Cancer treatment agents containing optically active azabicyclo ring derivatives

Abstract

The present invention relates to optically active azabicyclo derivatives useful as pharmaceuticals, pharmaceutically acceptable salts thereof, and suitable methods, dosages and uses of pharmaceutical compositions containing them.

Description

[Technical Field]

[0001] This invention relates to optically active azabicyclo ring derivatives useful as pharmaceuticals, pharmaceutically acceptable salts thereof, and preferred methods of use, dosages, and applications of pharmaceutical compositions containing these. [Background technology]

[0002] MLL leukemia accounts for approximately 6-7% of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), with approximately 1,100 new cases diagnosed annually in the United States. The main fusion partner genes that cause MLL leukemia are reported to be AF9, ELL, ENL, AF10, and AF6 in AML, and AF4, ENL, and AF9 in ALL (Non-Patent Literature 1).

[0003] It is hypothesized that MLL fusion proteins, formed by fusing with a fusion partner gene in this way, cause uncontrolled proliferation of undifferentiated hematopoietic cells, leading to leukemia (Non-Patent Literature 2). It has been reported that MLL fusion proteins first bind to menin and form a complex. Therefore, it is expected that inhibiting the first step, the binding of MLL fusion proteins to menin, can prevent carcinogenesis caused by MLL fusion proteins (Non-Patent Literature 3).

[0004] In prostate cancer, MLL has been reported to act as a co-activator of androgen signaling. Therefore, small molecule inhibitors that target the inhibition of binding between menin and MLL fusion proteins are expected to be useful as therapeutic agents for this cancer (Non-Patent Literature 4). In breast cancer, menin has been reported to act as a co-activator of estrogen signaling. Therefore, small molecule inhibitors that target the inhibition of binding between menin and MLL fusion protein are expected to be useful as therapeutic agents for this cancer (Non-Patent Literature 5). In Ewing's sarcoma, liver cancer, and p53-mutated cancers, menin or MLL has been reported to be important for tumor growth, and small molecule inhibitors that target the inhibition of binding between menin and MLL fusion proteins are expected to be useful as therapeutic agents for these cancers (Non-Patent Literature 6).

[0005] Recently, an optically active azabicyclo ring derivative targeting the inhibition of binding between menin and MLL fusion protein was reported in Patent Document 1. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2020 / 045334 [Non-patent literature]

[0007] [Non-Patent Document 1] Look A. T, Science, 278 (5340): 1059-1064 (1997) [Non-Patent Document 2] Yokoyama A, et al., Cell 123 (2): 207-218 (2005) [Non-Patent Document 3] Yokoyama A, et al., Cancer Cell. 14(1): 34-46 (2008) [Non-Patent Document 4] Malik, R. et al., Nature Medicine. 21(4):344-352 (2015) [Non-Patent Document 5] Imachi, H et al., Breast Cancer Res Treat. 122(2):395-407 (2010) [Non-Patent Document 6] Svoboda, LK et al., Oncotargrt. 8(1):458-471 (2017)

Summary of the Invention

Problems to be Solved by the Invention

[0008] An object of the present invention is to provide an invention related to the dosage and administration of an optically active azabicyclic ring derivative that exhibits excellent anticancer activity by inhibiting the binding between menin and MLL fusion protein, and to provide a useful therapeutic agent and a treatment method for tumors having specific gene mutations using the above derivative and a combination drug.

[0009] More specifically, the present inventors provide a technology related to a medicament containing 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter, may also be referred to as "free form" or "free form of the present compound"), or a pharmaceutically acceptable salt thereof (hereinafter, both may also be referred to as "the present compound" or "the compound of the present invention").

Means for Solving the Problems

[0010] As a result of intensive studies, the present inventors have found that a medicament containing 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof exhibits excellent anticancer activity with high safety at specific dosages and administrations. In addition, it has been found that the anticancer activity can be further enhanced by using a combination drug in addition to the above medicament, and the present invention has been completed.

[0011] That is, the present invention is as follows.

[0012] [Item 1] A pharmaceutical product for treating or preventing cancer, comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as "free form") or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, characterized in that it is administered orally to the subject.

[0013] [Section 2] The pharmaceutical product according to item 1, characterized in that it is administered orally once a day to the target of the pharmaceutical product.

[0014] [Section 3] The pharmaceutical product according to item 1, characterized in that it is administered orally twice a day to the target of the pharmaceutical product.

[0015] [Section 4] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 40 mg when converted to a free form.

[0016] [Section 5] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 60 mg when converted to a free form.

[0017] [Section 6] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 80 mg when converted to a free form.

[0018] [Section 7] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 100 mg when converted to a free form.

[0019] [Section 8] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 120 mg when converted to a free form.

[0020] [Section 9] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 140 mg when converted to a free form.

[0021] [Section 10] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 180 mg when converted to a free form.

[0022] [Section 11] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 200 mg when converted to a free form.

[0023] [Section 12] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 220 mg when converted to a free form.

[0024] [Section 13] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 240 mg when converted to a free form.

[0025] [Section 14] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 260 mg when converted to a free form.

[0026] [Section 15] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 280 mg when converted to a free form.

[0027] [Section 16] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 300 mg when converted to a free form.

[0028] [Section 17] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 320 mg when converted to a free form.

[0029] [Section 18] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 340 mg when converted to a free form.

[0030] [Section 19] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 360 mg when converted to a free form.

[0031] [Section 20] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 380 mg when converted to a free form.

[0032] [Section 21] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 400 mg when converted to a free form.

[0033] [Section 22] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 500 mg when converted to a free form.

[0034] [Section 23] A pharmaceutical product according to any of items 1 to 3, wherein the single dose of the active ingredient is 600 mg when converted to a free form.

[0035] [Section 24] A pharmaceutical product according to any of items 1 to 23, used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is at least one selected from antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-coordinate compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

[0036] [Section 25] A pharmaceutical product of any of items 1 to 23, used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is (1) Venetoclax and azacitidine (2) Cytarabine and daunorubicin, and (3) Gilteritinib A pharmaceutical product, which is at least one of the following.

[0037] [Section 26] Any of the medications listed in items 1-23, administered once daily in combination with gilteritinib.

[0038] [Section 27] Any of the medications listed in items 1-23, administered in combination with 120 mg of gilteritinib.

[0039] [Section 28] Cancer is leukemia, polycythemia vera, malignant lymphoma, B-cell lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer, any of the medicines in items 1-27.

[0040] [Section 29] The cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer, and any of the medications listed in items 1-27.

[0041] [Section 30] Cancer is leukemia, and any of the medications listed in items 1-27.

[0042] [Section 31] A drug for which leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia, as specified in items 28-30.

[0043] [Section 32] The medicine of paragraph 31, in which acute leukemia is MLL acute leukemia, MLL partial tandem duplication acute leukemia, or NPM1 mutation acute leukemia.

[0044] [Section 33] The drug in paragraph 31, where acute leukemia is MLL acute leukemia or NPM1 mutation acute leukemia.

[0045] [Section 34] Acute leukemia is acute myeloid leukemia with MLL rearrangement, as defined in item 31.

[0046] [Section 35] The drug in paragraph 31, where acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

[0047] [Section 36] Acute leukemia is acute lymphoblastic leukemia with MLL rearrangement, as defined in item 31.

[0048] [Section 37] The drug in paragraph 31 is acute leukemia, which is relapsed or refractory acute lymphoblastic leukemia with MLL rearrangement.

[0049] [Section 38] Acute leukemia is acute myeloid leukemia with NPM1 mutation, as defined in item 31.

[0050] [Section 39] The drug in paragraph 31, in which acute leukemia is relapsed or refractory acute myeloid leukemia with an NPM1 mutation.

[0051] [Section 40] A drug of the type in paragraph 31, in which acute leukemia is characterized by high expression of the HOXa gene group or the MEIS gene group.

[0052] [Section 41] Cancer is a tumor associated with a p53 gain-of-function mutation, and any of the drugs listed in items 1-27.

[0053] [Section 42] A drug of any of items 1-27 in which cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, DNMT3A gene mutations, FLT gene mutations, and MLL translocations.

[0054] [Section 43] A drug of any of items 1-27 in which cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, FLT gene mutations, and MLL translocations.

[0055] [Section 44] A drug of any of items 1-27 in which cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

[0056] [Section 45] A pharmaceutical according to any of items 1 to 44, administered to a subject having at least one genetic abnormality selected from NPM1 gene mutations, DNMT3A gene mutations, FLT gene mutations, and MLL translocations.

[0057] [Section 46] A pharmaceutical product according to any of items 1 to 44, administered to a subject having at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

[0058] [Section 47] Any of the drugs listed in items 1 to 44, administered to subjects with NPM1 gene mutations.

[0059] [Section 48] Subjects with NPM1 gene mutations (1) A step of detecting NPM1 gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the NPM1 gene mutation detected in step (1) is present. The medicines of item 47, determined based on the following.

[0060] [Section 49] Any of the pharmaceuticals listed in items 1 to 44, administered to subjects with MLL translocations.

[0061] [Section 50] Subjects with MLL translocations (1) A step of detecting MLL translocation in cancer cells obtained from the target, and (2) A step to determine whether or not the MLL translocation detected in step (1) is present. The medicines of item 49, determined based on the following.

[0062] [Section 51] Any of the pharmaceuticals listed in items 1 to 44, administered to subjects with FLT gene mutations.

[0063] [Section 52] Subjects with FLT gene mutations (1) A step of detecting FLT gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the FLT gene mutation detected in step (1) is present. The medicine of item 51, determined based on the following.

[0064] [Section 53] Any of the drugs listed in items 1 to 44, administered to subjects with a DNMT3A gene mutation.

[0065] [Section 54] Subjects with DNMT3A gene mutations (1) A step of detecting DNMT3A gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the DNMT3A gene mutation detected in step (1) is present. The medicines of item 53, determined based on the following.

[0066] Furthermore, the present invention is as follows: [Section A1] The use of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as "free form") or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, as an active ingredient in the manufacture of a pharmaceutical product for the treatment or prevention of cancer, which is administered orally to a subject in need of treatment or prevention.

[0067] [Section A2] The use of item A1, characterized in that the pharmaceutical is administered orally once a day to the target.

[0068] [Section A3] The use of item A1, characterized in that the pharmaceutical is administered orally twice a day to the target.

[0069] [Section A4] Use of any of items A1 to A3, where the single dose of the active ingredient is 40 mg when converted to the free form.

[0070] [Section A5] Use of any of items A1 to A3, where the single dose of the active ingredient is 60 mg when converted to the free form.

