is more preferably phenyl,

and each of R ¹ and R ² independently represents -H, a halogen atom, -NO ₂ , -CF ₃ , -CH ₃ , -C(CH ₃ ) ₃ or phenyl.

In order to achieve the above object, the present inventors performed various evaluation experiments after synthesizing various compounds in order to ensure the reliability of compounds having high PDE9A inhibitory activity and high selectivity for them and their use, and finally, the present invention was completed by confirming that that the compounds of the present invention are suitable for the purposes of the present invention.

Non-limiting examples of preferred compounds of the present invention include those listed in Table 1 below and their pharmaceutically acceptable salts.

In addition, in the present invention, as shown in Scheme 1 below, it is proposed

method A for obtaining a compound represented by chemical formula 1 by reacting a compound represented by chemical formula 2 with a compound represented by chemical formula 3; and

method B for preparing a compound represented by chemical formula 1 by reacting a compound represented by chemical formula 4 with a compound represented by chemical formula 5.

[Diagram 1]

In scheme 1A and R correspond to the definitions given in chemical formula 1.

Next, the production method represented by Scheme 1 according to the present invention will be described in detail.

The compound represented by the chemical formula 1 according to the present invention can be obtained by adding a pyrazolpyrimidinone compound represented by the chemical formula 2 as a starting material to a benzoxazole compound represented by the chemical formula 3 in the presence of a base (method A), as well as by adding a thioxo compound , represented by the chemical formula 4 as a starting material, to a halogen compound represented by the chemical formula 5, in the presence of a base (method B) as shown in Scheme 1 above. Specific examples are given below.

How to obtain

As shown in Scheme 1, the compound represented by the chemical formula 1 can be obtained by reacting the compound represented by the chemical formula 2 and the compound represented by the chemical formula 3 (method A), or by reacting the compound represented by the chemical formula 4, and the compound represented by the chemical formula 5 (method B) in the presence of a base.

In this case, the base is used to accelerate the reaction and increase the yield, and available bases include organic bases, for example, N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]- 7-undecene (DBU) or inorganic bases such as sodium bicarbonate, cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. They can be used singly or in combination and in an equivalent amount or in excess.

In addition, solvents that can be used in this reaction include ethereal solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane; aromatic hydrocarbon solvents such as benzene, toluene and xylene; dimethylformamide (DMF); dimethyl sulfoxide; acetonitrile and the like. They can be used singly or in combination. The reaction temperature is from 0°C to the boiling point of the solvent.

Preparation of 1 starting material (compound represented by chemical formula 2)

The compound of Chemical Formula 2, which is the starting material of Scheme 1, can be produced according to a production method including the step of obtaining a compound represented by Chemical Formula 8 by reacting a compound represented by Chemical Formula 6 with a compound represented by Chemical Formula 7 (stage 1); and

the step of reacting the compound represented by the chemical formula 8 obtained in said step 1 to obtain the compound represented by the chemical formula 2 (step 2) as shown in Scheme 2 below.

[Diagram 2]

In scheme 2, A corresponds to the definition given in chemical formula 1.

The following is a detailed description of the production method shown in Scheme 2.

In the production method shown in Scheme 2, step 1 is the step of obtaining a compound represented by the chemical formula 8 by reacting the compound represented by the chemical formula 6 with the compound represented by the chemical formula 7. Specifically, this is the step of obtaining the compound represented by the chemical formula 7. the chemical formula 8, due to the condensation reaction of the halide represented by the chemical formula 6, under basic conditions.

In the above reaction, the compound represented by the chemical formula 6 was a commercially available compound.

In addition, the bases used in this reaction include organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in excess.

In addition, the reaction solvent is an ether solvent such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, a lower alcohol such as methanol, ethanol, propanol and butanol, dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), acetonitrile, water, etc., which can be used alone or in combination, and the reaction temperature is from 0°C to the boiling point of the solvent.

In the production method shown in Scheme 2, step 2 is a step of obtaining a compound represented by the chemical formula 2 by reacting the compound represented by the chemical formula 8 obtained in step 1. In particular, in this step, the pyrazolpyrimidinone compound represented by the chemical formula the formula 2 is obtained by hydrolyzing the halogen compound represented by the chemical formula 8, which is obtained in step 1, under basic conditions.

In this reaction, the base includes inorganic bases such as sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, cesium carbonate, barium hydroxide, and the like, and can be used alone or in combination in an equivalent amount or in excess.

In addition, solvents that can be used in the reaction include ethereal solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohol-based solvents such as methanol and ethanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, water, and the like. They can be used singly or in combination. The reaction temperature is from 0°C to the boiling point of the solvent.

Getting 2 starting material (compound represented by chemical formula 3 or 5)

The compound according to the chemical formula 3, which is the raw material of the scheme 1, can be obtained in accordance with the production method, including the step of obtaining the compound represented by the chemical formula 5 by bringing into the interaction of the compound represented by the chemical formula 9 (step 1); a step of obtaining a compound represented by the chemical formula 10 by reacting the compound represented by the chemical formula 5 obtained in step 1 (step 2); and a step of obtaining a compound represented by the chemical formula 3 by reacting the compound represented by the chemical formula 10 obtained in step 2 (step 3) as shown in Scheme 3 below.

[Diagram 3]

In Reaction Scheme 3, R corresponds to the definition in chemical formula 1.

This document describes in detail the production method shown in Scheme 3.

In the production method shown in Scheme 3, step 1 is a step in which the compound represented by the chemical formula 5 is obtained from the compound represented by the chemical formula 9. Specifically, this is the step of obtaining the compound represented by the chemical formula 5 by aminophenol condensation reaction , represented by the chemical formula 9, under basic conditions.

In the above reaction, the compound represented by the chemical formula 9 was a commercially available compound.

In addition, the bases used in this reaction include organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in excess.

In addition, the reaction solvent is an ether solvent such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, a lower alcohol such as methanol, ethanol, propanol and butanol, dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), acetonitrile, water, etc., which can be used alone or in combination, and the reaction temperature is from 0°C to the boiling point of the solvent.

In the production method shown in Scheme 3, step 2 is the step of obtaining a compound represented by the chemical formula 10 by reacting the compound represented by the chemical formula 5 obtained in step 1. Specifically, this is the step of obtaining a thioacetyl compound represented by the chemical formula formula 10 by replacing the halogen compound represented by the chemical formula 5 obtained in step 1.

However, solvents that can be used in this reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohol-based solvents such as methanol and ethanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, acetone, water, and the like. They can be used singly or in combination. The reaction temperature is from 0°C to the boiling point of the solvent.

In the production method shown in Scheme 3, step 3 is a step of obtaining a compound represented by chemical formula 3 by reacting a compound represented by chemical formula 10 obtained in step 2. Specifically, this is a step of obtaining a thiol compound represented by chemical formula 3. formula 3 by deprotecting the thioacetyl compound represented by the chemical formula 10 obtained in step 2.

In this reaction, the bases used in said reaction include organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like, and they can be used in an equivalent amount or in excess.

In addition, the reaction solvent includes an ether solvent such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, a lower alcohol such as methanol, ethanol, propanol and butanol, dimethylformamide (DMF ), dimethyl sulfoxide (DMSO), acetonitrile, water, etc. They can be used alone or in combination, and the reaction temperature is from 0°C to the boiling point of the solvent.

Getting 3 starting material (compound represented by the chemical formula 4)

The compound of Chemical Formula 4, which is the starting material of Scheme 1, can be produced according to a production method including the step of obtaining a compound represented by Chemical Formula 12 by reacting a compound represented by Chemical Formula 11 with a compound represented by Chemical Formula 7 (stage 1); a step of obtaining a compound represented by the chemical formula 13 by reacting the compound represented by the chemical formula 12 obtained in step 1 (step 2); and a step of obtaining a compound represented by the chemical formula 4 by reacting the compound represented by the chemical formula 13 obtained in step 2 (step 3) as shown in Scheme 4 below.

[Diagram 4]

In Reaction Scheme 4, A corresponds to the definition in chemical formula 1.

This document describes in detail the production method shown in Scheme 4.

In the production method shown in Scheme 4, step 1 is the step of obtaining a compound represented by the chemical formula 12 by reacting the compound represented by the chemical formula 11 with the compound represented by the chemical formula 7. Specifically, this is the step of obtaining the compound represented by the chemical formula 7. Specifically, this is the step of obtaining the compound represented by the chemical formula 12 the chemical formula 12 by the condensation reaction of the acrylate compound represented by the chemical formula 11 with a hydrazine compound under basic conditions.

In the above reaction, the compound represented by the chemical formula 11 was a commercially available compound.

In addition, the bases used in this reaction include organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like. They can be used in an equivalent amount or in excess.

In addition, the reaction solvent includes an ether solvent such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, a lower alcohol such as methanol, ethanol, propanol and butanol, dimethylformamide (DMF ), dimethyl sulfoxide (DMSO), acetonitrile, water, etc. They can be used alone or in combination, and the reaction temperature is from 0°C to the boiling point of the solvent.

In the production method shown in Scheme 4, step 2 is the step of obtaining a compound represented by the chemical formula 13 by reacting the compound represented by the chemical formula 12 obtained in step 1. In particular, this is the step of obtaining a compound represented by a thiourea derivative, represented by the chemical formula 13 by adding an amine compound represented by the chemical formula 12 obtained in Step 1 to a thioisocyanate compound.

Meanwhile, solvents that can be used in this reaction include ethereal solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane, aromatic hydrocarbon solvents such as benzene, toluene and xylene, alcohol-based solvents such as methanol and ethanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, water, and the like. They can be used singly or in combination. The reaction temperature is from 0°C to the boiling point of the solvent.

In the production method shown in Scheme 4, step 3 is a step of obtaining a compound represented by chemical formula 4 by reacting a compound represented by chemical formula 13 obtained in step 2. Specifically, this is a step of obtaining a thioxo compound represented by chemical formula 4, by cyclization of the thiourea compound represented by the chemical formula 13, obtained in step 2.

Here, the bases used in said reaction include organic bases such as pyridine, triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and inorganic bases such as sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and the like. They can be used in an equivalent amount or in excess.

In addition, the reaction solvent is an ether solvent such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane, an aromatic hydrocarbon solvent such as benzene, toluene and xylene, a lower alcohol such as methanol, ethanol, propanol and butanol, dimethylformamide ( DMF), dimethyl sulfoxide (DMSO), acetonitrile, water, etc. They can be used alone or in combination, and the reaction temperature is from 0°C to the boiling point of the solvent.

In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound according to chemical formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In yet another embodiment, the present invention provides a method of treating a disease or condition comprising administering a therapeutically effective amount of a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof, said disease or condition being a phosphodiesterase 9A related disease.

Thus, the present invention provides a medical use, characterized in that a compound according to the chemical formula 1 according to the present invention or a pharmaceutically acceptable salt thereof is used as an active ingredient. In one embodiment, the implementation of the medical application according to the present invention is a disease associated with phosphodiesterase 9A.

In one embodiment, the associated disease associated with phosphodiesterase 9A is a neurological disease or a psychiatric disease. In one embodiment, the neurological or psychiatric disorder is Alzheimer's disease, Huntington's disease, Lewy body dementia, or Pick's syndrome.

In yet another embodiment, the phosphodiesterase 9A-associated disease is heart failure, particularly cardiac output-sparing heart failure or sickle cell anemia.

The compounds of the present invention are usually administered in a therapeutically effective amount. The compounds of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route of administration, and at an effective dosage for the intended treatment. Typically, effective doses are from about 0.001 to about 100 mg/kg body weight/day, preferably from about 0.01 to about 50 mg/kg/day, and are administered in single or multiple doses. Suitable dosage levels may be less than the lower end of this range, depending on the age, type of animal and the disease or condition being treated. In other cases, even higher dosages can be used without negative side effects. Higher dosages can be divided into several smaller dosages for administration during the day. Methods for determining the appropriate dosage are well known in the art to which the present invention pertains, and for example Remington: The Science and Practice°f Pharmacy, Mack Publishing Co., 20th ed., 2000 can be used.

For the treatment of the above diseases or conditions, the compounds described herein or their pharmaceutically acceptable salts can be administered by the following methods.

Oral administration

The compounds described herein can be administered orally, including by ingestion, so that they enter the gastrointestinal tract or are absorbed into the bloodstream directly from the oral cavity (eg, buccal or sublingual administration).

Suitable formulations for oral administration include solid, liquid, gel or powder formulations and are presented in dosage forms such as tablet, lozenge, capsule, granule or powder.

Compositions for oral administration can be made in both immediate and modified release, including delayed or sustained release, optionally with an enteric coating.

Liquid formulations may include solutions, syrups and suspensions, which can be used in soft or hard capsules. Such formulations may include a pharmaceutically acceptable carrier such as water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also contain one or more of emulsifying and/or suspending agents.

In a tablet dosage form, the amount of drug present may be from about 0.05 to about 95% by weight, more typically from about 2 to about 50% by weight of the dosage form. In addition, the tablets may contain a disintegrant, the content of which is from 0.5 to 35% by weight, more typically from about 2 to about 25% by weight of the dosage form. Examples of disintegrants include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

Suitable lubricants in a tablet may be present in amounts from about 0.1 to about 5% by weight and include, but are not limited to, talc, silica, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like.

Suitable binders for use in a tablet include, but are not limited to, gelatin, polyethylene glycol, carbohydrates, gums, starch, polyvinyl pyrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like. Suitable diluents for use in a tablet include, but are not limited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, microcrystalline cellulose, and starch.

Suitable solubilizers for use in a tablet may be present in amounts from about 0.1 to about 3% by weight and include polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, diethylene glycol monoethyl ether, dimethyl isosorbide, polyethylene glycol, castor oil (natural or hydrogenated), HCOR ™ (Nikkol), but not limited to oleyl ether, Gelucire™, caprylic/caprylic acid mono/diglyceride, sorbitan fatty acid esters and Solutol HS™.

parenteral administration

The compounds of the present invention can be administered directly to the bloodstream, muscles or internal organs. Suitable routes of parenteral administration include intravenous, intramuscular, subcutaneous, intra-arterial, intraperitoneal, intrathecal, intracranial, and the like. Suitable devices for parenteral administration include injection (including syringes with and without needles) and infusion methods.

