Pyrazolopyrimidine derivative and anti-cancer pharmaceutical composition containing the same as an 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, as an active ingredient, a novel pyrazolopyrimidine compound as a TTK inhibitor, or a pharmaceutically acceptable salt thereof, and to a health food composition for preventing or ameliorating tumors, which contains, as an active ingredient, the pyrazolopyrimidine compound. [Background technology]

[0002] Therapeutic agents used in cancer treatment include taxanes and vinca alkaloids, which act on microtubules to stabilize or destabilize microtubule dynamics. These disrupt normal mitotic spindle function, preventing proper chromosome attachment and inducing mitotic arrest. This arrest is enforced by the spindle assembly checkpoint, preventing sister chromatids from separating to form two daughter cells. Prolonged mitotic arrest can drive 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 treatments have necessitated the development of new pharmaceutical compositions for cancer treatment.

[0004] The role of genes involved in the spindle assembly checkpoint in normal development and their potential role in diseases such as cancer has been extensively studied (Weaver BA et al., ; Musacchio A et al., ). Many components are phosphorylated during mitosis, some of which are kinases, one of which is the dual-specificity kinase TTK. TTK expression is overexpressed in numerous cancer cell lines and tumor types and is associated with highly proliferative cells and tissues. Silencing 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. TTK inhibitors may also 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 tumors of various patients. Therefore, TTK inhibitors are being actively investigated as potential anticancer drugs.

[0007] Under these circumstances, the inventors of the present invention measured the degree of inhibition of various kinase activities using a panel assay and confirmed the suppression of pTTK expression in triple-negative breast cancer and colon cancer cells. They identified novel pyrazolopyrimidine-based compounds that potently inhibit TTK and have excellent kinase selectivity, leading to the completion of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0008] An object of the present invention is to provide compounds having a novel pyrazolopyrimidine skeleton that potently inhibit TTK and have 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 pharmaceutically acceptable salt thereof:

[0010] [ka]

[0011] During the ceremony,

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

[0013] The substituted aryl, heteroaryl, or heterocycloalkyl may be substituted by one or more hydrogen atoms in the ring, independently selected from halogen, C1-C6 alkyl, haloC1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkoxy, C1-C6 alkoxyC1-C6 alkoxy, C(=O), carbamoyl, C1-C6 alkyl, Carbamoyl , C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamido, or C3-C6 cycloalkyl Carbamoyl is replaced by;

[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 hydrogen atoms 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 may be selected from the group consisting of aryl, cycloalkyl, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclohexane-17, cyclohexane-18, cyclohexane-19, cyclohexane-20, cyclohexane-21, cyclohexane-22, cyclohexane-23, cyclohexane-24, cyclohexane-25, cyclohexane-26, cyclohexane-27, cyclohexane-28, cyclohexane-29, cyclohexane-30, cyclohexane-31, cyclohexane-32, cyclohexane-33, cyclohexane-34, cyclohexane-35, cyclohexane-36, cyclohexane-37, cyclohexane-38, cyclohexane-39, cyclohexane-40, cyclohexane-41, cyclohexane-42, cyclohexane-43, cyclohexane-44, cyclohexane-45, cyclohexane-46, cyclohexane-47, cyclohexane-58, cyclohexane-59 ... Carbamoyl 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 pharmaceutically acceptable salt thereof:

[0020] [ka]

[0021] During the ceremony,

[0022] R1 is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, or 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 may be such that one or more hydrogen atoms 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, C(=O), carbamoyl, C1-C6 alkyl Carbamoyl , C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamido, or C3-C6 cycloalkyl Carbamoyl is replaced by;

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

[0025] TIFF0007807025000003.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 pharmaceutically acceptable salt thereof:

[0032] [ka]

[0033] During the ceremony,

[0034] R1 is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, or 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 may be such that one or more hydrogen atoms 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, C(=O), carbamoyl, C1-C6 alkyl Carbamoyl , C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamido, or C3-C6 cycloalkyl Carbamoyl is replaced by;

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

[0037] TIFF0007807025000005.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 pharmaceutically acceptable salt thereof:

[0042] [ka]

[0043] During the ceremony,

[0044] R1 is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, or 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 may be such that one or more hydrogen atoms 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, C(=O), carbamoyl, C1-C6 alkyl Carbamoyl , C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamido, or C3-C6 cycloalkyl Carbamoyl is replaced by;

[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 pharmaceutically acceptable salt thereof:

[0053] [ka]

[0054] During the ceremony,

[0055] R1 is substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole, substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, or 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 may be such that one or more hydrogen atoms 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, C(=O), carbamoyl, C1-C6 alkyl Carbamoyl, C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, C3-C6 cycloalkylcarboxamido, or C3-C6 cycloalkyl Carbamoyl is replaced by;

[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 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 pharmaceutically 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 substituted or unsubstituted pyridine, substituted or unsubstituted pyrazole, substituted or unsubstituted imidazole, substituted or unsubstituted furan, substituted or unsubstituted thiazole, substituted or unsubstituted pyrimidine, substituted or unsubstituted triazole, substituted or unsubstituted oxadiazole, substituted or unsubstituted oxazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted 1,3,4-oxadiazolone, substituted or unsubstituted benzimidazole, substituted or unsubstituted indazole, substituted or unsubstituted benzoxazole;

[0064] The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, benzimidazole, indazole, benzoxazole, or 1,3,4-oxadiazolone may be such that one or more hydrogen atoms in the ring are 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 alkyl, Carbamoyl , C1-C6 alkyloxycarbonyl, C1-C6 alkylsulfonamino, or C3-C6 cycloalkyl Carbamoyl is replaced by ;

[0065] The preparation methods and reaction conditions for the pyrazolopyrimidine skeleton compounds having various structures of the following Chemical Formula 1 of 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] Furthermore, in the present invention, the compound represented by the above Chemical Formula 1 relates to a compound characterized in that it is any one selected from the group of compounds below, or a hydrate, solvate, prodrug, or pharmaceutically 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-benzo[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 (compounds 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 (compounds 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 (compounds 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 (compounds 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] 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);

[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 Hydro -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)-N 6 -(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 pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable carrier.