[0071] [Section A6] Use of any of items A1 to A3, where the single dose of the active ingredient is 80 mg when converted to the free form.

[0072] [Section A7] Use of any of items A1 to A3, where the single dose of the active ingredient is 100 mg when converted to the free form.

[0073] [Section A8] Use of any of items A1 to A3, where the single dose of the active ingredient is 120 mg when converted to the free form.

[0074] [Section A9] Use of any of items A1 to A3, where the single dose of the active ingredient is 140 mg when converted to the free form.

[0075] [Section A10] Use of any of items A1 to A3, where the single dose of the active ingredient is 180 mg when converted to the free form.

[0076] [Section A11] Use of any of items A1 to A3, where the single dose of the active ingredient is 200 mg when converted to the free form.

[0077] [Section A12] Use of any of items A1 to A3, where the single dose of the active ingredient is 220 mg when converted to the free form.

[0078] [Section A13] Use of any of items A1 to A3, where the single dose of the active ingredient is 240 mg when converted to the free form.

[0079] [Section A14] Use of any of items A1 to A3, where the single dose of the active ingredient is 260 mg when converted to the free form.

[0080] [Section A15] Use of any of items A1 to A3, where the single dose of the active ingredient is 280 mg when converted to the free form.

[0081] [Section A16] Use of any of items A1 to A3, where the single dose of the active ingredient is 300 mg in free form.

[0082] [Section A17] Use of any of items A1 to A3, where the single dose of the active ingredient is 320 mg when converted to the free form.

[0083] [Section A18] Use of any of items A1 to A3, where the single dose of the active ingredient is 340 mg when converted to the free form.

[0084] [Section A19] Use of any of items A1 to A3, where the single dose of the active ingredient is 360 mg when converted to the free form.

[0085] [Section A20] Use of any of items A1 to A3, where the single dose of the active ingredient is 380 mg when converted to the free form.

[0086] [Section A21] Use of any of items A1 to A3, where the single dose of the active ingredient is 400 mg when converted to the free form.

[0087] [Section A22] Use of any of items A1 to A3, where the single dose of the active ingredient is 500 mg when converted to the free form.

[0088] [Section A23] Use of any of items A1 to A3, where the single dose of the active ingredient is 600 mg when converted to the free form.

[0089] [Section A24] Use of any of items A1 to A23, wherein the pharmaceutical product is used in combination with another drug or a pharmaceutically acceptable salt thereof, and the other drug is at least one selected from antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-coordinate compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

[0090] [Section A25] The pharmaceutical product is used in combination with another drug or a pharmaceutically acceptable salt thereof, and the other drug is (1) Venetoclax and azacitidine (2) Cytarabine and daunorubicin, and (3) Gilteritinib Use of any of items A1 to A23, which is at least one selected from the above.

[0091] [Section A26] The drug is administered once daily in combination with gilteritinib, as described in any of items A1 to A23.

[0092] [Section A27] The drug is administered in combination with 120 mg of gilteritinib, as described in any of items A1 to A23.

[0093] [Section A28] If the cancer is leukemia, polycythemia vera, malignant lymphoma, B-cell lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer, use of any of items A1-A27.

[0094] [Section A29] Use of any of items A1-A27 if the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

[0095] [Section A30] If the cancer is leukemia, use any of items A1-A27.

[0096] [Section A31] Use of any of items A28-A30, where leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

[0097] [Section A32] Use of item A31 if acute leukemia is MLL acute leukemia, MLL partial tandem overlapping acute leukemia, or NPM1 mutation acute leukemia.

[0098] [Section A33] Use of item A31 if acute leukemia is MLL acute leukemia or NPM1 mutation acute leukemia.

[0099] [Section A34] Use of item A31, where acute leukemia is acute myeloid leukemia with MLL rearrangement.

[0100] [Section A35] Use of item A31 when acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

[0101] [Section A36] Use of clause A31, where acute leukemia is acute lymphoblastic leukemia with MLL rearrangement.

[0102] [Section A37] Use of clause A31: Acute leukemia is relapsed or refractory acute lymphoblastic leukemia with MLL rearrangement.

[0103] [Section A38] Use of item A31, where acute leukemia is acute myeloid leukemia with NPM1 mutation.

[0104] [Section A39] Use of item A31 when acute leukemia is relapsed or refractory acute myeloid leukemia with NPM1 mutation.

[0105] [Section A40] Use of item A31: Acute leukemia is a type of leukemia accompanied by high expression of the HOXa gene group or the MEIS gene group.

[0106] [Section A41] Use of any of items A1-A27, where cancer is a tumor with a p53 gain-of-function mutation.

[0107] [Section A42] Use of any of items A1-A27, where the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, DNMT3A gene mutations, FLT gene mutations, and MLL translocations.

[0108] [Section A43] Use of any of items A1-A27, where the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, FLT gene mutations, and MLL translocations.

[0109] [Section A44] Use of any of items A1-A27, where the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

[0110] [Section A45] Use of any of items A1 to A44, wherein the drug is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutations, DNMT3A gene mutations, FLT gene mutations, and MLL translocations.

[0111] [Section A46] Use of any of items A1 to A44, wherein the drug is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

[0112] [Section A47] Use of any of items A1 to A44, wherein the drug is administered to a subject having an NPM1 gene mutation.

[0113] [Section A48] Subjects with NPM1 gene mutations (1) A step of detecting NPM1 gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the NPM1 gene mutation detected in step (1) is present. The use of item A47 is determined based on the following.

[0114] [Section A49] Use of any of items A1 to A44, in which the drug is administered to a subject having an MLL translocation.

[0115] [Section A50] Subjects with MLL translocations (1) A step of detecting MLL translocation in cancer cells obtained from the target, and (2) A step to determine whether or not the MLL translocation detected in step (1) is present. The use of item A49 is determined based on the following.

[0116] [Section A51] The use of any of items A1 to A44, wherein the drug is administered to a subject having an FLT gene mutation.

[0117] [Section A52] Subjects with FLT gene mutations (1) A step of detecting FLT gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the FLT gene mutation detected in step (1) is present. The use of item A51 is determined based on the following.

[0118] [Section A53] Use of any of items A1 to A44, wherein the drug is administered to a subject having a DNMT3A gene mutation.

[0119] [Section A54] Subjects with DNMT3A gene mutations (1) A step of detecting DNMT3A gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the DNMT3A gene mutation detected in step (1) is present. The use of item A53 is determined based on the following.

[0120] Furthermore, the present invention is as follows: [Section B1] A method for treating or preventing cancer, characterized by orally administering a therapeutically effective amount of 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as "free form") or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, to a subject in need of treatment or prevention.

[0121] [Section B2] The method of item B1, characterized in that the active ingredient is administered orally once a day.

[0122] [Section B3] The method of item B1, characterized in that the active ingredient is administered orally twice a day.

[0123] [Section B4] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 40 mg when converted to the free form.

[0124] [Section B5] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 60 mg when converted to the free form.

[0125] [Section B6] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 80 mg when converted to the free form.

[0126] [Section B7] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 100 mg when converted to the free form.

[0127] [Section B8] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 120 mg when converted to the free form.

[0128] [Section B9] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 140 mg when converted to the free form.

[0129] [Section B10] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 180 mg when converted to the free form.

[0130] [Section B11] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 200 mg when converted to the free form.

[0131] [Section B12] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 220 mg when converted to the free form.

[0132] [Section B13] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 240 mg when converted to the free form.

[0133] [Section B14] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 260 mg when converted to the free form.

[0134] [Section B15] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 280 mg when converted to the free form.

[0135] [Section B16] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 300 mg when converted to the free form.

[0136] [Section B17] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 320 mg when converted to the free form.

[0137] [Section B18] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 340 mg when converted to the free form.

[0138] [Section B19] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 360 mg when converted to the free form.

[0139] [Section B20] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 380 mg when converted to the free form.

[0140] [Section B21] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 400 mg when converted to the free form.

[0141] [Section B22] One of the methods described in items B1 to B3, in which the single dose of the active ingredient is 500 mg when converted to the free form.

[0142] [Section B23] One of the methods described in items B1 to B3, wherein the single dose of the active ingredient is 600 mg when converted to the free form.

[0143] [Section B24] The method according to any of items B1 to B23, wherein the active ingredient is administered in combination with another drug or a pharmaceutically acceptable salt thereof, and the other drug is at least one selected from antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-coordinate compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

[0144] [Section B25] The active ingredient is administered in combination with another drug or a pharmaceutically acceptable salt thereof, and the other drug is (1) Venetoclax and azacitidine (2) Cytarabine and daunorubicin, and (3) Gilteritinib One of the methods in items B1 to B23, which is selected from at least one of the options.

[0145] [Section B26] The active ingredient is administered once daily in combination with gilteritinib, using one of the methods described in items B1 to B23.

[0146] [Section B27] Administered in combination with 120 mg of the active ingredient gilteritinib, using one of the methods described in items B1 to B23.

[0147] [Section B28] The cancer is leukemia, polycythemia vera, malignant lymphoma, B-cell lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer, by any of the methods in items B1 to B27.

[0148] [Section B29] The cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer, according to any of the methods in items B1-B27.

[0149] [Section B30] The cancer is leukemia, using one of the methods described in sections B1 to B27.

[0150] [Section B31] The leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia, as described in any of items B28-B30.

[0151] [Section B32] The method of item B31, wherein the acute leukemia is MLL acute leukemia, MLL partial tandem duplication acute leukemia, or NPM1 mutation acute leukemia.

[0152] [Section B33] The method of item B31, wherein the acute leukemia is MLL acute leukemia or NPM1 mutation acute leukemia.

[0153] [Section B34] The method described in item B31 defines acute leukemia as acute myeloid leukemia with MLL rearrangement.

[0154] [Section B35] The method of item B31, where acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

[0155] [Section B36] The method described in item B31 defines acute leukemia as acute lymphoblastic leukemia with MLL rearrangement.

[0156] [Section B37] The method of item B31, where acute leukemia is relapsed or refractory acute lymphoblastic leukemia with MLL rearrangement.

[0157] [Section B38] The method described in item B31 defines acute leukemia as acute myeloid leukemia with an NPM1 mutation.

[0158] [Section B39] The method of item B31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with an NPM1 mutation.

[0159] [Section B40] The method described in item B31, wherein the acute leukemia is a leukemia accompanied by high expression of the HOXa gene group or the MEIS gene group.