Compositions for parenteral administration can be made both with immediate and modified release, including delayed or delayed.

Most parenteral formulations are aqueous solutions containing excipients, including salts, buffering agents, and isotonic agents.

Parenteral formulations may also be prepared in anhydrous form (eg by lyophilization) or in the form of sterile non-aqueous solutions. Such forms can be used with a suitable carrier medium, such as sterile water. When preparing parenteral solutions, solubility enhancers can also be used.

Local application

The compounds of the present invention may be applied topically to the skin or administered transdermally. Topical formulations may include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical formulations may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. .P. Topical application can also be carried out using electroporation, iontophoresis, phonophoresis, and the like.

Compositions for topical application can be made both with immediate and modified release, including delayed or sustained release.

Positive Effects

The present invention provides a compound capable of exhibiting various pharmacological activities by inhibiting PDE 9A activity, a pharmaceutical composition containing said compound as an active ingredient, a medical use thereof (especially for the treatment or alleviation of neuropathic diseases and psychiatric diseases), and a method for treating or preventing comprising administering to an individual in need thereof.

Invention principle

The present invention will be described in more detail based on the following examples, however, they are not intended to limit the essence of the present invention. In addition, those skilled in the art will be able to add various modifications and changes to the present invention to the extent that the essence of the present invention does not change.

<Production Example 1> Production of 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Obtaining tert-butyl-2-(tetrahydro-4H-pyran-4-ylidene)hydrazine-1-carboxylate

3 g of tetrahydro-4H-pyran-4-one (29.96 mmol) was dissolved in 60 ml of hexane, 3.96 g of tert-butylcarbazite (29.96 mmol) was added, followed by stirring under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 6.4 g of the title compound (29.95 mmol) in 100% yield.

Rf = 0.19 (hexane:ethyl acetate = 1:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.65 (br s, 1H), 3.69 (t, J = 5.7 Hz, 2H), 3.60 (t, J = 5.7 Hz, 2H), 2.41 (t, J = 5.7 Hz, 2H), 2.27 (t, J = 5.7 Hz, 2H), 1.43 (s, 9H)

Step 2: Preparation of tert-butyl-2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate

6.4 g of tert-butyl 2-(tetrahydro-4H-pyran-4-ylidene)hydrazine-1-carboxylate (29.95 mmol) obtained in step 1 was dissolved in 80 ml of THF, 12.7 g of triacetoxyborohydride was added sodium (59.92 mmol) and stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was extracted with 30 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:2, v/v) to give 6 g of the title compound (27.74 mmol) in 92% yield.

Rf = 0.38 (hexane:ethyl acetate = 1:2, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 6.24 (br s, 1H), 3.95-3.99 (m, 2H), 3.38-3.43 (m, 2H), 3.05 -3.11(m, 1H), 1.75-1.81(m, 2H), 1.40-1.52(m, 11H)

Step 3: Preparation of (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride

6 g of tert-butyl 2-(tetrahydro-2H-pyran-4-yl)hydrazine-1-carboxylate (27.74 mmol) obtained in step 2 was dissolved in 60 ml of methanol and hydrochloric acid was added, followed by stirring at 50 °C for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give 4 g of the title compound (26.21 mmol) in 94% yield.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.25 (br s, 1H), 3.83-3.92(m, 2H), 3.23-3.31 (m, 2H), 3 .08-3.18 (m, 1H), 1.84-1.95 (m, 2H), 1.41-1.54 (m, 2H)

Step 4: Preparation of 4,6-dichloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

5.55 g of 2,4,6-trichloropyrimidin-5-carbaldehyde (26.21 mmol) was dissolved in 60 ml of ethanol and 4 g of (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride (26.21 mmol) was added, obtained in the above step 3, and 14 ml of N,N-diisopropylethylamine (78.63 mmol) at -78 °C and stirred for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 6.5 g of the title compound (23.80 mmol) in 91% yield.

Rf = 0.20 (hexane:ethyl acetate = 9:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 4.96-5.03 (m, 1H), 3.98-4.02 (m, 2H), 3, 56-3.61 (m, 2H), 2.10-2.19 (m, 2H), 1.90-1.95 (m, 2H)

Step 5: Preparation of 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

6.5 g of 4,6-dichloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (23.80 mmol) obtained in Step 4 above was dissolved in 50 ml of THF and added 25 ml of 2N. sodium hydroxide (47.60 mmol) and the mixture was stirred at reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid and the precipitated solid was filtered to give 5.4 g of the title compound (21.20 mmol) in 89% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.21 (br s, 1H), 8.11 (s, 1H), 4.75-4.81 (m, 1H), 3.95-3 .99 (m, 2H), 3.51-3.56 (m, 2H), 2.05-2.12 (m, 2H), 1.81-1.86 (m, 2H)

<Production Example 2> Production of benzo[d]oxazol-2-ylmethanethiol

Step 1: Preparation of 2-(chloromethyl)benzo[d]oxazole

500 mg of 2-aminophenol (4.58 mmol) was dissolved in 15 ml of xylene, and 0.55 ml of chloroacetyl chloride (6.87 mmol) was added at 0°C, followed by stirring. After 30 minutes, 0.7 ml of triethylamine (5.04 mmol) was added and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=7:1, v/v) to give 600 g of the title compound (3.58 mmol) in 78% yield.

Rf = 0.47 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.76-7.80 (m, 2H), 7.41-7.48 (m, 2H), 5.07 (s, 2H)

Step 2: Preparation of S-(benzo[d]oxazol-2-ylmethyl)ethanethioate

280 mg of 2-(chloromethyl)benzo[d]oxazole (1.67 mmol) obtained in Step 1 was dissolved in 8 ml of acetone, and 286 mg of potassium thioacetate (2.50 mmol) was added, followed by stirring for 1 hour at 60 °C After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 290 mg of the title compound (1.39 mmol) in 84% yield.

Rf = 0.28 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.68-7.73 (m, 1H), 7.49-7.54 (m, 1H), 7.30-7.37 (m, 2H), 4.41 (s, 2H), 2.45(s, 3H)

Step 3: Preparation of benzo[d]oxazol-2-ylmethanethiol

290 mg of S-(benzo[d]oxazol-2-ylmethyl)ethanethioate (1.39 mmol) obtained in step 1 was dissolved in a mixture of 4 ml of methanol and 1 ml of water and 386 mg of potassium carbonate (2.79 mmol) was added followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was extracted with 30 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure, obtaining 170 mg of the title compound (1.03 mmol) with 74% exit.

Rf = 0.40 (hexane:ethyl acetate = 3:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.70-7.73 (m, 1H), 7.49-7.55 (m, 1H), 7.32-7.39 (m, 2H), 4.17 (s, 1.3H ), 3.99 (d, J = 8.3 Hz, 0.7H), 2.24 (t, J = 8.3 Hz, 0.4H), 1.65 (s, 0.6H)

<Example 1> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one

50 mg 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in the above Production Example 1 was dissolved in 3 ml of DMF, and 65 mg of benzo[d]oxazol-2-ylmethanethiol (0.39 mmol) obtained in Production Example 2 and 83 mg of potassium carbonate (0.60 mmol) were added. The mixture was stirred at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 55 mg of the title compound (0.14 mmol) in 72% yield.

Rf = 0.21 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.65 (br s, 1H), 7.95 (s, 1H), 7.68-7.71 (m, 2H), 7.33-7 .39 (m, 2H), 4.80 (s, 2H), 4.50-4.57 (m, 1H), 3.84-3.89 (m, 2H), 3.35-3.40 (m, 2H), 1.89-1.97 (m, 2H), 1.51-1.56 (m, 2H)

<Production Example 3> Production of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Preparation of 4,6-dichloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine

2 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (9.44 mmol) was dissolved in 30 ml of ethanol and 0.9 ml of phenylhydrazine hydrochloride (9.44 mmol) and 4.8 ml of N,N-diisopropylethylamine (28 .32 mmol) at -78°C followed by stirring for 3 hours. After completion of the reaction, the resulting product was extracted with 300 ml of ethyl acetate, washed with 200 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=20:1, v/v) to give 1.7 g of the title compound (6.41 mmol) in 68% yield.

Rf = 0.50 (hexane:ethyl acetate = 10:1, v/v)

¹ H NMR (300 MHz, CD ₃ OD) δ 8.35 (s, 1H), 8.17 (d, J = 8.5 Hz, 2H), 7.59 (dd, J = 8.5, 7 .6 Hz, 2H), 7.44 (dd, J = 7.6, 7.6 Hz, 1H)

Step 2: Preparation of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

1.9 g of 4,6-dichloro-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (8.98 mmol) obtained in step 1 was dissolved in 20 ml of THF, 10 ml of 2N hydrochloric acid were added. sodium hydroxide (17.96 mmol) and the mixture was stirred at reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid and the precipitated solid was filtered to give 2.2 g of the title compound (8.98 mmol) in 99% yield.

Rf = 0.23 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.47 (br s, 1H), 8.35 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7, 58 (dd, J=8.0, 7.4Hz, 2H), 7.43 (dd, J=7.4, 7.4Hz, 1H)

<Example 2> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

60 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.24 mmol) obtained in Preparation Example 2 was dissolved in 5 ml of DMF and 150 mg of benzo[d]oxazol-2-ylmethanethiol (0.91 mmol) obtained in Production Example 2 and 186 mg of potassium carbonate (1.35 mmol) were added, followed by stirring at 60° C. for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 70 mg of the title compound (0.19 mmol) in 78% yield.

Rf = 0.27 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.96 (br s, 1H), 8.22 (s, 1H), 7.93 (d, J = 7.8 Hz, 2H), 7, 69 (dd, J = 8.8, 8.3 Hz, 2H), 7.45 (dd, J = 7.8, 7.5 Hz, 2H), 7.32-7.38 (m, 3H) , 5.75(s, 2H)

<Production Example 4> Production of (5-methylbenzo[d]oxazol-2-yl)methanethiol

Step 1: Preparation of 2-(chloromethyl)-5-methylbenzo[d]oxazole

500 mg of 2-amino-4-methylphenol (4.06 mmol) was dissolved in 15 ml of xylene, and 0.48 ml of chloroacetyl chloride (6.09 mmol) was added at 0°C, followed by stirring. After 30 minutes, 0.62 ml of triethylamine (4.47 mmol) was added and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 240 mg of the title compound (1.32 mmol) in 33% yield.

Rf = 0.54 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.54 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H ), 4.76(s, 2H), 2.49(s, 3H)

Step 2: Preparation of S-((-5-methylbenzo[d]oxazol-2-yl)methyl)ethanethioate

220 mg of 2-(chloromethyl)-5-methylbenzo[d]oxazole (1.21 mmol) obtained in step 1 was dissolved in 6 ml of acetone, and 208 mg of potassium thioacetate (1.82 mmol) was added, followed by stirring at 60° C within 1 hour. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 250 mg of the title compound (1.13 mmol) in 93% yield.

Rf = 0.40 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.49 (s, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.16 (d, J = 8.3 Hz, 1H ), 4.40 (s, 2H), 2.47 (s, 3H), 2.45 (s, 3H)

Step 3: Preparation of (5-methylbenzo[d]oxazol-2-yl)methanethiol

230 mg of S-((-5-methylbenzo[d]oxazol-2-yl)methyl)ethanethioate (1.04 mmol) obtained in step 2 was dissolved in a mixture of 4 ml of methanol and 1 ml of water and 287 mg of potassium carbonate was added (2.08 mmol) followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 170 mg of the title compound (0.95 mmol) in 91% yield.

Rf = 0.17 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.49 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.3 Hz, 1H), 3.96 (d, J = 8.4 Hz, 2H), 2.48 (s, 3H), 2.23 (t, J = 8.4 Hz, 1H)

<Example 3> Preparation of 6-(((5-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

50 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in Preparation Example 2 was dissolved in 5 ml of DMF and 100 mg of (5-methylbenzo[d]oxazol-2-yl)methanethiol (0.55 mmol) obtained in the above Production Example 4 and 83 mg of potassium carbonate (0.60 mmol) were added, followed by stirring at 60°C for within 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 60 mg of the title compound (0.15 mmol) in 77% yield.

Rf = 0.27 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.91 (br s, 1H), 7.94 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.49 (s, 1H), 7.47 (dd, J = 7.8, 7.4 Hz, 2H), 7.36 (dd, J = 7.4, 7.4 Hz , 1H), 7.18 (d, J = 8.5 Hz, 1H), 4.79 (s, 2H), 2.38 (s, 3H)

<Production Example 5> Production of (5-fluorobenzo[d]oxazol-2-yl)methanethiol

Step 1: Preparation of 2-(chloromethyl)-5-methylbenzo[d]oxazole

500 mg of 2-amino-4-fluorophenol (3.93 mmol) was dissolved in 15 ml of xylene, and 0.50 ml of chloroacetyl chloride (5.90 mmol) was added at 0°C, followed by stirring. After 30 minutes, 0.60 ml of triethylamine (4.32 mmol) was added and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 200 mg of the title compound (1.08 mmol) in 27% yield.

Rf = 0.56 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃)δ 7.52 (dd, J = 8.9, 4.8 Hz, 1H), 7.45 (dd, J = 8.1, 2.5 Hz, 1H), 7.16 (ddd, J = 9.1, 8.9, 2.5Hz, 1H), 4.76(s, 2H)

Step 2: Preparation of S-((-5-fluorobenzo[d]oxazol-2-yl)methyl)ethanethioate

180 mg of 2-(chloromethyl)-5-fluorobenzo[d]oxazole (0.97 mmol) obtained in step 1 was dissolved in 6 ml of acetone, and 166 mg of potassium thioacetate (1.45 mmol) was added, followed by stirring at 60° C within 1 hour. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 210 mg of the title compound (0.93 mmol) in 96% yield.

Rf = 0.44 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.45 (dd, J = 8.8, 4.2 Hz, 1H), 7.39 (dd, J = 8.3, 2.7 Hz, 1H), 7.09 (ddd, J = 9.0, 8.8, 2.7Hz, 1H), 4.40(s, 2H), 2.46(s, 3H)

Step 3: Preparation of (5-fluorobenzo[d]oxazol-2-yl)methanethiol

190 mg of S-((-5-fluorobenzo[d]oxazol-2-yl)methyl)ethanethioate (0.84 mmol) obtained in step 2 was dissolved in a mixture of 4 ml of methanol and 1 ml of water and 233 mg of potassium carbonate was added (1.69 mmol) followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 115 mg of the title compound (0.63 mmol) in 75% yield.

