KR20210076693A - Fused pyrimidine derivatives substituted with a nitrogen-containing heterocyclic ring and their pharmaceutical use - Google Patents

Abstract

The present application relates to a condensed pyrimidine derivative substituted with a nitrogen-containing heterocyclic ring, and a pharmaceutical use thereof. The present invention provides a compound represented by chemical formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer comprising the compound.

Description

Fused pyrimidine derivatives substituted with a nitrogen-containing heterocyclic ring and their pharmaceutical use

The present application relates to a condensed pyrimidine derivative substituted with a nitrogen-containing heterocycle and a pharmaceutical use thereof.

Adenosine (Adenosine) is a substance that performs many physiological functions through a specific cell membrane receptor, mediated by the receptor, has a wide range of physiological activities including immune and inflammatory responses. In particular, cancer cells produce 5 to 50 times more adenosine than normal cells. A high concentration of adenosine induces the activation of A2A receptors and thus protects itself by showing an immunosuppressive effect. An antagonist of A2A receptors is an immunosuppressive mechanism of these cancer cells. to show anticancer effect.

There are four A2A adenosine receptors (A1, A2A, A2B, A3) and they are linked to heteromeric G protein. The A2A and A2B receptors are each linked to the Gs subtype of Gα proteins. When these receptors are stimulated, the receptor conformation changes, which induces release of the activated Gs subunit from the Gβρ dimer, and then hydrolyses intracellular ATP into cyclic AMP (cAMP). cAMP synthesis is responsible for activating PKA and phosphorylation of other substrates. In T cells, the type I PKA isoform mainly exists near the T cell receptor, and when the action of PKA is increased by the increased cAMP level, the TCR signaling process is inhibited, contributing to the induction of various diseases.

Modulation of these adenosine receptors has been proposed as a target for various diseases to date. For example, the modulation of adenosine A1 receptors is a neurological disorder, asthma, and heart failure and renal failure, etc., an antagonist of adenosine A2A receptors is Parkinson's disease, etc., the modulation of adenosine A2B receptors is a chronic lung disease including asthma, etc., adenosine A3 receptors Control has been proposed for asthma and chronic obstructive pulmonary disease, glaucoma, cancer, and stroke. Initially, A2A receptor antagonists were developed for Parkinson's disease, but now large pharmaceutical companies are actively developing them as promising immuno-oncology targets. Several studies have reported that A2A antagonists enhance anti-tumor immunity. The A2A receptor is widely expressed in leukocytes. When the A2A receptor of T cells is activated, it reduces TCR-mediated cytotoxicity and cytokine production, and induces inhibition of T cell proliferation and expansion of Treg cells.

Immune checkpoint inhibitors (PD-1 or PD-L1 antibody) showed high efficacy and safety in the immuno-oncology market, but only 20-30% of patients with PD-1/PD-L1 overexpression were statistically significant. It showed limitations in which efficacy could not be confirmed. Therefore, many clinical trials are currently underway for immune checkpoint inhibitors as combination therapy with A2A receptor antagonists. The most advanced drug is Ciforadenant (CPI-444) from Vernalis in clinical I/II, followed by AZD 4635 from Astrazeneca and PBF-509 from Novartis.

Republic of Korea Patent No. 10-0937620

One aspect is to provide a fused pyrimidine derivative substituted with a nitrogen-containing heterocycle having an adenosine A2A receptor antagonistic effect.

Another aspect is to provide a pharmaceutical use of a fused pyrimidine derivative substituted with a nitrogen-containing heterocycle having an adenosine A2A receptor antagonistic effect.

Another aspect is to provide a pharmaceutical use of the derivative for the prevention or treatment of cancer.

Other objects and advantages of the present application will become more apparent from the following detailed description in conjunction with the appended claims and drawings. Content not described in this specification will be sufficiently recognized and inferred by those skilled in the technical field of the present application or a similar technical field, so the description thereof will be omitted.

Each description and embodiment disclosed in this application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. In addition, it cannot be seen that the scope of the present application is limited by the detailed description described below.

One aspect provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof of formula (I):

[Formula I]

.

.

Another aspect provides a pharmaceutical composition for preventing or treating cancer comprising the compound of Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

The compound of Formula I, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to an aspect exhibits antagonistic action on adenosine A2A receptor, thereby treating cancer, for example, an immunocancer agent It can be applied as a combination preparation with

Accordingly, the compound of Formula I, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to an aspect may be utilized as an active ingredient of a pharmaceutical composition for preventing or treating cancer.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited by the following examples.

One aspect provides a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the following formula (I):

[Formula I]

.

.

In the above formula (I),

Cy contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl or heterocycloalkyl ring;

R is a phenyl group or a pyridine group substituted with _{R 1} , R ₂ and R _{3 ;}

R ₁ , R ₂ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, carbonyl group, amide group, nitro group, amino group, substituted or unsubstituted C ₁ -C ₅ alkyl group, substituted or unsubstituted C ₂ -C ₅ alkenyl group, substituted or unsubstituted C ₂ -C ₅ alkynyl group, substituted or unsubstituted C ₁ -C ₃ haloalkyl group, substituted or unsubstituted C ₁ -C ₃ aminoalkyl group, or substituted or an unsubstituted C ₁ -C ₅ alkoxy group;

R' is hydrogen, halogen, cyano group, substituted or unsubstituted C ₁ -C ₅ alkyl group, substituted or unsubstituted C ₂ -C ₅ alkenyl group, substituted or unsubstituted C ₂ -C ₅ alkynyl group, substituted or unsubstituted C _3- C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ -C ₁₀ aryl, or substituted or unsubstituted C ₄ -C ₁₀ heteroaryl;

Het is a 5-membered heteroaryl or heterocycloalkyl ring containing 1 to 3 nitrogen atoms, substituted with _{R 4} , R ₅ and R _{6 ;} and

R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, substituted or unsubstituted C ₁ -C ₅ alkyl group, substituted or unsubstituted C ₂ -C ₅ alkenyl group, substituted an unsubstituted C ₂ -C ₅ alkynyl group, a substituted or unsubstituted C ₁ -C ₃ haloalkyl group, a substituted or unsubstituted C ₃ -C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ -C ₁₀ aryl, or substituted or unsubstituted C ₄ -C ₁₀ heteroaryl.

As used herein, the term “halogen” may be F, Cl, Br, or I.

As used herein, the term “alkyl,” unless otherwise stated, refers to a straight-chain, or branched, hydrocarbon residue, which may be substituted or unsubstituted. The alkyl group may include, without limitation, all possible isomers thereof such as, for example, methyl, ethyl, propyl, butyl, pentyl, or isopropyl, isobutyl, and t-butyl.

As used herein, the term “alkenyl” refers to an alkyl group containing one or more double bonds, which may be substituted or unsubstituted, unless otherwise stated. The alkenyl group may be, for example, prop-1-ene, but-1-ene, but-2-ene, 3-methylbut-1-ene, pent-1-ene, etc., all possible Isomers may include without limitation.

As used herein, the term "alkynyl" refers to an alkyl group containing one or more triple bonds, which may be substituted or unsubstituted, unless otherwise indicated. The alkynyl group may be, for example, prop-1-yne, but-1-yne, pent-1-yne, etc., and may include all possible isomers thereof without limitation.

As used herein, the term “cycloalkyl,” unless otherwise stated, refers to saturated monocyclic and polycyclic hydrocarbon rings, which may be substituted or unsubstituted, generally having the specified number of carbon atoms, including the ring. The cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

As used herein, the term "heterocycloalkyl" refers to, unless otherwise stated, a monocyclic substituted or unsubstituted monocyclic containing one or more heteroatoms selected from B, N, O, S, P(=O), Si and P. , represents a cyclic alkyl. Examples include, but are not limited to, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, thiomorpholinyl, imidazolidinyl, tetrahydrofuryl, and the like.

As used herein, the term "haloalkyl" is meant to include monohaloalkyl and polyhaloalkyl, which may be substituted or unsubstituted, unless otherwise stated. The terms halogen and alkyl are as described above.

As used herein, unless otherwise stated, the term "alkoxy" refers to a straight-chain or branched hydrocarbon moiety, which may be substituted or unsubstituted, connected by oxygen. The alkoxy may include, without limitation, all possible isomers thereof, such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

As used herein, the term “aryl” refers to an aromatic group that may be substituted or unsubstituted, and includes, for example, C ₃ -C ₁₀ aryl, C ₃ -C ₈ aryl, or C ₃ -C ₆ aryl, unless otherwise indicated. and alternating (resonance) double bonds between adjacent carbon atoms or suitable heteroatoms. For example, it may include, without limitation, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, or all possible isomers thereof.

As used herein, the term "heteroaryl" refers to, unless otherwise stated, monocyclic or bicyclic or more containing one or more heteroatoms selected from B, N, O, S, P(=O), Si and P, substituted or an aromatic group, which may be unsubstituted. Examples of monocyclic heteroaryl include pyrazolyl, pyrrolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridine yl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl and the like. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso quinolinyl, purinyl, furopyridinyl, oxochromene, dioxoisoindoline, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl and the like.

As used herein, the term “aminoalkyl” refers to a group formed by combining an alkyl and an amino group as defined above. Examples include -NHCH ₃ , -NHCH ₂ CH ₃ , -NHCH(CH ₃ ) ₂ , -N(CH ₃ ) ₂ , -NCH ₃ (CH ₂ CH ₃ ), -NCH ₃ (CH(CH ₃ ) ₂ ) and groups similar thereto, but are not limited thereto.

In the present specification, the numerical range indicated using the term “to” refers to a range including the numerical values described before and after the term “to” as the lower limit and the upper limit, respectively.

As used herein, the term "solvate" may refer to a compound of the present invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor may be solvents that are volatile, non-toxic, and/or suitable for administration to humans.

As used herein, the term “stereoisomer” may refer to a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but optically or sterically different, and specifically, a diastereomer, enantiomer, geometric isomer, or It may be a conformational isomer.

In addition, the compound can be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, for example, the salt is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malic acid Ronic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methane It may be a salt derived from sulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or the like.

A pharmaceutically acceptable salt of the compound is prepared by dissolving the compound of formula (I) in a water-miscible organic solvent, for example, acetone, methanol, ethanol, or acetonitrile, and adding an excess of organic acid or an aqueous solution of an inorganic acid followed by precipitation. Or it can be prepared by crystallization. Subsequently, after evaporating the solvent or excess acid from this mixture, it can be dried to obtain an addition salt, or it can be prepared by suction filtration of the precipitated salt.

In one embodiment, Cy contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl ring; R is a phenyl group or a pyridine group substituted with _{R 1} , R ₂ and R _{3 ;} R ₁ , R ₂ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, amino group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C _{3 is a} haloalkyl group, a C ₁ -C ₃ aminoalkyl group, or a C ₁ -C ₅ alkoxy group; R' is hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl; Het is a pyrazole group or a triazole group substituted with _{R 4} , R ₅ and R _{6 ;} and R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl.

또는

로서, Cy의 질소 원자와 결합되고; R₁, R₂ 및 R₃는 독립적으로 수소, 할로젠, 히드록시기, 티올기, 아미노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C₁-C₃ 할로알킬기, C₁-C₃ 아미노알킬기, 또는 C₁-C₅ 알콕시기이고; R'은 Cy의 탄소 원자와 결합되고, 수소, 할로젠, 시아노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C_3-C₈ 사이클로알킬기, C₃-C₁₀ 아릴, 또는 C₄-C₁₀ 헤테로아릴이고; Het은

또는

이고; 및 R₄, R₅ 및 R₆는 독립적으로 수소, 할로젠, 히드록시기, 티올기, 시아노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C₁-C₃ 할로알킬기, C_3-C₈ 사이클로알킬기, C₃-C₁₀ 아릴, 또는 C₄-C₁₀ 헤테로아릴일 수 있다.In one embodiment, Cy contains one or more nitrogen atoms, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl ring; R is

or

as, bonded to the nitrogen atom of Cy; R ₁ , R ₂ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, amino group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C _{3 is a} haloalkyl group, a C ₁ -C ₃ aminoalkyl group, or a C ₁ -C ₅ alkoxy group; R' is bonded to a carbon atom of Cy, hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl; Het

or

ego; and R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl.

또는

로서, Cy의 질소 원자와 결합되고; R₁ 및 R₃는 독립적으로 수소, 할로젠, 히드록시기, 티올기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C₁-C₃ 할로알킬기, 또는 C₁-C₅ 알콕시기이고, R₂는 수소, 할로젠, 아미노기 또는 C₁-C₅ 알콕시기이고; R'은 Cy의 탄소 원자와 결합되고, 수소, 할로젠, 시아노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C_3-C₈ 사이클로알킬기, C₃-C₁₀ 아릴, 또는 C₄-C₁₀ 헤테로아릴이고; Het은

또는

이고; 및 R₄, R₅ 및 R₆는 독립적으로 수소, 할로젠, 히드록시기, 티올기, 시아노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C₁-C₃ 할로알킬기, C_3-C₈ 사이클로알킬기, C₃-C₁₀ 아릴, 또는 C₄-C₁₀ 헤테로아릴일 수 있다.In one embodiment, Cy contains one or more nitrogen atoms, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl ring; R is

or

as, bonded to the nitrogen atom of Cy; R ₁ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, or a C ₁ -C ₅ alkoxy group, and R ₂ is hydrogen, halogen, an amino group or a C ₁ -C ₅ alkoxy group; R' is bonded to a carbon atom of Cy, hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl; Het

or

ego; and R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl.

또는

로서, Cy의 질소 원자와 결합되고; R₁ 및 R₃는 독립적으로 수소, 할로젠, 히드록시기, 티올기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C₁-C₃ 할로알킬기, 또는 C₁-C₅ 알콕시기이고, R₂는 수소, 할로젠, 아미노기 또는 C₁-C₅ 알콕시기이고; R'은 Cy의 탄소 원자와 결합되고, 수소, 할로젠, 시아노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C_3-C₈ 사이클로알킬기, C₃-C₁₀ 아릴, 또는 C₄-C₁₀ 헤테로아릴이고; Het은

또는

이고; 및 R₄, R₅ 및 R₆는 독립적으로 수소, 할로젠, 히드록시기, 티올기, 시아노기, C₁-C₅ 알킬기, C₂-C₅ 알케닐기, C₂-C₅ 알키닐기, C₁-C₃ 할로알킬기, C_3-C₈ 사이클로알킬기, C₃-C₁₀ 아릴, 또는 C₄-C₁₀ 헤테로아릴일 수 있다.In one embodiment, Cy together with the atom in the pyrimidine ring bonded to Cy forms a pyrazolopyrimidine, or a purine; R is

or

as, bonded to the nitrogen atom of Cy; R ₁ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, or a C ₁ -C ₅ alkoxy group, and R ₂ is hydrogen, halogen, an amino group or a C ₁ -C ₅ alkoxy group; R' is bonded to a carbon atom of Cy, hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl; Het

or

ego; and R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl.

In one embodiment, the compound of Formula I may be selected from the group consisting of the following compounds:

1-benzyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-3-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(1H-pyrazol-1-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-fluoro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluoro-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-fluoro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3,5-bis(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-methoxy-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(3-methoxy-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-methoxy-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2-methoxy-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-3-methylbenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

(S)-4-(1H-pyrazol-1-yl)-1-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-1H-pyra zolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(3-(tert-butyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;

1-(4-amino-2-fluorobenzyl)-4-(3-cyclopropyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(3-phenyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- 6-amine;

1-(4-amino-2-fluorobenzyl)-4-(4-chloro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri midin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine ;

1-(4-amino-2-fluorobenzyl)-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d ]pyrimidin-6-amine;

1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine -6-amine;

1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

4-(3-methyl-1H-pyrazol-1-yl)-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;

1-(4-amino-3-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(4-amino-3-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;

1-(4-amino-2-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;

3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-fluoro phenol;

3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenol;

1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;

1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-fluoro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- 6-amine;

1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d ]pyrimidin-6-amine;

1-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazol-4-ol;

1-(2,6-difluorobenzyl)-3-methyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluorobenzyl)-3-methyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;

1-(2,6-difluorobenzyl)-3-ethyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluorobenzyl)-3-ethyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;

3-cycloropropyl-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

3-cyclopropyl-1-(2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine -6-amine;

1-(2,6-difluorobenzyl)-3-ethynyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

1-(2,6-difluorobenzyl)-3-ethynyl-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;

3-chloro-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;

6-amino-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;

9-benzyl-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

6-(1H-pyrazol-1-yl)-9-(pyridin-2-ylmethyl)-9H-purin-2-amine;

9-(4-aminobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(3,5-bis(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-2-fluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-3-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-2-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-2,3-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-3-chlorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-2-fluoro-5-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-2-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-3-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-3,5-dimethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-(4-amino-3-ethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

9-((6-methylpyridin-2-yl)methyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;

2-(6-((2-amino-6-(1H-pyrazol-1-yl)-9H-purin-9-yl)methyl)pyridin-2-yl)propan-2-ol;

(R)-6-(1H-pyrazol-1-yl)-9-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-9H-purine -2-amine;

1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-3-carbonitrile;

1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-4-carbonitrile; and

9-(2,6-difluorobenzyl)-6-(4-(pyridin-4-yl)-1H-pyrazol-1-yl)-9H-purin-2-amine.

Hereinafter, a method for preparing the compound represented by Formula I will be described in detail.

As an example, the compound can be prepared using chemical transformations well known to those skilled in the art of organic/pharmaceutical chemistry according to the methods representatively shown in Schemes 1 to 7 below.

[Scheme 1]

When described in more detail with reference to Scheme 1 above,

Dissolving the compound A-2 in a _{mixed solvent of tetrahydrofuran (THF) and H 2} O, followed by a cyclization reaction with hydrazine monohydrate at 25° C. to 60° C. for 24 hours to prepare the compound of formula A-3 ;

A-3 compound is dissolved in N,N-dimethylformamide (DMF) solvent, which is potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) under the conditions provided, 25 ℃ a second step of preparing compound A-5 by nucleophilic substitution reaction with compound A-4 at 60° C. for 24 hours; and

A-5 compound is dissolved in N,N-dimethylformamide (DMF) solvent and potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) is provided, 25° C. to 60 A nucleophilic substitution reaction with the A-6 compound for 24 hours to prepare a compound represented by Formula I, or a nucleophilic substitution reaction under the same conditions and tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) A third step of preparing a compound represented by the formula (I) by selecting one or more of the solvents and reacting them with tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O) or palladium/carbon under pressure of hydrogen gas under pressure conditions in a third step Through a series of processes, the compound represented by the formula (I) can be prepared. Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 of Scheme 1 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ of Formula I.

[Scheme 2]

When described in more detail with reference to Scheme 2,

Dissolve compound A-3 in 1,2-dichloroethane (1,2-DCE) and N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) at reflux temperature for 12 to 24 hours a first step of preparing a compound of Formula B-1 by a halogenation reaction with

Dissolving the compound B-1 in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ), 25° C. to 60 a second step of preparing compound B-2 by nucleophilic substitution reaction with compound A-6 at ℃ for 24 hours; and

Dissolving the B-2 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ), 25° C. to 60 A nucleophilic substitution reaction with the A-4 compound for 24 hours to prepare a compound represented by Formula I, or a nucleophilic substitution reaction under the same conditions and tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) A third step of preparing a compound represented by the formula (I) by selecting one or more of the solvents and reacting them with tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O) or palladium/carbon under pressure of hydrogen gas under pressure conditions in a third step Through a series of processes, the compound represented by the formula (I) can be prepared. Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 of Scheme 2 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ of Formula I.

[Scheme 3]

When described in more detail with reference to Scheme 3,

Dissolving the B-2 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ), 25° C. to 60 A first step of preparing compound C-1 by nucleophilic substitution reaction with compound A-4 at ℃ for 24 hours; and

Dissolve the C-1 compound in an acetonitrile solvent and Sonogashira under conditions in which sodium cyanide, tetrakis(triphenylphosphine)palladium(0)(Pd(PPh ₃ ) ₄ , and copper(I) iodide are provided reacted to prepare a compound represented by Formula I, or trimethylsilylacetylene, copper (I) iodide, triphenylphosphine (PPh ₃ ), and bis(triphenylphosphine)palladium (II) die without a separate solvent Chloride (PdCl ₂ (PPh ₃ ) ₂ ) Through a series of processes including a second step of preparing a compound represented by Formula I by catalytic cyanation under the conditions provided, the compound represented by Formula I can be prepared Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 in Scheme 3 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ in Formula I can

[Scheme 4]

When described in more detail with reference to Scheme 4,

A-6 compound is selected from tetrahydrofuran (THF) or dichloromethane (DCM) solvent and replaced with tert-butyl carbazate at 30° C. for 12 to 24 hours, followed by dichloromethane (DCM) ) a first step of preparing compound D-1 by deprotection reaction of N-tert-butoxycarbonyl (N-Boc) in a solvent and acid conditions;

Dissolve the compound D-1 in N,N-dimethylformamide (DMF) solvent and provide potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) at 25° C. to 60 a second step of preparing compound D-2 by nucleophilic substitution reaction with compound A-2 at ℃ for 24 hours; and

Dissolving the D-2 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ), 25° C. to 60 A nucleophilic substitution reaction with the A-4 compound for 24 hours to prepare a compound represented by Formula I, or a nucleophilic substitution reaction under the same conditions and tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) A third step of preparing a compound represented by the formula (I) by selecting one or more of the solvents and reacting them with tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O) or palladium/carbon under pressure of hydrogen gas under pressure conditions in a third step Through a series of processes, the compound represented by the formula (I) can be prepared. Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 of Scheme 4 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ of Formula I.