[0130] Another aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of 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 an anti-cancer drug selected from taxane anti-cancer drugs (paclitaxel, docetaxel, carbazitaxel) as the other anti-cancer drug, and provides a composition and method for producing 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, neocabinostatin, 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 the like.

[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 anti-tumor 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] Also, 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 in which one or more hydrogen atoms have been 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 in which one or more hydrogen atoms of the alkyl group are replaced by a halo group, wherein the alkyl and halo groups are as defined above.

[0151] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group have been replaced with a halo group, where halo and alkoxy are as 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 includes 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 include, but are not limited to, thiazolyl, 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 pharmaceutically acceptable salt refers to a salt or complex of Chemical 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 pharmaceutically 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, mandeloate, and diphenylacetate). In addition to pharmaceutically 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 or inorganic acid, and filtering and drying the resulting precipitate, or by distilling the solvent and excess acid under reduced pressure, drying, and crystallizing the resulting precipitate 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 amount of alkali metal hydroxide or alkaline earth metal hydroxide, filtering the undissolved compound salt, and evaporating the filtrate to dryness. In this case, sodium, potassium, or calcium salts are pharmaceutically suitable for preparing the metal salt. The corresponding salts can also be obtained by reacting an alkali metal or alkaline earth metal salt with an appropriate 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 includes brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, cerebral meningioma, cerebral 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 cancer may be selected from the group consisting of, but is not limited to, tumor-negative breast cancer (TNBC), breast sporadic basal-like carcinoma (BLC), abdominal tumor, gastric cancer, liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), small intestine cancer, colon cancer, anal cancer, colon mucosal cell adenoma, bladder cancer, kidney cancer, male genital 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 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 of the present invention may be formulated into an appropriate form with a commonly used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" means that it is physiologically acceptable and does not normally cause allergic or similar reactions, such as gastrointestinal disorders or dizziness, 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, and aerosols, external preparations, suppositories, and sterile injection solutions, each by a conventional method.

[0162] Carriers, excipients, and diluents that can be included in the composition 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 parahydroxybenzoate, propyl parahydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, diluents or excipients commonly used, such as fillers, stabilizers, binders, disintegrants, and surfactants, are used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like. These solid formulations are prepared by mixing the compound of the present invention with at least one excipient, such as starch, microcrystalline cellulose, sucrose, lactose, low-substituted hydroxypropyl cellulose, and hypromellose. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Oral liquid formulations include suspensions, solutions, emulsions, syrups, etc., and may contain various excipients, such as wetting agents, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions 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, cocoa butter, lauric butter, glycerol, gelatin, etc. To prepare a parenteral dosage form, the pyrazolopyrimidine derivative compound of the above-mentioned Chemical Formula 1 or a pharmaceutically 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 a unit-dose form in ampoules or vials.

[0163] Pharmaceutical compositions 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, via various routes. All administration routes are contemplated, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, intradural, or intracerebrovascular injection. The dosage will vary depending on the age, sex, and weight of the subject being treated, the specific disease or pathological condition being 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 discretion. Determining the dosage based on these factors is within the skill of one of ordinary skill in the art. Generally, the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferred dosage is 1 mg / kg / day to 500 mg / kg / day. The dosage may be administered once a day or in multiple divided doses. The dosages listed above are not intended to limit the scope of the present invention in any way.

[0164] Additionally, the pharmaceutical compositions of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers to prevent or treat cancer. [Effects of the Invention]

[0165] The present invention relates to a pharmaceutical composition for preventing or treating tumors, which contains a novel pyrazolopyrimidine compound as a TTK inhibitor or a pharmaceutically acceptable salt thereof as an active ingredient, and a health food composition for preventing or ameliorating tumors, which contains the pyrazolopyrimidine compound as an active ingredient, and can be usefully used as a composition for preventing or treating cancer. [Brief explanation 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. [Figure 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. [Figure 3] 1 is a graph showing the results of observing the size of tumors over time in nude mice injected with the MDA-MB-231 cell line, in a drug administration control group (Control), a CFI-402257 treatment group, and an example treatment group according to the present invention. [Figure 4] 1 is a graph showing the results of observing changes in mouse body weight over time in a drug-administered control group (Control), a CFI-402257-treated group, and an example-treated group according to the present invention, for nude mice injected with the MDA-MB-231 cell line. [Figure 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] 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 INVENTION

[0167] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Preferred embodiments of the present invention will now 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] TIFF0007807025000017.tif115166

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

[0171] TIFF0007807025000018.tif45166

[0172] Compound 1 (4.63 g, 21.89 mmol) was dissolved in methanol (MeOH; 94 mL). Hydrazine monohydrate (NH2NH2·HO; 1.2 mL, 24.08 mmol) was dissolved in MeOH (10 mL) and added dropwise at -12 °C for 30 minutes while stirring. Triethylamine (TEA; 3.2 mL, 22.55 mmol) was dissolved in MeOH (10 mL) and added dropwise at -12 °C for 30 minutes, followed by stirring 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 hexane (Hx; 10 mL) was added. The resulting solid was removed by filtration. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (EA:Hx = 2:3) to give 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] TIFF0007807025000019.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 for 15 hours at 70 °C. The mixture was concentrated under reduced pressure, and EA (150 mL) was added to the residue. After washing with water (100 mL), the water was removed with sodium sulfate (NaSO). After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (EA:Hx = 1:8) to give compound 3 (19.50 g, 91%) as 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] TIFF0007807025000020.tif58166

[0180] Compound 3 (5.0 g, 18.60 mmol) was dissolved in ethanol (EtOH; 250 mL), followed by the addition of N,N-diisopropylethylamine (DIPEA; 4.2 mL, 24.18 mmol). Cyclohexylamine (2.75 mL, 24.18 mmol) was added dropwise at −15°C for 3 minutes, and the mixture was stirred 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). The aqueous layer (40 mL) was extracted with EA (20 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:Hx = 1:8) to give compound 4-1 (4.19 g, 67%) as a white solid.