Rf = 0.22 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.47 (dd, J = 8.8, 4.1 Hz, 1H), 7.40 (dd, J = 9.2, 2.5 Hz, 1H), 7.10 (ddd, J = 9.2, 8.8, 2.5 Hz, 1H), 3.97 (d, J = 8.2 Hz, 2H), 2.25 (t, J = 8.2 Hz, 1H)

<Example 4> Preparation of 6-(((5-fluorobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

50 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in Preparation Example 2 was dissolved in 5 ml of DMF and 90 mg of (5-fluorobenzo[d]oxazol-2-yl)methanethiol (0.49 mmol) obtained in Preparation Example 5 and 83 mg of potassium carbonate (0.60 mmol) were added, followed by stirring at 60° C. for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 54 mg of the title compound (0.14 mmol) in 69% yield.

Rf = 0.27 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.91 (br s, 1H), 8.22 (s, 1H), 7.90 (d, J = 8.3 Hz, 2H), 7, 72 (dd, J = 8.3, 4.7 Hz, 1H), 7.60 (dd, J = 9.2, 2.6 Hz, 1H), 7.46 (dd, J = 8.3, 7.4Hz, 2H), 7.36(dd, J=7.4, 7.4Hz, 1H), 7.22(ddd, J=9.1, 8.3, 2.6Hz, 1H ), 4.82(s, 2H)

<Production Example 6> Production of (6-methylbenzo[d]oxazol-2-yl)methanethiol

Step 1: Preparation of 2-(chloromethyl)-6-methylbenzo[d]oxazole

500 mg of 6-amino-m-cresol (4.00 mmol) was dissolved in 15 ml of xylene, and 0.48 ml of chloroacetyl chloride (6.09 mmol) was added at 0°C, followed by stirring. After 30 minutes, 0.62 ml of triethylamine (4.47 mmol) was added and the mixture was stirred under reflux for 3 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=20:1, v/v) to give 640 g of the title compound (3.52 mmol) in 88% yield.

Rf = 0.64 (hexane:ethyl acetate = 9:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.52 (dd, J = 8.9, 4.8 Hz, 1H), 7.45 (dd, J = 8.1, 2.5 Hz, 1H) , 7.16 (ddd, J = 9.1, 8.9, 2.5 Hz, 1H), 4.76 (s, 2H)

Step 2: Preparation of S-((-6-methylbenzo[d]oxazol-2-yl)methyl)ethanethioate

600 mg of 2-(chloromethyl)-6-methylbenzo[d]oxazole (3.30 mmol) obtained in step 1 was dissolved in 10 ml of acetone, and 566 mg of potassium thioacetate (4.96 mmol) was added, followed by stirring at 60° C within 1 hour. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 690 mg of the title compound (3.12 mmol) in 94% yield.

Rf = 0.18 (hexane:ethyl acetate = 9:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.57 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 7.15 (d, J = 8.0 Hz, 1H ), 4.39 (s, 2H), 2.48 (s, 3H), 2.44 (s, 3H)

Step 3: Preparation of (6-methylbenzo[d]oxazol-2-yl)methanethiol

500 mg of S-((-6-methylbenzo[d]oxazol-2-yl)methyl)ethanethioate (2.26 mmol) obtained in step 2 was dissolved in a mixture of 6 ml of methanol and 1 ml of water and 624 mg of potassium carbonate was added (4.52 mmol) followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was extracted with 50 ml of ethyl acetate, washed with 50 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 370 mg of the title compound (2.06 mmol) in 91% yield.

Rf = 0.36 (hexane:ethyl acetate = 3:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.58 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H ), 3.96 (d, J = 8.3 Hz, 2H), 2.50 (s, 3H), 2.22 (t, J = 8.3 Hz, 1H)

<Example 5> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

50 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in Preparation Example 2 was dissolved in 5 ml of DMF and 108 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.60 mmol) obtained in Preparation Example 6 and 83 mg of potassium carbonate (0.60 mmol) were added, followed by stirring at 60 °C for within 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 67 mg of the title compound (0.17 mmol) in 86% yield.

Rf = 0.27 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.94 (br s, 1H), 8.23 (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7, 57 (d, J = 8.2 Hz, 1H), 7.45-7.49 (m, 3H), 7.37 (dd, J = 7.5, 7.5 Hz, 1H), 7.16 (d, J = 8.2 Hz, 1H), 4.79 (s, 2H), 2.41 (s, 3H)

<Production Example 7> Production of (5-chlorobenzo[d]oxazol-2-yl)methanethiol

Step 1: Preparation of 2-chloro-N-(5-chloro-2-hydroxyphenyl)acetamide

1 g of 2-amino-4-chlorophenol (6.96 mmol) was dissolved in 20 ml of MC, and 0.83 ml of chloroacetyl chloride (10.44 mmol) was added at 0°C, followed by stirring. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=3:1, v/v) to give 1.3 g of the title compound (5.91 mmol) in 85% yield.

Rf = 0.20 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) 10.81 (br s, 1H), 6.94-6.98 (m, 2H), 6.90 (d, J = 2.0 Hz, 1H) , 4.59(s, 2H)

Step 2: Preparation of 5-chloro-2-(chloromethyl)benzo[d]oxazole

200 mg of 2-chloro-N-(5-chloro-2-hydroxyphenyl)acetamide (0.91 mmol) obtained in step 1 was dissolved in 5 ml of phenol and 78 mg of p-toluenesulfonyl acid (0.45 mmol)) was added followed by stirring under reflux for 3 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 180 mg of the title compound (0.89 mmol) in 98% yield.

Rf = 0.48 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.93 (d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.53 (dd , J = 8.6, 2.0 Hz, 1H), 5.09 (s, 2H)

Step 3: Preparation of S-((5-chlorobenzo[d]oxazol-2-yl)methyl)ethanethioate

180 mg of 5-chloro-2-(chloromethyl)benzo[d]oxazole (0.89 mmol) obtained in Step 2 was dissolved in 6 ml of acetone, and 152 mg of potassium thioacetate (1.33 mmol) was added, followed by stirring at 60 °C for 1 hour. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 200 mg of the title compound (0.83 mmol) in 93% yield.

Rf = 0.38 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.84 (d, J = 1.9 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.45 (dd , J = 8.5, 1.9 Hz, 1H), 4.47 (s, 2H), 2.43 (s, 3H)

Step 4: Preparation of (5-chlorobenzo[d]oxazol-2-yl)methanethiol

200 mg of S-((5-chlorobenzo[d]oxazol-2-yl)methyl)ethanethioate (0.83 mmol) obtained in step 3 was dissolved in a mixture of 5 ml of methanol and 1 ml of water and 229 mg of potassium carbonate ( 1.66 mmol) followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was extracted with 30 ml of ethyl acetate, washed with 30 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 160 mg of the title compound (0.80 mmol) in 96% yield.

Rf = 0.28 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.70 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 2.0 Hz, 1H), 3.97 (d, J = 8.2 Hz, 2H), 2.25 (t, J = 8.2 Hz, 1H)

<Example 6> Preparation of 6-(((5-chlorobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

60 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.24 mmol) obtained in Preparation Example 2 was dissolved in 5 ml of DMF and 150 mg of (5-chlorobenzo[d]oxazol-2-yl)methanethiol (0.75 mmol) obtained in Preparation Example 7 and 100 mg of potassium carbonate (0.72 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 95 mg of the title compound (0.23 mmol) in 96% yield.

Rf = 0.17 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.95 (br s, 1H), 8.23 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7, 83 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.3, 7.5 Hz, 2H), 7.42 (dd, J = 8.6, 2.1 Hz, 1H), 7.36 (dd, J = 7.5, 7.5 Hz, 1H), 4.84 (s, 2H)

<Production Example 8> (5-Bromobenzo[d]oxazol-2-yl)methanethiol production

Step 1: Preparation of 2-chloro-N-(5-bromo-2-hydroxyphenyl)acetamide

500 mg of 2-amino-4-bromophenol (2.66 mmol) was dissolved in 10 ml of MC, and 0.32 ml of chloroacetyl chloride (3.99 mmol) was added at 0°C, followed by stirring. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=3:1, v/v) to give 600 mg of the title compound (2.27 mmol) in 85% yield.

Rf = 0.23 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.37 (br s, 1H), 7.12 (dd, J = 8.5, 2.3 Hz, 1H), 6.98 (d, J = 2 .3 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 4.65 (s, 2H)

Step 2: Preparation of 5-bromo-2-(chloromethyl)benzo[d]oxazole

600 mg of 2-chloro-N-(5-bromo-2-hydroxyphenyl)acetamide (2.27 mmol) obtained in step 1 was dissolved in 8 ml of phenol and 195 mg of p-toluenesulfonyl acid (1.13 mmol) was added with followed by stirring under reflux for 3 hours. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 340 mg of the title compound (1.38 mmol) in 61% yield.

Rf = 0.50 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.65 (dd , J = 8.6, 2.0 Hz, 1H), 5.09 (s, 2H)

Step 3: Preparation of S-((5-bromobenzo[d]oxazol-2-yl)methyl)ethanethioate

320 mg of 5-bromo-2-(chloromethyl)benzo[d]oxazole (1.30 mmol) obtained in Step 2 was dissolved in 6 ml of acetone, and 222 mg of potassium thioacetate (1.95 mmol) was added, followed by stirring at 60 °C for 1 hour. After completion of the reaction, the resulting product was extracted with 100 ml of ethyl acetate, washed with 100 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 360 mg of the title compound (1.26 mmol) in 97% yield.

Rf = 0.39 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.97 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.57 (dd , J = 8.5, 1.7 Hz, 1H), 4.48 (s, 2H), 2.43 (s, 3H)

Step 4: Preparation of (5-bromobenzo[d]oxazol-2-yl)methanethiol

350 mg of S-((5-bromobenzo[d]oxazol-2-yl)methyl)ethanethioate (1.22 mmol) obtained in step 3 was dissolved in a mixture of 5 ml of methanol and 1 ml of water and 338 mg of potassium carbonate ( 2.45 mmol) followed by stirring at room temperature for 2 hours. After completion of the reaction, the resulting product was extracted with 30 ml of ethyl acetate, washed with 30 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 290 mg of the title compound (1.19 mmol) in 97% yield.

Rf = 0.30 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.85 (d, J = 1.9 Hz, 1H), 7.49 (dd, J = 8.5, 1.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 3.97 (d, J = 8.3 Hz, 2H), 2.25 (t, J = 8.3 Hz, 1H)

<Example 7> Preparation of 6-(((5-bromobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

60 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.24 mmol) obtained in Preparation Example 2 was dissolved in 5 ml of DMF and 180 mg of (5-bromobenzo[d]oxazol-2-yl)methanethiol (0.75 mmol) obtained in Preparation Example 8 and 100 mg of potassium carbonate (0.72 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, extraction was performed with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na2SO4), and the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 88 mg of the title compound (0.19 mmol) in 81% yield.

Rf = 0.28 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.95 (br s, 1H), 8.23 (s, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7, 91 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 1H), 7.54 (dd, J = 8.5, 1.9 Hz, 1H), 7.47 (dd, J = 8.5, 7.2 Hz, 2H), 7.36 (dd, J = 7.2, 7.2 Hz, 1H), 4.84 (s, 2H)

<Production Example 9> Production of 6-chloro-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Preparation of tert-butyl 2-(4,4-difluorocyclohexylidene)hydrazine-1-carboxylate

300 mg of 4,4-difluorocyclohexanone (2.24 mmol) was dissolved in 6 ml of hexane, 296 mg of t-butylcarbazite (2.24 mmol) was added, followed by stirring under reflux for 3 hours. After completion of the reaction, the resulting product was concentrated under reduced pressure to give 550 g of the title compound (2.24 mmol) in 100% yield.

Rf = 0.30 (hexane:ethyl acetate = 3:1, v/v)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.72 (br s, 1H), 2.45 (t, J = 6.4 Hz, 2H), 2.37 (t, J = 6.4 Hz, 2H), 1.99-2.12 (m, 4H), 1.43 (s, 9H)

Step 2: Preparation of tert-butyl-2-(4,4-difluorocyclohexyl)hydrazine-1-carboxylate

550 mg of tert-butyl 2-(4,4-difluorocyclohexylidene)hydrazine-1-carboxylate (2.21 mmol) obtained in step 1 was dissolved in 5 ml of THF and 950 mg of sodium triacetoxyborohydride (4.48 mmol) was added with followed by stirring at room temperature for 15 hours. After completion of the reaction, the resulting product was extracted with 30 ml of ethyl acetate, washed with 30 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=3:1, v/v) to give 465 mg of the title compound (1.86 mmol) in 84% yield.

Rf = 0.45 (hexane:ethyl acetate = 3:1, v/v)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.20 (br s, 1H), 4.38 (br s, 1H), 2.86-2.95 (m, 1H), 1.93- 2.11 (m, 2H), 1.59-1.83 (m, 4H), 1.41-1.49 (m, 2H), 1.38 (s, 9H)

Step 3: Preparation of (4,4-difluorocyclohexyl)hydrazine hydrochloride

465 mg of tert-butyl 2-(4,4-difluorocyclohexyl)hydrazine-1-carboxylate (1.86 mmol) obtained in Step 2 was dissolved in 5 ml of methanol, and hydrochloric acid was added thereto, followed by stirring at 50°C within 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 335 mg of the title compound (1.79 mmol) in 96% yield.

Rf = 0.00 (hexane:ethyl acetate = 3:1, v/v)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.05-3.12 (m, 1H), 1.96-2.09 (m, 4H), 1.79-1.91 (m, 2H ), 1.52-1.59 (m, 2H)

Step 4: Preparation of 4,6-dichloro-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine

340 mg of 2,4,6-trichloropyrimidine-5-carbaldehyde (1.61 mmol) was dissolved in 5 ml of ethanol and 300 mg of (4,4-difluorocyclohexyl)hydrazine hydrochloride (1.61 mmol) obtained in Step 3 above, and 0.86 ml of N,N-diisopropylethylamine (4.82 mmol) was added at -78°C, followed by stirring for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 360 mg of the title compound (1.17 mmol) in 73% yield.