[0160] [Section B41] The cancer is a tumor with a p53 gain-of-function mutation, as described in any of sections B1 to B27.

[0161] [Section B42] The cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, DNMT3A gene mutations, FLT gene mutations, and MLL translocations, according to any of the methods described in items B1 to B27.

[0162] [Section B43] The cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, FLT gene mutations, and MLL translocations, according to any of the methods described in items B1 to B27.

[0163] [Section B44] The cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations, according to any of the methods described in items B1 to B27.

[0164] [Section B45] The method according to any of items B1 to B44, wherein the subject has at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

[0165] [Section B46] The method according to any of items B1 to B44, wherein the subject has at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

[0166] [Section B47] The method according to any of items B1 to B44, wherein the subject has an NPM1 gene mutation.

[0167] [Section B48] Subjects with NPM1 gene mutations (1) A step of detecting NPM1 gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the NPM1 gene mutation detected in step (1) is present. The method of item B47, determined based on the above.

[0168] [Section B49] The method described in items B1 to B44 wherein the object has an MLL translocation.

[0169] [Section B50] Subjects with MLL translocations (1) A step of detecting MLL translocation in cancer cells obtained from the target, and (2) A step to determine whether or not the MLL translocation detected in step (1) is present. The method of item B49, determined based on the above.

[0170] [Section B51] The method according to items B1 to B44, wherein the subject has an FLT gene mutation.

[0171] [Section B52] Subjects with FLT gene mutations (1) A step of detecting FLT gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the FLT gene mutation detected in step (1) is present. The method of item B51, determined based on the above.

[0172] [Section B53] The method according to any of items B1 to B44, wherein the subject has a DNMT3A gene mutation.

[0173] [Section B54] Subjects with DNMT3A gene mutations (1) A step of detecting DNMT3A gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the DNMT3A gene mutation detected in step (1) is present. The method of item B53, determined based on the above. [Effects of the Invention]

[0174] The technology of this disclosure, when used in the dosage and administration provided herein, is useful as a therapeutic and / or prophylactic agent for leukemia, polycythemia vera, malignant lymphoma, B-cell lymphoma, myeloma, brain tumors, head and neck cancers, esophageal cancers, thyroid cancers, small cell lung cancers, non-small cell lung cancers, breast cancers, gastric cancers, gallbladder and bile duct cancers, liver cancers, hepatocellular carcinomas, pancreatic cancers, colon cancers, rectal cancers, anal cancers, choriocarcinomas, endometrial cancers, cervical cancers, ovarian cancers, bladder cancers, urothelial carcinomas, kidney cancers, renal cell carcinomas, prostate cancers, testicular tumors, testicular germ cell tumors, ovarian germ cell tumors, Wilms' tumors, malignant melanomas, neuroblastomas, osteosarcomas, Ewing's sarcomas, chondrosarcomas, soft tissue sarcomas, or skin cancers, and exhibits excellent anticancer activity against cancers with specific gene mutations. The technology described herein can be used in humans at doses that have been confirmed or are expected to be tolerable, and can be used as various therapeutic and / or prophylactic agents. Furthermore, the anticancer effect can be further enhanced by using this compound and concomitant agents.

[0175] The object of the present invention is to provide an invention relating to the usage and dosage of an optically active azabicyclo ring derivative that exhibits excellent anticancer activity by inhibiting the binding of menin to MLL fusion protein, and to provide a useful therapeutic agent and method for treating tumors with specific gene mutations when used in combination with other anticancer agents.

[0176] More specifically, the present inventors provide a technology related to pharmaceuticals comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof (hereinafter sometimes referred to as "the compound"). [Brief explanation of the drawing]

[0177] [Figure 1] Figure 1 shows the design of a clinical trial using this compound, which is a first-in-human (FIH) trial, a Phase 1 / 2 trial consisting of a Phase 1 dose escalation part and a Phase 2 dose expansion part. [Figure 2] Figure 2 shows a comparison of Cmax at the total doses of Group A and Group B. [Figure 3] Figure 3 shows a comparison of AUC at the total doses of Group A and Group B. [Figure 4] Figures 4A to 4D show the pharmacokinetic data at the data cut-off point in Example 6. [Figure 5] Figure 5 shows the maximum percentage change in gene expression of leukemia biomarkers (HOXA9, MEIS1, PBX3) and differentiation biomarker (CD11b) in bone marrow aspirates from MLLr or NPM1m AML patients, from which baseline and post-baseline samples were collected. All dose levels and time points are combined. [Figure 6]Figures 6A and 6B show the mean percentage change in the maximum gene expression of leukemia biomarkers (HOXA9, MEIS1, PBX3) and differentiation biomarker (CD11b) in bone marrow aspirates from patients at all dose levels from whom baseline and post-baseline samples were collected. [Figure 7] Figures 7A and 7B show the maximum percentage decrease (%) from baseline in myeloblasts. [Figure 8] Figure 8 shows the maximum percentage decrease (%) from baseline in myeloblasts. [Modes for carrying out the invention]

[0178] Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Therefore, singular articles (e.g., "a," "an," and "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0179] 5-Fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (the free form of this compound) has the following structure. [ka] Furthermore, in the phrase "this compound or its pharmaceutically acceptable salt, or its hydrate or solvate," "its hydrate or solvate" refers to the hydrate or solvate of this compound, and the hydrate or solvate of a pharmaceutically acceptable salt of this compound.

[0180] Examples of "pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. In addition, base addition salts include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminum salt, and organic base salts such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylateamine. Furthermore, "pharmaceutically acceptable salts" also include amino acid salts with basic or acidic amino acids such as arginine, lysine, ornithine, aspartic acid, or glutamic acid.

[0181] "The tartrate of this compound" refers to 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonane-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide 1L(+)-tartrate.

[0182] The compounds provided in this specification can include various stereochemical forms. The compounds of the present invention include not only optical isomers but also diastereomers, such as mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers resulting from structural asymmetry in certain compounds. The separation of individual isomers or the selective synthesis of individual isomers can be achieved by applying various methods known to those skilled in the art.

[0183] The compounds also include various hydrates, solvates and crystal polymorphs. Furthermore, the compounds of the present invention may be substituted with isotope elements (e.g., H (or D), 3 H (or T), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 35 S, <00000l0>F, 125 I, etc.), and these compounds are also included in the compounds of the present invention.

[0184] <0OO0858>Furthermore, the scope of the present disclosure also includes prodrugs of the compounds. In the present disclosure, a prodrug refers to a derivative that is hydrolyzed by acid or enzymatically decomposed in vivo to give the compound. For example, the amino group of the compound can be modified according to a conventional method to produce a prodrug. Specifically, compounds in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group, compounds in which the amino group is substituted with an alkoxycarbonyl group to form an alkoxycarbonylamino group, compounds in which the amino group becomes an alkanoyloxymethylamino group, and compounds in which the amino group becomes a hydroxylamine can be mentioned.

[0185] Regarding the terms in this specification, the following explanations are provided.

[0186] In some embodiments, the subject treated by the method described above is a mammal. The compound can be used for mammals, and the term “mammal” as used herein is used in its ordinary biological sense. Specifically, this includes humans, cattle, horses, dogs, cats, rats, and mice, but also many other species. In some further embodiments, the subject is a human.

[0187] When it is desired to obtain a pharmaceutically acceptable salt of this compound, if the compound is obtained in the form of a pharmaceutically acceptable salt, it can be purified as is. If it is obtained in the form of a free compound, it can be dissolved or suspended in a suitable organic solvent, and an acid or base can be added to form a salt by the usual method.

[0188] In the present invention, "combined agent" or "combination agent" refers to an antitumor agent that can be used in combination with the compound of the present invention, or combined with the compound of the present invention in a single pharmaceutical composition. Examples of "combination agents" include antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum coordination compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, and other antitumor agents. Specific examples of "concomitant drugs" include, for example, azacitidine, vorinostat, decitabine, romidepsin, idarubicin, daunorubicin, doxorubicin, enocitabine, cytarabine, mitoxantrone, thioguanine, etoposide, ifosfamide, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, ranimustine, all-trans retinoic acid, tamibarotene, cisplatin, carboplatin, oxaliplatin, irinotecan, bleomycin, mitomycin C, methotrexate, paclitaxel, docetaxel, gemcitabine, tamoxifen, thiotepa, tegafur, fluorouracil, and everolim. S, Temsirolimus, Gefitinib, Erlotinib, Imatinib, Crizotinib, Osimertinib, Afatinib, Dasatinib, Bosutinib, Vandetanib, Sunitinib, Axitinib, Pazopanib, Lenvatinib, Lapatinib, Nilotinib, Ibrutinib, Ceritinib, Alectinib, Tofacitinib, Baricitinib, Ruxolitinib, Ora Examples include parib, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab, vedotin, gemtuzumab, ozogamicin, inotuzumab, ozogamicin, venetoclax, and gilteritinib.

[0189] Examples of antitumor tyrosine kinase inhibitors include FLT3 inhibitors. Examples of FLT3 inhibitors include gilteritinib, quizartinib, and midostaurin. Gilteritinib is preferred as the FLT3 inhibitor.

[0190] Gilteritinib is preferably administered orally once daily, with a single dose of 80 mg and 120 mg of the active ingredient as a free form, and more preferably 120 mg as a free form.

[0191] When this compound is used in combination with gilteritinib 120 mg (free form equivalent) once daily, the pharmaceutical product containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is administered orally twice daily, with a preferred dose of the active ingredient per dose being 140 mg, 200 mg, or 300 mg of the compound of the present invention in terms of its free form equivalent.

[0192] When this compound is used in combination with gilteritinib 80 mg (free form equivalent) once daily, the pharmaceutical product containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is administered orally twice daily, with a preferred dose of 100 mg, 120 mg, or 140 mg of the compound of the present invention in free form equivalent.

[0193] Examples of concomitant medications used in this context include BCL-2 inhibitors. Examples of BCL-2 inhibitors include venetoclax.

[0194] Venetoclax is preferably administered orally once daily, with a preferred single dose of 100 mg, 200 mg, or 400 mg of the active ingredient in terms of free form.

[0195] In the case of a dose of Venetoclax 100 mg, the dose of Venetoclax starts with a 4-day dose escalation, administering 10 mg on the first day, 20 mg on the second day, 50 mg on the third day, and 100 mg on the fourth day, and then administering 100 mg daily on days 5 to 14 of each 28-day cycle. In the case of a dose of Venetoclax 200 mg, it starts with a 4-day dose escalation, starting from 20 mg on the first day, 50 mg on the second day, 100 mg on the third day, and 200 mg on the fourth day, and then administering 200 mg daily on days 5 to 14 of each 28-day cycle. In the case of a dose of Venetoclax 400 mg, it starts with a 3-day dose escalation, administering 100 mg on the first day, 200 mg on the second day, and 400 mg on the third day, and then administering 400 mg daily on days 4 to 14 of each 28-day cycle.

