KR20230104041A - Pyrazolopyrimidine derivatives and pharmaceutical composition for anticancer containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of tumors containing a novel pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient, including use in combination with other anticancer agents to prevent or treat cancer It can be usefully used as a composition for treatment.

Description

Pyrazolopyrimidine derivatives and pharmaceutical composition for anticancer containing the same as an active ingredient {Pyrazolopyrimidine derivatives and pharmaceutical composition for anticancer containing the same as an active ingredient}

The present invention provides a pharmaceutical composition for preventing or treating tumors containing a novel pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient as a TTK inhibitor, and a pharmaceutical composition for treating tumors with the pyrazolopyrimidine compound as an active ingredient. It relates to a health food composition for the prevention or improvement of.

Among the therapeutic agents used in the treatment of cancer are taxanes and vinca alkaloids that act on microtubules to stabilize or destabilize microtubule dynamics. They perturb normal mitotic spindle action, preventing correct chromosome attachment, and inducing mitotic arrest. This halt is enforced by the spindle assembly checkpoint and prevents the separation of sister chromatids to form two daughter cells. Prolonged arrest in mitosis either pushes the cell to mitotic exit without cytokinesis, or drives it into mitotic catastrophe, leading to cell death.

Although mitotic agents are widely used in the treatment of solid tumors, the side effects associated with these agents and the resistance of many types of tumors to current therapies require the development of new pharmaceutical compositions in the treatment of cancer.

The role played by genes involved in the spindle assembly checkpoint in normal development and their potential role in diseases such as cancer has been extensively studied (Weaver BA et al.,; Musacchio A et al.,). Many components are phosphorylated during mitosis, several of which are kinases, one of which is the dual specificity kinase TTK. TTK expression is associated with highly proliferative cells and tissues with overexpression observed in many cancer cell lines and tumor types, and TTK silencing in several species indicates its essential function in spindle assembly checkpoint signaling. Prevents cells from undergoing mitotic arrest in response to poison (Abrieu A et al.,; Stucke, VM et al.,).

These findings suggest that pharmacological inhibitors of TTK and other components of the spindle assembly checkpoint may be of therapeutic value in the treatment of proliferative diseases, including solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies. In addition, TTK inhibitors would be useful in the treatment of other disorders associated with uncontrolled cell proliferation.

TTK/Mps1, a dual specificity protein kinase, is a master regulator of mitosis, and its expression is increased in tumors of various patients, so TTK inhibitors are being actively reviewed for their potential as anticancer agents from various angles. .

Under this background, the inventors of the present invention measured the degree of inhibition of various kinase activities through a panel assay and confirmed the inhibition of pTTK expression in triple-negative breast cancer and colorectal cancer cells. The present invention was completed by identifying a novel compound with a pyrazolopyrimidine skeleton that strongly inhibits TTK and exhibits excellent kinase selectivity.

Abrieu A et al., Cell, 2001, 106, 8393 Musacchio A et al., Nat. Rev. Mol. Cell Biol., 2007, 8, 379-393 Stucke, VM et al., EMBO J., 2002, 21, 1723-1732 Weaver BA et al., Cancer cell, 2005, 8, 712

An object of the present invention is to provide a novel structured pyrazolopyrimidine skeleton compound that strongly inhibits TTK and has excellent selectivity for TTK.

The present invention relates to a compound comprising the following [Formula 1] consisting of a pyrazolopyrimidine derivative, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[Formula 1]

In the above formula,

R ₁ is a substituted or unsubstituted C ₆ -C ₁₂ aryl, a substituted or unsubstituted 5 to 12 membered heteroaryl, or a substituted or unsubstituted 5 to 12 membered heterocycloalkyl;

The substituted aryl, heteroaryl or heterocycloalkyl means that at least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ Alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C(=O), carbamoyl, C ₁ -C ₆ alkylaminoketone, C ₁ -C ₆ alkyloxycarbonyl, C ₁ -C ₆ alkyl substituted with sulfonamino or C ₃ -C ₆ cycloalkylaminoketone;

R ₂ is substituted or unsubstituted -NH-(C ₆ -C ₁₂ )aryl, substituted or unsubstituted -NH-(C ₃ -C ₆ )cycloalkyl, or substituted or unsubstituted -NH-(C ₃ -C ₆ )heterocycloalkyl, -NH-(CH ₂ ) _m -(C ₃ -C ₆ )heterocycloalkyl;

m is an integer of 0, 1 or 2; am.

The substituted aryl, cycloalkyl or heterocycloalkyl means that at least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halo C ₁ -C ₆ substituted with alkoxy;

R ₃ is substituted or unsubstituted -NH-(C ₆ -C ₁₂ )aryl or substituted or unsubstituted -NH-(C ₃ -C ₆ )cycloalkyl;

The substituted aryl or cycloalkyl means that at least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted triazole, C ₁ -C ₆ alkylaminoketone, substituted or unsubstituted - substituted with C(=0)-morpholine, substituted or unsubstituted -C(=0)-piperazine or substituted or unsubstituted -C(=0)NH-piperidine;

The substituted morpholine, piperazine, triazole, -C(=O)-morpholine, -C(=O)-piperazine or -C(=O)NH-piperidine has one or more hydrogens independently substituted by halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; do.

In addition, the present invention relates to a compound that is the following [Formula 2-1], or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[Formula 2-1]

In the above formula,

R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted isoxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole or substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzoimidazole, substituted or unsubstituted indazole, or substituted or unsubstituted benzoxazole;

The above substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole or 1,3,4- Oxadiazolone is a compound in which one or more hydrogens in the ring are independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ substituted with a cycloalkylaminoketone;

R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;

, 또는

로 치환되며; E is -NHR ₄ ;

, or

substituted with;

A is substituted with NH;

B is substituted with O, S or CH ₂ ;

D is substituted with O or NR ₄ ;

m is an integer of 0, 1 or 2;

n is an integer of 0 or 1;

In addition, the present invention relates to a compound that is the following [Formula 2-2], or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[Formula 2-2]

In the above formula,

R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced with;

R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;

, 또는

로 치환되며; E is -NHR ₄ ;

, or

substituted with;

D is substituted with O or NR ₄ ;

m is an integer of 0, 1 or 2;

n is an integer of 0 or 1;

In addition, the present invention relates to a compound that is the following [Formula 3-1], or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[Formula 3-1]

In the above formula,

R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced with;

R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;

D is substituted with O or NR ₄ ;

A is substituted with NH;

B is substituted with O, S or CH ₂ ;

n is an integer of 0 or 1;

In addition, the present invention relates to a compound that is the following [Formula 3-2], or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[Formula 3-2]

In the above formula,

R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced with;

R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;

D is substituted with O or NR ₄ ;

n is an integer of 0 or 1;

m is an integer of 0, 1 or 2;

In addition, the present invention is the [Formula 1], [Formula 2-1], [Formula 2-2], [Formula 3-1], [Formula 3-2] compound, or a hydrate, solvate, prodrug or It relates to a compound that is a pharmaceutically acceptable salt thereof.

[Formula 1], [Formula 2-1], [Formula 2-2], [Formula 3-1] or [Formula 3-2],

R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced by;

The preparation method and reaction conditions of the pyrazolopyrimidine skeleton compounds having various structures represented by Chemical Formula 1 of the present invention are as follows.

[Formula 1]

The compounds of the pyrazolopyrimidine skeleton represented by Formula 1 of the present invention are preferably the following [Scheme 1], [Scheme 2], [Scheme 3], [Scheme 4], [Scheme 5], [Scheme 6], [ It can be prepared by Reaction Scheme 7] or [Reaction Scheme 8].

[Scheme 1]

[Scheme 2]

[Scheme 3]

[Scheme 4]

[Scheme 5]

[Scheme 6]

[Scheme 7]

[Scheme 8]

In addition, in the present invention, the compound represented by Formula 1 relates to a compound, characterized in that any one selected from the group of compounds below, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

N ⁴ -cyclohexyl-3-(5-fluoropyridin-3-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine -4,6-diamine (Compound 8-1);

3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzamide (Compound 8-2);

methyl 4-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo Eight (Compound 8-3);

N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl )phenyl)cyclopropanecarboxamide (compound 8-4);

3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N -Methylbenzamide (Compound 8-5);

N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl )phenyl)methanesulfonamide (compound 8-6);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-7);

N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 8-8);

N ⁴ -Cyclohexyl-N ⁶ -(4-morpholinocyclohexyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-9);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (compounds 8-10);

N ⁴ -Cyclohexyl-3-(1-isopropyl-1H-imidazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 8-11);

N ⁴ -cyclohexyl-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[ 3,4-d] pyrimidine-4,6-diamine (Compound 8-12);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-13);

N ⁴ -cyclohexyl-3-(furan-2-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6 -diamines (compounds 8-14);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4; 6-diamine (compounds 8-15);

3-(1H-benzo[d]imidazol-5-yl)-N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-16);

N ⁴ -Cyclohexyl-3-(1H-indazol-5-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine (compounds 8-17);

N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 8-18);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-19);

N ⁴ -cyclohexyl-3-(isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4; 6-diamine (compounds 8-20);

3-(Isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[ 3,4-d] pyrimidine-4,6-diamine (Compound 8-21);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-2-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3 ,4-d] pyrimidine-4,6-diamine (Compound 8-22);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-23);

3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ -(tetrahydro-2H-pyran- 4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-24);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-25);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1H-pyrazol-4-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 8-26);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyridin-3-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3, 4-d] pyrimidine-4,6-diamine (Compound 8-27);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyridin-4-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3, 4-d] pyrimidine-4,6-diamine (Compound 8-28);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyrimidin-5-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3 ,4-d] pyrimidine-4,6-diamine (Compound 8-29);

N ⁴ -Cyclohexyl-3-(1-methyl-1H-pyrazol-4-yl)-N ⁶ -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine (compounds 8-30);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 11-1);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(1-methyl-1H-pyra zol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 11-2);

4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3-methoxy-N-methylbenzamide (compound 11-3);

(4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3-methoxyphenyl)(morpholino)methanone (Compound 11-4);

(4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (Compound 11-5);

4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 11-6);

N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 14-1);

N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 14-2);

5-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1 ,3,4-oxadiazol-2(3H)-one (Compound 14-3);

N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4; 6-diamine (compound 18-1);

N ⁴ -Cyclohexyl-3-(1H-imidazol-5-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine (Compound 18-2);

N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4 -d] pyrimidine-4,6-diamine (Compound 21-1);

N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 21-2);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-N ⁴ -(tetrahydro-2H-pyran -4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 21-3);

N ⁴ -Cyclohexyl-N ⁶ -(2-isopropoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 26-1);

4-(Cyclohexyloxy)-N-(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4 -d]pyrimidin-6-amine (Compound 26-2);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ -(1-methylpiperidin-4-yl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 28-1);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-5-yl)-N ⁴ -(tetra-2H-pyran-4-yl)-1H-pyrazolo[3, 4-d] pyrimidine-4,6-diamine (Compound 33-1);

3-methoxy-N-methyl-4-((3-(oxazol-5-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4 -d]pyrimidin-6-yl)amino)benzamide (Compound 33-2);

N ⁶ -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(oxazol-5-yl)-N ⁴ -(tetra hydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 33-3);

N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ -((tetrahydrofuran-2-yl)methyl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-34); and

3-(Isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ -((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3 ,4-d] pyrimidine-4,6-diamine (Compound 8-35);

Another aspect of the present invention is the prevention of cancer comprising a therapeutically effective amount of the compound represented by Formula 1, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier thereof. Or it provides a pharmaceutical composition for treatment.

In another aspect of the present invention, the compound has inhibitory activity against one or more protein kinases selected from the group consisting of TTK (h), ALK (h), IR (h) activated, IRR (h), and LTK (h) It provides a pharmaceutical composition for preventing or treating cancer, which is characterized in that it represents.

Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, wherein the compound exhibits inhibitory activity against TTK kinase.

Another aspect of the present invention provides a synergistic anti-cancer effect by co-administration of the compound represented by Formula 1 with other anti-cancer drugs, preferably other anti-cancer agents selected from taxane-based anti-cancer agents (paclitaxel, docetaxel, cabazitaxel). Provides a synergistic anti-cancer effect and composition with combined administration.

The other anti-cancer drugs include anti-tumor alkylating agents, anti-tumor antimetabolites, anti-tumor antibiotics, plant-derived anti-tumor agents, anti-tumor platinum complexes, anti-tumor camptothecin derivatives, anti-tumor kinase inhibitors, anti-tumor antibodies, hormonal anti-tumor agents. oncology agents, antitumor viral agents, or angiogenesis inhibitors.

The antitumor alkylating agent is nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide or carmu I'm Steen

The anti-tumor antimetabolite is methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifuridine, camofur, cytarabine, cytarabine oxphosphate, enocitabine , S-1, gemcitabine, fludarabine or pemetrexed disodium;

The antitumor antibiotics include actinomycin D, doxorubicin, daunorubicin, neocazinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pyrarubicin, epirubicin, ginostatin stimalamer, idarubicin, sirolimus or valrubicin;

the plant-derived antitumor agent is vincristine, vinblastine, vindesine, etoposide, sotrizoic acid, docetaxol, paclitaxel or vinorelbine;

the anti-tumor platinum complex is cisplatin, carboplatin, nedaplatin or oxaliplatin;

the antitumor camptothecin derivative is irinotecan, topotecan or camptothecin;

The anti-tumor kinase inhibitor is gefitinib, imatinib or erlotinib,

The anti-tumor antibody is cetuximab, bevacizumab, rituximab, bevacizumab, alemtuzumab or trastuzumab,

The hormonal antitumor agent is goserelin, leuprolide or tamoxifen,

The anti-tumor viral agent is Imlygic,

The angiogenesis inhibitors include avastin, bevacizumab, ranibizumab, pegaptanib, aflibercept, axitinib, cabozantinib, aflibercept, brivanib, tivozanib, Ramucirumab or motesanib.

In addition, the following terms in the present invention have the following meanings unless otherwise indicated. Any term not defined has an art-understood meaning.

The term “alkyl” refers to a single-bonded straight or branched hydrocarbon group having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl and hexyl.

The term “alkoxy” refers to an oxygen group to which a single bonded straight or branched saturated hydrocarbon having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms is bonded, and includes methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.

The term "alkoxyalkoxy" refers to an alkoxy group in which one or more hydrogen atoms of an alkoxy group are replaced by another alkoxy group, and alkoxy is as defined above.

The terms “halo” and “halogen” are used in their conventional sense to refer to fluoro, chloro, bromo or iodo substituents.

The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a halo group, and the alkyl and halo groups are as defined above.

The term “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group have been replaced with a halo group, and halo and alkoxy are as defined above.

The term "cycloalkyl" refers to a saturated hydrocarbon group having a single bond in a ring shape. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, adamantyl, nor including, but not limited to, bornyl and the like.

The term "aryl" means an aromatic substituent having at least one ring having a covalent pi electron system, and includes, but is not limited to, phenyl, benzyl, naphthyl, anthryl, indanyl, biphenyl, triphenyl, etc. don't

The term "heterocycloalkyl" refers to a ring-shaped single-bond saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and depends on the number and type of heteroatoms included in the ring and the number of carbon atoms. Ridinyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinil, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanil, diazepanil, oxazepanil, thia Zephanil, dioxothiazepanil, azetidinyl, azocanyl, tetrahydrofuranil, tetrahydroisoquinolinyl, tetrahydropyranil, tetrahydrobenzo[b]thiophenyl, oxazolidinyl, dioxanil, dioxolanil, azaspiro[5.5]undecanyl, azaspiro[3,3]heptanyl, or azaspiro[3.5]nonanyl and the like.

The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms included in the ring and the number of carbon atoms, pyridyl, pyrrolyl, Rolidinyl, pyridinyl, furanyl, quinolidinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl , thiazolyl, dibenzothiophenyl, dibenzofuranyl, dibenzoselenophene, thiophene, benzofuran, benzothiophenyl, benzoselenophenyl, carbazolyl, indolocarbazolyl, pyridylindolyl, Pyrrolodipyridinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl ; yl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, pteridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzofuropyridinyl, furodipyridine yl, benzoimidazolyl, benzoxazolyl, benzothienopyridinyl, thienodipyridinyl, benzoselenophenopyridinyl and selenophenodipyridinyl, and the like, but are not limited thereto.

In the present invention, the pharmaceutically acceptable salt means a salt or complex of Formula 1 having a desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid , salts formed with organic acids such as benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxyl rates (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinamoates, mandeloates and diphenylacetate). The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The present invention relates to a pharmaceutical composition for preventing or treating cancer using a pyrazolopyrimidine derivative.

The cancer means solid cancer or hematological cancer, and the solid cancer is brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, Oropharyngeal cancer, nasal cavity cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, oral squamous cell carcinoma, Barrett's esophageal epithelial sequelae, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, nerve Gliomas, breast cancer, male breast cancer, triple negative breast cancer (TNBC), sporadic breast cancer (BLC), abdominal tumor, stomach cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), small intestine cancer, colon cancer, anus Cancer, colon mucosal cell adenoma, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, ovarian adenocarcinoma, uterine sarcoma, vulvar intraepithelial tumor, vaginal cancer, external female It may be selected from the group consisting of genital cancer, female urethral cancer and skin cancer, but is not particularly limited thereto. In addition, the blood cancer may be selected from the group consisting of leukemia, malignant lymphoma, multiple myeloma, and aplastic anemia, but is not particularly limited thereto.

The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a generally used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans. In addition, the composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods.

Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. When formulated, it is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the compound of the present invention, for example, starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions for oral use, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used. In order to formulate a formulation for parenteral administration, the pyrazolopyrimidine derivative compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized, or an adjuvant such as a preservative, a stabilizer, a hydrating agent or an emulsification accelerator, a salt or buffer for osmotic pressure control , and other therapeutically useful substances may be mixed in water to prepare a solution or suspension, which may be prepared as an ampoule or vial unit dosage form.

A pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection. The dose depends on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the type of other drug used, and the prescription It will depend on judgment, etc. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.

In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of cancer.

The present invention provides a pharmaceutical composition for preventing or treating tumors containing a novel pyrazolopyrimidine compound or a pharmaceutically acceptable salt thereof as an active ingredient as a TTK inhibitor, and a pharmaceutical composition for treating tumors with the pyrazolopyrimidine compound as an active ingredient. It relates to a health food composition for preventing or improving, and can be usefully used as a composition for preventing or treating cancer.

Figure 1 summarizes the results of luminescence of specific proteins induced using a chemiluminescence enhancement kit to confirm the suppression of pTTK expression in MDA-MB-231 cells.
FIG. 2 summarizes the results of luminescence of a specific protein induced using a chemiluminescence enhancement kit to confirm suppression of pTTK expression in HCT116 cells.
Figure 3 shows the results of observing the size of cancer over time for a drug administration control group, a CFI-402257 treatment group, and an example treatment group according to the present invention in nude mice injected with MDA-MB-231 cell line. It is a graph that represents
Figure 4 shows the results of observation of changes in mouse body weight over time for a drug administration control group, a CFI-402257 treatment group, and an example treatment group according to the present invention in nude mice injected with MDA-MB-231 cell line. It is a graph that represents
Figure 5 shows the results of evaluation of cytotoxicity when an example compound according to the present invention and paclitaxel were applied to TTK-expressed MDA-MB-231 cells.
6 is a result of measuring changes in cell cycle distribution when an example compound according to the present invention and paclitaxel were applied to TTK-expressing MDA-MB-231 cells.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<Example A. Preparation of compound 8 according to Scheme 1>

[Scheme 1]

Preparation Example 1. Synthesis of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (Compound 2)

After dissolving compound 1 (4.63 g, 21.89 mmol) in methanol (MeOH; 94 mL) with stirring at -12°C, hydrazine monohydrate (NH ₂ NH ₂ H ₂ O; 1.2 mL, 24.08 mmol) was added to MeOH (10 mL) and added dropwise for 30 minutes. After dissolving triethylamine (TEA; 3.2 mL, 22.55 mmol) in MeOH (10 mL), the mixture was added dropwise at -12 °C for 30 minutes and stirred at room temperature for 40 minutes. The mixture was concentrated under reduced pressure, washed with ethyl acetate (EA; 30 mL), and the filtrate was concentrated under reduced pressure. After dissolving the residue in dichloromethane (MC; 7 mL), hexane (Hexane (Hx); 10 mL) was added to remove the resulting solid by filtration, and after concentration under reduced pressure, silica gel column chromatography (EA: Hx = 2: 3) to obtain 3.20 g of compound 2 as a pale yellow solid (77%).

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.50 (s, 1H), 14.64 (s, 1H).

Preparation Example 2. Synthesis of 3-bromo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (Compound 3)

After dissolving compound 2 (15.0 g, 79.30 mmol) in acetonitrile (MeCN; 150 mL), N-bromosuccinimide (NBS; 15.52 g, 87.23 mmol) was added and stirred at 70 ^° C for 15 hours. did After concentrating the mixture under reduced pressure, EA (150 mL) was added to the residue, washed with water (100 mL), dried with sodium sulfate (Na ₂ SO ₄ ), concentrated under reduced pressure, and silica gel column chromatography (EA:Hx = 1:8) to obtain 19.50 g (91%) of compound 3 as a white solid.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 14.97 (s, 1H).

Preparation Example 3-1. Synthesis of 3-Bromo-6-chloro-N-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 4-1)

After compound 3 (5.0 g, 18.60 mmol) was dissolved in ethanol (EtOH; 250 mL), N,N-diisopropylethylamine (DIPEA; 4.2 mL, 24.18 mmol) was added and cyclohexylamine (2.75 mL, 24.18 mmol) was added. ) was added dropwise for 3 minutes at -15 ° C and then stirred at room temperature for 21 hours. EA (100 mL) and tetrahydrofuran (THF; 20 mL) were added to the reactant, washed with water (40 mL), and the aqueous layer (40 mL) was extracted with EA (20 mL). The organic layers were combined, washed with brine (30 mL), dried, and then concentrated under reduced pressure (Na ₂ SO ₄ ). The residue was purified by silica gel column chromatography (EA:Hx = 1:8) to give 4.19 g (67%) of compound 4-1 as a white solid.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.16-1.26 (m, 1H), 1.32-1.42 (m, 2H), 1.44-1.53 (m, 2H), 1.56-1.64 (m, 1H), 1.68–1.76 (m, 2H), 1.86–1.94 (m, 2H), 4.02–4.14 (m, 1H), 6.70 (d, J = 8.1 Hz, 1H), 13.97 (br s, 1H).