Rf = 0.35 (hexane:ethyl acetate = 9:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 4.97-5.04 (m, 1H), 2.13-2.23 (m, 6H), 2, 03-2.07(m, 2H)

Step 5: Preparation of 6-chloro-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

340 mg of 4,6-dichloro-1-(4,4-difluorocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine (1.11 mmol) obtained in step 4 was dissolved in 5 ml of THF and 1, 2 ml 2 n. sodium hydroxide (2.21 mmol), followed by stirring under reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid, and the precipitated solid was filtered to give 320 mg of the title compound (1.11 mmol) in 99% yield.

Rf = 0.38 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 4.77-4.81 (m, 1H), 2.08-2.17 (m, 6H), 1, 94-2.00(m, 2H)

<Example 8> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-she

50 mg of 6-chloro-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.17 mmol) obtained in Preparation Example 9, was dissolved in 3 ml of DMF, and 43 mg of benzo[d]oxazol-2-ylmethanethiol (0.26 mmol) obtained in Preparation Example 2 and 70 mg of potassium carbonate (0.51 mmol) were added, followed by stirring at 60° C. within 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 57 mg of the title compound (0.13 mmol) in 80% yield.

Rf = 0.20 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.67 (br s, 1H), 7.96 (s, 1H), 7.68-7.71 (m, 2H), 7.34-7 .40 (m, 2H), 4.83 (s, 2H), 3.54-3.60 (m, 1H), 1.90-2.08 (m, 6H), 1.74-1.78 (m, 2H)

<Production Example 10> Production of 6-chloro-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Preparation of tert-butyl 2-(tetrahydro-4H-thiopyran-4-ylidene)hydrazine-1-carboxylate

3.3 g of tetrahydro-4H-thiopyran-4-one (28.40 mmol) was dissolved in 60 ml of hexane, and 4.13 g of tert-butylcarbazite (31.24 mmol) was added, followed by stirring under reflux for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 6.5 g of the title compound (28.40 mmol) in 100% yield.

Rf = 0.15 (hexane:ethyl acetate = 3:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.67 (br s, 1H), 2.73-2.76 (m, 2H), 2.65-2.68 (m, 2H), 2 .60-2.63 (m, 2H), 2.47-2.50 (m, 2H), 1.43 (s, 9H)

Step 2: Preparation of tert-butyl 2-(tetrahydro-2H-thiopyran-4-yl)hydrazine-1-carboxylate

6.4 g of tert-butyl 2-(tetrahydro-4H-thiopyran-4-ylidene)hydrazine-1-carboxylate (28.40 mmol) obtained in step 1 was dissolved in 80 ml of THF and 12 g of sodium triacetoxyborohydride ( 56.80 mmol) followed by stirring at room temperature for 15 hours. After completion of the reaction, the resulting product was extracted with 300 ml of ethyl acetate, washed with 300 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=2:1, v/v) to give 6.5 g of the title compound (27.97 mmol) in 98% yield.

Rf = 0.34 (hexane:ethyl acetate = 2:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.20 (br s, 1H), 4.28 (br s, 1H), 2.65-2.73 (m, 3H), 2.05- 2.49 (m, 2H), 1.93-1.98 (m, 2H), 1.34-1.43 (m, 1H)

Step 3: Preparation of (tetrahydro-2H-thiopyran-4-yl)hydrazine hydrochloride

6.5 g of tert-butyl 2-(tetrahydro-2H-thiopyran-4-yl)hydrazine-1-carboxylate (27.97 mmol) obtained in step 2 was dissolved in 60 ml of methanol, and hydrochloric acid was added, followed by stirring at 50°C for 3 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give 4.7 g of the title compound (27.97 mmol) in 94% yield.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 2.91-2.96 (m, 1H), 2.66-2.72 (m, 2H), 2.57-2.62 (m, 2H ), 2.25-2.29 (m, 2H), 1.53-1.60 (m, 2H)

Step 4: Preparation of 4,6-dichloro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine

5.9 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (27.97 mmol) was dissolved in 60 ml of ethanol and 4.7 g of (tetrahydro-2H-thiopyran-4-yl)hydrazine hydrochloride (27.97 mmol) was added ) obtained in step 3 and 15 ml of N,N-diisopropylethylamine (83.91 mmol) at -78°C, followed by stirring for 3 hours. After completion of the reaction, the resulting product was extracted with 200 ml of ethyl acetate, washed with 200 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 7 g of the title compound (24.20 mmol) in 86% yield.

Rf = 0.41 (hexane:ethyl acetate = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.57 (s, 1H), 4.78-4.85 (m, 1H), 2.93-2.98 (m, 2H), 2, 73-2.78 (m, 2H), 2.15-2.25 (m, 4H)

Step 5: Preparation of 6-chloro-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

7 g of 4,6-dichloro-1-(tetrahydro-2H-thiopyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (24.20 mmol) obtained in Step 4 above was dissolved in 50 ml THF and added 25 ml of 2N. sodium hydroxide (47.60 mmol), followed by stirring under reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid, and the precipitated solid was filtered to give 5.7 g of the title compound (21.05 mmol) in 87% yield.

Rf = 0.31 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.20 (br s, 1H), 8.11 (s, 1H), 4.56-4.63 (m, 1H), 2.88-2 .94 (m, 2H), 2.72-2.76 (m, 2H), 2.10-2.20 (m, 4H)

<Example 9> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one

50 mg 6-chloro-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.18 mmol) obtained in the above Production Example 10 was dissolved in 3 ml of DMF, and 46 mg of benzo[d]oxazol-2-ylmethanethiol (0.28 mmol) obtained in Production Example 2 and 75 mg of potassium carbonate (0.54 mmol) were added, followed by stirring at 60 °C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 62 mg (0.15 mmol) of the title compound in 86% yield.

Rf = 0.36 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.65 (br s, 1H), 7.94 (s, 1H), 7.69-7.72 (m, 2H), 7.34-7 .40 (m, 2H), 4.81 (s, 2H), 4.33-4.39 (m, 1H), 2.68-2.74 (m, 2H), 2.59-2.64 (m, 2H), 1.97-2.04 (m, 2H), 1.88-1.93 (m, 2H)

<Production Example 11> Production of 6-chloro-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Preparation of 4,6-dichloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine

1.95 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (9.21 mmol) was dissolved in 30 ml of ethanol and 1 g of cyclopropylhydrazine hydrochloride (9.21 mmol) and 4.8 ml of N,N-diisopropylethylamine (27 .63 mmol) at -78°C followed by stirring for 3 hours. After completion of the reaction, the resulting product was extracted with 200 ml of ethyl acetate, washed with 200 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 950 mg of the title compound (4.15 mmol) in 45% yield.

Rf = 0.45 (hexane:ethyl acetate = 10:1, v/v)

¹H NMR (500 MHz, CDCl₃)δ 8.10 (s, 1H), 3.88-3.92 (m, 1H), 1.35-1.38 (m, 2H), 1.21-1.25 (m, 2H)

Step 2: Preparation of 6-chloro-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

930 mg of 4,6-dichloro-1-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine (4.06 mmol) obtained in step 1 was dissolved in 12 ml of THF and 4 ml of 2N hydrochloric acid were added. sodium hydroxide (8.12 mmol), followed by stirring under reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid, and the precipitated solid was filtered to give 680 mg of the title compound (3.23 mmol) in 80% yield.

Rf = 0.28 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.20 (br s, 1H), 8.02 (s, 1H), 3.78-3.82 (m, 1H), 1.05-1 .15 (m, 4H)

<Example 10> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

50 mg of 6-chloro-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.24 mmol) obtained in Preparation Example 11 was dissolved in 3 ml of DMF and 59 mg of benzo[d]oxazol-2-ylmethanethiol (0.36 mmol) obtained in Production Example 2 and 100 mg of potassium carbonate (0.72 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 48 mg of the title compound (0.14 mmol) in 59% yield.

Rf = 0.28 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (br s, 1H), 7.89 (s, 1H), 7.69-7.72 (m, 2H), 7.34-7 .40 (m, 2H), 4.83 (s, 2H), 3.65-3.69 (m, 1H), 0.95-0.99 (m, 2H), 0.90-0.94 (m, 2H)

<Production Example 12> Production of 6-chloro-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Preparation of 4,6-dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine

2.22 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (10.49 mmol) was dissolved in 30 ml of ethanol and 1.16 g of isopropylhydrazine hydrochloride (10.49 mmol) and 5.5 ml of N,N-diisopropylethylamine were added (31.47 mmol) at -78°C followed by stirring for 3 hours. After completion of the reaction, the resulting product was extracted with 200 ml of ethyl acetate, washed with 200 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 2.1 g of the title compound (9.08 mmol) in 87% yield.

Rf = 0.48 (hexane:ethyl acetate = 10:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.16 (s, 1H), 5.16-5.22 (m, 1H), 1.60 (d, J = 6.7 Hz, 6H)

Step 2: Preparation of 6-chloro-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

2 g of 4,6-dichloro-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidine (8.65 mmol) obtained in step 1 was dissolved in 12 ml of THF and 8.6 ml of 2N hydrochloric acid were added. sodium hydroxide (17.13 mmol), followed by stirring under reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid, and the precipitated solid was filtered to give 1.7 g of the title compound (7.99 mmol) in 92% yield.

Rf = 0.29 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.16 (br s, 1H), 8.08 (s, 1H), 4.85-4.91 (m, 1H), 1.44 (d , J = 7.0 Hz, 6H)

<Example 11> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

50 mg of 6-chloro-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.23 mmol) obtained in Preparation 12 was dissolved in 3 ml of DMF and 58 mg of benzo[d]oxazol-2-ylmethanethiol (0.35 mmol) obtained in Production Example 2 and 100 mg of potassium carbonate (0.72 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 44 mg of the title compound (0.13 mmol) in 56% yield.

Rf = 0.44 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.60 (br s, 1H), 7.91 (s, 1H), 7.68-7.72 (m, 2H), 7.33-7 .39 (m, 2H), 4.79 (s, 2H), 4.70-4.75 (m, 1H), 1.22 (d, J = 6.5 Hz, 6H)

<Production Example 13> Production of 6-chloro-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

Step 1: Preparation of 4,6-dichloro-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine

4.39 g of 2,4,6-trichloropyrimidine-5-carbaldehyde (20.71 mmol) were dissolved in 50 ml of ethanol and 3.12 g of cyclohexylhydrazine hydrochloride (20.71 mmol) and 11 ml of N,N-diisopropylethylamine (62 .13 mmol) at -78°C followed by stirring for 3 hours. After completion of the reaction, the resulting product was extracted with 200 ml of ethyl acetate, washed with 200 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 5.2 g of the title compound (19.18 mmol) in 92% yield.

Rf = 0.39 (hexane:ethyl acetate = 10:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 4.75-4.82 (m, 1H), 2.01-2.08 (m, 2H), 1.93- 1.99 (m, 2H), 1.77-1.81 (m, 1H), 1.48-1.57 (m, 2H), 1.30-1.39 (m, 1H), 1, 01-1.04 (m, 2H)

Step 2: Preparation of 6-chloro-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

5 g of 4,6-dichloro-1-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidine (18 × 44 mmol) sodium hydroxide (36.88 mmol), followed by stirring under reflux for 15 hours. After completion of the reaction, the mixture was acidified with 6 N. hydrochloric acid and the precipitated solid was filtered to give 4.6 g of the title compound (18.20 mmol) in 98% yield.

Rf = 0.35 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.18 (br s, 1H0, 8.07 (s, 1H), 4.46-4.52 (m, 1H), 1.80-1, 87 (m, 4H), 1.66-1.69 (m, 1H), 1.40-1.48 (m, 2H), 1.18-1.25 (m, 1H)

<Example 12> Preparation of 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

50 mg of 6-chloro-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in Preparation Example 13 was dissolved in 3 ml of DMF and 49 mg of benzo[d]oxazol-2-ylmethanethiol (0.30 mmol) obtained in Preparation Example 2 and 83 mg of potassium carbonate (0.60 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 55 mg of the title compound (0.14 mmol) in 72% yield.

Rf = 0.27 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.61 (br s, 1H), 7.90 (s, 1H), 7.67-7.69 (m, 2H), 7.33-7 .39 (m, 2H), 4.79 (s, 2H), 4.25-4.31 (m, 1H), 1.56-1.74 (m, 7H), 1.26-1.34 (m, 2H), 1.16-1.21 (m, 1H)

<Example 13> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

50 mg of 6-chloro-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.17 mmol) obtained in the above Production Example 9 , was dissolved in 3 ml of DMF, and 61 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.34 mmol) obtained in Preparation Example 6 and 70 mg of potassium carbonate (0.51 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 60 mg of the title compound (0.14 mmol) in 82% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.67 (br s, 1H), 7.96 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7, 52 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.80 (s, 2H), 4.52-4.58 (m, 1H), 2.42 (s , 3H), 1.89-2.10 (m, 6H), 1.74-1.78 (m, 2H)

<Example 14> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

50 mg 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in in the above Production Example 1 was dissolved in 3 ml of DMF, and 72 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.40 mmol) obtained in the above Production Example 6 and 83 mg of potassium carbonate (0. 60 mmol) followed by stirring at 60 °C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 51 mg of the title compound (0.13 mmol) in 64% yield.

Rf = 0.40 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.65 (br s, 1H), 7.95 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7, 52 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.51-4.57 (m, 1H), 3.86-3 .89 (m, 2H), 3.37-3.41 (m, 2H), 2.42 (s, 3H), 1.90-1.98 (m, 2H), 1.52-1.55 (m, 2H)

<Example 15> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

50 mg 6-chloro-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.18 mmol) obtained in in the above Production Example 10 was dissolved in 3 ml of DMF, and 64 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.36 mmol) obtained in the above Production Example 6 and 75 mg of potassium carbonate (0. 54 mmol) followed by stirring at 60 °C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 59 mg of the title compound (0.14 mmol) in 78% yield.

