Cancer therapeutic agents containing optically active azabicyclo 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] 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. [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 U.S. It has been reported that the main fusion partner genes that cause MLL leukemia are AF9, ELL, ENL, AF10, and AF6 in AML, and AF4, ENL, and AF9 in ALL (Non-Patent Document 1).

[0003] It is speculated that MLL fusion proteins fused with fusion partner genes in this way induce unlimited proliferation of undifferentiated hematopoietic cells, leading to leukemia (Non-Patent Document 2). It has been reported that MLL fusion proteins first bind to menin to form a complex. Therefore, it is expected that cancer caused by MLL fusion proteins can be prevented by inhibiting the first step, the binding between MLL fusion proteins and menin (Non-Patent Document 3).

[0004] It has been reported that MLL acts as a coactivator of androgen signaling in prostate cancer, and therefore, small molecule inhibitors targeting the binding between menin and MLL fusion proteins are expected to be useful as therapeutic agents for this cancer (Non-Patent Document 4). It has been reported that menin acts as a coactivator of estrogen signaling in breast cancer, and therefore, small molecule inhibitors targeting the binding between menin and MLL fusion proteins are expected to be useful as therapeutic agents for this cancer (Non-Patent Document 5). It has been reported that menin or MLL is important for tumor growth in Ewing's sarcoma, liver cancer, and p53 gain-of-function mutant cancers, and small molecule inhibitors that target the binding between menin and MLL fusion proteins are expected to be useful as therapeutic agents for these cancers (Non-patent document 6).

[0005] Recently, an optically active azabicyclo derivative that targets inhibition of the 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 [Problem to be solved by the invention]

[0008] The objectives of the present invention are to provide an invention relating to the dosage regimen of an optically active azabicyclo derivative that exhibits excellent anticancer activity by inhibiting the binding between menin and MLL fusion protein, and to provide a useful therapeutic agent and treatment method for tumors with specific gene mutations using said derivative and a concomitant drug.

[0009] More specifically, the present inventors provide a technology related to a medicine 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}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter, also referred to as the "free form" or "the 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 problem]

[0010] As a result of extensive research, the present inventors have found that a pharmaceutical 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}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 together with high safety when administered in a specific dosage regimen. Furthermore, the present inventors have found that the anticancer activity can be further enhanced by using a concomitant drug in addition to the pharmaceutical, and have thus completed the present invention.

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

[0012] [Section 1] A pharmaceutical 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}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as the "free form") or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient, said pharmaceutical being orally administered to a subject.

[0013] [Section 2] Item 1. The pharmaceutical composition according to Item 1, which is orally administered to a subject once a day.

[0014] [Section 3] Item 1. The pharmaceutical composition of Item 1, which is orally administered to a subject twice a day.

[0015] [Section 4] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 40 mg calculated as the free form.

[0016] [Section 5] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 60 mg calculated as the free form.

[0017] [Section 6] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 80 mg calculated as the free form.

[0018] [Section 7] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 100 mg calculated as the free form.

[0019] [Section 8] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 120 mg calculated as the free form.

[0020] [Section 9] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 140 mg calculated as the free form.

[0021] [Section 10] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 180 mg calculated as the free form.

[0022] [Section 11] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 200 mg calculated as the free form.

[0023] [Section 12] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 220 mg calculated as the free form.

[0024] [Section 13] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 240 mg calculated as the free form.

[0025] [Section 14] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 260 mg calculated as the free form.

[0026] [Section 15] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 280 mg calculated as the free form.

[0027] [Section 16] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 300 mg calculated as the free form.

[0028] [Section 17] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 320 mg calculated as the free form.

[0029] [Section 18] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 340 mg calculated as the free form.

[0030] [Section 19] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 360 mg calculated as the free form.

[0031] [Section 20] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 380 mg calculated as the free form.

[0032] [Section 21] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 400 mg calculated as the free form.

[0033] [Section 22] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 500 mg calculated as the free form.

[0034] [Section 23] Item 4. The pharmaceutical of any one of Items 1 to 3, wherein the single dose of the active ingredient is 600 mg calculated as the free form.

