PYRAZOLOPYRIMIDINE DERIVATIVE AND ANTICANCER PHARMACEUTICAL COMPOSITION CONTAINING SAME AS ACTIVE INGREDIENT

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating tumors, which contains a novel pyrazolopyrimidine compound or a pharma- ceutical acceptable salt thereof as an active ingredient, and which can be usefully used as a composition for preventing or treating cancer by administering it in combination with other anticancer agents.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for preventing or treating tumors, which contains a novel pyrazolopyrimidine compound or a pharma- ceutical acceptable salt thereof as an active ingredient as a TTK inhibitor, and a health food composition for preventing or improving tumors, which contains the pyrazolopyrimidine compound as an active ingredient. [Background technology]

[0002] Therapeutic agents used in cancer treatment include taxanes and vinca alkaloids, which act on microtubules to stabilize or destabilize microtubule dynamics. They perturb normal mitotic spindle function, preventing correct chromosome attachment and inducing mitotic arrest. This arrest is enforced by the spindle assembly checkpoint, preventing the separation of sister chromatids to form two daughter cells. Prolonged arrest of mitosis can force cells into mitotic exit without cytokinesis or into mitotic catastrophe, leading to cell death.

[0003] Although mitotic agents are widely used in the treatment of solid tumors, the side effects associated with such agents and the resistance of various tumor types to current therapies have necessitated the development of new pharmaceutical compositions for the treatment of cancer.

[0004] The role that genes involved in the spindle assembly checkpoint have 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, some of which are kinases, one of which is the dual specificity kinase TTK. TTK expression is overexpressed in many cancer cell lines and tumor types, is associated with highly proliferating cells and tissues, and silencing of TTK in some species prevents cells from undergoing mitotic arrest in response to spindle poisons pointing to its essential function in spindle assembly checkpoint signaling (Abrieu A et al.,; Stucke, VM et al.,).

[0005] 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 disorders, including solid tumors such as carcinomas and sarcomas, and leukemias and lymphoid malignancies, and that TTK inhibitors may be useful in the treatment of other disorders associated with uncontrolled cell proliferation.

[0006] TTK / Mps1, a dual specificity protein kinase, is a master regulator of mitosis and its expression is increased in various patient tumors. Therefore, TTK inhibitors are being actively investigated as potential anticancer drugs.

[0007] Under such circumstances, the inventors of the present invention measured the degree of inhibition of various kinase activities using a panel assay and confirmed the inhibition of pTTK expression in triple-negative breast cancer and colon cancer cells. They confirmed a novel pyrazolopyrimidine-based compound that strongly inhibits TTK and has excellent kinase selectivity, and completed the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide a compound having a novel pyrazolopyrimidine skeleton that potently inhibits TTK and has excellent selectivity for TTK. [Means for solving the problem]

[0009] The present invention relates to a compound represented by the following formula (1), which is a pyrazolopyrimidine derivative: or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof.

[0010] [ka]

[0011] During the ceremony,

[0012] R1 is a substituted or unsubstituted C6-C 12 aryl, a substituted or unsubstituted heteroaryl having 5 to 12 atoms, or a substituted or unsubstituted heterocycloalkyl having 5 to 12 atoms;

[0013] The substituted aryl, heteroaryl, or heterocycloalkyl is one or more hydrogens in the ring are independently replaced with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkylaminoketone, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamide, or C3-C6 cycloalkylaminoketone;

[0014] R2 is a substituted or unsubstituted -NH-(C6-C 12 )aryl, substituted or unsubstituted -NH-(C3-C6)cycloalkyl, substituted or unsubstituted -NH-(C3-C6)heterocycloalkyl, or -NH-(CH2) m -(C3-C6)heterocycloalkyl, where m is an integer of 0, 1 or 2;

[0015] The substituted aryl, cycloalkyl, or heterocycloalkyl is one in which one or more hydrogens in the ring are independently replaced with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, or haloC1-C6 alkoxy;

[0016] R3 is a substituted or unsubstituted -NH-(C6-C 12 ) aryl, or substituted or unsubstituted -NH-(C3-C6)cycloalkyl;

[0017] The substituted aryl or cycloalkyl is one or more hydrogens in the ring are independently replaced by halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted triazole, C1-C6 alkylaminoketone, substituted or unsubstituted -C(=O)-morpholine, substituted or unsubstituted -C(=O)-piperazine, or substituted or unsubstituted -C(=O)NH-piperidine;

[0018] The substituted morpholine, piperazine, triazole, -C(=O)-morpholine, -C(=O)-piperazine, or -C(=O)NH-piperidine has one or more hydrogens independently replaced with halogen, C1-C6 alkyl, haloC1-C6 alkyl, or C1-C6 alkoxy.

[0019] The present invention also relates to a compound represented by the following formula 2-1: or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof:

[0020] [ka]

[0021] During the ceremony,

[0022] R1 is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

[0023] The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole is independently substituted with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkylamino ketone, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamide, or C3-C6 cycloalkylamino ketone;

[0024] R4 is substituted with hydrogen or C1-C6 alkyl;

[0025] TIFF2025502807000004.tif26166

[0026] A is substituted with NH;

[0027] B is substituted with O, S, or CH2;

[0028] D is replaced by O or NR4;

[0029] m is an integer of 0, 1 or 2;

[0030] n is an integer of 0 or 1;

[0031] The present invention also relates to a compound represented by the following formula 2-2: or a hydrate, solvate, prodrug, or pharma- ceutically acceptable salt thereof:

[0032] [ka]

[0033] During the ceremony,

[0034] R1 is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

[0035] The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole is independently substituted with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkylamino ketone, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamide, or C3-C6 cycloalkylamino ketone;

[0036] R4 is substituted with hydrogen or C1-C6 alkyl;

[0037] TIFF2025502807000006.tif26166

[0038] D is replaced by O or NR4;

[0039] m is an integer of 0, 1 or 2;

[0040] n is an integer of 0 or 1;

[0041] The present invention also relates to a compound represented by the following formula 3-1: or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof:

[0042] [ka]

[0043] During the ceremony,

[0044] R1 is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

[0045] The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole is independently substituted with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkylamino ketone, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamide, or C3-C6 cycloalkylamino ketone;

[0046] R4 is substituted with hydrogen or C1-C6 alkyl;

[0047] A is substituted with NH;

[0048] B is substituted with O, S, or CH2;

[0049] D is replaced by O or NR4;

[0050] m is an integer of 0, 1 or 2;

[0051] n is an integer of 0 or 1;

[0052] The present invention also relates to a compound represented by the following formula 3-2: or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof:

[0053] [ka]

[0054] During the ceremony,

[0055] R1 is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole;

[0056] The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole is independently substituted with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkylamino ketone, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamide, or C3-C6 cycloalkylamino ketone;

[0057] R4 is substituted with hydrogen or C1-C6 alkyl;

[0058] D is replaced by O or NR4;

[0059] m is an integer of 0, 1 or 2;

[0060] n is an integer of 0 or 1;

[0061] The present invention also relates to the compounds of the above-mentioned [Chemical Formula 1], [Chemical Formula 2-1], [Chemical Formula 2-2], [Chemical Formula 3-1], and [Chemical Formula 3-2], or hydrates, solvates, prodrugs, or pharma- ceutically acceptable salts thereof.

[0062] In the above [Chemical Formula 1], [Chemical Formula 2-1], [Chemical Formula 2-2], [Chemical Formula 3-1] or [Chemical Formula 3-2],

[0063] R1 is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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 benzimidazole, a substituted or unsubstituted indazole, a substituted or unsubstituted benzoxazole;

[0064] The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole, or 1,3,4-oxadiazolone is such that one or more hydrogens in the ring are independently replaced with halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkylamino ketone, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, or C3-C6 cycloalkylamino ketone;

[0065] The preparation methods and reaction conditions for the pyrazolopyrimidine skeleton compounds having various structures of the following Formula 1 according to the present invention are as follows.

[0066] [ka]

[0067] The pyrazolopyrimidine skeleton compound represented by the above Chemical Formula 1 of the present invention may be preferably prepared according to the following [Reaction Scheme 1], [Reaction Scheme 2], [Reaction Scheme 3], [Reaction Scheme 4], [Reaction Scheme 5], [Reaction Scheme 6], [Reaction Scheme 7], or [Reaction Scheme 8].

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka]

[0076] In addition, in the present invention, the compound represented by the above Chemical Formula 1 relates to a compound characterized by being any one selected from the following compound group, or a hydrate, solvate, prodrug, or pharma- ceutically acceptable salt thereof:

[0077] 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);

[0078] 3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzamide (compound 8-2);

[0079] Methyl 4-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzoate (compound 8-3);

[0080] N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)cyclopropanecarboxamide (compound 8-4);

[0081] 3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzamide (compound 8-5);

[0082] N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide (compound 8-6);

[0083] 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);

[0084] 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);

[0085] N 4 -Cyclohexyl-N 6 -(4-morpholinocyclohexyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compounds 8-9);

[0086] 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);

[0087] 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 (compounds 8-11);

[0088] 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 (compounds 8-12);

[0089] 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 (compounds 8-13);

[0090] N 4 -Cyclohexyl-3-(furan-2-yl)-N 6 -(2-Methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compounds 8-14);

[0091] 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);

[0092] 3-(1H-Benz[d]imidazol-5-yl)-N 4 -Cyclohexyl-N 6-(2-Methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compounds 8-16);

[0093] 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);

[0094] 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 (compounds 8-18);

[0095] 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 (compounds 8-19);

[0096] 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);

[0097] 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);

[0098] 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);

[0099] 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);

[0100] 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);

[0101] 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);

[0102] 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);

[0103] 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);

[0104] 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);

[0105] 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);

[0106] N 4 -Cyclohexyl-3-(1-methyl-1H-pyrazol-4-yl)-N 6 -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-30);

[0107] 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);

[0108] 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[3,4-d]pyrimidine-4,6-diamine (compound 11-2);

[0109] 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);

[0110] (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);

[0111] (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);

[0112] 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);

[0113] 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);

[0114] 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);

[0115] 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);

[0116] 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);

[0117] 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);

[0118] 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);

[0119] 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);

[0120] 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);

[0121] 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);

[0122] 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);

[0123] 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);

[0124] 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);

[0125] 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);

[0126] N 6 -(2-Methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(oxazol-5-yl)-N 4 -(Tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 33-3);

[0127] 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

[0128] 3-(Isoxazol-4-yl)-N6 -(2-Methoxy-4-morpholinophenyl)-N 4 -((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-35);

[0129] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, comprising a therapeutically effective amount of a compound represented by the above Chemical Formula 1, or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof, or a pharma-ceutically acceptable carrier thereof.

[0130] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, wherein the compound 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).

[0131] Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer, wherein the compound exhibits inhibitory activity against TTK kinase.

[0132] Another aspect of the present invention provides a synergistic anti-cancer effect when the compound represented by Chemical Formula 1 is administered in combination with another anti-cancer drug, preferably with an anti-cancer drug selected from taxane anti-cancer drugs (paclitaxel, docetaxel, carbazitaxel) as the other anti-cancer drug, and provides a composition and a synergistic anti-cancer effect.

[0133] The other anticancer drugs include antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum complexes, antitumor camptothecin derivatives, antitumor kinase inhibitors, antitumor antibodies, hormonal antitumor agents, antitumor viral agents, or angiogenesis inhibitors.

[0134] The antitumor alkylating agent is nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, or carmustine.

[0135] The antitumor antimetabolite is methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocphosphate, enocitabine, S-1, gemcitabine, fludarabine or pemetrexed disodium.

[0136] The antitumor antibiotic is actinomycin D, doxorubicin, daunorubicin, neocasinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus, or valrubicin.

[0137] The plant-derived antitumor agent is vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxol, paclitaxel or vinorelbine.

[0138] The antitumor platinum complex is cisplatin, carboplatin, nedaplatin or.

[0139] The antitumor camptothecin derivative is irinodecan, topotecan, or camptothecin.

[0140] The anti-tumor kinase inhibitor is gefitinib, imatinib, or erlotinib.

[0141] The anti-tumor antibody is cetuximab, bevacizumab, rituximab, alemtuzumab or trastuzumab.

[0142] The hormonal antitumor agent is goserelin, leuprolide, or tamoxifen.

[0143] The anti-tumor virus agent is Imlygic.

[0144] The angiogenesis inhibitor is avastin, bevacizumab, ranibizumab, pegaptanib, aflibercept, axitinib, carbozantinib, aflibercept, brivanib, tivozanib, ramucirumab, or motesanib.

[0145] Additionally, for purposes of the present invention, the following terms have the following meanings unless otherwise specified: Any term not defined has its art-understood meaning.

[0146] The term "alkyl" means a single-bonded straight or branched chain hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl, and hexyl.

[0147] The term "alkoxy" refers to an oxygen radical attached to a single bonded straight or branched chain saturated hydrocarbon having 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, including methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, 1-methylpropoxy, and the like.