Rf = 0.33 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (br s, 1H), 7.95 (s, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7, 52 (s, 1H), 7.18 (d, J = 7.9 Hz, 1H), 4.78 (s, 2H), 4.33-4.39 (m, 1H), 2.70-2 .75 (m, 2H), 2.62-2.66 (m, 2H), 2.42 (s, 3H), 1.97-2.05 (m, 2H), 1.89-1.93 (m, 2H)

<Example 16> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

50 mg of 6-chloro-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in Preparation Example 13 was dissolved in 3 ml of DMF and 72 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.40 mmol) obtained in Preparation Example 6 and 83 mg of potassium carbonate (0.60 mmol) were added, followed by stirring at 60°C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 55 mg of the title compound (0.14 mmol) in 70% yield.

Rf = 0.45 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.62 (br s, 1H), 7.90 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7, 50 (s, 1H), 7.17 (d, J = 8.1 Hz, 1H), 4.76 (s, 2H), 4.25-4.32 (m, 1H), 2.41 (s , 3H), 1.56-1.75 (m, 7H), 1.27-1.36 (m, 2H), 1.15-1.23 (m, 1H)

<Example 17> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

50 mg of 6-chloro-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.24 mmol) obtained in Preparation Example 11 was dissolved in 3 ml of DMF and 86 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.48 mmol) obtained in Preparation Example 6 and 100 mg of potassium carbonate (0.72 mmol) were added, followed by stirring at 60 °C for 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 50 mg of the title compound (0.14 mmol) in 59% yield.

Rf = 0.29 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (br s, 1H), 7.89 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7, 53 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.81 (s, 2H), 3.66-3.71 (m, 1H), 2.43 (s , 3H), 0.91-1.01 (m, 4H)

<Example 18> Preparation of 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

50 mg of 6-chloro-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.24 mmol) obtained in Preparation Example 12 was dissolved in 3 ml of DMF and 82 mg of (6-methylbenzo[d]oxazol-2-yl)methanethiol (0.46 mmol) obtained in the above Production Example 6 and 95 mg of potassium carbonate (0.69 mmol) were added, followed by stirring at 60 °C in within 3 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 56 mg of the title compound (0.16 mmol) in 68% yield.

Rf = 0.21 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.60 (br s, 1H), 7.92 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7, 52 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 4.76 (s, 2H), 4.71-4.75 (m, 1H), 2.42 (s , 3H), 1.23 (d, J = 6.5 Hz, 6H)

<Production Example 14> Production of 1-(benzo[d]oxazol-2-yl)ethane-1-thiol

1 g of 2-aminophenol (9.16 mmol) was dissolved in 20 ml of toluene, and 1 ml of thiolactic acid (9.16 mmol) was added, followed by stirring under reflux for 5 hours. Then 1.6 g of p-toluenesulfonic acid (9.16 mmol) was added and stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 50 ml of ethyl acetate, washed with 50 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=2:1, v/v) to give 240 mg of the title compound (1.33 mmol) in 15% yield.

Rf = 0.50 (hexane:ethyl acetate = 2:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.71-7.73 (m, 1H), 7.53-7.55 (m, 1H), 7.35-7.37 (m, 2H), 4.34-4.39 (m, 1H), 2.42 (d, J = 7.4 Hz, 1H), 1.90 (d, J = 6.9 Hz, 2H)

<Example 19> Preparation of 6-((1-(benzo[d]oxazol-2-yl)ethyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4 -she

50 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in Preparation Example 3 was dissolved in 3 ml of DMF and 55 mg of 1-(benzo[d]oxazol-2-yl)ethan-1-thiol (0.30 mmol) obtained in Preparation Example 14 and 83 mg of potassium carbonate (0.61 mmol) were added, followed by 60° stirring C within 1 hour. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 49 mg of the title compound (0.13 mmol) in 63% yield.

Rf = 0.37 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.90 (br s, 1H), 8.25 (s, 1H), 7.96-7.99 (m, 2H), 7.74 (d , J = 7.1 Hz, 1H), 7.70 (d, J = 7.1 Hz, 1H), 7.51-7.54 (m, 2H), 7.34-7.40 (m, 3H), 5.38-5.42 (m, 1H), 1.89 (d, J = 5.1 Hz, 3H)

<Example 20> Preparation of 6-((1-benzo[d]oxazol-2-yl)ethyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one

25 mg of 6-chloro-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.08 mmol) obtained in the above Production Example 9 , was dissolved in 3 ml of DMF, and 55 mg of 1-(benzo[d]oxazol-2-yl)ethan-1-thiol (0.30 mmol) obtained in the above Preparation 14 and 36 mg of potassium carbonate (0. 24 mmol) followed by stirring at 60 °C for 1 hour. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 30 mg of the title compound (0.07 mmol) in 80% yield.

Rf = 0.33 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.65 (br s, 1H), 7.97 (s, 1H), 7.71-7.74 (m, 2H), 7.36-7 .42 (m, 2H), 5.43 (q, J = 7.4 Hz, 1H), 4.55-4.61 (m, 1H), 2.07-2.17 (m, 4H), 1.96-2.01 (m, 2H), 1.89 (d, J = 7.4 Hz, 3H), 1.83-1.90 (m, 1H), 1.74-1.76 ( m, 1H)

<Example 21> Preparation of 6-((1-benzo[d]oxazol-2-yl)ethyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[ 3,4-d]pyrimidin-4-one

30 mg 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.12 mmol) obtained in of the above Production Example 1, was dissolved in 3 ml of DMF and 42 mg of 1-(benzo[d]oxazol-2-yl)ethane-1-thiol (0.23 mmol) obtained in the above Production Example 14, and 50 mg of carbonate was added potassium (0.37 mmol) followed by stirring at 60°C for 1 hour. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 17 mg of the title compound (0.04 mmol) in 36% yield.

Rf = 0.33 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.63 (br s, 1H), 7.96 (s, 1H), 7.71-7.73 (m, 2H), 7.35-7 .40 (m, 2H), 5.37 (q, J = 7.3 Hz, 1H), 4.50-4.56 (m, 1H), 3.87-3.93 (m, 2H), 3.36-3.45 (m, 2H), 1.90-2.04 (m, 2H), 1.87 (d, J = 7.3 Hz, 3H), 1.63-1.66 ( m, 1H), 1.47-1.51(m, 1H)

<Production Example 15> Production of 1-(6-methylbenzo[d]oxazol-2-yl)ethane-1-thiol

1 g of 2-amino-5-methylphenol (8.12 mmol) was dissolved in 10 ml of toluene, and 0.72 ml of thiolactic acid (8.13 mmol) was added, followed by stirring at 100°C for 24 hours. After completion of the reaction, the residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to obtain 384 mg of the title compound (1.83 mmol) in 22% yield.

Rf = 0.48 (hexane:ethyl acetate = 5:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H ), 4.31-4.37 (m, 1H), 2.50 (s, 3H), 2.40 (d, J = 7.5 Hz, 1H), 1.88 (d, J = 7, 1Hz, 3H)

<Example 22> Preparation of 1-(4,4-difluorocyclohexyl)-6-((1-(6-methylbenzo[d]oxazol-2-yl)ethyl)thio)-1,5-dihydro-4H-pyrazolo[3 ,4-d]pyrimidin-4-one

50 mg of 6-chloro-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.17 mmol) obtained in the above Production Example 9 , was dissolved in 3 ml of DMF, and 72 mg of 1-(6-methylbenzo[d]oxazol-2-yl)ethane-1-thiol (0.35 mmol) obtained in the above Production Example 15 and 72 mg of potassium carbonate ( 0.52 mmol) followed by stirring at 60 °C for 1 hour. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 60 mg of the title compound (0.13 mmol) in 75% yield.

Rf = 0.18 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.67 (br s, 1H), 7.98 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7, 53 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H), 5.40 (q, J = 7.0 Hz, 1H), 4.54-4.59 (m, 1H ), 2.42 (s, 3H), 1.91-2.19 (m, 7H), 1.87 (d, J = 7.0 Hz, 3H), 1.73-1.76 (m, 1H)

<Example 23> Preparation of 6-((1-(6-methylbenzo[d]oxazol-2-yl)ethyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H -pyrazolo[3,4-d]pyrimidin-4-one

50 mg 6-chloro-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.20 mmol) obtained in the above Production Example 1 was dissolved in 3 ml of DMF, and 84 mg of 1-(6-methylbenzo[d]oxazol-2-yl)ethane-1-thiol (0.40 mmol) obtained in the above Production Example 15 was added, and 83 mg potassium carbonate (0.60 mmol) followed by stirring at 60 °C for 1 hour. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 50 mg of the title compound (0.12 mmol) in 66% yield.

Rf = 0.11 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.62 (br s, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7, 53 (s, 1H), 7.19 (d, J = 8.2 Hz, 1H), 5.35 (q, J = 7.1 Hz, 1H), 4.51-4.57 (m, 1H ), 3.98-3.95 (m, 2H), 3.38-3.47 (m, 2H), 2.42 (s, 3H), 1.87-2.06 (m, 2H), 1.86 (d, J = 7.1 Hz, 3H), 1.65-1.68 (m, 1H), 1.48-1.51 (m, 1H)

<Example 24> Preparation of 6-((1-(6-methylbenzo[d]oxazol-2-yl)ethyl)thio)-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H -pyrazolo[3,4-d]pyrimidin-4-one

50 mg 6-chloro-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.18 mmol) obtained in in the above Production Example 10 was dissolved in 3 ml of DMF, and 77 mg of 1-(6-methylbenzo[d]oxazol-2-yl)ethane-1-thiol (0.37 mmol) obtained in the above Production Example 15 was added, and 75 mg potassium carbonate (0.54 mmol) followed by stirring at 60 °C for 1 hour. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 62 mg of the title compound (0.14 mmol) in 77% yield.

Rf = 0.19 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.61 (br s, 1H), 7.96 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7, 53 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H), 5.37 (q, J = 7.0 Hz, 1H), 4.34-4.40 (m, 1H ), 2.66-2.82 (m, 4H), 2.42 (s, 3H), 1.96-2.12 (m, 3H), 1.88-1.91 (m, 1H), 1.86 (d, J = 7.0 Hz, 3H)

<Production Example 16> (5-Phenylbenzo[d]oxazol-2-yl)methanethiol production

Step 1: Preparation of 5-bromo-2-methylbenzo[d]oxazole

220 mg of 2-amino-4-bromophenol (1.17 mmol) was dissolved in 0.43 ml of triethylisoacetate (2.34 mmol) and 7 μl of acetic acid (0.12 mmol), followed by stirring at 100 °C for 0. 5 o'clock. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 10 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:1, v/v) to give 228 mg of the title compound (1.07 mmol) in 92% yield.

Rf = 0.36 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.81 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 8.6, 1.4 Hz, 1H), 7.37 (d, J = 8.6 Hz , 1H), 2.67(s, 3H)

Step 2: Preparation of 2-methyl-5-phenylbenzo[d]oxazole

210 mg of 5-bromo-2-methylbenzo[d]oxazole (0.99 mmol) obtained in step 1 was dissolved in a mixture of dioxane and water and 181 mg of phenylboronic acid (1.48 mmol), 40 mg of Pd(dppf) were added )Cl ₂ (0.05 mmol) and 410 mg of potassium carbonate (2.97 mmol), followed by stirring under reflux for 1 hour. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=4:1, v/v) to give 199 mg of the title compound (0.95 mmol) in 96% yield.

Rf = 0.25 (hexane:ethyl acetate = 5:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.87 (s, 1H), 7.64 (d, J = 7.3 Hz, 2H), 7.54-7.55 (m, 2H), 7.48 (dd, J = 7, 5, 7.3 Hz, 2H), 7.38 (dd, J = 7.3, 7.3 Hz, 1H), 2.69 (s, 3H)

Step 3: Preparation of 2-(bromomethyl)-5-phenylbenzo[d]oxazole

199 mg of 2-methyl-5-phenylbenzo[d]oxazole (0.95 mmol) obtained in step 2 was dissolved in chlorobenzene and 169 mg of N-bromosuccinimide (0.95 mmol), 31 mg of AIBN (azobisobutylonitrile) (0 .19 mmol) followed by stirring under reflux for 2 hours. After completion of the reaction, the residue was purified by column chromatography (hexane:ethyl acetate=8:1, v/v) to obtain 110 mg of the title compound (0.38 mmol) in 40% yield.

Rf = 0.30 (hexane:ethyl acetate = 8:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.94 (s, 1H), 7.61-7.66 (m, 4H), 7.49 (dd, J = 7.7, 7.4 Hz, 2H), 7.40 (dd, J = 7.4, 7.4Hz, 1H), 4.64(s, 2H)

Step 4: Preparation of S-((5-phenylbenzo[d]oxazol-2-yl)methyl)ethanethioate

100 mg of 2-(bromomethyl)-5-phenylbenzo[d]oxazole (0.34 mmol) obtained in Step 3 was dissolved in acetone, and 59 mg of potassium thioacetate (0.52 mmol) was added, followed by stirring at 50°C in within 1 hour. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, and dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) to obtain 95 mg of the title compound (0.33 mmol) in 96% yield.

Rf = 0.23 (hexane:ethyl acetate = 6:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.58-7.62 (m, 4H), 7.48 (dd, J = 7.7, 7.4 Hz, 2H), 7.39 (dd, J = 7.4, 7.4Hz, 1H), 4.44(s, 2H), 2.47(s, 3H)

Step 5: Preparation of (5-phenylbenzo[d]oxazol-2-yl)methanethiol

90 mg of S-((5-phenylbenzo[d]oxazol-2-yl)methyl)ethanoate (0.32 mmol) obtained in step 4 was dissolved in 6 ml of a mixture of methanol and water and 131 mg of potassium carbonate (0.32 mmol) was added. 95 mmol) followed by stirring at room temperature for 1 hour. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, and dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) to give 75 mg of the title compound (0.31 mmol) in 99% yield.

Rf = 0.14 (hexane:ethyl acetate = 3:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.58-7.63 (m, 4H), 7.49 (dd, J = 7.8, 7.5 Hz, 2H), 7.39 (dd, J = 7.5, 7.5 Hz, 1H), 4.01 (d, J = 8.1 Hz, 2H), 2.27 (t, J = 8.1 Hz, 1H)

<Example 25> Preparation of 1-phenyl-6-(((5-phenylbenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

38 mg of 6-chloro-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (0.15 mmol) obtained in Preparation Example 3 was dissolved in 3 ml of DMF and 75 mg of (5-phenylbenzo[d]oxazol-2-yl)methanethiol (0.31 mmol) obtained in Preparation Example 16 and 128 mg of potassium carbonate (0.93 mmol) were added, followed by stirring at 60°C for 1 hour. After completion of the reaction, the resulting product was extracted with 10 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol=20:1, v/v) to give 50 mg of the title compound (0.11 mmol) in 71% yield.