[Scheme 5]

When described in more detail with reference to Scheme 5,

A first step of preparing compound E-1 by dissolving compound A-2 in diethyl ether solvent and performing Grignard reaction at -78°C to 25°C for 2 hours to 12 hours;

E-1 compound is dissolved in 1,2-dichloroethane (1,2-DCE) solvent, and _{under the condition that an oxidizing agent of manganese dioxide (MnO 2} ) is provided, the compound E-2 is oxidized at 24° C. for 24 hours. a second step of manufacturing;

E-2 compound is dissolved in tetrahydrofuran (THF) solvent, and N,N-diisopropylethylamine (DIPEA) is provided under basic conditions for cyclization reaction with D-1 compound for 24 hours at 25° C. to E- 3 A third step of preparing a compound; and

E-3 compound is dissolved in N,N-dimethylformamide (DMF) solvent, and potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) Under the conditions provided, 25 ℃ to 60 A nucleophilic substitution reaction with the A-4 compound for 24 hours to prepare a compound represented by Formula I, or a nucleophilic substitution reaction under the same conditions and tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) A fourth step of preparing a compound represented by Formula I by selecting one or more of the solvents and reacting them with tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O) or palladium/carbon under pressure of hydrogen gas under pressure conditions Through a series of processes, the compound represented by the formula (I) can be prepared. Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 of Scheme 5 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ of Formula I.

[Scheme 6]

When described in more detail with reference to Scheme 6,

Dissolving the G-1 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) at 25° C. to 60 The first step of preparing the G-2 compound by nucleophilic substitution reaction with the A-4 compound at °C for 24 hours, provided that when R _a4 , R _a5 , and R _a6 are H, the G-1 compound is reacted with methanol (MeOH ) Dissolved in a solvent, subjected to a substitution reaction with hydrazine monohydrate, and cyclized with 1,1,3,3-tetramethoxypropane under acid conditions at 25° C. to 45° C. for 24 hours, which can replace the nucleophilic substitution reaction. ; and

Dissolving the G-2 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) at 25° C. to 60 A nucleophilic substitution reaction with the A-6 compound for 24 hours to prepare a compound represented by Formula I, or a nucleophilic substitution reaction under the same conditions and tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) A second step of preparing a compound represented by the formula (I) by selecting one or more of the solvents and reacting them with tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O) or palladium/carbon under pressure of hydrogen gas under pressure conditions Through a series of processes, the compound represented by the formula (I) can be prepared. Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 of Scheme 6 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ of Formula I.

[Scheme 7]

When described in more detail with reference to Scheme 7,

Dissolving the G-1 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ) at 25° C. to 60 A first step of preparing compound H-1 by nucleophilic substitution reaction with compound A-6 at ℃ for 24 hours; and

Dissolving the H-1 compound in N,N-dimethylformamide (DMF) solvent and providing potassium carbonate (K ₂ CO ₃ ) or cesium carbonate (Cs ₂ CO ₃ ), 25° C. to 60 A nucleophilic substitution reaction with the A-4 compound for 24 hours to prepare a compound represented by Formula I, or a nucleophilic substitution reaction under the same conditions and tetrahydrofuran (THF), methanol (MeOH), or ethanol (EtOH) A second step of preparing a compound represented by the formula (I) by selecting one or more of the solvents and reacting them with tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O) or palladium/carbon under pressure of hydrogen gas under pressure conditions; When R _a4 , R _a5 , and R _a6 are H, the H-1 compound is dissolved in a solvent of methanol (MeOH) and subjected to a substitution reaction with hydrazine monohydrate and 1,1,3,3-tetramethoxypropane and 25 under acid conditions. Through a series of processes including the second step, which can replace the nucleophilic substitution reaction by cyclization at ℃ to 45 ℃ for 24 hours, the compound represented by the formula (I) can be prepared. Here, R _a1 , R _a2 , R _a3 , R _a4 , R _a5 and R _a6 of Scheme 7 may correspond to _{R 1} , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ of Formula I.

Another aspect provides a pharmaceutical composition for preventing or treating cancer, comprising the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by Formula I as an active ingredient.

As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in an individual experiencing or exhibiting the pathology or sign of the disease, condition or disorder, i.e., inhibiting the disease, condition or disorder. , preventing further development of the pathology and/or symptom, or ameliorating the disease, e.g., ameliorating the disease, condition or disorder in an individual experiencing or exhibiting the pathology or symptom of the disease, condition or disorder, i.e. , to reversing pathology and/or symptoms, such as reducing disease severity.

As used herein, the term "preventing" or "prevention" refers to preventing a disease, e.g., a disease in an individual who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited the pathology or signs of the disease. , to prevent a condition or disorder.

As used herein, the term "subject" refers to a subject in need of treatment for a disease, and more specifically, a human or non-human primate, mouse, mammal such as dog, cat, horse, and cow. means

"Cancer", which is a disease to be prevented or treated by the pharmaceutical composition, is defined as an aggressive characteristic in which cells divide and grow ignoring normal growth limits, an invasive characteristic that penetrates into surrounding tissues, and other in vivo characteristics. It is a generic term for diseases caused by cells with metastatic properties that spread to sites. Examples of the cancer include lung cancer, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma tumor, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer.

According to one embodiment, the pharmaceutical composition comprising a compound represented by Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient has antagonistic action on adenosine A2A receptor. By showing, it can be used to treat cancer.

In one embodiment, the pharmaceutical composition may include conventional pharmaceutically acceptable carriers, excipients or additives. The pharmaceutical composition may be formulated according to a conventional method, and various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, etc. or parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration can be manufactured with

When the pharmaceutical composition is prepared in the form of an oral dosage form, examples of additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, stearic acid calcium, gelatin, talc, surfactant, suspending agent, emulsifying agent, diluent, and the like. When the pharmaceutical composition of the present invention is prepared in the form of an injection, the additive or carrier includes water, saline, aqueous glucose solution, similar sugar solution, alcohol, glycol, ether (eg, polyethylene glycol 400), oil, fatty acid, fatty acid ester , glycerides, surfactants, suspending agents, emulsifiers, and the like.

The dosage of the pharmaceutical composition is an amount effective for treatment or prevention of an individual or patient, and may be administered orally or parenterally as desired. When administered orally, 0.01 to 1 kg of body weight per day based on the active ingredient When administered parenterally, it is administered in an amount of 1000 mg, more specifically, 0.1 to 300 mg, 0.01 to 100 mg, more specifically, 0.1 to 50 mg per kg of body weight per day based on the active ingredient. It can be administered in 1 to several divided doses as much as possible. The dose to be administered to a specific individual or patient should be determined in light of several related factors such as the patient's weight, age, sex, health condition, diet, administration time, administration method, and disease severity, and may be appropriately adjusted or decreased by an expert. It should be understood that the above dosage is not intended to limit the scope of the present invention in any way. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start a dose of a compound of the invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. can increase

In one embodiment, the pharmaceutical composition includes within its scope a pharmaceutical composition comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds according to one embodiment, alone or in combination with a pharmaceutical carrier. Optionally, a compound according to one embodiment may be administered alone, in combination with a compound according to another embodiment, or concurrently, separately or sequentially with one or more other therapeutic agents, such as an anti-cancer agent or other pharmaceutically active substance. have. The anti-cancer agent includes, for example, an anti-cancer agent, an anti-angiogenesis agent, an anti-inflammatory agent, and an immunosuppressive agent, for example, CTLA-4, PD-1, PD-L1, etc. It may be an immune anticancer agent including an immune checkpoint inhibitor.

In addition, as is known in the art, other combination therapies for the treatment of cancer are also within the scope of the present invention. See, for example, International Publication No. WO2015006520, the entire contents of which may be incorporated by reference for the purposes or claims cited herein.

Another aspect is a method for preventing or treating cancer comprising administering to an individual the compound represented by Formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same; and a pharmaceutical use of the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the above formula (I) for the prevention or treatment of cancer; Provided is a pharmaceutical use of the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the above formula (I) for the manufacture of a therapeutic agent for cancer.

[Example]

Example 1: Preparation of 1-benzyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

1-1. Preparation of 4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: Preparation of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Dissolve 2-amino-4,6-dichloropyrimidine-5-carbaldehyde ( S1 , 5g, 26.04mmol) in tetrahydrofuran (THF) and H ₂ O mixed solvent, and triethylamine (TEA, 4.4ml, 31.25mmol) and hydrazine monohydrate (1.53ml, 31.25mmol) were added, followed by stirring at room temperature for 5 hours. Then, the reaction mixture was concentrated, the resulting solid was filtered, washed with distilled water, dried, and the next reaction was carried out without further purification.

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.26 (br s, 1H), 7.95 (s, 1H), 7.16 (br s, 2H).

Step 2: Preparation of 4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The intermediate compound ( S2 , 1g, 5.90mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (DMF), and pyrazole (410mg, 5.90mmol) and cesium carbonate (Cs ₂ CO) ₃ , 1.64 g, 11.80 mmol) was added. Thereafter, the reaction mixture was heated to 60° C. and stirred for 1 day. The reaction mixture was diluted with dichloromethane (DCM) and washed with distilled water. After drying over magnesium sulfate, filtration, and concentration, the concentrate was purified by silica gel chromatography to obtain the target compound ( S3 , 450 mg, 2 steps 38%).

¹ H NMR (DMSO-d6, 400 MHz): δ 13.25 (s, 1H), 7.95 (s, 1H), 7.14 (br s, 2H).

1-2. Preparation of 1-benzyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The compound of Example 1-1 ( S3 , 25mg, 0.12mmol) was dissolved in anhydrous tetrahydrofuran (THF), sodium hydride (2.4mg, 0.10mmol) was added at 0°C, and then benzylbromide (12ul, 0.10) mmol) and stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate (EA), washed with water, dried over magnesium sulfate, filtered and concentrated, and the concentrated solution was purified by silica gel chromatography to obtain the target compound ( 1 , 10 mg, 28%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.65 - 8.64 (m, 1H), 8.30 (s, 1H), 8.05 (m, 1H), 7.35 - 7.21 (m, 5H), 7.11 (s, 2H) ), 6.70 - 6.69 (m, 1H), 5.45 (s, 2H).

Example 2: Preparation of 1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

After dissolving the compound of Example 1-1 ( S3 , 50mg, 0.25mmol) in anhydrous tetrahydrofuran (THF), sodium hydride (11mg, 0.27mmol) and 2,6-difluorobenzylbromide at 0°C (57 mg, 0.27 mmol) was added and stirred at 0° C. for 1 hour. The reaction mixture was diluted with ethyl acetate (EA), washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated, and the concentrated solution was purified by silica gel chromatography to obtain the target compound ( 2 , 43 mg, 53%). ) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (m, 1H), 8.21 (s, 1H), 8.03 - 8.02 (m, 1H), 7.50 - 7.42 (m, 1H), 7.16 - 7.10 (m) , 4H), 6.69 - 6.68 (m, 1H), 5.44 (s, 2H).

Example 3: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

단계 1: 1-(4-나이트로-3-(트리플루오로메틸)벤질)-4-(1H-피라졸-1-일)-1H-피라졸로[3,4-d]피리미딘-6-아민의 제조

Step 1: 1-(4-Nitro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

In Example 2, the addition amount of the compound of Example 1-1 ( S3 , 80mg, 0.40mmol) and sodium hydride (18mg, 0.44mmol) was changed, and 2,6-fluorobenzylbromide (57mg, 0.27mmol) Instead of using 4-(bromomethyl)-1-nitro-2-(trifluoromethyl)benzene (124 mg, 0.44 mmol), stirring for 3 hours instead of stirring for 1 hour, sodium bicarbonate An intermediate compound (S4 , 62 mg, 39%) was obtained in the same manner as in Example 2, except that brine was used instead of the aqueous solution.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 - 8.61 (m, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.27 - 7.11 (m, 3H), 6.79 - 6.75 (m) , 2H), 6.69 (s, 1H), 5.61 (s, 2H).

Step 2: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

The intermediate compound ( S4 , 62mg, 0.15mmol) prepared in step 1 was dissolved in ethanol (EtOH) and tin (II) chloride dihydrate (SnCl ₂ .2H ₂ O 173mg, 0.77mmol) was added thereto at 60°C for 6 days. stirred for a while. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 3 , 20 mg, 35%) got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 - 8.61 (m, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.27 - 7.11 (m, 3H), 6.79 - 6.75 (m) , 2H), 6.69 (s, 1H), 5.61 (s, 2H), 5.28 (s, 2H).

Example 4: 1-(4-amino-2-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

Step 1: 1-(4-nitro-2-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

In Example 2, the addition amount of the compound of Example 1-1 ( S3 , 80mg, 0.40mmol) and sodium hydride (18mg, 0.44mmol) was changed, and 2,6-fluorobenzylbromide (57mg, 0.27mmol) Instead of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (0.124g, 0.44mmol), the same process as in Example 2 was performed, except that the intermediate compound ( S5 , 35 mg, 22%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.63 (m, 1H), 8.28 (s, 1H), 8.05 (m, 1H), 7.10 (s, 2H), 6.93 (m, 1H), 6.70 - 6.65 (m, 2H), 6.59 - 6.57 (m, 1H), 5.57 (s, 2H).

Step 2: 1-(4-amino-2-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

For the intermediate compound ( S5 , 35mg, 0.08mmol) prepared in step 1 above, the addition amount of tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 100mg, 0.44mmol) in step 2 of Example 3 was changed, and the same process as in Step 2 of Example 3 was performed, except that instead of stirring at 60° C. for 6 days, the mixture was stirred at 50° C. for 3 hours, and the target compound ( 4 , 8 mg, 25%) got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.63 (m, 1H), 8.28 (s, 1H), 8.05 (m, 1H), 7.10 (s, 2H), 6.93 (m, 1H), 6.70 - 6.65 (m, 2H), 6.59 - 6.57 (m, 1H), 5.57 (s, 2H), 5.40 (s, 2H).

Example 5: Preparation of 1-(4-amino-3-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: Preparation of 1-(4-nitro-3-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

In Example 2, the addition amount of the compound of Example 1-1 ( S3 , 80 mg, 0.39 mmol) and sodium hydride (18 mg, 0.44 mmol) was changed, and 2,6-difluorobenzyl bromide (57 mg, 0.27 mmol) ) instead of 1-(bromomethyl)-3-fluoro-4-nitrobenzene (102mg, 0.43mmol), the same process as in Example 2 was performed, except that the intermediate compound ( S6 , 75mg, 53%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.63 - 8.62 (m, 1H), 8.34 (s, 1H), 8.15 - 8.11 (m, 1H), 8.06 - 8.05 (m, 1H), 7.40 (dd , 1H), 7.15 - 7.14 (m, 3H), 6.71 - 6.70 (m, 1H), 5.58 (s, 2H).

Step 2: Preparation of 1-(4-amino-3-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound ( S6 , 71mg, 0.20mmol) prepared in step 1 above, in step 2 of Example 3, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 228mg, 1.01mmol) was added The same process as in Step 2 of Example 3, except that, instead of stirring at 60° C. for 6 days, stirring at 50° C. for 5 hours, and recrystallizing the concentrate from ethyl acetate/hexane (EA/Hex) to obtain the target compound ( 5 , 10mg, 15%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 - 8.61 (m, 1H), 8.24 (s, 1H), 8.03 (m, 1H), 7.09 (s, 2H), 6.89 (dd, 1H), 6.79 - 6.77 (m, 1H), 6.71 - 6.66 (m, 2H), 5.24 (s, 2H), 5.12 (s, 2H).

Example 6: Preparation of 1-(4-amino-2-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: Preparation of 1-(4-nitro-2-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

In Example 2, the addition amount of the compound of Example 1-1 ( S3 , 80mg, 0.40mmol) and sodium hydride (18mg, 0.44mmol) was changed, and 2,6-fluorobenzylbromide (57mg, 0.27mmol) Instead, 1- (bromomethyl) -2-fluoro-4-nitrobenzene (102 mg, 0.44 mmol) was used, except that the same process as in Example 2 was performed, and the intermediate compound ( S7 , 54 mg, 39) %) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.63 - 8.62 (m, 1H), 8.32 (s, 1H), 8.18 - 8.15 (m, 1H), 8.05 - 8.03 (m, 2H), 7.33 - 7.29 (m, 1H), 7.16 (m, 2H), 6.70 - 6.69 (m, 1H), 5.76 (s, 2H), 5.60 (s, 2H).

Step 2: Preparation of 1-(4-amino-2-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

To the intermediate compound (S7 , 43mg, 0.12mmol) prepared in step 1, in step 2 of Example 3, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 139mg, 0.62mmol) the amount of addition By performing the same process as in step 2 of Example 3 above, except that, instead of stirring at 60 ° C. for 6 days, stirring at 50 ° C. for 5 hours, the target compound ( 6 , 10 mg, 25%) was obtained. got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (m, 1H), 8.23 (s, 1H), 8.03 (m, 1H), 7.07 (s, 2H), 6.89 - 6.85 (m, 1H), 6.69 - 6.68 (m, 1H), 6.32 - 6.29 (m, 2H), 5.41 (s, 2H), 5.25 (s, 2H).

Example 7: Preparation of 4-(1H-pyrazol-1-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The compound of Example 1-1 ( S3 , 84mg, 0.42mmol) was dissolved in N,N-dimethylformamide (DMF) and 1-(bromomethyl)-3-(trifluoromethyl)benzene (100mg, 0.42mmol) and potassium carbonate (K ₂ CO ₃ , 87 mg, 0.63 mmol) were added, and the mixture was heated to 50° C. and stirred for 1 day. The reaction mixture was diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 7 , 87 mg, 58%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.70 - 8.55 (m, 1 H), 8.31 (s, 1 H), 8.07 - 8.04 (m, 1 H), 7.69 - 7.55 (m, 3 H) , 7.46 (d, 1 H), 7.15 (s, 2 H), 6.70 (dd, 1 H), 5.55 (s, 2 H).

Example 8: 1-(4-fluoro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 79 mg, 0.39 mmol) and potassium carbonate (K ₂ CO ₃ , 81 mg, 0.58 mmol) was changed, and 1- (bromomethyl)- 4-(bromomethyl)-1-fluoro-2-(trifluoromethyl)benzene (100 mg, 0.39 mmol) was used instead of 3-(trifluoromethyl)benzene (100 mg, 0.42 mmol), The same process as in Example 7 was performed to obtain the target compound ( 8 , 82 mg, 56%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.03 (s, 1H), 8.96 (d, 1H), 8.38 (s, 1H), 8.01 (d, 1H), 7.45 - 7.30 (m, 4H), 7.01 (t, 1H), 5.40 (s, 2H).

Example 9: 1-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrizolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 79 mg, 0.39 mmol) and potassium carbonate (K ₂ CO ₃ , 81 mg, 0.58 mmol) was changed, and 1- (bromomethyl)- Except that 1-(bromomethyl)-3-fluoro-5-(trifluoromethyl)benzene (100 mg, 0.39 mmol) was used instead of 3-(trifluoromethyl)benzene (100 mg, 0.42 mmol), The same process as in Example 7 was performed to obtain the target compound ( 9 , 85 mg, 58%).

¹ H-NMR (DMSO-d6, 400MHz): δ 8.62 (d, 1H), 8.33 (s, 1H), 8.07 - 8.04 (m, 1H), 7.64 (d, 1H), 7.46 (s, 1H), 7.34 (d, 1H), 7.16 (s, 2H), 6.72 - 6.69 (m, 1H), 5.56 (s, 2H).

Example 10: 1-(2-fluoro-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 79 mg, 0.39 mmol) and potassium carbonate (K ₂ CO ₃ , 81 mg, 0.58 mmol) was changed, and 1- (bromomethyl)- Except for using 2-(bromomethyl)-1-fluoro-4-(trifluoromethyl)benzene (100 mg, 0.39 mmol) instead of 3-(trifluoromethyl)benzene (100 mg, 0.42 mmol), The same process as in Example 7 was performed to obtain the target compound ( 10 , 90 mg, 62%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.30 (s, 1H), 8.07 - 8.03 (m, 1H), 7.80 (dd, 1H), 7.63 - 7.58 (m, 1H) ), 7.50 (t, 1H), 7.16 (s, 2H), 6.69 (dd, 1H), 5.55 (s, 2H).

Example 11: 1-(2-fluoro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 79 mg, 0.39 mmol) and potassium carbonate (K ₂ CO ₃ , 81 mg, 0.58 mmol) was changed, and 1- (bromomethyl)- Except that 1-(bromomethyl)-2-fluoro-3-(trifluoromethyl)benzene (100 mg, 0.39 mmol) was used instead of 3-(trifluoromethyl)benzene (100 mg, 0.42 mmol), The same process as in Example 7 was performed to obtain the target compound ( 11 , 70 mg, 48%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.30 (s, 1H), 8.07 - 8.04 (m, 1H), 7.75 (t, 1 H), 7.46 (t, 1 H) ), 7.38 (t, 1 H), 7.17 (s, 2 H), 6.71 - 6.68 (m, 1 H), 5.56 (s, 2 H).