Preparation Example 3-2. Synthesis of 3-Bromo-6-chloro-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 4-2)

Compound 3 (400 mg, 1.49 mmol) with 4-amino tetrahydropyrene (181 mg, 1.79 mmol), 286 mg of compound 4-2 was obtained as a white solid (57%) by the same method as for compound 4-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.67-1.92 (m, 4H), 3.44 (td, J = 11.6, 2.6 Hz, 2H), 3.84-3.95 (m, 2H), 4.23-4.40 (m , 1H), 6.90 (d, J = 7.9 Hz, 1H), 14.00 (s, 1H).

Preparation Example 3-3. Synthesis of 3-Bromo-6-chloro-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 4-3)

Compound 3 (400 mg, 1.49 mmol), 4-amino-1-methylpiperidine (204 mg, 1.79 mmol), 220 mg of compound 4-3 was obtained as a white solid (42%) by the same method as for compound 4-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.68-1.82 (m, 2H), 1.83-1.93 (m, 2H), 2.06-2.18 (m, 2H), 2.22 (s, 3H), 2.72-2.82 (m, 2H), 4.04–1.15 (m, 1H), 6.80 (d, J = 7.9 Hz, 1H).

Preparation Example 3-4. Synthesis of 3-Bromo-6-chloro-N-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 4-4)

Compound 3 (3g, 11.20mmol) was prepared from (tetrahydrofuran-2-yl)methanamine (1.38mL, 13.44mmol) in the same manner as for Compound 4-1 to obtain 1.9g of Compound 4-4 as a white solid (51%). .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.54 - 1.66 (m, 1H), 1.85 (s, 3H), 3.53 - 3.70 (m, 3H), 3.81 (s, 1H), 4.10 (s, 1H) ), 7.22 (s, 1H).

Preparation Example 4-1. Synthesis of 3-Bromo-6-chloro-N-cyclohexyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 5-1)

After dissolving compound 4-1 (4.19 g, 12.67 mmol) and cesium carbonate (Cs ₂ CO ₃ ; 4.95 g, 15.20 mmol) in N,N-dimethylformamide (DMF; 63 mL), p-methyl Toxybenzyl chloride (PMBCl; 1.80 mL, 13.30 mmol) was added dropwise and stirred at 30° C. for 12 hours. EA (150 mL) was added to the mixture, washed with water (80 mL), and the aqueous layer was extracted with EA (40 mL). The organic layers were combined, washed with water (20 X 2 mL), dried, and then concentrated under reduced pressure (Na ₂ SO ₄ ). The residue was separated by silica gel column chromatography (EA:Hx = 1:9) to give 3.71 g (64%) of compound 5-1 as a white solid.

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.14-1.25 (m, 1H), 1.31-1.42 (m, 2H), 1.44-1.58 (m, 2H), 1.56-1.64 (m, 1H), 1.68-1.76 (m, 2H), 1.86-1.92 (m, 2H), 3.72 (s, 3H), 4.05-4.14 (m, 1H), 5.34 (s, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H).

Preparation Example 4-2. 3-Bromo-6-chloro-1-(4-methoxybenzyl)-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 5-2 ) synthesis

From compound 4-2 (1.45 g, 4.35 mmol), 1.38 g of compound 5-2 was obtained as a white solid (68%) in the same manner as in compound 5-1 .

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.68-1.90 (m, 4H), 3.44 (td, J = 11.3, 2.6 Hz, 2H), 3.72 (s, 3H), 3.89 (dt, J = 11.8, 3.8 Hz, 2H), 4.25–4.39 (m, 1H), 5.35 (s, 2H), 6.89 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H).

Preparation Example 4-3. 3-Bromo-6-chloro-1-(4-methoxybenzyl)-N-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 5-4) synthesis

From compound 4-4 (1.5 g, 4.51 mmol), 0.912 g of compound 5-4 was obtained as a white solid (45%) in the same manner as in compound 5-1 .

^OneH NMR (300 MHz, Chloroform-d) δ 1.43 (d, J = 1.0 Hz, 1H), 1.62 (s, 3H), 2.00 (d, J = 31.8 Hz, 4H), 3.58 (dt, J = 13.1, 6.2 Hz, 1H), 3.75 - 3.98 (m, 7H), 4.63 (d, J = 4.5 Hz, 1H), 5.38 (s, 2H), 6.58 (s, 1H), 6.86 (s, 3H), 7.31 ( s, 3H).

Preparation Example 5-1. 3-bromo-N ⁴ -cyclohexyl-N ⁶ Synthesis of -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 6-1)

After dissolving compound 5-1 (3.71 g, 8.23 mmol) and 2-methoxy-4-morpholinoaniline (2.05 g, 9.87 mmol) in 2-butanol (2-BuOH; 45 mL), trifluoroacetic acid (TFA; 0.63 mL, 8.23 mmol) was added and stirred at 110° C. for 22 hours. After concentrating the mixture under reduced pressure, water (20 mL) was added to the residue, and then saturated aqueous sodium bicarbonate solution (sat'd NaHCO ₃ ) was added to adjust the pH to 7, followed by extraction with EA (60 mL). Water was removed from the organic layer (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:2) to give 4.89 g (89%) of compound 6-1 as a light gray solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.19-1.26 (m, 1H), 1.31-1.46 (m, 4H), 1.56-1.63 (m, 1H), 1.68-1.75 (m, 2H), 1.90 -1.96 (m, 2H), 3.06-3.11 (m, 4H), 3.71 (s, 3H), 3.73-3.76 (m, 4H), 3.84 (s, 3H), 3.99-4.07 (m, 1H), 5.23 (s, 2H), 6.09 (d, J = 7.9 Hz, 1H), 6.50 (dd, J = 8.9, 2.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 8.9) 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H).

Preparation Example 5-2. 3-bromo-N ⁴ -cyclohexyl-1-(4-methoxybenzyl)-N ⁶ Synthesis of -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 6-2)

100 mg of compound 6-2 was obtained as a white solid from compound 5-1 (102 mg, 0.226 mmol) and trans-4-morpholinocyclohexan-1-amine (62 mg, 0.339 mmol) in the same manner as in compound 6-1 . (74%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.16-1.54 (m, 18H), 1.85-1.88 (m, 5H), 1.99-2.10 (m, 4H), 2.21-2.32 (m, 3H), 3.73 -3.85 (m, 4H), 4.01-4.11 (m, 1H), 4.95 (m, 1H),5,26 (s, 2H), 5.70 (m, 1H), 6.93 (d, J = 8.6 Hz, 2H ), 7.20 (d, J = 8.6 Hz, 2H),

Preparation Example 5-3. 3-Bromo-N ⁶ -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-N ⁴ Synthesis of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 6-3)

From compound 5-2 (150 mg, 0.33 mmol), 128 mg of compound 6-3 was obtained as a white solid (62%) in the same manner as in compound 6-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.60-1.71 (m, 2H), 1.85-1.92 (m, 2H), 3.07-3.11 (m, 4H), 3.41 (t, J = 11.2 Hz, 2H ), 3.71 (s, 3H), 3.73-3.77 (m, 4H), 3.83 (s, 3H), 3.86-3.92 (m, 2H), 1.17-4.27 (m, 1H), 5.23 (s, 2H), 6.24 (d, J = 7.6 Hz, 1H), 6.51 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.70 (s, 1H), 7.97 (br s, 1H).

Preparation Example 5-4. 3-Bromo-N ⁶ -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-N ⁴ Synthesis of -((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 6-4)

From compound 5-4 (912 mg, 2.014 mmol), 434 mg of compound 6-4 was obtained as a white solid (35%) in the same manner as in compound 6-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 3.09 (s, 4H), 3.52 (s, 1H), 3.65 (s, 2H), 3.73 (d, J = 16.3 Hz, 8H), 3.84 (s, 3H), 4.09 (d, J = 1.9 Hz, 1H), 5.24 (s, 2H), 6.65 (d, J = 2.5 Hz, 3H), 6.90 (s, 2H), 7.20 (s, 2H), 7.67 ( s, 1H), 8.02 (s, 1H).

Example 1. N ⁴ -cyclohexyl-3-(5-fluoropyridin-3-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-1)

It was prepared in two steps to remove Suzuki coupling and PMB according to the following reaction scheme.

Step 1. Compound 7-1 synthesis

Dioxane _- water ₍ Dioxane - H After dissolving in ₂ O; 4:1 in v/v, 2 mL), purging with argon gas for 5 minutes, tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ; 2 mg, 0.001 mmol) was added. After stirring at 100 ^° C for 2 hours. The mixture was dried with sodium sulfate (Na ₂ SO ₄ ), filtered through a celite pad, and the residue was washed with EA (5 mL) and the filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:3) to give 11.3 mg (55%) of compound 7-1 as a yellow solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ .78-2.1 (m, 9H), 3.15 (t, J = 4.7 Hz, 4H), 3.77 (s, 3H), 3.90 (t, J = 4.7 Hz, 4H) ), 3.94 (s, 3H), 4.12–4.21 (m, 1H), 5.44 (s, 2H), 6.57 (s, 2H), 6.85 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.44 (s, 1H), 7.74 (d, J = 9.0 Hz, 1H), 8.10 (s, 1H), 8.55 (d, J = 2.8 Hz, 2H), 8.74 (s, 1H) .

Step 2. Preparation of compound 8-1

After dissolving compound 7-1 (11.3 mg, 0.01 mmol) in trifluoroacetic acid (TFA; 1 mL), methanesulfonic acid (MsOH; 0.1 mL) was added dropwise, followed by stirring at 60° C. for 2 hours. After concentrating the mixture under reduced pressure, the pH was adjusted to 7 with sat'd sodium bicarbonate. After adding ethyl acetate (EA; 5 mL) and washing with water (5 mL), the organic extract was dried over sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate = 1:2) to give 4.9 mg of compound 8-1 as a pale yellow solid (53%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.11-1.21 (m, 1H), 1.23-1.43 (m, 4H), 1.59 (d, J = 12.9 Hz, 1H), 1.69 (d, J = 10.1 Hz, 2H), 1.92 (d, J = 10.1 Hz, 2H), 3.09 (t, J = 4.7 Hz, 4H), 3.76 (t, J = 4.6 Hz, 4H), 3.86 (s, 3H), 3.97- 4.10 (m, 1H), 6.14 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 6.66 (s, 1H), 7.47 (s, 1H), 7.92 (d, J = 9.7 Hz, 1H), 8.04 (d, J = 8.7 Hz, 1H), 8.65 (d, J = 2.8 Hz, 1H), 8.72 (s, 1H), 13.19 (s, 1H).

Example 2. 3-(4-(Cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzamide (Compound 8-2 ) manufacturing

Step 1. Compound 7-2 synthesis

From compound 6-1 (50 mg, 0.08 mmol) and N-cyclopropyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (35 mg, 0.12 mmol) 42.4 mg of compound 7-2 was obtained as a light brown solid (75%) in the same manner as in compound 7-1 .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 0.53-0.57 (m, 2H), 0.67-0.72 (m, 2H), 1.14-1.26 (m, 3H), 1.28-1.37 (m, 2H), 1.49-1.62 (m, 3H), 1.85-1.92 (m, 2H), 2.84-2.90 (m, 1H), 3.09 (t, J = 4.7 Hz, 4H), 3.70 (s, 3H), 3.75 (t, J = 4.8 Hz, 4H), 3.87 (s, 3H), 3.98–4.06 (m, 1H), 5.35 (s, 2H), 5.64 (d, J = 5.9 Hz, 1H), 6.51 (dd, J = 8.9 , 2.6 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 7.51 (s, 1H), 7.60 (t, J = 7.7 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 1.8 Hz, 1H), 8.19 ( d, J = 8.8 Hz, 1H), 8.54 (d, J = 4.3 Hz, 1H).

Step 2. Preparation of compound 8-2

From compound 7-2 (42.4 mg, 0.06 mmol), 29 mg of compound 8-2 was obtained as a light brown solid (88%) in the same manner as in the step 2 compound 8-1 of Example 1.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.14-1.27 (m, 3H), 1.34 (q, J = 12.7, 11.7 Hz, 2H), 1.49-1.63 (m, 3H), 1.88-1.95 (m , 2H), 3.09 (t, J = 4.7 Hz, 4H), 3.75 (t, J = 4.6 Hz, 4H), 3.85 (s, 3H), 3.97–4.05 (s, 1H), 5.52 (d, J = 7.6 Hz, 1H), 6.49 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.0 Hz, 1H), 7.43 (s, 1H), 7.46 (s, 1H), 7.62 (t, J = 7.7 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 8.05–8.11 (m, 2H), 8.19 (s, 1H), 13.01 ( s, 1H).

Example 3. Methyl 4-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzoate (Compound 8- 3) Manufacturing

Step 1. Compound 7-3 synthesis

From compound 6-1 (60 mg, 0.09 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (26.0 mg, 0.14 mmol), 42 mg of compound 7-3 was obtained as a white solid in the same manner as in compound 7-1. (64%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.20-1.37 (m, 5H), 1.51-1.70 (m, 3H), 1.94 (d, J = 11.6 Hz, 2H), 2.64 (s, 3H), 3.04-3.15 (m, 4H), 3.71 (s, 3H), 3.73-3.78 (m, 4H), 3.87 (s, 3H), 3.98-4.04 (m, 1H), 5.36 (s, 2H), 5.80 ( d, J = 8.6 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 6.67 (s, 1H), 6.89 (d, J = 8.1 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.80 (d, J = 7.9 Hz, 2H), 8.10 (d, J = 7.9 Hz, 2H), 8.17 (d, J = 8.9 Hz, 1H).

Step 2. Compound 8-3 Preparation

29 mg of compound 8-3 was obtained as a light brown solid (88%) in the same manner as in the preparation of compound 8-1 in step 2 of Example 1.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.13-1.20 (m, 1H), 1.26 (q, J = 11.6 Hz, 2H), 1.36 (q, J = 12.8, 12.2 Hz, 2H), 1.58 ( d, J = 12.3 Hz, 1H), 1.66 (d, J = 12.3 Hz, 2H), 1.95 (d, J = 10.9 Hz, 2H), 2.65 (s, 3H), 3.06–3.14 (m, 4H), 3.74-3.78 (m, 4H), 3.86 (s, 3H), 3.99-4.08 (m, 1H), 5.67 (d, J = 7.5 Hz, 1H), 6.50 (d, J = 8.9 Hz, 1H), 6.66 (s, 1H), 7.47 (s, 1H), 7.82 (d, J = 7.1 Hz, 2H), 8.05 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 7.8 Hz, 2H), 13.12 (s, 1H).

Example 4. N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)cyclopropanecarboxamide (Compound 8-4) Preparation

Step 1. Synthesis of compound 7-4

From compound 6-1 (50 mg, 0.08 mmol) and (3-(cyclopropanecarboxamido)phenyl)boronic acid (25 mg, 0.12 mmol), 47.8 mg of compound 7-4 was obtained as a white solid in the same manner as in compound 7-1. (84%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 0.78-0.86 (m, 3H), 1.22-1.38 (m, 6H), 1.51-1.63 (m, 3H), 1.77-1.83 (m, 1H), 1.84-1.92 (m, 2H), 3.06-3.12 (m, 4H), 3.71 (s, 3H), 3.73-3.77 (m, 4H), 3.87 (s, 3H), 3.95-4.06 (m, 1H), 5.34 (s, 2H), 5.75 (d, J = 7.7 Hz, 1H), 6.51 (d, J = 8.8 Hz, 1H), 6.67 (s, 1H), 6.89 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.42-7.52 (m, 3H), 8.10 (s, 1H), 8.19 (d, J = 8.6 Hz, 1H) ), 10.40 (s, 1H).

Step 2. Preparation of compound 8-4

From compound 7-4 (15.7 mg, 0.02 mmol), 8.8 mg of compound 8-4 was obtained as a light brown solid (67%) in the same manner as in compound 8-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 0.81-0.84 (m, 3H), 1.12-1.38 (m, 6H), 1.50-1.63 (m, 3H), 1.78-1.84 (m, 1H), 1.85 -1.91 (m, 2H), 3.06-3.11 (m, 4H), 3.73-3.78 (m, 4H), 3.85 (s, 3H), 3.97-4.07 (m, 1H), 5.66 (d, J = 7.6 Hz) , 1H), 6.48 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 7.29–7.31 (m, 1H), 7.40 (s, 1H), 7.44–7.50 ( m, 2H), 8.07 (d, J = 8.7 Hz, 1H), 8.13 (s, 1H), 10.41 (s, 1H), 12.94 (s, 1H).

Example 5. 3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzamide (compound 8-5) Manufacturing

Step 1. Synthesis of compound 7-5

From compound 6-1 (50 mg, 0.08 mmol) and N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (32 mg, 0.12 mmol) 32.5 mg of compound 7-5 was obtained as a brown solid (59%) in the same manner as in compound 7-1 .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 0.83-0.92 (m, 2H), 1.17-1.34 (m, 4H), 1.48-1.61 (m, 2H), 1.85-1.92 (m, 2H), 2.80 (d, J = 4.4 Hz, 3H), 3.09 (t, J = 4.8 Hz, 4H), 3.70 (s, 3H), 3.75 (t, J = 4.8 Hz, 4H), 3.87 (s, 3H), 3.98-4.05 (m, 1H), 5.36 (s, 2H), 5.66 (d, J = 7.4 Hz, 1H), 6.52 (dd, J = 8.5, 2.4 Hz, 1H), 6.67 (d, J = 2.5 Hz) , 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.51 (s, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.78 (d , J = 7.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 8.11 (d, J = 16.8 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 8.55 (q, J = 4.1 Hz, 1H).

Step 2. Compound 8-5 Preparation

From compound 7-5 (32.5 mg, 0.04 mmol), 10.5 mg of compound 8-5 was obtained in the form of a light brown solid (39%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.16-1.28 (m, 3H), 1.29-1.39 (m, 2H), 1.48-1.62 (m, 3H), 1.85-1.93 (m, 2H), 2.81 (d, J = 4.4 Hz, 3H), 3.06–3.11 (m, 4H), 3.72–3.78 (m, 4H), 3.85 (s, 3H), 3.99–4.06 (m, 1H), 5.53 (d, J = 7.6 Hz, 1H), 6.49 (dd, J = 8.9, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.43 (s, 1H), 7.63 (t, J = 7.7 Hz, 1H) ), 7.80 (dt, J = 7.7, 1.3 Hz, 1H), 7.92 (dt, J = 7.8, 1.4 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.13–8.16 (m, 1H) , 8.56 (q, J = 4.2 Hz, 1H), 13.02 (br s, 1H).

Example 6. N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide (Compound 8-6) Preparation

Step 1. Synthesis of compounds 7-6

From compound 6-1 (50 mg, 0.08 mmol) and (3-(methylsulfonamido)phenyl)boronic acid (26 mg, 0.12 mmol), 48.5 mg of compound 7-6 was obtained as a white solid in the same manner as in compound 7-1 . (84%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.20-1.39 (m, 5H), 1.51-1.67 (m, 3H), 1.86-1.95 (m, 2H), 3.04 (s, 3H), 3.06-3.11 (m, 4H), 3.70 (s, 3H), 3.73-3.77 (m, 4H), 3.87 (s, 3H), 3.94-4.01 (m, 1H), 5.34 (s, 2H), 5.64 (d, J = 7.5 Hz, 1H), 6.49-6.54 (m, 1H), 6.65-6.68 (m, 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.30 −7.36 (m, 2H), 7.44–7.51 (m, 3H), 8.17 (d, J = 8.9 Hz, 1H), 9.94 (s, 1H).

Step 2. Preparation of compounds 8-6

From compound 7-6 (16.5 mg, 0.02 mmol), 5.5 mg of compound 8-6 was obtained in the form of a light brown solid (40%) in the same manner as in the preparation of compound 8-1 .

¹ H-NMR (500 MHz, DMSO-d ₆ ) δ 1.25 (q, J = 10.7, 10.1 Hz, 3H), 1.35 (q, J = 11.9, 11.4 Hz, 2H), 1.51-1.65 (m, 3H) , 1.88–1.95 (m, 2H), 3.05 (s, 3H), 3.08 (t, J = 4.8 Hz, 4H), 3.75 (t, J = 4.8 Hz, 4H), 3.85 (s, 3H), 3.95– 4.04 (m, 1H), 5.54 (d, J = 7.6 Hz, 1H), 6.46-6.51 (m, 1H), 6.65 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H) ), 7.35 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 7.46 (s, 1H), 7.50 (t, J = 7.8 Hz, 1H), 8.05 (d, J = 8.7 Hz, 1H) ), 9.96 (br s, 1H), 12.96 (s, 1H).

Example 7. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-7) manufacturing

Step 1. Synthesis of compounds 7-7

Compound 6-1 (30 mg, 0.04 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 mg, 0.07 mmol) to obtain 48.5 mg of compound 7-7 as a mixture in the same manner as in the preparation of compound 7-1 , and used for the next reaction.

Step 2. Preparation of compounds 8-7

From compound 7-7 (50.8 mg, 0.08 mmol), 13.6 mg of compound 8-7 was obtained as a brown solid (33%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.16-1.43 (m, 5H), 1.52-1.73 (m, 3H), 1.90-2.03 (2H), 3.08 (t, J = 4.8 Hz, 4H), 3.75 (t, J = 4.8 Hz, 4H), 3.85 (s, 3H), 3.93 (s, 3H), 3.98–4.04 (m, 1H), 5.61 (d, J = 7.7 Hz, 1H), 6.48 (dd , J = 8.9, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.39 (s, 1H), 7.71 (s, 1H), 8.04 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 12.78 (s, 1H).