Rf = 0.35 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.96 (br s, 1H), 8.24 (s, 1H), 7.95-7.97 (m, 3H), 7.78 (d , J = 8.7 Hz, 1H), 7.65-7.69 (m, 3H), 7.45-7.51 (m, 4H), 7.35-7.39 (m, 2H), 4.86(s, 2H)

<Production Example 17> Preparation of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one

Step 1: Preparation of ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate

5 g of ethyl (E)-2-cyano-3-ethoxyacrylate (30 mmol) was dissolved in 100 ml of ethanol, and 3.9 g of phenylhydrazine (36 mmol) was added, followed by stirring under reflux for 15 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to obtain 7 g of the title compound (30 mmol) in 100% yield.

Rf = 0.30 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.75 (s, 1H), 7.55-7.45 (m, 4H), 7.41-7.34 (m, 1H), 5.36 (br s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H)

Step 2: Preparation of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

7 g of ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (30 mmol) obtained in step 1 was dissolved in 60 ml of tetrahydrofuran and 4.95 ml of benzoylisothiocyanate (39 mmol) was added, after which it was stirred with reflux for 13 hours. Then 92 ml of 2N was added. sodium hydroxide and stirred the mixture under reflux for 30 minutes. After completion of the reaction, it was neutralized with 2 N. hydrochloric acid and acetic acid was added to precipitate a solid. The residue was purified with water, hexane and dichloromethane to give 4.48 g of the title compound (18.34 mmol) in 60% yield.

Rf = 0.15 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.27 (br s, 1H), 10.46 (s, 1H), 8.13 (s, 1H), 7.87 (d, J = 7 .6 Hz, 2H), 7.68-7.47 (m, 3H)

<Production Example 18> Preparation of 2-(chloromethyl)-4-methylbenzo[d]oxazole

300 mg of 2-amino-3-methylphenol (2.44 mmol) was dissolved in 6 ml of xylene, and 0.29 ml of chloroacetyl chloride (3.66 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.37 ml of triethylamine (2.68 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 30 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 363 mg of the title compound (2.0 mmol) in 82% yield.

Rf = 0.5 (hexane:ethyl acetate = 10:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.36 (d, J = 8.2 Hz, 1H), 7.28-7.24 (m, 1H), 7.15 (d, J = 7.4 Hz, 1H), 4.77 (s, 2H), 2.62 (s, 3H).

<Example 26> Preparation of 6-(((4-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazole[3,4-d]pyrimidin-4 -she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in methanol and 33 mg of 2-(chloromethyl)-4-methylbenzo[d]oxazole (0.18 mmol) obtained in Preparation Example 18 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the resulting product was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 55 mg of the title compound (0.14 mmol) in 86% yield.

Rf = 0.3 (hexane:ethyl acetate = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 8.06 (d, J = 8.1 Hz, 2H), 7.53-7.44 (m, 3H) , 7.40-7.38 (m, 1H), 7.26-7.23 (m, 1H), 7.15 (d, J = 7.3 Hz, 1H), 4.82 (s, 2H ), 2.48(s, 3H)

<Production Example 19> Production of 5-(t-butyl)-2-(chloromethyl)benzo[d]oxazole

200 mg of 2-amino-4-(tert-butyl)phenol (1.21 mmol) was dissolved in 5 ml of xylene, and 0.14 ml of chloroacetyl chloride (1.81 mmol) was added slowly, followed by stirring at 0°C for 2 hours . Then 0.19 ml of triethylamine (1.33 mmol) was added and stirred at reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=20:1, v/v) to give 154 mg of the title compound (0.69 mmol) in 57% yield.

Rf = 0.55 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.77 (s, 1H), 7.50-7.46 (m, 2H), 4.76 (s, 2H), 1.40 (s, 9H)

<Example 27> Preparation of 6-(((5-(tert-butyl)benzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one

20 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.08 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 20 mg of 5-(tert-butyl)-2-(chloromethyl)benzo[d]oxazole (0.09 mmol) obtained in the above Preparation 19 and 0.05 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to obtain 36 mg of the title compound (0.08 mmol) in 100% yield.

Rf = 0.3 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.17 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.57 (d, J = 8.6 Hz, 1H), 7.49-7.45 (m, 2H), 7.43-7.41 (d, J = 8.6 Hz, 1H), 7.36- 7.34(m, 1H), 4.78(s, 2H), 1.30(s, 9H)

<Production Example 20> Production of 2-(chloromethyl)-6-nitrobenzo[d]oxazole

200 mg of 2-amino-5-nitrophenol (1.30 mmol) was dissolved in 5 ml of xylene, and 0.16 ml of chloroacetyl chloride (1.95 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.2 ml of triethylamine (1.43 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 190 mg of the title compound (0.89 mmol) in 67% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 8.47 (s, 1H), 8.33 (d, J = 8.8, 1H), 7.87 (d, J = 8.8, 1H), 4.82 (s, 2H)

<Example 28> Preparation of 6-(((6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 38 mg of 2-(chloromethyl)-6-nitrobenzo[d]oxazole (0.18 mmol) obtained in Preparation Example 20 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 22 mg of the title compound (0.05 mmol) in 32% yield.

Rf = 0.3 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.59 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 8.8, 2.3 Hz, 1H), 8 .20 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 7.7 Hz, 2H), 7.52-7.45 (m, 2H), 7.39-7.36(m, 1H), 4.90(s, 2H)

<Production Example 21> Production of 2-(chloromethyl)-5-nitrobenzo[d]oxazole

400 mg of 2-amino-4-nitrophenol (2.60 mmol) was dissolved in 5 ml of xylene, and 0.32 ml of chloroacetyl chloride (3.90 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.4 ml of triethylamine (2.86 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 20 ml of ethyl acetate, washed with 20 ml of inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 42 mg of the title compound (0.19 mmol) in 8% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 8.66 (d, J = 2.2 Hz, 1H), 8.38 (dd, J = 9.0, 2.2 Hz, 1H), 7.69 (d, J = 9.0 Hz , 1H), 4.80(s, 2H)

<Example 29> Preparation of 6-(((5-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0×16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 37 mg of 2-(chloromethyl)-5-nitrobenzo[d]oxazole (0.17 mmol) obtained in Preparation Example 21 and 0.05 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 28 mg of the title compound (0.06 mmol) in 41% yield.

Rf = 0.3 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.96 (s, 1H), 8.58 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 9.0, 2.3 Hz, 1H), 8.21 (s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7 .48 (dd, J = 7.7, 8.1 Hz, 2H), 7.36 (d, J = 7.7 Hz, 1H), 4.90 (s, 2H)

<Production Example 22> Production of 2-(chloromethyl)-4-nitrobenzo[d]oxazole

600 mg of 2-amino-3-nitrophenol (3.89 mmol) was dissolved in 10 ml of xylene, 0.66 ml of chloroacetyl chloride (5.83 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.6 ml of triethylamine (4.27 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 508 mg of the title compound (2.39 mmol) in 61% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 8.27 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.61 (dd, J = 8.2, 8.2 Hz , 1H), 4.90(s, 2H)

<Example 30> Preparation of 6-(((4-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 38 mg of 2-(chloromethyl)-4-nitrobenzo[d]oxazole (0.17 mmol) obtained in Preparation Example 22 and 0.05 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 34 mg of the title compound (0.08 mmol) in 50% yield.

Rf = 0.3 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 8.24 (s, 1H), 8.17-8.14 (m, 1H), 8.01-7, 96 (m, 3H), 7.60 (d, J = 8.2 Hz, 1H), 7.55-7.52 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H ), 4.13(s, 2H)

<Production Example 23> Production of 5-chloro-2-(chloromethyl)-6-nitrobenzo[d]oxazole

500 mg of 2-amino-4-chloro-5-nitrophenol (2.65 mmol) was dissolved in 8 ml of xylene, and 0.32 ml of chloroacetyl chloride (3.97 mmol) was added slowly, followed by stirring at 0° C. for 2 hours. Then 0.41 ml of triethylamine (2.91 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 329 mg of the title compound (1.33 mmol) in 50% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.15 (s, 1H), 7.94 (s, 1H), 4.80 (s, 2H)

<Example 31> Preparation of 6-(((5-nitro-6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d ]pyrimidin-4-one

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 45 mg of 5-chloro-2-(chloromethyl)-6-nitrobenzo[d]oxazole (0.17 mmol) obtained in Production Example 23 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 22 mg of the title compound (0.05 mmol) in 29% yield.

Rf = 0.2 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.63 (s, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 8.18 (s, 1H), 7 .96-7.93 (m, 1H), 7.86-7.84 (m, 1H), 7.51-7.47 (m, 2H), 7.37 (d, J = 7.5 Hz , 1H), 4.90(s, 2H)

<Production Example 24> Production of 5,7-dichloro-2-(chloromethyl)-benzo[d]oxazole

500 mg of 2-amino-4,6-dichlorophenol (2.81 mmol) was dissolved in 10 ml of xylene, and 0.34 ml of chloroacetyl chloride (4.21 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.43 ml of triethylamine (3.09 mmol) was added and stirred at reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 470 mg of the title compound (1.99 mmol) in 71% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.62 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 1.9 Hz, 1H), 4.77 (s, 2H)

<Example 32> Preparation of 6-(((5,7-dichlorobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine -4-she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 43 mg of 5,7-dichloro-2-(chloromethyl)-benzo[d]oxazole (0.17 mmol) obtained in Preparation Example 24 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 11 mg of the title compound (0.02 mmol) in 15% yield.

Rf = 0.3 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.20 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 1.9 Hz , 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.45 (t, J = 7.8 Hz, 2H), 7.34 (t, J = 7.3 Hz, 1H ), 4.86(s, 2H)

<Production Example 25> Production of 2-(chloromethyl)-5,7-dimethylbenzo[d]oxazole

500 mg of 2-amino-4,6-dimethylphenol (3.64 mmol) was dissolved in 10 ml of xylene, and 0.44 ml of chloroacetyl chloride (5.46 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.56 ml of triethylamine (4.00 mmol) was added and stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 479 mg of the title compound (2.45 mmol) in 67% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.31 (s, 1H), 6.95 (s, 1H), 4.71 (s, 2H), 2.46 (s, 3H), 2.38 (s, 3H)

<Example 33> Preparation of 6-(((5,7-dimethylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine -4-she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 35 mg of 2-(chloromethyl)-5,7-dimethylbenzo[d]oxazole (0.17 mmol) obtained in Preparation Example 24 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 17 mg of the title compound (0.04 mmol) in 26% yield.

Rf = 0.3 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 7.99 (d, J = 7.9 Hz, 2H), 7.45 (dd, J = 7.9, 7.3Hz, 2H), 7.37(d, J = 7.3Hz, 1H), 7.30(s, 1H), 7.00(s, 1H), 4.80(s, 2H) , 2.38(s, 3H), 2.34(s, 3H)

<Production Example 26> Production of 2-(chloromethyl)-5-methoxybenzo[d]oxazole

412 mg of 2-amino-4-methoxyphenol (2.96 mmol) was dissolved in 10 ml of xylene, and 0.35 ml of chloroacetyl chloride (4.44 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.45 ml of triethylamine (3.25 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=20:1, v/v) to give 254 mg of the title compound (1.29 mmol) in 43% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.48-7.38 (m, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.99 (dd, J = 9.0, 2.6 Hz, 1H) , 4.74(s, 2H), 3.86(s, 3H)

<Example 34> Preparation of 6-(((5-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 36 mg of 2-(chloromethyl)-5methoxybenzo[d]oxazole (0.17 mmol) obtained in Preparation Example 25 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 15 mg of the title compound (0.04 mmol) in 23% yield.

Rf = 0.2 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.94 (s, 1H), 8.24 (s, 1H), 7.94 (d, J = 7.9 Hz, 2H), 7.59 (d, J = 8.9 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.25 (d , J = 2.5 Hz, 1H), 6.94 (dd, J = 8.9, 2.6 Hz, 1H), 4.80 (s, 2H), 3.77 (s, 3H)

<Production Example 27> Production of 2-(chloromethyl)-6-methoxybenzo[d]oxazole

412 mg of 2-amino-5-methoxyphenol (2.96 mmol) was dissolved in 10 ml of xylene, and 0.35 ml of chloroacetyl chloride (4.44 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.45 ml of triethylamine (3.25 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=20:1, v/v) to give 236 mg of the title compound (1.19 mmol) in 40% yield.

Rf = 0.4 (hexane:ethyl acetate = 4:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.58 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.8, 2.4 Hz , 1H), 4.72(s, 2H), 3.83(s, 3H)

<Example 35> Preparation of 6-(((6-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -she

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 36 mg of 2-(chloromethyl)-6-methoxybenzo[d]oxazole (0.17 mmol) obtained in Preparation Example 26 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 25 mg of the title compound (0.06 mmol) in 38% yield.

Rf = 0.2 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.93 (s, 1H), 8.24 (s, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.50 (t, J = 7.7 Hz, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.30 (d , J = 2.4 Hz, 1H), 6.93 (dd, J = 8.8, 2.4 Hz, 1H), 4.79 (s, 2H), 3.79 (s, 3H)

<Production Example 28> Production of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]oxazole

776 mg of 2-amino-4-(trifluoromethyl)phenol (4.38 mmol) was dissolved in 12 ml of xylene, 0.52 ml of chloroacetyl chloride (6.57 mmol) was added slowly, followed by stirring at 0°C for 2 hours. Then 0.67 ml of triethylamine (4.82 mmol) was added and the mixture was stirred under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 40 ml of ethyl acetate, washed with 40 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=10:1, v/v) to give 275 mg of the title compound (1.17 mmol) in 27% yield.

Rf = 0.5 (hexane:ethyl acetate = 4:1, v/v)

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.09-8.02 (m, 1H), 7.73-7.64 (m, 2H), 4.81 (s, 2H)

<Example 36> Preparation of 1-phenyl-6-(((5-(trifluoromethyl)benzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one

40 mg of 1-phenyl-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.16 mmol) obtained in Preparation Example 17 was dissolved in 3 ml of methanol, and 41 mg of 2-(chloromethyl)-5-(trifluoromethyl)benzo[d]oxazole (0.17 mmol) obtained in Preparation Example 27 and 0.1 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 25 mg of the title compound (0.06 mmol) in 34% yield.