[0035] [Section 24] 24. The pharmaceutical according to any one of Items 1 to 23, which is used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is at least one selected from the group consisting of antineoplastic alkylating agents, antineoplastic antimetabolites, antineoplastic antibiotics, plant-derived antineoplastic agents, antineoplastic platinum coordination compounds, antineoplastic camptothecin derivatives, antineoplastic tyrosine kinase inhibitors, antineoplastic serine-threonine kinase inhibitors, antineoplastic phospholipid kinase inhibitors, antineoplastic 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] The pharmaceutical agent according to any one of Items 1 to 23, 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 The pharmaceutical is at least one selected from the group consisting of:

[0037] [Section 26] Item 24. The pharmaceutical agent according to any one of Items 1 to 23, which is administered once daily in combination with gilteritinib.

[0038] [Section 27] Item 24. The pharmaceutical agent of any one of Items 1 to 23, which is administered in combination with 120 mg of gilteritinib.

[0039] [Section 28] 28. The pharmaceutical composition of any one of items 1 to 27, 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, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriothelial carcinoma, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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.

[0040] [Section 29] Item 28. The pharmaceutical agent according to any one of Items 1 to 27, wherein the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

[0041] [Section 30] Item 28. The pharmaceutical agent according to any one of Items 1 to 27, wherein the cancer is leukemia.

[0042] [Section 31] Item 31. The pharmaceutical agent according to any one of Items 28 to 30, wherein the leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

[0043] [Section 32] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is MLL acute leukemia, MLL partial tandem duplication acute leukemia, or NPM1-mutated acute leukemia.

[0044] [Section 33] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is MLL acute leukemia or NPM1-mutated acute leukemia.

[0045] [Section 34] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is acute myeloid leukemia associated with MLL rearrangement.

[0046] [Section 35] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia associated with MLL rearrangement.

[0047] [Section 36] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is acute lymphoblastic leukemia associated with MLL rearrangement.

[0048] [Section 37] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is relapsed or refractory acute lymphoblastic leukemia associated with MLL rearrangement.

[0049] [Section 38] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is acute myeloid leukemia with an NPM1 mutation.

[0050] [Section 39] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia associated with an NPM1 mutation.

[0051] [Section 40] Item 32. The pharmaceutical agent according to Item 31, wherein the acute leukemia is leukemia accompanied by high expression of the HOXa gene group or the MEIS gene group.

[0052] [Section 41] Item 28. The pharmaceutical agent according to any one of Items 1 to 27, wherein the cancer is a tumor associated with a p53 gain-of-function mutation.

[0053] [Section 42] Item 28. The pharmaceutical agent according to any one of Items 1 to 27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

[0054] [Section 43] Item 28. The pharmaceutical agent according to any one of Items 1 to 27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, FLT gene mutation, and MLL translocation.

[0055] [Section 44] Item 28. The pharmaceutical agent according to any one of Items 1 to 27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation and MLL translocation.

[0056] [Section 45] Item 45. The pharmaceutical agent according to any one of Items 1 to 44, which is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

[0057] [Section 46] Item 45. The pharmaceutical agent according to any one of Items 1 to 44, which is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation and MLL translocation.

[0058] [Section 47] Item 45. The pharmaceutical agent according to any one of Items 1 to 44, which is administered to a subject having an NPM1 gene mutation.

[0059] [Section 48] Subjects with NPM1 gene mutations (1) detecting an NPM1 gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the NPM1 gene mutation detected in step (1). Item 47. A medicine as defined in paragraph 47, determined based on the

[0060] [Section 49] Item 45. The pharmaceutical agent according to any one of Items 1 to 44, which is administered to a subject having an MLL translocation.

[0061] [Section 50] Subjects with MLL translocations (1) detecting an MLL translocation in cancer cells obtained from a subject; and (2) determining the presence or absence of the MLL translocation detected in step (1); Item 49. A medicine as defined in claim 49, determined based on the

[0062] [Section 51] Item 45. The pharmaceutical agent according to any one of Items 1 to 44, which is administered to a subject having an FLT gene mutation.