[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] TIFF0007807025000021.tif51166

[0184] Compound 4-2 (286 mg, 57%) was obtained as a white solid 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] TIFF0007807025000022.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] TIFF0007807025000023.tif45166

[0192] Compound 4-4 (1.9 g, 51%) was obtained as a white solid 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] TIFF0007807025000024.tif58166

[0196] Compound 4-1 (4.19 g, 12.67 mmol) and cesium carbonate (CsCO; 4.95 g, 15.20 mmol) were dissolved in N,N-dimethylformamide (DMF; 63 mL). p-Methoxybenzyl chloride (PMBCl; 1.80 mL, 13.30 mmol) was added dropwise at 0 °C and the mixture was stirred at 30 °C for 12 h. EA (150 mL) was added to the mixture, which was then washed with water (80 mL). The aqueous layer was extracted with EA (40 mL). The combined organic layers were washed with water (20 × 2 mL), dried over NaSO, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:9) to give compound 5-1 (3.71 g, 64%) as a white solid.

[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] TIFF0007807025000025.tif51166

[0200] Compound 5-2 (1.38 g, 68%) was obtained as a white solid 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] Manufacturing 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] TIFF0007807025000026.tif51166

[0204] Compound 4-4 (1.5 g, 4.51 mmol) was produced by the same method as compound 5-1, and compound 5-4 was obtained as a white solid of 0.912 g (45%).

[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] Manufacturing 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] TIFF0007807025000027.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), followed by the addition of trifluoroacetic acid (TFA; 0.63 mL, 8.23 ​​mmol) and stirring at 110 °C for 22 h. The mixture was concentrated under reduced pressure, and water (20 mL) was added to the residue. The pH was adjusted to 7 with saturated aqueous sodium bicarbonate (NaHCO3) and extracted with EA (60 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:2) to give compound 6-1 (4.89 g, 89%) 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] Preparation 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] TIFF0007807025000028.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 in the preparation of 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] Manufacturing 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] TIFF0007807025000029.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 in the preparation of 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] TIFF0007807025000030.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 PMB removal, according to the following reaction scheme.

[0224] TIFF0007807025000031.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), and potassium carbonate (KCO; 9 mg, 0.06 mmol) were dissolved in dioxane-water (Dioxane-H2O; 4:1 in v / v, 2 mL). After purging with argon gas for 5 minutes, tetrakis(triphenylphosphine)palladium (Pd(PPh3)4; 2 mg, 0.001 mmol) was added and stirred at 100 °C for 2 hours. The mixture was dried over sodium sulfate (Na2SO4) and filtered through a celite pad. The residue was washed with EA (5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:Hx = 1:3) to give compound 7-1 (11.3 mg, 55%) as a yellow solid.

[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), and methanesulfonic acid (MSOH; 0.1 mL) was added dropwise. The mixture was stirred at 60 °C for 2 h. 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). The extract was dried over sodium sulfate (NaSO) 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 as 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] TIFF0007807025000032.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) by the same method as the production 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. Synthesis of Compound 8-2

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

[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] TIFF0007807025000033.tif102166

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

[0242] Compound 7-3 (42 mg, 64%) was obtained as a white solid 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 H 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] Stage 2. Compound 8-3 manufacturing

[0245] Compound 8-1 in step 2 of Example 1 was produced by the same method, and compound 8-3 was obtained as a light brown solid, 29 mg (88%).

[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] TIFF0007807025000034.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] Stage 2. Compound 8-4 manufacturing

[0253] Compound 7-4 (15.7 mg, 0.02 mmol) was produced by the same method as compound 8-1, and compound 8-4 was obtained as a light brown solid, 8.8 mg (67%).

[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] TIFF0007807025000035.tif96166

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

[0258] Compound 7-5 was obtained 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, as a brown solid (32.5 mg, 59%).

[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] TIFF0007807025000036.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] 1H 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] Stage 2. Compound 8-6 manufacturing

[0269] Compound 7-6 (16.5 mg, 0.02 mmol) was produced by the same method as compound 8-1, and compound 8-6 was obtained as a light brown solid in the form of 5.5 mg (40%).

[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] TIFF0007807025000037.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] Stage 2. Compound 8-7 manufacturing

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

[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] TIFF0007807025000038.tif108166

[0280] Stage 1. Synthesis of Compounds 7-8

[0281] Compound 7-8 was obtained as a pale brown solid (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 7-8 (75.1 mg, 0.12 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 28.1 mg of compound 8-8 as a pale brown solid (46%).

[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] TIFF0007807025000039.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 7-9 (34.0 mg, 0.05 mmol) was treated in the same manner as in the preparation of compound 8-1 in Step 2 of Example 1 to give 7.1 mg of compound 8-9 as a white solid (26%).

[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] TIFF0007807025000040.tif102166

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

[0296] Compound 7-10 (40 mg, 80%) was obtained as a white solid 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 in the preparation of compound 7-1.

[0297] 1H 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] Stage 2. Manufacturing of Compounds 8-10

[0299] Compound 7-10 (40 mg, 0.0641 mmol) was produced by the same method as compound 8-1 in step 2 of Example 1, and compound 8-10 was obtained as a white solid of 18.8 mg (58.7%).

[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] TIFF0007807025000041.tif108166

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

[0304] Compound 7-11 (98 mg, 94.2%) was obtained as a white solid 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] TIFF0007807025000042.tif108166

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

[0312] Compound 7-12 (55 mg, 99%) was obtained as a white solid 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] Segment 2. Preparation of Compound 8-12

[0315] Compound 7-12 (55 mg, 0.0833 mmol) was produced by the same method as compound 8-1 in step 2 of Example 1, and compound 8-12 was obtained as a light brown solid, 24 mg (54%).