Example 12: 1-(3,5-bis(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 66 mg, 0.33 mmol) and potassium carbonate (K ₂ CO ₃ , 68 mg, 0.49 mol) was changed, and 1- (bromomethyl)- The above run except that 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (100 mg, 0.33 mmol) was used instead of 3-(trifluoromethyl)benzene (100 mg, 0.42 mmol). In the same manner as in Example 7, the target compound ( 12 , 67mg, 48%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.34 (s, 1H), 8.09 - 8.04 (m, 2H), 7.91 (s, 2H), 7.17 (s, 2H), 6.70 (dd, 1H), 5.65 (s, 2H).

Example 13: 1-(4-methoxy-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 80mg, 0.37mmol) and potassium carbonate (K ₂ CO ₃ , 77mg, 0.56mmol) was changed, and 1- (bromomethyl)- 4-(bromomethyl)-1-methoxy-2-(trifluoromethyl)benzene (100mg, 0.37mmol) was used instead of 3-(trifluoromethyl)benzene (100mg, 0.42mmol), 50°C The same process as in Example 7 was performed, except that instead of stirring for 1 day at 40° C. for 8 hours, the target compound ( 13 , 66 mg, 46%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.28 (s, 1H), 8.06 - 8.03 (m, 1H), 7.56 - 7.53 (m, 1H), 7.48 (d, 1H) ), 7.23 (d, 1H), 7.14 (s, 2H), 6.71 - 6.68 (m, 1H), 5.43 (s, 2H), 3.85 (s, 3H).

Example 14: 1-(3-methoxy-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 80mg, 0.37mmol) and potassium carbonate (K ₂ CO ₃ , 77mg, 0.56mmol) was changed, and 1- (bromomethyl)- 1-(bromomethyl)-3-methoxy-5-(trifluoromethyl)benzene (100mg, 0.37mmol) was used instead of 3-(trifluoromethyl)benzene (100mg, 0.42mmol), 50°C The same process as in Example 7 was performed, except that instead of stirring for 1 day at 40° C. for 8 hours, the target compound ( 14 , 73 mg, 51%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.30 (s, 1H), 8.04 (d, 1H), 7.20 - 7.08 (m, 4H), 7.05 (s, 1H), 6.69 (dd, 1H), 5.49 (s, 2H), 3.79 (s, 3H).

Example 15: 1-(2-methoxy-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 80 mg, 0.37 mmol) and potassium carbonate (K ₂ CO ₃ , 8 mg, 0.56 mmol) was changed, and 1- (bromomethyl)- 2-(bromomethyl)-1-methoxy-4-(trifluoromethyl)benzene (100mg, 0.37mmol) was used instead of 3-(trifluoromethyl)benzene (100mg, 0.42mmol), 50 °C The same process as in Example 7 was performed, except that instead of stirring for 1 day at 40° C. for 1 day, the target compound ( 15 , 79 mg, 55%) was obtained.

¹ H-NMR (DMSO-d6, 400MHz): δ 8.69 - 8.45 (m, 1H), 8.32 (s, 1H), 8.07 - 8.04 (m, 1H), 7.68 (d, 1H), 7.24 (d, 1H) ), 7.13 (br s, 2H), 7.05 (s, 1H), 6.72 - 6.69 (m, 1H), 5.44 (s, 2H), 3.90 (s, 3H).

Example 16: 1-(2-methoxy-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 80mg, 0.37mmol) and potassium carbonate (K ₂ CO ₃ , 77mg, 0.56mmol) was changed, and 1- (bromomethyl)- 1-(bromomethyl)-2-methoxy-3-(trifluoromethyl)benzene (100mg, 0.37mmol) was used instead of 3-(trifluoromethyl)benzene (100mg, 0.42mmol), 50°C The same process as in Example 7 was performed, except that instead of stirring for 1 day at 40° C. for 1 day, the target compound ( 16 , 60 mg, 42%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.63 (d, 1 H), 8.32 (s, 1 H), 8.05 (s, 1 H), 7.62 (d, 1 H), 7.29 - 7.12 (m , 4 H), 6.70 (s, 1 H), 5.56 (s, 2 H), 3.98 - 3.87 (m, 3 H).

Example 17: Preparation of 1-(4-amino-3-methylbenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: Preparation of 1-(3-methyl-4-nitrobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 100mg, 0.49mmol) and potassium carbonate (K ₂ CO ₃ , 137mg, 0.99mmol) was changed, and 1- (bromomethyl)- 4-(bromomethyl)-2-methyl-1-nitrobenzene (125.7 mg, 0.54 mmol) was used instead of 3-(trifluoromethyl)benzene (100 mg, 0.42 mmol), and heated to 50 ° C. Instead of stirring for one day, the mixture was heated to 40° C. and stirred for 2 hours, and the same process as in Example 7 was performed, except that brine was used instead of distilled water, to obtain an intermediate compound ( S8 , 49 mg, 18.7%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.31 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.31 (s, 1H), 7.20 - 7.17 (m, 1H), 7.13 (s, 2H), 6.70 - 6.69 (m, 1H), 5.51 (s, 2H), 2.51 (s, 3H).

Step 2: Preparation of 1-(4-amino-3-methylbenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound ( S8 , 49mg, 0.16mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 157.8 mg, 0.69 mmol) in step 2 of Example 3 The amount of addition was changed, and instead of stirring at 60° C. for 6 days, it was heated to 70° C. and stirred for 1 day, ethyl acetate (EA) instead of dichloromethane (DCM) and brine instead of distilled water were used, except that The same process as in Step 2 of Example 3 was performed to obtain the target compound ( 17 , 16 mg, 36%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.61 (d, 1H), 8.21 (s, 1H), 8.02 (d, 1H), 7.05 (s, 2H), 6.85 - 6.81 (m, 2H), 6.68 - 6.67 (m, 1H), 6.51 (d, 1H), 5.19 (s, 1H), 4.81 (s, 2H), 1.99 (s, 3H).

Example 18: (S)-4-(1H-pyrazol-1-yl)-1-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl) Preparation of -1H-pyrazolo[3,4-d]pyrimidin-6-amine

In Example 7, only the addition amount of the compound of Example 1-1 ( S3 , 81.15 mg, 0.29 mmol) and potassium carbonate (K ₂ CO ₃ , 68 mg, 0.49 mmol) was changed, and 1- (bromomethyl) (S)-2-(bromomethyl)-6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridine (50 mg, 0.24 mmol), stirred at room temperature for 1 day instead of heating to 50 ° C. and stirring for 1 day, and performing the same process as in Example 7, except that brine was used instead of distilled water, and the target compound ( 18 , 49 mg, 50%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.62 (d, 1H), 8.31 (s, 2H), 8.05 (d, 1H), 7.73 (t, 1H), 7.32 (s, 1H), 7.11 ( s, 2H), 6.82 (d, 1H), 6.70 - 6.69 (m, 1H), 5.50 (s, 2H), 4.52 - 4.51 (m, 2H), 4.25 - 4.23 (m, 1H), 3.78 - 3.72 ( m, 2H), 3.70 - 3.64 (m, 2H), 1.97 - 1.93 (m, 2H).

Example 19: 1-(4-amino-2-fluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

19-1. Preparation of 4-chloro-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: Preparation of tert-butyl 2-(2-fluoro-4-nitrobenzyl)hydrazine-1-carboxylate

After dissolving 1-(bromomethyl)-2-fluoro-4-nitrobenzene ( S9 , 842mg, 3.60mmol) in chloroform (CHCl ₃ )/N,N-dimethylformamide (DMF), here tert-Butyl hydrazine carboxylate (523mg, 3.96mmol) and N,N-diisopropylethylamine (DIPEA, 0.94ml, 5.40mmol) were added, and the mixture was heated to 65°C and stirred for 1 day. The reaction mixture was diluted with dichloromethane (DCM) and washed with distilled water. After drying over magnesium sulfate, filtration, and concentration, the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S10 , 698 mg, 68%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.02 (dd, 1H), 7.96 - 7.91 (m, 1H), 7.61 (t, 1H), 6.01 (br s, 1H), 4.36 (br s, 1H) , 4.14 (d, 2H), 1.52 - 1.39 (s, 9H).

Step 2: Preparation of (2-fluoro-4-nitrobenzyl)hydrazine

After dissolving the intermediate compound (S10 , 698mg, 2.45mmol) prepared in step 1 in dichloromethane (DCM), 1,4-dioxane solution (6.1ml) containing 4M hydrogen chloride at 0°C , 24.50 mmol) was added and stirred at room temperature for 6 hours. The reaction mixture was concentrated and the next reaction was carried out without further purification.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.16 - 8.07 (m, 2H), 7.89 - 7.71 (m, 1H), 4.30 (s, 2H).

Step 3: Preparation of 4-chloro-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The intermediate compound (S11 , 2.45 mmol) prepared in step 2 was dissolved in tetrahydrofuran (THF)/N,N-dimethylformamide (DMF), and then N,N-diisopropylethylamine (DIPEA) , 1.3ml, 7.35mmol) and 2-amino-4,6-dichloropyrimidine-5-carbaldehyde ( S1 , 470mg, 2.45mmol) were added, and the mixture was heated to 50°C and stirred for 5 hours. The reaction mixture was diluted with dichloromethane (DCM) and washed with distilled water. After drying over magnesium sulfate, filtration and concentration, the concentrate was purified by silica gel chromatography to obtain the target compound ( S12 , 332 mg, 2 steps 42%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.03 - 7.88 (m, 3H), 7.30 - 7.22 (m, 1H), 5.58 (s, 2H), 5.28 (br s, 2H).

19-2. Preparation of 1-(4-amino-2-fluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: 1-(2-Fluoro-4-nitrobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

After dissolving the compound of Example 19-1 ( S12 , 150mg, 0.46mmol) in 1,4-dioxane, 4-methylpyrazole (0.2ml, 1.39mmol) and cesium carbonate (Cs ₂ CO ₃ , 454 mg, 1.39 mmol) was added, and the mixture was heated to 40° C. and stirred for 7 days. The reaction mixture was diluted with dichloromethane (DCM) and washed with distilled water. After drying over magnesium sulfate, filtration, and concentration, the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S13 , 56 mg, 33%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.02 (br s, 2H), 6.86 (t, 1H), 6.28 (s, 1H), 6.31 (s, 1H), 5.41 (s, 2H), 2.14 (s, 3H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

The intermediate compound ( S13 , 56mg, 0.15mmol) prepared in step 1 was dissolved in tetrahydrofuran (THF), palladium hydroxide/carbon was added thereto, and the mixture was stirred at room temperature and pressurized hydrogen gas for 5 hours. . The reaction mixture was filtered through a celite pad and the filtrate was concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 19 , 22mg, 44%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1H), 8.19 (s, 1H), 7.86 (s, 1H), 7.02 (br s, 2H), 6.86 (t, 1H), 6.28 (s, 1H), 6.31 (s, 1H), 5.41 (s, 2H), 5.24 (s, 2H), 2.14 (s, 3H).

Example 20: 1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

20-1. Preparation of 4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The intermediate compound (S2 , 3g, 17.60 mmol) prepared in step 2 of Example 1-1 was dissolved in N,N-dimethylformamide (DMF, 140 ml), and thereafter, 3-methyl-1H-pyra Sol (5.696ml, 70.76mmol) and potassium carbonate (K ₂ CO ₃ , 23g, 70.76mmol) were added, heated to 125° C., and stirred for 1 day. The reaction mixture was diluted with dichloromethane (DCM), washed with brine, dried over magnesium sulfate, filtered and concentrated, and the concentrate was recrystallized from ethyl acetate/hexane (EA/Hex). The recrystallized filtrate was purified by silica gel chromatography to obtain the target compound ( S14 , 1.78 g, 46%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 13.02 (s, 1H), 8.49 (d, 1H), 8.24 (s, 1H), 6.81 (s, 2H), 6.48 (d, 1H), 2.36 (s) , 3H).

20-2. Preparation of 1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

Step 1: 1-(2-Fluoro-4-nitrobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

After dissolving the compound of Example 20-1 ( S14 , 50mg, 0.23mmol) in dimethylformamide (DMF), 1-(bromomethyl)-2-fluoro-4-nitrobenzene (81.5) mg, 0.34 mmol) and potassium carbonate (K ₂ CO ₃ , 64 mg, 0.46 mmol) were added and stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate (EA), washed with brine, and the organic layer was dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S15 , 55 mg, 64.3%). got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (d, 1H), 8.33 (s, 1H), 8.17 - 8.14 (m, 1H), 8.04 - 8.02 (m, 1H), 7.82 - 7.24 (t) , 1H), 7.08 (s, 2H), 6.51 (d, 1H), 5.59 (s, 2H), 2.36 (s, 3H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

After dissolving the intermediate compound (S15 , 52.90mg, 0.14mmol) prepared in step 1 in ethanol (EtOH), tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 162 mg, 0.71 mmol) was added thereto. and heated to 60° C. and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (EA), washed with brine, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 20 , 32 mg, 66.7%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (d, 1H), 8.23 (s, 1H), 6.99 (s, 2H), 6.84 (t, 1H), 6.49 (d, 1H), 6.31 - 6.28 (m, 2H), 5.39 (s, 2H), 5.24 (s, 2H), 2.35 (s, 3H).

Example 21: 1-(4-amino-2-fluorobenzyl)-4-(3-(tert-butyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

Step 1: 4-(3-(tert-Butyl)-1H-pyrazol-1-yl)-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

In step 1 of Example 19-2, the compound of Example 19-1 ( S12 , 200mg, 0.62mmol) was dissolved in 1,4-dioxane and N,N-dimethylformamide (DMF), cesium carbo The amount of nate (Cs ₂ CO ₃ , 606 mg, 1.86 mmol) was changed, and 3-tert-butyl-1H-pyrazole (231 mg, 1.86 mmol) was used instead of 4-methylpyrazole (0.2 ml, 1.39 mmol) and , An intermediate compound (S16 , 72 mg, 28%) was obtained in the same manner as in Step 1 of Example 19-2, except that instead of stirring for 7 days, the mixture was stirred for 4 days.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.48 (d, 1H), 8.23 (s, 1H), 7.02 (br s, 2H), 6.82 (t, 1H), 6.64 (d, 1H), 6.34 - 6.25 (m, 2H), 5.41 (s, 2H), 1.35 (s, 9H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-(tert-butyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

For the intermediate compound ( S16 , 72mg, 0.17mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 5 hours Instead of heating to 40 ° C. and stirring for 1 day, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 21 , 39 mg, 61%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.48 (d, 1H), 8.23 (s, 1H), 7.02 (br s, 2H), 6.82 (t, 1H), 6.64 (d, 1H), 6.34 - 6.25 (m, 2H), 5.41 (s, 2H), 5.25 (s, 2H), 1.35 (s, 9H).

Example 22: 1-(4-amino-2-fluorobenzyl)-4-(3-cyclopropyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

Step 1: 4-(3-Cyclopropyl-1H-pyrazol-1-yl)-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In step 1 of Example 19-2, the compound of Example 19-1 ( S12 , 200mg, 0.62mmol) was dissolved in 1,4-dioxane and N,N-dimethylformamide (DMF), cesium carbo The amount of nate (Cs ₂ CO ₃ , 606 mg, 1.86 mmol) was changed, and 3-cyclopropyl-1H-1,2-pyrazole (0.2 ml, 1.86 mmol) was replaced with 4-methylpyrazole (0.2 ml, 1.39 mmol). ) was used, and the same process as in Step 1 of Example 19-2 was carried out, except for stirring for 1 day instead of stirring for 7 days, to obtain an intermediate compound ( S17 , 117 mg, 48%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.45 (d, 1H), 8.21 (s, 1H), 7.04 - 6.96 (m, 2H), 6.83 (t, 1H), 6.42 (d, 1H), 6.32 - 6.26 (m, 2H), 5.40 (s, 2H), 2.11 - 2.03 (m, 1H), 1.07 - 0.96 (m, 2H), 0.87 - 0.82 (m, 2H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-cyclopropyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

For the intermediate compound ( S17 , 117mg, 0.29mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 3 hours Instead of heating to 40 ℃ and stirring for 1 day, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 22 , 40 mg, 38%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.45 (d, 1H), 8.21 (s, 1H), 7.04 - 6.96 (m, 2H), 6.83 (t, 1H), 6.42 (d, 1H), 6.32 - 6.26 (m, 2H), 5.40 (s, 2H), 5.24 (s, 2H), 2.11 - 2.03 (m, 1H), 1.07 - 0.96 (m, 2H), 0.87 - 0.82 (m, 2H).

Example 23: 1-(4-amino-2-fluorobenzyl)-4-(3-phenyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

Step 1: 1-(2-Fluoro-4-nitrobenzyl)-4-(3-phenyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

In step 1 of Example 19-2 _{, the amount of cesium carbonate (Cs 2} CO ₃ , 450 mg, 1.39 mmol) was changed, and 3-phenyl-1-instead of 4-methylpyrazole (0.2 ml, 1.39 mmol) 1H-Pyrazole (201 mg, 1.40 mmol) was used, and the same process as in Step 1 of Example 19-2 was performed, except that the mixture was stirred for 5 days instead of stirring for 7 days, and the intermediate compound ( S18 , 96 mg, 47%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.66 (d, 1H), 8.44 (s, 1H), 8.07 (d, 2H), 7.55 - 7.41 (m, 3H), 7.22 (d, 1H), 7.08 (br s, 2H), 6.85 (t, 1H), 6.34 - 6.27 (m, 2H), 5.41 (s, 2H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-phenyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

For the intermediate compound ( S18 , 96mg, 0.22mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 3 hours Instead of heating to 40 ° C. and stirring for 1 day, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 23 , 42 mg, 47%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.66 (d, 1H), 8.44 (s, 1H), 8.07 (d, 2H), 7.55 - 7.41 (m, 3H), 7.22 (d, 1H), 7.08 (br, 2H), 6.85 (t, 1H), 6.34 - 6.27 (m, 2H), 5.41 (s, 2H), 5.28 (s, 2H).

Example 24: 1-(4-amino-2-fluorobenzyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d ]Preparation of pyrimidin-6-amine

Step 1: 1-(2-Fluoro-4-nitrobenzyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d ]Preparation of pyrimidin-6-amine

In step 1 of Example 19-2 _{, the amount of cesium carbonate (Cs 2} CO ₃ , 453 mg, 1.39 mmol) was changed, and 3- (trifluoro) instead of 4-methylpyrazole (0.2 ml, 1.39 mmol) methyl)-1H-pyrazole (187mg, 1.40mmol) was used, and the same process as in Step 1 of Example 19-2 was performed, except that the stirring was performed for 1 day instead of stirring for 7 days, and the intermediate compound ( S19 , 95mg, 52%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.77 (dd, 1H), 8.17 (s, 1H), 7.24 (br s, 2H), 7.16 (d, 1H), 6.86 (t, 1H), 6.32 - 6.26 (m, 2H), 5.41 (s, 2H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

After dissolving the intermediate compound (S19 , 95mg, 0.23mmol) prepared in step 1 in ethanol (EtOH), a concentrated aqueous hydrogen chloride solution (Conc. HCl(aq), 0.38ml, 4.52mmol) and tin ( II) Chloride dihydrate (SnCl ₂ ·2H ₂ O, 153 mg, 0.68 mmol) was added, and the mixture was heated to 45° C. and stirred for 1 day. The reaction mixture was filtered through a celite pad and the filtrate was concentrated, and the concentrated solution was purified by silica gel chromatography to obtain the target compound ( 24 , 33 mg, 36%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.77 (dd, 1H), 8.17 (s, 1H), 7.24 (br s, 2H), 7.16 (d, 1H), 6.86 (t, 1H), 6.32 - 6.26 (m, 2H), 5.41 (s, 2H), 5.27 (s, 2H).

Example 25: 1-(4-amino-2-fluorobenzyl)-4-(4-chloro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

Step 1: 4-(3-Chloro-1H-pyrazol-1-yl)-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

In step 1 of Example 19-2 _{, the amount of cesium carbonate (Cs 2} CO ₃ , 303 mg, 0.93 mmol) was changed, and 4-chloro-1H- instead of 4-methylpyrazole (0.2 ml, 1.39 mmol) Pyrazole (95.3 mg, 0.93 mmol) was used, and the same process as in Step 1 of Example 19-2 was performed, except that instead of heating to 40 ° C and stirring for 7 days, the mixture was stirred at room temperature for 1 day. , an intermediate compound ( S20 , 108 mg, 50%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.84 - 8.54 (m, 1H), 8.20 - 8.15 (m, 2H), 7.12 (br s, 2H), 6.88 (t, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 5.41 (s, 2H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-chloro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

For the intermediate compound ( S20 , 108mg, 0.28mmol) prepared in step 1 above, in step 2 of Example 24, aqueous hydrogen chloride solution (Conc. HCl(aq), 0.23ml, 2.80mmol) and tin (II) ) Chloride dihydrate (SnCl ₂ ·2H ₂ O, 104 mg, 0.56 mmol) was carried out in the same manner as in Step 2 of Example 24, except that the target compound ( 25 , 32 mg, 32%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.84 - 8.54 (m, 1H), 8.20 - 8.15 (m, 2H), 7.12 (br s, 2H), 6.88 (t, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 5.41 (s, 2H), 5.25 (s, 2H).