[0063] [Section 52] Subjects with FLT gene mutations (1) detecting a FLT gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the FLT gene mutation detected in step (1). Item 51. A medicine as defined in claim 51, determined based on the

[0064] [Section 53] Item 45. The pharmaceutical agent according to any one of Items 1 to 44, which is administered to a subject having a DNMT3A gene mutation.

[0065] [Section 54] Subjects with DNMT3A gene mutations (1) detecting a DNMT3A gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the DNMT3A gene mutation detected in step (1). Item 53. A medicine as defined in paragraph 53, determined based on the

[0066] The present invention is also as follows. [Section A1] 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}pyrimidin-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 as an active ingredient in the manufacture of a medicament for treating or preventing cancer, to be orally administered to a subject in need of treatment or prevention.

[0067] [Section A2] The use of paragraph A1, wherein the medicament is orally administered to the subject once daily.

[0068] [Section A3] The use of paragraph A1, wherein the medicament is orally administered to the subject twice daily.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0089] [Section A24] The use according to any of Items A1 to A23, wherein the pharmaceutical agent is used in combination with another drug or a pharmaceutically acceptable salt thereof, and the other drug is at least one or more selected from 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, 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 agent 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, wherein the compound is at least one selected from the group consisting of:

[0091] [Section A26] The use of any of paragraphs A1 to A23, wherein the medicament is administered once daily in combination with gilteritinib.

[0092] [Section A27] The use of any of paragraphs A1 to A23, wherein the medicament is administered in combination with 120 mg of gilteritinib.

[0093] [Section A28] The use of any of paragraphs A1 to A27, 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, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriothelial carcinoma, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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.

[0094] [Section A29] The use of any of paragraphs A1 to A27, wherein the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

[0095] [Section A30] The use of any of paragraphs A1 to A27, wherein the cancer is leukemia.

[0096] [Section A31] The use of any of paragraphs A28 to A30, wherein the leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

[0097] [Section A32] Use of paragraph A31 wherein the acute leukemia is MLL acute leukemia, MLL partial tandem duplication acute leukemia, or NPM1 mutated acute leukemia.

[0098] [Section A33] Use of paragraph A31 wherein the acute leukemia is MLL acute leukemia or NPM1 mutated acute leukemia.

[0099] [Section A34] Use of paragraph A31, wherein the acute leukemia is acute myeloid leukemia with MLL rearrangements.

[0100] [Section A35] Use of paragraph A31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

[0101] [Section A36] Use of paragraph A31, wherein the acute leukemia is acute lymphoblastic leukemia with an MLL rearrangement.

[0102] [Section A37] Use of paragraph A31, wherein the acute leukemia is relapsed or refractory acute lymphoblastic leukemia with an MLL rearrangement.

[0103] [Section A38] Use of paragraph A31 wherein the acute leukemia is acute myeloid leukemia with an NPM1 mutation.

[0104] [Section A39] The use of paragraph A31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with an NPM1 mutation.

[0105] [Section A40] Use of paragraph A31, wherein the acute leukemia is a leukemia associated with high expression of the HOXa gene group or the MEIS gene group.

[0106] [Section A41] The use of any of paragraphs A1 to A27, wherein the cancer is a tumor with a p53 gain-of-function mutation.

[0107] [Section A42] The use of any of paragraphs A1 to A27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

[0108] [Section A43] The use of any of paragraphs A1 to A27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, FLT gene mutation, and MLL translocation.

[0109] [Section A44] The use of any of paragraphs A1 to A27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutations and MLL translocations.

[0110] [Section A45] The use according to any one of items A1 to A44, wherein the medicament is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

[0111] [Section A46] The use according to any one of items A1 to A44, wherein the medicament is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation and MLL translocation.

[0112] [Section A47] The use according to any one of items A1 to A44, wherein the medicament is administered to a subject having an NPM1 gene mutation.

[0113] [Section A48] Subjects with NPM1 gene mutations (1) detecting an NPM1 gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the NPM1 gene mutation detected in step (1). The use of paragraph A47, as determined pursuant to

[0114] [Section A49] The use of any of paragraphs A1 to A44, wherein the medicament is administered to a subject having an MLL translocation.