Example 8. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-8) Manufacturing

Step 1. Synthesis of compounds 7-8

Compound from compound 6-1 (500 mg, 0.80 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (234 mg, 1.20 mmol) In the same manner as in the preparation of 7-1 , 286.9 mg of compound 7-8 was obtained as a light brown solid (58%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.21-1.39 (m, 5H), 1.52-1.60 (m, 1H), 1.60-1.66 (m, 2H), 1.91-1.97 (m, 2H), 3.04 -3.11 (m, 4H), 3.70 (s, 3H), 3.73-3.77 (m, 4H), 3.86 (s, 3H), 3.96-4.01 (m, 1H), 5.29 (s, 2H), 5.66 (d , J = 7.6 Hz, 1H), 6.50 (dd, J = 8.9, 2.6 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 7.23 (d , J = 8.7 Hz, 2H), 7.45 (s, 1H), 7.78 (br s, 1H), 8.08 (br s, 1H), 8.20 (d, J = 8.8 Hz, 1H), 13.22 (s, br 1H) ).

Step 2. Preparation of compounds 8-8

From compound 7-8 (75.1 mg, 0.12 mmol), 28.1 mg of compound 8-8 was obtained as a light brown solid (46%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.16-1.32 (m, 3H), 1.32-1.42 (m, 2H), 1.54-1.68 (m, 3H), 1.90-2.02 (m, 2H), 3.08 (t, J = 4.7 Hz, 4H), 3.75 (t, J = 4.7 Hz, 4H), 3.85 (s, 3H), 3.95–4.06 (m, 1H), 5.55 (d, J = 7.6 Hz, 1H) , 6.48 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.37 (s, 1H), 7.82 (br s, 1H), 8.09 (d, J = 8.8 Hz) , 1H), 12.77 (s, 1H), 13.20 (br s, 1H).

Example 9. N ⁴ -cyclohexyl-N ⁶ Preparation of -(4-morpholinocyclohexyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-9)

Step 1. Synthesis of compounds 7-9

34.0 mg of compound 7-9 was obtained as a mixture from compound 6-2 (30 mg, 0.05 mmol) and pyridin-3-ylboronic acid (10 mg, 0.07 mmol) in the same manner as in compound 7-1 and used in the next step did

Step 2. Preparation of compounds 8-9

From compound 7-9 (34.0 mg, 0.05 mmol), 7.1 mg of compound 8-9 was obtained as a white solid (26%) in the same manner as in the preparation of compound 8-1 in step 2 of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.07-1.41 (m, 9H), 1.45-1.73 (m, 3H), 1.77-2.07 (m, 6H), 2.09-2.27 (m, 1H), 2.39 -2.50 (m, 4H), 3.49-3.62 (m, 4H), 3.65 (s, 1H), 4.02 (s, 1H), 5.23-5.69 (m, 1H), 6.50 (d, J = 6.5 Hz, 1H) ), 7.53 (s, 1H), 8.00 (d, J = 6.5 Hz, 1H), 8.63 (s, 1H), 8.81 (s, 1H), 12.65–13.14 (m, 1H).

Example 10. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-10) manufacturing

Step 1. Synthesis of compounds 7-10

From compound 6-1 (50 mg, 0.08 mmol) and 1-methylpyrazole-5-boronic acid (20 mg, 0.1043 mmol), 40 mg of compound 7-10 was obtained as a white solid in the same manner as in compound 7-1 ( 80%).

^1H NMR (300 MHz, DMSO-d ₆ ) δ 0.86 (d, J = 2.1 Hz, 1H), 1.24 (s, 10H), 1.34 (s, 1H), 1.58 (d, J = 22.3 Hz, 3H) , 3.09 (t, J = 4.9 Hz, 5H), 3.71 (s, 3H), 3.75 (t, J = 4.8 Hz, 5H), 3.88 (d, J = 13.6 Hz, 6H), 5.36 (s, 2H) , 5.74 (d, J = 7.5 Hz, 1H), 6.49 - 6.54 (m, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.55 - 7.66 (m, 6H), 8.15 (d, J = 8.7 Hz, 1H).

Step 2. Preparation of compounds 8-10

From compound 7-10 (40 mg, 0.0641 mmol), 18.8 mg of compound 8-10 was obtained as a white solid (58.7%) in the same manner as in Example 1 for preparing compound 8-1 in step 2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.35 (d, J = 11.6 Hz, 2H), 1.61 (s, 3H), 1.88 - 1.99 (m, 3H), 3.06 - 3.10 (m, 4H), 3.73 - 3.76 (m, 4H), 3.84 (s, 3H), 3.89 - 3.92 (m, 3H), 4.00 (s, 1H), 5.62 (d, J = 7.7 Hz, 1H), 6.48 (dd, J = 8.8, 2.6 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 6.65 (d, J = 2.7 Hz, 1H), 7.48 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H) , 8.01 (d, J = 8.8 Hz, 1H), 13.20 (s, 1H).

Example 11. N ⁴ -cyclohexyl-3-(1-isopropyl-1H-imidazol-4-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-11)

Step 1. Synthesis of compounds 7-11

Compound 6-1 (50 mg, 0.08 mmol) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazole (113 mg, 0.4818 mmol) to obtain 98 mg of compound 7-11 as a white solid (94.2%) in the same manner as in the preparation of compound 7-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (d, J = 2.8 Hz, 3H), 1.35 (d, J = 5.7 Hz, 2H), 1.46 (d, J = 6.7 Hz, 9H), 1.78 (s, 3H), 1.99 (s, 3H), 3.08 (t, J = 4.8 Hz, 4H), 3.70 (s, 3H), 3.75 (t, J = 4.8 Hz, 4H), 3.87 (s, 3H) , 4.12 (s, 2H), 4.48 (q, J = 6.7 Hz, 1H), 5.29 (s, 2H), 6.48 - 6.52 (m, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.88 ( d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 7.31 (s, 1H), 7.60 (t, J = 6.7 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 8.00 (d, J = 1.4 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 10.76 (d, J = 7.4 Hz, 1H).

Step 2. Preparation of compounds 8-11

From compound 7-11 (95 mg, 0.1457mmol), 23.5 mg of compound 8-11 was obtained as a white solid (30%) in the same manner as in the step 2 compound 8-1 of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.46 (dt, J = 8.4, 4.2 Hz, 9H), 1.58 (s, 2H), 1.77 (s, 3H), 1.99 (d, J = 2.0 Hz, 3H), 3.07 (dd, J = 6.9, 3.4 Hz, 4H), 3.74 (d, J = 6.0 Hz, 4H), 3.84 - 3.87 (m, 3H), 4.11 (s, 1H), 4.47 - 4.53 (m , 1H), 6.47 (d, J = 8.6 Hz, 1H), 6.64 (d, J = 2.9 Hz, 1H), 7.22 (s, 1H), 7.70 - 7.74 (m, 1H), 7.98 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 10.65 (d, J = 7.5 Hz, 1H), 12.59 (s, 1H).

Example 12. N ⁴ -cyclohexyl-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-12)

Step 1. Synthesis of compounds 7-12

Compound 6-1 (50 mg, 0.08 mmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25 mg , 0.12 mmol) to obtain 55 mg of compound 7-12 as a white solid (99%) in the same manner as in compound 7-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.62 (d, J = 7.2 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.66 - 7.54 (m, 6H), 7.38 (s, 1H), 7.21 (d, J= 8.4 Hz, 2H), 6.88 (d, J= 8.5 Hz, 2H), 6.66 (d, J= 2.3 Hz, 2H) ), 6.51 (d, J= 8.0 Hz, 2H), 5.32 (s, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.75 (t, J= 4.8 Hz, 4H), 3.70 (s , 3H), 3.11 - 3.06 (m, 4H), 2.08 (s, 3H), 1.88 - 1.19 (m, 21H).

Step 2. Preparation of compounds 8-12

From compound 7-12 (55 mg, 0.0833 mmol), 24 mg of compound 8-12 was obtained as a light brown solid (54%) in the same manner as in Example 1 for preparing compound 8-1 in step 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.34 (q, J = 10.6, 9.7 Hz, 6H), 1.66 (s, 3H), 1.96 (d, J = 10.0 Hz, 2H), 3.09 (t, J = 4.8 Hz, 5H), 3.76 (t, J = 4.8 Hz, 5H), 5.76 (d, J = 7.6 Hz, 1H), 6.49 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 7.42 (s, 1H), 8.03 - 8.12 (m, 3H), 8.55 (s, 1H), 12.94 (s, 1H).

Example 13. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-13) manufacturing

Step 1. Synthesis of compounds 7-13

Compound 6-1 (50 mg, 0.08 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20 mg, 0.1043 mmol) to obtain 40 mg of compound 7-13 as a white solid (80%) in the same manner as in the preparation of compound 7-1 .

^1H NMR (300 MHz, DMSO-d ₆ ) δ 0.86 (d, J = 2.1 Hz, 1H), 1.24 (s, 10H), 1.34 (s, 1H), 1.58 (d, J = 22.3 Hz, 3H) , 3.09 (t, J = 4.9 Hz, 5H), 3.71 (s, 3H), 3.75 (t, J = 4.8 Hz, 5H), 3.88 (d, J = 13.6 Hz, 6H), 5.36 (s, 2H) , 5.74 (d, J = 7.5 Hz, 1H), 6.49 - 6.54 (m, 1H), 6.60 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 2.6 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.55 - 7.66 (m, 6H), 8.15 (d, J = 8.7 Hz, 1H).

Step 2. Preparation of compounds 8-13

From Compound 7-13 (55 mg, 0.0881 mmol), 23.2 mg of Compound 8-13 was obtained as a white solid (52%) in the same manner as in Example 1 for preparing Compound 8-1 in Step 2.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.44 (q, J = 9.4, 8.9 Hz, 6H), 1.62 (s, 1H), 1.77 (s, 3H), 2.01 - 2.11 (m, 3H), 3.08 (t, J = 4.8 Hz, 4H), 3.72 - 3.78 (m, 4H), 3.85 (s, 3H), 3.96 (s, 3H), 6.48 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (dd, J = 10.2, 2.4 Hz, 2H), 7.29 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 8.14 (d, J = 8.7 Hz, 1H), 9.53 (d, J = 7.3 Hz, 1H), 12.80 (s, 1H).

Example 14. N ⁴ -cyclohexyl-3-(furan-2-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-14)

Step 1. Synthesis of compounds 7-14

From compound 6-1 (50 mg, 0.08 mmol) and furan-2-ylboronic acid (12 mg, 0.1043 mmol), 14 mg of compound 7-14 was obtained as a white solid (28 %).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (d, J = 2.9 Hz, 11H), 1.35 (d, J = 5.7 Hz, 7H), 1.74 (d, J = 11.6 Hz, 3H), 3.07 - 3.11 (m, 4H), 3.70 (s, 3H), 3.75 (t, J = 4.8 Hz, 5H), 3.86 (s, 3H), 5.32 (s, 2H), 6.48 - 6.53 (m, 1H), 6.64 - 6.73 (m, 3H), 6.88 (d, J = 7.9 Hz, 3H), 7.09 - 7.13 (m, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.52 (s, 1H), 7.96 - 7.99 (m, 1H), 8.15 (d, J = 8.8 Hz, 1H), 9.05 (s, 1H).

Step 2. Preparation of compounds 8-14

From compound 7-14 (14 mg, 0.0229 mmol), 4.7 mg (42.7%) of compound 8-14 was obtained in the form of a light brown solid in the same manner as in the preparation of compound 8-1 in step 2 of Example 1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.27 - 1.49 (m, 8H), 1.61 (s, 2H), 1.68 - 1.79 (m, 3H), 1.95 - 2.08 (m, 3H), 3.07 - 3.11 (m, 4H), 3.74 - 3.77 (m, 4H), 3.85 (d, J = 1.4 Hz, 3H), 4.10 (s, 1H), 6.49 (dd, J = 8.6, 2.2 Hz, 1H), 6.65 ( d, J = 2.0 Hz, 1H), 6.71 (dt, J = 3.3, 1.6 Hz, 1H), 6.91 (d, J = 3.4 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 7.43 ( s, 1H), 7.96 (d, J = 1.8 Hz, 1H), 8.05 (dd, J = 8.7, 1.3 Hz, 1H), 13.04 (s, 1H).

Example 15. N ⁴ -cyclohexyl-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-3-(thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-15)

Step 1. Synthesis of compounds 7-15

Compound 7-1 from compound 6-1 (50 mg, 0.08 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (42 mg, 0.2007 mmol) In the same manner as in the preparation, 17.6 mg of compounds 7-15 were obtained as a mixture.

Step 2. Preparation of compounds 8-15

From compound 7-15 (17.6 mg, 0.0287 mmol), 11.4 mg of compound 8-15 was obtained as a white solid (80.0%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.35 (d, J = 8.0 Hz, 5H), 1.59 (d, J = 12.9 Hz, 2H), 1.68 (s, 3H), 1.99 (d, J = 6.6 Hz, 3H), 3.09 (t, J = 4.8 Hz, 4H), 3.76 (d, J = 4.3 Hz, 4H), 3.85 (s, 3H), 4.03 (d, J = 7.0 Hz, 1H), 6.01 (d, J = 7.7 Hz, 1H), 6.49 (dd, J = 8.8, 2.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 7.49 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H), 8.17 (s, 1H), 9.19 (s, 1H), 13.15 (s, 1H).

Example 16. 3-(1H-benzo[d]imidazol-5-yl)-N ⁴ -cyclohexyl-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-16)

Step 1. Synthesis of compounds 7-16

14.5 mg of compound 7-16 was obtained as a pale brown solid from compound 6-1 (50 mg, 0.08 mmol) and 1H-benzimidazole-5-boronic acid (25 mg, 0.1043 mmol) in the same manner as in compound 7-1 . (27.8%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (d, J = 2.0 Hz, 9H), 1.33 - 1.40 (m, 3H), 1.51 - 1.60 (m, 4H), 1.91 (s, 4H), 3.71 (s, 4H), 3.79 (d, J = 11.9 Hz, 4H), 3.88 (s, 1H), 3.97 (s, 3H), 4.08 (t, J = 10.3 Hz, 4H), 4.44 (t, J = 11.3 Hz, 3H), 5.41 (s, 2H), 5.76 (s, 1H), 6.91 (d, J = 8.7 Hz, 2H), 7.29 - 7.33 (m, 2H), 7.49 (s, 1H), 7.71 (s, 2H), 7.97 (d, J = 2.4 Hz, 1H), 8.33 (s, 1H), 8.62 (d, J = 9.0 Hz, 1H), 12.71 (d, J = 18.7 Hz, 1H).

Step 2. Preparation of compounds 8-16

From compound 7-16 (14.5 mg, 0.0219 mmol), 1.3 mg of compound 8-16 was obtained in the form of a light brown solid (11.8%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, Methanol-d ₄ ) δ 1.44 (d, J = 9.8 Hz, 4H), 1.62 (s, 4H), 2.03 (s, 3H), 3.14 (t, J = 4.8 Hz, 3H) , 3.83 - 3.90 (m, 3H), 4.03 - 4.20 (m, 2H), 6.57 (dd, J = 8.9, 2.6 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 25.9 Hz, 2H), 8.34 (t, J = 4.4 Hz, 2H).

Example 17. N ⁴ -cyclohexyl-3-(1H-indazol-5-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-17)

Step 1. Synthesis of compounds 7-17

From compound 6-1 (50 mg, 0.08 mmol) and 1H-Indazole-5-boronic acid (17 mg, 0.1043 mmol), 49 mg of compound 7-17 was obtained as a white solid in the same manner as in compound 7-1 . (94.2%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.21 (d, J = 17.6 Hz, 9H), 1.34 (s, 2H), 1.54 (s, 3H), 1.91 (s, 3H), 3.10 (t, J = 4.7 Hz, 4H), 3.71 (d, J = 0.9 Hz, 3H), 3.76 (t, J = 4.5 Hz, 4H), 3.88 (s, 3H), 4.03 (d, J = 8.1 Hz, 1H) , 5.35 (s, 2H), 5.63 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 8.9 Hz, 1H), 6.68 (s, 1H), 6.90 (d, J = 8.4 Hz, 2H) , 7.29 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 7.62 (d, J = 8.6 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 8.02 (s, 1H) , 8.18 (d, J = 1.4 Hz, 1H), 8.22 (d, J = 8.8 Hz, 1H), 13.27 (s, 1H).

Step 2. Preparation of compounds 8-17

From compound 7-17 (49 mg, 0.0742 mmol), 11.2 mg of compound 8-17 was obtained as a white solid (28%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.04 - 1.42 (m, 10H), 1.53 (s, 3H), 1.91 (s, 3H), 3.09 (t, J = 4.8 Hz, 4H), 3.75 ( t, J = 4.7 Hz, 4H), 3.86 (s, 3H), 4.03 (s, 1H), 5.51 (d, J = 7.6 Hz, 1H), 6.49 (dd, J = 8.8, 2.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 7.41 (s, 1H), 7.63 (dd, J = 8.4, 1.5 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H) ), 8.09 (d, J = 8.9 Hz, 1H), 8.18 (s, 1H), 12.89 (s, 1H), 13.26 (s, 1H).

Example 18. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-18) manufacturing

Step 1. Synthesis of compounds 7-18

Compound 7-18 was prepared from Compound 6-1 (50 mg, 0.08 mmol) and (2-Methyl-1,3-benzoxazol-6-yl) boronic acid (18.5 mg, 0.1043 mmol) in the same manner as in Compound 7-1 . in the form of a white solid to give 51 mg (94.4%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.10 - 1.42 (m, 10H), 1.58 (s, 4H), 1.89 (s, 3H), 2.67 (s, 3H), 3.10 (t, J = 4.8 Hz, 4H), 3.71 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 3.87 (s, 3H), 4.03 (d, J = 6.7 Hz, 1H), 5.36 (s, 2H), 5.75 (d, J = 7.8 Hz, 1H), 6.52 (dd, J = 8.9, 2.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.51 (s, 1H), 7.55 - 7.66 (m, 4H), 7.80 (d, J = 8.2 Hz, 1H), 7.87 - 7.88 (m, 1H), 8.20 (d, J = 8.8 Hz, 1H).

Step 2. Preparation of compounds 8-18

From compound 7-18 (51 mg, 0.0755 mmol), 21.6 mg of compound 8-18 was obtained as a white solid (51.4%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.11 - 1.42 (m, 8H), 1.55 (d, J = 22.4 Hz, 3H), 1.91 (d, J = 11.2 Hz, 3H), 2.67 (d, J = 3.6 Hz, 3H), 3.09 (dt, J = 6.8, 3.8 Hz, 4H), 3.76 (dt, J = 6.6, 3.7 Hz, 4H), 3.86 (d, J = 3.6 Hz, 3H), 4.01 - 4.06 (m, 1H), 5.62 (d, J = 7.7 Hz, 1H), 6.50 (dt, J = 9.1, 3.1 Hz, 1H), 6.66 (t, J = 3.0 Hz, 1H), 7.43 (d, J = 3.3 Hz, 1H), 7.62 (dq, J = 8.2, 1.6 Hz, 1H), 7.81 (dd, J = 8.2, 3.5 Hz, 1H), 7.89 (q, J = 1.5 Hz, 1H), 8.08 (dd , J = 8.9, 3.4 Hz, 1H), 12.99 (d, J = 3.2 Hz, 1H).

Example 19. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-19) manufacturing

Step 1. Synthesis of compounds 7-19

Compound 6-1 ( 60 mg, 0.096 mmol) was dissolved in DMF (1 mL), purged with argon gas to remove oxygen, and 1-methyl-4-(tributylstannyl)-1H-imidazole (56.9 mg, 0.153 mmol) and After adding Pd(PPh ₃ ) ₄ (5.54 mg, 0.0048 mmol) and lithium chloride (LiCl; 2 mg, 0.048 mmol), the mixture was stirred in a Biotage microwave reactor at 120° C. for 40 minutes. After completion of the reaction, 1M potassium fluoride (KF; 5 mL) was added, stirred at room temperature for 30 minutes, and then extracted with EA (20 mL X 2). After sieving the organic layer with water (5 mL X 2), water was removed (Na ₂ SO ₄ ), concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (EA:Hx= 3:1) to obtain compound 7-19 . Yielded 57.1 mg (95.4%) as a white solid.

^1H NMR (500 MHz, DMSO) δ 10.66 (d, J = 7.7 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 7.31 (s, 1H), 7.23 - 7.12 (m, 2H), 6.92 - 6.83 (m, 2H), 6.65 (d, J = 2.6 Hz, 1H), 6.50 (dd, J = 8.9, 2.7 Hz, 1H), 5.28 (s, 2H), 4.12 (s, 1H), 3.87 (s, 3H), 3.78 - 3.72 (m, 4H), 3.71 (d, J = 11.2 Hz, 6H) , 3.11 - 3.03 (m, 4H), 1.97 (d, J = 13.4 Hz, 2H), 1.76 (s, 2H), 1.57 (s, 1H), 1.50 - 1.33 (m, 5H), 1.26 (d, J = 16.3 Hz, 2H).

Step 2. Preparation of compounds 8-19

From compound 7-19 (47 mg, 0.075 mmol), 27.0 mg of compound 8-19 was obtained in the form of a yellow solid (71.8%) in the same manner as in the preparation of compound 8-1 .

^1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 10.65 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.61 (s, 1H), 7.31 (s, 1H), 6.66 (s, 1H), 6.49 (d, J = 9.4 Hz, 1H), 4.13 (s, 1H), 3.97 - 3.58 (m, 10H), 3.08 (d, J = 4.2 Hz) , 4H), 1.96 (t, J = 6.7 Hz, 2H), 1.78 (d, J = 5.9 Hz, 2H), 1.58 (t, J = 7.9 Hz, 1H), 1.45 (t, J = 8.8 Hz, 5H) ).

Example 20. N ⁴ -cyclohexyl-3-(isoxazol-4-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-20)

Step 1. Synthesis of compounds 7-20

Preparation of compound 7-1 from compound 6-1 (100mg, 0.161mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (63mg, 0.321mmol) In the same manner, 48 mg of compound 7-20 was obtained (49%).