Example 26: 1-(4-amino-2-fluorobenzyl)-4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

Step 1: 4-(4-Bromo-1H-pyrazol-1-yl)-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

In step 1 of Example 19-2 , the addition amount of the compound of Example 19-1 ( S12 , 200 mg, 0.62 mmol) and cesium carbonate (Cs ₂ CO ₃ , 606 mg, 1.86 mmol) was changed, and 4-methyl Example 19-2 above, except that 4-bromo-1H-pyrazole (274 mg, 1.86 mmol) was used instead of pyrazole (0.2 ml, 1.39 mmol) and stirred for 1 day instead of stirring for 7 days The same process as in step 1 was performed to obtain an intermediate compound ( S21 , 150 mg, 56%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.72 (d, 1H), 8.21 - 8.16 (m, 2H), 7.12 (br s, 2H), 6.87 (t, 1H), 6.31 (s, 1H) , 6.28 (s, 1H), 5.42 (s, 2H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

For the intermediate compound ( S21 , 150mg, 0.34mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 5 hours Instead of heating to 40 °C and stirring for 1 day, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 26 , 30mg, 22%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.72 (d, 1H), 8.21 - 8.16 (m, 2H), 7.12 (br s, 2H), 6.87 (t, 1H), 6.28 (s, 1H) , 6.31 (s, 1H), 5.42 (s, 2H), 5.25 (s, 2H).

Example 27: 1-(4-amino-2-fluorobenzyl)-4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4 -d] Preparation of pyrimidin-6-amine

Step 1: 4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3,4 -d] Preparation of pyrimidin-6-amine

In step 1 of Example 19-2 , the addition amount of the compound of Example 19-1 ( S12 , 320 mg, 0.99 mmol) and cesium carbonate (Cs ₂ CO ₃ , 645 mg, 1.98 mmol) was changed, and 4-methyl The above example, except that 4-chloro-3,5-dimethylpyrazole (388 mg, 2.97 mmol) was used instead of pyrazole (0.2 ml, 1.39 mmol) and stirred for 3 days instead of 7 days. The same process as in Step 1 of 19-2 was performed to obtain an intermediate compound ( S22 , 92 mg, 22%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.19 (s, 1H), 7.06 (br s, 2H), 6.83 (t, 1H), 6.33 - 6.27 (m, 2H), 5.40 (br s, 2H) ), 2.75 (s, 3H), 2.31 (s, 3H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4- d] Preparation of pyrimidin-6-amine

For the intermediate compound ( S22 , 92mg, 0.22mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 5 hours Instead ^{of heating to 40 o} C and stirring for 5 hours, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 27 , 32 mg, 38%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.19 (s, 1H), 7.06 (br s, 2H), 6.83 (t, 1H), 6.33 - 6.27 (m, 2H), 5.40 (br s, 2H) ), 5.25 (s, 2H), 2.75 (s, 3H), 2.31 (s, 3H).

Example 28: 1-(4-amino-2-fluorobenzyl)-4-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine Preparation of -6-amine

Step 1: 1-(2-Fluoro-4-nitrobenzyl)-4-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine Preparation of -6-amine

In step 1 of Example 19-2 , the addition amount of the compound of Example 19-1 ( S12 , 300 mg, 0.93 mmol) and cesium carbonate (Cs ₂ CO ₃ , 909 mg, 2.79 mmol) was changed, and 4-methyl Example 19-, except that 1H-1,2,4-triazole (321 mg, 4.65 mmol) was used instead of pyrazole (0.2ml, 1.39mmol) and stirred for 5 days instead of stirring for 7 days The same process as in Step 1 of 2 was performed to obtain an intermediate compound ( S23 , 143 mg, 43%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.34 (s, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 7.23 (br s, 2H), 6.89 (t, 1H), 6.33 - 6.27 (m, 2H), 5.42 (s, 2H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

For the intermediate compound ( S23 _{, 143mg, 0.40mmol) prepared in step 1, palladium hydroxide (Pd(OH) 2} , 10ww/ instead of palladium hydroxide/carbon in step 2 of Example 19-2) %, 11 mg), and the same process as in Step 2 of Example 19-2 was carried out, except that the mixture was stirred for 6 hours instead of stirring for 5 hours, to obtain the target compound ( 28 , 36 mg, 28%). got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.34 (s, 1H), 8.48 (s, 1H), 8.21 (s, 1H), 7.23 (br s, 2H), 6.89 (t, 1H), 6.33 - 6.27 (m, 2H), 5.42 (s, 2H), 5.27 (s, 2H).

Example 29: 1-(4-amino-2-fluorobenzyl)-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3 Preparation of ,4-d]pyrimidin-6-amine

Step 1: 4-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-1-(2-fluoro-4-nitrobenzyl)-1H-pyrazolo[3 Preparation of ,4-d]pyrimidin-6-amine

In step 1 of Example 19-2, the compound of Example 19-1 ( S12 , 200mg, 0.62mmol) was dissolved in 1,4-dioxane and N,N-dimethylformamide (DMF), cesium carbo The amount of nate (Cs ₂ CO ₃ , 606 mg, 1.86 mmol) was changed, and 3,5-dimethyl-1,2,4-triazole (362 mg, 3.72) instead of 4-methylpyrazole (0.2 ml, 1.39 mmol) mmol) and, ^{instead of warming to 40 o} C and stirring for 7 days, warming to 85 ^o C and stirring for 1 day was carried out, and the same procedure as in Step 1 of Example 19-2 was carried out, Compound ( S24 , 115 mg, 48%) was obtained.

¹ H-NMR (DMSO-d6, 400MHz): δ 8.27 (d, 1H), 8.16 (dd, 1H), 8.04 (dd, 1H), 7.30 - 7.21 (m, 3H), 5.60 (s, 2H), 2.90 - 2.85 (m, 3H), 2.37 (s, 3H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3, Preparation of 4-d]pyrimidin-6-amine

For the intermediate compound ( S24 , 115mg, 0.30mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 5 hours Instead ^{of heating to 40 o} C and stirring for 1 day, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 29 , 16 mg, 15%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.17 (s, 1H), 7.17 (br s, 2H), 6.84 (t, 1H), 6.34 - 6.26 (m, 2H), 5.42 (s, 2H) , 5.26 (s, 2H), 2.87 (s, 3H), 2.36 (s, 3H).

Example 30: 1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4- d] Preparation of pyrimidin-6-amine

Step 1: 1-(2-Fluoro-4-nitrobenzyl)-4-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4- d] Preparation of pyrimidin-6-amine

In step 1 of Example 19-2, the compound of Example 19-1 ( S12 , 200mg, 0.62mmol) was dissolved in 1,4-dioxane and N,N-dimethylformamide (DMF), cesium carbo The amount of nate (Cs ₂ CO ₃ , 606 mg, 1.86 mmol) was changed, and 3-methyl-1H-1,2,4-triazole (155 mg, 1.86 mmol) was replaced with 4-methylpyrazole (0.2 ml, 1.39 mmol). ) was used, and the same process as in Step 1 of Example 19-2 was carried out, except ^{that instead of heating to 40 o} C and stirring for 7 days, heating to 45 ^{o C and stirring for 4 days, the intermediate compound} ( S25 , 62 mg, 27%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.19 (s, 1H), 8.20 (s, 1H), 7.18 (br s, 2H), 6.87 (t, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 5.42 (s, 2H), 2.45 (s, 3H).

Step 2: 1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d ]Preparation of pyrimidin-6-amine

For the intermediate compound ( S25 , 62mg, 0.17mmol) prepared in step 1, palladium/carbon was used instead of palladium hydroxide/carbon in step 2 of Example 19-2, and stirred at room temperature for 5 hours Instead ^{of heating to 40 o} C and stirring for 1 day, the same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 30 , 26 mg, 42%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.19 (s, 1H), 8.20 (s, 1H), 7.18 (br s, 2H), 6.87 (t, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 5.42 (s, 2H), 5.26 (s, 2H), 2.45 (s, 3H).

Example 31: Preparation of 1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

In step 1 of Example 20-2 , only the addition amount of the compound of Example 20-1 ( S14 , 30 mg, 0.14 mmol) and potassium carbonate (K ₂ CO ₃ , 38 mg, 0.28 mmol) was changed, and 1-( Step 1 of Example 20-2, except that (bromomethyl)benzene (0.02 ml, 0.14 mmol) was used instead of bromomethyl)-2-fluoro-4-nitrobenzene (81.5 mg, 0.34 mmol) By performing the same process as, the target compound ( 31 , 46mg, 47%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (d, 1H), 8.28 (s, 1H), 7.34 - 7.26 (m, 3H), 7.198 (s, 2H), 7.02 (s, 2H), 6.50 (d, 1H), 5.42 (s, 2H), 2.36 (s, 3H).

Example 32: 1-(2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

In step 1 of Example 20-2 , only the addition amount of the compound of Example 20-1 ( S14 , 30 mg, 0.14 mmol) and potassium carbonate (K ₂ CO ₃ , 38 mg, 0.28 mmol) was changed, and 1-( Except for using 2-(bromomethyl)-1,3-difluorobenzene (28 mg, 0.14 mmol) instead of bromomethyl)-2-fluoro-4-nitrobenzene (81.5 mg, 0.34 mmol) , The same process as in Step 1 of Example 20-2 was performed to obtain the target compound ( 32 , 24.90 mg, 52.3%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (d, 1H), 8.20 (s, 1H), 7.47 - 7.43 (m, 1H), 7.14 - 7.10 (m, 2H), 7.05 (s, 2H) ), 6.49 (d, 1H), 5.42 (s, 2H), 2.34 (s, 3H).

Example 33: 4-(3-methyl-1H-pyrazol-1-yl)-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

Step 1: Preparation of tert-butyl 2-(2,3,6-trifluorobenzyl)hydrazine-1-carboxylate

After dissolving 2,3,6-trifluorobenzyl bromide ( S26 , 0.13ml, 1.00mmol) in N,N-dimethylformamide (DMF), tert-butyl carbazate (159mg, 1.20mmol) And cesium carbonate (Cs ₂ CO ₃ , 178 mg, 1.30 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S27 , 137.4 mg, 49.7%). got it

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.17 - 7.03 (m, 1H), 6.85 - 6.80 (m, 1H), 6.01 (br s, 1H), 4.37 (br s, 1H), 1.44 (s, 9H).

Step 2: Preparation of (2,3,6-trifluorobenzyl)hydrazine hydrochloride

After dissolving the intermediate compound (S27 , 137.4mg, 0.50mmol) prepared in step 1 in dichloromethane (DCM), 1,4-dioxane solution containing 4M hydrogen chloride at ^{0 o C (0.62ml,} 2.49 mmol) was added and stirred at room temperature for 1 day. The reaction mixture was concentrated and the next reaction was carried out without further purification.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.31 (br s, 2H), 7.55 - 7.50 (m, 1H), 7.21 - 7.16 (m, 1H), 4.09 (s, 2H).

Step 3: Preparation of 4-chloro-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The intermediate compound ( S28 , 99mg, 0.47mmol) prepared in step 2 was dissolved in N,N-dimethylformamide (DMF), and then N,N-diisopropylethylamine (DIPEA, 0.25ml, 1.41) mmol) and 2-amino-4,6-dichloropyrimidine-5-carbaldehyde ( S1 , 89.4 mg, 0.47 mmol) were added, and the mixture ^{was heated to 50 o} C and stirred for 4 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S29 , 87.8 mg, 59.6%). got it

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.87 (s, 1H), 7.15 - 7.10 (m, 1H), 6.88 - 6.83 (m, 1H), 5.52 (s, 2H), 5.28 (br s, 2H) ).

Step 4: 4-(3-Methyl-1H-pyrazol-1-yl)-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

After dissolving the intermediate compound (S29 , 85mg, 0.27mmol) prepared in step 3 in N,N-dimethylformamide (DMF), thereto 3-methylpyrazole (22ul, 0.27mmol) and cesium carbonate (Cs ₂ CO ₃ , 105 mg, 0.30 mmol) was added and stirred at room temperature for 1 day. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 33 , 68.4 mg, 70.5%). got it

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.47 (s, 1H), 8.46 (s, 1H), 7.15 - 7.07 (m, 1H), 6.88 - 6.82 (m, 1H), 6.28 (s, 1H) , 5.55 (s, 2H), 5.11 (br s, 2H), 2.42 (s, 3H).

Example 34: 1-(4-amino-2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

Step 1: 1-(2,6-difluoro-4-nitrobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

In step 1 of Example 20-2, 2-(bromomethyl)-1,3-difluoro instead of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (81.5 mg, 0.34 mmol) The steps of Example 20-2, except that rho-5-nitrobenzene (88 mg, 0.34 mmol) was used, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was recrystallized from ethyl acetate (EA). By performing the same process as in 1, the target compound ( S30 , 60mg, 66.9%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.48 (d, 1H), 8.22 (s, 1H), 8.09 (d, 2H), 7.08 (s, 2H), 6.49 (d, 1H), 5.51 ( s, 2H), 2.34 (s, 3H).

Step 2: 1-(4-amino-2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine Preparation of -6-amine

For the intermediate compound ( S30 , 57mg, 0.14mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 166mg, 0.73mol) in step 2 of Example 20-2 was changed, stirred for 6 hours instead of stirring for 4 hours, dried over magnesium sulfate, filtered, concentrated, and the concentrate was recrystallized from dichloromethane (DCM)/methanol (MeOH) except that , The same process as in Step 2 of Example 20-2 was performed to obtain the target compound ( 34 , 19 mg, 36.5%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.48 (d, 1H), 8.18 (s, 1H), 6.99 (s, 1H), 6.48 (d, 1H), 6.19 (d, 2H), 5.79 ( s, 2H), 5.21 (s, 2H), 2.34 (s, 3H).

Example 35: 1-(4-amino-3-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

Step 1: 1-(3-Fluoro-4-nitrobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

In step 1 of Example 20-2, 4-(bromomethyl)-2-fluoro-1 instead of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (81.5 mg, 0.34 mmol) - The same process as in Step 1 of Example 20-2 was performed, except that nitrobenzene (65.3 mg, 0.27 mmol) was used, to obtain the target compound ( S31 , 46 mg, 47%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.50 (d, 1H), 8.34 (s, 1H), 8.14 - 8.10 (m, 1H), 7.40 - 7.37 (m, 1H), 7.13 - 7.07 (m) , 3H), 6.51 (d, 1H), 5.56 (s, 2H), 2.37 (s, 3H).

Step 2: 1-(4-amino-3-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

For the intermediate compound ( S31 , 49mg, 0.17mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 34 mg, 0.09 mmol) in step 2 of Example 20-2 The same process as in Step 2 of Example 20-2 was performed, except that the addition amount was changed and the mixture was stirred at 70°C for 1 day instead of stirring at 60°C for 4 hours, and the target compound ( 35 , 28mg, 70%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (d, 2H), 8.25 (s, 1H), 7.01 (s, 2H), 6.89 - 6.86 (m, 1H), 6.78 - 6.76 (m, 1H) ), 6.70 - 6.66 (m, 1H), 6.49 (d, 1H), 5.23 (s, 2H), 5.10 (s, 2H), 2.35 (s, 3H).

Example 36: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

Step 1: 4-(3-methyl-1H-pyrazol-1-yl)-1-(4-nitro-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

In step 1 of Example 20-2, 4-(bromomethyl)-1-nitro-2 instead of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (81.5 mg, 0.34 mmol) -(trifluoromethyl)benzene (99mg, 0.34mmol) was carried out in the same manner as in step 1 of Example 20-2, except that the target compound ( S32 , 46mg, 47%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.53 (s, 1H), 8.48 (d, 1H), 7.83 (d, 1H), 7.78 (s, 1H), 7.59 - 7.57 (m, 1H), 6.31 (d, 1H), 5.58 (s, 2H), 5.11 (s, 2H), 2.42 (s, 3H).

Step 2: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

For the intermediate compound ( S32 , 28mg, 0.06mmol) prepared in step 1, methanol (MeOH) was used instead of tetrahydrofuran (THF) in step 2 of Example 19-2, and palladium hydroxide / Palladium / carbon was used instead of carbon, and instead of stirring at room temperature for 5 hours, it ^{was heated to 30 o} C and stirred for 3 days, the reaction mixture was filtered through a celite pad and the filtrate was concentrated and purified. The same process as in Step 2 of Example 19-2 was performed to obtain the target compound ( 36 , 26 mg, 103%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (d, 1H), 8.25 (s, 1H), 7.26 (d, 1H), 7.16 (d, 1H), 7.03 (s, 2H), 6.77 ( d, 1H), 6.49 (d, 1H), 5.60 (s, 2H), 5.26 (s, 2H), 3.33 (s, 3H).

Example 37: 1-(4-amino-2-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

Step 1: 4-(3-methyl-1H-pyrazol-1-yl)-1-(4-nitro-2-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

1-(bromomethyl)-4-nitro-2 instead of 1-(bromomethyl)-2-fluoro-4-nitrobenzene (81.5 mg, 0.34 mmol) in step 1 of Example 20-2 -(trifluoromethyl)benzene (79mg, 0.27mmol) was carried out in the same manner as in step 1 of Example 20-2, except that the target compound ( S33 , 31mg, 31.9%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.59 (m, 2H), 8.50 (d, 1H), 8.23 - 8.20 (m, 1H), 6.93 (d, 1H), 6.33 (d, 1H), 5.80 (s, 2H), 5.09 (s, 2H), 2.44 (s, 3H).

Step 2: 1-(4-amino-2-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

For the intermediate compound ( S33 , 28mg, 0.06mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 75.5 mg, 0.33 mmol) in step 2 of Example 20-2 ), stirred for 6 hours instead of stirring for 4 hours, dried over magnesium sulfate, filtered and concentrated, and the concentrate was recrystallized from methylene chloride (MC)/methanol (MeOH), The same process as in Step 2 of Example 20-2 was performed to obtain the target compound ( 37 , 15.8 mg, 61%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.50 (d, 1H), 8.29 (s, 1H), 7.01 (s, 2H), 6.93 (d, 1H), 6.65 (d, 1H), 6.53 - 6.50 (m, 2H), 5.55 (s, 2H), 5.39 (s, 2H), 2.36 (s, 3H).

Example 38: 3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)- Preparation of 4-fluorophenol

Step 1: Preparation of methyl 5-(benzyloxy)-2-fluorobenzoate

Methyl 2-fluoro-5-hydroxybenzoate ( S34 , 1g, 5.88mmol) was dissolved in N,N-dimethylformamide (DMF), and then benzyl bromide (0.80ml, 7.05mmol) and potassium carboxylate were dissolved therein. Bonate (K ₂ CO ₃ , 1.06 g, 7.64 mmol) was added and stirred at room temperature for 1 day. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S35 , 1.45 g, 95%). got it

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.51 (d, 1H), 7.50 - 7.38 (m, 5H), 7.13 - 7.03 (m, 2H), 5.07 (s, 2H), 3.93 (s, 3H) .

Step 2: Preparation of (5-(benzyloxy)-2-fluorophenyl)methanol

The intermediate compound ( S35 , 497.40mg, 1.91mmol) prepared in step 1 was dissolved in tetrahydrofuran (THF), and lithium aluminum hydride (LAH, 87.30mg, 2.30mmol) was added thereto and 3 hours at room temperature. stirred for a while. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S36 , 443 mg, 99%). .

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.43 - 7.33 (m, 5H), 7.06 - 7.04 (m, 1H), 6.96 (t, 1H), 6.86 - 6.82 (m, 1H), 5.04 (s, 2H), 4.73 (d, 2H).

Step 3: Preparation of 4-(benzyloxy)-2-(bromomethyl)-1-fluorobenzene

After dissolving the intermediate compound (S36 , 443mg, 1.91mmol) prepared in step 2 in dichloromethane (DCM), tetrabromomethane (CBr ₄ , 665mg, 2mmol) and triphenylphosphine (PPh) ₃ , 521 mg, 1.98 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S37 , 505.9 mg, 73%). got it

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.41 - 7.33 (m, 5H), 7.05 - 6.96 (m, 2H), 6.89 - 6.87 (m, 1H), 5.03 (s, 2H), 4.48 (s, 2H).

Step 4: Preparation of tert-butyl 2-(5-(benzyloxy)-2-fluorobenzyl)hydrazine-1-carboxylate

For the intermediate compound ( S37 , 503mg, 1.70mmol) prepared in step 3, the addition amount of tert-butyl carbazate (270.3mg, 2.05mmol) was changed in step 1 of Example 33, and cesium carbohydrate Triethylamine (TEA, 0.3 ml, 2.21 mmol) was used instead of nate (Cs ₂ CO ₃ , 178 mg, 1.30 mmol), stirred for 2 hours instead of 3 hours, and ethyl instead of dichloromethane (DCM) Except for using acetate (EA), the same process as in Step 1 of Example 33 was performed to obtain an intermediate compound ( S38 , 129 mg, 22%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.46 - 7.35 (m, 5H), 7.19 - 7.15 (m, 2H), 7.03 (s, 1H), 5.09 (s, 2H), 4.04 (s, 2H) ).

Step 5: Preparation of (5-(benzyloxy)-2-fluorobenzyl)hydrazine hydrochloride

For the intermediate compound ( S38 , 129mg, 0.37mmol) prepared in step 4, methylene chloride (MC) was used instead of dichloromethane (DCM) in step 2 of Example 33, and 4M hydrogen chloride was 4N hydrogen chloride (0.5ml, 1.86mmol) was used instead of the containing 1,4-dioxane solution (0.62ml, 2.49mmol), and was stirred for 2 hours instead of stirring for 1 day. The same process as in step 2 of 33 was performed to obtain an intermediate compound ( S39 , 104 mg, 99%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.43 - 7.31 (m, 5H), 6.99 - 6.94 (m, 2H), 6.85 - 6.82 (m, 1H), 5.03 (s, 2H), 4.01 (s, 2H), 1.50 (s, 9H).