[0148] The term "alkoxyalkoxy" refers to an alkoxy group having one or more hydrogen atoms replaced by another alkoxy group, where alkoxy is as defined above.

[0149] The terms "halo" and "halogen" are used in the conventional sense to refer to a fluoro, chloro, bromo or iodo substituent.

[0150] The term "haloalkyl" refers to an alkyl group having one or more hydrogen atoms replaced by a halo group, where the alkyl and halo groups are as previously described.

[0151] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group is replaced by a halo group, where halo and alkoxy are defined above.

[0152] The term "cycloalkyl" refers to a cyclic, single-bonded, saturated hydrocarbon group, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[3.1.1]heptyl, spiro[4.5]decyl, spiro[5.5]undecyl, adamantyl, norbornyl, and the like.

[0153] The term "aryl" refers to an aromatic substituent having at least one ring with a shared pi electron system, including, but not limited to, phenyl, benzyl, naphthyl, anthryl, indanyl, biphenyl, triphenyl, and the like.

[0154] The term "heterocycloalkyl" refers to a cyclic, single-bonded, saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and includes, but is not limited to, aziridinyl, pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azetidinyl, azocanyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrobenzo[b]thiophenyl, oxazolidinyl, dioxanyl, dioxolanyl, azaspiro[5.5]undecanyl, azaspiro[3,3]heptanyl, or azaspiro[3.5]nonanyl, depending on the number and type of heteroatoms contained in the ring and the number of carbon atoms.

[0155] 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 contained in the ring and the number of carbon atoms, can be selected from pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, furanyl, quinolizinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyranyl, thiophenyl, thiazolyl, dibenzothiophenyl, dibenzofuranyl, dibenzoselenophene, thiophene, benzofuran, benzothiophenyl, benzoselenophenyl, carbazolyl, indolecarbazolyl, pyridylindolyl, pyrrolodipyridinyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, oxadiazolyl, oxato Examples of such aryl groups include, but are not limited to, riazolyl, dioxazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, oxazinyl, oxathiazinyl, oxadiazinyl, indolyl, benzimidazolyl, inzolyl, indoxazinyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, phthalazinyl, phtheridinyl, xanthenyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, benzopropylidinyl, prodipyridinyl, benzimidazolyl, benzoxazolyl, benzothienopyridinyl, thienodipyridinyl, benzoselenophenopyridinyl, and selenophenodipyridinyl.

[0156] In the present invention, the pharma- ceutically acceptable salt refers to a salt or complex of Formula 1 that has the 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 salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds may also be administered in the form of pharma- ceutically acceptable quaternary salts known to those skilled in the art, including, in particular, chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (e.g., benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandelloate, and diphenylacetate). In addition to pharma-ceutically acceptable salts, the compounds of formula 1 of the present invention may also include any salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

[0157] The acid addition salt according to the present invention can be prepared by a conventional method. For example, the acid addition salt can be prepared by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., adding an organic acid or an inorganic acid, filtering and drying the resulting precipitate, or by distilling the solvent and an excess amount of acid under reduced pressure, drying, and crystallizing in an organic solvent.

[0158] Pharmaceutically acceptable metal salts can also be prepared using bases. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in a solution of an excess of alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharma- ceutical suitable to prepare sodium, potassium, or calcium salts as metal salts. The corresponding salts can also be obtained by reacting alkali metal or alkaline earth metal salts with a suitable silver salt (e.g., silver nitrate).

[0159] The present invention relates to a pharmaceutical composition for preventing or treating cancer using a pyrazolopyrimidine derivative.

[0160] The cancer means a solid cancer or a blood cancer, and the solid cancer is a brain tumor, a benign astrocytoma, a malignant astrocytoma, a pituitary adenoma, a brain meningioma, a brain lymphoma, an oligodendroglioma, a craniopharyngioma, an ependymoma, a brain stem tumor, a head and neck tumor, a laryngeal cancer, an oropharyngeal cancer, a nasal cavity cancer, a nasopharyngeal cancer, a salivary gland cancer, a hypopharyngeal cancer, a thyroid cancer, an oral cancer, an oral squamous cell carcinoma, an epithelial sequela of Barrett's esophagus, a breast tumor, a small cell lung cancer, a non-small cell lung cancer, a thymic cancer, a paraseptal tumor, an esophageal cancer, a glioma, a breast cancer, a male breast cancer, a triple tumor, a pulmonary ... The cancer may be selected from the group consisting of, but is not limited to, tumor-negative breast cancer (TNBC), breast sporadic basal-like cancer (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 neoplasia, vaginal cancer, female external genital cancer, female urethral cancer, and skin cancer. In addition, the blood cancer may be selected from the group consisting of, but is not limited to, leukemia, malignant lymphoma, multiple myeloma, and aplastic anemia.

[0161] The pharmaceutical composition according to the present invention may be formulated in an appropriate form together with a commonly used pharma- ceutically acceptable carrier. "Pharmaceutically acceptable" means that it is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, or similar reactions when administered to humans. In addition, the composition may be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions, by a conventional method.

[0162] The carrier, excipient and diluent that may be included in the composition may include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, it is prepared using a diluent or excipient that is commonly used, such as a filler, stabilizer, binder, disintegrant, or surfactant. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose or lactose, low-substituted hydroxypropyl cellulose, hypromellose, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, resistant solutions, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. in addition to water and liquid paraffin, which are commonly used simple diluents. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspension solvents may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin, etc. In order to prepare a dosage form for parenteral administration, the pyrazolopyrimidine derivative compound of the above-mentioned Chemical Formula 1 or a pharma- ceutically acceptable salt thereof is sterilized or mixed with auxiliary agents such as preservatives, stabilizers, hydrating agents or emulsifying agents, salts for adjusting osmotic pressure or buffers, and other therapeutically useful substances in water to prepare a solution or suspension, which can be made into an ampoule or vial unit dosage form.

[0163] The pharmaceutical composition containing the compound of formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as rodents, livestock, and humans by various routes. All manner of administration is contemplated, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebrovascular injection. The dosage will vary depending 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 administration time, the administration route, the absorption, distribution, and excretion rate of the drug, the type of other drugs used, and the prescriber's judgment. Determination of the dosage based on such factors is within the level of one of ordinary skill in the art, and generally, the dosage ranges from 0.01 mg / kg / day to about 2000 mg / kg / day. More preferably, the dosage is from 1 mg / kg / day to 500 mg / kg / day. The dosage may be administered once a day or in multiple divided doses. The dosage is not intended to limit the scope of the present invention in any way.

[0164] Additionally, the pharmaceutical compositions of the present invention may be used alone or in conjunction with methods involving surgery, hormonal therapy, chemotherapy, and biological response modifiers to prevent or treat cancer. Effect of the Invention

[0165] The present invention relates to a pharmaceutical composition for preventing or treating tumors, which contains a novel pyrazolopyrimidine compound or a pharma- ceutical acceptable salt thereof as an active ingredient as a TTK inhibitor, and a health food composition for preventing or improving tumors, which contains the pyrazolopyrimidine compound as an active ingredient, and can be usefully used as a composition for preventing or treating cancer. [Brief description of the drawings]

[0166] [Figure 1] To confirm the suppression of pTTK expression in MDA-MB-231 cells, the results of luminescence of specific proteins induced using an enhanced chemiluminescence kit are summarized and shown below. [Diagram 2] To confirm the suppression of pTTK expression in HCT116 cells, the results of luminescence of specific proteins induced using an enhanced chemiluminescence kit are summarized and shown below. [Diagram 3] 1 is a graph showing the results of observing the size of cancer over time in a drug administration control group (Control), a CFI-402257 treatment group, and an example treatment group according to the present invention in nude mice injected with the MDA-MB-231 cell line. [Figure 4] 1 is a graph showing the results of observing changes in mouse body weight over time in a drug administration control group (Control), a CFI-402257 treatment group, and an example treatment group according to the present invention, for nude mice injected with the MDA-MB-231 cell line. [Diagram 5] 1 shows the results of evaluating the cytotoxicity of an example compound according to the present invention and paclitaxel when applied to MDA-MB-231 cells expressing TTK. [Figure 6] FIG. 1 shows the results of measuring changes in cell cycle distribution when an example compound according to the present invention and paclitaxel were applied to MDA-MB-231 cells expressing TTK. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0167] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 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 embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the concept of the present invention to those skilled in the art.

[0168] Example A. Preparation of Compound 8 according to Reaction Scheme 1

[0169] TIFF2025502807000018.tif115166

[0170] Production example 1. 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (compound 2) synthesis

[0171] TIFF2025502807000019.tif45166

[0172] Compound 1 (4.63 g, 21.89 mmol) was dissolved in methanol (MeOH; 94 mL), and then hydrazine monohydrate (NH2NH2·H2O; 1.2 mL, 24.08 mmol) was dissolved in MeOH (10 mL) and added dropwise for 30 minutes while stirring at -12 °C. Triethylamine (TEA; 3.2 mL, 22.55 mmol) was dissolved in MeOH (10 mL), and then added dropwise for 30 minutes at -12 °C, and then 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. The residue was dissolved in dichloromethane (MC; 7 mL), and then hexane (Hx; 10 mL) was added, and the solid formed was removed by filtration. After concentration under reduced pressure, the mixture was separated by silica gel column chromatography (EA:Hx = 2:3) to obtain compound 2 as a pale yellow solid (3.20 g, 77%).

[0173] 1 H-NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 14.64 (s, 1H).

[0174] Production example 2. 3-bromo-4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (compound 3) synthesis

[0175] TIFF2025502807000020.tif45166

[0176] Compound 2 (15.0 g, 79.30 mmol) was dissolved in acetonitrile (MeCN; 150 mL), N-bromosuccinimide (NBS; 15.52 g, 87.23 mmol) was added, and the mixture was stirred at 70° C. for 15 hours. The mixture was concentrated under reduced pressure, and EA (150 mL) was added to the residue, which was then washed with water (100 mL), and the moisture was removed with sodium sulfate (Na2SO4). After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (EA:Hx=1:8) to obtain 19.50 g (91%) of compound 3 in the form of a white solid.

[0177] 1H-NMR (300 MHz, DMSO-d6) δ 14.97 (s, 1H).

[0178] Production example 3-1. 3-Bromo-6-chloro-N-cyclohexyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 4-1) synthesis

[0179] TIFF2025502807000021.tif58166

[0180] 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 dropwise at -15 °C for 3 minutes, followed by stirring at room temperature for 21 hours. EA (100 mL) and tetrahydrofuran (THF; 20 mL) were added to the reaction mixture, which was then 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), removed with water (Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:Hx = 1:8) to give compound 4-1 as a white solid (4.19 g, 67%).

[0181] 1 H-NMR (500 MHz, DMSO-d6) 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).

[0182] Production example 3-2. 3-Bromo-6-chloro-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 4-2) synthesis

[0183] TIFF2025502807000022.tif51166

[0184] Compound 4-2 was obtained as a white solid (286 mg, 57%) from compound 3 (400 mg, 1.49 mmol) and 4-aminotetrahydropyrene (181 mg, 1.79 mmol) by the same preparation method as for compound 4-1.

[0185] 1 H NMR (300 MHz, DMSO-d6) 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).

[0186] Production example 3-3. 3-Bromo-6-chloro-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 4-3) synthesis

[0187] TIFF2025502807000023.tif45166

[0188] Compound 4-3 (220 mg, 42%) was obtained as a white solid from compound 3 (400 mg, 1.49 mmol) and 4-amino-1-methylpiperidine (204 mg, 1.79 mmol) by the same preparation method as for compound 4-1.

[0189] 1 H NMR (300 MHz, DMSO-d6) 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).

[0190] Production example 3-4. 3-Bromo-6-chloro-N-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 4-4) synthesis

[0191] TIFF2025502807000024.tif45166

[0192] Compound 4-4 was obtained as a white solid (1.9 g, 51%) from compound 3 (3 g, 11.20 mmol) and (tetrahydrofuran-2-yl)methanamine (1.38 mL, 13.44 mmol) by the same preparation method as for compound 4-1.

[0193] 1 H NMR (500 MHz, DMSO-d6) 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).

[0194] Production example 4-1. 3-Bromo-6-chloro-N-cyclohexyl-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 5-1) synthesis

[0195] TIFF2025502807000025.tif58166

[0196] Compound 4-1 (4.19 g, 12.67 mmol) and cesium carbonate (Cs2CO3; 4.95 g, 15.20 mmol) were dissolved in N,N-dimethylformamide (DMF; 63 mL), and p-methoxybenzyl chloride (PMBCl; 1.80 mL, 13.30 mmol) was added dropwise at 0°C and stirred at 30°C for 12 hours. EA (150 mL) was added to the mixture, and the mixture was washed with water (80 mL), and the aqueous layer was extracted with EA (40 mL). The organic layers were combined, washed with water (20X2 mL), and then dehydrated (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx=1:9) to obtain 3.71 g of compound 5-1 as a white solid (64%).

[0197] 1 H-NMR (500 MHz, DMSO-d6) 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).