¹ H NMR (500 MHz, Chloroform-d) δ 1.45 (s, 3H), 1.66 (s, 1H), 1.79 (s, 2H), 2.14 (d, J = 8.8 Hz, 2H), 3.13 (s, 4H) ), 3.76 (s, 3H), 3.84 - 3.95 (m, 9H), 4.16 - 4.25 (m, 1H), 5.23 - 5.37 (m, 3H), 6.55 (s, 2H), 6.84 (d, J = 8.6 Hz, 2H), 7.28 - 7.32 (m, 2H), 7.42 (s, 1H), 7.44 - 7.50 (m, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.67 (dd, J = 11.6, 7.6 Hz, 1H), 8.50 (d, J = 8.7 Hz, 1H).

Step 2. Synthesis of compounds 8-20

Compound 7-20 (30 mg, 0.0491 mmol) was obtained in the same manner as in the preparation of Compound 8-1, and 24 mg of Compound 8-20 (99%) was obtained.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.23 (s, 1H), 1.36 (d, J = 10.6 Hz, 4H), 1.60 (s, 1H), 1.75 (s, 2H), 1.86 (s, 1H), 3.07 (s, 4H), 3.59 (s, 4H), 3.75 (s, 5H), 3.84 (s, 4H), 6.46 (d, J = 10.0 Hz, 1H), 6.64 (d, J = 2.6 Hz, 1H), 7.24 (s, 1H), 7.37 (s, 1H), 8.02 (s, 1H), 8.13 (d, J = 8.7 Hz, 1H), 8.62 (d, J = 7.2 Hz, 1H), 12.52 (s, 1H).

Example 21. 3-(Isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-21)

Step 1. Preparation of compounds 7-21

Preparation of compound 7-1 from compound 6-3 (100mg, 0.160mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (62mg, 0.320mmol) In the same manner, 57 mg of compound 7-21 was obtained (58%).

¹ H NMR (500 MHz, Chloroform-d) δ 1.66 (d, J = 7.6 Hz, 2H), 2.08 - 2.16 (m, 3H), 3.14 (s, 4H), 3.59 (d, J = 2.2 Hz, 2H) ), 3.76 (s, 3H), 3.89 (s, 4H), 3.93 (s, 3H), 3.95 (s, 2H), 4.04 (d, J = 11.7 Hz, 2H), 4.42 (d, J = 6.9 Hz) , 1H), 5.32 (s, 3H), 6.55 (s, 2H), 6.84 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 8.47 (d, J = 8.6 Hz, 1H).

Step 2. Preparation of compounds 8-21

From compound 7-21 (57 mg, 0.091 mmol), 30 mg of compound 8-21 was obtained as an off-white solid (66%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.35 (s, 3H), 1.61 (s, 2H), 1.76 (s, 2H), 2.36 (s, 1H), 2.64 (s, 1H), 3.07 ( s, 3H), 3.59 (s, 2H), 3.75 (s, 3H), 3.84 (s, 2H), 6.46 (s, 1H), 6.64 (s, 2H), 7.24 (s, 1H), 7.37 (s , 1H), 8.02 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 8.61 (s, 1H), 12.52 (s, 1H).

Example 22. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-2-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-22)

Step 1. Preparation of compounds 7-22

Compound 6-3 (100 mg, 0.1601 mmol) and LiCl (3.4 mg, 0.080 mmol) were put in DMF (1 mL), 2-(tributylstannyl)oxazole (0.01 mL, 0.3202 mmol) was added, oxygen was removed, and Pd (PPh ₃ ) After adding ₄ (3.4 mg, 0.008 mmol), the mixture was stirred at 120 ^° C for 40 minutes. The mixture was filtered through a celite pad, washed with EA (10 mL), and the organic layer was washed with water (10 mL), dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:1) to give 37 mg of compound 7-22 (37%).

Step 2. Preparation of compounds 8-22

Compound 7-22 (37 mg, 0.063 mmol) was obtained in the same manner as in Example 1 for preparing compound 8-1 , to obtain 11 mg of compound 8-22 in the form of an off-white solid (37%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.38 (s, 1H), 9.59 (d, J = 7.2 Hz, 1H), 8.31 (s, 1H), 7.98 (d, J = 8.7 Hz, 1H) , 7.55 (d, J = 9.4 Hz, 2H), 6.65 (d, J = 2.5 Hz, 1H), 6.50 (dd, J = 8.9, 2.5 Hz, 1H), 4.28 (s, 1H), 3.91 (d, J = 11.8 Hz, 2H), 3.84 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 3.53 (t, J = 10.2 Hz, 2H), 3.09 (t, J = 4.8 Hz, 4H) , 2.05 (d, J = 12.7 Hz, 2H), 1.65 - 1.51 (m, 2H).

Example 23. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-23)

Step 1. Synthesis of compounds 7-23

Compound 6-3 (30 mg, 0.04 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15 mg, 0.07 mmol) to obtain 29.1 mg of compound 7-23 as a light brown solid (96%) in the same manner as in the preparation of compound 7-1 .

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.47-1.62 (m, 2H), 1.88-1.99 (m, 2H), 3.03-3.11 (m, 4H), 3.43 (t, J = 11.2 Hz, 2H), 3.70 (s, 3H), 3.71-3.78 (m, 4H), 3.80-3.84 (m, 2H), 3.85 (s, 3H), 3.91 (s, 3H), 4.13-4.23 (m, 1H) , 5.29 (s, 2H), 5.89 (d, J = 7.3 Hz, 1H), 6.52 (dd, J = 8.9, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.50 (s, 1H), 7.71 (s, 1H), 8.04 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H).

Step 2. Preparation of compounds 8-23

From compound 7-23 (27.8 mg, 0.04 mmol), 13.4 mg of compound 8-23 was obtained in the form of a light brown solid (59%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.47-1.67 (m, 2H), 1.90-2.02 (m, 2H), 3.03-3.15 (m, 4H), 3.39-3.51 (m, 2H), 3.72 -3.79 (m, 4H), 3.84 (s, 3H), 3.85-3.90 (m, 2H), 3.93 (s, 3H), 4.12-4.27 (m, 1H), 5.78 (d, J = 7.4 Hz, 1H ), 6.50 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.43 (s, 1H), 7.73 (s, 1H), 8.01–8.10 (m, 2H) , 12.79 (s, 1H).

Example 24. 3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-24)

Step 1. Synthesis of compound 7-24

Compound 6-3 (50 mg, 0.08 mmol) and 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (29 mg , 0.12 mmol) to obtain 56.3 mg of compound 7-24 as a white solid (>99%) in the same manner as in compound 7-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.42 - 1.21 (m, 7H), 1.62 (d, J = 28.0 Hz, 4H), 1.97 (s, 2H), 3.09 (t, J = 4.9 Hz , 4H), 3.71 (s, 3H), 3.79 - 3.72 (m, 4H), 3.87 (s, 3H), 5.32 (s, 2H), 5.93 (d, J= 7.5 Hz, 1H), 6.51 (dd, J= 8.9, 2.5 Hz, 1H), 6.67 (d, J= 2.5 Hz, 1H), 6.92 - 6.80 (m, 2H), 7.28 - 7.15 (m, 2H), 7.50 (s, 1H), 7.90 (s , 1H), 8.08 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.55 (s, 1H).

Step 2. Preparation of compounds 8-24

From compound 7-24 (22 mg, 0.03 mmol), 29 mg of compound 8-24 was obtained in the form of a light brown solid (>99%) in the same manner as in the preparation of compound 8-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.58 (dt, J= 11.8, 5.6 Hz, 2H), 2.00 - 1.89 (m, 3H), 3.12 - 3.06 (m, 5H), 3.48 - 3.38 ( m, 4H), 3.75 (dd, J= 6.0, 3.6 Hz, 5H), 3.84 (s, 7H), 4.18 (dd, J= 7.0, 3.7 Hz, 1H),

5.99 (d, J= 7.4 Hz, 1H), 6.51 - 6.47 (m, 1H), 6.65 (d, J= 2.5 Hz, 1H), 7.46 (s, 1H), 8.02 (d, J= 8.8 Hz, 1H) ), 8.09 (d, J = 3.4 Hz, 1H), 8.53 (s, 1H), 12.95 (s, 1H).

Example 25. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-25)

Step 1. Synthesis of compound 7-25

Compound 6-3 (50 mg, 0.08 mmol) and 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25 mg, 0.12 mmol) to obtain 54.2 mg of compound 7-25 as a white solid (>99%) in the same manner as in the preparation of compound 7-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.88 - 1.19 (m, 21H), 2.08 (s, 3H), 3.11 - 3.06 (m, 4H), 3.70 (s, 3H), 3.75 (t, J= 4.8 Hz, 4H), 3.87 (s, 3H), 3.96 (s, 3H), 5.32 (s, 2H), 6.51 (d, J= 8.0 Hz, 2H), 6.66 (d, J= 2.3 Hz, 2H), 6.88 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 7.38 (s, 1H), 7.66 - 7.54 (m, 6H), 7.85 (d, J= 2.4 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 9.62 (d, J = 7.2 Hz, 1H).

Step 2. Preparation of compounds 8-25

From compound 7-25 (22 mg, 0.03 mmol), 24 mg of compound 8-25 was obtained as a white solid (>99%) in the same manner as in the preparation of compound 8-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.68 - 1.54 (m, 4H), 2.09 (d, J = 12.9 Hz, 4H), 3.08 (t, J = 4.9 Hz, 6H), 3.53 (t , J= 11.0 Hz, 4H), 3.75 (t, J= 4.7 Hz, 6H), 3.85 (s, 4H), 3.97 (s, 9H), 4.24 (s, 1H), 6.49 (dd, J= 8.9, 2.6 Hz, 2H), 6.66 (dd, J= 12.1, 2.4 Hz, 3H), 7.34 (s, 1H), 7.84 (d, J= 2.3 Hz, 1H), 8.09 (d, J= 8.8 Hz, 2H) , 9.61 (d, J = 6.8 Hz, 1H), 12.83 (s, 1H).

Example 26. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1H-pyrazol-4-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-26)

Step 1. Synthesis of compounds 7-26

Compound from compound 6-3 (50 mg, 0.08 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23.3 mg, 0.12 mmol) In the same manner as in the preparation of 7-1 , 15 mg of compound 7-26 was obtained as a white solid (28%).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.88 - 1.19 (m, 21H), 2.08 (s, 3H), 3.11 - 3.06 (m, 4H), 3.70 (s, 3H), 3.75 (t, J= 4.8 Hz, 4H), 3.87 (s, 3H), 3.96 (s, 3H), 5.32 (s, 2H), 6.51 (d, J= 8.0 Hz, 2H), 6.66 (d, J= 2.3 Hz, 2H), 6.88 (d, J= 8.5 Hz, 2H), 7.21 (d, J= 8.4 Hz, 2H), 7.38 (s, 1H), 7.66 - 7.54 (m, 6H), 7.85 (d, J= 2.4 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 9.62 (d, J = 7.2 Hz, 1H).

Step 2. compound 8-26 preparation

From compound 7-26 (15 mg, 0.02 mmol), 13 mg of compound 8-26 was obtained as a white solid (>99%) in the same manner as in the preparation of compound 8-1 .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 1.56 - 1.44 (m, 3H), 1.95 (d, J = 12.4 Hz, 2H), 3.08 (t, J = 4.9 Hz, 4H), 3.44 (t , J= 11.2 Hz, 4H), 3.75 (t, J= 4.8 Hz, 4H), 3.82 (s, 1H), 3.84 (s, 3H), 4.19 (d, J= 11.2 Hz, 1H), 5.72 (d , J= 7.5 Hz, 1H), 6.49 (dd, J= 9.0, 2.5 Hz, 1H), 6.65 (d, J= 2.6 Hz, 1H), 7.40 (s, 1H), 7.83 (s, 1H), 8.05 (d, J = 8.8 Hz, 2H), 12.77 (s, 1H), 13.17 (s, 1H).

Example 27. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyridin-3-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-27)

Step 1. Synthesis of compound 7-27

From compound 6-3 (30 mg, 0.04 mmol) and 3-pyridinylboronic acid (9 mg, 0.07 mmol), 31.3 mg of compound 7-27 was obtained as a light brown solid (100%) in the same manner as in compound 7-1 . .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.41-1.58 (m, 2H), 1.83-1.93 (m, 2H), 3.04-3.13 (m, 4H), 3.35-3.46 (m, 2H), 3.70 (s, 3H), 3.71-3.78 (m, 4H), 3.78-3.83 (m, 2H), 3.86 (s, 3H), 4.12-4.26 (m, 1H), 5.36 (s, 2H), 6.19 (d) , J = 7.4 Hz, 1H), 6.53 (dd, J = 9.0, 2.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.27 (d , J = 8.4 Hz, 2H), 7.49–7.61 (m, 2H), 7.98–8.06 (m, 1H), 8.08–8.20 (m, 1H), 8.63 (dd, J = 4.8, 1.6 Hz, 1H), 8.82-8.85 (m, 1H).

Step 2. Preparation of compounds 8-27

From compound 7-27 (30.3 mg, 0.04 mmol), 5.6 mg of compound 8-27 was obtained in the form of a light brown solid (22%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.41-1.60 (m, 2H), 1.84-1.94 (m, 2H), 3.05-3.14 (m, 4H), 3.36-3.47 (m, 2H), 3.72 -3.79 (m, 4H), 3.79-3.88 (m, 2H), 3.84 (s, 3H), 4.13-4.31 (m, 1H), 6.04 (d, J = 7.4 Hz, 1H), 6.50 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.49 (s, 1H), 7.51–7.57 (m, 1H), 7.99–8.06 (m, 2H), 8.64 (dd, J = 4.8, 1.7 Hz, 1H), 8.86 (dd, J = 2.2, 0.9 Hz, 1H), 13.11 (s, 1H).

Example 28. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyridin-4-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-28)

Step 1. Synthesis of compounds 7-28

From compound 6-3 (15 mg, 0.02 mmol) and 4-pyridinylboronic acid (5 mg, 0.03 mmol), 17.5 mg of compound 7-28 was obtained as a white solid (100%) in the same manner as in compound 7-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.48-1.60 (m, 2H), 1.87-1.94 (m, 2H), 3.08-3.12 (m, 4H), 3.41 (t, J = 11.3 Hz, 2H ), 3.70 (m, 3H), 3.73-3.78 (m, 4H), 3.81-3.84 (m, 2H), 3.85 (s, 3H), 4.16-4.25 (m, 1H), 5.36 (s, 2H), 6.26 (d, J = 7.3 Hz, 1H), 6.53 (dd, J = 8.9, 2.6 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.87–6.91 (m, 2H), 7.26 (d , J = 8.7 Hz, 2H), 7.60 (s, 1H), 7.63–7.65 (m, 2H), 8.10 (d, J = 9.7 Hz, 1H), 8.66–8.70 (m, 2H).

Step 2. Preparation of compounds 8-28

From compound 7-28 (15 mg, 0.02 mmol), 11.4 mg of compound 8-28 was obtained in the form of a light brown solid (94%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.50-1.59 (m, 2H), 1.88-1.95 (m, 2H), 3.09 (t, J = 4.8 Hz, 4H), 3.42 (t, J = 10.9 Hz, 2H), 3.75 (t, J = 4.7 Hz, 4H), 3.84 (s, 3H), 3.85–3.87 (m, 2H), 4.18–4.27 (m, 1H), 6.12 (d, J = 7.3 Hz) , 1H), 6.50 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.52 (s, 1H), 7.66 (d, J = 5.6 Hz, 2H), 7.99 (d, J = 8.8 Hz, 1H), 8.69 (d, J = 5.6 Hz, 2H), 13.21 (s, 1H).

Example 29. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyrimidin-5-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-29)

Step 1. Synthesis of compound 7-29

From compound 6-3 (15 mg, 0.02 mmol) and boronic acid (9 mg, 0.07 mmol), 17.4 mg of compound 7-29 was obtained as a light yellow solid (57%) in the same manner as in compound 7-1 .

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 1.47-1.62 (m, 2H), 1.88-1.99 (m, 2H), 3.03-3.11 (m, 4H), 3.43 (t, J = 11.2 Hz, 2H), 3.70 (s, 3H), 3.71-3.78 (m, 4H), 3.80-3.84 (m, 2H), 3.85 (s, 3H), 3.91 (s, 3H), 4.13-4.23 (m, 1H) , 5.29 (s, 2H), 5.89 (d, J = 7.3 Hz, 1H), 6.52 (dd, J = 8.9, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 7.22 (d, J = 8.6 Hz, 2H), 7.50 (s, 1H), 7.71 (s, 1H), 8.04 (s, 1H), 8.15 (d, J = 8.8 Hz, 1H).

Step 2. Preparation of compounds 8-29

From compound 7-29 (17.7 mg, 0.02 mmol), 5.7 mg of compound 8-29 was obtained in the form of a gray solid (39%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.43-1.60 (m, 2H), 1.81-1.97 (m, 2H), 3.04-3.16 (m, 4H), 3.36-3.47 (m, 2H), 3.71 -3.80 (m, 4H), 3.85 (s, 3H), 3.86-3.92 (m, 2H), 4.13-4.31 (m, 1H), 6.46-6.58 (m, 2H), 6.66 (s, 1H), 7.52 (s, 1H), 8.00 (d, J = 8.7 Hz, 1H), 9.02 (s, 2H), 9.24 (s, 1H), 13.25 (br s, 1H).

Example 30. N ⁴ -cyclohexyl-3-(1-methyl-1H-pyrazol-4-yl)-N ⁶ Preparation of -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-30)

Step 1. Synthesis of compound 7-30

Compound 6-2 (30 mg, 0.05 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16 mg, 0.07 mmol) to obtain 32.1 mg of compound 7-30 , which was used in the next step.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.21 (dd, J = 35.5, 11.3 Hz, 14H), 1.64 (s, 5H), 1.93 (d, J = 48.5 Hz, 9H), 2.16 (s, 1H), 3.56 (d, J = 5.4 Hz, 4H), 3.70 (s, 3H), 3.90 (s, 3H), 4.03 (dd, J = 14.8, 7.6 Hz, 2H), 5.20 (s, 2H), 5.37 (s, 1H), 5.58 (s, 1H), 6.53 (s, 1H), 6.67 (s, 1H), 6.86 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 7.25 (s , 1H), 7.66 (s, 1H), 7.99 (s, 1H).

Step 2. Preparation of compounds 8-30

From compound 7-30 (32.1 mg, 0.05 mmol), 5.2 mg of compound 8-30 was obtained as a white solid (20%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.16-1.39 (m, 9H), 1.50-1.76 (m, 3H), 1.83-2.03 (m, 6H), 2.15 (t, J = 8.9 Hz, 1H ), 2.47 (t, J = 4.5 Hz, 4H), 3.56 (t, J = 4.6 Hz, 4H), 3.63 (s, 1H), 3.92 (s, 3H), 4.01 (s, 1H), 5.29–5.37 (m, 1H), 6.42 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.99 (s, 1H), 12.34–12.71 (m, 1H).

<Example B. Preparation of compound 11 according to Scheme 2>

[Scheme 2]

Example 31. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4, Preparation of 6-diamine (Compound 11-1)

Step 1. Synthesis of compound 9-1

Dioxane _{: water} ( 4 :1 in v/ v, 10 mL), purged with argon gas to remove oxygen, and after adding Pd(PPh ₃ ) ₄ (84.3 mg, 0.033 mmol), the mixture was stirred at 100°C for 2 hours. Water (10 mL) was added to the mixture and extracted with EA (20 mL X 2). Water was removed from the organic layer (Na ₂ SO ₄ ), and the mixture was concentrated under reduced pressure after filtration. The residue was separated by silica gel column chromatography (EA:Hx = 2:1) to give 422 mg (42.2%) of formula 9-1 as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ -d ₆ ) δ 7.69 (s, 2H), 7.31 (d, J = 6.3 Hz, 2H), 6.81 (d, J = 6.4 Hz, 2H), 5.53 (d, J = 6.0 Hz, 1H), 5.41 (s, 2H), 4.24–4.18 (m, 1H), 3.97 (s, 3H), 3.74 (s, 3H), 2.03–1.97 (m, 2H), 1.69–1.57 (m, 2H), 1.49–1.39 (m, 2H), 1.27–1.14 (m, 4H).

Step 2. Synthesis of compound 10-1

After dissolving compound 9-1 (60 mg, 0.13 mmol) in 2-Butanol (1 mL), 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (44.2 mg, 0.2 mmol) and K ₂ CO ₃ (29.4 mg, 0.21 mmol) is added. The reaction mixture was purged with argon gas for 5 minutes to remove oxygen, and after adding Pd ₂ dba ₃ (30.4 mg, 0.033 mmol) and X-Phos (23.4 mg, 0.049 mmol), the mixture was stirred at 110° C. for one day. The mixture was filtered through a celite pad, washed with EA (10 mL), and the combined filtrate was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH = 97:3) to give 38.9 mg (45.9%) of compound 10-1 as a pink solid.

^1H NMR (500 MHz, CDCl ₃ ) δ 8.54 (d, J = 9.4 Hz, 1H), 7.70 (d, J = 19.1 Hz, 2H), 7.40 - 7.32 (m, 3H), 6.87 - 6.79 (m, 2H), 6.60 - 6.53 (m, 2H), 5.38 (s, 2H), 5.24 (d, J = 7.8 Hz, 1H), 4.19 - 4.09 (m, 1H), 3.97 (s, 3H), 3.92 (s , 3H), 3.76 (s, 3H), 3.19 (t, J = 4.9 Hz, 4H), 2.63 (t, J = 4.9 Hz, 4H), 2.38 (s, 3H), 2.05 (d, J = 9.7 Hz) , 2H), 1.67 (ddd, J = 36.2, 9.2, 4.2 Hz, 5H), 1.44 (q, J = 12.1 Hz, 2H), 1.26 - 1.18 (m, 3H).