Rf = 0.25 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 8.20 (s, 1H), 8.16-8.12 (m, 1H), 7.96-7, 90 (m, 3H), 7.75 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 7.7, 8.1 Hz, 2H), 7.35 (dd, J = 7.5, 7.7Hz, 1H), 4.88(s, 2H)

<Production Example 29> Production of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one

Step 1: Preparation of ethyl 5-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-carboxylate

1 g of ethyl (E)-2-cyano-3-ethoxyacrylate (5.91 mmol) was dissolved in 30 ml of ethanol, and 1.32 g of (4,4-difluorocyclohexyl)hydrazine (7.09 mmol) was added, followed by stirring under reflux. refrigerator for 15 hours. After completion of the reaction, the resulting product was extracted with 50 ml of ethyl acetate, washed with 50 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=3:1, v/v) to give 1.16 g of the title compound (4.31 mmol) in 73% yield.

Rf = 0.40 (hexane:ethyl acetate = 3:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.65 (s, 1H), 5.03 (br s, 2H), 429 (q, J = 8.0 Hz, 2H), 3.95-3.90 (m, 1H), 2, 34-2.27 (m, 4H), 2.08-1.84 (m, 4H), 1.36 (t, J = 8.0 Hz, 4H)

Step 2: Preparation of ethyl 5-(3-benzoylthioureido)-1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-carboxylate

200 mg of ethyl 5-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-carboxylate (0.73 mmol) obtained in step 1 was dissolved in 5 ml of tetrahydrofuran and 0.12 ml of benzoylisothiocyanate ( 0.87 mmol) followed by stirring under reflux for 2 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by column chromatography (hexane:ethyl acetate=2:1, v/v) to obtain 312 mg of the title compound (0.72 mmol) in 98% yield.

Rf = 0.55 (hexane:ethyl acetate = 2:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 12.17 (s, 1H), 9.44 (s, 1H), 8.01 (s, 1H), 7.97 (d, J = 7.8 Hz, 2H), 7.73 (dd , J = 7.8 Hz, 7.8 Hz, 1H), 7.61 (dd, J = 7.8 Hz, 7.8 Hz, 2H), 4.29 (q, J = 7.3 Hz, 2H), 2.42-2.26 (m, 4H), 2.16-2.10 (m, 2H), 1.91-1.80 (m, 2H), 1.30 (t, J= 7.3Hz, 3H)

Step 3: Preparation of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one

100 mg of ethyl 5-(3-benzoylthioureido)-1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-carboxylate (0.23 mmol) obtained in step 2 was dissolved in 3 ml of ethanol and 44 mg of tert sodium α-butoxide (0.46 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the mixture was neutralized with 1 N. hydrochloric acid to precipitate a solid which was purified with water, ether and ethyl acetate to give 50 mg of the title compound (0.17 mmol) in 76% yield.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.44 (br s, 1H), 12.19 (br s, 1H), 7.96 (s, 1H), 4.77 (s, 1H) , 2.37-1.81 (m, 8H)

<Example 37> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 33 mg of 2-(chloromethyl)-6-nitrobenzo[d]oxazole (0.15 mmol) obtained in the above Production Example 20 and 0.08 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 48 mg of the title compound (0.10 mmol) in 75% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.71 (d, J = 2.3 Hz, 1H), 8.29 (dd, J = 8.8, 2.3 Hz, 1H), 7 .95 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 4.90 (s, 2H), 4.54-4.49 (m, 1H), 2.09- 1.89(m, 6H), 1.78-1.68(m, 2H)

<Example 38> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((5-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

24 mg 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.08 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 20 mg of 2-(chloromethyl)-5-nitrobenzo[d]oxazole (0.09 mmol) obtained in the above Production Example 21 and 0.05 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 41 mg of the title compound (0.09 mmol) in 63% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.69 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 8.9, 2.3Hz, 1H), 8.00(d, J = 9.0Hz, 1H), 7.95(s, 1H), 4.90(s, 2H), 4.55(s, 1H) , 2.10-1.90 (m, 6H), 1.79-1.71 (m, 2H)

<Example 39> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((4-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one obtained in the above Production Example 29 (0 ,14 mmol), was dissolved in 3 ml of methanol, and 33 mg of 2-(chloromethyl)-4-nitrobenzo[d]oxazole (0.15 mmol) obtained in the above Preparation 22 and 0.08 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 13 mg of the title compound (0.03 mmol) in 21% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.54 (s, 1H), 7.98 (s, 1H), 7.35-7.16 (m, 3H), 4.93-4, 81 (m, 1H), 4.18 (s, 2H), 2.12-1.96 (m, 5H), 1.95-1.83 (m, 3H)

<Example 40> Preparation of 6-(((5-chloro-6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 38 mg of 5-chloro-2-(chloromethyl)-6-nitrobenzo[d]oxazole (0.15 mmol) obtained in the above Production Example 23 and 0.08 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 70 mg of the title compound (0.14 mmol) in 100% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.82 (s, 1H), 7.95 (s, 1H), 4.89 (s, 1H), 4 .55-4.47 (m, 1H), 2.29-1.70 (m, 8H)

<Example 41> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((4-methylbenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 28 mg of 2-(chloromethyl)-4-methylbenzo[d]oxazole (0.15 mmol) obtained in Production Example 18 and 0.08 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 39 mg of the title compound (0.09 mmol) in 66% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

1H NMR (500 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.27 (dd, J = 8.0, 7, 6 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 4.83 (s, 2H), 4.67-4.54 (m, 1H), 2.49 (s, 3H), 2.18-1.96 (m, 5H), 1.95-1.77 (m, 3H)

<Example 42> Preparation of 6-(((5-(tert-butyl)benzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H- pyrazolo[3,4-d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in the above Production Example 29 was dissolved in 3 ml of methanol, and 34 mg of 5-(tert-butyl)-2-(chloromethyl)benzo[d]oxazole (0.15 mmol) obtained in the above Production Example 19 was added, and 0.08 ml 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the resulting product was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 64 mg of the title compound (0.13 mmol) in 97% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.67 (s, 1H), 7.95 (s, 1H), 7.64 (d, J = 2.9 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.44 (dd, J = 8.6, 2.9 Hz, 1H), 4.79 (s, 2H), 4.55-4.50 ( m, 1H), 2.09-1.86 (m, 6H), 1.76-1.71 (m, 2H), 1.32 (s, 9H)

<Example 43> Preparation of 6-(((5,7-dichlorobenzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3 ,4-d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 36 mg of 5,7-dichloro-2-(chloromethyl)benzo[d]oxazole (0.15 mmol) obtained in the above Production Example 24 and 0.08 ml of 2 n. sodium hydroxide followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 17 mg of the title compound (0.03 mmol) in 25% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.94 (s, 1H), 7.85 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.9 Hz , 1H), 4.85 (s, 2H), 4.55-4.50 (m, 1H), 2.12-1.74 (m, 8H)

<Example 44> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((5,7-dimethylbenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3 ,4-d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 30 mg of 5,7-dimethyl-2-(chloromethyl)benzo[d]oxazole (0.15 mmol) obtained in the above Production Example 25 and 0.08 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 22 mg of the title compound (0.05 mmol) in 36% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.95 (s, 1H), 7.27 (s, 1H), 7.02 (s, 1H), 4.79 (s, 2H), 4 .59 (s, 1H), 2.38 (d, J = 19.4 Hz, 5H), 2.04 (q, J = 10.9, 9.9 Hz, 4H), 1.91 (d, J = 8.3 Hz, 2H), 1.79 (d, J = 11.3 Hz, 2H)

<Example 45> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((5-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 30 mg of 5-methoxy-2-(chloromethyl)benzo[d]oxazole (0.15 mmol) obtained in the above Production Example 26 and 0.08 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 43 mg of the title compound (0.09 mmol) in 70% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.67 (s, 1H), 7.96 (s, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.23 (d, J=2.5Hz, 1H), 6.96(dd, J=8.9, 2.6Hz, 1H), 4.80(s, 2H), 4.63-4.48( m, 1H), 3.78 (s, 3H), 2.14-1.87 (m, 6H), 1.81-1.74 (m, 2H)

<Example 46> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((6-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one

40 mg of 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) obtained in of the above Production Example 29 was dissolved in 3 ml of methanol, and 30 mg of 6-methoxy-2-(chloromethyl)benzo[d]oxazole (0.15 mmol) obtained in Production Example 27 and 0.08 ml of 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 23 mg of the title compound (0.05 mmol) in 37% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.66 (s, 1H), 7.97 (s, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.7, 2.4 Hz, 1H), 4.79 (s, 2H), 4.60 (s, 1H) , 3.80 (s, 3H), δ 2.16-1.88 (m, 6H), 1.86-1.73 (m, 2H)

<Example 47> Preparation of 1-(4,4-difluorocyclohexyl)-6-(((5-(trifluoromethyl)benzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[ 3,4-d]pyrimidin-4-one

40 mg 1-(4,4-difluorocyclohexyl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.14 mmol) prepared in in the above Production Example 29 was dissolved in 3 ml of methanol, and 36 mg of 5-(trifluoromethyl)-2-(chloromethyl)benzo[d]oxazole (0.15 mmol) obtained in the above Production Example 28 and 0.08 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 53 mg of the title compound (0.11 mmol) in 78% yield.

Rf = 0.25 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.71 (s, 1H), 8.15 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.90 (s, 1H), 7.77 (dd, J = 8.7, 1.8 Hz, 1H), 4.86 (s, 2H), 4.51 (s, 1H), 2.10-1, 93 (m, 6H), 1.76-1.70 (m, 2H)

<Production Example 30> Preparation of 1-(Tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one

Step 1: Preparation of ethyl 5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate

2.08 g of ethyl (E)-2-cyano-3-ethoxyacrylate (12.3 mmol) was dissolved in 30 ml of ethanol and 2.25 g of (tetrahydro-2H-pyran-4-yl)hydrazine (14.76 mmol) was added ) followed by stirring under reflux for 15 hours. After completion of the reaction, the resulting product was extracted with 50 ml of ethyl acetate, washed with 50 ml of an inorganic salt solution, dried over anhydrous sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=1:1, v/v) to give 2.2 g of the title compound (9.22 mmol) in 75% yield.

Rf = 0.50 (hexane:ethyl acetate = 1:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 7.66 (s, 1H), 5.04 (br s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 4.19-4.10 (m, 2H), 4.08-3.94(m, 1H), 3.60-3.45(m, 2H), 2.40-2.20(m, 2H), 1.92-1.80(m, 2H ), 1.36 (t, J = 7.1 Hz, 3H)

Step 2: Preparation of ethyl 5-(3-benzoylthioureido)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate

2.20 g of ethyl 5-amino-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-carboxylate (9.22 mmol) obtained in step 1 was dissolved in 30 ml of tetrahydrofuran and added 1.48 ml of benzoyl isothiocyanate (11.06 mmol), followed by stirring under reflux for 2 hours. After completion of the reaction, the resulting product was concentrated under reduced pressure and purified with hexane to give 3.54 g of the title compound (8.74 mmol) in 95% yield.

Rf = 0.60 (hexane:ethyl acetate = 1:1, v/v)

¹H NMR (500 MHz, CDCl₃) δ 12.16 (br s, 1H), 9.53 (br s, 1H), 8.02 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.71 (dd, J = 7.4 Hz, 7.4 Hz, 1H), 7.60 (dd, J = 7.4 Hz, 7.4 Hz, 2H), 4.44-4.34 (m, 1H ), 4.28 (q, J = 7.1 Hz, 2H), 4.17-4.09 (m, 2H), 3.58-3.50 (m, 2H), 2.37-2, 30 (m, 2H), 2.10-2.00 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H)

Step 3: Preparation of 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one

100 mg of ethyl 5-3-benzoylthioureido)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-carboxylate (0.25 mmol) obtained in step 2 was dissolved in 3 ml of ethanol and 0.75 ml of 2N was added. sodium hydroxide (1.50 mmol) followed by stirring under reflux for 30 minutes. After completion of the reaction, it was neutralized with 1 N. hydrochloric acid to precipitate a solid which was purified with water and hexane to give 30 mg of the title compound (0.12 mmol) in 48% yield.