Step 6: Preparation of 1-(5-(benzyloxy)-2-fluorobenzyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound ( S39 , 104mg, 0.37mmol) prepared in step 5, 2-amino-4,6-dichloropyrimidine-5-carbaldehyde ( S1 , 71mg) in step 3 of Example 33 , 0.37mmol) and N,N-diisopropylethylamine (DIPEA, 0.12ml, 0.74mmol) change the amount of addition ^{, heated to 50 o} C and stirred at room temperature for 3 hours instead of stirring for 4 hours, and the die Except for using ethyl acetate (EA) instead of chloromethane (DCM), the same process as in step 3 of Example 33 was performed to obtain an intermediate compound ( S40 , 70.1 mg, 50%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.90 (s, 1H), 7.33 - 7.25 (m, 5H), 6.99 (t, 1H), 6.84 - 6.82 (m, 1H), 6.63 - 6.61 (m, 1H), 5.34 (s, 2H), 4.94 (s, 2H).

Step 7: 1-(5-(benzyloxy)-2-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine Preparation of -6-amine

For the intermediate compound ( S40 , 70.1mg, 0.18mmol) prepared in step 6, 3-methylpyrazole (15ul, 0.18mmol) and cesium carbonate (Cs ₂ CO _{3 in step 4 of Example 33)} , 70mg, 0.20mmol), and stirring for 6 hours instead of stirring for 1 day, except that ethyl acetate (EA) was used instead of dichloromethane (DCM), step 4 of Example 33 By performing the same process as, an intermediate compound ( S41 , 15mg, 19%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.50 - 8.48 (m, 2H), 7.31 - 7.25 (m, 5H), 6.99 - 6.95 (m, 1H), 6.79 (t, 1H), 6.61 - 6.56 ( m, 1H), 6.30 (s, 1H), 5.51 (s, 2H), 5.15 (s, 2H), 4.89 (s, 2H), 2.42 (s, 3H).

Step 8: 3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4 -Production of fluorophenols

The intermediate compound ( S41 , 15mg, 0.03mmol) prepared in step 7 was dissolved in tetrahydrofuran (THF), palladium/carbon (3mg) was added thereto, and then stirred at room temperature and hydrogen gas pressurized conditions for 1 day. did. The reaction mixture was filtered through a celite pad, the filtrate was diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 38 , 7mg). , 70%) was obtained.

¹ H-NMR (CD ₃ OD, 400 MHz): δ 8.47 (s, 1H), 8.30 (s, 1H), 6.82 (t, 1H), 6.57 - 6.54 (m, 1H), 6.30 - 6.21 (m, 2H) ), 5.35 (s, 2H), 2.23 (s, 3H).

Example 39: 3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenol manufacture of

Step 1: Preparation of 1-(benzyloxy)-3-(bromomethyl)benzene

(3-(benzyloxy)phenyl)methanol ( S42 , 1g, 4.67mmol) was dissolved in dichloromethane (DCM) and triphenylphosphine (PPh ₃ , 1.27g, 4.85mmol), tetrabromomethane (CBr) ₄ , 1.63 g, 4.90 mmol) was added at 0° C. and stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to obtain an intermediate compound ( S43 , 1.08 g, 84%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.45 - 7.32 (m, 5H), 7.26 (t, 1H), 7.03 - 6.92 (m, 2H), 6.90 (d, 1H), 5.07 (s, 2H) , 4.51 (s, 2H).

Step 2: Preparation of tert-butyl 2-(3-(benzyloxy)benzyl)hydrazine-1-carboxylate

For the intermediate compound (S43 , 1.07 g, 3.86 mmol) prepared in step 1 above, in step 1 of Example 33, tert-butyl carbazate (612.3 mg, 4.63 mmol) and cesium carbonate (Cs ₂ CO ₃ , 1.63 g, 5.02 mmol) was changed and the intermediate compound ( S44 , 488 mg) was carried out in the same manner as in Step 1 of Example 33, except that the mixture was stirred for 5 hours instead of stirring for 3 hours. , 39%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.43 - 7.39 (m, 4H), 7.35 - 7.33 (m, 2H), 7.01 (br s, 1H), 6.95 (dd, 2H), 5.04 (s, 2H) ), 1.47 (s, 9H).

Step 3: Preparation of (3-(benzyloxy)benzyl)hydrazine hydrochloride

For the intermediate compound ( S44 , 382.4mg, 1.16mmol) prepared in step 2, 1,4-dioxane solution (1.5ml, 5.82mmol) containing 4M hydrogen chloride in step 2 of Example 33 The same process as in Step 2 of Example 33 was performed, except that the addition amount was changed, and the mixture was stirred for 2 hours instead of stirring for 1 day.

¹ H-NMR (CD ₃ OD, 400 MHz): δ 7.46 (d, 2H), 7.41 - 7.33 (m, 4H), 7.12 - 7.03 (m, 3H), 5.13 (s, 2H), 3.33 (s, 2H) ).

Step 4: Preparation of 1-(3-(benzyloxy)benzyl)-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound (S45 , 0.89mmol) prepared in step 3, in step 3 of Example 33, N,N-diisopropylethylamine (DIPEA, 0.3ml, 1.78mmol) and 2-amino-4 , The addition amount of 6-dichloropyrimidine-5-carbaldehyde ( S1 , 170mg, 0.89mmol) was changed, and the step 3 of Example 33 above, except that the mixture was stirred for 1 hour instead of stirring for 4 hours The same process was performed to obtain an intermediate compound ( S46 , 116.3 mg, 2 steps 36%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.88 (s, 1H), 7.36 - 7.29 (m, 3H), 7.26 - 7.21 (m, 2H), 6.89 - 6.85 (m, 4H), 5.49 (br s) , 2H), 5.40 (s, 2H), 4.96 (s, 2H).

Step 5: of 1-(3-(benzyloxy)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine Produce

For the intermediate compound ( S46 , 112 mg, 0.31 mmol) prepared in step 4, 3-methylpyrazole (24.6ul, 0.31 mmol) and cesium carbonate (Cs ₂ CO in step 4 of Example 33) ₃ , 120mg, 0.34mmol) was changed and the intermediate compound (S47 , 41mg, 32) was carried out in the same manner as in step 4 of Example 33, except that the mixture was stirred for 3 hours instead of stirring for 1 day. %) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.49 (s, 2H), 7.39 - 7.28 (m, 6H), 7.22 (t, 1H), 6.89 - 6.85 (m, 3H), 5.45 (s, 2H) , 5.06 (br s, 2H), 5.00 (s, 2H), 2.42 (s, 3H).

Step 6: of 3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenol Produce

The intermediate compound ( S47 , 40mg, 0.10mmol) prepared in step 5 was dissolved in tetrahydrofuran (THF), and palladium/carbon was added thereto, followed by stirring at room temperature under pressure of hydrogen gas for 1 day. The reaction mixture was filtered through a pad of Celite, the filtrate was concentrated, and the resultant was purified by silica gel chromatography to obtain the target compound ( 39 , 28 mg, 88%).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 8.47 (s, 1H), 8.27 (s, 1H), 7.02 (t, 1H), 6.68 - 6.53 (m, 3H), 6.29 (s, 1H), 5.34 (s, 2H), 2.17 (s, 3H).

Example 40: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

Step 1: Preparation of 4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

After dissolving the intermediate compound (S2 , 200mg, 1.17mmol) prepared in step 2 of Example 1-1 in N,N-dimethylformamide (DMF), 4-methyl-1H-pyrazole (0.38) ml, 4.71mmol) and cesium carbonate (Cs ₂ CO ₃ , 1.53 g, 4.71 mmol) were added, heated to reflux, and stirred for 1 day. The reaction mixture was diluted with ethyl acetate (EA), washed with brine, dried over magnesium sulfate, filtered and concentrated, and the concentrate was recrystallized from ethyl acetate (EA) to obtain an intermediate compound ( S48 , 90 mg, 35%). .

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.05 (s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 7.85 (s, 1H), 6.83 (s, 2H), 2.14 ( s, 3H).

Step 2: 4-(4-methyl-1H-pyrazol-1-yl)-1-(4-nitro-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

After dissolving the intermediate compound (S48 , 50mg, 0.23mmol) prepared in step 1 in N,N-dimethylformamide (DMF), 4-(bromomethyl)-1-nitro-2-( Trifluoromethyl) benzene (99 mg, 0.34 mmol) and potassium carbonate (K ₂ CO ₃ , 64 mg, 0.46 mmol) were added and stirred at room temperature for 1 day. The reaction mixture was diluted with ethyl acetate (EA), washed with brine, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S49 , 47 mg, 48%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (s, 1H), 8.34 (s, 1H), 7.84 - 7.79 (m, 2H), 7.69 (s, 1H), 7.59 (d, 1H), 5.57 (s, 2H), 5.12 (s, 2H), 2.18 (s, 3H).

Step 3: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

The intermediate compound ( S49 , 40mg, 0.09mmol) prepared in step 2 was dissolved in methanol (MeOH), palladium/carbon (8mg) was added thereto, and the mixture was stirred under hydrogen pressure for 1 day. The reaction mixture was filtered through a Celite filter, the filtrate was concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 40 , 30 mg, 81%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1H), 8.21 (s, 1H), 7.86 (s, 1H), 7.27 (d, 1H), 7.18 (d, 1H), 7.03 ( s, 2H), 6.77 (d, 1H), 5.60 (s, 2H), 5.26 (s, 2H), 2.14 (s, 3H).

Example 41: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-fluoro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d ]Preparation of pyrimidin-6-amine

Step 1: Preparation of 4-(4-fluoro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The addition amount of the intermediate compound (S2 , 200mg, 1.18mmol) was changed in step 1 of Example 40, and 4-fluoro-1H-pyrazole (101.50mg, instead of 4-methylpyrazole (0.38ml, 4.71mmol)) 1.18 mmol) was used, _{potassium carbonate (K 2} CO _{3 , 326 mg, 2.36 mmol) was used instead of cesium carbonate (Cs 2} CO ₃ , 1.53 g, 4.71 mmol), and the mixture was heated to reflux and stirred for 1 day. Instead of heating to 90° C. and stirring for 5 hours, the reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, and the same as in step 1 of Example 40, except that the recrystallization process was not performed. The process was carried out to obtain an intermediate compound ( S50 , 132 mg, 51%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.15 (s, 1H), 8.62 - 8.58 (m, 1H), 8.21 - 8.15 (m, 2H), 6.94 (s, 2H).

Step 2: 4-(4-Fluoro-1H-pyrazol-1-yl)-1-(4-nitro-3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d ]Preparation of pyrimidin-6-amine

For the intermediate compound ( S50 , 132mg, 0.60mmol) prepared in step 1 above, in step 2 of Example 40, 4-(bromomethyl)-1-nitro-2-(trifluoromethyl)benzene (342 mg, 1.21 mmol) and potassium carbonate (K ₂ CO ₃ , 167 mg, 1.21 mmol) were changed, and the reaction mixture was diluted with dichloromethane (DCM) and washed with distilled water except that, The same process as in Step 2 of Example 40 was performed to obtain an intermediate compound ( S51 , 134 mg, 53%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.61 (d, 1H), 8.30 (d, 1H), 8.21 (d, 1H), 8.12 (d, 1H), 7.97 (s, 1H), 7.60 ( d, 1H), 7.19 (br s, 2H), 5.65 (s, 2H).

Step 3: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-fluoro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

For the intermediate compound ( S51 , 134mg, 0.32mmol) prepared in step 2, using tetrahydrofuran (THF) instead of methanol (MeOH) in step 3 of Example 40, and stirring at room temperature for 1 day Instead, the same process as in Step 3 of Example 40 was performed, except that the mixture was heated to 40° C. and stirred for 7 hours, to obtain the target compound ( 41 , 40 mg, 32%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.60 (d, 1 H), 8.22 - 8.16 (m, 2 H), 7.27 (s, 1 H), 7.20 - 7.10 (m, 3 H), 6.77 (d, 1 H), 5.61 (s, 2 H), 5.27 (s, 2 H).

Example 42: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3 Preparation of ,4-d]pyrimidin-6-amine

Step 1: Preparation of 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

The amount of the intermediate compound ( S2 , 100mg, 0.58mmol) and cesium carbonate (Cs ₂ CO ₃ , 384mg, 1.17mmol) was changed in step 1 of Example 40, and 4-methylpyrazole (0.38ml, 4.71) mmol) instead of 4- (trifluoromethyl) pyrazole (120 mg, 0.88 mmol), and the same process as in Example 40, except that the recrystallization process was not performed, the intermediate compound ( S52) , 66 mg, 41.7%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.25 (s, 1H), 9.09 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.03 (s, 2H).

Step 2: 1-(4-Nitro-3-(trifluoromethyl)benzyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3 Preparation of ,4-d]pyrimidin-6-amine

For the intermediate compound ( S52 , 60mg, 0.22mmol) prepared in step 1 above, in step 2 of Example 40, 4-(bromomethyl)-1-nitro-2-(trifluoromethyl)benzene (95 mg, 0.44 mmol) and potassium carbonate (K ₂ CO ₃ , 62 mg, 0.44 mmol) The same process as in Step 2 of Example 40 was performed, except that the addition amount was changed, and the intermediate compound ( S53 , 68 mg, 64.7%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.10 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 8.23 (d, 1H), 7.98 (s, 1H), 7.62 ( d, 1H), 7.28 (s, 2H), 5.67 (s, 2H).

Step 3: 1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3, Preparation of 4-d]pyrimidin-6-amine

For the intermediate compound ( S53 , 52.7mg, 0.11mmol) prepared in step 2, the addition amount of palladium/carbon (12mg) was changed in step 3 of Example 40, and a Celite pad was used instead of a Celite filter. Except that, the same process as in step 3 of Example 40 was performed to obtain the target compound ( 42 , 38 mg, 77%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.08 (s, 1H), 8.51 (s, 1H), 8.23 (s, 1H), 7.28 - 7.17 (m, 4H), 6.77 (d, 1H), 5.62 (s, 2H), 5.29 (s, 2H).

Example 43: 1-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazole-4- manufacture of ol

Step 1: 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-1H-pyrazolo[ Preparation of 3,4-d]pyrimidin-6-amine

In step 1 of Example 40, the intermediate compound ( S2 , 500mg, 2.94mmol) and cesium carbonate (Cs ₂ CO ₃ , 1.44g, 4.42mmol) were added in different amounts, and 4-methylpyrazole (0.38ml, 4.71 mmol) instead of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (858 mg, 4.42 mmol), and heated to reflux An intermediate compound (S54 , 155 mg, 15.5%) was obtained by performing the same process as in step 1 of Example 40, except that stirring was performed at room temperature for 7 hours instead of stirring for 1 day, and the recrystallization process was not performed. .

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.13 (s, 1H), 8.80 (s, 1H), 8.20 (d, 1H), 8.10 (s, 1H), 6.92 (s, 1H), 1.25 ( s, 12H).

Step 2: 1-(2,6-difluorobenzyl)-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Preparation of pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound ( S54 , 150mg, 1.45mmol) prepared in step 1 above, in step 2 of Example 40, 4-(bromomethyl)-1-nitro-2-(trifluoromethyl)benzene (99mg, 0.34mmol) instead of 2-(bromomethyl)-1,3-difluorobenzene (284.4mg, 1.37mmol), potassium carbonate (K ₂ CO ₃ , 64mg, 0.46mmol) cesium carbohydrate Bonate (Cs ₂ CO ₃ , 298.4 mg, 1.91 mmol) was used, and the same process as in Step 2 of Example 40 was performed, except that the mixture was stirred under reflux instead of stirring at room temperature, and the following without separate purification The reaction proceeded.

Step 3: 1-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazol-4-ol manufacture of

After dissolving the intermediate compound (S55 , 95mg) prepared in step 2 in tetrahydrofuran (THF), 2M sodium hydroxide (0.15ml, 0.31mmol) and 30% hydrogen peroxide (32μl, 0.31mmol) were added thereto. was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (EA), washed with brine, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 43 , 8 mg, 11%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.47 (s, 1H), 8.11 (s, 1H), 7.97 (d, 1H), 7.69 (d, 1H), 7.47- 7.43 (m, 1H), 7.13 - 7.09 (m, 2H), 7.03 (s, 2H), 5.41 (s, 2H).

Example 44: 1-(2,6-difluorobenzyl)-3-methyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

Step 1: Preparation of 1-(2-amino-4,6-dichloropyrimidin-5-yl)ethan-1-ol

2-amino-4,6-dichloropyrimidine-5-carbaldehyde ( S1 , 1g, 5.20mmol) was dissolved in diethyl ether, and then 1M methylmagnesium bromide (1M MeMgBr, 26ml) ^{at -78 o C.} , 26.00 mmol) was added and stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrogen chloride, diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to purify the intermediate compound ( S56 , 330mg). , 31%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.39 (s, 2H), 5.19 (s, 1H), 5.16 - 5.13 (m, 1H), 1.43 (d, 3H).

Step 2: Preparation of 1-(2-amino-4,6-dichloropyrimidin-5-yl)ethan-1-one

After dissolving the intermediate compound (S56 , 200mg, 0.96mmol) prepared in step 1 in 1,2-dichloroethane (1,2-DCE), manganese dioxide (MnO ₂ , 314mg, 2.35mmol) was added thereto and heated to 70° C. and stirred for 12 hours. The reaction mixture was concentrated, washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S57 , 57 mg, 29%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 5.41 (s, 2H), 2.58 (s, 3H).

Step 3: Preparation of 4-chloro-1-(2,6-difluorobenzyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

After dissolving the intermediate compound (S57 , 20mg, 0.09mmol) prepared in step 2 in tetrahydrofuran (THF), (2,6-difluorobenzyl)hydrazine (36mg, 1.94mmol) and N,N -Diisopropylethylamine (DIPEA, 51 μl, 2.91 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S58 , 16 mg, 53%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.48 - 7.41 (m, 1H), 7.30 (s, 2H), 7.14 (t, 2H), 5.32 (s, 2H), 2.32 (s, 3H).

Step 4: 1-(2,6-difluorobenzyl)-3-methyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine manufacture of

After dissolving the intermediate compound (S58 , 16mg, 0.05mmol) prepared in step 3 in N,N-dimethylformamide (DMF), pyrazole (3.5mg, 0.05mmol) and cesium carbonate (Cs ₂ CO ₃ , 17mg, 0.05mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 44 , 16 mg, 88%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.56 (d, 1H), 7.80 (t, 1H), 7.28 - 7.24 (m, 1H), 6.90 - 6.87 (t, 2H), 6.48 - 6.47 (m, 1H), 5.48 (s, 2H), 5.20 (s, 1H), 2.69 (s, 3H).

Example 45: 1-(2,6-difluorobenzyl)-3-methyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

In step 4 of Example 44 , the addition amount of the intermediate compound (S59 , 50mg, 0.16mmol) and cesium carbonate (Cs ₂ CO ₃ , 54mg, 0.17mmol) was changed, and pyrazole (3.5mg, 0.05mmol) was replaced Except for using 3-methyl pyrazole (13 μl, 0.16 mmol), the same procedure as in step 4 of Example 44 was performed to obtain the target compound ( 45 , 16 mg, 88%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.45 (d, 1H), 7.31 - 7.29 (m, 1H), 6.91 - 6.86 (m, 2H), 6.27 (d, 1H), 5.43 (s, 2H) , 5.03 (s, 2H), 2.72 (s, 3H), 2.37 (s, 3H).

Example 46: 1-(2,6-difluorobenzyl)-3-ethyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

Step 1: Preparation of 1-(2-amino-4,6-dichloropyrimidin-5-yl)propan-1-ol

In step 1 of Example 44, 3M ethylmagnesium bromide (3M EtMgBr, 26ml, 26.00mmol) was used instead of 1M methylmagnesium bromide (1M MeMgBr, 26ml, 26.00mmol), and 1N hydrogen chloride instead of ammonium chloride (NH ₄ Cl) Except for using , the same process as in step 1 of Example 44 was performed to obtain an intermediate compound ( S60 , 330 mg, 31%).

¹ H-NMR (DMSO-d6, 400MHz): δ 7.39 (s, 2H), 5.22 (d, 1H), 4.91 - 4.86 (m, 1H), 1.91 - 1.75 (m, 2H), 0.84 (t, 3H) ).

Step 2: Preparation of 1-(2-amino-4,6-dichloropyrimidin-5-yl)propan-1-one

For the intermediate compound ( S60 _{, 340mg, 1.53mmol) prepared in step 1, manganese dioxide (MnO 2} , 3.20g, 36.74mmol) in step 2 of Example 44. Except for changing the amount of addition, The same process as in step 2 of Example 44 was performed to obtain an intermediate compound ( S61 , 82 mg, 24%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 5.40 (s, 2H), 2.91 - 2.82 (m, 2H), 1.24 - 1.20 (t, 3H).

Step 3: Preparation of 4-chloro-1-(2,6-difluorobenzyl)-3-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound (S61 , 82mg, 0.37mmol) prepared in step 2, in step 3 of Example 44 (2,6-difluorobenzyl)hydrazine ( S58 , 108mg, 0.56mmol) and N, Except for changing the amount of N-diisopropylethylamine (DIPEA, 0.19ml, 1.11mmol), the same process as in step 3 of Example 44 was performed, to obtain an intermediate compound ( S62 , 16mg, 42%) got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.46 - 7.42 (m, 2H), 7.29 (d, 2H), 7.13 (t, 2H), 5.33 (s, 2H), 2.86 - 2.80 (m, 2H) ), 1.19 (t, 3H).