Step 3. Compound 11-1 Preparation

From compound 10-1 (31.7 mg, 0.049 mmol), 2.4 mg of compound 11-1 was obtained as a green solid (9.5%) in the same manner as in the preparation of compound 8-1 .

^1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 8.10 - 7.99 (m, 2H), 7.70 (s, 1H), 7.36 (s, 1H), 6.63 (d, J = 2.5 Hz, 1H ), 6.47 (dd, J = 8.9, 2.5 Hz, 1H), 5.58 (d, J = 7.7 Hz, 1H), 4.24 (dd, J = 5.7, 2.3 Hz, 1H), 4.10 (s, 1H), 4.00 (dt, J = 9.7, 4.1 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.17 (s, 4H), 3.11 (t, J = 4.9 Hz, 4H), 2.25 (s, 3H), 1.99 - 1.89 (m, 3H), 1.61 (ddt, J = 30.0, 12.7, 4.6 Hz, 3H), 1.44 - 1.26 (m, 7H).

Example 32. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[ Synthesis of 3,4-d] pyrimidine-4,6-diamine (Compound 11-2)

Step 1. Synthesis of compound 10-2

From compound 9-1 (60 mg, 0.13 mmol) and 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (32.5 mg, 0.16 mmol), the compound 10- 20.1 mg of compound 10-2 was obtained as a brown solid (24.4%) by the same preparation method as in 1 .

^1H NMR (300 MHz, CDCl ₃ ) δ 8.87 (d, J = 8.5 Hz, 1H), 8.17 (s, 1H), 7.79 - 7.71 (m, 2H), 7.70 (s, 1H), 7.42 - 7.30 ( m, 3H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 6.88 - 6.78 (m, 2H), 5.42 (s, 2H), 5.33 (d, J = 7.9 Hz, 1H), 4.25 - 4.11 (m, 1H), 3.98 (d, J = 7.2 Hz, 6H), 3.77 (d, J = 16.4 Hz, 6H), 2.05 (d, J = 12.5 Hz, 2H), 1.79 - 1.56 (m, 3H) , 1.45 (q, J = 11.8 Hz, 2H), 1.31 - 1.19 (m, 3H).

Step 2. Compound 11-2 Preparation

From compound 10-2 (20 mg, 0.032 mmol), 8.1 mg of compound 11-2 was obtained as a white solid (50.9%) by the same method as for compound 11-1 .

¹ H NMR (300 MHz, CDCl ₃ ) δ 10.52 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H), 8.16 (s, 1H), 7.83 - 7.66 (m, 3H), 7.32 (d, J = 1.9 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.41 (d, J = 7.8 Hz, 1H), 4.19 (d, J = 10.0 Hz, 1H), 3.99 (d, J = 10.0 Hz, 1H). 13.1 Hz, 6H), 3.77 (s, 3H), 2.09 (d, J = 12.2 Hz, 2H), 1.71 (t, J = 19.4 Hz, 4H), 1.47 (q, J = 12.1 Hz, 2H), 1.36 - 1.17 (m, 6H).

Example 33. 4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 Synthesis of -methoxy-N-methylbenzamide (Compound 11-3)

Step 1. Compound 10-3 synthesis

From compound 9-1 (60 mg , 0.13 mmol) and 4-amino-3-methoxy-N-methylbenzamide (27.7 mg, 0.16 mmol), compound 10-3 was obtained as a white solid by the same preparation method as in compound 10-1. mg was obtained (60.6%).

^1H NMR (500 MHz, CDCl ₃ ) δ 8.78 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 11.1 Hz, 2H), 7.70 (s, 1H), 7.46 (d, J = 1.9 Hz , 1H), 7.35 (d, J = 8.6 Hz, 2H), 7.28 (dd, J = 8.4, 1.9 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.17 (q, J = 4.7 Hz, 1H) , 5.40 (s, 2H), 5.33 (d, J = 7.9 Hz, 1H), 4.21 - 4.12 (m, 1H), 3.99 (d, J = 7.6 Hz, 6H), 3.75 (s, 3H), 3.02 ( d, J = 4.8 Hz, 3H), 2.06 (dd, J = 12.6, 4.5 Hz, 2H), 1.79 - 1.60 (m, 5H), 1.51 - 1.39 (m, 3H), 1.35 - 1.16 (m, 8H) .

Step 2. Compound 11-3 Preparation

From compound 10-3 (37 mg, 0.062 mmol), 9.1 mg of compound 11-3 was obtained as a white solid (30.8%) by the same method as for compound 11-1 .

^1H NMR (300 MHz, CDCl ₃ ) δ 10.64 (s, 1H), 8.65 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 6.7 Hz, 3H), 7.44 (d, J = 1.9 Hz) , 1H), 7.25 - 7.15 (m, 1H), 6.24 (d, J = 5.0 Hz, 1H), 5.41 (d, J = 7.8 Hz, 1H), 4.17 (d, J = 8.9 Hz, 1H), 3.98 (d, J = 13.9 Hz, 6H), 3.00 (d, J = 4.8 Hz, 3H), 2.08 (d, J = 12.6 Hz, 2H), 1.71 (t, J = 19.1 Hz, 3H), 1.47 (q , J = 12.1 Hz, 2H), 1.25 (d, J = 10.5 Hz, 3H).

Example 34. (4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Preparation of 3-methoxyphenyl)(morpholino)methanone (Compound 11-4)

Step 1. Synthesis of compound 10-4

Compound 10-4 was obtained as a white solid from compound 9-1 (54 mg, 0.12 mmol) and (4-amino-3-methoxyphenyl)(morpholino)methanone (45 mg, 0.19 mmol) in the same manner as in compound 10-1 . 48.1 mg was obtained (73.7%)

^1H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J = 8.2 Hz, 1H), 7.76 - 7.64 (m, 3H), 7.34 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 6.87 - 6.77 (m, 2H), 5.40 (s, 2H), 5.32 (d, J = 7.9 Hz, 1H), 4.22 - 4.11 (m, 1H), 3.96 (d, J = 4.6 Hz, 6H), 3.73 (d, J = 15.6 Hz, 11H), 2.06 (d, J = 10.8 Hz, 2H), 1.68 (ddt, J = 30.7, 13.0, 3.9 Hz, 3H), 1.54 - 1.36 (m , 2H), 1.26 - 1.14 (m, 3H).

Step 2. Compound 11-4 Preparation

From compound 10-4 (27.1 mg, 0.042 mmol), 11.1 mg of compound 11-4 was obtained as a white solid (50.2%) by the same method as for compound 11-1 .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.07 - 6.94 (m, 2H), 5.96 (s, 1H), 4.11 (d, J = 9.1 Hz, 1H), 4.02 (s, 3H), 3.93 (s, 3H), 3.71 (s, 8H), 2.06 (t, J = 8.6 Hz, 2H), 1.85 - 1.60 (m, 3H), 1.34 (dq, J = 50.7, 11.9 Hz, 5H).

Example 35. (4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- Preparation of 3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (Compound 11-5)

Step 1. Synthesis of compound 10-5

Compound 9-1 (60 mg, 0.13 mmol) and (4-amino-3-methoxyphenyl) (4-methylpiperazin-1-yl) methanone (39.6 mg, 0.16 mmol) were prepared by the same preparation method as Compound 10-1 . Yield 60.2 mg (68.1 %) of 10-5 as a yellow solid.

^1H NMR (500 MHz, CDCl ₃ ) δ 8.75 (d, J = 8.7 Hz, 1H), 7.73 (s, 1H), 7.69 (d, J = 4.4 Hz, 2H), 7.38 - 7.32 (m, 2H) , 7.06 - 7.00 (m, 2H), 6.87 - 6.79 (m, 2H), 5.41 (s, 2H), 5.32 (d, J = 7.8 Hz, 1H), 4.21 - 4.11 (m, 1H), 3.97 (d , J = 7.5 Hz, 6H), 3.76 (s, 7H), 2.45 (s, 4H), 2.33 (s, 3H), 2.10 - 2.00 (m, 2H), 1.72 (dt, J = 12.6, 4.3 Hz, 2H), 1.68 - 1.59 (m, 1H), 1.44 (dddd, J = 14.7, 11.7, 7.6, 3.7 Hz, 2H), 1.23 (hept, J = 7.8 Hz, 3H).

Step 2. Compound 11-5 Preparation

From compound 10-5 (44 mg, 0.066 mmol), 12.1 mg of compound 11-5 was obtained as a white solid (33.7%) by the same method as for compound 11-1 .

^1H NMR (500 MHz, CDCl ₃ ) δ 10.42 (s, 1H), 8.66 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 16.8 Hz, 2H), 7.66 (s, 1H), 7.01 (d, J = 6.5 Hz, 2H), 5.38 (d, J = 7.8 Hz, 1H), 4.23 - 4.10 (m, 1H), 3.98 (d, J = 36.4 Hz, 7H), 3.70 (s, 4H) , 2.40 (d, J = 54.2 Hz, 7H), 2.13 - 2.02 (m, 2H), 1.79 - 1.70 (m, 2H), 1.66 (d, J = 12.9 Hz, 1H), 1.46 (q, J = 12.5 Hz, 2H), 1.34 - 1.26 (m, 4H).

Example 36. 4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-3 Preparation of -methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 11-6)

Step 1. Synthesis of compound 10-6

Compound 9-1 (60 mg, 0.13 mmol) and 4-amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (41.8 mg, 0.16 mmol) were prepared by the same preparation method as Compound 10-1 . Yielded 48.2 mg of compound 10-6 as a green solid (54.7%)

^1H NMR (400 MHz, CDCl ₃ ) δ 8.77 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 10.3 Hz, 2H), 7.43 (d, J = 1.9 Hz) , 1H), 7.41 - 7.30 (m, 3H), 6.87 - 6.79 (m, 2H), 6.70 (d, J = 8.1 Hz, 1H), 5.39 (s, 2H), 5.33 (d, J = 7.8 Hz, 1H), 4.27 - 4.11 (m, 2H), 3.98 (d, J = 4.1 Hz, 6H), 3.75 (s, 3H), 3.34 (d, J = 12.2 Hz, 4H), 2.72 (td, J = 12.0 , 3.7 Hz, 2H), 2.65 (s, 3H), 2.18 (tt, J = 14.1, 7.3 Hz, 4H), 2.04 (dt, J = 12.8, 4.2 Hz, 2H), 1.76 - 1.67 (m, 2H) , 1.46 (dt, J = 14.7, 11.2 Hz, 2H), 1.29 (dd, J = 12.4, 5.6 Hz, 3H).

Step 2. Compound 11-6 Preparation

From compound 10-6 (35.6 mg, 0.052 mmol), 13.1 mg of compound 11-6 was obtained as a yellow solid (47.5%) by the same method as for compound 11-1 .

^1H NMR (300 MHz, CDCl ₃ ) δ 8.66 (d, J = 8.5 Hz, 1H), 7.84 - 7.65 (m, 3H), 7.39 (d, J = 1.8 Hz, 1H), 7.24 - 7.18 (m, 1H), 6.06 (d, J = 8.1 Hz, 1H), 5.79 (s, 1H), 5.39 (d, J = 7.9 Hz, 1H), 4.18 (s, 2H), 3.99 (d, J = 13.5 Hz, 6H), 2.90 (d, J = 11.3 Hz, 2H), 2.35 (s, 3H), 2.21 (t, J = 11.5 Hz, 3H), 2.04 (s, 5H), 1.81 - 1.64 (m, 5H), 1.55 - 1.40 (m, 2H), 1.25 (d, J = 10.1 Hz, 4H).

<Example C. Preparation of compound 14 according to Scheme 3>

[Scheme 3]

Example 37. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 14-1) Preparation

Step 1. Compound 12-1 synthesis

Compound 6-1 (3.10 g, 5 mmol), molybdenum hexacarbonyl (Mo(CO) ₆ ; 1.60 g, 6 mmol), tert-Butyl carbazate (2.0 g, 15 mmol) were mixed with Dioxane (30 mL), 1,8-diazabicyclo[5.4.0]undencen-7 (DBU; 2.2 mL, 15 mmol) was added, oxygen was removed by purging with argon gas, and Pd (dppf) After adding Cl ₂ (180 mg, 0.012 mmol), the mixture was stirred at 110°C for 10 minutes. The reaction mixture was concentrated and separated by silica gel column chromatography (EA:Hx=1:2) to obtain 2.03 g of tert-butyl hydrazine carboxylate as a white solid (58%).

After dissolving tert-butyl hydrazine carboxylate (1.5 g, 2.1372 mmol) in MC (10.0 mL), TFA (20 mL) was added and stirred at room temperature for 16 hours. After concentrating the reactant under reduced pressure, the pH was adjusted to 7 with sat'd NaHCO ₃ aqueous solution, EA (50 mL) was added, washed with water (50 mL), and then water was removed (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:1) to give 800 mg of compound 12-1 as a pale brown solid (66%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.36 (s, 8H), 1.58 (s, 2H), 1.73 (s, 3H), 3.09 (t, J = 4.8 Hz, 5H), 3.71 (s, 3H), 3.75 (t, J = 4.8 Hz, 5H), 3.86 (s, 3H), 4.60 (s, 2H), 5.33 (s, 2H), 6.51 (dd, J = 8.9, 2.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.48 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H), 9.40 (d, J = 7.6 Hz, 1H), 9.91 (s, 1H).

Step 2. Compound 13-1 synthesis

Compound 12-1 (60 mg, 0.10 mmol) N,N-dimethylformamide dimethyl acetal (DMF-DMA ; 1 mL) and stirred at 100°C for 2 hours. Hx (2 mL) was added to the reaction mixture, and the resulting solid was dissolved in MeCN (1 mL) after filtration, and a drop of AcOH and methylamine (2M in THF; 0. 2 mL, 0.4 mmol) were added thereto, followed by 85 ° C for 24 hours. After stirring at room temperature, the resulting solid was filtered to obtain 20.1 mg of compound 13-1 as a brown solid (32.4%).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.75 (d, J = 8.2 Hz, 1H), 7.76 - 7.64 (m, 3H), 7.34 (d, J = 8.5 Hz, 2H), 7.02 (d, J = 7.8 Hz, 2H), 6.87 - 6.77 (m, 2H), 5.40 (s, 2H), 5.32 (d, J = 7.9 Hz, 1H), 4.22 - 4.11 (m, 1H), 3.96 (d, J = 4.6 Hz, 6H), 3.73 (d, J = 15.6 Hz, 11H), 2.06 (d, J = 10.8 Hz, 2H), 1.68 (ddt, J = 30.7, 13.0, 3.9 Hz, 3H), 1.54 - 1.36 (m , 2H), 1.26 - 1.14 (m, 3H).

Step 3. Compound 14-1 Preparation

From compound 13-1 (23 mg, 0.037 mmol), 13.1 mg of compound 14-1 was obtained as a white solid in the same manner as in the preparation of compound 8-1 . (70.2%)

^1H NMR (500 MHz, CDCl ₃ ) δ 1.38 (d, J = 11.8 Hz, 1H), 1.60 - 1.43 (m, 3H), 1.64 (d, J = 12.5 Hz, 1H), 1.85 (dq, J = 12.7, 4.4 Hz, 3H), 2.10 (dd, J = 11.6, 5.7 Hz, 2H), 3.19 - 3.04 (m, 4H), 3.87 (d, J = 6.5 Hz, 7H), 4.08 (s, 3H), 4.26 - 4.13 (m, 1H), 6.52 (d, J = 8.9 Hz, 2H), 7.33 (s, 1H), 8.12 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 10.25 (d , J = 7.4 Hz, 1H), 11.28 (s, 1H).

Example 38. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 14-2) manufacturing

Step 1. Compound 13-2 Preparation

Compound 12-1 (60 mg, 0.10 mmol) Dissolve in formamide (1 mL) and stir at 100°C for 1 hour. After concentrating the reaction mixture, the resulting solid was dissolved in phosphorus oxychloride (POCl3; 2mL) and stirred at 100°C for 24 hours. The reaction mixture was cooled to room temperature and added slowly to ice water (10 mL), and the resulting solid was filtered to obtain 43.0 mg of compound 13-2 as a brown solid (70.5%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.37 - 1.46 (m, 4H), 1.53 (s, 1H), 1.74 (s, 3H), 1.87 - 2.04 (m, 4H), 3.08 (d, J = 6.0 Hz, 4H), 3.71 (s, 3H), 3.75 (t, J = 4.7 Hz, 4H), 3.86 (d, J = 1.6 Hz, 3H), 5.39 (d, J = 5.9 Hz, 2H), 6.50 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 2.9 Hz, 1H), 6.90 (d, J = 8.4 Hz, 2H), 7.19 - 7.27 (m, 2H), 7.53 (d, J = 6.4 Hz, 1H), 8.07 - 8.17 (m, 2H), 11.70 (d, J = 22.5 Hz, 1H).

Step 2. Compound 14-2 Preparation

From compound 13-2 (22 mg, 0.0359 mmol), 9.8 mg of compound 14-2 was obtained as a yellow solid in the same manner as in the preparation of compound 8-1 (50.5%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.39 (dt, J = 19.7, 10.5 Hz, 7H), 1.58 (s, 1H), 1.74 (s, 2H), 1.96 (d, J = 11.9 Hz, 2H), 3.05 - 3.11 (m, 4H), 3.75 (t, J = 4.8 Hz, 4H), 3.84 (s, 3H), 6.48 (dd, J = 8.8, 2.6 Hz, 1H), 6.64 (d, J = 2.5 Hz, 1H), 7.42 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 9.35 (d, J = 7.8 Hz, 1H), 9.90 (s, 1H), 13.26 (s, 1H) ).

Example 39. 5-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1,3,4 Preparation of -oxadiazol-2(3H)-one (Compound 14-3)

Step 1. Preparation of compound 13-3

After dissolving compound 12-1 (30 mg, 0.05 mmol) in THF (2 mL), 1,1'-carbonyldiimidazole (CDI; 12 mg, 0.075 mmol) was added and stirred at 60°C for 14 hours. The reaction mixture was concentrated and separated by silica gel column chromatography (MC:MeOH = 10:1) to obtain 13 mg of compound 13-3 as a light gray solid (41%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.36 (s, 4H), 1.37 - 1.45 (m, 3H), 1.57 (s, 1H), 1.71 (d, J = 12.6 Hz, 2H), 1.94 - 2.00 (m, 2H), 3.09 (t, J = 4.7 Hz, 4H), 3.71 (s, 3H), 3.75 (s, 4H), 3.85 (s, 3H), 4.07 (s, 1H), 5.35 (s , 2H), 6.51 (dd, J = 8.7, 2.5 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.3 Hz) , 2H), 7.63 (s, 1H).

Step 2. Compound 14-3 Preparation

From compound 13-3 (13 mg, 0.0207 mmol), 4.6 mg of compound 14-3 was obtained as a yellow solid in the same manner as in the preparation of compound 8-1 . (46%)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.71 (s, 6H), 1.92 (s, 5H), 3.09 (dd, J = 5.8, 3.7 Hz, 5H), 3.76 (t, J = 4.8 Hz, 6H), 3.84 (s, 4H), 4.10 (s, 1H), 6.49 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.71 (d, J = 7.9 Hz, 1H), 7.52 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 8.24 (s, 1H), 13.41 (s, 1H).

<Example D. Preparation of compound 18 according to Scheme 4>

[Scheme 4]

Example 40. N ⁴ -cyclohexyl-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-3-(oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 18-1)

Step 1. Synthesis of compound 15-1

Chemical Formula 6-1 (6.81 g, 10.9385 mmol), potassium vinyltrifluoroborate (CH ₂ =CHBF ₃ K; 2.93 g, 21.8770 mmol), potassium carbonate (K ₂ CO ₃ ) (4.5 g, 32.8155 mmol) toluene: After dissolving in EtOH (ethanol) = 3: 1 (200 mL), oxygen was removed by purging with argon gas, and Pd (PPh ₃ ) ₄ (1.26 g, 1.0938 mmol) was added and stirred at 80 ^° C for 14 hours. did After concentrating the mixture under reduced pressure, EA (200 mL) was added, washed with water (200 mL), and water was removed (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:3) to give 5.26 g (84.4%) of compound 15-1 as a pale brown solid.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.17 (dd, J = 9.8, 6.7 Hz, 1H), 1.30 - 1.49 (m, 5H), 1.65 (d, J = 12.8 Hz, 1H), 1.76 ( d, J = 12.3 Hz, 3H), 1.92 (d, J = 12.1 Hz, 2H), 2.09 (d, J = 1.7 Hz, 1H), 3.07 - 3.10 (m, 4H), 3.71 (d, J = 1.7 Hz, 3H), 3.75 (t, J = 4.8 Hz, 4H), 3.86 (d, J = 1.8 Hz, 3H), 4.11 (s, 1H), 5.28 (s, 2H), 5.37 (dd, J = 11.0 , 2.1 Hz, 1H), 5.92 (dd, J = 17.1, 2.1 Hz, 1H), 6.48 - 6.53 (m, 2H), 6.66 (t, J = 2.1 Hz, 1H), 6.87 - 6.90 (m, 2H) , 7.16 - 7.24 (m, 3H), 7.41 (s, 1H), 8.17 (d, J = 8.8 Hz, 1H).

Step 2. Compound 16-1 synthesis

After dissolving compound 15-1 (5.26 g, 9.2327 mmol) and NMO (2.68 g, 18.4655 mmol) in THF : H ₂ O = 3:1, OsO ₄ (2.5 wt% in H ₂ O; 8.4 mL) was added. After slowly adding dropwise, the mixture was stirred at 0 ^° C for 1 hour. After concentrating the mixture under reduced pressure, ethyl acetate (200 mL) was added thereto, washed with water (200 mL), and then water was removed (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 1:1) to give the dihydroxy compound as a yellow solid (4.2g) (75.4%).