[0196] Examples of epigenetic-related molecular inhibitors include, for example, azacitidine.

[0197] Azacitidine is preferably administered intravenously once a day, and the single dose of the active ingredient is 75 mg / m in terms of the free form. 2 is preferred.

[0198] [[ID=​​​​​​​​​​​​​​When used in combination with (in terms of free form), a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is orally administered twice a day, and the dose of the active ingredient per administration is preferably 140 mg, 200 mg, and 300 mg in terms of the free form of the compound of the present invention.

[0201] The present compound is used in combination with venetoclax 400 mg (in terms of free form) once a day and azacitidine 75 mg / m once a day 2 When used in combination with (in terms of free form), a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is orally administered twice a day, and the dose of the active ingredient per administration is preferably 140 mg, 200 mg, and 300 mg in terms of the free form of the compound of the present invention.

[0202] The administration interval between the present compound and the concomitant medicament is not limited, and they may be administered simultaneously or at different times. Alternatively, the present compound and the concomitant medicament may be used as a combined preparation. The dose of the concomitant medicament can be appropriately selected based on the clinically used doses. And the mixing ratio between the present compound and the concomitant medicament can be appropriately selected according to the administration subject, administration route, target disease, symptoms, combination, etc.

[0203] "MOLM-13 cells" are a human acute myeloid leukemia cell line having the MLL-AF9 fusion protein and the FLT3-ITD mutation.

[0204] "OCI-AML3 cells" are a human acute myeloid leukemia cell line having the NPM1 mutation and the DNMT3A mutation.

[0205] The number of times of oral administration of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, includes once a day, twice a day, three times a day or four times a day, preferably once a day or twice a day, and more preferably twice a day.

[0206] "XXX mg in free form equivalent" means that a single dose of the active ingredient equal to the number of moles of free form in the indicated weight (XXX mg) is administered. For example, the dose of the tartrate salt of this compound is calculated using the following formula. [Dosage of tartrate of this compound] = [Dosage of free compound] × [Molecular weight of tartrate of this compound (740.83)] / [Molecular weight of free compound (590.74)] For example, "20 mg in free form" corresponds to 25 mg of the tartrate salt of this compound, and is calculated using the following formula. [Dosage of this compound tartrate] = 20 mg × [Molecular weight of this compound tartrate (740.83)] / [Molecular weight of this compound (free form) (590.74)] = 25 mg Similar calculations can be performed for other forms of salts, hydrates, solvates, etc.

[0207] The single oral dose of this compound or its pharmaceutically acceptable salt, or its hydrate or solvate, in pharmaceuticals is calculated as 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 2 50mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410m g, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 5 80mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 670mg, 680mg, 690mg, 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760 mg, 770mg, 780mg, 790mg, 800mg, 810mg, 820mg, 830mg, 840mg, 850mg, 860mg, 870mg, 880mg, 890mg, 900mg, 910mg, 920mg, Examples include 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, and 1200 mg. The range between any two of these arbitrarily selected doses is also included.

[0208] The single oral dose of this compound or its pharmaceutically acceptable salt, or its hydrate or solvate in a pharmaceutical product, is preferably 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 630 mg, 640 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, and 74 mg. 0mg, 750mg, 760mg, 770mg, 780mg, 790mg, 800mg, 810mg, 820mg, 830mg, 840mg, 850mg, 860mg, 8 70mg, 880mg, 890mg, 900mg, 910mg, 920mg, 930mg, 940mg, 950mg, 960mg, 970mg, 980mg, 990mg, 1 Examples include 000mg, 1010mg, 1020mg, 1030mg, 1040mg, 1050mg, 1060mg, 1070mg, 1080mg, 1090mg, 1100mg, 1110mg, 1120mg, 1130mg, 1140mg, 1150mg, 1160mg, 1170mg, 1180mg, 1190mg, and 1200mg. The range between any two of these arbitrarily selected doses is also included.

[0209] More preferably, the single oral dose of the compound in a pharmaceutical product or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, when converted to the free form of the compound, is 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 630 mg, 640 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, and 740 mg. Furthermore, the range between these two arbitrarily selected dosages is also included.

[0210] A single oral dose of the compound in a pharmaceutical product, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, is more preferably 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, and 600 mg, and also includes the range between any two of these doses.

[0211] The most preferred single oral doses of the compound in a pharmaceutical product, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, when converted to the free form of the compound, are 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, and 500 mg. The range between any two of these doses is also included.

[0212] A single oral dose of the compound in a pharmaceutical product, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, in terms of the free form of the compound, may be 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, and 400 mg, respectively. The range between any two of these doses is also included.

[0213] A single oral dose of the compound in a pharmaceutical product, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, in terms of the free form of the compound, may be 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, and 500 mg, in other preferred embodiments. The range between any two of these doses is also included.

[0214] A single oral dose of the compound in a pharmaceutical product, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, in terms of the free form of the compound, may be, in other more preferred embodiments, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, and 500 mg. The range between any two of these doses is also included.

[0215] A single oral dose of the compound in a pharmaceutical product, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, may, in other more preferred embodiments, be 360 ​​mg, 380 mg, 400 mg, 420 mg, and 440 mg, respectively, when converted to the free form of the compound. The range between any two of these doses is also included.

[0216] The single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a medicament, when converted to the free form of the present compound, is, as another most preferred embodiment, 300 mg.

[0217] The single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a medicament, when converted to the free form of the present compound, is, as another most preferred embodiment, 400 mg.

[0218] The medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably administered orally twice a day, and the single dose of the active ingredient, when converted to the free form of the present compound, is preferably 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, and 600 mg. Also, the single dose includes the range between any two of these optionally selected doses.

[0219] The medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably administered orally twice a day, and the single dose of the active ingredient, when converted to the free form of the present compound, is preferably 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, and 400 mg. Also, the single dose includes the range between any two of these optionally selected doses.

[0220] Pharmaceuticals containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, are preferably administered orally twice daily. The single dose of the active ingredient, converted to the free form of the compound, is more preferably 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, and 500 mg. The single dose also includes the range between any two of these arbitrarily selected doses.

[0221] Pharmaceuticals containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, are preferably administered orally twice daily. The single dose of the active ingredient, converted to the free form of the compound, is most preferably 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, and 500 mg. The single dose also includes a range between any two of these arbitrarily selected doses.

[0222] Pharmaceuticals containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, are preferably administered orally twice daily. The single dose of the active ingredient, converted to the free form of the compound, may be 360 ​​mg, 380 mg, 400 mg, 420 mg, and 440 mg in other preferred embodiments. The single dose may also encompass a range between any two of these arbitrarily selected doses.

[0223] Pharmaceuticals containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, are preferably administered orally twice daily, and the single dose of the active ingredient, when converted to the free form of the compound, is 300 mg in another more preferred embodiment.

[0224] Pharmaceuticals containing this compound or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, are preferably administered orally twice daily, and the single dose of the active ingredient, when converted to the free form of the compound, may be 400 mg in another embodiment.

[0225] This compound, or a pharmaceutically acceptable salt thereof, or its hydrate or solvate, may be administered orally directly or as a suitable formulation. Dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, patches, and poultices. The formulations are manufactured by known methods using pharmaceutically acceptable additives.

[0226] Depending on the purpose, additives such as excipients, disintegrants, binders, fluidizers, lubricants, coating agents, solvents, solubilizers, thickeners, dispersants, stabilizers, sweeteners, and flavorings can be used. Examples of additives used here include lactose, lactose monohydrate, mannitol, D-mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, sodium starch glycolate, partially pregelatinized starch, carmellose, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium dioxide, light anhydrous silicic acid, and talc.

[0227] One embodiment of the above-mentioned formulation is formulation A, which contains the following components. (i) the tartrate salt of this compound (ii) D-mannitol (iii) Partially pregelatinized starch (iv) Croscarmellose sodium (v) Hydroxypropylcellulose, and (vi) Sodium stearyl fumarate

[0228] One embodiment of the above-mentioned formulation is formulation B, which contains the following components. (i) the tartrate salt of this compound (ii) Lactose hydrate (iii) Crystalline cellulose (iv) Carmellose (v) Light anhydrous silicic acid, and (vi) Sodium stearyl fumarate

[0229] The above-mentioned formulation A or formulation B can be used in the following examples. [Examples]

[0230] The present invention will be described in more detail below with reference to examples, but the technical scope of the present invention is not limited thereto. In the following examples, the tartrate salt of the compound is used as the active ingredient, and (1) study design considerations, (2) subject enrollment, and all doses (mg) shown in Examples 1-13 are doses (mg) converted to the free compound. For example, "20 mg" means 20 mg of the compound of the present invention (free compound), and in this case the weight of the tartrate salt of the compound used is 25 mg.

[0231] (1) Considerations for clinical trial design This clinical trial using the compound is a Phase 1 / 2 First-In-Heat (FIH) trial, including a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The trial design is shown in Figure 1. Initially, only provisional dose levels of 40, 60, 80, 100, 120, and 140 mg BID were planned, but since there are currently no safety concerns, provisional dose levels (180, 240, 320, 420, 560, and 740 mg BID) were added to the trial. In the dose escalation phase, subjects were assigned to different treatment groups depending on whether or not they were concomitantly treated with a potent or moderate CYP3A4 / 5 inhibitor, such as an azole antifungal agent, as follows: Group A: Subjects who have not received an azole antifungal agent (or isabconazole within 21 days) within 7 days prior to the first administration of this compound. Group B: Subjects who were receiving prophylactic antifungal therapy with posaconazole, voriconazole, or fluconazole at the time of enrollment. The safety of each dose level was assessed by the SRC, which consisted of all principal investigators and specific trial team members from the sponsor participating in the study. The doses recommended by the BLRM method were treated as guidelines and integrated with a review of clinical assessments of toxicity information, as well as other available data, including safety, PK, pharmacodynamic, and laboratory data.