[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] TIFF0007807025000043.tif108166

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

[0320] Compound 7-13 (40 mg, 80%) was obtained as a white solid 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 7-13 (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 of compound 8-13 as a white solid (52%).

[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] TIFF0007807025000044.tif108166

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

[0328] Compound 7-14 was obtained in the form of a white solid (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] 1H 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] Segment 2. Preparation of compound 8-14

[0331] Compound 7-14 (14 mg, 0.0229 mmol) was produced by the same method as compound 8-1 in step 2 of Example 1. Compound 8-14 was obtained as a light brown solid in the form of 4.7 mg (42.7%).

[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] TIFF0007807025000045.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 7-15 (17.6 mg, 0.0287 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 11.4 mg of compound 8-15 in the form of a white solid (80.0%).

[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] TIFF0007807025000046.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 in 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] Segment 2. Preparation of compound 8-16

[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)

[0349] TIFF0007807025000047.tif89166

[0350] Synthesis of compounds 7-17, stage 1.

[0351] Compound 6-1 (50 mg, 0.08 mmol) and 1H-インダゾール-5-ボロン acid (17 mg, 0.1043m mol), Compound 7-1 was produced by the same method, and Compound 7-17 was obtained as a white solid in the form of 49 mg (94.2%).

[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] Stage 2. Preparation of Compound 8-17

[0354] Compound 7-17 (49 mg, 0.0742 mmol) was produced by the same method as compound 8-1, and compound 8-17 was obtained as a white solid in the form of 11.2 mg (28%).

[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] TIFF0007807025000048.tif96166

[0358] Synthesis of compounds 7-18 in stage 1.

[0359] Compound 7-18 was obtained in the form of a white solid (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] TIFF0007807025000049.tif108166

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

[0367] Compound 6-1 (60 mg, 0.096 mmol) was dissolved in DMF (1 mL) and purged with argon gas to remove oxygen. 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 min in a Biotage microwave reactor. After completion of the reaction, 1 M potassium fluoride (KF; 5 mL) was added and stirred at room temperature for 30 min, followed by extraction with EA (20 mL x 2). The organic layer was washed with water (5 mL × 2), then the moisture was removed (Na2SO4), and 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 7-19 (47 mg, 0.075 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 27.0 mg of compound 8-19 in the form of a yellow solid (71.8%).

[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] TIFF0007807025000050.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] Synthesis of compound 8-20 (stage 2)

[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] TIFF0007807025000051.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 in the preparation of 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] TIFF0007807025000052.tif45166

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

[0391] Compound 6-3 (100 mg, 0.1601 mmol) and LiCl (3.4 mg, 0.080 mmol) were dissolved in DMF (1 mL), 2-(tributylstannyl)oxazole (0.01 mL, 0.3202 mmol) was added, and the mixture was deoxygenated. Pd(PPh3)4 (3.4 mg, 0.008 mmol) was added, and the mixture was stirred at 120 °C for 40 min. The mixture was filtered through a celite pad and washed with EA (10 mL). The organic layer was washed with water (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:HX = 2:1) to give compound 7-22 (37 mg, 37%).

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

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

[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] TIFF0007807025000053.tif102166

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

[0398] Compound 7-23 (29.1 mg, 96%) was obtained as a light brown solid 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 7-23 (27.8 mg, 0.04 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 13.4 mg of compound 8-23 in the form of a pale brown solid (59%).

[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] TIFF0007807025000054.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 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] Stage 2. Compound 8-24 manufacturing

[0409] Compound 7-24 (22 mg, 0.03 mmol) was produced by the same method as compound 8-1, and compound 8-24 was obtained as a light brown solid in the form of 29 mg (>99%).

[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] TIFF0007807025000055.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 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] Stage 2. Compound 8-25 manufacturing

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

[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] TIFF0007807025000056.tif108166

[0422] Step 1. Synthesis of Compounds 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 in 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 Compounds 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] TIFF0007807025000057.tif96166

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

[0431] Compound 7-27 (31.3 mg, 100%) was obtained as a light brown solid 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] 1H 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] Stage 2. Compound 8-27 manufacturing

[0434] Compound 7-27 (30.3 mg, 0.04 mmol) was produced by the same method as compound 8-1, and compound 8-27 was obtained as a light brown solid in the form of 5.6 mg (22%).

[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] TIFF0007807025000058.tif96166

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

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

[0440] 1H 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] Stage 2. Compound 8-28 manufacturing

[0442] Compound 7-28 (15 mg, 0.02 mmol) was produced by the same method as compound 8-1, and compound 8-28 was obtained as a light brown solid in the form of 11.4 mg (94%).

[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 Preparation of -(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (compound 8-29)

[0445] TIFF0007807025000059.tif96166

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

[0447] Compound 6-3 (15 mg, 0.02 mmol) and とボロン 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] Segment 2. Compound 8-29 manufacturing

[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] TIFF0007807025000060.tif83166

[0454] Step 1. Synthesis of Compounds 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 7-30 (32.1 mg, 0.05 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 5.2 mg of compound 8-30 in the form of a white solid (20%).

[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] TIFF0007807025000061.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] TIFF0007807025000062.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). The mixture was purged with argon gas to remove oxygen, and Pd(PPh3)4 (84.3 mg, 0.033 mmol) was added and stirred at 100 °C for 2 h. Water (10 mL) was added to the mixture, which was then extracted with EA (20 mL x 2). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 2:1) to give 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) and then 2-methoxy-4-(4-methylpiperazin-1-yl)alanine (44.2 mg, 0.2 mmol) and K2CO3 (29.4 mg, 0.21 mmol) were added. 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. The mixture was then stirred at 110 °C for 1 day. The mixture was filtered through a pad of celite, 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, 9.5%) was obtained as a green solid 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] TIFF0007807025000063.tif108166

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

[0476] Compound 10-2 (20.1 mg, 24.4%) was obtained as a brown solid from compound 9-1 (60 mg, 0.13 mmol) and 2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline (32.5 mg, 0.16 mmol) by the same preparation method as for compound 10-1.