After dissolving the above dihydroxy compound (4.2g, 6.96mmol) in THF : H ₂ O = 3:1, NaIO ₄ (2.68 g, 20.8706 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After concentrating the mixture under reduced pressure, ethyl acetate (200 mL) was added, washed with water (200 mL), and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:MC = 1:20) to give formula 16-1 as a brown solid (70.7%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.39 (q, J = 10.3, 9.7 Hz, 5H), 1.59 (s, 1H), 1.72 (s, 2H), 1.99 (s, 2H), 3.10 ( t, J = 4.8 Hz, 4H), 3.72 (s, 3H), 3.73 - 3.77 (m, 4H), 3.85 (s, 3H), 4.03 (q, J = 7.1 Hz, 1H), 5.42 (s, 2H) ), 6.52 (dd, J = 8.9, 2.5 Hz, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.88 - 6.93 (m, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.69 (s, 1H), 7.89 (d, J = 7.7 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 9.82 (s, 1H).

Step 3. Compound 17-1 synthesis

Compound 16-1 (200mg, 0.35 mmol), p-toluenesulfonylmethyl isocyanide (TosMIC; 75 mg, 0.38 mmol), and K ₂ CO ₃ (145 mg, 1.05 mmol) were added to MeOH (5 mL). After that, the mixture was stirred at 50 ^° C for 1 hour. EA (25 mL) was added to the mixture, washed with water (25 mL), dried, and then concentrated under reduced pressure (Na ₂ SO ₄ ). The residue was separated by silica gel column chromatography (EA:HX:MC = 2:1:1) to give 166 mg of compound 17-1 as a pale brown solid. (78%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.25 (s, 2H), 1.41 (t, J = 9.6 Hz, 5H), 1.63 (d, J = 12.8 Hz, 1H), 1.75 (s, 3H) , 2.01 (d, J = 9.2 Hz, 3H), 3.10 (t, J = 4.8 Hz, 4H), 3.71 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 3.86 (s, 3H) , 4.07 (s, 1H), 5.35 (s, 2H), 6.52 (dd, J = 8.8, 2.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 5.6 Hz, 2H), 8.12 (d, J = 8.8 Hz, 1H) , 8.64 (s, 1H).

Step 4. Compound 18-1 Preparation

From Chemical Formula 17-1 (417 mg, 0.6828 mmol), 245 mg of Compound 18-1 was obtained as a white solid (73.3%) in the same manner as in the preparation of Compound 8-1 .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.41 (t, J = 9.3 Hz, 5H), 1.63 (d, J = 12.5 Hz, 1H), 1.74 (s, 3H), 2.01 (d, J = 11.1 Hz, 3H), 3.09 (t, J = 4.8 Hz, 4H), 3.75 (dd, J = 5.9, 3.6 Hz, 4H), 3.85 (s, 3H), 4.09 (s, 1H), 6.49 (dd, J = 8.8, 2.6 Hz, 1H), 6.65 - 6.68 (m, 2H), 7.50 (s, 1H), 7.59 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 8.63 (s, 1H) ), 13.23 (s, 1H).

Example 41. N ⁴ -cyclohexyl-3-(1H-imidazol-5-yl)-N ⁶ Preparation of -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 18-2)

Step 1. Synthesis of compound 17-2

Compound 16-1 (50mg, 0.0875 mmol), p-toluenesulfonylmethyl isocyanide (TosMIC; 19 mg, 0.095 mmol), and K ₂ CO ₃ (36 mg, 0.262 mmol) were added to MeOH (2mL). , and stirred at 50 ^° C for 1 hour. EA (5 mL) was added to the mixture, washed with water (5 mL), dried, and concentrated under reduced pressure (Na ₂ SO ₄ ). Ammonia (7M in MeOH; 1 mL) was added to the residue and stirred under reflux for 4 hours to obtain 9 mg of crude compound 17-2 .

¹ H NMR (300 MHz, Chloroform-d) δ 1.26 (s, 4H), 1.50 (s, 5H), 1.83 (s, 3H), 2.11 (s, 2H), 3.06 - 3.18 (m, 4H), 3.75 (s, 3H), 3.89 (t, J = 4.7 Hz, 4H), 3.91 (s, 3H), 5.40 (s, 2H), 6.54 (dd, J = 4.7, 2.3 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 7.28 - 7.38 (m, 3H), 7.60 (dd, J = 2.1, 1.3 Hz, 1H), 7.68 (d, J = 1.3 Hz, 1H), 8.60 (d, J = 9.5 Hz, 1H), 9.26 (s, 1H), 10.28 (d, J = 7.5 Hz, 1H).

Step 2. Compound 18-2 Preparation

From compound 17-2 (9 mg), 1.7 mg of compound 18-2 was obtained as a light gray solid in the same manner as in the preparation of compound 8-1 .

¹ H NMR (400 MHz, Chloroform-d) δ 1.51 (t, J = 9.1 Hz, 3H), 1.84 (s, 5H), 2.11 (s, 3H), 3.12 (t, J = 4.8 Hz, 3H), 3.89 (d, J = 4.0 Hz, 5H), 4.22 (s, 1H), 6.54 (s, 1H), 7.30 (s, 1H), 7.64 (s, 1H), 7.72 (s, 1H), 8.44 (d , J = 8.8 Hz, 1H), 9.38 (s, 1H), 10.42 (s, 1H).

<Example E. Preparation of compound 21 according to Scheme 5>

[Scheme 5]

Example 42. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 21- 1) Manufacturing

It was prepared through a three-step process from compound 6-1 according to Scheme 5 above.

Step 1. Synthesis of compound 19-1

After dissolving the compound 6-1 (1.87 g, 3.003 mmol) and cuprous iodide (CuI; 57 mg, 10% mmol) in dimethylformamide (DMF; 25 mL) and triethylamine (TEA; 5 mL) , trimethylsilylactylene (0.6 mL, 4.2051 mmol) was added, oxygen was removed by purging with argon gas, PdCl ₂ (PPh ₃ ) ₂ (105 mg, 5% mmol) was added, gas was removed, and stirring was performed at 80 ^o C for 2 hours. did After concentrating the mixture under reduced pressure, the residue was separated by silica gel column chromatography (EA:HX = 1:2), and the obtained compound was dissolved in tetrahydrofuran (20 mL) and then tetra-n-butylammonium fluoride (TBAF; 1.3 mL, 1.2 eq) was added and stirred at room temperature for 1 hour. After concentrating the mixture under reduced pressure, ethyl acetate (50 mL) was added, washed with water (50 mL), and then water was removed (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 1:2) to give 1.18 g of compound 19-1 as a pale brown solid (69%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (d, J = 2.8 Hz, 2H), 1.36 (d, J = 12.2 Hz, 8H), 1.70 (s, 3H), 1.96 (s, 3H) , 3.09 (t, J = 4.8 Hz, 4H), 3.71 (s, 3H), 3.75 (t, J = 4.8 Hz, 4H), 3.85 (s, 3H), 4.03 (s, 1H), 4.74 (s, 1H), 5.27 (s, 2H), 5.77 (s, 1H), 6.00 (d, J = 7.7 Hz, 1H), 6.48 - 6.54 (m, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.61 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H).

Step 2. Compound 20-1 synthesis

After dissolving the compound 19-1 (114 mg, 0.15 mmol) and cuprous iodide (CuI; 4 mg, 10% mmol) in dimethylformamide (DMF): methanol (MeOH) = 9: 1 (2 mL), Trimethylsilyl azide (0.040 mL, 0.3 mmol) was added and stirred at 100 ^° C for 6 hours. After concentrating the mixture under reduced pressure, EA (10 mL) was added thereto, washed with water (10 mL), and then water was removed (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:3) to give 87 mg (76%) of compound 20-1 as a pale brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.44 (d, J = 8.4 Hz, 5H), 1.59 (s, 1H), 1.77 (s, 2H), 2.01 (s, 2H), 2.19 (s, 1H), 3.06 - 3.11 (m, 4H), 3.70 (s, 3H), 3.75 (dd, J = 5.9, 3.6 Hz, 4H), 3.87 (s, 3H), 4.14 (s, 1H), 5.34 (s , 2H), 6.51 (dd, J = 8.9, 2.5 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 6.89 (d, J = 9.0 Hz, 3H), 7.19 - 7.25 (m, 2H) , 7.45 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.43 (s, 1H), 9.52 (s, 1H).

Step 3. Compound 21-1 Preparation

48 mg (68%) of compound 21-1 was obtained as a white solid from Formula 20-1 (87 mg, 0.1424 mmol) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.43 (d, J = 8.7 Hz, 5H), 1.79 (s, 3H), 1.96 - 2.06 (m, 3H), 3.09 (t, J = 4.8 Hz, 4H), 3.73 - 3.78 (m, 4H), 3.86 (s, 3H), 3.96 (s, 1H), 4.12 (s, 1H), 6.49 (dd, J = 8.9, 2.5 Hz, 1H), 6.66 (d , J = 2.6 Hz, 1H), 7.36 (s, 1H), 8.12 (d, J = 8.8 Hz, 1H), 8.68 - 8.76 (m, 1H), 9.66 (d, J = 7.4 Hz, 1H), 12.98 (s, 1H).

Example 43. N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 21-2) Preparation

Step 1. Compound 20-2 Preparation

The compound 19-1 (400 mg, 0.7046 mmol) was added with sodium azide (100 mg) and iodomethane (0.1 mL) in dimethyl sulfoxide (20 mL). ) and then dissolved in the mixture stirred for 12 hours, copper sulfate pentahydrate (14 mg, 8% mmol) and sodium L-ascorbate (27 mg, 20% mmol) were added. The mixture was stirred at room temperature for 12 hours or longer. Ethyl acetate (100 mL) was added to the mixture, washed with water (100 mL), dried, and then concentrated under reduced pressure (Na ₂ SO ₄ ). The residue was separated by silica gel column chromatography (EA:HX = 1:1) to give compound 20-2 in the form of a pale brown solid. (74%)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.40 - 1.62 (m, 6H), 1.77 (s, 3H), 1.97 (s, 2H), 2.55 (s, 1H), 3.09 (s, 4H), 3.70 (s, 3H), 3.75 (d, J = 4.9 Hz, 3H), 3.87 (s, 3H), 4.14 (s, 4H), 5.33 (s, 2H), 6.52 (d, J = 8.6 Hz, 1H) ), 6.66 (d, J = 3.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.45 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 8.58 (s, 1H), 9.74 (d, J = 7.2 Hz, 1H).

Step 2. Compound 21-2 Preparation

Compound 21-2 was obtained in the form of a light brown solid from compound 20-2 (327 mg, 0.5234 mmol) in the same manner as in the preparation of compound 8-1 . (59%)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.44 (d, J = 9.5 Hz, 5H), 1.57 (s, 1H), 1.78 (s, 3H), 1.98 (d, J = 9.2 Hz, 3H) , 3.08 (d, J = 5.0 Hz, 4H), 3.75 (d, J = 4.9 Hz, 4H), 3.86 (d, J = 1.8 Hz, 3H), 4.15 (d, J = 1.8 Hz, 3H), 6.49 (d, J = 8.9 Hz, 1H), 6.65 (s, 1H), 7.36 (s, 1H), 8.11 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 9.66 (d, J = 7.5 Hz, 1H), 12.94 (s, 1H).

Example 44. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 21-3)

Step 1. Synthesis of compound 19-3

Compound 19-3 was obtained in the form of a light brown solid from compound 6-3 (1.87 g, 2.9942 mmol) in the same manner as in the preparation of compound 19-1 . (64%)

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.23 (d, J = 2.1 Hz, 2H), 1.34 (s, 1H), 1.55 - 1.64 (m, 2H), 1.88 - 1.98 (m, 3H), 3.09 (t, J = 4.7 Hz, 5H), 3.71 (s, 3H), 3.75 (t, J = 4.8 Hz, 5H), 3.84 (s, 3H), 3.87 (d, J = 13.3 Hz, 3H), 4.22 (s, 1H), 4.69 (s, 1H), 5.27 (s, 2H), 6.11 (s, 1H), 6.52 (dd, J = 8.9, 2.6 Hz, 1H), 6.65 (d, J = 2.5 Hz) , 1H), 6.89 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 3.9 Hz, 2H), 8.04 (s, 1H).

Step 2. Synthesis of compound 20-3

From compound 19-3 (57 mg, 0.1000 mmol), 32 mg of compound 20-3 was obtained as a white solid (51.6%) in the same manner as in the preparation of compound 20-2 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.23 (d, J = 2.7 Hz, 5H), 1.34 (s, 1H), 1.54 - 1.60 (m, 2H), 2.04 (s, 3H), 3.09 ( t, J = 4.9 Hz, 4H), 3.70 (s, 3H), 3.74 (d, J = 5.0 Hz, 4H), 3.86 (s, 3H), 4.14 (s, 3H), 5.33 (s, 2H), 6.53 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.86 - 6.90 (m, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.47 (s, 1H) ), 7.69 (s, 1H), 8.18 (d, J = 8.7 Hz, 1H), 8.58 (s, 1H), 9.77 (d, J = 7.2 Hz, 1H).

Step 3. Compound 21-3 Preparation

From compound 20-3 (32 mg, 0.0510 mmol), 19.4 mg of compound 21-3 was obtained in the form of a light brown solid (77.6%) in the same manner as in the preparation of compound 8-1 .

^1H NMR (300 MHz, DMSO-d ₆ ) δ 1.09 (t, J = 7.0 Hz, 1H), 1.57 (dq, J = 8.3, 4.5, 3.7 Hz, 2H), 2.05 (d, J = 12.1 Hz, 3H), 3.09 (t, J = 4.8 Hz, 4H), 3.38 (q, J = 7.0 Hz, 1H), 3.47 - 3.63 (m, 3H), 3.75 (t, J = 4.8 Hz, 4H), 3.85 ( s, 3H), 3.86 - 3.96 (m, 3H), 4.16 (s, 3H), 4.33 (s, 1H), 6.50 (dd, J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz) , 1H), 7.41 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 8.56 (s, 1H), 9.72 (d, J = 7.2 Hz, 1H), 12.97 (s, 1H).

<Example F. Preparation of compound 26 according to Scheme 6>

[Scheme 6]

Example 45. N ⁴ -cyclohexyl-N ⁶ -(2-isopropoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 26-1) manufacturing

Step 1. Compound 22 synthesis

After dissolving compound 3 (10.75g, 40.43 mmol) in MC-THF (1:1 in v/v, 300 mL), 1,3-dihydropyran (30 mL, 328.8 mmol) and PTSA (2.01 g, 10.6 mmol) After addition, the mixture was stirred at room temperature for 15 hours. After the reaction was concentrated under reduced pressure, dissolved in EA (200 mL), washed with saturated NaHCO ₃ aqueous solution (100 mL) and brine (100 mL), dried (MgSO ₄ ), and concentrated under reduced pressure to obtain 11.77 g of compound 22 as a white solid ( 83.2%) was obtained.

¹ H NMR (300 MHz, CDCl ₃ ) δ 1.61-1.83 (m, 3H), 1.93-2.18 (m, 2H), 2.39-2.45 (m, 1 H), 3.78-3.85 (m, 1H), 4.10-4.19 (m, 1H), 6.01 (dd, J = 8.9, 3.0 Hz, 1H), 8.20 (s, 1H).

Step 2. Compound 23-1 synthesis

After dissolving compound 22 (100 mg, 0.286 mmol) in THF/IPA (1:4, 2 mL), cyclohexylamine (0.052 mL, 0.457 mmol) was added, followed by stirring at room temperature for 4 hours. The reactants were concentrated under reduced pressure and separated by silica gel column chromatography (EA:Hx = 1:10) to obtain 91.1 mg of compound 23-1 as a white solid (77.1%).

^1H NMR (400 MHz, CDCl ₃ ) δ 6.11 (d, J = 8.2 Hz, 1H), 5.84 (dd, J = 10.6, 2.5 Hz, 1H), 4.30 - 4.17 (m, 1H), 4.09 (dp, J = 11.8, 1.9 Hz, 1H), 3.76 (td, J = 11.6, 2.5 Hz, 1H), 2.44 (tdd, J = 12.6, 10.5, 4.2 Hz, 1H), 2.06 (ddt, J = 12.8, 9.1, 3.7 Hz, 3H), 1.91 - 1.82 (m, 1H), 1.81 - 1.61 (m, 5H), 1.61 - 1.58 (m, 1H), 1.49 (dtt, J = 14.1, 11.0, 3.4 Hz, 2H), 1.39 - 1.22 (m, 3H).

Step 3. Synthesis of Compound 24-1

Dioxane _{: water} ( 4 :1 in v/ v, 2 mL), purging with argon gas to remove oxygen, adding Pd(PPh ₃ ) ₄ (18.4 mg, 0.0159 mmol), removing the gas, and in a microwave reactor at 120 ^o C for 1 hour. Stir. Water (20 mL) was added to the mixture and extracted with EA (20 mL X 2). Water was removed from the organic layer (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:5 1:5) to give 64.7 mg (32.2%) of compound 24-1 as a white solid.

^1H NMR (400 MHz, CDCl ₃ ) δ 8.17 (q, J = 5.7, 5.0 Hz, 1H), 8.08 (q, J = 6.4, 4.7 Hz, 1H), 5.96 (dq, J = 11.2, 4.8, 3.9 Hz, 1H), 5.50 (tt, J = 7.7, 4.0 Hz, 1H), 4.13 (d, J = 11.9 Hz, 1H), 3.97 (t, J = 4.2 Hz, 3H), 3.88 - 3.69 (m, 1H) ), 2.57 (q, J = 11.3 Hz, 1H), 2.18 - 2.10 (m, 1H), 1.97 - 1.82 (m, 5H), 1.67 - 1.56 (m, 4H), 1.51 (dt, J = 11.0, 5.5 Hz, 3H), 1.24 (d, J = 3.4 Hz, 4H).

Step 4. Compound 25-1 synthesis

After dissolving chemical 24-1 (32 mg, 0.077 mmol) in 2-Butanol (1 mL), 2-isopropoxy-4-morpholinoaniline (21.7 mg, 0.092 mmol) and K ₂ CO ₃ (17.0 mg, 0.123 mmol) are added. Oxygen was removed by purging with argon gas for 5 minutes, and after adding Pd ₂ dba ₃ (17.6 mg, 0.019 mmol) and X-phos (13.5 mg, 0.028 mmol), the mixture was stirred at 110° C. for one day. The reaction was filtered (celite pad) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH =99:1) to give 36.3 mg of compound 25-1 as a white solid (76.7%).

^1H NMR (300 MHz, CDCl ₃ ) δ 8.59 - 8.49 (m, 1H), 7.76 (d, J = 3.0 Hz, 2H), 7.42 (s, 1H), 6.54 (d, J = 7.1 Hz, 2H) , 5.84 (dd, J = 10.7, 2.4 Hz, 1H), 5.36 - 5.21 (m, 1H), 4.67 - 4.52 (m, 1H), 4.15 (d, J = 11.1 Hz, 2H), 3.98 (s, 3H) ), 3.92 - 3.84 (m, 4H), 3.82 (d, J = 10.7 Hz, 1H), 3.17 - 3.06 (m, 4H), 2.58 (dd, J = 16.1, 7.0 Hz, 1H), 2.08 (s, 3H), 1.91 (d, J = 13.1 Hz, 1H), 1.70 (d, J = 37.7 Hz, 9H), 1.42 (d, J = 6.1 Hz, 8H), and 1.32 - 1.12 (m, 5H).

Step 5. Compound 26-1 Preparation

After dissolving compound 25-1 (36 mg, 0.058 mmol) in MeOH (2 mL), 6N HCl (0.1 mL) was added at 0 ^° C, and the mixture was heated to room temperature and stirred for 2 hours. After concentrating the reactant under reduced pressure, saturated NaHCO ₃ aqueous solution (20 mL) was added thereto, followed by extraction with ethyl acetate (20 mL X 2). After removing moisture from the organic layer (Na ₂ SO ₄ ) and concentrating under reduced pressure, the residue was separated by silica gel column chromatography (MC:MeOH = 97:3) to obtain 16.6 mg of compound 26-1 as a white solid (53.4%). ).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.77 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.31 (s, 1H), 6.66 (d, J = 2.5 Hz, 1H), 6.49 (dd, J = 8.9, 2.5 Hz, 1H), 5.76 (s, 1H), 5.67 (d, J = 7.5 Hz, 1H), 4.65 ( p, J = 6.0 Hz, 1H), 4.00 (s, 1H), 3.93 (s, 3H), 3.74 (dd, J = 6.0, 3.5 Hz, 4H), 3.05 (t, J = 4.8 Hz, 4H), 1.99 (d, J = 10.2 Hz, 2H), 1.65 (s, 2H), 1.31 (t, J = 6.2 Hz, 11H).

Example 46. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ Preparation of -phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 26-2)

Step 1. Compound 23-2 synthesis

After dissolving compound 22 (200 mg, 0.57 mmol) in isopropyl alcohol (IPA) (2.0 mL), aniline (0.06 mL, 0.68 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.68 mmol) were added. After addition, stir at 40 degrees for 1 hour. After completion of the reaction, the produced solid was filtered to obtain 175 mg of Compound 23-2 in the form of a white solid. (75.4%).

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.62 (s, 2H), 1.67 - 1.85 (m, 2H), 1.86 - 1.99 (m, 1H), 2.05 - 2.18 (m, 1H), 2.48 (tdd, J = 12.7, 10.4, 4.2 Hz, 1H), 3.78 (td, J = 11.7, 2.6 Hz, 1H), 4.06 - 4.19 (m, 1H), 5.91 (dd, J = 10.6, 2.6 Hz, 1H), 7.20 ( t, J = 7.4 Hz, 1H), 7.37 - 7.48 (m, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.94 (s, 1H).