[0198] Production 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

[0199] TIFF2025502807000026.tif51166

[0200] Compound 5-2 was obtained as a white solid (1.38 g, 68%) from compound 4-2 (1.45 g, 4.35 mmol) in the same manner as in the preparation of compound 5-1.

[0201] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0202] Production Example 4-3. Synthesis of 3-Bromo-6-chloro-1-(4-methoxybenzyl)-N-((tetrahydrofuran-2-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 5-4)

[0203] TIFF2025502807000027.tif51166

[0204] 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 the production of compound 5-1.

[0205] 1 H 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).

[0206] Production Example 5-1. 3-bromo-N 4 -cyclohexyl-N 6-(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 6-1) synthesis

[0207] TIFF2025502807000028.tif51166

[0208] Compound 5-1 (3.71 g, 8.23 ​​mmol) and 2-methoxy-4-morpholinoaniline (2.05 g, 9.87 mmol) were dissolved in 2-butanol (2-BuOH; 45 mL), trifluoroacetic acid (TFA; 0.63 mL, 8.23 ​​mmol) was added, and the mixture was stirred at 110°C for 22 hours. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue, and then saturated aqueous sodium bicarbonate (sat'd NaHCO3) was added to adjust the pH to 7, and the mixture was extracted with EA (60 mL). The organic layer was removed with water (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx=1:2) to obtain 4.89 g (89%) of compound 6-1 as a pale gray solid.

[0209] 1 H NMR (500 MHz, DMSO-d6) 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 = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H).

[0210] Example 5-2. 3-bromo-N 4 -cyclohexyl-1-(4-methoxybenzyl)-N 6 -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 6-2) synthesis

[0211] TIFF2025502807000029.tif58166

[0212] Compound 6-2 (100 mg, 74%) was obtained as a white solid from compound 5-1 (102 mg, 0.226 mmol) and trans-4-morpholinocyclohexane-1-amine (62 mg, 0.339 mmol) in the same manner as compound 6-1.

[0213] 1 H NMR (500 MHz, DMSO-d6) 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),

[0214] Example 5-3. 3-Bromo-N 6 -(2-methoxy-4-morpholinophenyl)-1-(4-methoxybenzyl)-N 4 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 6-3) synthesis

[0215] TIFF2025502807000030.tif45166

[0216] Compound 6-3 (128 mg, 62%) was obtained as a white solid from compound 5-2 (150 mg, 0.33 mmol) in the same manner as compound 6-1.

[0217] 1 H NMR (500 MHz, DMSO-d6) 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).

[0218] 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)

[0219] TIFF2025502807000031.tif45166

[0220] Compound 6-4 (434 mg, 35%) was obtained as a white solid from compound 5-4 (912 mg, 2.014 mmol) in the same manner as in the preparation of compound 6-1.

[0221] 1H NMR (500 MHz, DMSO-d6) 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).

[0222] Example 1. 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) production

[0223] It was prepared in two steps, Suzuki coupling and removal of PMB, according to the following reaction scheme.

[0224] TIFF2025502807000032.tif96166

[0225] Step 1. Synthesis of compound 7-1

[0226] Compound 6-1 (20 mg, 0.03 mmol), 3-fluoropyrrolidine-5-boronic acid (7 mg, 0.04 mmol), potassium carbonate (K2CO3; 9 mg, 0.06 mmol) were dissolved in dioxane-water (Dioxane-H2O; 4:1 in v / v, 2 mL), purged with argon gas for 5 minutes, added tetrakis(triphenylphosphine)palladium (Pd(PPh3)4; 2 mg, 0.001 mmol), and stirred at 100 ° C for 2 hours. The mixture was dehydrated with sodium sulfate (Na2SO4), 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 obtain 11.3 mg of compound 7-1 as a yellow solid (55%).

[0227] 1 H NMR (500 MHz, CDCl3) 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).

[0228] Step 2. Preparation of compound 8-1

[0229] Compound 7-1 (11.3 mg, 0.01 mmol) was dissolved in trifluoroacetic acid (TFA; 1 mL), methanesulfonic acid (MsOH; 0.1 mL) was added dropwise, and the mixture was stirred at 60° C. for 2 hours. The mixture was concentrated under reduced pressure, and the pH was adjusted to 7 with saturated sodium bicarbonate. Ethyl acetate (EA; 5 mL) was added, and the organic extract was washed with water (5 mL), dried over sodium sulfate (Na2SO4), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=1:2) to obtain 4.9 mg of compound 8-1 in the form of a pale yellow solid (53%).

[0230] 1 H NMR (500 MHz, DMSO-d6) 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).

[0231] Example 2. Production of 3-(4-(Cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzamide (compound 8-2)

[0232] TIFF2025502807000033.tif89166

[0233] Step 1. Synthesis of compound 7-2

[0234] Compound 7-2 was obtained as a light brown solid (42.4 mg, 75%) 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) in the same manner as in the preparation of compound 7-1.

[0235] 1 H-NMR (500 MHz, DMSO-d6) 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).

[0236] Step 2. Preparation of compound 8-2

[0237] Compound 8-2 (29 mg, 88%) was obtained as a light brown solid from compound 7-2 (42.4 mg, 0.06 mmol) in the same manner as in the preparation of compound 8-1 in Step 2 of Example 1.

[0238] 1 H NMR (500 MHz, DMSO-d6) 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).

[0239] Example 3. Production of Methyl 4-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)benzoate (compound 8-3)

[0240] TIFF2025502807000034.tif102166

[0241] Step 1. Synthesis of compound 7-3

[0242] Compound 7-3 was obtained as a white solid (42 mg, 64%) from compound 6-1 (60 mg, 0.09 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (26.0 mg, 0.14 mmol) in the same manner as in the preparation of compound 7-1.

[0243] 1 1H NMR (400 MHz, DMSO-d6) 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).

[0244] Step 2. Preparation of Compound 8-3

[0245] Compound 8-3 was obtained as a light brown solid (29 mg, 88%) in the same manner as the preparation of Compound 8-1 in Step 2 of Example 1.

[0246] 1H NMR (500 MHz, DMSO-d6) 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).

[0247] 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) production

[0248] TIFF2025502807000035.tif83166

[0249] Step 1. Synthesis of compound 7-4

[0250] Compound 7-4 was obtained as a white solid (47.8 mg, 84%) from compound 6-1 (50 mg, 0.08 mmol) and (3-(cyclopropanecarboxamido)phenyl)boronic acid (25 mg, 0.12 mmol) in the same manner as in the preparation of compound 7-1.

[0251] 1H-NMR (400 MHz, DMSO-d6) 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).

[0252] Step 2. Preparation of Compound 8-4

[0253] From Compound 7-4 (15.7 mg, 0.02 mmol), Compound 8-4 was obtained as a light brown solid (8.8 mg, 67%) in the same manner as the preparation of Compound 8-1.

[0254] 1H NMR (500 MHz, DMSO-d6) 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).

[0255] Example 5. Production of 3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-N-methylbenzamide (compound 8-5)

[0256] TIFF2025502807000036.tif96166

[0257] Step 1. Synthesis of compound 7-5

[0258] Compound 7-5 was obtained as a brown solid (32.5 mg, 59%) 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) in the same manner as in the preparation of compound 7-1.

[0259] 1H-NMR (500 MHz, DMSO-d6) 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).

[0260] Stage 2. Production of Compound 8-5

[0261] Compound 7-5 (32.5 mg, 0.04 mmol) was produced by the same method as compound 8-1, and compound 8-5 was obtained as a light brown solid in the form of 10.5 mg (39%).

[0262] 1H NMR (500 MHz, DMSO-d6) 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).

[0263] Example 6. Preparation of N-(3-(4-(cyclohexylamino)-6-((2-methoxy-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)methanesulfonamide (Compound 8-6)

[0264] TIFF2025502807000037.tif89166

[0265] Stage 1. Synthesis of compounds 7-6

[0266] Compound 6-1 (50 mg, 0.08 mmol) (3-(メチルスルホンアミド)フェニル)ボロン acid (26 mg, 0 .12 mmol), compound 7-1 was produced by the same method, and compound 7-6 was obtained as a white solid, 48.5 mg (84%).

[0267] 11H NMR (400 MHz, DMSO-d6) 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).

[0268] Step 2. Preparation of Compound 8 - 6

[0269] 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%) by the same method as the preparation of compound 8 - 1.

[0270] 1H-NMR (500 MHz, DMSO-d6) 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).

[0271] 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) production

[0272] TIFF2025502807000038.tif102166

[0273] Step 1. Synthesis of compound 7-7

[0274] Compound 7-7 (48.5 mg) was obtained as a mixture from compound 6-1 (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) in the same manner as in the preparation of compound 7-1, and was used in the next reaction.

[0275] Step 2. Production of Compound 8-7

[0276] From Compound 7-7 (50.8 mg, 0.08 mmol), 13.6 mg of Compound 8-7 was obtained in the form of a brown solid (33%) by the same method as the production of Compound 8-1.

[0277] 1 H NMR (300 MHz, DMSO-d6) 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).

[0278] 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) Production

[0279] TIFF2025502807000039.tif108166

[0280] Step 1. Synthesis of Compound 7-8

[0281] Compound 7-8 was obtained as a light brown solid in an amount of 286.9 mg (58%) 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 compound 7-1.

[0282] 1 H NMR (500 MHz, DMSO-d6) 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).

[0283] Step 2. Preparation of compound 8-8

[0284] Compound 8-8 (28.1 mg, 46%) was obtained as a light brown solid from compound 7-8 (75.1 mg, 0.12 mmol) in the same manner as in the preparation of compound 8-1.

[0285] 1H NMR (500 MHz, DMSO-d6) 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).

[0286] Example 9. N 4 -cyclohexyl-N 6 -(4-morpholinocyclohexyl)-3-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-9) production

[0287] TIFF2025502807000040.tif96166

[0288] Step 1. Synthesis of compounds 7-9

[0289] Compound 7-9 (34.0 mg) 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 the preparation of compound 7-1, and was used in the next step.

[0290] Step 2. Preparation of Compounds 8-9

[0291] Compound 8-9 (7.1 mg, 26%) was obtained as a white solid from compound 7-9 (34.0 mg, 0.05 mmol) in the same manner as in the preparation of compound 8-1 in Step 2 of Example 1.

[0292] 1 H NMR (400 MHz, DMSO-d6) 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).

[0293] 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) production

[0294] TIFF2025502807000041.tif102166

[0295] Step 1. Synthesis of compounds 7-10

[0296] Compound 7-10 was obtained as a white solid (40 mg, 80%) from compound 6-1 (50 mg, 0.08 mmol) and 1-methylpyrazole-5-boronic acid (20 mg, 0.1043 mmol) in the same manner as for the preparation of compound 7-1.

[0297] 11H NMR (300 MHz, DMSO-d6) 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).

[0298] Step 2. Preparation of Compounds 8-10

[0299] From Compound 7-10 (40 mg, 0.0641 mmol), Compound 8-10 was obtained as a white solid (18.8 mg, 58.7%) in the same manner as in the preparation of Compound 8-1 in Step 2 of Example 1.

[0300] 1H NMR (400 MHz, DMSO-d6) 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).

[0301] Example 11. 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) production

[0302] TIFF2025502807000042.tif108166

[0303] Step 1. Synthesis of compounds 7-11

[0304] Compound 7-11 was obtained as a white solid (98 mg, 94.2%) from 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) in the same manner as in the preparation of compound 7-1.

[0305] 1H NMR (300 MHz, DMSO-d6) 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).

[0306] Stage 2. Production of Compounds 8-11

[0307] Compound 7-11 (95 mg, 0.1457 mmol) was produced by the same method as compound 8-1 in step 2 of Example 1. Compound 8-11 was in the form of a white solid and 23.5 mg was obtained (30%).

[0308] 1H NMR (400 MHz, DMSO-d6) 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).

[0309] Example 12. 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) production

[0310] TIFF2025502807000043.tif108166

[0311] Step 1. Synthesis of compounds 7-12

[0312] Compound 7-12 was obtained as a white solid (55 mg, 99%) from 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) in the same manner as in the preparation of compound 7-1.

[0313] 1H-NMR (400 MHz, DMSO-d6) 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).

[0314] Step 2. Preparation of Compounds 8 - 12

[0315] From compound 7 - 12 (55 mg, 0.0833 mmol), compound 8 - 12 was obtained as a light brown solid (24 mg, 54%) in the same manner as in the preparation of compound 8 - 1 in Step 2 of Example 1.

[0316] 1 H NMR (300 MHz, DMSO-d6) 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).

[0317] 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) production

[0318] TIFF2025502807000044.tif108166

[0319] Step 1. Synthesis of compounds 7-13

[0320] Compound 7-13 was obtained as a white solid (40 mg, 80%) from 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) in the same manner as in the preparation of compound 7-1.

[0321] 1 H NMR (300 MHz, DMSO-d6) 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).