Rf=0.00 (hexane:ethyl acetate=1:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.48 (br s, 1H), 12.17 (br s, 1H), 7.95 (s, 1H), 4.91-4.82 ( m, 1H), 4.08-3.91 (m, 2H), 3.55-3.45 (m, 2H), 2.10-1.90 (m, 2H), 1.90-1, 76(m, 2H)

<Example 48> Preparation of 6-(((6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 37 mg of 2-(chloromethyl)-6-nitrobenzo[d]oxazole (0.16 mmol) obtained in the above Production Example 20 and 0.09 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 24 mg of the title compound (0.06 mmol) in 36% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 2.2 Hz, 1H), 8.28 (dd, J = 8.8, 2.2 Hz, 1H), 7 .95 (s, 1H), 7.92 (s, 1H), 4.88 (s, 2H), 4.52-4.43 (m, 1H), 3.87-3.82 (m, 2H ), 3.45-3.36 (m, 2H), 1.95-1.87 (m, 2H), 1.52-1.48 (m, 2H)

<Example 49> Preparation of 6-(((5-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 37 mg of 2-(chloromethyl)-5-nitrobenzo[d]oxazole (0.16 mmol) obtained in the above Production Example 21 and 0.09 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 41 mg of the title compound (0.09 mmol) in 60% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 8.60 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 9.0, 2.3Hz, 1H), 8.00(d, J=9.0Hz, 1H), 7.94(s, 1H), 4.87(s, 2H), 4.53-4.46( m, 1H), 3.89-3.82 (m, 2H), 3.42-3.36 (m, 2H), 1.96-1.88 (m, 2H), 1.54-1, 50(m, 2H)

<Example 50> Preparation of 6-(((4-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 37 mg of 2-(chloromethyl)-4-nitrobenzo[d]oxazole (0.16 mmol) obtained in the above Production Example 22 and 0.09 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 26 mg of the title compound (0.06 mmol) in 39% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.97 (s, 1H), 7.29 (dd, J = 7.5, 2.2 Hz, 1H), 7.25-7.18 ( m, 2H), 4.90-4.84 (m, 1H), 4.18 (s, 2H), 3.90-3.86 (m, 2H), 3.39-3.35 (m, 2H), 2.04-1.96(m, 2H), 1.77-1.70(m, 2H)

<Example 51> Preparation of 6-(((5-chloro-6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro -4H-pyrazolo[3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 43 mg of 5-chloro-2-(chloromethyl)-6-nitrobenzo[d]oxazole (0.16 mmol) obtained in the above Production Example 23 was added, and 0.09 ml 2N sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water, ether and ethyl acetate to give 20 mg of the title compound (0.04 mmol) in 27% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.21 (s, 1H), 7.96 (s, 1H), 4.87 (s, 2H), 4 .47-4.40(m, 1H), 3.89-3.81(m, 2H), 3.40-3.37(m, 2H), 1.93-1.86(m, 2H) , 1.53-1.48 (m, 2H)

<Example 52> Preparation of 6-(((4-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 32 mg of 2-(chloromethyl)-4-methylbenzo[d]oxazole (0.16 mmol) obtained in Production Example 18 and 0.09 ml of 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 14 mg of the title compound (0.03 mmol) in 22% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.58 (br s, 1H), 7.95 (s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7, 25 (dd, J = 8.1, 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 4.81 (s, 2H), 4.62-4.55 (m, 1H), 3.89 (dd, J = 11.0, 4.4 Hz, 2H), 3.41-3.36 (m, 2H), 2.49 (s, 3H), 2, 04-1.91(m, 2H), 1.65-1.61(m, 2H)

<Example 53> Preparation of 6-(((5-(tert-butyl)benzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5- dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 39 mg of 5-(tert-butyl)-2-(chloromethyl)benzo[d]oxazole (0.16 mmol) obtained in the above Production Example 19 was added, and 0.09 ml 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the resulting product was concentrated under reduced pressure and purified by column chromatography (dichloromethane:methanol=100:1, v/v) to obtain 23 mg of the title compound (0.05 mmol) in 33% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.94 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 8.6 Hz , 1H), 7.42 (dd, J = 8.7, 2.0 Hz, 1H), 4.77 (s, 2H), 4.55-4.49 (m, 1H), 3.87- 3.84 (m, 2H), 3.39-3.35 (m, 2H), 1.99-1.90 (m, 2H), 1.56-1.50 (m, 2H), 1, 31(s, 9H)

<Example 54> Preparation of 6-(((5,7-dichlorobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H -pyrazolo[3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 41 mg of 5,7-dichloro-2-(chloromethyl)benzo[d]oxazole (0.16 mmol) obtained in Production Example 24 was added, and 0. 09 ml 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 41 mg of the title compound (0.09 mmol) in 57% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.67 (br s, 1H), 7.95 (s, 1H), 7.86 (d, J = 1.9 Hz, 1H), 7, 69 (d, J = 1.9 Hz, 1H), 4.85 (s, 2H), 4.54-4.45 (m, 1H), 3.88-3.84 (m, 2H), 3 .39-3.34 (m, 2H), 1.98-1.90 (m, 2H), 1.58-1.54 (m, 2H)

<Example 55> Preparation of 6-(((5,7-dimethylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H -pyrazolo[3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 34 mg of 5,7-dimethyl-2-(chloromethyl)benzo[d]oxazole (0.16 mmol) obtained in the above Production Example 25 was added, and 0 .09 ml 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 22 mg of the title compound (0.05 mmol) in 36% yield.

Rf = 0.30 (dichloromethane:methanol = 20:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.62 (br s, 1H), 7.94 (s, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7, 00 (s, 1H), 4.78 (s, 2H), 4.61-4.55 (m, 1H), 3.88-3.84 (m, 2H), 3.41-3.35 ( m, 2H), 2.41 (s, 3H), 2.35 (s, 3H), 2.00-1.90 (m, 2H), 1.62-1.58 (m, 2H)

<Example 56> Preparation of 6-((6-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[ 3,4-d]pyrimidin-4-one

40 mg 1-(tetrahydro-2H-pyran-4-yl)-6-thioxo-1,5,6,7-tetrahydro-4H-pyrazolo[3,4-d]pyridin-4-one (0.15 mmol ) obtained in the above Production Example 30 was dissolved in 3 ml of methanol, and 35 mg of 6-methoxy-2-(chloromethyl)benzo[d]oxazole (0.16 mmol) obtained in the above Production Example 27 was added, and 0.09 ml 2 n. sodium hydroxide, followed by stirring under reflux for 12 hours. After completion of the reaction, the precipitated solid was purified with water and ethyl acetate to give 48 mg of the title compound (0.12 mmol) in 74% yield.

Rf = 0.20 (dichloromethane:methanol = 10:1, v/v)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 7.95 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.33 (d, J=2.4Hz, 1H), 6.94(dd, J=8.7, 2.4Hz, 1H), 4.76(s, 2H), 4.64-4.53( m, 1H), 3.94-3.86(m, 2H), 3.79(s, 3H), 3.46-3.38(m, 2H), 2.03-1.90(m, 2H), 1.62-1.55 (m, 2H)

The chemical structural formulas of the compounds obtained in examples 1-56 are summarized and presented in the following table.

Table 1

At

measures

Chemical structure

Phosphodiesterase 9A inhibitory activity of exemplary compounds according to the present invention was tested based on a polarization assay (IMAP-FP rapid screen kit) provided by MDS (MDS Analytical Technologies, Sunyvale, CA, USA). As a buffer solution, a reaction solution (a reaction solution containing 0.01% Tween 20 provided by MDS was diluted 5 times, then 5 mM DTT was added) and a polarization detection solution (A and B binding solution provided by MDS were mixed at a ratio of 3:1 and the IMAP binding agent was added at a ratio of 1/600). Received 100 μm substrate (substrate Fl-cGMP; MDS) and 3.6 μg/ml of PDE9A enzyme (ab54113; abcam). 3.6 μg/ml PDE9A substrate and 100 μM were diluted to 20 ng/ml (final reaction concentration: 5 ng/ml) and 400 nM (final reaction concentration: 100 nM), respectively. The buffer solution used for all dilution and preparation processes was a 1x reaction solution with 1 mM DTT added, and the polarization detection solution was used to induce polarization in the final step.

The resulting samples were dispensed into black microplates (Multiwell 384-well plates, #3573, Corning Life Sciences, Lowell, MA, USA) using a 16-channel pipette (multi 16-channel, Finnpipette, Thermo Scientific, Essex, UK). The total reaction volume per well was 20 μl. However, 10 µl of 2% DMSO, 5 µl of substrate solution and 5 µl of reaction solution were used as a negative control, and 10 µl of 2% DMSO, 5 µl of substrate solution and 5 µl of PDE9A solution were used as a positive control. As the experimental group, 10 μl of the compound obtained in the example, 5 μl of the substrate solution and 5 μl of the PDE9A solution were used. After pretreatment of compound and enzyme for about 10 minutes, 5 μl of cGMP was added to induce an enzymatic reaction before enzyme and substrate reaction. During the reaction, each compound, enzyme, and substrate occupied 50%, 25%, and 25% of the total volume, respectively, and were obtained at high concentrations (2-, 4-, and 4-fold, respectively) just prior to addition. After the enzymatic reaction, the mixture was slightly shaken for 1 minute and the enzymatic reaction was induced at room temperature for 1 hour. Then, 60 µl of a pre-prepared polarization detection solution was added to induce polarization.

Nanoparticles consisting of trivalent metal ions were mixed in a solution for detecting fluorescence, which was combined with phosphoric acid under the influence of an enzymatic reaction to increase the molecular weight and induce polarization. After incubation for 2 hours at room temperature, the polarization value (fluorescence polarization, FP) was measured using a multi-label counter (Envision, PerkinElmer, Turku, Finland) (emission wavelength: P-535 nm, S-535 nm, excitation wavelength: 480 nm), expressing the result as an IC ₅₀ value, which is the concentration of a compound that inhibits PDE9A in vitro by 50% (Table 2).

table 2

Example No. PDE9A (IC ₅₀ , μM) Example No. PDE9A (IC ₅₀ , μM) 1 0.005 31 38.9% 2 0.049 32 27.7% 3 0.081 33 0.95 four 0.083 34 0.12 five 0.049 35 83.6% 6 0.19 36 34.1 7 0.10 37 0.074 8 0.005 38 0.045 nine 0.006 39 0.077 10 0.22 40 1.66 eleven 0.006 41 0.022 12 0.004 42 0.13 13 0.012 43 0.12 fourteen 0.004 44 0.015 15 0.010 45 0.008 sixteen 0.006 46 0.003 17 0.19 47 0.12 eighteen 0.004 48 0.023 nineteen 0.028 49 0.032 20 0.006 50 0.13 21 0.003 51 0.035 22 0.006 52 0.017 23 0.002 53 0.045 24 0.005 54 0.019 25 10.3% 55 0.010 26 0.14 56 0.003 27 6.63 28 51.5% 29 2.40 thirty 1.72

In Table 2, the % values represent the mean % inhibition of PDE9A at a compound concentration of 10 μM.

Claims (72)

1. The compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof, [Chemical formula 1]

while in the chemical formula 1 A is phenyl, linear or branched C _1-5 alkyl, unsubstituted or substituted with one or two halogen atoms, 3-6 membered cycloalkyl unsubstituted or substituted with one or two halogen atoms, or 3-6 membered heterocycloalkyl containing nitrogen, oxygen or sulfur as a heteroatom, and each of R ¹ and R ² is independently -H, a halogen atom, -NO ₂ , -CF ₃ , phenyl, linear or branched C _1-5 alkyl, unsubstituted or substituted with one or two halogen atoms, or linear or branched C _{1 -5} alkoxy group, unsubstituted or substituted by one or two halogen atoms, with the proviso that when A is phenyl, either of R ¹ and R ² is not hydrogen. 2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that A is phenyl, linear or branched C _1-5 alkyl, unsubstituted or substituted with one or two halogen atoms, 3-6 membered cycloalkyl, unsubstituted or substituted one or two halogen atoms, or a 3-6 membered heterocycloalkyl containing nitrogen, oxygen or sulfur as a heteroatom, and each of R ¹ and R ² is independently -H, a halogen atom, -NO ₂ , -CF ₃ , phenyl, linear or branched C _1-5 alkyl, unsubstituted or substituted with one or two halogen atoms, or linear or branched C _{1 -5} alkoxy group, unsubstituted or substituted by one or two halogen atoms. 3. A compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that A is phenyl,

or

and each of R ¹ and R ² independently represents -H, a halogen atom, -NO ₂ , -CF ₃ , -CH ₃ , -C(CH ₃ ) ₃ or phenyl. 4. A compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that said compound is 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -he, 6-(((5-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5-fluorobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5-chlorobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5-bromobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4 -he, 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((benzo[d]oxazol-2-ylmethyl)thio)-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-cyclohexyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-cyclopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((6-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-isopropyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((1-(benzo[d]oxazol-2-yl)ethyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-((1-benzo[d]oxazol-2-yl)ethyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4 -he, 6-((1-benzo[d]oxazol-2-yl)ethyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d ]pyrimidin-4-one, 1-(4,4-difluorocyclohexyl)-6-((1-(6-methylbenzo[d]oxazol-2-yl)ethyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one, 6-((1-(6-methylbenzo[d]oxazol-2-yl)ethyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one, 6-((1-(6-methylbenzo[d]oxazol-2-yl)ethyl)thio)-1-(tetrahydro-2H-thiopyran-4-yl)-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one, 1-phenyl-6-(((5-phenylbenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((4-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazol[3,4-d]pyrimidin-4-one, 6-(((5-(tert-butyl)benzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4 -he, 6-(((6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((4-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5-nitro-6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4- he, 6-(((5,7-dichlorobenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5,7-dimethylbenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((5-Methoxybenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 6-(((6-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, 1-phenyl-6-(((5-(trifluoromethyl)benzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one , 1-(4,4-difluorocyclohexyl)-6-(((6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 1-(4,4-difluorocyclohexyl)-6-(((5-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 1-(4,4-difluorocyclohexyl)-6-(((4-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 6-(((5-chloro-6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 1-(4,4-difluorocyclohexyl)-6-(((4-methylbenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 6-(((5-(tert-butyl)benzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4 -d]pyrimidin-4-one, 6-(((5,7-dichlorobenzo[d]oxazol-2-yl)methyl)thio)-1-(4,4-difluorocyclohexyl)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one, 1-(4,4-difluorocyclohexyl)-6-(((5,7-dimethylbenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one, 1-(4,4-difluorocyclohexyl)-6-(((5-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 1-(4,4-difluorocyclohexyl)-6-(((6-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine- 4-he, 1-(4,4-difluorocyclohexyl)-6-(((5-(trifluoromethyl)benzo[d]oxazol-2-yl)methyl)thio)-1,5-dihydro-4H-pyrazolo[3,4-d ]pyrimidin-4-one, 6-(((6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 6-(((5-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 6-(((4-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 6-(((5-chloro-6-nitrobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[ 3,4-d]pyrimidin-4-one, 6-(((4-methylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d] pyrimidin-4-one, 6-(((5-(tert-butyl)benzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo [3,4-d]pyrimidin-4-one, 6-(((5,7-dichlorobenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one, 6-(((5,7-dimethylbenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3, 4-d]pyrimidin-4-one or 6-(((6-methoxybenzo[d]oxazol-2-yl)methyl)thio)-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4- d]pyrimidin-4-one. 5. Pharmaceutical composition for the treatment or prevention of a disease associated with phosphodiesterase 9A, containing a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of paragraphs. 1-4 as an active ingredient and a pharmaceutically acceptable carrier. 6. Pharmaceutical composition according to claim 5, characterized in that said disease is a neurological disease or mental illness. 7. Pharmaceutical composition according to claim 6, characterized in that said neurological or psychiatric disorder is Alzheimer's disease, Huntington's disease, dementia with Lewy bodies or Pick's syndrome. 8. Pharmaceutical composition according to claim 5, characterized in that said disease is heart failure, in particular heart failure with preservation of cardiac output, or sickle cell anemia.