Step 2. Synthesis of compound 24-2

Compound 23-2 (175 mg, 0.43 mmol), 1-methylpyrazole-4-boronic acid (108.4 mg, 0.86 mmol) and potassium carbonate (K ₂ CO ₃ ) (237.7 mg, 1.72 mmol) were mixed with Dioxane: H ₂ O ( 4:1 in v/v, 2 mL), purged with argon gas to remove oxygen, add Pd(PPh ₃ ) ₄ (32.8 mg, 0.028 mmol), remove the gas, and heat in a microwave reactor at 110 ^o C for 1 hour. Water (10 mL) was added to the mixture and extracted with ethyl acetate (20 mL X 2). The combined organic layers were filtered over sodium sulfate (Na ₂ SO ₄ ) and concentrated under reduced pressure. The mixture was subjected to silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 71.2 mg of compound 24-2 as a white solid. (40.4%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.61 (d, J = 8.8 Hz, 1H), 1.72 - 1.84 (m, 2H), 1.93 (d, J = 13.6 Hz, 1H), 2.10 (d, J = 5.0 Hz, 1H), 2.49 - 2.61 (m, 1H), 3.83 (td, J = 11.6, 2.4 Hz, 1H), 4.04 (s, 3H), 4.12 - 4.18 (m, 1H), 5.98 (dd, J = 10.8, 2.5 Hz, 1H), 7.15 (tt, J = 7.1, 1.1 Hz, 1H), 7.37 (tt, J = 7.5, 2.1 Hz, 2H), 7.43 - 7.49 (m, 1H), 7.59 - 7.65 ( m, 2H), 7.82 - 7.87 (m, 2H).

Step 3. Synthesis of Compound 25-2

After dissolving Chemical Formula 24-2 (71.2 mg, 0.174 mmol) in 2 mL of 2-Butanol, Chemical Formula aniline (46.02 mg, 0.208 mmol) and potassium carbonate (38.4 mg, 0.278 mmol) were added. Oxygen was removed by purging with argon gas for 5 minutes, and tris(dibenzylideneacetone)dipalladium(0) (39.3 mg, 0.043 mmol) and Xphos (28.6 mg, 0.06 mmol) were added and stirred at 110°C for 1 hour. do. The mixture was concentrated under reduced pressure after filtering through a celite pad. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to give 38.7 mg of compound 25-2 as a white solid. (38.2%).

^1H NMR (400 MHz, DMSO) δ 4.23 (s, 3H), 7.32 (s, 1H), 7.46 (d, J = 7.6 Hz, 2H), 8.01 (s, 1H), 8.33 (d, J = 1.7 Hz, 1H), 8.86 (s, 1H), 11.03 (s, 1H).

Step 4. Compound 26-2 Preparation

After dissolving Chemical Formula 25-2 (38.7 mg, 0.066 mmol) in 2 mL of methanol, 0.1 mL of 6N HCl was added at 0 °C, and the mixture was stirred for 1 hour while switching to room temperature. After completion of the reaction, methanol was blown off, sodium bicarbonate (10 mL) was added to the mixture, and extraction was performed with ethyl acetate (20 mL X 2). The residue was purified by silica gel column chromatography (dichloromethane:methanol = 19:1) to give 17.5 mg of compound 26-2 as a white solid. (53.3%).

¹ H NMR (400 MHz, DMSO) δ 3.11 (dd, J = 5.7, 3.9 Hz, 4H), 3.72 - 3.83 (m, 7H), 3.94 (s, 3H), 6.47 (dd, J = 8.7, 2.6 Hz , 1H), 6.65 (d, J = 2.6 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 2H), 7.64 (d, J = 7.8 Hz, 2H) ), 7.79 (q, J = 13.7, 12.9 Hz, 4H), 8.14 (s, 1H), 12.93 (s, 1H).

<Example G. Preparation of compound 28 according to Scheme 7>

[Scheme 7]

Example 47. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ Preparation of -(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 28-1)

Step 1. Compound 27-1 synthesis

After adding TFA (44.2 μL) to 2-butanol (2-BuOH; 5 mL), 2-methoxy-4-morpholinoaniline (126 mg, 0.60 mmol in THF 1 mL) was added dropwise for 3 minutes at room temperature. Compound 4-3 (190 mg, 0.54 mmol in THF 3 mL) was added dropwise to the mixture over 3 minutes, and then the mixture was stirred at 110°C for 14 hours. After adjusting the pH of the reaction mixture to 7 with sat'd NaHCO ₃ aqueous solution, EA (8 mL) was added, washed with water (3 mL), dried, and concentrated under reduced pressure (Na ₂ SO ₄ ). The residue was separated by silica gel column chromatography (MC: MeOH = 10:1) to give 21 mg of compound 27-1 (7.3%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.19-1.26 (m, 1H), 1.31-1.46 (m, 4H), 1.56-1.63 (m, 1H), 1.68-1.75 (m, 2H), 1.90 -1.96 (m, 2H), 3.06-3.11 (m, 4H), 3.71 (s, 3H), 3.73-3.76 (m, 4H), 3.84 (s, 3H), 3.99-4.07 (m, 1H), 5.23 (s, 2H), 6.09 (d, J = 7.9 Hz, 1H), 6.50 (dd, J = 8.9, 2.6 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 8.9) 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H).

Step 2. Compound 28-1 Preparation

From compound 27-1 (20 mg, 0.03 mmol) and boronate (13 mg, 0.05 mmol), 11.3 mg of compound 28-1 was obtained in the form of a light brown solid (56%) in the same manner as in compound 7-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 1.30-1.46 (m, 2H), 2.04-2.14 (m, 3H), 2.42-2.49 (m, 2H), 2.52-2.57 (m, 1H), 2.72 (s, 3H), 3.55-3.59 (m, 4H), 4.22-4.26 (m, 4H), 4.40 (s, 3H), 4.46 (s, 3H), 4.58-4.65 (m, 1H), 6.09 (d) , J = 7.5 Hz, 1H), 7.01 (dd, J = 8.9, 2.6 Hz, 1H), 7.18 (d, J = 2.6 Hz, 1H), 7.80 (s, 1H), 8.19 (s, 1H), 8.42 (s, 1H), 8.94 (d, J = 8.8 Hz, 1H).

<Example H. Preparation of compound 33 according to Scheme 8>

[Scheme 8]

Example 48. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-5-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 33-1)

Step 1. Preparation of Compound 29

From compound 5-2 (1.0 g, 2.208 mmol), 633 mg of compound 29 was obtained (71%) in the same manner as in the preparation of compound 16-1 in Example 40.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.37 - 7.33 (m, 1H), 7.33 - 7.24 (m, 1H), 7.18 (d, J = 8.7 Hz, 2H), 6.91 - 6.85 (m, 2H) ), 6.02 (dd, J = 17.1, 1.9 Hz, 1H), 5.50 - 5.41 (m, 1H), 5.37 (s, 2H), 4.37 (d, J = 8.6 Hz, 1H), 3.95 - 3.86 (m, 2H), 3.71 (s, 3H), 3.47 - 3.36 (m, 2H), 1.79 (d, J = 5.7 Hz, 4H).

Step 2. Preparation of Compound 30

From compound 29 (623 mg, 1.557 mmol), 480 mg of compound 30 was obtained (77%) in the same manner as in the preparation of compound 16-1 in Example 40.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 8.39 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 5.53 (s, 2H), 4.26 (dd, J = 7.4, 3.6 Hz, 1H), 3.88 (dt, J = 11.7, 4.0 Hz, 2H), 3.52 (ddd, J = 12.0, 10.4 , 2.5 Hz, 2H), 2.01 (d, J = 8.5 Hz, 2H), and 1.63 - 1.50 (m, 2H).

Step 3. Preparation of compound 31

From compound 30 (100 mg, 0.2488 mmol), 65 mg of compound 31 was obtained (60%) in the same manner as in the preparation of compound 17-1 in Example 40.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 7.67 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.92 - 6.87 (m, 2H), 5.45 (s, 2H), 4.31 (d, J = 10.4 Hz, 1H), 3.90 (d, J = 11.7 Hz, 2H), 3.49 (d, J = 2.3 Hz, 2H), 1.94 (d, J = 12.6 Hz, 2H), 1.77 - 1.63 (m, 2H).

Step 4. Preparation of compound 32-1.

Compound 31 (50 mg, 0.1134 mmol), 2-methoxy-4-morpholinoaniline (28 mg, 0.136 mmol), potassium carbonate (23 mg, 0.1701 mmol), XPhos (19 mg, 0.039 mmol) were mixed with 2-butanol (1 mL). ) After removing oxygen, Pd (dba) ₃ (225 mg, 0.028 mmol) was added and stirred at 110 ^° C for 12 hours. The mixture was filtered through a celite pad, washed with EA (20 mL), and the organic layer was washed with water (10 mL), dried, and concentrated under reduced pressure (Na ₂ SO ₄ ). The residue was subjected to silica gel column chromatography (EA: HX = 2:1) to give 19 mg (27%) of compound 32-1 .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.62 (d, J = 2.1 Hz, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 2.2 Hz, 1H) , 7.22 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 7.3 Hz, 1H), 6.65 (s, 1H), 6.52 (d, J = 7.3 Hz, 1H). 8.6 Hz, 1H), 5.34 (s, 2H), 4.25 (s, 1H), 3.91 (s, 2H), 3.85 (s, 3H), 3.75 (s, 4H), 3.70 (d, J = 2.0 Hz, 3H), 3.46 (s, 2H), 3.09 (s, 4H), 1.97 (d, J = 12.6 Hz, 3H), 1.65 (d, J = 11.4 Hz, 2H).

Step 5. Preparation of compound 33-1.

4 mg of compound 33-1 was obtained from compound 32-1 (10 mg, 0.0163 mmol) in the same manner as in compound 8-1 (50%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.26 (s, 1H), 8.62 (s, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 6.71 (d, J = 7.4 Hz, 1H), 6.65 (d, J = 2.6 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 4.28 (s, 1H), 3.91 (d, J = 11.7 Hz, 2H), 3.84 (s, 3H), 3.76 (s, 4H), 3.48 (s, 2H), 3.10 (t, J = 4.9 Hz, 4H), 2.00 (d, J = 12.7 Hz, 3H), 1.73 - 1.62 (m, 3H).

Example 49. 3-methoxy-N-methyl-4-((3-(oxazol-5-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4 -d] pyrimidin-6-yl) amino) benzamide (Compound 33-2) Preparation

Step 1. Compound 32-2 Preparation

Chemical 31 (50 mg, 0.1134 mmol), 4-amino-3-methoxy-N-methylbenzamide (24 mg, 0.136 mmol), 42 mg of compound 32-2 was obtained in the same manner as in compound 32-1 (63%).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.64 (d, J = 2.8 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.35 (s, 1H), 7.86 (s, 1H) , 7.62 (d, J = 2.8 Hz, 1H), 7.52 (d, J = 11.2 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.96 (d, J = 7.3 Hz, 1H), 6.90 (d, J = 7.9 Hz, 2H), 5.42 (s, 2H), 4.34 (s, 1H), 3.95 (d, J = 3.2 Hz, 3H), 3.92 (s, 2H), 3.70 (s, 3H) , 3.53 (d, J = 11.6 Hz, 3H), 2.80 (d, J = 4.2 Hz, 3H), 2.02 - 1.97 (m, 2H), 1.70 (d, J = 11.9 Hz, 2H).

Step 2. Compound 33-2 Preparation

From compound 32-2 (30 mg, 0.0513 mmol), 5.1 mg of compound 33-2 was obtained in the same manner as in compound 8-1 (16%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.47 (s, 1H), 8.65 (s, 1H), 8.56 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 4.9 Hz, 1H) , 7.78 (s, 1H), 7.63 (s, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.49 (s, 1H), 6.90 (d, J = 7.4 Hz, 1H), 4.34 (s, 1H), 3.95 (s, 3H), 3.92 (s, 2H), 3.53 (t, J = 11.2 Hz, 2H), 2.80 (d, J = 4.4 Hz, 3H), 2.02 (d, J = 15.0 Hz, 3H), 1.70 (d, J = 9.8 Hz, 2H).

Example 50. N ⁶ -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(oxazol-5-yl)-N ⁴ Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 33-3)

Step 1. Preparation of Compound 32-3

Preparation of compound 32-1 from compound 31 (50 mg, 0.1134 mmol), 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (27 mg, 0.136 mmol) In the same manner, 17 mg of compound 32-3 was obtained (24%) and used in the next step.

Step 2. Preparation of Compound 33-3

From compound 32-3 (17 mg, 0.027 mmol), 2.1 mg of compound 33-3 was obtained in the same manner as in compound 8-1 (16%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.47 (s, 1H), 8.65 (d, J = 2.3 Hz, 1H), 8.62 (dd, J = 8.2, 2.2 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.37 (s, 1H), 7.33 (dd, J = 8.3, 2.2 Hz, 1H), 6.90 - 6.85 (m, 1H), 4.36 (s, 1H), 3.97 (d, J = 2.3 Hz, 3H), 3.92 (s, 2H), 3.78 (d, J = 2.3 Hz, 3H), 3.51 (d, J = 11.3 Hz, 3H), 2.03 (d, J = 11.7 Hz, 2H), 1.70 (d, J = 12.2 Hz, 2H).

Example 51. N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ Preparation of -((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-34)

Step 1. Preparation of compounds 7-34

Compound 6-4 (100mg, 0.160mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50mg, 0.240mmol) 96mg of compound 7-34 in the form of a brown solid was obtained in the same manner as in the preparation of compound 7-1 in Example 1 (96%).

^1H NMR (500 MHz, Chloroform-d) δ 1.26 (s, 1H), 1.64 (d, J = 7.7 Hz, 1H), 1.91 (tdd, J = 9.1, 7.1, 3.7 Hz, 2H), 2.05 (s , 2H), 3.13 (s, 4H), 3.47 (s, 1H), 3.76 (s, 4H), 3.91 (s, 9H), 3.97 (s, 3H), 4.11 (s, 2H), 5.40 (s, 2H), 5.72 (s, 1H), 6.55 (s, 2H), 6.84 (s, 2H), 7.26 (s, 1H), 7.36 (s, 3H), 7.75 (d, J = 32.8 Hz, 2H), 8.55 (d, J = 8.5 Hz, 1H).

Step 2. Preparation of compounds 8-34

Compound 7-34 (96 mg, 0.149 mmol) was obtained in the same manner as in Example 1 for preparing compound 8-1 , to obtain 43 mg (57%) of compound 8-34 in the form of an off-white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.59 (s, 1H), 1.83 (s, 3H), 3.09 (d, J = 4.7 Hz, 4H), 3.45 (dq, J = 14.1, 8.1, 7.0 Hz, 1H), 3.67 (s, 2H), 3.75 (s, 5H), 3.84 (s, 3H), 3.92 (s, 3H), 4.04 (s, 2H), 5.95 (s, 1H), 6.49 (dd , J = 8.8, 2.5 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 7.40 (s, 1H), 7.70 (d, J = 0.8 Hz, 1H), 8.01 (s, 2H), 12.82 (s, 1H).

Example 52. 3-(Isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ Preparation of -((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-35)

Step 1. Preparation of compounds 7-35

Compound 7-1 was prepared from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (47mg, 0.240mmol) from compound 6-4 (100mg, 0.160mmol) and In the same manner, 20 mg of compound 7-35 was obtained (27%).

¹ H NMR (400 MHz, Chloroform-d) δ 1.26 (s, 2H), 1.69 (ddt, J = 16.6, 12.4, 6.0 Hz, 1H), 1.94 (d, J = 6.9 Hz, 2H), 3.13 (s , 4H), 3.67 (s, 1H), 3.76 (s, 3H), 3.78 - 3.85 (m, 2H), 3.88 (s, 4H), 3.92 (s, 3H), 3.94 (s, 3H), 4.17 ( tq, J = 7.1, 3.5, 3.1 Hz, 1H), 5.33 (s, 2H), 5.57 (s, 1H), 6.55 (s, 2H), 6.85 (s, 2H), 7.33 (s, 2H), 7.42 (s, 1H), 8.51 (s, 1H).

Step 2. Preparation of compounds 8-35

From compound 7-35 (20 mg, 0.0326 mmol), 2 mg of compound 8-35 was obtained as a white solid (13%) in the same manner as in the preparation of compound 8-1 .

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.91 (s, 2H), 1.29 (d, J = 36.2 Hz, 6H), 1.64 - 1.97 (m, 5H), 3.07 (s, 3H), 3.47 ( s, 1H), 3.60 (s, 4H), 3.80 (d, J = 29.2 Hz, 7H), 4.00 - 4.11 (m, 1H), 6.49 (s, 1H), 6.65 (s, 1H), 7.31 (d , J = 9.2 Hz, 2H), 7.96 (s, 1H), 8.09 (s, 1H), 8.53 (s, 1H), 12.56 (s, 1H).

<Experimental Example 1. Evaluation of TTK activity inhibition ability>

In order to measure the TTK activity inhibitory ability of the compound represented by Formula 1 according to the present invention, the following experiment was performed.

Recombinant human TTK protein was mixed with the compound in a reaction solution (8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL MBP, 10 mM Magnesium acetate, 45 uM [gamma-33P-ATP]) and reacted at room temperature for 40 minutes let it Then, the reaction was terminated by adding phosphoric acid to a concentration of 0.5%, and 10 μl of the reaction solution was dropped onto the P30 filter. The dripped filter was washed 4 times in 0.425% phosphoric acid solution for 4 minutes, washed once more in methanol, dried, and the activity of TTK was measured through scintillation counting. The activity value from the group without the compound was set as 100% of control to calculate the degree of TTK inhibition by the compound, and the TTK inhibitory activity of the example compounds is summarized in Table 1 below.

compound IC ₅₀ (nM) compound IC ₅₀ (nM) compound 8-6 ++ compound 11-3 +++ Compounds 8-7 + compound 11-4 +++ compound 8-8 ++ compound 11-5 ++ Compounds 8-12 ++ compound 14-1 ++ Compounds 8-13 +++ compound 14-2 ++ Compounds 8-14 ++ compound 14-3 ++ Compounds 8-15 +++ compound 18-1 +++ Compounds 8-16 ++ compound 18-2 ++ Compounds 8-18 ++ compound 21-2 +++ Compounds 8-19 ++ compound 21-3 ++ Compounds 8-20 +++ compound 26-1 ++ Compounds 8-21 ++ compound 26-2 +++ Compounds 8-22 +++ compound 28-1 ++ Compounds 8-23 +++ compound 33-1 +++ Compounds 8-24 +++ compound 33-2 +++ Compounds 8-25 +++ compound 33-3 +++ Compounds 8-27 +++ Compounds 8-34 +++ Compounds 8-28 +++ Compounds 8-35 +++ Compounds 8-30 + Comparative Example 1 (CFI-402257) ++ compound 11-2 +++ -: >300 nM IC ₅₀ values, +: 100~300 nM IC ₅₀ values
++: 30~100 nM IC ₅₀ values, +++: <30 nM IC ₅₀ values

Therefore, as confirmed in Experimental Example 1, the compound represented by Chemical Formula 1 according to the present invention has an excellent effect of inhibiting TTK activity and can be usefully used as a TTK activity inhibitor, as well as preventing cancer caused therefrom. It can be usefully used as a preventive or therapeutic composition.

<Experimental Example 2. Evaluation of activity inhibitory ability for kinase>

Table 2 below shows the results of the kinase activity inhibitory ability of compound 8-8 at a concentration of 500 nM.

kinase Activity % Inhibition % ALK(h) 2 98 IR(h), activated 8 92 IRR(h) 7 93 LTK(h) 2 98 TTK(h) -7 107

Five kinases, including ALK (h), IR (h) activated, IRR (h), and LTK (h), including TTK (h) targeted by the present invention, were identified as kinases that were inhibited by 90% or more. In particular, it was confirmed that 500 nM compound 8-8 completely inhibited TTK activity and also had inhibitory activity against other kinases.

<Experimental Example 3. Evaluation of cytotoxicity in TTK-expressed MDA-MB-231 cells>

In order to measure the cytotoxicity of the compound represented by Formula 1 according to the present invention on MDA-MB-231 cells, the following experiment was performed.

After injecting 2,000 cells of the MDA-MB-231 triple-negative breast cancer cell line purchased from ATCC into each well of a 96-well plate in a volume of 90 μL, the concentration of the example compound of the present invention was 10 μM. , 3 μM, 1 μM, 0.3 μM, 0.1 μM and 0 μM were added to each well and cultured in a cell incubator at 37° C. for 5 days. After 5 days, 10 μL of Cyto X solution (manufacturer: LPS solution) was added to each well, and absorbance was measured at 450 nm using an Epoch microplate spectrophotometer (manufacturer: BioTek Instruments Inc.) according to product instructions. did For cytotoxicity, the amount of cells was calculated using the measured value to calculate the IC ₅₀ value in the cytotoxicity of each compound, and the cytotoxicity results of the example compounds in MDA-MB-231 cells are shown in Table 3 below. was

compound number in MDA-MB-231
IC ₅₀ (nM) compound number in MDA-MB-231
IC ₅₀ (nM) compound 8-2 + Compounds 8-30 + compound 8-4 ++ compound 11-2 ++++ compound 8-5 + compound 11-3 ++++ compound 8-6 + compound 11-4 +++ Compounds 8-7 +++ compound 11-5 ++ compound 8-8 ++++ compound 14-1 ++++ Compounds 8-12 +++ compound 14-2 +++ Compounds 8-13 ++ compound 14-3 +++ Compounds 8-14 +++ compound 18-1 ++++ Compounds 8-15 +++ compound 18-2 ++ Compounds 8-16 ++ compound 21-2 ++++ Compounds 8-17 ++ compound 21-3 +++ Compounds 8-18 +++ compound 26-1 +++ Compounds 8-19 +++ compound 26-2 + Compounds 8-20 ++++ compound 28-1 ++ Compounds 8-21 ++ compound 33-1 ++++ Compounds 8-22 ++ compound 33-2 +++ Compounds 8-23 ++ compound 33-3 ++ Compounds 8-24 +++ Compounds 8-34 + Compounds 8-25 +++ Compounds 8-35 + Compounds 8-27 ++ Comparative Example 1 (CFI-402257) ++++ Compounds 8-28 +++ +: >1000 nM IC ₅₀ values, ++: 500~1000 nM IC ₅₀ values
+++: 150-500 nM IC ₅₀ values, ++++: <150 nM IC ₅₀ values

Looking at Table 3, it can be seen that the cytotoxic IC ₅₀ values of many of the compounds of the examples according to the present invention in MDA-MB-231 cells are equivalent to those of Comparative Example 1 (CFI-402257).