[0322] Step 2. Preparation of compounds 8-13

[0323] Compound 8-13 (55 mg, 0.0881 mmol) was treated in the same manner as in the preparation of compound 8-1 in Step 2 of Example 1 to give 23.2 mg (52%) of compound 8-13 as a white solid.

[0324] 1 H NMR (300 MHz, DMSO-d6) 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).

[0325] Example 14. N 4 -cyclohexyl-3-(furan-2-yl)-N 6 -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-14) production

[0326] TIFF2025502807000045.tif108166

[0327] Step 1. Synthesis of compounds 7-14

[0328] Compound 7-14 was obtained in the form of a white solid in 14 mg (28%) from compound 6-1 (50 mg, 0.08 mmol) and furan-2-ylboronic acid (12 mg, 0.1043 mmol) in the same manner as in the preparation of compound 7-1.

[0329] 11H NMR (300 MHz, DMSO-d6) 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).

[0330] Step 2. Preparation of Compounds 8-14

[0331] From compound 7-14 (14 mg, 0.0229 mmol), compound 8-14 was obtained as a light brown solid (4.7 mg, 42.7%) in the same manner as in the preparation of compound 8-1 in Step 2 of Example 1.

[0332] 1H NMR (400 MHz, DMSO-d6) 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).

[0333] Example 15. N 4 -cyclohexyl-N 6 -(2-methoxy-4-morpholinophenyl)-3-(thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-15) production

[0334] TIFF2025502807000046.tif108166

[0335] Step 1. Synthesis of compounds 7-15

[0336] Compound 7-15 (17.6 mg) was obtained as a mixture 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 production of compound 7-1.

[0337] Step 2. Preparation of compounds 8-15

[0338] Compound 8-15 was obtained in the form of a white solid in an amount of 11.4 mg (80.0%) from compound 7-15 (17.6 mg, 0.0287 mmol) in the same manner as in the preparation of compound 8-1.

[0339] 1 H NMR (400 MHz, DMSO-d6) 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).

[0340] Example 16. 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) production

[0341] TIFF2025502807000047.tif89166

[0342] Step 1. Synthesis of compounds 7-16

[0343] Compound 7-16 (14.5 mg, 27.8%) was obtained as a light 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 for the preparation of compound 7-1.

[0344] 1 H NMR (300 MHz, DMSO-d6) 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).

[0345] Stage 2. Compound 8-16 production

[0346] Compound 7-16 (14.5 mg, 0.0219 mmol) was produced by the same method as compound 8-1, and compound 8-16 was obtained as a light brown solid in the form of 1.3 mg (11.8%).

[0347] 1 H NMR (300 MHz, Methanol-d4) 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).

[0348] Example 17. N 4 -cyclohexyl-3-(1H-indazol-5-yl)-N 6 -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 8-17) Production

[0349] TIFF2025502807000048.tif89166

[0350] Step 1. Synthesis of Compound 7-17

[0351] 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 in the form of a white solid (94.2%) by the same method as the production of Compound 7-1.

[0352] 1 H NMR (300 MHz, DMSO-d6) 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).

[0353] Step 2. Production of Compound 8-17

[0354] From Compound 7-17 (49 mg, 0.0742 mmol), Compound 8-17 was obtained as a white solid (11.2 mg, 28%) in the same manner as the production of Compound 8-1.

[0355] 1 H NMR (400 MHz, DMSO-d6) 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).

[0356] 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) Production

[0357] TIFF2025502807000049.tif96166

[0358] Step 1. Synthesis of Compound 7-18

[0359] Compound 7-18 was obtained in the form of a white solid in the form of 51 mg (94.4%) 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 the preparation of compound 7-1.

[0360] 1 H NMR (300 MHz, DMSO-d6) 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).

[0361] Step 2. Preparation of compounds 8-18

[0362] Compound 7-18 (51 mg, 0.0755 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 21.6 mg of compound 8-18 in the form of a white solid (51.4%).

[0363] 1H NMR (400 MHz, DMSO-d6) 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).

[0364] Example 19. N 4 -cyclohexyl-N 6 Production of -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-imidazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-19)

[0365] TIFF2025502807000050.tif108166

[0366] Stage 1. Synthesis of compounds 7-19

[0367] 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), Pd(PPh3)4 (5.54 mg, 0.0048 mmol), and lithium chloride (LiCl; 2 mg, 0.048 mmol) were added and stirred at 120 ° C for 40 minutes in a Biotage microwave reactor. After the reaction was completed, 1M potassium fluoride (KF; 5 mL) was added and stirred at room temperature for 30 minutes, and then extracted with EA (20 mL × 2). The organic layer was washed with water (5 mLX2), and then the moisture was removed (Na2SO4). After concentration under reduced pressure, the residue was separated by silica gel column chromatography (EA:Hx=3:1) to obtain 57.1 mg of compound 7-19 as a white solid (95.4%).

[0368] 1 H 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).

[0369] Step 2. Preparation of Compounds 8-19

[0370] Compound 8-19 was obtained in the form of a yellow solid in an amount of 27.0 mg (71.8%) from compound 7-19 (47 mg, 0.075 mmol) in the same manner as in the preparation of compound 8-1.

[0371] 1 H 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).

[0372] Example 20. N 4 -cyclohexyl-3-(isoxazol-4-yl)-N 6 -(2-methoxy-4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-20) production

[0373] TIFF2025502807000051.tif45166

[0374] Step 1. Synthesis of compounds 7-20

[0375] Compound 7-20 (48 mg, 49%) was obtained from compound 6-1 (100 mg, 0.161 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (63 mg, 0.321 mmol) in the same manner as in the preparation of compound 7-1.

[0376] 1H 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).

[0377] Stage 2. Synthesis of Compounds 8-20

[0378] Compound 7-20 (30 mg, 0.0491 mmol) was produced by the same method as compound 8-1 and 24 mg of compound 8-20 was obtained (99%).

[0379] 1 H NMR (500 MHz, DMSO-d6) 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).

[0380] Example 21. 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) production

[0381] TIFF2025502807000052.tif45166

[0382] Step 1. Preparation of Compounds 7-21

[0383] Compound 7-21 (57 mg, 58%) was obtained from compound 6-3 (100 mg, 0.160 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (62 mg, 0.320 mmol) in the same manner as in the preparation of compound 7-1.

[0384] 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).

[0385] Step 2. Preparation of Compounds 8-21

[0386] Compound 7-21 (57 mg, 0.091 mmol) was treated in the same manner as compound 8-1 to give 30 mg of compound 8-21 as a cream-colored solid (66%).

[0387] 1 H NMR (500 MHz, DMSO-d6) 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).

[0388] Example 22. 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) production

[0389] TIFF2025502807000053.tif45166

[0390] Step 1. Preparation of Compound 7-22

[0391] Compound 6-3 (100 mg, 0.1601 mmol) and LiCl (3.4 mg, 0.080 mmol) were added to DMF (1 mL), 2-(tributylstannyl)oxazole (0.01 mL, 0.3202 mmol) was added, oxygen was removed, Pd(PPh3)4 (3.4 mg, 0.008 mmol) was added, and 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), then water was removed (Na2SO4), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:1) to obtain 37 mg of compound 7-22 (37%).

[0392] Step 2. Preparation of Compounds 8-22

[0393] Compound 7-22 (37 mg, 0.063 mmol) was treated in the same manner as in the preparation of compound 8-1 in Example 1 to give 11 mg (37%) of compound 8-22 in the form of a cream-colored solid.

[0394] 1 H NMR (300 MHz, DMSO-d6) 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).

[0395] Example 23. 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) production

[0396] TIFF2025502807000054.tif102166

[0397] Step 1. Synthesis of compounds 7-23

[0398] Compound 7-23 was obtained as a light brown solid in an amount of 29.1 mg (96%) from 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) in the same manner as in the preparation of compound 7-1.

[0399] 1 H-NMR (300 MHz, DMSO-d6) 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).

[0400] Step 2. Preparation of Compounds 8-23

[0401] Compound 8-23 (27.8 mg, 0.04 mmol) was prepared in the same manner as in the preparation of compound 8-1 to give 13.4 mg (59%) of a light brown solid.

[0402] 1H NMR (300 MHz, DMSO-d6) 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).

[0403] Example 24: 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) production

[0404] TIFF2025502807000055.tif102166

[0405] Step 1. Synthesis of compounds 7-24

[0406] Compound 7-24 was obtained as a white solid (56.3 mg, >99%) from 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) in the same manner as for the preparation of compound 7-1.

[0407] 1H-NMR (400 MHz, DMSO-d6) 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).

[0408] Step 2. Production of Compound 8-24

[0409] 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%) by the same method as the production of Compound 8-1.

[0410] 1 H-NMR (400 MHz, DMSO-d6) 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),

[0411] 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).

[0412] Example 25. 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) production

[0413] TIFF2025502807000056.tif108166

[0414] Step 1. Synthesis of Compounds 7-25

[0415] Compound 7-25 was obtained as a white solid (54.2 mg, >99%) from 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) in the same manner as for the preparation of compound 7-1.

[0416] 1H-NMR (400 MHz, DMSO-d6) 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).

[0417] Step 2. Production of Compound 8-25

[0418] From Compound 7-25 (22 mg, 0.03 mmol), 24 mg of Compound 8-25 was obtained in the form of a white solid (>99%) by the same method as the production of Compound 8-1.

[0419] 1 H-NMR (400 MHz, DMSO-d6) 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).

[0420] Example 26. N6 -(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) production

[0421] TIFF2025502807000057.tif108166

[0422] Step 1. Synthesis of Compound 7-26

[0423] Compound 7-26 (15 mg, 28%) was obtained as a white solid 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 for the preparation of compound 7-1.

[0424] 1 H-NMR (400 MHz, DMSO-d6) 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).

[0425] Step 2. Preparation of Compound 8-26

[0426] Compound 7-26 (15 mg, 0.02 mmol) was used to obtain 13 mg of compound 8-26 in the form of a white solid (>99%) in the same manner as in the preparation of compound 8-1.

[0427] 1 H-NMR (400 MHz, DMSO-d6) 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).

[0428] Example 27. 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) production

[0429] TIFF2025502807000058.tif96166

[0430] Step 1. Synthesis of compounds 7-27

[0431] Compound 7-27 was obtained as a light brown solid (31.3 mg, 100%) from compound 6-3 (30 mg, 0.04 mmol) and 3-pyridinylboronic acid (9 mg, 0.07 mmol) in the same manner as in the preparation of compound 7-1.

[0432] 11H NMR (300 MHz, DMSO-d6) 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).

[0433] Step 2. Preparation of Compound 8-27

[0434] From compound 7-27 (30.3 mg, 0.04 mmol), compound 8-27 was obtained as a light brown solid (5.6 mg, 22%) in the same manner as the preparation of compound 8-1.

[0435] 1H NMR (300 MHz, DMSO-d6) 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).

[0436] Example 28. 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) production

[0437] TIFF2025502807000059.tif96166

[0438] Step 1. Synthesis of compounds 7-28

[0439] Compound 7-28 was obtained as a white solid (17.5 mg, 100%) from compound 6-3 (15 mg, 0.02 mmol) and 4-pyridinylboronic acid (5 mg, 0.03 mmol) in the same manner as for the preparation of compound 7-1.

[0440] 11H NMR (500 MHz, DMSO-d6) 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).

[0441] Step 2. Preparation of Compound 8 - 28

[0442] From compound 7 - 28 (15 mg, 0.02 mmol), compound 8 - 28 was obtained as a light brown solid (11.4 mg, 94%) in the same manner as the preparation of compound 8 - 1.

[0443] 1H NMR (500 MHz, DMSO-d6) 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).

[0444] Example 29. 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)

[0445] TIFF2025502807000060.tif96166

[0446] Stage 1. Synthesis of compound 7-29

[0447] Compound 6-3 (15 mg, 0.02 mmol) and ボロン acid (9 mg, 0.07 mmol) were produced by the same method as compound 7-1, and compound 7-29 was obtained as a pale yellow solid of 17.4 mg (57%).

[0448] 1H-NMR (300 MHz, DMSO-d6) 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).

[0449] Stage 2. Compound 8-29 production

[0450] Compound 7-29 (17.7 mg, 0.02 mmol) was produced by the same method as compound 8-1, and compound 8-29 was obtained as a gray solid in the form of 5.7 mg (39%).

[0451] 1 H NMR (300 MHz, DMSO-d6) 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).

[0452] Example 30. N 4-cyclohexyl-3-(1-methyl-1H-pyrazol-4-yl)-N 6 -(4-morpholinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-30) production

[0453] TIFF2025502807000061.tif83166

[0454] Step 1. Synthesis of Compound 7-30

[0455] Compound 7-30 (32.1 mg) was obtained from 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), which was used in the next step.

[0456] 1 H NMR (400 MHz, DMSO-d6) 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).

[0457] Step 2. Preparation of Compound 8-30

[0458] Compound 8-30 (5.2 mg, 20%) was obtained in the form of a white solid from compound 7-30 (32.1 mg, 0.05 mmol) in the same manner as in the preparation of compound 8-1.