[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. Compound 11-2 manufacturing

[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] TIFF0007807025000064.tif96166

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

[0484] Compound 10-3 was obtained as a white solid (48.9 mg, 60.6%) from compound 9-1 (60 mg, 0.13 mmol) and 4-amino-3-methoxy-N-methylbenzamide (27.7 mg, 0.16 mmol) by the same preparation method as for 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. Preparation 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] TIFF0007807025000065.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 H 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] Segment 2. Compound 11-4 manufacturing

[0495] Compound 10-4 (27.1 mg, 0.042 mmol) was obtained by the same manufacturing method as the aforementioned compound 11-1 and compound 11-4 was obtained as a white solid of 11.1 mg (50.2%).

[0496] 1 H 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] TIFF0007807025000066.tif96166

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

[0500] Compound 10-5 (60.2 mg, 68.1%) was obtained as a yellow solid 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 synthesis method as for 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 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] TIFF0007807025000067.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, 1H), 5.79 (s, 1H), 5.39 (d, J = 7.9 Hz, 1H), 4.18 (s, 2H), 3.99 (d, J = 13.5 Hz, 6H), 2.90 (d, J = 11.3 Hz, 2H), 2.35 (s, 3H), 2.21 (t, J = 11.5 Hz, 3H), 2.04 (s, 5H), 1.81 - 1.64 (m, 5H), 1.55 - 1.40 (m, 2H), 1.25 (d, J = 10.1 Hz, 4H).

[0513] <Example C. Production of compound 14 of the reaction formula 3による>

[0514] TIFF0007807025000068.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] TIFF0007807025000069.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 (2.0 g, 15 mmol) were dissolved in dioxane (30 mL). 1,8-diazabicyclo[5.4.0]undecene-7 (DBU; 2.2 mL, 15 mmol) was added, and the mixture was purged with argon to remove oxygen. Pd(dppf)Cl2 (180 mg, 0.012 mmol) was added and stirred at 110 °C for 10 min. The reaction mixture was concentrated and separated by silica gel column chromatography (EA:Hx = 1:2). The intermediate tert-butyl hydrazine carboxylate was obtained as a white solid (2.03 g, 58%).

[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, the pH was adjusted to 7 with saturated aqueous NaHCO3, EA (50 mL) was added, and the mixture was washed with water (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:Hx = 1:1) to give compound 12-1 (800 mg, 66%) as a light brown solid.

[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). One drop of AcOH and methylamine (2 M in THF; 0.2 mL, 0.4 mmol) were added, followed by stirring at 85 °C for 24 hours. The mixture was then cooled to room temperature and the resulting solid was filtered to give compound 13-1 (20.1 mg) 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. Compound 14-1 manufacturing

[0525] Compound 13-1 (23 mg, 0.037 mmol) was produced by the same method as compound 8-1. Compound 14-1 was obtained as a white solid and 13.1 mg was obtained. (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] TIFF0007807025000070.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 (43.0 mg) as a brown solid (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] TIFF0007807025000071.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 (41%) of compound 13-3 as a pale gray solid.

[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] Segment 2. Compound 14-3 manufacturing

[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 reaction formula 4による>

[0544] TIFF0007807025000072.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] TIFF0007807025000073.tif77166

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

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

[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:HO = 3:1, and then OsO (2.5 wt% in HO; 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. After washing with water (200 mL), the water was removed (NaSO) and the mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 1:1) to obtain the dihydroxy compound (4.2 g) as a yellow solid (75.4%).

[0552] The dihydroxy compound (4.2 g, 6.96 mmol) was dissolved in THF:HO = 3:1, and NaIO (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. After washing with water (200 mL), the organic layer was stripped (NaSO) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:MC = 1:20) to obtain Formula 16-1 as 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), then the water was removed (Na2SO4), and the mixture was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:HX:MC = 2:1:1) to give compound 17-1 (166 mg) 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 (t, J = 4.8 Hz, 4H), 3.71 (s, 3H), 3.76 (t, J = 4.8 Hz, 4H), 3.86 (s, 3H), 4.07 (s, 1H), 5.35 (s, 2H), 6.52 (dd, J = 8.8, 2.5 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 5.6 Hz, 2H), 8.12 (d, J = 8.8 Hz, 1H), 8.64 (s, 1H).

[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] TIFF0007807025000074.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), then the water was removed (Na2SO4), and the mixture was concentrated under reduced pressure. Ammonia (7 M in MeOH; 1 mL) was added to the residue, and the mixture was refluxed and stirred for 4 hours to give crude compound 17-2 (9 mg).

[0564] 1H 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] Stage 2. Preparation of Compound 18-2

[0566] Compound 17-2 (9 mg) was produced by the same method as compound 8-1, and compound 18-2 was obtained as a light gray solid of 1.7 mg.

[0567] 1 H NMR (400 MHz, Chloroform-d) δ 1.51 (t, J = 9.1 Hz, 3H), 1.84 (s, 5H), 2.11 (s, 3H), 3.12 (t, J = 4.8 Hz, 3H), 3.89 (d, J = 4.0 Hz, 5H), 4.22 (s, 1H), 6.54 (s, 1H), 7.30 (s, 1H), 7.64 (s, 1H), 7.72 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 9.38 (s, 1H), 10.42 (s, 1H).

[0568] <Example E. Production of reaction compound 21 of the formula 5による>

[0569] TIFF0007807025000075.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] TIFF0007807025000076.tif96166

[0572] It was prepared from compound 6-1 through a three-step process according to Reaction Scheme 5.