[0115] [Section A50] Subjects with MLL translocations (1) detecting an MLL translocation in cancer cells obtained from a subject; and (2) determining the presence or absence of the MLL translocation detected in step (1); The use of paragraph A49, as determined in accordance with

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

[0117] [Section A52] Subjects with FLT gene mutations (1) detecting a FLT gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the FLT gene mutation detected in step (1). The use of paragraph A51, as determined on the basis of

[0118] [Section A53] The use according to any one of items A1 to A44, wherein the medicament is administered to a subject having a DNMT3A gene mutation.

[0119] [Section A54] Subjects with DNMT3A gene mutations (1) detecting a DNMT3A gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the DNMT3A gene mutation detected in step (1). The use of paragraph A53, as determined on the basis of

[0120] Furthermore, the present invention is as follows. [Section B1] A method for treating or preventing cancer, comprising 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}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as the "free form") or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient to a subject in need of such treatment or prevention.

[0121] [Section B2] The method according to paragraph B1, wherein the active ingredient is orally administered once a day.

[0122] [Section B3] The method according to paragraph B1, wherein the active ingredient is orally administered twice daily.

[0123] [Section B4] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 40 mg in terms of the free form.

[0124] [Section B5] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 60 mg in terms of the free form.

[0125] [Section B6] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 80 mg in terms of the free form.

[0126] [Section B7] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 100 mg calculated as the free form.

[0127] [Section B8] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 120 mg in terms of the free form.

[0128] [Section B9] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 140 mg in terms of the free form.

[0129] [Section B10] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 180 mg in terms of the free form.

[0130] [Section B11] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 200 mg in terms of the free form.

[0131] [Section B12] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 220 mg in terms of the free form.

[0132] [Section B13] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 240 mg in terms of the free form.

[0133] [Section B14] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 260 mg in terms of the free form.

[0134] [Section B15] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 280 mg in terms of the free form.

[0135] [Section B16] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 300 mg in terms of the free form.

[0136] [Section B17] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 320 mg in terms of the free form.

[0137] [Section B18] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 340 mg in terms of the free form.

[0138] [Section B19] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 360 mg in terms of the free form.

[0139] [Section B20] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 380 mg in terms of the free form.

[0140] [Section B21] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 400 mg in terms of the free form.

[0141] [Section B22] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 500 mg in terms of the free form.

[0142] [Section B23] The method according to any one of paragraphs B1 to B3, wherein the single dose of the active ingredient is 600 mg in terms of the free form.

[0143] [Section B24] The method according to any one 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 the group consisting of 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, 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 The method according to any one of items B1 to B23, wherein the method is at least one selected from the following:

[0145] [Section B26] The method of any of paragraphs B1 to B23, wherein the active ingredient is administered once daily in combination with gilteritinib.

[0146] [Section B27] The method of any of paragraphs B1 to B23, wherein the active ingredient is administered in combination with 120 mg of gilteritinib.

[0147] [Section B28] The method of any of paragraphs B1 to B27, 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, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriothelial carcinoma, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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.

[0148] [Section B29] The method of any of paragraphs B1 to B27, wherein the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

[0149] [Section B30] The method of any of paragraphs B1-B27, wherein the cancer is leukemia.

[0150] [Section B31] The method of any of paragraphs B28 to B30, wherein the leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myelogenous leukemia.

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

[0152] [Section B33] The method of paragraph B31 wherein the acute leukemia is MLL acute leukemia or NPM1 mutated acute leukemia.

[0153] [Section B34] The method of paragraph B31 wherein the acute leukemia is acute myeloid leukemia with an MLL rearrangement.

[0154] [Section B35] The method of paragraph B31 wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangements.

[0155] [Section B36] The method of paragraph B31 wherein the acute leukemia is acute lymphoblastic leukemia with an MLL rearrangement.

[0156] [Section B37] The method of paragraph B31 wherein the acute leukemia is relapsed or refractory acute lymphoblastic leukemia with an MLL rearrangement.

[0157] [Section B38] The method of paragraph B31 wherein the acute leukemia is acute myeloid leukemia with an NPM1 mutation.

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

[0159] [Section B40] The method of paragraph B31, wherein the acute leukemia is leukemia associated with high expression of the HOXa gene group or the MEIS gene group.