[0459] 1 H NMR (500 MHz, DMSO-d6) 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).

[0460] <Example B. Production of reaction compound 11 of Formula 2>

[0461] TIFF2025502807000062.tif64166

[0462] 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-4,6-diamine (Compound 11-1)

[0463] TIFF2025502807000063.tif108166

[0464] Stage 1. Synthesis of compound 9-1

[0465] Compound 5-1 (1.0 g, 2.22 mmol), 1-methylpyrazole-4-boronic acid (370 mg, 1.33 mmol), and K2CO3 (613 mg, 4.44 mmol) were dissolved in dioxane:water (4:1 in v / v, 10 mL), then purged with argon gas to remove oxygen, Pd(PPh3)4 (84.3 mg, 0.033 mmol) was added, and the mixture was stirred at 100°C for 2 hours. Water (10 mL) was added to the mixture, and it was extracted with EA (20 mLX2). The organic layer was removed with water (Na2SO4), filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx=2:1) ​​to obtain 422 mg of formula 9-1 as a white solid (42.2%).

[0466] 1 H-NMR (300 MHz, CDCl3-d6) 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).

[0467] Step 2. Synthesis of compound 10-1

[0468] Compound 9-1 (60 mg, 0.13 mmol) was dissolved in 2-butanol (1 mL), followed by the addition of 2-methoxy-4-(4-methylpiperazin-1-yl)alanine (44.2 mg, 0.2 mmol) and K2CO3 (29.4 mg, 0.21 mmol). The reaction mixture was purged with argon gas for 5 min to remove oxygen, and Pd2dba3 (30.4 mg, 0.033 mmol) and X-Phos (23.4 mg, 0.049 mmol) were added and stirred at 110 °C for 1 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 compound 10-1 as a pink solid, 38.9 mg (45.9%).

[0469] 1 H NMR (500 MHz, CDCl3) 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).

[0470] Step 3. Preparation of compound 11-1

[0471] Compound 11-1 (2.4 mg) was obtained as a green solid (9.5%) from compound 10-1 (31.7 mg, 0.049 mmol) in the same manner as in the preparation of compound 8-1.

[0472] 1 H 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).

[0473] 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[3,4-d]pyrimidine-4,6-diamine (compound 11-2) synthesis

[0474] TIFF2025502807000064.tif108166

[0475] Stage 1. Synthesis of compound 10-2

[0476] Compound 9-1 (60 mg, 0.13 mmol) 2-メトキシ-4-(4-メチル-4H-1,2,4-トリアゾール-3-イル)アニリン(3 2.5 mg, 0.16 mmol), the same manufacturing method as the aforementioned compound 10-1, and the same manufacturing method as the compound 10-2, and 20.1 mg of the compound 10-2 was obtained as a brown solid (24.4%).

[0477] 1H NMR (300 MHz, CDCl3) 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).

[0478] Stage 2. Preparation of Compound 11-2

[0479] Compound 10-2 (20 mg, 0.032 mmol) was obtained by the same manufacturing method as the aforementioned compound 11-1 and compound 11-2 was obtained as a white solid of 8.1 mg (50.9%).

[0480] 1 H NMR (300 MHz, CDCl3) 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 = 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).

[0481] Example 33. Synthesis of 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)

[0482] TIFF2025502807000065.tif96166

[0483] Step 1. Synthesis of Compound 10-3

[0484] From Compound 9-1 (60 mg, 0.13 mmol) and 4-amino-3-methoxy-N-methylbenzamide (27.7 mg, 0.16 mmol), 48.9 mg (60.6%) of Compound 10-3 was obtained as a white solid by the same production method as Compound 10-1.

[0485] 1 H NMR (500 MHz, CDCl3) 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).

[0486] Step 2. Production of Compound 11-3

[0487] Compound 11-3 (9.1 mg, 30.8%) was obtained as a white solid from compound 10-3 (37 mg, 0.062 mmol) by the same preparation method as for compound 11-1.

[0488] 1 H NMR (300 MHz, CDCl3) 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).

[0489] Example 34. (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) production

[0490] TIFF2025502807000066.tif102166

[0491] Step 1. Synthesis of compound 10-4

[0492] Compound 10-4 was obtained as a white solid (48.1 mg, 73.7%) 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 compound 10-1.

[0493] 1 1H NMR (400 MHz, CDCl3) 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).

[0494] Step 2. Preparation of Compound 11-4

[0495] From Compound 10-4 (27.1 mg, 0.042 mmol), Compound 11-4 was obtained as a white solid (11.1 mg, 50.2%) by the same production method as that of the above Compound 11-1.

[0496] 1 1H NMR (400 MHz, CDCl3) 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).

[0497] Example 35. (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) Production

[0498] TIFF2025502807000067.tif96166

[0499] Step 1. Synthesis of compound 10-5

[0500] Compound 10-5 was obtained as a yellow solid (60.2 mg, 68.1%) from compound 9-1 (60 mg, 0.13 mmol) and (4-amino-3-methoxyphenyl)(4-methoxypiperazin-1-yl)methanone (39.6 mg, 0.16 mmol) by the same preparation method as compound 10-1.

[0501] 1 H NMR (500 MHz, CDCl3) 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).

[0502] Step 2. Preparation of compound 11-5

[0503] Compound 11-5 (12.1 mg, 33.7%) was obtained as a white solid from compound 10-5 (44 mg, 0.066 mmol) by the same preparation method as that for compound 11-1.

[0504] 1 H NMR (500 MHz, CDCl3) 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).

[0505] Example 36. Production of 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)

[0506] TIFF2025502807000068.tif89166

[0507] Step 1. Synthesis of compound 10-6

[0508] Compound 10-6 was obtained as a green solid (48.2 mg, 54.7%) from 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) in the same manner as compound 10-1.

[0509] 1 H NMR (400 MHz, CDCl3) 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).

[0510] Stage 2. Production of Compound 11-6

[0511] Compound 10-6 (35.6 mg, 0.052 mmol) was obtained by the same manufacturing method as the aforementioned compound 11-1 and compound 11-6 was obtained as a yellow solid of 13.1 mg (47.5%).

[0512] 1H NMR (300 MHz, CDCl3) 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, 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).

[0513] <Example C. Production of reaction compound 14 of Formula 3>

[0514] TIFF2025502807000069.tif51166

[0515] 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)

[0516] TIFF2025502807000070.tif96166

[0517] Stage 1. Synthesis of compound 12-1

[0518] Compound 6-1 (3.10 g, 5 mmol), molybdenum hexacarbonyl (Mo(CO)6; 1.60 g, 6 mmol), and tert-butyl carbazate (tert-butyl carbazate; 2.0 g, 15 mmol) were dissolved in dioxane (30 mL), and then 1,8-diazabicyclo[5.4.0]undecene-7 (DBU; 2.2 mL, 15 mmol) was added, and the mixture was purged with argon gas to remove oxygen. Pd(dppf)Cl2 (180 mg, 0.012 mmol) was added, and 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), and 2.03 g (58%) of the intermediate tert-butyl hydrazine carboxylate was obtained as a white solid.

[0519] tert-Butyl hydrazine carboxylate (1.5 g, 2.1372 mmol) was dissolved in MC (10.0 mL), TFA (20 mL) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 7 with sat'd NaHCO3 aqueous solution, EA (50 mL) was added, and the mixture was washed with water (50 mL), after which moisture was removed (Na2SO4), and the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx=1:1) to obtain 800 mg of compound 12-1 as a light brown solid (66%).

[0520] 1H NMR (300 MHz, DMSO-d6) 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).

[0521] Step 2. Synthesis of compound 13-1

[0522] Compound 12-1 (60 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide dimethylacetal (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 filtered and dissolved in MeCN (1 mL), and one drop of AcOH and methylamine (2 M in THF; 0.2 mL, 0.4 mmol) were added. The mixture was stirred at 85 ° C for 24 hours, cooled to room temperature, and the resulting solid was filtered to obtain 20.1 mg of compound 13-1 as a brown solid. (32.4%)

[0523] 1H NMR (400 MHz, CDCl3) 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).

[0524] Stage 3. Production of Compound 14-1

[0525] Compound 13-1 (23 mg, 0.037 mmol) was produced by the same method as compound 8-1, and compound 14-1 was obtained as a white solid of 13.1 mg. (70.2%)

[0526] 1 H NMR (500 MHz, CDCl3) 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).

[0527] Example 38. N4 -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) production

[0528] TIFF2025502807000071.tif39166

[0529] Step 1. Preparation of compound 13-2

[0530] Compound 12-1 (60 mg, 0.10 mmol) was dissolved in formamide (1 mL) and stirred at 100° C. for 1 hour. After concentrating the reaction mixture, the resulting solid was dissolved in phosphorus oxychloride (POCl3; 2 mL) and stirred at 100° C. for 24 hours. The reaction mixture was cooled to room temperature and slowly added to ice water (10 mL). The resulting solid was filtered to give compound 13-2 as a brown solid (43.0 mg). (70.5%)

[0531] 1 H NMR (300 MHz, DMSO-d6) 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).

[0532] Step 2. Preparation of compound 14-2

[0533] Compound 14-2 (9.8 mg) was obtained as a yellow solid from compound 13-2 (22 mg, 0.0359 mmol) in the same manner as in the preparation of compound 8-1 (50.5%).

[0534] 1 H NMR (400 MHz, DMSO-d6) 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).

[0535] Example 39. Production of 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)

[0536] TIFF2025502807000072.tif39166

[0537] Step 1. Preparation of compound 13-3

[0538] Compound 12-1 (30 mg, 0.05 mmol) was dissolved in THF (2 mL), and then 1,1'-carbonyldiimidazole (CDI; 12 mg, 0.075 mmol) was added and stirred for 14 hours at 60° C. The reaction mixture was concentrated and then separated by silica gel column chromatography (MC:MeOH=10:1) to obtain 13 mg of compound 13-3 as a pale gray solid (41%).

[0539] 1 H NMR (500 MHz, DMSO-d6) 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).

[0540] Stage 2. Preparation of Compound 14-3

[0541] Compound 13-3 (13 mg, 0.0207 mmol) was produced by the same method as compound 8-1. Compound 14-3 was obtained as a yellow solid and 4.6 mg was obtained. (46%)

[0542] 1 H NMR (300 MHz, DMSO-d6) 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).

[0543] <Example D. Production of compound 18 of the reaction formula 4による>

[0544] TIFF2025502807000073.tif108166

[0545] Example 40. 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) production

[0546] TIFF2025502807000074.tif77166

[0547] Step 1. Synthesis of compound 15-1

[0548] Chemical formula 6-1 (6.81 g, 10.9385 mmol), potassium vinyltrifluoroborate (CH2=CHBF3K; 2.93 g, 21.8770 mmol), potassium carbonate (K2CO3) (4.5 g, 32.8155 mmol) were dissolved in toluene:EtOH (ethanol) = 3:1 (200 mL), then purged with argon gas to remove oxygen, Pd(PPh3)4 (1.26 g, 1.0938 mmol) was added, and the mixture was stirred at 80 ° C for 14 hours. After concentrating the mixture under reduced pressure, EA (200 mL) was added, washed with water (200 mL), removed water (Na2SO4), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:3) to obtain 5.26 g of compound 15-1 as a light brown solid (84.4%).

[0549] 1H NMR (500 MHz, DMSO-d6) 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).

[0550] Step 2. Synthesis of compound 16-1

[0551] Compound 15-1 (5.26 g, 9.2327 mmol) and NMO (2.68 g, 18.4655 mmol) were dissolved in THF:H2O=3:1, and then OsO4 (2.5 wt% in H2O; 8.4 mL) was slowly added dropwise and stirred at 0°C for 1 hour. The mixture was concentrated under reduced pressure, and then ethyl acetate (200 mL) was added, washed with water (200 mL), removed water (Na2SO4), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX=1:1) to obtain the dihydroxy compound as a yellow solid (4.2 g) (75.4%).

[0552] The dihydroxy compound (4.2 g, 6.96 mmol) was dissolved in THF:H2O = 3:1, and NaIO4 (2.68 g, 20.8706 mmol) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and then ethyl acetate (200 mL) was added and washed with water (200 mL), after which the organic layer was dehydrated (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:MC = 1:20) to obtain formula 16-1 in the form of a brown solid (70.7%).

[0553] 1 H NMR (300 MHz, DMSO-d6) 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).

[0554] Step 3. Synthesis of compound 17-1

[0555] Compound 16-1 (200 mg, 0.35 mmol), p-toluenesulfonylmethyl isocyanide (TosMIC; 75 mg, 0.38 mmol), and K2CO3 (145 mg, 1.05 mmol) were added to MeOH (5 mL) and stirred at 50° C. for 1 hour. EA (25 mL) was added to the mixture, which was washed with water (25 mL), and then the water was removed (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:HX:MC=2:1:1) to obtain 166 mg of compound 17-1 as a light brown solid. (78%)

[0556] 1 H NMR (500 MHz, DMSO-d6) 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 , 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).