Step 4: 1-(2,6-difluorobenzyl)-3-ethyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine manufacture of

For the intermediate compound ( S62 , 50mg, 0.15mmol) prepared in step 3, pyrazole (10mg, 0.16mmol) and cesium carbonate (Cs ₂ CO ₃ , 52mg, 0.17 in step 4 of Example 44) mmol), the same procedure as in step 4 of Example 44 was performed except that the amount of addition was changed to obtain the target compound ( 46 , 9 mg, 17%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.54 (d, 1H), 7.81 (t, 1H), 7.29 - 7.23 (m, 1H), 6.91 (t, 2H), 6.48 (t, 1H), 5.50 (s, 2H), 5.11 (s, 2H), 3.23 - 3.20 (m, 2H), 1.13 (t, 3H).

Example 47: 1-(2,6-difluorobenzyl)-3-ethyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

For the intermediate compound (S62 , 25mg, 0.07mmol) prepared in step 3 of Example 46, 3-methyl-1H-pyrazole instead of pyrazole (3.5mg, 0.05mmol) in step 4 of Example 44 (6 μl, 0.07 mmol) was used, and the same process as in step 4 of Example 44 was performed except that the amount of _{cesium carbonate (Cs 2} CO _{3 , 26 mg, 0.08 mmol) was changed, and the target compound} ( 47 , 5mg, 2%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.44 (d, 1H), 7.42 - 7.21 (m, 1H), 6.99 (t, 2H), 6.27 (t, 1H), 5.56 (s, 2H), 5.03 (s, 2H), 3.26 - 3.20 (m, 2H), 2.46 (s, 3H), 1.13 (t, 3H).

Example 48: 3-Cycloropropyl-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- Preparation of 6-amine

Step 1: Preparation of (2-amino-4,6-dichloropyrimidin-5-yl)(cyclopropyl)methanol

The amount of 2-amino-4,6-dichloropyrimidine-5-carbaldehyde ( S1 , 500 mg, 2.60 mmol) was changed in step 1 of Example 44, and tetrahydrofuran (THF) instead of diethyl ether , 1M methylmagnesium bromide (1M MeMgBr, 26ml, 26.00mmol) instead of 0.7M cyclopropylmagnesium bromide (0.7M CyclopropylMgBr, 18.6ml, 13.02mmol), 1N hydrogen chloride instead of ammonium chloride (NH ₄ Cl) solution was used Except that, the same process as in step 1 of Example 44 was performed to obtain an intermediate compound ( S63 , 330 mg, 57%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.43 (s, 2H), 5.31 (d, 1H), 4.18 - 4.14 (m, 1H), 1.59 - 1.53 (m, 1H), 0.48 - 0.40 (m) , 1H), 0.39 - 0.34 (m, 2H), 0.20 - 0.14 (m, 1H).

Step 2: Preparation of (2-amino-4,6-dichloropyrimidin-5-yl)(cyclopropyl)methanone

With respect to the intermediate compound (S63 , 210mg, 0.89mmol) prepared in step 1, in step 2 of Example 44, manganese dioxide (MnO ₂ , 3.20g, 36.74mmol) Except for changing the amount of addition, In the same manner as in step 2 of Example 44, an intermediate compound ( S64 , 37 mg, 20%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 5.38 (s, 2H), 2.29 - 2.23 (m, 1H), 1.37 - 1.32 (m, 2H), 1.18 - 1.15 (m, 2H).

Step 3: Preparation of 4-chloro-3-cyclopropyl-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound ( S64 , 37mg, 0.16mmol) prepared in step 2, in step 3 of Example 44 (2,6-difluorobenzyl)hydrazine ( S58 , 46mg, 0.24mmol) and N, Except for changing the amount of N- diisopropylethylamine (DIPEA, 83 μl, 0.48 mmol), the same process as in step 3 of Example 44 was performed, to obtain an intermediate compound (S65 , 47 mg, 88%) .

¹ H-NMR (CDCl ₃ , 400 MHz): δ 7.52 - 7.21 (m, 1H), 6.99 (t, 2H), 5.38 (s, 2H), 5.15 (s, 2H), 2.35 - 2.30 (m, 1H) , 0.89 (t, 4H).

Step 4: 3-Cyclopropyl-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

For the intermediate compound ( S65 , 47mg, 0.14mmol) prepared in step 3, pyrazole (10mg, 0.14mmol) and cesium carbonate (Cs ₂ CO ₃ , 47mg, 0.15) in step 4 of Example 44 mmol), the same procedure as in step 4 of Example 44 was performed except that the amount of addition was changed to obtain the target compound ( 48 , 19 mg, 37%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.56 (d, 1H), 7.80 (t, 1H), 7.28 - 7.20 (m, 1H), 6.89 - 6.84 (t, 2H), 6.49 - 6.48 (t, 1H), 5.54 (s, 2H), 5.16 (s, 2H), 3.02 - 3.00 (m, 1H), 0.98 - 0.84 (m, 4H).

Example 49: 3-cyclopropyl-1-(2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

For the intermediate compound (S65 , 78mg, 0.23mmol) prepared in step 3 of Example 48, 3-methylpyrazole (19mg, 0.23 mmol) and the same process as in Example 44, except that the amount of cesium carbonate (Cs ₂ CO ₃ , 77 mg, 0.25 mmol) was changed, and the target compound ( 49 , 14 mg, 16%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.45 (d, 1H), 7.25 - 7.20 (m, 1H), 6.89 - 6.84 (t, 2H), 6.28 (d, 1H), 5.43 (s, 2H) , 5.25 (s, 2H), 2.98 - 2.92 (m, 1H), 0.95 - 0.90 (m, 2H), 0.88 - 0.84 (m, 2H).

Example 50: 1-(2,6-difluorobenzyl)-3-ethynyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

Step 1: Preparation of 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine

After dissolving the intermediate compound (S2 , 200mg, 1.18mmol) prepared in step 2 of Example 1-1 in 1,2-dichloroethane (1,2-DCE), thereto N-bromosuccinimide (NBS, 272 mg, 1.53 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was concentrated, diluted with dichloromethane (DCM), washed with distilled water, and filtered to obtain an intermediate compound (S66 , 200 mg, 68%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.54 (s, 1H), 7.36 (s, 2H).

Step 2: Preparation of 3-bromo-4-chloro-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

After dissolving the intermediate compound (S66 , 200mg, 0.80mmol) prepared in step 1 in N,N-dimethylformamide (DMF), 2,6-difluorobenzyl bromide (174mg, 0.85mmol) and Potassium hydroxide (45 mg, 0.85 mmol) was added and stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S67 , 852 mg, 57%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.60 (s, 2H), 7.51 - 7.44 (m, 1H), 7.17 - 7.11 (m, 2H), 5.37 (s, 2H).

Step 3: 3-Bromo-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

After dissolving the intermediate compound (S67 , 180mg, 0.48mmol) prepared in step 2 in N,N-dimethylformamide (DMF), pyrazole (40mg, 0.58mmol) and cesium carbonate (Cs ₂ CO ₃ , 313 mg, 0.96 mmol) was added, and the mixture was heated to 40° C. and stirred for 12 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S68 , 128 mg, 63%). .

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.44 - 8.43 (m, 1H), 7.86 - 7.84 (m, 1H), 7.62 (d, 1H), 7.32 -7.24 (m, 1H), 6.93 - 6.86 ( m, 2H), 6.51 - 6.50 (m, 1H), 5.54 (s, 2H), 5.30 - 5.29 (m, 1H).

Step 4: 1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3,4-d ]Preparation of pyrimidin-6-amine

After dissolving the intermediate compound (S68 , 60mg, 0.15mmol) prepared in step 3 in triethylamine (TEA), trimethylsilylacetylene (44ul, 0.31mmol), copper (I) iodide (4.10mg, 0.02 mmol), triphenylphosphine (PPh ₃ , 7.60 mg, 0.03 mmol), and bis(triphenylphosphine)palladium(II) dichloride (PdCl ₂ (PPh ₃ ) ₂ , 10 mg, 0.02 mmol) were added and It was warmed to 70° C. and stirred for 4 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, and the next reaction was carried out without further purification.

Step 5: 1-(2,6-difluorobenzyl)-3-ethynyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

After dissolving the intermediate compound (S69 , 60mg, 0.14mmol) prepared in step 4 in tetrahydrofuran (THF), tetrabutylammonium fluoride (TBAF, 280ul, 0.28mmol) was added thereto and at room temperature for 2 hours stirred. The reaction mixture was diluted with ethyl acetate (EA), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 50 , 9.6 mg, 18%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.56 (d, 1H), 7.85 (d, 1H), 7.31 - 7.23 (m, 1H), 6.92 - 6.85 (m, 2H), 6.51 - 6.50 (m, 1H), 5.55 (s, 2H), 5.27 (s, 2H), 3.26 (s, 1H).

Example 51: 1-(2,6-difluorobenzyl)-3-ethynyl-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d] Preparation of pyrimidin-6-amine

Step 1: 3-Bromo-1-(2,6-difluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)pyrazolo[3,4-d]pyrimidine-6 -Preparation of amines

For the intermediate compound ( S67 , 300 mg, 0.80 mmol) prepared in step 2 of Example 50, 4-methylpyrazole (102 μl, 1.20 mmol) was used, and the amount of cesium carbonate (Cs ₂ CO ₃ , 521 mg, 1.60 mmol) was changed, and instead of heating to 50 ° C. and stirring for 12 hours, heating to 50 ° C. and stirring for 1 day, An intermediate compound (S70 , 245 mg, 34%) was obtained in the same manner as in step 3 of Example 50, except that ethyl acetate (EA) was used instead of dichloromethane (DCM).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.25 (s, 1H), 7.78 (s, 1H), 7.51 - 7.47 (m, 1H), 7.31 (s, 2H), 7.17 - 7.11 (m, 2H) ), 5.43 (s, 2H), 2.13 (s, 3H).

Step 2: 1-(2,6-difluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-3-((trimethylsilyl)ethynyl)-1H-pyrazolo[3 Preparation of ,4-d]pyrimidin-6-amine

After dissolving the intermediate compound (S70 , 100 mg, 0.23 mmol) prepared in step 1 in triethylamine (TEA), trimethylsilylacetylene (71 μl, 0.50 mmol), copper (I) iodide (CuI, 6.80 mg, 0.04 _{mmol), triphenylphosphine (PPh 3} , 12.4 mg, 0.05 mmol), and bis(triphenylphosphine)palladium dichloride (PdCl ₂ (PPh ₃ ) ₂ , 16.7 mg, 0.02 mmol) were added. and heated to 70° C. and stirred for 1 day. The reaction mixture was cooled to room temperature, neutralized with 2N aqueous hydrogen chloride solution, diluted with ethyl acetate (EA), and washed with distilled water. After drying over magnesium sulfate, filtration, and concentration, the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S71 , 45 mg, 43%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.38 (s, 1H), 7.66 (s, 1H), 7.29 (m, 1H), 6.88 (t, 2H), 5.56 (s, 2H), 5.18 (s) , 2H), 2.18 (s, 3H), 0.26 (s, 9H).

Step 3: 1-(2,6-difluorobenzyl)-3-ethynyl-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri Preparation of midin-6-amine

For the intermediate compound ( S71 , 42mg, 0.10mmol) prepared in step 2 above, in step 5 of Example 50, the addition amount of tetrabutylammonium fluoride (TBAF, 192 μl, 0.19 mmol) was changed except that , The same process as in step 5 of Example 50 was performed to obtain the target compound ( 51 , 24 mg, 69%).

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.32 (s, 1H), 7.68 (s, 1H), 7.29 (m, 1H), 6.90 (t, 2H), 5.55 (s, 2H), 5.18 (s) , 2H), 3.26 (s, 1H), 2.17 (s, 3H).

Example 52: 3-chloro-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- Preparation of amines

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

In step 1 of Example 50, N-chlorosuccinimide (NCS, 314 mg, 2.35 mmol) was used instead of N-bromosuccinimide (NBS, 272 mg, 1.53 mmol), and step 1 of Example 50 and The same process was performed to obtain an intermediate compound ( S72 , 40 mg, 18%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.42 (s, 1H), 7.38 (s, 2H).

Step 2: Preparation of 3,4-dichloro-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine

For the intermediate compound ( S72 , 300mg, 1.47mmol) prepared in step 1 above, in step 2 of Example 50, 2,6-difluorobenzyl bromide (320mg, 1.54mmol) and potassium hydroxide (86mg) , 1.54 mmol) was carried out in the same manner as in step 2 of Example 50, except that the amount of addition was changed, to obtain an intermediate compound ( S73 , 354 mg, 73%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.63 (s, 2H), 7.50 - 7.45 (m, 1H), 7.15 - 7.11 (m, 2H), 5.36 (s, 2H).

Step 3: 3-Chloro-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine manufacture of

For the intermediate compound ( S73 _{, 150mg, 0.45mmol) prepared in step 2, pyrazole (27mg, 0.41mmol) and cesium carbonate (Cs 2} CO ₃ , 152 mg, 0.50) in step 3 of Example 50 mmol), the same process as in step 3 of Example 50 was performed, except that the target compound ( 52 , 45 mg, 40%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.47 (d, 1H), 7.86 (t, 1H), 7.32 - 7.25 (m, 1H), 6.93 - 6.88 (m, 2H), 6.51 - 6.50 (m, 1H), 5.51 (s, 2H), 5.26 (s, 1H).

Example 53: 6-amino-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3- Preparation of carbonitrile

After dissolving the compound of Example 52 ( 52 , 35 mg, 0.10 mmol) in acetonitrile, sodium cyanide (4.7 mg, 0.10 mmol), tetrakis (triphenylphosphine) palladium (0) (Pd ( PPh ₃ ) ₄ , 12 mg, 0.01 mmol), and copper (I) iodide (18 mg, 0.10 mmol) were added, and the mixture was heated to 110° C. using a microwave synthesizer and stirred for 1 hour and 30 minutes. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 53 , 5.8 mg, 17%). got it

¹ H-NMR (CDCl ₃ , 400 MHz): δ 8.52 (d, 1H), 7.95 (d, 1H), 7.36 - 7.28 (m, 1H), 6.95 - 6.89 (m, 2H), 6.54 - 6.53 (m, 1H), 5.58 (s, 2H), 5.30 (s, 2H).

Example 54: Preparation of 9-benzyl-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

54-1. Preparation of 6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 6-hydrazinyl-9H-purin-2-amine

6-Chloro-9H-purin-2-amine ( S74 , 5g, 29.49mmol) was dissolved in methanol (MeOH), cooled to 0 ℃, hydrazine monohydrate (27.53ml, 884.61mmol) was slowly added and heated to 50 ℃ Stirred for 3 hours. The reaction mixture was concentrated, the resulting solid was filtered using a small amount of methanol (MeOH) and dried, and the next reaction was carried out without further purification.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.29 (br s, 1H), 7.64 (br s, 1H), 5.76 (br s, 2H), 4.38 (br s, 2H).

Step 2: Preparation of 6-(1H-pyrazol-1-yl)-9H-purin-2-amine

The intermediate compound ( S75 , 2.9g, 17.56mmol) prepared in step 1 was dissolved in methanol (MeOH) and cooled to 0° C. to obtain a methanol (MeOH) solution (1.25M, 140ml, 175.60mmol) containing hydrogen chloride. Slowly added. At the same temperature, 1,1,3,3-tetramethoxypropane (3.5ml, 21.07mmol) was slowly added, warmed to room temperature, stirred for 2 hours, heated to 45° C., and stirred for 1 day. The reaction mixture was cooled to 0° C., and a saturated aqueous sodium bicarbonate solution (sat. NaHCO ₃ (aq)) was slowly added to adjust the pH to 7, the reaction solvent was removed, and the intermediate compound ( S76 ) was prepared without separate purification. prepared.

¹ H-NMR (DMSO-d6, 400 MHz): δ 13.65 (br s, 1H), 8.57 (s, 1H), 8.15 (d, 1H), 7.34(s, 1H), 6.68 (t, 1H), 6.33 (br s, 2H).

54-2. Preparation of 9-benzyl-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

After dissolving the compound of Example 54-1 ( S76 , 210mg, 1.04mmol) in N,N-dimethylformamide (DMF), benzyl bromide (0.15ml, 1.25mmol) and potassium carbonate (K ₂ CO ₃ , 413 mg, 2.98 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 54 , 90 mg, 29%). .

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (d, 1H), 8.27 (s, 1H), 7.91 - 7.88 (m, 1H), 7.39 - 7.26 (m, 5H), 6.81 (s, 2H) ), 6.67 - 6.64 (m, 1H), 5.34 (s, 2H).

Example 55: Preparation of 6-(1H-pyrazol-1-yl)-9-(pyridin-2-ylmethyl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 200 mg, 0.99 mmol) and potassium carbonate (K ₂ CO ₃ , 413 mg, 2.98 mmol) was changed, and benzyl bromide (0.15 ml, 1.25mmol) instead of 2-(bromomethyl)pyridine hydrobromide (277mg, 1.09mmol), the same procedure as in Example 54-2 was performed, except that the target compound ( 55 , 30mg, 12%) was got it

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.11 (d, 1 H), 8.50 (dt, 1 H), 8.26 (s, 1 H), 7.91 - 7.89 (m, 1 H), 7.79 (td) , 1 H), 7.31 (dd, 1 H), 7.21 (d, 1 H), 6.77 (s, 2 H), 6.67 (dd, 1 H), 5.46 (s, 2 H).

Example 56: Preparation of 9-(4-aminobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 300 mg, 1.49 mmol) and potassium carbonate (K ₂ CO ₃ , 618 mg, 4.48 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) was used instead of 4-nitrobenzyl bromide (387 mg, 1.79 mmol), and the same procedure as in Example 54-2 was performed, except that the mixture was stirred for 2 hours instead of stirring for 1 hour, and an intermediate compound ( S77 , 260mg, 52%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (d, 1H), 8.31 (s, 1H), 8.22 (d, 2H) 7.92 - 7.90 (m, 1H), 7.48 (d, 2H), 6.83 (s, 2H), 6.67 (dd, 1H), 5.51 (s, 2H).

Step 2: Preparation of 9-(4-aminobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

After dissolving the intermediate compound (S77 , 147mg, 0.44mmol) prepared in step 1 in ethanol (EtOH), tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 296mg, 1.31mmol) and concentrated Aqueous hydrogen chloride solution (Conc. HCl (aq), 0.8 ml, 8.74 mmol) was slowly added, heated to 50° C., and stirred for 1 day. The reaction mixture was diluted with dichloromethane (DCM) and washed with a saturated aqueous sodium bicarbonate solution (sat. NaHCO ₃ (aq)) and distilled water. After drying over magnesium sulfate, filtration and concentration, the concentrate was purified by silica gel chromatography to obtain the target compound ( 56 , 12 mg, 5%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.08 (d, 1 H), 8.16 (s, 1 H), 7.88 (d, 1 H), 7.03 (m, 2 H), 6.78 (s, 2) H), 6.64 (dd, 1 H), 6.51 (m, 2 H), 5.11 (d, 4 H).

Example 57: Preparation of 9-(2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the amount of the compound of Example 54-1 ( S76 , 200 mg, 0.99 mmol) and potassium carbonate (K ₂ CO ₃ , 201 mg, 1.49 mmol) was changed, and benzyl bromide (0.15 ml, Example 54-, except that 2-(bromomethyl)-1,3-difluorobenzene (308 mg, 1.49 mmol) was used instead of 1.25 mmol) and stirred for 2 hours instead of stirring for 1 hour 2, the target compound ( 57 , 155mg, 48%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.03(s, 1H), 7.49 (m, 1H), 7.16 (t, 2H), 6.89(s, 2H), 5.34(s, 2H).

Example 58: Preparation of 9-(3,5-bis(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 100 mg, 0.50 mmol) and potassium carbonate (K ₂ CO ₃ , 104 mg, 0.75 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) was used instead of 3,5-bis(trifluoromethyl)benzyl bromide (0.1ml, 0.55mmol), and the same procedure as in Example 54-2, except that stirring was performed overnight instead of stirring for 1 hour. to obtain the target compound ( 58 , 91 mg, 42.6%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.07 (dd, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 8.03 (s, 2H), 7.90 (s, 1H), 6.82 ( s, 2H), 6.66 (s, 1H), 5.33 (s, 2H).

Example 59: Preparation of 9-(4-amino-2-fluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(2-fluoro-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 100 mg, 0.50 mmol) and potassium carbonate (K ₂ CO ₃ , 103 mg, 0.75 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) instead of 1-(bromomethyl)-2-fluoro-4-nitro-benzene (175 mg, 0.75 mmol), and instead of stirring at room temperature for 1 hour, it was heated to 50° C. and stirred for 2 hours. After that, the reaction mixture was cooled to room temperature, and the same process as in Example 54-2 was performed except that dichloromethane (DCM) was diluted with ethyl acetate (EA) instead of dichloromethane (DCM), and the intermediate compound ( S78 , 30 mg, 17%) was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz): δ 9.04 (d, 1H), 8.03 - 7.99 (m, 2H), 7.93 (d, 1H), 7.88 (s, 1H), 7.43 (t, 1H), 6.55 (q, 1H), 5.44 (s, 2H), 5.13 (s, 2H).