[0160] [Section B41] The method according to any one of paragraphs B1 to B27, wherein the cancer is a tumor with a p53 gain-of-function mutation.

[0161] [Section B42] The method according to any one of paragraphs B1 to B27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

[0162] [Section B43] The method according to any one of paragraphs B1 to B27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, FLT gene mutation, and MLL translocation.

[0163] [Section B44] The method according to any one of paragraphs B1 to B27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation and MLL translocation.

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

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

[0167] [Section B48] Subjects with NPM1 gene mutations (1) detecting an NPM1 gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the NPM1 gene mutation detected in step (1). The method of paragraph B47 is determined based on the

[0168] [Section B49] The method of any of paragraphs B1-B44, wherein the subject has an MLL translocation.

[0169] [Section B50] Subjects with MLL translocations (1) detecting an MLL translocation in cancer cells obtained from a subject; and (2) determining the presence or absence of the MLL translocation detected in step (1); The method of paragraph B49 is determined based on the

[0170] [Section B51] The method according to any one of Items B1 to B44, wherein the subject has a mutation in the FLT gene.

[0171] [Section B52] Subjects with FLT gene mutations (1) detecting a FLT gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the FLT gene mutation detected in step (1). The method of paragraph B51 is determined based on the

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

[0173] [Section B54] Subjects with DNMT3A gene mutations (1) detecting a DNMT3A gene mutation in cancer cells obtained from a subject; and (2) Step to determine the presence or absence of the DNMT3A gene mutation detected in step (1). The method of paragraph B53 is determined based on the [Effects of the Invention]

[0174] The technology of the present disclosure, by using the compounds of the present disclosure in the dosage regimens provided herein, is useful as a therapeutic and / or preventive agent for 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, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriothelial carcinoma, endometrial cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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, and shows excellent anticancer activity against cancers with specific gene mutations. Although not limited thereto, the presently disclosed technology can be used as various therapeutic and / or preventive agents by administering the compound at a dose that has been confirmed or is expected to be tolerated by humans. Furthermore, the use of the present compound and a concomitant drug can further enhance the anti-cancer effect.

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

[0176] More specifically, the present inventors provide a technology related to a medicine 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 (hereinafter, also referred to as "the present compound"). [Brief explanation of the drawings]

[0177] [Figure 1] Figure 1 shows the study design for the clinical trial with this compound, where the clinical trial is a first-in-human (FIH) study, a Phase 1 / 2 study consisting of a Phase 1 dose-escalation part and a Phase 2 dose-expansion part. [Figure 2] Figure 2 shows a comparison of Cmax between Groups A and B at all doses. [Figure 3] Figure 3 shows a comparison of AUC between Groups A and B at all doses. [Figure 4] 4A to 4D show the pharmacokinetic data at the data cut point in Example 6. [Figure 5] Figure 5 shows the maximum percent change in gene expression of leukemia biomarkers (HOXA9, MEIS1, PBX3) and differentiation biomarkers (CD11b) in bone marrow aspirates from MLLr or NPM1m AML patients for whom baseline and post-baseline samples were collected, across all dose levels and time points combined. [Figure 6]Figures 6A and 6B show the mean maximum percent change in gene expression of leukemia biomarkers (HOXA9, MEIS1, PBX3) and differentiation biomarker (CD11b) in bone marrow aspirates from patients at all dose levels for whom baseline and post-baseline samples were collected. [Figure 7] Figures 7A and 7B show the maximum percent decrease from baseline in bone marrow blasts. [Figure 8] FIG. 8 shows the maximum percent decrease from baseline in bone marrow blasts. DETAILED DESCRIPTION OF THE INVENTION

[0178] Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Thus, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In case of conflict, the present specification (including definitions) will control.

[0179] 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 (the free form of this compound) has the following structure: [ka] In addition, the term "hydrate or solvate thereof" in "the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof" intends a hydrate or solvate of the present compound, and a hydrate or solvate of a pharmaceutically acceptable salt of the present compound.

[0180] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. For example, acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate, and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate. 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-dibenzylethylamine. 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] "Tartrate salt of the compound" means 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 1L(+)-tartrate salt.