[0557] Stage 4. Compound 18-1 Manufacturing

[0558] Chemical formula 17-1 (417 mg, 0.6828 mmol) was produced by the same method as compound 8-1, and compound 18-1 was obtained as a white solid of 245 mg (73.3%).

[0559] 1H NMR (400 MHz, DMSO-d6) 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).

[0560] Example 41. 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) production

[0561] TIFF2025502807000075.tif39166

[0562] Step 1. Synthesis of compound 17-2

[0563] Compound 16-1 (50 mg, 0.0875 mmol), p-toluenesulfonylmethyl isocyanide (TosMIC; 19 mg, 0.095 mmol), and K2CO3 (36 mg, 0.262 mmol) were added to MeOH (2 mL) and stirred at 50° C. for 1 hour. EA (5 mL) was added to the mixture, which was washed with water (5 mL), and then the water was removed (Na2SO4) and concentrated under reduced pressure. Ammonia (7 M 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.

[0564] 11H 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).

[0565] Step 2. Production of Compound 18-2

[0566] 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 the production of Compound 8-1.

[0567] 1 1H 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).

[0568] <Example E. Production of Compound 21 according to Reaction Scheme 5>

[0569] TIFF2025502807000076.tif58166

[0570] 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) production

[0571] TIFF2025502807000077.tif96166

[0572] According to Reaction Scheme 5, compound 6-1 was prepared through a three-step process.

[0573] Step 1. Synthesis of compound 19-1

[0574] The compound 6-1 (1.87 g, 3.003 mmol), cuprous iodide (CuI; 57 mg, 10% mmol) were dissolved in dimethylformamide (DMF; 25 mL) and triethylamine (TEA; 5 mL), trimethylsilylacetylene (0.6 mL, 4.2051 mmol) was added, and the mixture was purged with argon gas to remove oxygen, and PdCl2(PPh3)2 (105 mg, 5% mmol) was added, and the gas was removed and stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (EA:HX=1:2). The obtained compound was dissolved in tetrahydrofuran (20 mL), and then tetra-n-butylammonium fluoride (TBAF; 1.3 mL, 1.2 eq) was added, followed by stirring at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and then ethyl acetate (50 mL) was added. After washing with water (50 mL), moisture was removed (Na2SO4), and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX=1:2) to obtain 1.18 g (69%) of compound 19-1 as a light brown solid.

[0575] 1H NMR (300 MHz, DMSO-d6) 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).

[0576] Step 2. Synthesis of compound 20-1

[0577] The compound 19-1 (114 mg, 0.15 mmol) and copper (I) iodide (CuI; 4 mg, 10% mmol) were dissolved in dimethylformamide (DMF):methanol (MeOH) = 9:1 (2 mL), trimethylsilyl azide (0.040 mL, 0.3 mmol) was added, and the mixture was stirred at 100 ° C for 6 hours. The mixture was concentrated under reduced pressure, and then EA (10 mL) was added. After washing with water (10 mL), moisture was removed (Na2SO4), and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:3) to obtain 87 mg of compound 20-1 as a light brown solid (76%).

[0578] 11H NMR (400 MHz, DMSO-d6) 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).

[0579] Step 3. Preparation of Compound 21-1

[0580] From Chemical Formula 20-1 (87 mg, 0.1424 mmol), 48 mg of Compound 21-1 was obtained as a white solid (68%) in the same manner as the preparation of Compound 8-1.

[0581] 1 1H NMR (300 MHz, DMSO-d6) 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).

[0582] 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) production

[0583] TIFF2025502807000078.tif45166

[0584] Step 1. Preparation of compound 20-2

[0585] Compound 19-1 (400 mg, 0.7046 mmol) was dissolved in dimethyl sulfoxide (20 mL) containing sodium azide (100 mg) and iodomethane (0.1 mL) and stirred for 12 hours. After dissolving in the mixture, copper sulfate pentahydrate (14 mg, 8% mmol) and sodium L-ascorbate (27 mg, 20% mmol) were added and stirred at room temperature for 12 hours or more. Ethyl acetate (100 mL) was added to the mixture, washed with water (100 mL), removed water (Na2SO4), and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:HX=1:1) to obtain compound 20-2 in the form of a light brown solid. (74%)

[0586] 1H NMR (400 MHz, DMSO-d6) 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).

[0587] Stage 2. Production of Compound 21-2

[0588] Compound 20-2 (327 mg, 0.5234 mmol) was produced by the same method as compound 8-1, and compound 21-2 was obtained in the form of a light brown solid. (59%)

[0589] 1 H NMR (400 MHz, DMSO-d6) 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).

[0590] Example 44. 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) production

[0591] TIFF2025502807000079.tif89166

[0592] Step 1. Synthesis of Compound 19-3

[0593] From Compound 6-3 (1.87 g, 2.9942 mmol), Compound 19-3 was obtained in the form of a light brown solid by the same method as the production of Compound 19-1. (64%)

[0594] 1 H NMR (500 MHz, DMSO-d6) 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).

[0595] Step 2. Synthesis of Compound 20-3

[0596] Compound 20-3 was obtained in the form of a white solid in an amount of 32 mg (51.6%) from compound 19-3 (57 mg, 0.1000 mmol) in the same manner as in the preparation of compound 20-2.

[0597] 1 H NMR (300 MHz, DMSO-d6) 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).

[0598] Step 3. Preparation of compound 21-3

[0599] Compound 21-3 was obtained in the form of a light brown solid in an amount of 19.4 mg (77.6%) from compound 20-3 (32 mg, 0.0510 mmol) in the same manner as in the preparation of compound 8-1.

[0600] 1H NMR (300 MHz, DMSO-d6) 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).

[0601] <Example F. Production of compound 26 of the reaction formula 6による>

[0602] TIFF2025502807000080.tif115166

[0603] 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) production

[0604] TIFF2025502807000081.tif83166

[0605] Stage 1. Synthesis of compound 22

[0606] Compound 3 (10.75 g, 40.43 mmol) was dissolved 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) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, dissolved in EA (200 mL), washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried (MgSO4), and concentrated under reduced pressure to give compound 22 as a white solid (11.77 g, 83.2%).

[0607] 1 H NMR(300MHz, CDCl3) 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, 3.0Hz, 1H), 8.20 (s, 1H).

[0608] Step 2. Synthesis of compound 23-1

[0609] Compound 22 (100 mg, 0.286 mmol) was dissolved in THF / IPA (1:4, 2 mL), cyclohexylamine (0.052 mL, 0.457 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and then 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%).

[0610] 1H NMR (400 MHz, CDCl3) 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).

[0611] Step 3. Synthesis of compound 24-1

[0612] Compound 23-1 (200 mg, 0.483 mmol), 1-methylpyrazole-4-boronic acid (80.98 mg, 0.642 mmol), and K2CO3 (133.5 mg, 0.966 mmol) were dissolved in dioxane:water (4:1 in v / v, 2 mL), purged with argon gas to remove oxygen, added Pd(PPh3)4 (18.4 mg, 0.0159 mmol), removed gas, and stirred in a microwave reactor at 120 °C for 1 h. The mixture was added with water (20 mL) and extracted with EA (20 mL x 2). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:5) to give compound 24-1 as a white solid (64.7 mg, 32.2%).

[0613] 1H NMR (400 MHz, CDCl3) 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).

[0614] Step 4. Synthesis of compound 25-1

[0615] Chemical compound 24-1 (32 mg, 0.077 mmol) was dissolved in 2-butanol (1 mL), and then 2-isopropoxy-4-morpholinoaniline (21.7 mg, 0.092 mmol) and K2CO3 (17.0 mg, 0.123 mmol) were added. The mixture was purged with argon gas for 5 minutes to remove oxygen, and Pd2dba3 (17.6 mg, 0.019 mmol) and X-phos (13.5 mg, 0.028 mmol) were added and the mixture was stirred at 110 °C for 1 day. The reaction was filtered (cellulite pad) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH = 99:1) to give compound 25-1 as a white solid, 36.3 mg. (76.7%)

[0616] 1H NMR (300 MHz, CDCl3) 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), 1.32 - 1.12 (m, 5H).

[0617] Step 5. Preparation of compound 26-1

[0618] Compound 25-1 (36 mg, 0.058 mmol) was dissolved in MeOH (2 mL), and then 6N HCl (0.1 mL) was added at 0°C, and the mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and then saturated NaHCO3 aqueous solution (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mLX2). The organic layer was dehydrated (Na2SO4), concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (MC:MeOH=97:3), and 16.6 mg of compound 26-1 was obtained as a white solid (53.4%).

[0619] 1H NMR (300 MHz, DMSO-d6) 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).

[0620] Example 46. N 6 -(2-methoxy-4-morpholinophenyl)-3-(1-methyl-1H-pyrazol-4-yl)-N 4 -phenyl-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 26-2) production

[0621] TIFF2025502807000082.tif108166

[0622] Step 1. Synthesis of compound 23-2

[0623] Compound 22 (200 mg, 0.57 mmol) was dissolved in isopropyl alcohol (IPA) (2.0 mL), and then aniline (0.06 mL, 0.68 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.68 mmol) were added and stirred at 40° C. for 1 hour. After the reaction was completed, the solid formed was filtered to obtain 175 mg of compound 23-2 in the form of a white solid. (75.4%)

[0624] 1H NMR (500 MHz, CDCl3) 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).

[0625] Step 2. Synthesis of compound 24-2

[0626] Compound 23-2 (175 mg, 0.43 mmol), 1-methylpyrazole-4-boronic acid (108.4 mg, 0.86 mmol), and potassium carbonate (K2CO3) (237.7 mg, 1.72 mmol) were dissolved in dioxane:H2O (4:1 in v / v, 2 mL), purged with argon gas to remove oxygen, charged with Pd(PPh3)4 (32.8 mg, 0.028 mmol), degassed, and stirred in a microwave reactor at 110 °C for 1 h. The mixture was charged with water (10 mL) and extracted with ethyl acetate (20 mLX2). The combined organic layer was filtered over sodium sulfate (Na2SO4) 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 in the form of a white solid. (40.4%).

[0627] 1H NMR (400 MHz, CDCl3) 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).

[0628] Step 3. Synthesis of compound 25-2

[0629] Formula 24-2 (71.2 mg, 0.174 mmol) was dissolved in 2 mL of 2-butanol, and then aniline (46.02 mg, 0.208 mmol) and potassium carbonate (38.4 mg, 0.278 mmol) were added. The mixture was purged with argon gas for 5 minutes to remove oxygen, and tris(dibenzylideneacetone)dipalladium(0) (39.3 mg, 0.043 mmol) and XPhos (28.6 mg, 0.06 mmol) were added, followed by stirring at 110°C for 1 hour. The mixture was concentrated under reduced pressure after filtering through a cellulite pad. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 38.7 mg of compound 25-2 in the form of a white solid. (38.2%)

[0630] 1 H 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).

[0631] Step 4. Preparation of compound 26-2

[0632] Formula 25-2 (38.7 mg, 0.066 mmol) was dissolved in 2 mL of methanol, and 0.1 mL of 6N HCl was added at 0°C, and the mixture was allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, the methanol was removed, and sodium bicarbonate (10 mL) was added to the mixture, which was then extracted with ethyl acetate (20 mL x 2). The residue was subjected to silica gel column chromatography (dichloromethane:methanol = 19:1) to obtain 17.5 mg of compound 26-2 in the form of a white solid. (53.3%)

[0633] 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).

[0634] Example G. Preparation of Compound 28 via Reaction Scheme 7

[0635] TIFF2025502807000083.tif51166

[0636] Example 47. 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) production

[0637] TIFF2025502807000084.tif96166

[0638] Step 1. Synthesis of compound 27-1

[0639] TFA (44.2 μL) was added to 2-butanol (2-BuOH; 5 mL), and then 2-methoxy-4-morpholinoaniline (126 mg, 0.60 mmol in THF 1 mL) was added dropwise at room temperature for 3 minutes. Compound 4-3 (190 mg, 0.54 mmol in THF 3 mL) was added dropwise to the mixture for 3 minutes, and then the mixture was stirred at 110° C. for 14 hours. The reaction mixture was adjusted to pH 7 with sat'd NaHCO3 aqueous solution, and then EA (8 mL) was added. After washing with water (3 mL), moisture was removed (Na2SO4), and the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH=10:1) to obtain 21 mg of compound 27-1 (7.3%).

[0640] 1 H NMR (500 MHz, DMSO-d6) 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 = 8.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H).

[0641] Step 2. Preparation of compound 28-1

[0642] Compound 27-1 (20 mg, 0.03 mmol) and boronate (13 mg, 0.05 mmol) were used to obtain 11.3 mg (56%) of compound 28-1 in the form of a light brown solid in the same manner as in the preparation of compound 7-1.

[0643] 1 H NMR (500 MHz, DMSO-d6) 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).