Step 2: Preparation of 9-(4-amino-2-fluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S78 , 40mg, 0.13mmol) prepared in step 1 above, in step 2 of Example 56, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 127 mg, 0.56 mmol) was added , and without using a concentrated aqueous hydrogen chloride solution (Conc. HCl (aq)) and a saturated aqueous sodium bicarbonate solution (sat. NaHCO ₃ (aq)), instead of stirring for 1 day, for 4 hours Except for stirring, the same process as in step 2 of Example 56 was performed to obtain the target compound ( 59 , 5 mg, 12%).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 8.93 (d, 2H), 7.85 (s, 1H), 7.80 (s, 1H), 7.03 (t, 1H), 6.52 (s, 1H), 6.49 - 6.29 (m, 2H), 5.13 (s, 2H).

Example 60: Preparation of 9-(4-amino-3-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(4-nitro-3-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 300 mg, 1.49 mmol) and potassium carbonate (K ₂ CO ₃ , 227 mg, 1.64 mmol) was changed, and benzyl bromide (0.15 ml, 1.25mmol) instead of 4-(bromomethyl)-1-nitro-2-(trifluoromethyl)benzene (466mg, 1.64mmol), and heated to 50℃ instead of stirring at room temperature for 1 hour to 2 After stirring for a period of time, the reaction mixture was cooled to room temperature, and the same process as in Example 54-2 was performed except that dichloromethane (DCM) was diluted with ethyl acetate (EA) instead of dichloromethane (DCM), and the intermediate compound ( S79) , 50 mg, 8%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 11.17 (d, 1H), 9.53 (d, 1H), 9.14 (s, 1H), 8.94 (s, 1H), 8.21 (s, 1H), 8.00 ( s, 1H), 6.83 (s, 1H), 5.76 (s, 2H).

Step 2: Preparation of 9-(4-amino-3-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S79 , 50mg, 0.12mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 140mg, 0.62mmol) in step 2 of Example 56 , and without using a concentrated aqueous hydrogen chloride solution (Conc. HCl (aq)) and a saturated aqueous sodium bicarbonate solution (sat. NaHCO ₃ (aq)), instead of stirring for 1 day, for 4 hours Except for stirring, the same process as in Step 2 of Example 56 was performed to obtain the target compound ( 60 , 6 mg, 13%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.07 (d, 1H), 8.22 (s, 1H), 7.88 (d, 1H), 7.39 (d, 1H), 7.29 (d, 1H), 6.79 ( m, 3H), 6.64 (q, 1H), 5.65 (s, 2H), 5.17 (s, 2H).

Example 61: Preparation of 9-(4-amino-2-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 6-chloro-9- (4-nitro-2- (trifluoromethyl) benzyl) -9H-purin-2-amine

After dissolving 6-chloro-9H-purin-2-amine ( S74 , 100mg, 0.59mmol) in N,N-dimethylformamide (DMF), 1- (bromomethyl)-4-nitro- 2-(trifluoromethyl)benzene (184 mg, 0.65 mmol) and potassium carbonate (K ₂ CO ₃ , 90 mg, 0.65 mmol) were added, and the mixture was heated to 50° C. and stirred for 19 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered, and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S80 , 103 mg, 47%). .

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.51 (d, 1H), 8.41 - 8.38 (m, 1H), 8.26 (s, 1H), 7.09 (d, 1H), 7.00 (s, 2H), 5.65 (s, 2H), 2.53 (s, 3H).

Step 2: Preparation of 6-hydrazino-9-(4-nitro-2-(trifluoromethyl)benzyl)-9H-purin-2-amine

The intermediate compound ( S80 , 90mg, 0.24mmol) prepared in step 1 was dissolved in methanol (MeOH), hydrazine monohydrate (75ul, 2.42mmol) was added thereto, heated to 40°C, and stirred for 19 hours. The reaction mixture was concentrated and the resulting solid was filtered to obtain an intermediate compound ( S81 , 70 mg, 78%) without further purification.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.58 (br s, 1H), 8.50 (d, 1H), 8.46 - 8.43 (m, 1H), 7.83 (s, 1H), 6.93 (d, 1H) , 5.99 (s, 2H), 5.55 (s, 2H), 4.44 (br s, 2H).

Step 3: Preparation of 9-(4-nitro-2-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

After dissolving the intermediate compound (S81 , 279mg, 0.76mmol) prepared in step 2 in methanol (MeOH), 1,1,3,3-tetramethoxypropane (124ul, 0.76mmol) and 1.25M hydrogen 12.28 ml of a methanol (MeOH) solution containing chloride was added at 0 °C, then heated to 40 °C and stirred for 22 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with an aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by recrystallization to obtain an intermediate compound ( S82 , 222mg, 73%) got

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.11 (d, 1H), 8.52 (d, 1H), 8.42 - 8.39 (m, 1H), 8.30 (s, 1H), 7.39 (d, 1H), 7.09 (d, 1H), 6.84 (s, 2H), 6.69 - 6.68 (m, 1H), 5.69 (s, 2H).

Step 4: Preparation of 9-(4-amino-2-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

The intermediate compound ( S82 , 202 mg, 0.50 mmol) prepared in step 3 was dissolved in methanol (MeOH), and 50 mg of palladium/carbon was added thereto, followed by stirring at room temperature for 5 days. The reaction mixture was diluted with dichloromethane (DCM) and filtered through a celite pad, the filtrate was concentrated, and the concentrated solution was purified by silica gel chromatography to obtain the target compound ( 61 , 16 mg, 9%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (d, 1H), 8.00 (s, 1H), 7.90 (s, 1H), 6.96 (d, 1H), 6.81 (s, 2H), 6.78 - 6.76 (m, 1H), 6.72 - 6.70 (m, 1H), 6.67 - 6.66 (m, 1H), 5.66 (s, 2H), 5.30 (s, 2H).

Example 62: Preparation of 9-(4-amino-2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(2,6-difluoro-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the amount of the compound of Example 54-1 ( S76 , 200 mg, 0.99 mmol) and potassium carbonate (K ₂ CO ₃ , 201 mg, 1.49 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) was used instead of 2-(bromomethyl)-1,3-difluoro-5-nitrobenzene (375 mg, 1.49 mmol), and was stirred for 2 hours instead of stirring for 1 hour, In the same manner as in Example 54-2, an intermediate compound ( S83 , 50 mg, 14%) was obtained.

¹ H-NMR (DMSO-d6, 400MHz): δ 9.03 (d, 1H), 8.21 (s, 1H), 8.11 - 8.08 (dq, 2H), 7.88 (d, 1H), 6.74 (s, 2H), 6.64 - 6.63 (dd, 1H), 5.49 (s, 2H).

Step 2: Preparation of 9-(4-amino-2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

After the intermediate compound ( S83 , 50mg, 0.13mmol) prepared in step 1 was dissolved in acetone, an excess of Raney Nickel was added thereto, and stirred for 3 hours at room temperature and pressurized hydrogen gas. The reaction mixture was concentrated and purified by silica gel chromatography to obtain the target compound ( 62 , 5.3 mg, 9%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.05 (d, 1H), 7.95 (s, 1H), 7.87 (s, 1H), 6.75 (s, 2H), 6.64 (d, 1H), 6.22 ( d, 2H), 5.91 (s, 2H) 5.14 (s, 2H).

Example 63: Preparation of 9-(4-amino-2,3-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(2,3-difluoro-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 100 mg, 0.49 mmol) and potassium carbonate (K ₂ CO ₃ , 101 mg, 0.74 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) instead of 2-(bromomethyl)-1,3-difluorobenzene (125 mg, 0.49 mmol), and after stirring for 2 hours instead of stirring for 1 hour, the filtrate of the reaction mixture was filtered An intermediate compound (S84 , 35.4 mg, 24%) was obtained in the same manner as in Example 54-2, except that the mixture was diluted with ethyl acetate (EA) and sodium sulfate was used instead of magnesium sulfate.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.07 (d, 1H), 8.26 (s, 1H), 7.98 - 7.94 (dq, 1H), 7.90 (d, 1H), 7.10 - 7.06 (dq, 1H) ), 6.83 (s, 2H), 6.76 (dq, 1H), 6.67 (dd, 1H), 5.54 (s, 2H).

Step 2: Preparation of 9-(4-amino-2,3-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

The intermediate compound (S84 , 35.4 mg, 0.10 mmol) prepared in step 1 was subjected to the same process as in step 2 of Example 62 to obtain the target compound ( 63 , 5.0 mg, 15%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.07 (d, 1H), 8.12 (s, 1H), 7.88 (d, 1H), 6.79 (s, 2H), 6.76 (dq, 1H), 6.65 ( t, 1H), 6.53 - 6.49 (dq, 1H), 5.58 (s, 2H), 5.21 (s, 2H).

Example 64: Preparation of 9-(4-amino-3-chlorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(3-chloro-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 200 mg, 0.99 mmol) and potassium carbonate (K ₂ CO ₃ , 315 mg, 2.28 mmol) was changed, and benzyl bromide (0.15 ml, Example 54 above, except that 4-(bromomethyl)-2-chloro-1-nitrobenzene (191 mg, 0.76 mmol) was used instead of 1.25 mmol) and stirred for 1 day instead of stirring for 1 hour The same process as -2 was performed to obtain the target compound ( S85 , 145 mg, 56%).

¹ H-NMR (DMSO-d6, 400MHz): δ 9.08 (d, 1H), 8.29 (s, 1H), 8.07 (d, 1H), 7.92 - 7.86 (m, 1H), 7.73 (d, 1H), 7.40 (dd, 1H), 6.83 (s, 2H), 6.66 (dd, 1H), 5.46 (s, 2H).

Step 2: Preparation of 9-(4-amino-3-chlorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S85 , 145mg, 0.43mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 288 mg, 1.27 mmol) and concentration in step 2 of Example 56 Change the amount of hydrogen chloride aqueous solution (Conc. HCl (aq), 0.72 ml, 8.60 mmol), and _{without using a saturated aqueous sodium bicarbonate solution (sat. NaHCO 3} (aq)) at 50 ° C. Instead of heating and stirring for 1 day, the same process as in Step 2 of Example 56 was performed, except that the mixture was heated to 45° C. and stirred for 2 hours to obtain the target compound ( 64 , 47 mg, 32%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.07 (s, 1 H), 8.21 (s, 1 H), 7.88 (s, 1 H), 7.23 (s, 1 H), 7.03 (d, 1 H), 6.82 - 6.72 (m, 3 H), 6.65 (d, 1 H), 5.40 (s, 2 H), 5.13 (s, 2 H).

Example 65: Preparation of 9-(4-amino-2-fluoro-5-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(2-fluoro-5-methyl-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 244 mg, 1.21 mmol) and potassium carbonate (K ₂ CO ₃ , 502 mg, 3.63 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) instead of 1-(bromomethyl)-2-fluoro-5-methyl-4-nitrobenzene (300 mg, 1.12 mmol), except that the same process as in Example 54-2 was performed, , the target compound ( S86 , 395 mg, 42%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.07 (d, 1H), 8.24 (s, 1H), 7.96 - 7.89 (m, 2H), 7.39 (d, 1H), 6.82 (s, 2H), 6.67 - 6.65 (m, 1H), 5.45 (s, 2H), 2.32 (s, 3H).

Step 2: Preparation of 9-(4-amino-2-fluoro-5-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S86 , 231 mg, 0.62 mmol) prepared in step 1, tin (II) chloride dihydrate (SnCl ₂ ·2H ₂ O, 423 mg, 1.87 mmol) and concentration in step 2 of Example 56 Change the amount of hydrogen chloride aqueous solution (Conc. HCl (aq), 1.1 ml, 12.48 mmol), and _{without using a saturated aqueous sodium bicarbonate solution (sat. NaHCO 3} (aq)) for 1 day Except for stirring for 4 hours instead of stirring, the same process as in Step 2 of Example 56 was performed to obtain the target compound ( 65 , 93 mg, 44%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.08 (d, 1H), 8.14 (s, 1H), 7.91 - 7.88 (m, 1H), 6.79 (s, 2H), 6.65 (dd, 1H), 6.51 (d, 1H), 6.01 (d, 1H), 5.26 (s, 2H), 5.14 (s, 2H), 2.06 (s, 3H).

Example 66: Preparation of 9-(4-amino-2-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(2-methyl-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 50 mg, 0.25 mmol) and potassium carbonate (K ₂ CO ₃ , 52 mg, 0.37 mmol) was changed, and benzyl bromide (0.15 ml, 1.25mmol) instead of 1-(bromomethyl)-2-methyl-4-nitrobenzene (86mg, 0.373mmol), and instead of stirring at room temperature for 1 hour, it was heated to 50° C. and stirred for 19 hours. Except, the same process as in Example 54-2 was performed to obtain an intermediate compound ( S87 , 69 mg, 79%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.10 (d, 1H), 8.23 (s, 1H), 8.17 - 8.15 (m, 1H), 8.00 (m, 1H), 7.91 (d, 1H), 6.91 (d, 1H), 6.81 (s, 2H), 6.68 - 6.67 (m, 1H), 5.46 (s, 2H), 2.53 (s, 3H).

Step 2: Preparation of 9-(4-amino-2-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

The intermediate compound ( S87 , 68mg, 0.15mmol) prepared in step 1 was dissolved in methanol (MeOH), and 15 mg of palladium/carbon was added thereto, followed by stirring at room temperature for 1 day. The reaction mixture was diluted with dichloromethane (DCM), filtered through a celite pad, the filtrate was concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 66 , 12 mg, 20%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.08 (d, 1H), 7.97 (s, 1H), 7.89 (s, 1H), 6.78 - 6.76 (m, 3H), 6.65 (m, 1H), 6.41 (m, 1H), 6.36 - 6.33 (m, 1H), 5.11 (s, 2H), 5.05 (s, 2H), 2.18 (s, 3H).

Example 67: Preparation of 9-(4-amino-3-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 6-chloro-9-(3-methyl-4-nitrobenzyl)-9H-purin-2-amine

6-Chloro-9H-purin-2-amine ( S74 , 167 mg, 0.98 mmol) and potassium carbonate (K ₂ CO ₃ , 150 mg, 1.08 mmol) in step 1 of Example 61 were changed in 19 The same process as in step 1 of Example 61 was performed, except that the mixture was stirred for 21 hours instead of stirring for an hour, and the concentrate was recrystallized from dichloromethane (DCM) instead of purified by silica gel chromatography, and the intermediate compound ( S88 , 306mg, 97%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.26 (s, 1H), 7.98 - 7.96 (m, 1H), 7.38 (s, 1H), 7.26 - 7.23 (m, 1H), 6.97 (s, 2H) ), 5.39 (s, 2H), 2.53 (s, 3H).

Step 2: Preparation of 6-hydrazino-9-(3-methyl-4-nitrobenzyl)-9H-purin-2-amine

For the intermediate compound ( S88 , 306mg, 0.96mmol) prepared in step 1, change the amount of hydrazine monohydrate (149ul, 4.80mmol) added in step 2 of Example 61, 24 instead of stirring for 19 hours Except for stirring for a period of time, the same process as in Step 2 of Example 61 was performed to obtain an intermediate compound ( S89 , 254 mg, 84%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.49 (br s, 1H), 7.98 - 7.93 (m, 1H), 7.82 (s, 1H), 7.32 (s, 1H), 7.18 (dd, 1H) , 5.96 (s, 2H), 5.29 (s, 2H), 4.42 (br s, 2H), 2.50 (s, 3H).

Step 3: Preparation of 9-(3-methyl-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S89 , 214mg, 0.68mmol) prepared in step 2, 1,1,3,3-tetramethoxypropane (112ul, 0.68mmol) and 1.25M hydride in step 3 of Example 61 The addition amount of methanol (MeOH) solution (11.02 ml) containing rosen chloride was changed, stirred for 6 hours instead of stirring for 22 hours, and the concentrate was purified by silica gel chromatography instead of recrystallization. The same process as in step 3 of Example 61 was performed to obtain an intermediate compound ( S90 , 144 mg, 60%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (dd, 1H), 8.29 (s, 1H), 7.98 (d, 1H), 7.90 (dd, 1H), 7.39 (s, 1H), 7.26 ( dd, 1H), 6.82 (s, 2H), 6.67 - 6.66 (m, 1H), 5.43 (s, 2H), 2.51 (s, 3H).

Step 4: Preparation of 9-(4-amino-3-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S90 , 143mg, 0.41mmol) prepared in step 3, using a mixed solvent of ethyl acetate (EA) and methanol (MeOH) instead of methanol (MeOH) in step 4 of Example 61, palladium / Changed the amount of carbon (48 mg), stirred for 23 hours instead of stirring for 5 days, filtered through a celite pad, except that a separate concentration and purification process was not performed, except that step 4 of Example 61 Using the same procedure, the target compound ( 67 , 19 mg, 15%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (dd, 1H), 8.29 (s, 1H), 7.98 (d, 1H), 7.90 (dd, 1H), 7.39 (s, 1H), 7.26 ( dd, 1H), 6.82 (s, 2H), 6.67 - 6.66 (m, 1H), 5.43 (s, 2H), 5.32 (s, 2H), 2.51 (s, 3H)

Example 68: 9-(4-amino-3,5-dimethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(3,5-dimethyl-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 100 mg, 0.50 mmol) and potassium carbonate (K ₂ CO ₃ , 85 mg, 0.75 mmol) was changed, and benzyl bromide (0.15 ml, 1.25mmol) instead of 5-(bromomethyl)-1,3-dimethyl-2-nitrobenzene (100mg, 0.50mmol), and instead of stirring at room temperature for 1 hour, it was heated to 50° C. for 2 hours The intermediate compound (S91 , 38 mg, 26) was stirred, and in the same manner as in Example 54-2, except that ethyl acetate (EA) was used instead of dichloromethane (DCM) and sodium sulfate was used instead of magnesium sulfate. %) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (d, 1H), 8.26 (s, 1H), 7.89 (dd, 1H), 7.17 (s, 2H), 6.80 (m, 2H), 6.66 - 6.65 (dd, 1H), 5.34 (s, 2H), 2.18 (s, 6H).

Step 2: Preparation of 9-(4-amino-3,5-dimethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

For the intermediate compound ( S91 , 38mg, 0.11mmol) prepared in step 1, after filtering the reaction mixture in step 2 of Example 62 through a celite pad, the filtrate was concentrated and purified, except that In the same manner as in step 2 of Example 62, the target compound ( 68 , 5.3 mg, 9%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.08 (d, 1H), 8.14 (s, 1H), 7.87 (d, 1H), 6.81 (s, 2H), 6.77 (m, 2H), 6.64 ( dd, 1H), 5.07 (s, 2H), 4.59 (s, 2H), 2.03 (s, 6H).

Example 69: Preparation of 9-(4-amino-3-ethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 9-(3-ethyl-4-nitrobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 94 mg, 0.55 mmol) and potassium carbonate (K ₂ CO ₃ , 153 mg, 1.10 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) was used instead of 4-(bromomethyl)-2-ethyl-1-nitrobenzene (149 mg, 0.61 mmol), stirred for 1 day instead of stirring for 1 hour, dichloromethane (DCM) ) instead of a dichloromethane (DCM) solution containing 5% methanol (MeOH), except that brine was used instead of distilled water, the same process as in Example 54-2 was performed, and the intermediate compound ( S92 , 128 mg, 69%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.09 (d, 1H), 8.29 (s, 1H), 7.91 - 7.89 (m, 2H), 7.46 (d, 1H), 7.24 - 7.22 (m, 1H) ), 6.81 (s, 2H), 6.67 - 6.65 (m, 1H), 5.43 (s, 2H), 2.81 - 2.79 (m, 2H), 1.19 - 1.15 (m, 3H).

Step 2: Preparation of 9-(4-amino-3-ethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

The intermediate compound ( S92 , 46mg, 0.12mmol) prepared in step 1 and 12mg of 10% palladium/carbon were dissolved in a mixed solvent of ethyl acetate (EA) and methanol (MeOH) and stirred for 1 day under hydrogen pressure. After the reaction mixture was filtered through a pad of Celite, the filtrate was concentrated, and the concentrated solution was recrystallized from dichloromethane (DCM) to obtain the target compound ( 69 , 23 mg, 54%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.08 (d, 1H), 8.15 (s, 1H), 7.88 (d, 1H), 6.98 (d, 1H), 6.89 - 6.87 (m, 1H), 6.78 (s, 2H), 6.64 - 6.63 (m, 1H), 6.54 (d, 1H), 5.10 (s, 2H), 4.89 (s, 2H), 2.42 - 2.36 (m, 2H), 1.17 - 1.07 ( m, 3H).

Example 70: Preparation of 9-((6-methylpyridin-2-yl)methyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 402 mg, 2.00 mmol) and potassium carbonate (K ₂ CO ₃ , 830 mg, 6.00 mmol) was changed, and benzyl bromide (0.15 ml, 1.25 mmol) was used instead of 2-(bromomethyl)-6-methylpyridine (372 mg, 2.00 mmol), and instead of stirring at room temperature for 1 hour, it was heated to 45° C. and stirred for 1 day. In the same manner as in Example 54-2, the target compound ( 70 , 128 mg, 21%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.11 (d, 1 H), 8.26 (s, 1 H), 7.90 (d, 1 H), 7.65 (t, 1 H), 7.17 (d, 1 H), 6.88 (d, 1 H), 6.78 (s, 2 H), 6.66 (dd, 1 H), 5.39 (s, 2 H), 2.43 (s, 3 H).