[0232] (2) Registration of subjects At the data cutoff point, in the Phase 1 dose escalation portion of this study, a total of 14 subjects were enrolled in Group A at the 40 mg BID (N=2), 80 mg BID (N=4), 100 mg BID (N=2), and 120 mg BID (N=6) dose levels, and a total of 10 subjects were enrolled in Group B at the 40 mg BID (N=4) and 60 mg BID (N=6) dose levels (Table 1). Upon completion of dose-limiting toxicity (DLT) assessments for each cohort, the SRC determined the following doses based on DLTs and other available data, including safety, PK, pharmacodynamics, and laboratory data, with reference to recommendations from a Bayesian logistic regression model (BLRM). When the Safety Review Committee (SRC) determined that the 80 mg BID cohort of Group A was safe based on evaluations of two subjects, the SRC decided to initiate Group B with 40 mg BID. Importantly, at the initiation of Group B, enrollment was limited to patients positive for specific genetic abnormalities in both Group A and Group B. Therefore, the SRC decided that Group A would continue with 80 mg BID, and Group B would begin with 40 mg BID in patients positive for these specific genetic abnormalities. These specific genetic abnormalities are those that indicate the potential efficacy of the compound, such as MLLr and NPM1m. By narrowing the population to subjects more likely to respond to the compound of the present invention, a more accurate assessment of potential toxicity in the target population can be determined. Dose escalation was determined after all subjects in each dose level cohort had completed at least Cycle 1. All available data were presented along with BLRM predictions of toxicity probabilities at potential next dose levels, and the SRC then determined the dose for the next cohort. [Table 1]

[0233] Example 1: Safety evaluation of the compound At the data cutoff time, no DLTs occurred in any of the 24 subjects enrolled in this clinical trial (Table 2). At least one adverse event (TEAE) occurred in all 24 subjects under administration of the study drug. The incidence of Grade 3 or Grade 4 TEAEs was similar in Group A (5 subjects, 35.7%) and Group B (4 subjects, 28.6%), and in Group B (3 subjects, 30.0%) and Group B (2 subjects, 20.0%). Three subjects in Group B experienced treatment-related Grade 3 TEAEs (increased aspartate aminotransferase, leukocytosis, and hypertriglyceridemia), but all were temporary and resolved. Serious TEAEs were reported in 9 subjects (64.3%) in Group A and 6 subjects (60.0%) in Group B. Only one serious TEAE (two differentiation syndromes confirmed in one subject in Group A) was determined to be treatment-related by the principal investigator. Table 6 shows details of serious TEAEs. During the study period, five patients (35.7%) in Group A and three patients (30.0%) in Group B died due to TEAEs, but in all cases, a link to the treatment was ruled out. Furthermore, two out of five patients in Group A and two out of three patients in Group B died due to disease progression during the study (see Table 5). One TEAE in Group A and two in Group B were associated with the compound that led to discontinuation of the drug. No TEAEs associated with the treatment that led to discontinuation or reduction of medication were reported at that time. The adverse events (AEs) observed to date were consistent with those seen in patients with relapsed / refractory AML under other treatments (e.g., anemia, hypokalemia, nausea, fatigue, headache, etc.). The AE profile was generally consistent between Group A and Group B. Most of the TEAEs determined to be associated with this compound were Grade 1 or Grade 2. Table 4 lists TEAEs that occurred in 20% or more of either Group A or Group B, regardless of causal relationship with this compound, and Table 4 lists all TEAEs determined to be associated with this compound. As shown in Tables 2 and 5, serious adverse events (SAEs) occurred in a total of 15 patients, of which 9 (64.3%) were in Group A and 6 (60.0%) were in Group B. These SAEs are common complications in AML patients, and with the exception of one patient who experienced two SAEs of differentiation syndrome (which the principal investigator assessed as being related to this compound), all other SAEs were determined to be unrelated to this compound. The case in which latent differentiation syndrome occurred was a 63-year-old woman with TP53 mutation-positive AML. She was enrolled in Group A and received 80 mg BID. Differentiation syndrome was diagnosed based on an increase in white blood cell count with a decrease in blast percentage observed in association with the administration of the compound during late cycle 1 and early cycle 2. However, the evaluation of this case was complicated by disease progression of AML (myeloblasts increased from 11% at baseline to 53% on day 28 of cycle 1), transfusion adverse events, and pneumonia due to a potential fungal infection. Although the differentiation syndrome, a SAE, resolved, the patient subsequently died shortly thereafter from intracranial hemorrhage secondary to disease progression of AML (platelet count was 20,000 / μL the day before the onset of intracranial hemorrhage, suggesting disease progression of AML). The principal investigator noted that differentiation syndrome was not the cause of the subject's death. To date, differentiation syndrome has not occurred in other cases, nor in MLLr or NPM1m-positive cases. Eight SAEs (5 in Group A and 3 in Group B) resulted in death. In all cases, the principal investigator and sponsor assessed that these were not related to the compound, and it was highly likely that they were secondary to disease progression of AML or complications associated with AML. Overall, the types and frequencies of TEAEs expressed in Group A and Group B were similar. The only SAE determined to be related was differentiation syndrome, which occurred in one patient in Group A, as mentioned above. Other SAEs, including the one that resulted in death, were associated with complications due to AML relapse or disease progression. At present, no safety findings specific to the subjects in Group B have been observed, and no clear difference in the safety profile of this compound was found between Group A and Group B. [Table 2] TIFF0007833619000004.tif146166 [Table 3] TIFF0007833619000006.tif230158 [Table 4] [Table 5] TIFF0007833619000009.tif181166

[0234] Example 2: Pharmacokinetic evaluation of the compound In this study of the compound, PK samples were collected from up to 24 subjects administered in Group A (40, 80, 100, and 120 mg BID) and Group B (40 and 60 mg BID) (Table 6). Significant variability was observed among patients with preliminary PK. In group A, a dose-dependent increasing trend in exposure was observed at previously evaluated dose levels (40 mg, 80 mg, 100 mg, and 120 mg BID). In group B, current data for evaluating the dose-dependent nature of drug exposure ranged from 40 mg to 60 mg BID. mean plasma t 1 / 2 (If available) the absorption time ranges from 2.82 to 5.64 hours in group A and from 2.61 to 7.29 hours in group B, indicating relatively rapid absorption, with T2 appearing within 2 hours after administration. max The exposure level reached [value missing]. When comparing the exposure level on day 1 of cycle 2 with the exposure level on day 1 of cycle 1, minimal or no drug accumulation was observed due to repeated administration. The effect of concomitant use of azole antifungal agents on exposure to this compound was evaluated. As shown in the available PK data summarized in Table 6, the exposure level of group B 40 mg BID (C max and AUC lastThe exposure levels were similar to those of Group A (40 mg BID), and furthermore, the exposure levels of Group B (60 mg BID) were close to those of Group A (40 mg BID). Due to the large variability in exposure levels and the small sample size at each dose level, it was difficult to draw conclusions at this point in the study. However, comparing Group A and Group B with the PK data obtained so far suggests that azoles do not have a large or dramatic effect on exposure levels of this compound. [Table 6]

[0235] Example 3: Evaluation of the efficacy of this compound In this study, signs of clinical efficacy were observed, including a decrease and normalization of myeloblasts, disappearance of blasts in peripheral blood, and a response based on the European LeukemiaNet 2017 Response Criteria. One MLLr-positive patient enrolled in 120 mg BID in Group A achieved MLFS (morphological leukemia-free state), while one MLLr-positive patient enrolled in azole 60 mg BID in Group B achieved CRh (complete remission with partial hematological recovery) and CRi (complete remission with incomplete hematological recovery). Significant changes in several biomarkers were also observed, including decreases in HOXA9, PBX3, and MEIS1, and increases in CD11b. These changes were particularly pronounced in MLLr or NPM1m-positive patients.

[0236] Example 4: Patient Registration (1) At the data cutoff date, a total of 43 acute leukemia patients were enrolled in the Phase 1 dose escalation part of this study, with dose levels of 40-200 mg BID (n=23) in Group A and 40-200 mg (n=20) in Group B. Baseline characteristics are shown in Table 7. [Table 7] TIFF0007833619000012.tif57156

[0237] (2) At the data cutoff date, a total of 57 acute leukemia patients were enrolled in the Phase 1 dose escalation part of this study, with dose levels of 40-300 mg BID (n=27) in Group A and 40-300 mg (n=30) in Group B. Baseline characteristics are shown in Table 8. [Table 8] TIFF0007833619000014.tif219156

[0238] (3) At the time of data cut, 81 patients (31 in Group A and 50 in Group B) were enrolled. The median age was 57.1 years (range 20–89 years), 56.8% were female, and 93.8% had AML. The median number of previous treatments was 3 (range 1–9). 23 patients (28.4%) had previously received allogeneic stem cell transplantation, 63 patients (77.8%) had previously received venetoclax, and 5 patients (6.2%) had previously received menin inhibitors. MLLr was reported in 42 patients (51.9%), and NPM1m was reported in 20 patients (24.7%).

[0239] Example 5: Safety evaluation of the compound (1) No DLTs were observed at any dose level from 40 to 200 mg. The majority of TEAEs were Grade 1 or Grade 2 and were managed with supportive therapy. In this study, there were no cases of permanent discontinuation of treatment due to drug-related AEs, and no treatment-related deaths were observed. Regardless of causality, a table of TEAEs in 20% or more of patients is shown in Table 9, and a table of all TEAEs related to this compound in 2 or more patients is shown in Table 10. No treatment-related QT interval prolongation events were reported. One suspected case of differentiation syndrome was reported in a patient with a TP-53 mutation in relation to the compound of the present invention, but no suspected cases of differentiation syndrome were reported in patients with MLLr or NPM1m. [Table 9] [Table 10]

[0240] The above (1) test was continued, and the following results were obtained. (2) DLT was not observed at any dose level of 40–300 mg BID. TEAEs assessed as related to the compound in ≥10% of cases were vomiting (15.5%) and nausea (12.1%). Grade >3 TEAEs in ≥10% of cases included pneumonia (17.2%), sepsis and febrile neutropenia (15.5% each), anemia (13.8%), and thrombocytopenia (12.1%), all of which were assessed as unrelated to the investigational drug. The possibility of syndrome of differentiation (DS) was recorded in 3 patients. Two patients discontinued treatment, but none discontinued treatment, and there were no deaths due to DS. One patient reported associated asymptomatic grade 3 QT prolongation in the presence of another QT-prolonging agent, but required temporary discontinuation and subsequent dose reduction, and there were no recurrences.