[0644] Example H. Preparation of Compound 33 via Reaction Scheme 8

[0645] TIFF2025502807000085.tif121166

[0646] Example 48. N 6 -(2-methoxy-4-morpholinophenyl)-3-(oxazol-5-yl)-N 4 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 33-1) production

[0647] TIFF2025502807000086.tif96166

[0648] Step 1. Preparation of compound 29

[0649] From compound 5-2 (1.0 g, 2.208 mmol), 633 mg of compound 29 was obtained in the same manner as in the production of compound 16-1 in Example 40 (71%).

[0650] 1 H NMR (300 MHz, DMSO-d6) 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).

[0651] Step 2. Production of compound 30

[0652] From compound 29 (623 mg, 1.557 mmol), 480 mg of compound 30 was obtained in the same manner as in the production of compound 16-1 in Example 40 (77%).

[0653] 1 H NMR (300 MHz, DMSO-d6) 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), 1.63 - 1.50 (m, 2H).

[0654] Step 3. Production of compound 31

[0655] Compound 31 (65 mg, 60%) was obtained from compound 30 (100 mg, 0.2488 mmol) in the same manner as in the production of compound 17-1 in Example 40.

[0656] 1 H NMR (300 MHz, DMSO-d6) 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).

[0657] Step 4. Preparation of compound 32-1

[0658] Compound 31 (50 mg, 0.1134 mmol), 2-methoxy-4-morpholinoaniline (28 mg, 0.136 mmol), potassium carbonate (23 mg, 0.1701 mmol), and XPhos (19 mg, 0.039 mmol) were added to 2-butanol (1 mL), and 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 and washed with EA (20 mL), and the organic layer was washed with water (10 mL), and the water was removed (Na2SO4), and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX=2:1) ​​to obtain 19 mg of compound 32-1 (27%).

[0659] 1H NMR (500 MHz, DMSO-d6) 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 = 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).

[0660] Stage 5. Production of Compound 33-1

[0661] Compound 32-1 (10 mg, 0.0163 mmol) was produced by the same method as compound 8-1, and compound 33-1 was obtained as 4 mg (50%).

[0662] 1 H NMR (300 MHz, DMSO-d6) 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).

[0663] Example 49. Preparation of 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)

[0664] TIFF2025502807000087.tif51166

[0665] Stage 1. Compound 32-2 Production

[0666] Chemical 31 (50mg, 0.1134mmol), 4-アミン-3-メトキシ-N-メチルベンズアミド (24 mg, 0.136 mmol), compound 32-1 was produced by the same method, and compound 32-2 was obtained as 42 mg (63%).

[0667] 1 H NMR (500 MHz, DMSO-d6) 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).

[0668] Stage 2. Compound 33-2 Production

[0669] Compound 33-2 (5.1 mg, 16%) was obtained from compound 32-2 (30 mg, 0.0513 mmol) in the same manner as in the preparation of compound 8-1.

[0670] 1 H NMR (300 MHz, DMSO-d6) 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).

[0671] Example 50. N 6 -(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-3-(oxazol-5-yl)-N 4 -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 33-3) production

[0672] TIFF2025502807000088.tif51166

[0673] Step 1. Preparation of compound 32-3

[0674] Compound 32-3 (17 mg, 24%) was obtained from compound 31 (50 mg, 0.1134 mmol) and 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (27 mg, 0.136 mmol) in the same manner as in the preparation of compound 32-1, and was used in the next step.

[0675] Stage 2. Production of Compound 33-3

[0676] Compound 32-3 (17 mg, 0.027 mmol) was produced by the same method as compound 8-1, and compound 33-3 was produced using the same method as 2.1 mg (16%).

[0677] 1 H NMR (400 MHz, DMSO-d6) 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).

[0678] Example 51. 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)

[0679] TIFF2025502807000089.tif45166

[0680] Stage 1. Compound 7-34 Production

[0681] Compound 6-4 (100 mg, 0.160 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.240 mmol) were used in the same manner as in the preparation of compound 7-1 in Example 1 to give 96 mg of compound 7-34 in the form of a brown solid (96%).

[0682] 1 H 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).

[0683] Step 2. Preparation of Compound 8-34

[0684] Compound 7-34 (96 mg, 0.149 mmol) was treated in the same manner as in the preparation of compound 8-1 in Example 1 to give 43 mg (57%) of compound 8-34 in the form of a cream-colored solid.

[0685] 1H NMR (300 MHz, DMSO-d6) 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).

[0686] Example 52. 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) production

[0687] TIFF2025502807000090.tif45166

[0688] Step 1. Preparation of compound 7-35

[0689] Compound 7-35 (20 mg, 27%) was obtained from compound 6-4 (100 mg, 0.160 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (47 mg, 0.240 mmol) in the same manner as in the preparation of compound 7-1.

[0690] 1H 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).

[0691] Step 2. Preparation of compound 8-35

[0692] Compound 7-35 (20 mg, 0.0326 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 2 mg of compound 8-35 as a white solid (13%).

[0693] 1 H NMR (300 MHz, DMSO-d6) 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).

[0694] <Experimental Example 1. Evaluation of TTK activity inhibition ability>

[0695] In order to measure the TTK activity inhibitory ability of the compound represented by Chemical Formula 1 according to the present invention, the following experiment was carried out.

[0696] Recombinant human TTK protein was mixed with the compound in a reaction solution (8mM MOPS pH 7.0, 0.2mM EDTA, 0.33mg / mL MBP, 10mM magnesium acetate, 45uM [gamma-33P-ATP]) and reacted at room temperature for 40 minutes. Then, phosphoric acid was added to make it 0.5% to terminate the reaction, and 10μl of the reaction solution was dripped onto a P30 filter. The dripped filter was washed with 0.425% phosphoric acid solution for 4 minutes four times, washed once more with methanol, dried, and TTK activity was measured by scintillation counting. The activity value obtained from the group without the compound was determined as 100% of control, and the degree of TTK inhibition by the compound was converted, and the TTK inhibitory activity of the example compounds was summarized in Table 1 below.

[0697] [Table 1]

[0698] Therefore, as confirmed in Experimental Example 1, the compound represented by Chemical Formula 1 according to the present invention has excellent effect of inhibiting TTK activity, and therefore can be usefully used as a TTK activity inhibitor and also as a composition for preventing or treating cancer induced thereby.

[0699] <Experimental Example 2. Evaluation of kinase activity inhibition ability>

[0700] The results of the kinase activity inhibitory ability of compound 8-8 at a concentration of 500 nM are shown in Table 2 below.

[0701] [Table 2]

[0702] The five kinases that were confirmed to be inhibited by 90% or more were ALK(h), including TTK(h), which is the target of the present invention, IR(h) activated, IRR(h), and LTK(h). In particular, it was confirmed that 500 nM compound 8-8 completely inhibited TTK activity and also had inhibitory activity against other kinases.

[0703] <Experimental Example 3. Cytotoxicity evaluation in TTK-expressing MDA-MB-231 cells>

[0704] In order to measure the cytotoxicity of the compound represented by Chemical Formula 1 according to the present invention to MDA-MB-231 cells, the following experiment was carried out.

[0705] MDA-MB-231 triple negative breast cancer cell line purchased from ATCC was injected into each well of a 96-well plate at a volume of 90 μL, and then the compound of the present invention was added to each well at concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, and 0 μM, and cultured in a cell incubator at 37°C for 5 days. After 5 days, 10 μL of Cyto X solution (manufactured by LPS solution) was added to each well, and the absorbance was measured at 450 nm using an Epoch microplate spectrophotometer (manufactured by BioTek Instruments) according to the product instructions. The cytotoxicity was calculated using the measured value to calculate the amount of cells, and the IC value of the cytotoxicity of each compound was calculated. 50 The values ​​were calculated, and the cytotoxicity results of the example compounds in MDA-MB-231 cells are shown in Table 3 below.

[0706] [Table 3]

[0707] As shown in Table 3, many of the example compounds according to the present invention had IC 50It can be seen that the value is at the same level as that of Comparative Example 1 (CFI-402257). Therefore, as confirmed in Experimental Example 2, the compound represented by Chemical Formula 1 according to the present invention has excellent effect of inhibiting TTK activity in MDA-MB-231 cells, and therefore can be usefully used as a TTK activity inhibitor and can also be usefully used as a composition for preventing or treating cancer induced thereby.

[0708] <Experimental Example 4. Confirmation of pTTK expression inhibition in MDA-MB-231 cells by western blotting method>

[0709] From the above-mentioned Experimental Example 3, it was found that this compound caused cell death in MDA-MB-231 cells expressing TTK, and Western blotting was performed to confirm whether TTK protein is involved in this cell death.

[0710] MDA-MB-231 cells were prepared in 200,000 cells per well of a 6-well plate, and then treated with 50 ng / mL nocodazole and cultured for one day. Then, the example compounds of the present invention were administered to determine the IC 50 After adding the appropriate concentration, the cells were incubated for 4 hours, and RIPA solution was added to dissolve the cells. To confirm the expression of TTK and pTTK in the samples, primary antibodies specific to each protein (TTK primary antibody manufacturer: Cell Signaling Technology, thr33 and ser37 phosphorylated TTK detection manufacturer: Invitrogen) and secondary antibodies were used, diluted 1:10,000. The luminescence of specific proteins induced using an Enhanced Chemiluminescence kit (ECL, Santa Cruz Biotechnology) was obtained and analyzed using a ChemiDoc XRS+ system, and the results are summarized in Figure 1.

[0711] The compound represented by Chemical Formula 1 according to the present invention has IC50 It can be confirmed that at the concentration level, pTTK expression is completely inhibited equivalent to Comparative Example 1 (CFI-402257).

[0712] <Experimental Example 5. Cytotoxicity evaluation in HCT116 cells expressing TTK>

[0713] In order to measure the cytotoxicity of the compound represented by Formula 1 according to the present invention to HCT116 cells, the following experiment was carried out.

[0714] HCT116 colon cancer cell line purchased from ATCC was injected into each well of a 96-well plate at a volume of 90 μL, 2,000 cells per well, and the example compounds of the present invention were added to each well at concentrations of 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, and 0 μM, and cultured in a cell incubator at 37° C. for 5 days. After 5 days, the cell mass was measured using the CCK8 test method, and the cytotoxicity was evaluated by the IC 50 The values ​​were calculated, and the cytotoxicity results of the example compounds in HCT116 cells are shown in Table 4 below.

[0715] [Table 4]

[0716] As shown in Table 4, many of the example compounds according to the present invention have cytotoxic IC 50 It can be seen that the value is equal to or lower than that of Comparative Example 1 (CFI-402257). Therefore, the compound represented by Chemical Formula 1 according to the present invention has excellent effect of inhibiting TTK activity in HCT116 cells, and therefore can be usefully used as a TTK activity inhibitor and a composition for preventing or treating cancer induced by the TTK activity inhibitor.

[0717] <Experimental Example 6. Confirmation of pTTK expression inhibition in HCT116 cells by western blotting method>

[0718] From the above-mentioned Experimental Example 5, it was found that this compound caused cell death in HCT116 cells expressing TTK, and Western blotting was carried out to confirm whether TTK protein is involved in this cell death.

[0719] HCT116 cells were prepared in 200,000 cells per well of a 6-well plate, and then treated with 50 ng / mL nocodazole and cultured for one day. Then, the example compounds of the present invention were administered to determine the IC 50 After adding the solution according to the concentration, the cells were cultured for 4 hours, and RIPA solution was added to dissolve the cells. To confirm the expression of TTK and pTTK in the samples, primary antibodies specific to each protein (TTK primary antibody manufacturer: Cell Signaling Technology, thr33 and ser37 phosphorylated TTK detection manufacturer: Invitrogen) and secondary antibodies diluted 1:10000 were used. The luminescence of specific proteins induced using an Enhanced Chemiluminescence kit (ECL, Santa Cruz Biotechnology) was obtained and analyzed using a ChemiDoc XRS+ system, and the results are summarized in Figure 2.

[0720] The compounds represented by Chemical Formula 1 according to the present invention have IC 50 It can be confirmed that pTTK expression is completely inhibited at the same concentration level as Comparative Example 1 (CFI-402257).

[0721] <Experimental Example 7. Evaluation of efficacy of MDA-MB-231 on nude mice>

[0722] 5-week-old female nude mice were inoculated with 5 × 10 MDA-MB-231 cells. 6 The tumor size was reduced to about 50 mm. 3When the tumor size reached 100%, the mice were divided into groups of 5 and orally administered with each drug at a dose of 6 mg / kg every day for 4 weeks. The changes in body weight and tumor size were measured, and the results are shown in Figures 3 and 4.

[0723] 3 is a graph showing the results of observing the tumor size over time in a drug-administered control group (Control), a Comparative Example 1 (CFI-402257) treatment group, and an Example treatment group in nude mice injected with the MDA-MB-231 cell line. As can be seen in FIG. 3, the tumor size in the control group increased significantly over time, while the tumor size in the Example compound treatment group according to the present invention and Comparative Example 1 (CFI-402257) treatment group decreased. In particular, the tumor size in the Example compound treatment group was significantly suppressed compared to the Comparative Example 1 (CFI-402257) treatment group.