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

[0574] Compound 6-1 (1.87 g, 3.003 mmol) and 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. PdCl(PPh) was added (105 mg, 5% mmol), and the mixture was degassed 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 resulting compound was dissolved in tetrahydrofuran (20 mL). Tetra-n-butylammonium fluoride (TBAF; 1.3 mL, 1.2 eq) was added and the mixture was stirred 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 (NaSO), 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] Compound 19-1 (114 mg, 0.15 mmol) and cuprous iodide (CuI; 4 mg, 10% mmol) were dissolved in dimethylformamide (DMF):methanol (MeOH) = 9:1 (2 mL), followed by the addition of trimethylsilyl azide (0.040 mL, 0.3 mmol) and stirring at 100 °C for 6 hours. The mixture was concentrated under reduced pressure, and then EA (10 mL) was added. The mixture was washed with water (10 mL), then dehydrated (NaSO), and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (EA:HX = 2:3) to obtain 87 mg (76%) of compound 20-1 as a light brown solid.

[0578] 1H 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] Stage 3. Compound 21-1 manufacturing

[0580] Chemical formula 20-1 (87 mg, 0.1424 mmol) was produced by the same method as compound 8-1, and compound 21-1 was obtained as a white solid, 48 mg (68%).

[0581] 1 H 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] TIFF0007807025000077.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) with sodium azide (100 mg) and iodomethane (0.1 mL) and stirred for 12 hours. After dissolving the compound in the solution, 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. Ethyl acetate (100 mL) was added to the mixture, which was then washed with water (100 mL), removed with NaSO, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (EA:HX = 1:1) to obtain compound 20-2 as 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. Compound 21-2 manufacturing

[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)

[0591] TIFF0007807025000078.tif89166

[0592] Synthesis of compound 19-3, stage 1.

[0593] Compound 6-3 (1.87 g, 2.9942 mmol) was produced by the same method as compound 19-1, and compound 19-3 was obtained in the form of a light brown solid. (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] Synthesis of compound 20-3 (stage 2)

[0596] Compound 20-3 was obtained in the form of a white solid (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 (19.4 mg, 77.6%) was obtained in the form of a light brown solid 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] TIFF0007807025000079.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] TIFF0007807025000080.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 h. The reaction mixture was concentrated under reduced pressure, dissolved in EA (200 mL), washed with saturated aqueous NaHCO (100 mL) and brine (100 mL), dried over MgSO, and concentrated under reduced pressure to give compound 22 (11.77 g, 83.2%) as a white solid.

[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 give compound 23-1 (91.1 mg, 77.1%) as a white solid.

[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) and purged with argon gas to remove oxygen. Pd(PPh3)4 (18.4 mg, 0.0159 mmol) was added, degassed, and stirred in a microwave reactor at 120 °C for 1 h. Water (20 mL) was added to the mixture, which was then 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 (64.7 mg, 32.2%) as a white solid.

[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] Compound 24-1 (32 mg, 0.077 mmol) was dissolved in 2-butanol (1 mL), followed by the addition of 2-isopropoxy-4-morpholinoaniline (21.7 mg, 0.092 mmol) and K2CO3 (17.0 mg, 0.123 mmol). 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. The mixture was then stirred at 110 °C for 1 day. The reaction mixture was filtered (through a cellulose pad) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH = 99:1) to give compound 25-1 (36.3 mg) as a white solid (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. The mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of saturated aqueous NaHCO3 (20 mL) and extraction with ethyl acetate (20 mL x 2). The organic layer was then dried (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH = 97:3) to obtain 16.6 mg (53.4%) of compound 26-1 as a white solid.

[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] TIFF0007807025000081.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 the mixture was stirred at 40° C. for 1 hour. After the reaction was completed, the resulting solid 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:HO (4:1 in v / v, 2 mL) and purged with argon gas to remove oxygen. Pd(PPh3)4 (32.8 mg, 0.028 mmol) was added, degassed, and stirred in a microwave reactor at 110 °C for 1 h. The mixture was added with water (10 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were 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 compound 24-2 (71.2 mg) as 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, followed by the addition of aniline (46.02 mg, 0.208 mmol) and potassium carbonate (38.4 mg, 0.278 mmol). 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. The mixture was stirred at 110 °C for 1 hour. The mixture was filtered through a cellulose pad and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:1) to obtain 38.7 mg of compound 25-2 as 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. The mixture was then allowed to warm to room temperature and stirred for 1 hour. After the reaction was completed, the methanol was removed, and the mixture was added with sodium bicarbonate (10 mL) and extracted with ethyl acetate (20 mL x 2). The residue was purified by silica gel column chromatography (dichloromethane:methanol = 19:1) to obtain 17.5 mg of compound 26-2 as 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] TIFF0007807025000082.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] TIFF0007807025000083.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 over 3 minutes. Compound 4-3 (190 mg, 0.54 mmol in THF 3 mL) was added dropwise to the mixture over 3 minutes, followed by stirring at 110 °C for 14 hours. The reaction mixture was adjusted to pH 7 with saturated aqueous NaHCO3, and then EA (8 mL) was added. After washing with water (3 mL), the mixture was dried (Na2SO4) and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (MC:MeOH = 10:1) to give 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 in the same manner as in the preparation of compound 7-1 to give 11.3 mg (56%) of compound 28-1 in the form of a pale brown solid.

[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] TIFF0007807025000084.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] TIFF0007807025000085.tif96166

[0648] Step 1. Preparation of Compound 29

[0649] Compound 5-2 (1.0 g, 2.208 mmol) was produced by the same method as compound 16-1 in Example 40, and compound 29 was obtained as 633 mg (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] Stage 2. Manufacturing of Compound 30

[0652] Compound 29 (623 mg, 1.557 mmol) was produced by the same method as compound 16-1 in Example 40, and compound 30 was obtained as 480 mg (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] Stage 3. Manufacturing 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 dissolved in 2-butanol (1 mL). After removing oxygen, Pd(dba) (225 mg, 0.028 mmol) was added and stirred at 110 °C for 12 h. The mixture was filtered through a celite pad and washed with EA (20 mL). The organic layer was washed with water (10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA:HX = 2:1) to give compound 32-1 (19 mg, 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] TIFF0007807025000086.tif51166

[0665] Stage 1. Preparation of Compound 32-2

[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 manufacturing

[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] TIFF0007807025000087.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] Step 2. Preparation of compound 33-3

[0676] Compound 32-3 (17 mg, 0.027 mmol) was treated in the same manner as in the preparation of compound 8-1 to give 2.1 mg of compound 33-3 (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) production

[0679] TIFF0007807025000088.tif45166

[0680] Step 1. Preparation of Compound 7-34

[0681] Compound 7-34 (96 mg, 96%) was obtained in the form of a brown solid from 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) in the same manner as in the preparation of compound 7-1 in Example 1.