Example 71: of 2-(6-((2-amino-6-(1H-pyrazol-1-yl)-9H-purin-9-yl)methyl)pyridin-2-yl)propan-2-ol Produce

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 85 mg, 0.42 mmol) and potassium carbonate (K ₂ CO ₃ , 175 mg, 1.26 mmol) was changed, and benzyl bromide (0.15 ml, 1.25mmol) instead of 2-(6-(bromomethyl)pyridin-2-yl)propan-2-ol ( S93 , 122mg, 0.38mmol), and heated to 45℃ instead of stirring at room temperature for 1 hour Except for stirring for 2 days, the same procedure as in Example 54-2 was performed to obtain the target compound ( 71 , 42 mg, 32%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.11 (d, 1 H), 8.26 (s, 1 H), 7.90 (d, 1 H), 7.73 (t, 1 H), 7.54 (d, 1 H), 6.94 (d, 1 H), 6.75 (s, 2 H), 6.66 (dd, 1 H), 5.43 (s, 2 H), 5.17 (s, 1 H), 1.32 (s, 6 H) .

Example 72: (R)-6-(1H-pyrazol-1-yl)-9-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl) Preparation of -9H-purin-2-amine

In Example 54-2, the addition amount of the compound of Example 54-1 ( S76 , 59.15 mg, 0.29 mmol) and potassium carbonate (K ₂ CO ₃ , 122 mg, 0.88 mmol) was changed, and benzyl bromide (0.15 ml) , 1.25mmol) instead of (R)-2-(bromomethyl)-6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridine ( S94 , 61.5mg, 0.29mmol) was used, and at room temperature Instead of stirring for 1 hour, the same process as in Example 54-2 was performed, except that the mixture was heated to 45° C. and stirred for 1 day, to obtain the target compound ( 72 , 54 mg, 48%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.11 (d, 1 H), 8.26 (s, 1 H), 7.92 - 7.89 (m, 1 H), 7.78 (t, 1 H), 7.34 (d , 1 H), 7.02 (d, 1 H), 6.78 (s, 2 H), 6.67 (dd, 1 H), 5.44 (s, 2 H), 4.49 (s, 2 H), 4.25 - 4.20 (m , 1 H), 3.77 - 3.61 (m, 4 H), 1.93 (td, 2 H).

Example 73: Preparation of 1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-3-carbonitrile

Step 1: Preparation of 1-(2-amino-9H-purin-6-yl)-1H-pyrazole-3-carbonitrile

After dissolving 6-chloro-9H-purin-2-amine ( S74 , 500mg, 2.95mmol) in N,N-dimethylformamide (DMF), potassium carbonate (K ₂ CO ₃ , 448 mg, 3.24) mmol) and 1H-pyrazole-3-carbonitrile (302 mg, 3.24 mmol) were added, and the mixture was heated to 100° C. and stirred for 1 day. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain an intermediate compound ( S95 , 250 mg, 37.4%). .

¹ H-NMR (CD ₃ OD, 400 MHz): δ 8.97 (dd, 1H), 8.21 (s, 1H), 7.10 (dd, 2H).

Step 2: Preparation of 1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-3-carbonitrile

The intermediate compound ( S95 , 112.8mg, 0.50mmol) prepared in step 1 was dissolved in N,N-dimethylformamide (DMF) and 60% sodium hydride (NaH, 22mg, 0.55mmol) was added at 0° C. After stirring for 30 minutes, 2,6-difluorobenzyl bromide (124.2 mg, 0.60 mmol) was added and stirred at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was purified by silica gel chromatography to obtain the target compound ( 73 , 108 mg, 61.3%). .

¹ H-NMR (CDCl ₃ , 400 MHz): δ 9.25 (dd, 1H), 7.88 (s, 1H). 7.38 - 7.33 (m, 1H), 6.99 - 6.94 (m, 2H), 6.90 (dd, 1H), 5.39 (s, 2H).

Example 74: Preparation of 1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-4-carbonitrile

Step 1: Preparation of 1-(2-amino-9H-purin-6-yl)-1H-pyrazole-4-carbonitrile

Except for using 1H-pyrazole-4-carbonitrile (302mg, 3.24mmol) instead of 1H-pyrazole-3-carbonitrile (302mg, 3.24mmol) in step 1 of Example 73, the above Example The same process as in step 1 of 73 was performed to obtain an intermediate compound ( S96 , 285 mg, 42.7%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 7.57 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H).

Step 2: Preparation of 1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-4-carbonitrile

The intermediate compound (S96 , 150mg, 0.66mmol) prepared in step 1 was subjected to the same process as in step 2 of Example 73 to obtain the target compound ( 74 , 122mg, 52.6%).

¹ H-NMR (CD ₃ OD, 400 MHz): δ 9.53 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.46 - 7.44 (m, 1H), 7.09 - 7.05 (m, 2H) ), 5.50 (s, 2H).

Example 75: Preparation of 9-(2,6-difluorobenzyl)-6-(4-(pyridin-4-yl)-1H-pyrazol-1-yl)-9H-purin-2-amine

Step 1: Preparation of 6-chloro-9-(2,6-difluorobenzyl)-9H-purin-2-amine

In step 1 of Example 73, 6-chloro-9H-purin-2-amine ( S74 , 1.86g, 10.98mmol) and potassium carbonate (K ₂ CO ₃ , 2.28g, 16.50mmol) were added by changing the amount of , The intermediate compound ( S97 , 2.6g) was carried out in the same manner as in step 1 of Example 73, except that the mixture was stirred at room temperature instead of stirring by heating to 100°C, and the concentrate was recrystallized instead of purified by silica gel chromatography. , 80.2%) was obtained.

¹ H-NMR (DMSO-d6, 400 MHz): δ 8.09 (s, 1H), 7.49 - 7.45 (m, 1H), 7.15 (t, 2H), 6.68 (br s, 2H), 5.35 (s, 2H) .

Step 2: Preparation of 9-(2,6-difluorobenzyl)-6-(4-(pyridin-4-yl)-1H-pyrazol-1-yl)-9H-purin-2-amine

After dissolving the intermediate compound (S97 , 50mg, 0.17mmol) prepared in step 1 in N,N-dimethylformamide (DMF), potassium carbonate (K ₂ CO ₃ , 28.2 mg, 0.20 mmol) and 4-(1H-pyrazol-4-yl)pyridine (145.16mg, 0.18mmol) were added, and the mixture was heated to 100°C and stirred for 1 day. The reaction mixture was diluted with dichloromethane (DCM), washed with distilled water, dried over magnesium sulfate, filtered and concentrated, and the concentrate was recrystallized to obtain the target compound ( 75 , 42.2 mg, 61.4%).

¹ H-NMR (DMSO-d6, 400 MHz): δ 9.51 (s, 1H), 8.59 - 8.58 (m, 2H), 8.54 (s, 1H), 8.18 (s, 1H), 7.74 (dd, 2H), 7.51 - 7.47 (m, 1H), 7.17 (t, 2H), 6.82 (br s, 2H), 5.42 (s, 2H).

[Test Example]

Test Example 1: Ligand binding assay for human adenosine A2A receptor

(1) Experimental process

In order to analyze the binding of the compounds prepared in Examples 1 to 75 to the human adenosine A2A receptor, a ligand binding assay for Tag-lite® human adenosine A2A receptor was performed. Reagents were purchased from Cisbio (Tag-lite Adenosine A2A labeled Cells, ready-to-use (transformed & labeled), 200 tests* (Part# C1TT1A2A), Tag-lite Buffer (5X concentrate) 100 mL (Part# LABMED) ), Adenosine A2A Receptor red antagonist Fluorescent Ligand (Part# L0058RED)). In addition, the Tag-lite® adenosine A2A receptor ligand binding assay provided by Cisbio was performed as a homogeneous alternative to the ligand binding assay using a radioisotope when compound profiling was performed. Specifically, the assay was performed in the following order with reference to the protocol provided by Cisbio.

1-1. Prepare Working Tag-lite Buffer (TLB) 1X

After determining the amount of Tag-lite buffer 1X required for the assay, 100ml Tag-lite buffer 5X was thawed. Tag-lite buffer 1X was prepared by diluting Tag-lite buffer 5X in distilled water 5 times and gently mixed.

1-2. compound dilution

A 30 mM DMSO stock was prepared for each test substance in an Eppendorf tube. 20ul each of the 30mM DMSO stock was transferred to a 96-well plate, and then serially diluted 1/10 from 30mM to 0.003uM using DMSO. The test substances serially diluted in each 96 well were transferred to another 96-well plate by 2ul using a multichannel pipette (Integra, VOYAGER pipette), and then 148ul of TLB 1X was added to prepare a 4X working solution.

1-3. Fluorescent ligand preparation

The given fluorescent ligand concentration was indicated on the vial label. After centrifuging the ligand vial, a working solution of 80 nM was prepared by diluting the fluorescent ligand stock with TLB 1X based on the concentration indicated on the vial label.

1-4. Preparation of unlabeled ligand

In order to confirm a non-specific signal, DMSO stock for unlabeled ligand (unlabeled ligand, ZM241,385) was prepared in an Eppendorf tube, and a 100X working solution stock (40uM) was prepared using TLB 1X.

1-5. Cell thawing and preparation

A falcon tube containing 5 mL of cold TLB 1X was prepared. Labeled frozen cells (1 vial) were manually stirred in a water bath at 37°C for 1-2 min until all ice was melted. Thawed cells were rapidly transferred by pipetting into Falcon tubes containing TLB 1X. Centrifugation was performed at 1200G for 5 minutes. After gently removing the supernatant by suction, the remaining pellet was suspended using 1ml 1X TLB. Afterwards, gently mix by pipetting up and down several times. 1.7 ml of 1X TLB was added and gently mixed again by pipetting up and down several times. The cells were briefly stored at room temperature for the next procedure.

1-6. Competitive binding analysis

First, 10ul of the cells thawed in 1-5 were dispensed into 384 wells (Greiner bio, 784075) designated with a mechanical multichannel pipette (Integra, VOYAGER pipette). As soon as each of the test substances diluted in 1-2 was suspended with a multi-channel pipette for 96 wells, 5ul was dispensed into designated 384 wells using a mechanical multi-channel pipette (Integra, VOYAGER pipette). To confirm specific binding, 5ul of TLB 1X and 5ul of the solution prepared in 1-4 were also dispensed into designated 384 wells, respectively. 5ul of the fluorescent ligand working solution prepared in 1-3 was dispensed into designated 384wells. After reacting at room temperature for 1 hour, a 384-well plate was inserted into a plate reader (Biotek, Synergy H4), and the signal was analyzed.

1-7. data analysis

The acceptor and donor emission signals of each well were calculated by the following equation. The HTRF ratio for each concentration calculated for each test substance was entered into Sigmaplot 12.5, and K _i for each test substance was calculated.

[Equation 1]

(2) Experimental results

The results of the ligand binding assay for the human adenosine A2A receptor are shown in Table 1 below.

Example hA2A K _i (nM) Example hA2A K _i (nM) 3 A 57 A 7 B 59 A 8 A 60 A 9 C 61 C 10 A 62 A 11 B 63 B 13 B 64 A 14 C 65 B 15 C 67 A 17 A 68 C 40 A 69 A 41 A 70 C 42 B 71 C 43 B 72 C 54 B 73 C 55 C 74 A 56 C

On the other hand, the classification range of the ligand binding assay results for human adenosine A2A receptor in Table 1 is as follows.

- A : K _i ≤ 25 nM

- B : 25 nM < K _{i ≤ 100} nM

- C : K _i > 100 nM

As shown in Table 1 above, Examples 3, 8, 10, 17, 40, 41, 57, 59, 60, 62, 64, 67, 69, 74 binding to A2A receptor K _i ≤ 25 nM level was confirmed in

The above description of the present invention is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive.

Claims (13)

A compound of formula (I), a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof:
[Formula I]

In the above formula (I),
Cy contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl or heterocycloalkyl ring;
R is a phenyl group or a pyridine group substituted with _{R 1} , R ₂ and R _{3 ;}
R ₁ , R ₂ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, carbonyl group, amide group, nitro group, amino group, substituted or unsubstituted C ₁ -C ₅ alkyl group, substituted or unsubstituted C ₂ -C ₅ alkenyl group, substituted or unsubstituted C ₂ -C ₅ alkynyl group, substituted or unsubstituted C ₁ -C ₃ haloalkyl group, substituted or unsubstituted C ₁ -C ₃ aminoalkyl group, or substituted or an unsubstituted C ₁ -C ₅ alkoxy group;
R' is hydrogen, halogen, cyano group, substituted or unsubstituted C ₁ -C ₅ alkyl group, substituted or unsubstituted C ₂ -C ₅ alkenyl group, substituted or unsubstituted C ₂ -C ₅ alkynyl group, substituted or unsubstituted C _3- C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ -C ₁₀ aryl, or substituted or unsubstituted C ₄ -C ₁₀ heteroaryl;
Het is a 5-membered heteroaryl or heterocycloalkyl ring containing 1 to 3 nitrogen atoms, substituted with _{R 4} , R ₅ and R _{6 ;} and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, substituted or unsubstituted C ₁ -C ₅ alkyl group, substituted or unsubstituted C ₂ -C ₅ alkenyl group, substituted an unsubstituted C ₂ -C ₅ alkynyl group, a substituted or unsubstituted C ₁ -C ₃ haloalkyl group, a substituted or unsubstituted C ₃ -C ₈ cycloalkyl group, a substituted or unsubstituted C ₃ -C ₁₀ aryl, or substituted or unsubstituted C ₄ -C ₁₀ heteroaryl. The method according to claim 1,
Cy contains one or more heteroatoms selected from nitrogen, oxygen and sulfur, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl ring;
R is a phenyl group or a pyridine group substituted with _{R 1} , R ₂ and R _{3 ;}
R ₁ , R ₂ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, amino group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C _{3 is a} haloalkyl group, a C ₁ -C ₃ aminoalkyl group, or a C ₁ -C ₅ alkoxy group;
R' is hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₃ -C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl;
Het is a pyrazole group or a triazole group substituted with _{R 4} , R ₅ and R _{6 ;} and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ - A compound of Formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, which is a C ₃ haloalkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₁₀ aryl, or a C ₄ -C _{10 heteroaryl.} The method according to claim 1,
Cy contains one or more nitrogen atoms, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl ring;
R is

or

as, bonded to the nitrogen atom of Cy;
R ₁ , R ₂ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, amino group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C _{3 is a} haloalkyl group, a C ₁ -C ₃ aminoalkyl group, or a C ₁ -C ₅ alkoxy group;
R' is bonded to a carbon atom of Cy, hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl;
Het

or

ego; and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ - A compound of Formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, which is a C ₃ haloalkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₁₀ aryl, or a C ₄ -C _{10 heteroaryl.} The method according to claim 1,
Cy contains one or more nitrogen atoms, and together with the atoms in the pyrimidine ring bonded to Cy, form a 5-membered heteroaryl ring;
R is

or

as, bonded to the nitrogen atom of Cy;
R ₁ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, or a C ₁ -C ₅ alkoxy group, and R ₂ is hydrogen, halogen, an amino group or a C ₁ -C ₅ alkoxy group;
R' is bonded to a carbon atom of Cy, hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl;
Het

or

ego; and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ - A compound of Formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, which is a C ₃ haloalkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₁₀ aryl, or a C ₄ -C _{10 heteroaryl.} 5. The method according to claim 4,
R ₁ and R ₃ are independently hydrogen, halogen, hydroxy group, C ₁ -C ₅ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₅ alkoxy group, and R ₂ is hydrogen, halogen, amino group, or a C ₁ -C ₅ alkoxy group;
R' is bonded to a carbon atom of Cy and is hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkynyl group, C ₃ -C ₈ cycloalkyl group; and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, cyano group, C ₁ -C ₅ alkyl group, C ₁ -C ₃ haloalkyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl , or C ₄ -C ₁₀ heteroaryl, a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof. The method according to claim 1,
Cy together with the atom in the pyrimidine ring bonded to Cy forms pyrazolopyrimidine, or purine;
R is

or

as, bonded to the nitrogen atom of Cy;
R ₁ and R ₃ are independently hydrogen, halogen, hydroxyl group, thiol group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ -C ₃ haloalkyl group, or a C ₁ -C ₅ alkoxy group, and R ₂ is hydrogen, halogen, an amino group or a C ₁ -C ₅ alkoxy group;
R' is bonded to a carbon atom of Cy, hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl, or C ₄ -C ₁₀ heteroaryl;
Het

or

ego; and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, thiol group, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkenyl group, C ₂ -C ₅ alkynyl group, C ₁ - A compound of Formula I, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof, which is a C ₃ haloalkyl group, a C ₃ -C ₈ cycloalkyl group, a C ₃ -C ₁₀ aryl, or a C ₄ -C _{10 heteroaryl.} 7. The method of claim 6,
R ₁ and R ₃ are independently hydrogen, halogen, hydroxy group, C ₁ -C ₅ alkyl group, C ₁ -C ₃ haloalkyl group, or C ₁ -C ₅ alkoxy group, and R ₂ is hydrogen, halogen, amino group, or a C ₁ -C ₅ alkoxy group;
R' is bonded to a carbon atom of Cy and is hydrogen, halogen, cyano group, C ₁ -C ₅ alkyl group, C ₂ -C ₅ alkynyl group, C ₃ -C ₈ cycloalkyl group; and
R ₄ , R ₅ and R ₆ are independently hydrogen, halogen, hydroxyl group, cyano group, C ₁ -C ₅ alkyl group, C ₁ -C ₃ haloalkyl group, C _{3 -} C ₈ cycloalkyl group, C ₃ -C ₁₀ aryl , or C ₄ -C ₁₀ heteroaryl, a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof. The compound of formula (I), solvate, stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, which is selected from the group consisting of:
1-benzyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-3-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
4-(1H-pyrazol-1-yl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-fluoro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2-fluoro-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2-fluoro-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(3,5-bis(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-methoxy-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(3-methoxy-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2-methoxy-5-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2-methoxy-3-(trifluoromethyl)benzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-3-methylbenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
(S)-4-(1H-pyrazol-1-yl)-1-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-1H-pyra zolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(3-(tert-butyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;
1-(4-amino-2-fluorobenzyl)-4-(3-cyclopropyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(3-phenyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- 6-amine;
1-(4-amino-2-fluorobenzyl)-4-(4-chloro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(4-bromo-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyri midin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine ;
1-(4-amino-2-fluorobenzyl)-4-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d ]pyrimidin-6-amine;
1-(4-amino-2-fluorobenzyl)-4-(3-methyl-1H-1,2,4-triazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine -6-amine;
1-benzyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
4-(3-methyl-1H-pyrazol-1-yl)-1-(2,3,6-trifluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;
1-(4-amino-3-fluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(4-amino-3-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;
1-(4-amino-2-(trifluoromethyl)benzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;
3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-fluoro phenol;
3-((6-amino-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)phenol;
1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;
1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-fluoro-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine- 6-amine;
1-(4-amino-3-(trifluoromethyl)benzyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d ]pyrimidin-6-amine;
1-(6-amino-1-(2,6-difluorobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1H-pyrazol-4-ol;
1-(2,6-difluorobenzyl)-3-methyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2,6-difluorobenzyl)-3-methyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;
1-(2,6-difluorobenzyl)-3-ethyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2,6-difluorobenzyl)-3-ethyl-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6- amines;
3-cycloropropyl-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
3-cyclopropyl-1-(2,6-difluorobenzyl)-4-(3-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine -6-amine;
1-(2,6-difluorobenzyl)-3-ethynyl-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
1-(2,6-difluorobenzyl)-3-ethynyl-4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-6 -amines;
3-chloro-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine;
6-amino-1-(2,6-difluorobenzyl)-4-(1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carbonitrile;
9-benzyl-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
6-(1H-pyrazol-1-yl)-9-(pyridin-2-ylmethyl)-9H-purin-2-amine;
9-(4-aminobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(3,5-bis(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-2-fluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-3-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-2-(trifluoromethyl)benzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-2,6-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-2,3-difluorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-3-chlorobenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-2-fluoro-5-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-2-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-3-methylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-3,5-dimethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-(4-amino-3-ethylbenzyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
9-((6-methylpyridin-2-yl)methyl)-6-(1H-pyrazol-1-yl)-9H-purin-2-amine;
2-(6-((2-amino-6-(1H-pyrazol-1-yl)-9H-purin-9-yl)methyl)pyridin-2-yl)propan-2-ol;
(R)-6-(1H-pyrazol-1-yl)-9-((6-(((tetrahydrofuran-3-yl)oxy)methyl)pyridin-2-yl)methyl)-9H-purine -2-amine;
1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-3-carbonitrile;
1-(2-amino-9-(2,6-difluorobenzyl)-9H-purin-6-yl)-1H-pyrazole-4-carbonitrile; and
9-(2,6-difluorobenzyl)-6-(4-(pyridin-4-yl)-1H-pyrazol-1-yl)-9H-purin-2-amine. A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound of any one of claims 1 to 8, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 9, wherein the composition is adenosine A2A receptor (Adenosine A2A receptor) will exhibit an antagonistic action, the pharmaceutical composition. The method according to claim 9, wherein the cancer is lung cancer, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma Tumor, multiple myeloma, Ewing's sarcoma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer, the pharmaceutical composition. The pharmaceutical composition of claim 9, wherein the composition is administered in combination with other anticancer agents simultaneously, separately, or sequentially. The pharmaceutical composition of claim 9, wherein the composition is formulated in a pharmaceutically acceptable form including tablets, pills, powders, capsules, syrups, emulsions or microemulsions.