[0724] Figure 4 is a graph showing the results of observing changes in mouse body weight over time in a drug administration control group (Control), a Comparative Example 1 (CFI-402257) treatment group, and an Example treatment group for nude mice injected with the MDA-MB-231 cell line. As can be seen in Figure 4, it can be confirmed that the weight of the animals did not decrease over time in all experimental groups.

[0725] Therefore, as confirmed by the above experimental examples, the example compounds of the present invention have excellent effects of suppressing TTK activity in nude mice treated with MDA-MB-231, and therefore can be usefully used as TTK activity inhibitors and as compositions for preventing or treating cancers that may be induced thereby.

[0726] <Experimental Example 8. Cytotoxicity evaluation of TTK-expressing MDA-MB-231 cells when treated in combination with paclitaxel>

[0727] In order to measure the cytotoxicity when the Example compounds according to the present invention and paclitaxel were applied to MDA-MB-231 cells, the following experiment was carried out.

[0728] MDA-MB-231 triple negative breast cancer cell line purchased from ATCC was injected into each well of a 96-well plate at a volume of 90μL, 2,000 cells per well, and then paclitaxel was added at concentrations of 0μM, 0.001μM, and 0.003μM, and then the example compounds of the present invention were added at concentrations of 1μM, 0.3μM, 0.1μM, 0.03μM, 0.01μM, and 0μM to each well, and the cells were cultured in a cell incubator at 37℃ for 5 days. After 5 days, 10μL of Cyto X solution (LPS solution) was added to each well, and the absorbance was measured at 450nm using an Epoch microplate spectrophotometer (BioTek Instruments) according to the product instructions. The cytotoxicity was calculated using the measured value to calculate the amount of cells, and the IC value of the cytotoxicity of each compound was calculated. 50 The values ​​were calculated and the results are shown in FIG.

[0729] As a result, in the test group to which 0.001 μM paclitaxel was added, the IC 50 It was confirmed that the reduction in the IL-1 expression level was comparable to or greater than that of the combined treatment of paclitaxel and Comparative Example 1 (CFI-402257). As in Comparative Example 1, the possibility of combined administration of the Example drug with paclitaxel was confirmed.

[0730] <Experimental Example 9. Evaluation of cell cycle distribution in TTK-expressing MDA-MB-231 cells when treated in combination with paclitaxel>

[0731] The following experiment was carried out to measure changes in cell cycle distribution when the compound represented by Formula 1 according to the present invention and paclitaxel were co-administered to MDA-MB-231 cells.

[0732] 100,000 MDA-MB-231 triple negative breast cancer cell lines purchased from ATCC were injected into each well of a 6-well plate, and then paclitaxel was added at a concentration of 0 μM or 0.001 μM, and then the compound of the present invention was added at a concentration of 0 μM, 0.03 μM, or 0.1 μM to each well, and the cells were 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 the dark, and cultured for 30 minutes. The cell cycle distribution was analyzed using a Muse cell analyzer (manufacturer: Merck, Millipore), and the results are shown in FIG. 6.

[0733] As a result, it was confirmed that the normal cell cycle distribution observed in the control group was suppressed by adding the Example compound to the G1 and G2 / M cell distribution, and that a large number of cells were distributed as polyploids due to the inhibition of TTK, which was at a level equivalent to or higher than the results of Comparative Example 1 (CFI-402257). In addition, both Comparative Example 1 and the Example compound showed an enhanced change in cell distribution when simultaneously treated with 0.001 μM paclitaxel, so the Example drug of the present invention also showed a synergistic anticancer effect when administered in combination with paclitaxel.

[0734] <Formulation Example 1. Production of Powder>

[0735] The compound of the present invention (8 to 12 g) and lactose (1 g) were mixed and filled into an airtight cloth to prepare a powder.

[0736] <Formulation Example 2. Tablet Production>

[0737] 8 to 1100 mg of the compound of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropylcellulose, and 2 mg of magnesium stearate were mixed and compressed into tablets by a conventional tablet manufacturing method.

[0738] <Formulation Example 3. Production of Capsules>

[0739] After mixing 8 to 1100 mg of the compound of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropylcellulose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule manufacturing method, and charged into a gelatin capsule to produce a capsule.

[0740] <Formulation Example 4. Manufacturing of pills>

[0741] 8 to 190 mg of the compound of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and a small amount of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity were mixed and then made into 100 mg pills by a conventional method.

[0742] <Formulation Example 5. Manufacture of injections>

[0743] 8 to 110 mg of the compound of the present invention, an appropriate amount of sterile distilled water for injection, and an appropriate amount of a pH adjusting agent were mixed, and then the above-mentioned ingredient contents were prepared per ampoule (2 ml) according to a conventional injection manufacturing method.

Claims

1. The following chemical formula 1: 【Chemistry 1】 (In the formula, R １ is a substituted or unsubstituted C ６ -C １２ aryl, a substituted or unsubstituted heteroaryl of 5 to 12 atoms, or a substituted or unsubstituted heterocycloalkyl of 5 to 12 atoms; The substituted aryl, heteroaryl, or heterocycloalkyl may be selected from the group consisting of aryl, heteroaryl, and heterocycloalkyl, each of which is independently selected from the group consisting of halogen, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C(=O), carbamoyl, C １ -C ６ Alkylaminoketones, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ Cycloalkylcarboxamide, or C ３ -C ６ substituted with a cycloalkylaminoketone; R ２ is a substituted or unsubstituted -NH-(C ６ -C １２ ) aryl, substituted or unsubstituted —NH—(C ３ -C ６ ) cycloalkyl, substituted or unsubstituted —NH—(C ３ -C ６ ) heterocycloalkyl, or —NH—(CH ２ ) ｍ - (C ３ -C ６ ) heterocycloalkyl (m is an integer of 0, 1, or 2); The substituted aryl, cycloalkyl, or heterocycloalkyl may be selected from the group consisting of aryl, cycloalkyl, and heterocycloalkyl, each of which is independently selected from one or more hydrogen atoms in the ring, halogen, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy or haloC １ -C ６ substituted with alkoxy; R ３ is a substituted or unsubstituted -NH-(C ６ -C １２ ) aryl, or substituted or unsubstituted —NH—(C ３ -C ６ ) cycloalkyl; The substituted aryl or cycloalkyl may be selected from the group consisting of aryl, cycloalkyl, and cycloalkyl. １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC 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 substituted with an alkylaminoketone, a substituted or unsubstituted -C(=O)-morpholine, a substituted or unsubstituted -C(=O)-piperazine, or a substituted or unsubstituted -C(=O)NH-piperidine; The substituted morpholine, piperazine, triazole, -C(=O)-morpholine, -C(=O)-piperazine, or -C(=O)NH-piperidine is selected from the group consisting of substituted morpholine, piperazine, triazole, -C(=O)-morpholine, -C(=O)-piperazine, and -C(=O)NH-piperidine. １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ substituted with alkoxy; or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof. A compound characterized by:

2. The following chemical formula 2-1: 【Chemistry 2】 (In the formula, R １ is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole; The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole may be such that one or more hydrogen atoms in the ring are independently replaced with a halogen, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C(=O), carbamoyl, C １ -C ６ Alkylaminoketones, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ Cycloalkylcarboxamide, or C ３ -C ６ substituted with a cycloalkylaminoketone; R ４ is hydrogen or C １ -C ６ substituted with alkyl; 【change】 A is substituted with NH; B is O, S, or CH ２ is replaced by; D is O or NR ４ is replaced by; m is an integer of 0, 1 or 2; n is an integer of 0 or 1; or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof. The compound of claim 1.

3. The following chemical formula 2-2: 【Chemistry 3】 (In the formula, R １ is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole; The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole may be such that one or more hydrogen atoms in the ring are independently replaced with a halogen, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C(=O), carbamoyl, C １ -C ６ Alkylaminoketones, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ Cycloalkylcarboxamide, or C ３ -C ６ substituted with a cycloalkylaminoketone; R ４ is hydrogen or C １ -C ６ substituted with alkyl; 【change】 D is O or NR ４ is replaced by; m is an integer of 0, 1 or 2; n is an integer of 0 or 1; or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof. The compound of claim 1.

4. The following chemical formula 3-1: 【Chemistry 4】 (In the formula, R １ is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole; The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole may be such that one or more hydrogen atoms in the ring are independently replaced with a halogen, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C(=O), carbamoyl, C １ -C ６ Alkylaminoketones, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ Cycloalkylcarboxamide, or C ３ -C ６ substituted with a cycloalkylaminoketone; R ４ is hydrogen or C １ -C ６ substituted with alkyl; A is substituted with NH; B is O, S, or CH ２ is replaced by; D is O or NR ４ is replaced by; m is an integer of 0, 1 or 2; n is an integer of 0 or 1; or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof. A compound characterized by:

5. The following chemical formula 3-2: 【Chemistry 5】 (In the formula, R １ is a substituted or unsubstituted pyridine, a substituted or unsubstituted pyrazole, a substituted or unsubstituted imidazole, a substituted or unsubstituted furan, a substituted or unsubstituted thiazole, a substituted or unsubstituted pyrimidine, a substituted or 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, a substituted or unsubstituted benzoxazole, a substituted or unsubstituted 1,3,4-oxadiazolone, a substituted or unsubstituted benzimidazole, a substituted or unsubstituted indazole, or a substituted or unsubstituted benzoxazole; The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, 1,3,4-oxadiazolone, benzimidazole, indazole, or benzoxazole may be such that one or more hydrogen atoms in the ring are independently replaced with a halogen, C １ -C ６ Alkyl, haloC １ -C ６ Alkyl, C １ -C ６ Alkoxy, HaloC １ -C ６ Alkoxy, C １ -C ６ Alkoxy C １ -C ６ Alkoxy, C(=O), carbamoyl, C １ -C ６ Alkylaminoketones, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ Cycloalkylcarboxamide, or C ３ -C ６ substituted with a cycloalkylaminoketone; R ４ is hydrogen or C １ -C ６ substituted with alkyl; D is O or NR ４ is replaced by; m is an integer of 0, 1 or 2; n is an integer of 0 or 1; or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof. A compound characterized by:

6. The compound represented by the above 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)benzoate (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 (compounds 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 (compounds 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 (compounds 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-diamine (compound 8-14); N ４ -Cyclohexyl-N ６ -(2-Methoxy-4-morpholinophenyl)-3-(thiazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 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 (compound 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 (compound 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 (compound 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-pyrazol-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 -(Tetrahydro-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); Selected from the group consisting of 2. The compound of claim 1, or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof.

7. A therapeutically effective amount of a compound according to any one of claims 1 to 6, or a hydrate, solvate, prodrug or pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. A pharmaceutical composition for preventing or treating cancer, comprising:

8. The pharmaceutical composition 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). The pharmaceutical composition for preventing or treating cancer according to claim 7.

9. The pharmaceutical composition exhibits inhibitory activity against TTK kinase. The pharmaceutical composition for preventing or treating cancer according to claim 8.

10. The cancer is a solid cancer or a hematological cancer. The pharmaceutical composition for preventing or treating cancer according to claim 7.

11. The solid cancers include brain tumors, benign astrocytoma, malignant astrocytoma, pituitary adenoma, brain meningioma, brain lymphoma, oligodendroglioma, craniopharyngioma, ependymoma, brain stem 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, epithelial sequelae of Barrett's esophagus, breast tumor, small cell lung cancer, non-small cell lung cancer, thymic carcinoma, paraseptal tumor, esophageal cancer, glioma, breast cancer, male breast cancer, triple myeloma, esophageal cancer ... the tumor is any one of: transverse basal-like carcinoma (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, large intestine cancer, anal cancer, colon mucosal cell adenoma, bladder cancer, kidney cancer, male genital tract tumor, penile cancer, prostate cancer, female genital tract tumor, cervical cancer, endometrial cancer, ovarian cancer, ovarian adenocarcinoma, uterine sarcoma, vulvar intraepithelial neoplasia, vaginal cancer, female external genital tract cancer, female urethral cancer, and skin cancer. The pharmaceutical composition for preventing or treating cancer according to claim 10.

12. The blood cancer is any one of leukemia, malignant lymphoma, multiple myeloma, and aplastic anemia. The pharmaceutical composition for preventing or treating cancer according to claim 10.

13. A compound according to any one of claims 1 to 6 and an anticancer drug. A pharmaceutical composition for preventing or treating cancer, comprising:

14. The anticancer drug is selected from taxane anticancer drugs, antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor drugs, antitumor platinum complexes, antitumor camptothecin derivatives, antitumor kinase inhibitors, antitumor antibodies, hormonal antitumor drugs, antitumor viral drugs, and angiogenesis inhibitors. The pharmaceutical composition for preventing or treating cancer according to claim 13.

15. The taxane anticancer drug is selected from paclitaxel, docetaxel, or carbazitaxel. The pharmaceutical composition for preventing or treating cancer according to claim 13.

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