[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 subjected to the same procedure as in the preparation of compound 8-1 in Example 1 to give 43 mg of compound 8-34 in the form of a cream-colored solid (57%).

[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] TIFF0007807025000089.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 inhibitory 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 compounds in a reaction solution (8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg / mL MBP, 10 mM magnesium acetate, 45 μM [gamma-33P-ATP]) and incubated at room temperature for 40 minutes. The reaction was terminated by adding phosphoric acid to a concentration of 0.5%, and 10 μl of the reaction solution was instilled onto a P30 filter. The instilled filter was washed four times with 0.425% phosphoric acid solution for 4 minutes, then washed once more with methanol, dried, and TTK activity was measured by scintillation counting. The activity value obtained from the compound-free group was set as 100% of control, and the degree of TTK inhibition by the compound was calculated. The TTK inhibitory activity of the example compounds is 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 an excellent effect of inhibiting TTK activity, and therefore can be usefully used as a TTK activity inhibitor and as a composition for preventing or treating cancers induced by TTK activity.

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

[0700] The results of the inhibitory effect of compound 8-8 at a concentration of 500 nM on kinase activity 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), the target of the present invention, IR(h) activated, IRR(h), and LTK(h). In particular, 500 nM compound 8-8 was confirmed to completely inhibit TTK activity while also exhibiting 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 10 μM, 3 μM, 1 μM, 0.3 μM, 0.1 μM, and 0 μM concentrations of the example compounds of the present invention were added to each well and cultured in a cell incubator at 37°C for 5 days. After 5 days, 10 μL of Cyto X solution (manufactured by LPS Solution) was added to each well, and absorbance was measured at 450 nm using an Epoch microplate spectrophotometer (manufactured by BioTek Instruments) according to the manufacturer's instructions. Cytotoxicity was calculated using the measured cell amount, and the IC value for 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 can be seen from Table 3, many of the example compounds according to the present invention had cytotoxic 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 an excellent effect of inhibiting TTK activity in MDA-MB-231 cells, and therefore can be usefully used as a TTK activity inhibitor and as a composition for preventing or treating cancer induced by TTK activity.

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

[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 experiments were carried out to confirm whether TTK protein was involved in this cell death.

[0710] MDA-MB-231 cells were prepared in 200,000 cells per well of a 6-well plate, treated with 50 ng / mL of nocodazole, and cultured for 1 day. Then, the compound of the present invention was tested for cytotoxicity at an IC 50 After adding the appropriate concentrations, the cells were incubated for 4 hours, and the resulting cells were lysed with RIPA solution. To confirm the expression of TTK and pTTK in the samples, protein-specific primary antibodies (TTK primary antibody manufacturer: Cell Signaling Technology, thr33 and ser37 phosphorylated TTK detection manufacturer: Invitrogen) and secondary antibodies were used at a 1:10,000 dilution. Specific protein luminescence was induced using an Enhanced Chemiluminescence kit (ECL, Santa Cruz Biotechnology) and analyzed using a ChemiDoc XRS+ system. 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 at the same level as in Comparative Example 1 (CFI-402257).

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

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

[0714] HCT116 colon cancer cell line purchased from ATCC was placed in each well of a 96-well plate at a volume of 90 μL, 2,000 cells per well, and then 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 the cells were 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 of each compound 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 can be seen from Table 4, many of the example compounds according to the present invention have cytotoxic IC 50 It can be seen that the values ​​are comparable to or lower than those of Comparative Example 1 (CFI-402257). Therefore, the compound represented by Chemical Formula 1 according to the present invention has an excellent effect of inhibiting TTK activity in HCT116 cells, and therefore can be usefully used as a TTK activity inhibitor and as a composition for preventing or treating cancer induced by TTK activity.

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

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

[0719] HCT116 cells were prepared in 200,000 cells per well of a 6-well plate, treated with 50 ng / mL of nocodazole, and cultured for 1 day. Then, the compound of the present invention was administered at an IC 50 After adding the appropriate concentrations, the cells were incubated for 4 hours, and the resulting cells were lysed with RIPA solution. To confirm the expression of TTK and pTTK in the samples, protein-specific primary antibodies (TTK primary antibody manufacturer: Cell Signaling Technology, thr33 and ser37 phosphorylated TTK detection manufacturer: Invitrogen) and secondary antibodies were used at a 1:10,000 dilution. Specific protein luminescence was induced using an Enhanced Chemiluminescence kit (ECL, Santa Cruz Biotechnology) and analyzed using a ChemiDoc XRS+ system. The results are summarized in Figure 2.

[0720] The compounds of the present invention represented by Chemical Formula 1 all exhibited 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 the efficacy of MDA-MB-231 in nude mice>

[0722] 5 x 10 MDA-MB-231 cells were injected into 5-week-old female nude mice. 6 The tumor size was reduced to approximately 50 mm. 3When the tumor size reached 100%, the animals 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] Figure 3 is a graph showing the results of monitoring tumor size over time in nude mice injected with the MDA-MB-231 cell line, including a drug-treated control group (Control), a Comparative Example 1 (CFI-402257)-treated group, and an Example treatment group. As can be seen in Figure 3, the control group showed a significant increase in tumor size over time, while the Example compound-treated group and Comparative Example 1 (CFI-402257)-treated group showed a decrease in tumor size. In particular, the Example compound-treated group showed a significant suppression of tumor size compared to the Comparative Example 1 (CFI-402257)-treated group.