[0182] The compounds provided herein can include various stereochemical forms.The compounds of the present invention include not only optical isomers but also diastereomers, for example, mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers that arise as a result of structural asymmetry in certain compounds.Separation of individual isomers or selective synthesis of individual isomers can be achieved by applying various methods known to those skilled in the art.

[0183] The compounds of the present invention also include various hydrates, solvates and crystalline polymorphs. Furthermore, the compounds of the present invention may contain isotopes (e.g., 2 H (or D), 3 H (or T), 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 35 S, 18 F, 125 I, etc.), and these compounds are also included in the compounds of the present invention.

[0184] Furthermore, the scope of the present disclosure also includes prodrugs of the present compounds. In the present disclosure, a prodrug refers to a derivative that is decomposed in vivo by acid hydrolysis or enzymatically to give the present compound. For example, a prodrug can be produced by modifying the amino group of the present compound according to a conventional method. Specific examples include 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 is alkanoyloxymethylamino group, and compounds in which the amino group is hydroxylamine.

[0185] The terms used in this specification are explained below.

[0186] In some embodiments, the subject treated by the above method is a mammal. The compounds can be used in mammals, and the term "mammal" is used herein in its normal biological sense. Thus, specifically, it includes humans, cows, 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 the present compound, if the present compound is obtained in the form of a pharmaceutically acceptable salt, it may be purified as is, or if the compound is obtained in the free form, it may be dissolved or suspended in an appropriate organic solvent, and an acid or base may be added to form a salt by a conventional method.

[0188] In the present invention, a "drug to be used in combination" or a "concomitant drug" refers to an antitumor drug that can be used in combination with the compound of the present invention or can be combined with the compound of the present invention in one pharmaceutical composition. Examples of the "concomitant drug" 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 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. serotoninib, temsirolimus, gefitinib, erlotinib, imatinib, crizotinib, osimertinib, afatinib, dasatinib, bosutinib, vandetanib, sunitinib, axitinib, pazopanib, lenvatinib, lapatinib, nilotinib, ibrutinib, ceritinib, alectinib, tofacitinib, baricitinib, ruxolitinib, and ora These 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, midostaurin, etc. Preferred FLT3 inhibitors are gilteritinib.

[0190] Gilteritinib is preferably administered orally once a day, and the single dose of the active ingredient is preferably 80 mg or 120 mg in terms of the free form, more preferably 120 mg in terms of the free form.

[0191] When the present compound is used in combination with 120 mg of gilteritinib (equivalent to the free form) once a day, a medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is orally administered twice a day, and the single dose of the active ingredient is preferably 140 mg, 200 mg, or 300 mg, equivalent to the free form of the compound of the present invention.

[0192] When the present compound is used in combination with 80 mg of gilteritinib (equivalent to the free form) once a day, a medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is orally administered twice a day, and the single dose of the active ingredient is preferably 100 mg, 120 mg, or 140 mg, equivalent to the free form of the compound of the present invention.

[0193] Examples of concomitant drugs used here include BCL-2 inhibitors, such as venetoclax.

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

[0195] For the 100 mg dose of venetoclax, venetoclax is administered with a 4-day dose titration of 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, and 100 mg on day 4, followed by 100 mg daily on days 5-14 of each 28-day cycle. For the 200 mg dose of venetoclax, venetoclax is administered with a 4-day dose titration of 20 mg on day 1, 50 mg on day 2, 100 mg on day 3, and 200 mg on day 4, followed by 200 mg daily on days 5-14 of each 28-day cycle. For the 400 mg dose of venetoclax, venetoclax is administered with a 3-day dose titration of 100 mg on day 1, 200 mg on day 2, and 400 mg on day 3, followed by 400 mg daily on days 4-14 of each 28-day cycle.

[0196] Examples of epigenetics-related molecule inhibitors include azacytidine.

[0197] Azacitidine is preferably administered intravenously once daily, with a single dose of the active ingredient of 75 mg / m2 in free form. 2 is preferred.

[0198] Azacitidine 75 mg / m 2 will be administered intravenously or subcutaneously once daily on days 1 to 7 of each 28-day cycle.