[0241] (3) No DLTs were observed in any of the 57 patients at any dose level from 40 to 300 mg. In this study, no treatment was permanently discontinued due to drug-related adverse events, and no treatment-related deaths were observed. Table 11 shows treatment-related adverse events in 10% or more of the patients. Tables 12 and 13 show non-hematological or hematological TEAEs in 10% or more of the patients, regardless of causal relationship. Table 14 shows non-hematological changes in 10% or more of the patients. Differentiation syndrome (DS) was reported in 3 patients, none of which resulted in permanent discontinuation of treatment. No DS prophylactic medication was used at the start of treatment. Some patients showed hematological differentiation without presenting significant systemic symptoms, and these were not evaluated as DS. [Table 11] [Table 12] [Table 13] [Table 14]

[0242] (4) At the data cutoff time, the dose level increased from 40 mg BID to 300 mg BID (n=81), but no DLTs were observed. TEAEs assessed as being associated with this compound in ≥10% of patients were vomiting (14.8%) and nausea (12.3%). Grade 3 nausea and vomiting were reported in one patient. Regardless of association, TEAEs occurring in ≥20% of patients included nausea (37.0%), vomiting (29.6%), febrile neutropenia (22.2%), decreased appetite, diarrhea, and hypokalemia (21.0% each). No grade 3 or higher QTc prolongation was reported in association with this compound. Grade 1 QTc prolongation was reported in 2 patients (2.4%), and grade 2 QTc prolongation was reported in 2 patients (2.4%). The possibility of differentiation syndrome was reported in 9 patients (11.1%).

[0243] Example 6: Pharmacokinetic evaluation of the compound (1) In this study, PK samples were collected from up to 42 patients administered in Group A (40, 80, 100, 120, 140, and 200 mg BID dose groups) and Group B (40, 60, 100, and 200 mg BID dose groups) (Table 15). The mean apparent half-life ranged from approximately 2 to 5 hours in Group A and from approximately 3 to 7 hours in Group B. Absorption was rapid, reaching maximum concentration within 2 hours after administration. A dose-dependent increase in exposure was observed, and there was almost no drug accumulation with repeated administration. The data to date suggest that azoles do not significantly affect exposure to this compound (Figures 2 and 3). [Table 15]

[0244] The above (1) test was continued, and the following results were obtained. (2) In this study, PK samples were collected from patients in Group A (40, 80, 100, 120, 140, 200, and 300 mg BID dose groups) and Group B (40, 60, 100, 200, and 300 mg BID dose groups) (Table 16). The mean apparent half-life ranged from approximately 2 to 4 hours in Group A and from approximately 3 to 7 hours in Group B. Absorption was rapid, reaching maximum concentration within 2 hours after administration. A dose-dependent increase in exposure was observed, and drug accumulation with repeated administration was minimized. The data to date suggest that azoles do not significantly affect exposure to this compound. [Table 16]

[0245] (3) Figures 4A to 4D show pharmacokinetic data at the data cutoff point. 1 / 2 The exposure time ranged from 2 to 6 hours in group A (without azole) and 3 to 7 hours in group B (with azole). Dose-related increases in exposure were observed at doses of 140 mg or higher (BID), and accumulation with repeated administration was almost not observed. Previous pharmacokinetic data have not confirmed any significant drug interactions (>~2 times) with azole.

[0246] Example 7: Pharmacodynamic evaluation of the compound (1) Figure 5 shows the mean maximum percentage change in gene expression of leukemia biomarkers (HOXA9, MEIS1, PBX3) and differentiation biomarker (CD11b) in bone marrow aspirates from MLLr or NPM1m AML patients from whom baseline and post-baseline samples were collected. All dose levels and time points are combined. A clear decrease in HOXA9, PBX3, and MEIS1 and an increase in CD11b were observed.

[0247] (2) Figures 6A and 6B show the mean maximum percentage change in gene expression of leukemia biomarkers (HOXA9, MEIS1, PBX3) and differentiation biomarker (CD11b) in bone marrow aspirates from patients at all dose levels from which baseline and post-baseline samples were collected. In patients with targeted mutations, a clear decrease in HOXA9, PBX3, and MEIS1 and an increase in CD11b were observed.

[0248] Example 8: Evaluation of the clinical activity of this compound (1) Of the 43 patients enrolled, 17 had MLLr, 9 had NPM1m, 19 were evaluable at the time of data extraction, and 5 responded to ELN 2017 (Figure 7A). In group B with 200 mg BID, 4 evaluable patients had either MLLr or NPM1m (n=1 and 3, respectively), with 1 patient achieving CRh / CRi, 1 achieving CRi, and 1 achieving MLFS. Two additional MLLr patients also achieved a response with ELN2017 at low dose levels (CRh / CRi and MLFS).

[0249] The above (1) test was continued, and the following results were obtained. (2) Of the 58 patients, 26 had MLLr and 14 had NPM1m. Among all patients with MLLr or NPM1m who were treated with a BID of 140 mg or higher and had no prior menin inhibitor treatment and completed one cycle (n=22), the ORR (CR+CRi+MLFS) was 45% (10 / 22) and the CR+CRh rate was 23% (5 / 22). In patients with MLLr or NPM1m who had not received menin inhibitors and completed one cycle, the ORR and CR+CRh rates across all dose levels (BID 40 mg to BID 300 mg) were 32% (12 / 38) and 16% (6 / 38), respectively (Figure 7B).

[0250] (3) Myeloblast reduction was observed in patients with MLLr or NPM1m (Figure 8). Of the patients enrolled in BID ≥140 mg, 12 MLLr patients and 9 NPM1m patients were evaluable at the data cutoff. Table 17 shows the response according to the ELN2017 criteria. In MLLr patients, the CR+CRh rate was 17% (2 out of 12 patients), and the objective response rate (ORR; CR+CRh+CRi+MLFS) was 67% (8 out of 12 patients). In NPM1m patients, the CR+CRh rate was 33% (3 out of 9 patients), and the ORR was 44% (4 out of 9 patients). [Table 17] (4) At the data cut point, 35 patients with MLLr or NPM1m who had not previously received menin inhibitors were treated with an effective dose of the compound (BID of 140 mg or more in group A or B). Among the 22 patients with MLLr (20 AML cases, 2 ALL cases), the objective response rate (ORR) according to ELN 2017 (CR+CRi+MLFS) was 59.1% (13 / 22), and CR+CRh was achieved in 22.7% (5 / 22 cases). Among the 13 NPM1m AML patients, the ORR was 53.8% (7 / 13), and CR+CRh was achieved in 23.1% (3 / 13). Among patients with other menin-sensitizing genetics, one patient (AML) with the CALM-AF10 fusion gene also achieved CR. Overall, the median time to objective response and the median time to CR+CRh were 1.0 month and 1.0 month, respectively.

[0251] Example 9: Evaluation of the efficacy of combined therapy on cell proliferation MOLM-13 cells and OCI-AML3 cells were obtained from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH). MOLM-13 cells were cultured in RPMI1640 medium containing 20% ​​fetal bovine serum and 1% penicillin / streptomycin at 37°C in the presence of 5% CO2. OCI-AML3 cells were cultured in MEM Alpha medium containing 20% ​​fetal bovine serum and 1% penicillin / streptomycin at 37°C in the presence of 5% CO2. MOLM-13 cells were seeded at a rate of 1600 cells per well in a 96-well plate. The compound was then added to a final concentration of 7.8–250 nmol / L, followed by the addition of venetoclax, azacitidine, cytarabine, daunorubicin, or gilteritinib to final concentrations of 3.9–125 nmol / L, 313–10000 nmol / L, 7.8–250 nmol / L, 0.78–25 nmol / L, and 3.9–125 nmol / L, respectively, and the cells were cultured for 7 days. OCI-AML3 cells were seeded at a rate of 1600 cells per well in a 96-well plate. The compound was then added to a final concentration of 7.8–250 nmol / L, followed by the addition of venetoclax, azacitidine, cytarabine, or daunorubicin to final concentrations of 156–5000 nmol / L, 313–10000 nmol / L, 313–10000 nmol / L, and 0.78–25 nmol / L, respectively, and the cells were cultured for 7 days. After the culture period, cell viability was calculated using PrestoBlue® Cell Viability Reagent (Invitrogen, A13261). Based on the cell viability, the Combination Index (CI) was calculated using CalcuSyn software (Biosoft). [Table 18] [Table 19] [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26]

[0252] In efficacy evaluation studies of combination therapies for cell proliferation, it was revealed that this compound exhibits excellent cell proliferation inhibitory effects in MOLM-13 cells when used in combination with venetoclax, azacitidine, cytarabine, daunorubicin, or gilteritinib. In OCI-AML3 cells, it was revealed that this compound exhibits excellent cell proliferation inhibitory effects when used in combination with venetoclax, azacitidine, or cytarabine.

[0253] Example 10: Evaluation of combination drug efficacy using tumor-bearing mice transplanted with MOLM-13 cells. The antitumor effects of this compound, venetoclax, and azacitidine were evaluated. The compound was weighed and dissolved in 0.5 w / v% methylcellulose 400 solution to concentrations of 20 mg / mL and 10 mg / mL. Venetoclax was weighed and suspended in a Phosal 50 propylene glycol (60%) / polyethylene glycol-400 (30%) / ethanol (10%) mixture to a concentration of 5 mg / mL. Azacitidine was weighed and dissolved in physiological saline to a concentration of 0.3 mg / mL. 5-week-old NOD.CB17-PrkdcSCID / J mice (female, Jackson Laboratory Japan) were injected with MOLM-13 cells (DSMZ) at a rate of 1 × 10⁻¹⁶. 6 Intradermal transplantation was performed around the ventral region to create a cell / mouse configuration. After confirming the engraftment of MOLM-13 cells 7 days after transplantation, the compound was orally administered to mice once daily for 15 days at a dose of 100 mg / kg or 200 mg / kg, and venetoclax at a dose of 50 mg / kg. Azacitidine was administered intraperitoneally once daily for 5 days at a dose of 3 mg / kg. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the compound administration. Tumor volume was calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) and the following formula. Tumor volume [mm] 3 ]=0.5×(minor diameter [mm]) 2 ×Longest diameter [mm] The control group, which received only the solvent, was compared with the test substance group, and the T / C ratio was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (Tumor volume at the end of administration in the test substance group - Tumor volume at the start of administration in the test substance group) / (Tumor volume at the end of administration in the control group - Tumor volume at the start of administration in the control group) × 100 Table 27 shows the T / C ratio (%) of tumor-bearing mice transplanted with MOLM-13 in each study. [Table 27]

[0254] In a combination drug efficacy evaluation study using tumor-bearing mice, it was revealed that this compound exhibits excellent antitumor effects when used in combination with venetoclax and azacitidine.