[0724] Figure 4 is a graph showing the results of monitoring the changes in mouse weight over time in nude mice injected with the MDA-MB-231 cell line, including the drug-administered control group (Control), the Comparative Example 1 (CFI-402257) treatment group, and the Example treatment group. As can be seen from Figure 4, there was no decrease in animal weight over time in any of the experimental groups.

[0725] Therefore, as confirmed by the above experimental examples, the example compounds according to the present invention have excellent effects of inhibiting 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 by TTK activity.

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

[0727] The following experiment was carried out to measure the cytotoxicity when the Example compounds according to the present invention and paclitaxel were co-administered to MDA-MB-231 cells.

[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 90 μL, and paclitaxel was added at concentrations of 0 μM, 0.001 μM, and 0.003 μM. Then, an example compound of the present invention was added to each well at concentrations of 1 μM, 0.3 μM, 0.1 μM, 0.03 μM, 0.01 μM, and 0 μM. The cells were then cultured in a cell incubator at 37°C for 5 days. After 5 days, 10 μL of Cyto X solution (LPS Solution) was added to each well, and absorbance was measured at 450 nm using an Epoch microplate spectrophotometer (BioTek Instruments) according to the manufacturer's instructions. Cytotoxicity was calculated using the measured values ​​to determine the IC value of each compound's cytotoxicity. 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 of the example compound treatment group was higher than that of the test group to which paclitaxel was not added. 50 It was confirmed that the reduction in IL-14 was equivalent to or greater than the efficacy obtained from the combined treatment of paclitaxel and Comparative Example 1 (CFI-402257), and similarly to Comparative Example 1, it was confirmed that the Example drug can be administered in combination with paclitaxel.

[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] MDA-MB-231 triple-negative breast cancer cell line purchased from ATCC was seeded at 100,000 cells per well of a 6-well plate, and paclitaxel was added at 0 μM or 0.001 μM. An example compound of the present invention was then added to each well at 0 μM, 0.03 μM, or 0.1 μM. The cells were then 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). The results are shown in Figure 6.

[0733] As a result, it was confirmed that the normal cell cycle distribution observed in the control group was suppressed by the addition of 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 greater 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 co-treated with 0.001 μM paclitaxel, so the Example drug of the present invention also showed a synergistic anti-cancer effect when co-administered with paclitaxel.

[0734] <Formulation Example 1. Manufacture of powder>

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

[0736] <Formulation Example 2. Tablet manufacturing>

[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 hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed and then compressed into tablets by a conventional tablet manufacturing method.

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

[0739] 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 hydroxypropyl cellulose, and 2 mg of magnesium stearate were mixed, and then the mixture was mixed according to a conventional method for producing capsules, and charged into a gelatin capsule to produce a capsule.

[0740] <Formulation Example 4. Manufacture 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 small amounts of dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives to inhibit hygroscopicity were mixed, and then 100 mg pills were prepared 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 adjuster were mixed, and then prepared according to a conventional method for preparing an injection with the above-mentioned ingredient content per ampoule (2 ml).

Claims

1. The following chemical formula 2-1: 【Chemistry 2】 Or, the following chemical formula 2-2: 【Transformation 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, The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, or 1,3,4-oxadiazolone 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 Alkylcarbamoyl, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ cycloalkylcarboxamide, or C ３ -C ６ substituted with cycloalkylcarbamoyl; 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, or pharmaceutically acceptable salt thereof. A compound characterized by:

2. 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, The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, or 1,3,4-oxadiazolone 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 Alkylcarbamoyl, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ cycloalkylcarboxamide, or C ３ -C ６ substituted with cycloalkylcarbamoyl; 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, or pharmaceutically acceptable salt thereof. A compound characterized by:

3. The following chemical formula 3-2: 【Transformation 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, The substituted pyridine, pyrazole, imidazole, furan, thiazole, pyrimidine, triazole, oxadiazole, oxazole, isoxazole, benzimidazole, indazole, benzoxazole, or 1,3,4-oxadiazolone 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 Alkylcarbamoyl, C １ -C ６ Alkyloxycarbonyl, C １ -C ６ Alkyl sulfone amino, C ３ -C ６ cycloalkylcarboxamide, or C ３ -C ６ substituted with cycloalkylcarbamoyl; 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, or pharmaceutically acceptable salt thereof. A compound characterized by:

4. The compound represented by the above formula 1 is 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 (compounds 8-13); 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); 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-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); 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 -(tetrahydro-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 10. The compound of claim 1, or a hydrate, solvate, or pharmaceutically acceptable salt thereof.

5. A therapeutically effective amount of a compound according to any one of claims 1 to 4, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition for preventing or treating cancer, comprising:

6. 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 5.

7. The pharmaceutical composition exhibits inhibitory activity against TTK kinase. The pharmaceutical composition for preventing or treating cancer according to claim 6.

8. The cancer is a solid cancer or a blood cancer. The pharmaceutical composition for preventing or treating cancer according to claim 5.

9. The solid tumors include brain tumors, benign astrocytoma, malignant astrocytoma, pituitary adenoma, cerebral meningioma, cerebral 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 cancer is any one of: tumor-negative breast cancer (TNBC), breast sporadic basal-like carcinoma (BLC), abdominal tumor, stomach 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 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 8.

10. 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 8.

11. A composition comprising the compound according to any one of claims 1 to 4 and an anticancer drug. A pharmaceutical composition for preventing or treating cancer, comprising:

12. The anticancer agent is selected from taxane anticancer agents, 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, and angiogenesis inhibitors. The pharmaceutical composition for preventing or treating cancer according to claim 11.

13. The taxane anticancer drug is selected from paclitaxel, docetaxel, or carbazitaxel. The pharmaceutical composition for preventing or treating cancer according to claim 12.

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