[0199] This compound was administered once daily at 100 mg venetoclax (free radical equivalent) and once daily at 75 mg / m azacitidine. 2 When used in combination with the compound of the present invention (in terms of the free form), a medicine containing the compound of the present invention or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is orally administered twice a day, and the single dose of the active ingredient is preferably 140 mg, 200 mg, and 300 mg in terms of the compound of the present invention in terms of the free form.

[0200] This compound was administered once daily at 200 mg venetoclax (free radical equivalent) and once daily at 75 mg / m azacitidine. 2When used in combination with the compound of the present invention (in terms of the free form), a medicine containing the compound of the present invention or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is orally administered twice a day, and the single dose of the active ingredient is preferably 140 mg, 200 mg, and 300 mg in terms of the free form of the compound of the present invention.

[0201] This compound was administered once daily at 400 mg venetoclax (free radical equivalent) and once daily at 75 mg / m azacitidine. 2 When used in combination with the compound of the present invention (in terms of the free form), a medicine containing the compound of the present invention or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is orally administered twice a day, and the single dose of the active ingredient 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 of the present compound and the concomitant drug is not limited, and they may be administered simultaneously or at staggered intervals. Alternatively, the present compound and the concomitant drug may be used as a combined preparation. The dose of the concomitant drug can be appropriately selected based on the dose used clinically. The blending ratio of the present compound and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc.

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

[0204] "OCI-AML3 cells" are a human acute myeloid leukemia cell line that harbors NPM1 and DNMT3A mutations.

[0205] The frequency of oral administration of a medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may be 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 of free form" means that a single dose of an active ingredient is administered that is equal to the number of moles of free form in the indicated weight (XXX mg). For example, the dose of the tartrate salt of the present compound is calculated by the following formula: [Dose of tartrate of this compound] = [Dose of this compound (free form)] × [Molecular weight of tartrate of this compound (740.83)] / [Molecular weight of this compound (free form) (590.74)] For example, "20 mg converted to the free form" corresponds to 25 mg of the tartrate salt of this compound, and is calculated using the following formula. [Dose of the tartrate salt of this compound] = 20 mg × [molecular weight of the tartrate salt of this compound (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 the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a medicine is 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, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 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, 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. Ranges between any two of these selected dosage amounts are also encompassed.

[0208] The single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in the medicament 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, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 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, 1 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 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, and ranges between any two of these selected dosage amounts are also encompassed.

[0209] A single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a medicament, calculated as the free form of the present compound, is more 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 740 mg. Also encompassed are ranges between any two of these selected dosage amounts.

[0210] A single oral dose of the present compound or its pharmaceutically acceptable salt, or its hydrate or solvate in the medicament, calculated as the free form of the present compound, 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. Ranges between any two of these doses are also encompassed.

[0211] The single oral dose of the present compound or its pharmaceutically acceptable salt, or its hydrate or solvate in the pharmaceutical preparation is most 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, and 500 mg, calculated as the free form of the present compound. Ranges between any two of these doses are also encompassed.

[0212] In another preferred embodiment, a single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a pharmaceutical composition is, in terms of the free form of the present compound, 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. Ranges between any two of these doses are also encompassed.

[0213] In another preferred embodiment, a single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a pharmaceutical preparation is, in terms of the free form of the present compound, 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. Ranges between any two of these doses are also encompassed.

[0214] In another more preferred embodiment, the single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in the pharmaceutical preparation is 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, and 500 mg, calculated as the free form of the present compound. Ranges between any two of these doses are also encompassed.

[0215] In another more preferred embodiment, the single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in the pharmaceutical preparation is 360 mg, 380 mg, 400 mg, 420 mg, or 440 mg, calculated as the free form of the present compound. Also included are ranges between these two arbitrarily selected doses.

[0216] In another most preferred embodiment, the single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in the pharmaceutical preparation is 300 mg, calculated as the free form of the present compound.

[0217] In another most preferred embodiment, the single oral dose of the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof in a pharmaceutical composition is, in terms of the free form of the present compound, An example is 400mg.

[0218] A medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered twice a day, and the single dose of the active ingredient, calculated as 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. The single dose also encompasses a range between these two arbitrarily selected doses.