[0255] Example 11: Evaluation of combination drug efficacy using tumor-bearing mice transplanted with MOLM-13 cells. The antitumor effects of this compound, cytarabine, and daunorubicin were evaluated. The compound was weighed and dissolved in 0.5 w / v% methylcellulose 400 solution to concentrations of 20 mg / mL and 10 mg / mL. Cytarabine (Cyloside Injection 200 mg / 10 mL, Nippon Shinyaku Co., Ltd.) was diluted with physiological saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to a concentration of 8 mg / mL. Daunorubicin (Daunomycin for Injection 20 mg, Meiji Seika Pharma Co., Ltd.) was dissolved in physiological saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to a concentration of 0.2 mg / mL. 8-week-old NOD.CB17-PrkdcSCID / J mice (female, Jackson Laboratory Japan) were injected with MOLM-13 cells (DSMZ) at a rate of 1 × 10⁻¹⁶. 6 Intradermal transplantation was performed around the ventral region to create a cell / mouse configuration. Six days after transplantation, engraftment of MOLM-13 cells was confirmed, and then the compound was orally administered to mice once daily for 17 days at a dose of 100 mg / kg or 200 mg / kg. Cytarabine was administered intraperitoneally to mice once daily for 5 days at a dose of 80 mg / kg. Daunorubicin was administered intravenously to mice once daily for 3 days at a dose of 1 mg / kg. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the compound administration. Tumor volume was calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) and the following formula. Tumor volume [mm] 3 ]=0.5×(minor diameter [mm]) 2 ×Longest diameter [mm] The control group, which received only the solvent, was compared with the test substance group, and the T / C ratio was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (Tumor volume at the end of administration in the test substance group - Tumor volume at the start of administration in the test substance group) / (Tumor volume at the end of administration in the control group - Tumor volume at the start of administration in the control group) × 100 Table 28 shows the T / C ratio (%) of tumor-bearing mice transplanted with MOLM-13 cells in each study. [Table 28]

[0256] In a combination drug efficacy evaluation study using tumor-bearing mice, it was revealed that this compound exhibits excellent antitumor effects when used in combination with cytarabine and daunorubicin.

[0257] Example 12: Evaluation of combination drug efficacy using tumor-bearing mice transplanted with MOLM-13 cells. The antitumor effects of this compound and gilteritinib were evaluated. The compound was weighed and dissolved in 0.5 w / v% methylcellulose 400 solution to concentrations of 20 mg / mL and 10 mg / mL. Gilteritinib was weighed and suspended in 0.5 w / v% methylcellulose 400 solution to a compound concentration of 3 mg / mL. 5-week-old NOD.CB17-PrkdcSCID / J mice (female, Jackson Laboratory Japan) were injected with MOLM-13 cells (DSMZ) at a rate of 1 × 10⁻¹⁶. 6 Intradermal transplantation was performed around the ventral region to create a cell / mouse configuration. Six days after transplantation, engraftment of MOLM-13 cells was confirmed. Then, the compound was orally administered to mice once daily for 18 days at a dose of 100 mg / kg or 200 mg / kg, and gilteritinib at a dose of 30 mg / kg. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the compound administration. Tumor volume was calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) and the following formula. Tumor volume [mm] 3 ]=0.5×(minor diameter [mm]) 2 ×Longest diameter [mm] The control group, which received only the solvent, was compared with the test substance group, and the T / C ratio was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (Tumor volume at the end of administration in the test substance group - Tumor volume at the start of administration in the test substance group) / (Tumor volume at the end of administration in the control group - Tumor volume at the start of administration in the control group) × 100 Table 29 shows the T / C ratio (%) of tumor-bearing mice transplanted with MOLM-13 cells in each study. [Table 29]

[0258] In a combination drug efficacy evaluation study using tumor-bearing mice, it was revealed that this compound exhibits excellent antitumor effects when used in combination with gilteritinib.

[0259] Example 13: Efficacy evaluation study of combination therapy using tumor-bearing mice transplanted with OCI-AML3 cells. The antitumor effects of this compound, venetoclax, and azacitidine were evaluated. The compound was weighed and dissolved in 0.5 w / v% methylcellulose 400 solution to achieve concentrations of 20 mg / mL and 10 mg / mL. Venetoclax was weighed and suspended in a Phosal 50 propylene glycol (60%) / polyethylene glycol-400 (30%) / ethanol (10%) mixture to achieve a concentration of 5 mg / mL. Azacitidine was weighed and dissolved in physiological saline to achieve a concentration of 0.3 mg / mL. Six-week-old NOD.CB17-PrkdcSCID / J mice (female, Jackson Laboratory Japan) were injected with OCI-AML3 cells (DSMZ) at a rate of 1 × 10⁻¹⁶. 6 Intradermal transplantation was performed around the ventral region to create a cell / mouse configuration. After confirming the engraftment of OCI-AML3 cells 11 days after transplantation, the compound was orally administered to mice once daily for 21 days at a dose of 100 mg / kg or 200 mg / kg, and venetoclax at a dose of 50 mg / kg. Azacitidine was administered intraperitoneally to mice once daily for 5 days at a dose of 3 mg / kg. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the compound administration. Tumor volume was calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) and the following formula. Tumor volume [mm] 3 ]=0.5×(minor diameter [mm]) 2 ×Longest diameter [mm] The control group, which received only the solvent, was compared with the test substance group, and the T / C ratio was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (Tumor volume at the end of administration in the test substance group - Tumor volume at the start of administration in the test substance group) / (Tumor volume at the end of administration in the control group - Tumor volume at the start of administration in the control group) × 100 Table 30 shows the T / C ratio (%) of tumor-bearing mice transplanted with OCI-AML3 cells in each study. [Table 30]

[0260] In a combination drug efficacy evaluation study using tumor-bearing mice, it was revealed that this compound exhibits excellent antitumor effects when used in combination with venetoclax and azacitidine.

[0261] Example 14: Efficacy evaluation study of combination therapy using tumor-bearing mice transplanted with OCI-AML3 cells. The antitumor effects of this compound, cytarabine, and daunorubicin were evaluated. The compound was weighed and dissolved in 0.5 w / v% methylcellulose 400 solution to concentrations of 20 mg / mL and 10 mg / mL. Cytarabine (Cyloside Injection 200 mg / 10 mL, Nippon Shinyaku Co., Ltd.) was diluted with physiological saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to a concentration of 8 mg / mL. Daunorubicin (Daunomycin for Injection 20 mg, Meiji Seika Pharma Co., Ltd.) was dissolved with physiological saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to a concentration of 0.2 mg / mL. 7-week-old NOD.CB17-PrkdcSCID / J mice (female, Jackson Laboratory Japan) were injected with OCI-AML3 cells (DSMZ) at a rate of 1 × 10⁻¹⁶ 6Intradermal transplantation was performed around the ventral region to create a cell / mouse configuration. After confirming the engraftment of OCI-AML3 cells 11 days after transplantation, the compound was orally administered to mice once daily for 21 days at a dose of 100 mg / kg or 200 mg / kg. Cytarabine was administered intraperitoneally to mice once daily for 5 days at a dose of 80 mg / kg. Daunorubicin was administered intravenously to mice once daily for 3 days at a dose of 1 mg / kg. Tumor volume was measured over time from the start of administration to evaluate the tumor volume reduction effect of the compound administration. Tumor volume was calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) and the following formula. Tumor volume [mm] 3 ]=0.5×(minor diameter [mm]) 2 ×Longest diameter [mm] The control group, which received only the solvent, was compared with the test substance group, and the T / C ratio was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (Tumor volume at the end of administration in the test substance group - Tumor volume at the start of administration in the test substance group) / (Tumor volume at the end of administration in the control group - Tumor volume at the start of administration in the control group) × 100 Table 31 shows the T / C ratio (%) of tumor-bearing mice transplanted with OCI-AML3 cells in each study. [Table 31]

[0262] In a combination drug efficacy evaluation study using tumor-bearing mice, it was revealed that this compound exhibits excellent antitumor effects when used in combination with cytarabine and daunorubicin.

[0263] Examples 1 to 8 described above may be carried out at doses of 400 mg / BID, 500 mg / BID, 600 mg / BID, or 700 mg / BID, respectively, when converted to the free form of the compound.

[0264] Reference Example 1: Estimation of Metabolites The metabolites of this compound were identified according to the following protocol.

[0265] (i) Sample information Human plasma: C1D1, C2D1, 80 mg, BID; at pre-death, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours.

[0266] (ii) Sample preparation Plasma samples were pooled for 0–12 hours using the AUC pooling method. A sample (100 μL) was extracted with 3 times the volume of ACN (1:4 MeOH / 0.1% formic acid in ACN) and centrifuged at 13,000 rpm for 5 minutes. The supernatant (350 μL) was transferred to a 96-well plate and dried to 100 μL for analysis.

[0267] (iii) Data processing Full LC / MS scan data was manually processed using Metabolynx to identify metabolites. Ion spectra of the products were obtained separately by UPLC-HRMS / MS, and the structures of the metabolites were assigned by MS / MS data interpretation.

[0268] (iv) Equipment UPLC system: Waters ACQUITY I-Class system (SN's: J14UFL436M, E14BUR170G) Mass analyzer: Waters Xevo G2 XS (SN: YEA499)

[0269] (v) UPLC conditions Mobile phase A: 0.1% formic acid / water Mobile phase B: 0.1% formic acid / ACN Gradient: Time / %B(0 / 5, 0.5 / 5, 8 / 30, 12 / 60, 12.3 / 95, 14.5 / 95, 14.6 / 5, 15 / 5) HPLC column: Phenomenex Kinetex Bi-Phenyl, 2.1 x 100 mm, 2.6 μm Flow rate (mL / min): 0.4 Injection volume (μL): 2 Mass spectral conditions Ionization: Positive ESI Sample cone: 30 V Capillary: 1.2 KV Source offset voltage: 80 V Source temperature: 115℃ Desolvent gas flow rate: 500 (L / Hr) Desolvent removal temperature: 500℃ reagent Water: Fisher, Optima LC / MS grade Acetonitrile: Fisher Optima LC / MS grade Formic acid: Fisher Optima LC / MS grade

[0270] (iv) Results Metabolites A and B of this compound were detected, and their structures are presumed to be as follows. [Table 32]

[0271] The safety of this compound has been confirmed at doses of 40-300 mg BID (Examples 1 and 5), and clinical results suggesting efficacy have been obtained at 60 mg BID in group B, 120 mg BID in group A (Example 3), and 140-300 mg BID in either group A or B (Example 8). Therefore, safety and efficacy can be ensured even at doses of 200 mg BID or higher. Furthermore, it was found that this compound exhibits a significant cell proliferation inhibitory effect when used in combination with venetoclax, azacitidine, cytarabine, daunorubicin, or gilteritinib (Example 9). In particular, in MOLM-13 cells, especially significant tumor growth inhibitory effects were observed with the combinations of "this compound with venetoclax and azacitidine," "this compound with cytarabine and daunorubicin," and "this compound with gilteritinib" (Examples 10-12). In OCI-AML3 cells, especially significant tumor growth inhibitory effects were observed with the combinations of "this compound with venetoclax and azacitidine" and "this compound with cytarabine and daunorubicin" (Examples 13 and 14). [Industrial applicability]

[0272] The pharmaceuticals disclosed herein comprise optically active azabicyclo ring derivatives or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, which may be used as pharmaceuticals for the treatment or prevention of cancer.