Therefore, as confirmed in Experimental Example 2, the compound represented by Formula 1 according to the present invention has an excellent effect of inhibiting TTK activity in MDA-MB-231 cells, and thus can be usefully used as a TTK activity inhibitor. , It can be usefully used as a composition for preventing or treating cancer caused therefrom.

<Experimental Example 4. Confirmation of suppression of pTTK expression in MDA-MB-231 cells by western blotting>

From Experimental Example 3 conducted above, it was found that this compound caused apoptosis in MDA-MB-231 in which TTK was expressed, and Western blotting was performed to confirm whether the TTK protein was involved in the apoptosis.

After preparing 200,000 MDA-MB-231 cells in each well of a 6-well plate, they are treated with 50 ng/mL of nocodazole and cultured for one day. Thereafter, the example compounds of the present invention were added according to the cytotoxic IC ₅₀ concentration, followed by incubation for 4 hours, lysis of cells obtained by adding RIPA solution, and each protein diluted 1:10000 to confirm the expression of TTK and pTTK in the sample A specific primary antibody (manufacturer of TTK primary antibody - Cell Signaling Technology, phosphorylation of thr33 and ser37 manufacturer - Invitrogen) and secondary antibody were used. The luminescence of a specific protein induced using the Enhanced Chemiluminescence kit (ECL, manufacturer - Santa Cruz Biotechnology) was obtained and analyzed using the ChemiDoc XRS+ system, and the results are summarized in FIG. 1 .

It can be seen that the compound represented by Formula 1 according to the present invention completely inhibited pTTK expression at the level of IC ₅₀ causing cytotoxicity in MDA-MB-231 cells, equivalent to Comparative Example 1 (CFI-402257).

<Experimental Example 5. Cytotoxicity evaluation in TTK-expressed HCT116 cells>

In order to measure the cytotoxicity of the compound represented by Formula 1 according to the present invention on HCT116 cells, the following experiment was performed.

After injecting HCT116 colorectal cancer cell line purchased from ATCC in a volume of 90 μL into each well of a 96-well plate, 2,000 cells were injected, and the concentration of the example compound of the present invention was 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM and 0 μM were added to each well, and cultured in a cell incubator at 37° C. for 5 days. After 5 days, the amount of cells was measured by the CCK8 test method, and the cytotoxicity of each compound was calculated by IC ₅₀ value. The cytotoxicity results of the example compounds in HCT116 cells are shown in Table 4 below.

compound number in HCT116
IC ₅₀ (nM) compound number in HCT116
IC ₅₀ (nM) compound 8-2 + Compounds 8-30 NA compound 8-4 + compound 11-2 ++++ compound 8-5 + compound 11-3 +++ compound 8-6 + compound 11-4 +++ Compounds 8-7 ++ compound 11-5 +++ compound 8-8 ++++ compound 14-1 +++ Compounds 8-12 +++ compound 14-2 +++ Compounds 8-13 ++ compound 14-3 ++++ Compounds 8-14 +++ compound 18-1 ++++ Compounds 8-15 +++ compound 18-2 ++ Compounds 8-16 ++++ compound 21-2 ++++ Compounds 8-17 ++ compound 21-3 ++++ Compounds 8-18 ++++ compound 26-1 ++ Compounds 8-19 ++ compound 26-2 + Compounds 8-20 ++++ compound 28-1 + Compounds 8-21 ++ compound 33-1 ++++ Compounds 8-22 ++++ compound 33-2 ++ Compounds 8-23 +++ compound 33-3 + Compounds 8-24 +++ Compounds 8-34 + Compounds 8-25 +++ Compounds 8-35 + Compounds 8-27 ++ Comparative Example 1 (CFI-402257) ++++ Compounds 8-28 +++ +: >1000 nM IC ₅₀ values, ++: 500~1000 nM IC ₅₀ values
+++: 150-500 nM IC ₅₀ values, ++++: <150 nM IC ₅₀ values

Looking at Table 4, it can be seen that the cytotoxic IC ₅₀ values of many of the compounds of the examples according to the present invention in HCT116 cells are equal to or lower than those of Comparative Example 1 (CFI-402257).

Therefore, the compound represented by Formula 1 according to the present invention has an excellent effect of inhibiting TTK activity in HCT116 cells, and thus can be usefully used as a TTK activity inhibitor, as well as a composition for preventing or treating cancer caused therefrom. can be used

<Experimental Example 6. Confirmation of inhibition of pTTK expression in HCT116 cells by western blotting>

From Experimental Example 5 conducted above, it was found that this compound caused apoptosis in HCT116 in which TTK was expressed, and western blotting was performed to confirm whether the TTK protein was involved in the apoptosis.

200,000 HCT116 cells were prepared in each well of a 6-well plate, treated with 50 ng/mL of nocodazole, and cultured for one day. Thereafter, the example compounds of the present invention were added according to the cytotoxic IC ₅₀ concentration, followed by incubation for 4 hours, lysis of cells obtained by adding RIPA solution, and each protein diluted 1:10000 to confirm the expression of TTK and pTTK in the sample A specific primary antibody (manufacturer of TTK primary antibody - Cell Signaling Technology, phosphorylation of thr33 and ser37 manufacturer - Invitrogen) and secondary antibody were used. The luminescence of a specific protein induced using the Enhanced Chemiluminescence kit (ECL, manufacturer - Santa Cruz Biotechnology) was obtained and analyzed using the ChemiDoc XRS+ system, and the results are summarized in FIG. 2 .

It can be seen that all of the compounds represented by Formula 1 according to the present invention completely inhibited pTTK expression at the level of IC ₅₀ causing cytotoxicity in HCT116 cells, equivalent to Comparative Example 1 (CFI-402257).

< Experimental Example 7. Efficacy evaluation on nude mice to which MDA-MB-231 is applied>

5 × 10 ⁶ MDA-MB-231 cells are subcutaneously injected into the flanks of 5-week-old female nude mice, and when the size of the tumor reaches about 50 mm ³ , the mice are divided into groups of 5 and each drug is orally administered. . At this time, the dose of the drug was administered daily for 4 weeks at 6 mg/kg, and the weight change and the size of the cancer were measured, and the results are shown in FIGS. 3 and 4.

Figure 3 is a result of observing the size of cancer over time for the drug administration control group (Control), Comparative Example 1 (CFI-402257) treatment group, and Example treatment group in nude mice injected with MDA-MB-231 cell line is a graph that represents Referring to Figure 3, the control group significantly increased the size of the cancer over time, and the example compound treatment group and Comparative Example 1 (CFI-402257) treatment group according to the present invention confirmed that the size of the cancer decreased. , In particular, it can be seen that the Example compound treatment group inhibits the size of cancer better than the Comparative Example 1 (CFI-402257) treatment group.

Figure 4 is a result of observing the change in mouse body weight over time for the drug administration control group (Control), Comparative Example 1 (CFI-402257) treatment group, and Example treatment group in nude mice injected with MDA-MB-231 cell line is a graph that represents Looking at Figure 4, it can be seen that the weight of the animals did not decrease over time in all experimental groups.

Therefore, as confirmed in the above experimental examples, the compound of the example according to the present invention has an excellent effect of inhibiting TTK activity in nude mice to which MDA-MB-231 is applied, and thus can be usefully used as a TTK activity inhibitor. It can be usefully used as a composition for preventing or treating cancer that can be caused from.

<Experimental Example 8. Evaluation of cytotoxicity when combined with pacalitaxel in TTK-expressed MDA-MB-231 cells>

In order to measure the cytotoxicity when the example compounds and paclitaxel according to the present invention were applied together to MDA-MB-231 cells, the following experiment was performed.

MDA-MB-231 triple-negative breast cancer cell line purchased from ATCC was injected into each well of a 96-well plate in a volume of 90 μL, 2,000 cells, and paclitaxel concentrations were 0 μM, 0.001 μM, and 0.003 μM, respectively. After addition to μM, concentrations of the compounds of the examples of the present invention were added to each well at concentrations of 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM and 0 μM, and incubated at 37 ° C for 5 days in a cell incubator. cultured. After 5 days, 10 μL of Cyto X solution (manufacturer: LPS solution) was added to each well, and absorbance was measured at 450 nm using an Epoch microplate spectrophotometer (manufacturer: BioTek Instruments Inc.) according to product instructions. did For cytotoxicity, the amount of cells was calculated using the measured value to calculate the IC ₅₀ value in the cytotoxicity of each compound, and the results are shown in FIG. 5 below.

As a result, in the test group to which 0.001 μM of paclitaxel was added, it was confirmed that the IC ₅₀ of the example compound-treated group was decreased compared to the test group to which paclitaxel was not added, which was obtained by the combined treatment of paclitaxel and Comparative Example 1 (CFI-402257). As in Comparative Example 1, the efficacy was equal to or higher than that, and the possibility of co-administration of the drug of Example with paclitaxel was confirmed.

<Experimental Example 9. Evaluation of cell cycle distribution in combination with paclitaxel in TTK-expressed MDA-MB-231 cells>

In order to measure changes in cell cycle distribution when the compound represented by Formula 1 according to the present invention and paclitaxel were applied together to MDA-MB-231 cells, the following experiment was performed.

After injecting 100,000 cells of the MDA-MB-231 triple-negative breast cancer cell line purchased from ATCC into each well of a 6-well plate, paclitaxel was added at concentrations of 0 μM and 0.001 μM, and then the present invention was performed. Example compounds were added to each well at a concentration of 0 μM, 0.03 μM, or 0.1 μM, and cultured in a cell incubator at 37° C. for 2 days. After 2 days, the cells were fixed with 70% ethanol, added to 200 μL of Muse Cell Cycle reagent in a shaded state, cultured for 30 minutes, and then the cell cycle distribution was analyzed with a Muse Cell Analyzer (manufacturer: Merck, Millipore). is shown in Figure 6.

As a result, it was confirmed that the normal cell cycle distribution observed in the control group was suppressed by the application of the Example compound, and the distribution of cells in G1 and G2/M was suppressed, and many cells were distributed in a polyploid by inhibition of TTK. 1 (CFI-402257) was equal to or better than the result. In addition, both of the compounds of Comparative Example 1 and Examples showed enhanced changes in their cell distribution when simultaneously treated with 0.001 μM of paclitaxel, so the example drugs of the present invention also showed a synergistic anticancer effect when co-administered with paclitaxel.

<Formulation Example 1. Preparation of Powder>

2 g of the compound 8-1 of the present invention and 1 g of lactose were mixed and filled into an airtight bag to prepare a powder.

<Formulation Example 2. Preparation of tablets>

After mixing 100 mg of the compound 8-1 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, tableting was performed according to a conventional tablet manufacturing method. manufactured.

<Formulation Example 3. Preparation of capsules>

After mixing 100 mg of Compound 8-1 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method. Capsules were prepared by mixing and filling gelatin capsules.

<Formulation Example 4. Preparation of pills>

90 mg of the compound 8-1 of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives that inhibit hygroscopicity were mixed in small amounts, and then 100 mg was prepared according to a conventional method. made a pill of

<Formulation Example 5. Preparation of Injections>

After mixing 10 mg of the compound 8-1 of the present invention, an appropriate amount of sterilized distilled water for injection, and an appropriate amount of a pH adjusting agent, the above ingredients were prepared per ampoule (2 ml) according to a conventional method for preparing an injection.

Claims (15)

Compounds of Formula 1 below, or hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof;
[Formula 1]

In the above formula,
R ₁ is a substituted or unsubstituted C ₆ -C ₁₂ aryl, a substituted or unsubstituted 5 to 12 membered heteroaryl, or a substituted or unsubstituted 5 to 12 membered heterocycloalkyl;
The substituted aryl, heteroaryl or heterocycloalkyl means that at least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ Alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, C(=O), carbamoyl, C ₁ -C ₆ alkylaminoketone, C ₁ -C ₆ alkyloxycarbonyl, C ₁ -C ₆ alkyl substituted with sulfonamino or C ₃ -C ₆ cycloalkylaminoketone;
R ₂ is substituted or unsubstituted -NH-(C ₆ -C ₁₂ )aryl, substituted or unsubstituted -NH-(C ₃ -C ₆ )cycloalkyl, or substituted or unsubstituted -NH-(C ₃ -C ₆ )heterocycloalkyl, -NH-(CH ₂ ) _m -(C ₃ -C ₆ )heterocycloalkyl;
m is an integer of 0, 1 or 2; am.
The substituted aryl, cycloalkyl or heterocycloalkyl means that at least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halo C ₁ -C ₆ substituted with alkoxy;
R ₃ is substituted or unsubstituted -NH-(C ₆ -C ₁₂ )aryl or substituted or unsubstituted -NH-(C ₃ -C ₆ )cycloalkyl;
The substituted aryl or cycloalkyl means that at least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ alkoxy, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted triazole, C ₁ -C ₆ alkylaminoketone, substituted or unsubstituted - substituted with C(=0)-morpholine, substituted or unsubstituted -C(=0)-piperazine or substituted or unsubstituted -C(=0)NH-piperidine;
The substituted morpholine, piperazine, triazole, -C(=O)-morpholine, -C(=O)-piperazine or -C(=O)NH-piperidine has one or more hydrogens independently substituted by halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy; do. According to claim 1,
a compound of Formula 2-1 below, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof;
[Formula 2-1]

In the above formula,
R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted isoxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole or substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzoimidazole, substituted or unsubstituted indazole, or substituted or unsubstituted benzoxazole;
The above substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole or 1,3,4- Oxadiazolone is a compound in which one or more hydrogens in the ring are independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ substituted with a cycloalkylaminoketone;
R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;
E is -NHR ₄ ;

, or

substituted with;
A is substituted with NH;
B is substituted with O, S or CH ₂ ;
D is substituted with O or NR ₄ ;
m is an integer of 0, 1 or 2;
n is an integer of 0 or 1; According to claim 1,
a compound of Formula 2-2 below, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof;
[Formula 2-2]

In the above formula,
R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;
The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced with;
R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;
E is -NHR ₄ ;

, or

substituted with;
D is substituted with O or NR ₄ ;
m is an integer of 0, 1 or 2;
n is an integer of 0 or 1; a compound of Formula 3-1 below, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof;
[Formula 3-1]

In the above formula,
R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;
The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced with;
R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;
D is substituted with O or NR ₄ ;
A is substituted with NH;
B is substituted with O, S or CH ₂ ;
n is an integer of 0 or 1; a compound of Formula 3-2 below, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof;
[Formula 3-2]

In the above formula,
R ₁ is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or an unsubstituted triazole, a substituted or unsubstituted oxadiazole, a substituted or unsubstituted oxazole, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole, or A substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzoimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;
The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole or 1,3,4-oxadiazolone is At least one hydrogen in the ring is independently halogen, C ₁ -C ₆ alkyl, halo C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C 1 -C ₆ alkoxy, C _{1 -C 6} alkoxy C ₁ -C ₆ Alkoxy, C(=O), Carbamoyl, C ₁ -C ₆ Alkylaminoketone, C ₁ -C ₆ Alkyloxycarbonyl, C ₁ -C ₆ Alkylsulfonamino or C ₃ -C ₆ Cycloalkylaminoketone is replaced with;
R ₄ is substituted by hydrogen or C ₁ -C ₆ alkyl;
D is substituted with O or NR ₄ ;
n is an integer of 0 or 1;
m is an integer of 0, 1 or 2; According to claim 1,
The compound represented by Formula 1 is
N ⁴ -cyclohexyl-3-(5-fluoropyridin-3-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine -4,6-diamine (Compound 8-1);
3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzamide (Compound 8-2);
methyl 4-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzo Eight (Compound 8-3);
N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl )phenyl)cyclopropanecarboxamide (compound 8-4);
3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N -Methylbenzamide (Compound 8-5);
N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl )phenyl)methanesulfonamide (compound 8-6);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-7);
N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 8-8);
N ⁴ -Cyclohexyl-N ⁶ -(4-morpholinocyclohexyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-9);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (compounds 8-10);
N ⁴ -Cyclohexyl-3-(1-isopropyl-1H-imidazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 8-11);
N ⁴ -cyclohexyl-3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[ 3,4-d] pyrimidine-4,6-diamine (Compound 8-12);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-13);
N ⁴ -cyclohexyl-3-(furan-2-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6 -diamines (compounds 8-14);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4; 6-diamine (compounds 8-15);
3-(1H-benzo[d]imidazol-5-yl)-N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-16);
N ⁴ -Cyclohexyl-3-(1H-indazol-5-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine (compounds 8-17);
N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(2-methylbenzo[d]oxazol-6-yl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 8-18);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4-d ]pyrimidine-4,6-diamine (Compound 8-19);
N ⁴ -cyclohexyl-3-(isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4; 6-diamine (compounds 8-20);
3-(Isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[ 3,4-d] pyrimidine-4,6-diamine (Compound 8-21);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-2-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3 ,4-d] pyrimidine-4,6-diamine (Compound 8-22);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-23);
3-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ -(tetrahydro-2H-pyran- 4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-24);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-3-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-25);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1H-pyrazol-4-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 8-26);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyridin-3-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3, 4-d] pyrimidine-4,6-diamine (Compound 8-27);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyridin-4-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3, 4-d] pyrimidine-4,6-diamine (Compound 8-28);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(pyrimidin-5-yl)-N ⁴ -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3 ,4-d] pyrimidine-4,6-diamine (Compound 8-29);
N ⁴ -Cyclohexyl-3-(1-methyl-1H-pyrazol-4-yl)-N ⁶ -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine (compounds 8-30);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 11-1);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(1-methyl-1H-pyra zol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 11-2);
4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3-methoxy-N-methylbenzamide (compound 11-3);
(4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3-methoxyphenyl)(morpholino)methanone (Compound 11-4);
(4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino) -3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (Compound 11-5);
4-((4-(cyclohexylamino)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)- 3-methoxy-N-(1-methylpiperidin-4-yl)benzamide (Compound 11-6);
N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 14-1);
N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 14-2);
5-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1 ,3,4-oxadiazol-2(3H)-one (Compound 14-3);
N ⁴ -cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4; 6-diamine (compound 18-1);
N ⁴ -Cyclohexyl-3-(1H-imidazol-5-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine- 4,6-diamine (compound 18-2);
N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4 -d] pyrimidine-4,6-diamine (Compound 21-1);
N ⁴ -Cyclohexyl-N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-1H-pyrazolo [3,4-d]pyrimidine-4,6-diamine (Compound 21-2);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-1,2,3-triazol-4-yl)-N ⁴ -(tetrahydro-2H-pyran -4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 21-3);
N ⁴ -Cyclohexyl-N ⁶ -(2-isopropoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4- d] pyrimidine-4,6-diamine (Compound 26-1);
4-(Cyclohexyloxy)-N-(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4 -d]pyrimidin-6-amine (Compound 26-2);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ -(1-methylpiperidin-4-yl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 28-1); N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(oxazole-5 -yl)-N ⁴ -(tetra-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 33-1);
3-methoxy-N-methyl-4-((3-(oxazol-5-yl)-4-((tetrahydro-2H-pyran-4-yl)amino)-1H-pyrazolo[3,4 -d]pyrimidin-6-yl)amino)benzamide (Compound 33-2);
N ⁶ -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(oxazol-5-yl)-N ⁴ -(tetra hydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 33-3);
N ⁶ -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N ⁴ -((tetrahydrofuran-2-yl)methyl)- 1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-34); and
3-(Isoxazol-4-yl)-N ⁶ -(2-methoxy-4-morpholinophenyl)-N ⁴ -((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3 ,4-d] pyrimidine-4,6-diamine (Compound 8-35);
A compound characterized in that it is selected from the group consisting of, or a hydrate, solvate, prodrug thereof, or a pharmaceutically acceptable salt thereof. Prevention or treatment of cancer comprising a therapeutically effective amount of the compound of any one of claims 1 to 6, or a hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier thereof. pharmaceutical composition for use. According to claim 7,
The pharmaceutical composition is characterized in that it exhibits inhibitory activity against one or more protein kinases selected from the group consisting of TTK (h), ALK (h), IR (h) activated, IRR (h), and LTK (h) A pharmaceutical composition for the prevention or treatment of cancer. According to claim 8,
The pharmaceutical composition is a pharmaceutical composition for preventing or treating cancer, characterized in that it exhibits inhibitory activity against TTK kinase. According to claim 7,
The cancer is a pharmaceutical composition for preventing or treating cancer, characterized in that solid cancer or hematological cancer. According to claim 10,
The solid cancers include brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, oral squamous cell carcinoma, Barrett's esophageal epithelial sequelae, thoracic tumor, small cell lung cancer, non-small cell lung cancer, thymic cancer, mediastinal tumor, esophageal cancer, glioma, breast cancer, male breast cancer, triple negative breast cancer (TNBC ), breast sporadic basal-like carcinoma (BLC), abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), small intestine cancer, colon cancer, anal cancer, colon mucosal cell adenoma, bladder cancer, kidney cancer, Male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, ovarian adenocarcinoma, uterine sarcoma, vulvar intraepithelial tumor, vaginal cancer, female external genital cancer, female urethral cancer and skin cancer A pharmaceutical composition for the prevention or treatment of cancer, characterized in that. According to claim 10,
The blood cancer is a pharmaceutical composition for preventing or treating cancer, characterized in that any one of leukemia, malignant lymphoma, multiple myeloma and aplastic anemia. Claims 1 to 6 of any one of the compounds and anti-cancer drugs characterized in that it comprises a combination administration of a pharmaceutical composition for the prevention or treatment of cancer. According to claim 13,
The anticancer agent is taxane-based anticancer agent, antitumor alkylating agent, antitumor antimetabolite, antitumor antibiotic, plant-derived antitumor agent, antitumor platinum complex, antitumor camptothecin derivative, antitumor kinase inhibitor, antitumor antibody, hormone A pharmaceutical composition for preventing or treating cancer, characterized in that it is selected from sexual antitumor agents, antitumor viral agents, and angiogenesis inhibitors. According to claim 13,
The taxane-based anticancer agent is a pharmaceutical composition for preventing or treating cancer, characterized in that selected from paclitaxel, docetaxel, or cabazitaxel.

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