Claims

1. A pharmaceutical product for treating or preventing cancer, comprising 5-fluoro-2-[(4-{7-[(1S,3S,4R)-5-methylidene-2-azabicyclo[2.2.2]octane-3-carbonyl]-2,7-diazaspiro[3.5]nonan-2-yl}pyrimidine-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as "free form") or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, characterized in that it is administered orally to the subject.

2. The pharmaceutical product according to claim 1, characterized in that it is administered orally once or twice a day to the target of the pharmaceutical product.

3. The pharmaceutical product according to claim 1, characterized in that it is administered orally twice a day to the target of the pharmaceutical product.

4. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 40 mg when converted to a free form.

5. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 60 mg when converted to a free form.

6. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 80 mg when converted to a free form.

7. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 100 mg when converted to a free form.

8. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 120 mg when converted to a free form.

9. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 140 mg when converted to a free form.

10. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 180 mg when converted to a free form.

11. The pharmaceutical product according to claim 1 or 2, wherein the single dose of the active ingredient is 200 mg when converted to a free form.

12. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 220 mg when converted to a free form.

13. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 240 mg when converted to a free form.

14. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 260 mg when converted to a free form.

15. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 280 mg when converted to a free form.

16. The pharmaceutical product according to claim 1 or 2, wherein the single dose of the active ingredient is 300 mg when converted to a free form.

17. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 320 mg when converted to a free form.

18. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 340 mg when converted to a free form.

19. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 360 mg when converted to a free form.

20. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 380 mg when converted to a free form.

21. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 400 mg when converted to a free form.

22. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 500 mg when converted to a free form.

23. A pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 600 mg when converted to a free form.

24. A pharmaceutical product according to any one of claims 1 to 3, used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is at least one selected from antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-coordinate compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

25. A pharmaceutical product according to any one of claims 1 to 3, which is used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is (1) Venetoclax and azacitidine (2) Cytarabine and daunorubicin, and (3) Gilteritinib A pharmaceutical product, which is at least one of the following.

26. A pharmaceutical product according to any one of claims 1 to 3, administered once daily in combination with gilteritinib.

27. A pharmacopoeia according to any one of claims 1 to 3, administered in combination with 120 mg of gilteritinib.

28. The pharmaceutical product according to any one of claims 1 to 3, wherein the cancer is leukemia, polycythemia vera, malignant lymphoma, B-cell lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

29. A pharmaceutical product according to any one of claims 1 to 3, wherein the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

30. A pharmaceutical product according to any one of claims 1 to 3, wherein the cancer is leukemia.

31. The pharmaceutical product according to claim 30, wherein the leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

32. The pharmaceutical product according to claim 31, wherein the acute leukemia is MLL acute leukemia, MLL partial tandem overlap acute leukemia, or NPM1 mutation acute leukemia.

33. The pharmaceutical product according to claim 31, wherein the acute leukemia is MLL acute leukemia or NPM1 mutation acute leukemia.

34. The pharmaceutical product according to claim 31, wherein the acute leukemia is acute myeloid leukemia with MLL rearrangement.

35. The pharmaceutical product according to claim 31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

36. The pharmaceutical product according to claim 31, wherein the acute leukemia is acute lymphoblastic leukemia with MLL rearrangement.

37. The pharmaceutical product according to claim 31, wherein the acute leukemia is relapsed or refractory acute lymphoblastic leukemia with MLL rearrangement.

38. The pharmaceutical product according to claim 31, wherein the acute leukemia is acute myeloid leukemia accompanied by an NPM1 mutation.

39. The pharmaceutical product according to claim 31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia accompanied by an NPM1 mutation.

40. The pharmaceutical product according to claim 31, wherein the acute leukemia is a leukemia accompanied by high expression of the HOXa gene group or the MEIS gene group.

41. A pharmaceutical product according to any one of claims 1 to 3, wherein the cancer is a tumor accompanied by a p53 gain-of-function mutation.

42. A pharmaceutical product according to any one of claims 1 to 3, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

43. A pharmaceutical product according to any one of claims 1 to 3, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations, FLT gene mutations, and MLL translocations.

44. A pharmaceutical product according to any one of claims 1 to 3, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

45. A pharmaceutical product according to any one of claims 1 to 3, administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

46. A pharmaceutical product according to any one of claims 1 to 3, administered to a subject having at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

47. A pharmaceutical product according to any one of claims 1 to 3, administered to a subject having an NPM1 gene mutation.

48. Subjects with NPM1 gene mutations (1) A step of detecting NPM1 gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the NPM1 gene mutation detected in step (1) is present. A pharmaceutical product according to claim 47, determined based on the above.

49. A pharmaceutical product according to any one of claims 1 to 3, administered to a subject having an MLL translocation.

50. MLL translocation thrombotic subjects (1) A step of detecting MLL translocations in cancer cells obtained from the target, and (2) A step to determine whether or not the MLL translocation detected in step (1) is present. A pharmaceutical product according to claim 49, determined based on the above.

51. A pharmaceutical product according to any one of claims 1 to 3, administered to a subject having an FLT gene mutation.

52. Subjects with FLT gene mutations (1) A step of detecting FLT gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the FLT gene mutation detected in step (1) is present. A pharmaceutical product according to claim 51, determined based on the above.

53. A pharmaceutical product according to any one of claims 1 to 3, administered to a subject having a DNMT3A gene mutation.

54. Subjects with DNMT3A gene mutations (1) A step of detecting DNMT3A gene mutations in cancer cells obtained from the target, and (2) A step to determine whether or not the DNMT3A gene mutation detected in step (1) is present. A pharmaceutical product according to claim 53, determined based on the above.

55. The pharmaceutical product according to any one of claims 1 to 3, wherein the single dose of the active ingredient is 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 200 mg, or 300 mg when converted to a free form.

56. The pharmaceutical product according to claim 3, wherein the single dose of the active ingredient is 200 mg or 300 mg when converted to a free form.

57. The pharmaceutical product according to claim 3, wherein the single dose of the active ingredient is 200 mg when converted to a free form.

58. The pharmaceutical product according to claim 3, wherein the single dose of the active ingredient is 300 mg when converted to a free form.

59. A pharmaceutical product according to any one of claims 56 to 58, used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is at least one selected from antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor agents, antitumor platinum-coordinate compounds, antitumor camptothecin derivatives, antitumor tyrosine kinase inhibitors, antitumor serine / threonine kinase inhibitors, antitumor phospholipid kinase inhibitors, antitumor monoclonal antibodies, interferons, biological response modifiers, hormone preparations, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

60. A pharmaceutical product used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is (1) Venetoclax and azacitidine (2) Cytarabine and daunorubicin, and (3) Gilteritinib A pharmaceutical product, which is at least one of the following.

61. A pharmaceutical product according to any one of claims 56 to 58, administered once daily in combination with gilteritinib.

62. A pharmaceutical product according to any one of claims 56 to 58, administered in combination with 120 mg of gilteritinib.

63. The pharmaceutical product according to any one of claims 56 to 58, wherein the cancer is leukemia, polycythemia vera, malignant lymphoma, B-cell lymphoma, myeloma, brain tumor, head and neck cancer, esophageal cancer, thyroid cancer, small cell lung cancer, non-small cell lung cancer, breast cancer, stomach cancer, gallbladder and bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriocarcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial carcinoma, kidney cancer, renal cell carcinoma, prostate cancer, testicular tumor, testicular germ cell tumor, ovarian germ cell tumor, Wilms' tumor, malignant melanoma, neuroblastoma, osteosarcoma, Ewing's sarcoma, chondrosarcoma, soft tissue sarcoma, or skin cancer.

64. The pharmaceutical product according to any one of claims 56 to 58, wherein the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

65. A pharmaceutical product according to any one of claims 56 to 58, wherein the cancer is leukemia.

66. The pharmaceutical product according to claim 65, wherein the leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

67. The pharmaceutical product according to claim 66, wherein the acute leukemia is MLL acute leukemia, MLL partial tandem overlap acute leukemia, or NPM1 mutation acute leukemia.

68. The pharmaceutical product according to claim 66, wherein the acute leukemia is MLL acute leukemia or NPM1 mutation acute leukemia.

69. The pharmaceutical product according to claim 66, wherein the acute leukemia is acute myeloid leukemia with MLL rearrangement.

70. The pharmaceutical product according to claim 66, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

71. The pharmaceutical product according to claim 66, wherein the acute leukemia is acute lymphoblastic leukemia with MLL rearrangement.

72. The pharmaceutical product according to claim 66, wherein the acute leukemia is relapsed or refractory acute lymphoblastic leukemia with MLL rearrangement.

73. The pharmaceutical product according to claim 66, wherein the acute leukemia is acute myeloid leukemia accompanied by an NPM1 mutation.

74. The pharmaceutical product according to claim 66, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia accompanied by an NPM1 mutation.

75. The pharmaceutical product according to claim 66, wherein the acute leukemia is a leukemia accompanied by high expression of the HOXa gene group or the MEIS gene group.

76. The pharmaceutical product according to claim 63, wherein the cancer is a tumor accompanied by a p53 gain-of-function mutation.

77. The pharmaceutical product of claim 63, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

78. The pharmaceutical product of claim 63, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, FLT gene mutation, and MLL translocation.

79. The pharmaceutical product of claim 63, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

80. The pharmaceutical product according to claim 63, administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

81. The pharmaceutical product according to claim 63, administered to a subject having at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

82. The pharmaceutical product according to claim 63, which is administered to a subject having an NPM1 gene mutation.

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