[0219] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered twice a day, and the single dose of the active ingredient, calculated as 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, or 400 mg. The single dose also encompasses a range between these two arbitrarily selected doses.

[0220] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered twice a day, and the single dose of the active ingredient, calculated as the free form of the present 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 encompasses a range between these two arbitrarily selected doses.

[0221] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered twice a day, and the single dose of the active ingredient, calculated as the free form of the present compound, is most preferably 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, or 500 mg. The single dose also encompasses a range between these two arbitrarily selected doses.

[0222] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered twice a day, and the single dose of the active ingredient, calculated as the free form of the present compound, is preferably 360 mg, 380 mg, 400 mg, 420 mg, or 440 mg in another preferred embodiment. The single dose also includes a range between these two arbitrarily selected doses.

[0223] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably administered orally twice a day, and in another more preferred embodiment, the single dose of the active ingredient is 300 mg, calculated as the free form of the present compound.

[0224] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered twice a day, and the single dose of the active ingredient, calculated as the free form of the present compound, is, in another embodiment, 400 mg.

[0225] The present compound or its pharmaceutically acceptable salt, or its hydrate or solvate can be orally administered directly or as an appropriate formulation. Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, patches, and poultices. The formulations are produced by known methods using pharmaceutically acceptable additives.

[0226] Depending on the purpose, additives that can be used include excipients, disintegrants, binders, fluidizing agents, lubricants, coating agents, solubilizers, solubilizers, thickeners, dispersants, stabilizers, sweeteners, flavorings, etc. Examples of additives that can be used here include lactose, lactose hydrate, 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 oxide, light anhydrous silicic acid, and talc.

[0227] One embodiment of the above formulation is formulation A containing the following ingredients. (i) Tartrate of the Compound (ii) D-mannitol (iii) Partially pregelatinized starch (iv) Croscarmellose sodium (v) hydroxypropyl cellulose, and (vi) sodium stearyl fumarate

[0228] One embodiment of the above formulation is formulation B containing the following ingredients. (i) Tartrate of the Compound (ii) Lactose hydrate (iii) Microcrystalline cellulose (iv) Carmellose (v) light anhydrous silicic acid, and (vi) sodium stearyl fumarate

[0229] Formulation A or Formulation B described above can be used in the following examples. [Example]

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

[0231] (1) Clinical trial design considerations This clinical trial using this compound is a Phase 1 / 2 FIH study, including a Phase 1 dose-escalation part and a Phase 2 dose-expansion part. The study design is shown in Figure 1. Initially, only tentative dose levels of 40, 60, 80, 100, 120, and 140 mg BID were planned, but because there are currently no safety concerns, tentative dose levels (180, 240, 320, 420, 560, and 740 mg BID) have been added to the study. In the dose-escalation portion, subjects were enrolled into different treatment arms depending on whether they were taking concomitant azole antifungals that are strong or moderate CYP3A4 / 5 inhibitors, as follows: Group A: Subjects who have not received an azole antifungal agent within 7 days (or within 21 days in the case of isavuconazole) prior to the first administration of this compound Group B: Subjects receiving antifungal prophylaxis with posaconazole, voriconazole, or fluconazole at the time of enrollment The safety of each dose level was evaluated by an SRC comprised of all participating investigators and selected study team members from the sponsor. The dose recommendations in the BLRM method were used as a guideline and were integrated with a clinical evaluation of toxicity information and a review of other available data, including safety, PK, pharmacodynamic, and laboratory data.

[0232] (2) Subject enrollment At the time of data cutoff, a total of 14 subjects were enrolled in the Phase 1 dose-escalation part of this study at dose levels of 40 mg BID (N=2), 80 mg BID (N=4), 100 mg BID (N=2), and 120 mg BID (N=6) in Group A, and a total of 10 subjects were enrolled at dose levels of 40 mg BID (N=4) and 60 mg BID (N=6) in Group B (Table 1). Upon completion of dose-limiting toxicity (DLT) assessment for each cohort, the next dose was determined by the SRC based on DLT and other available data, including safety, PK, pharmacodynamic, and laboratory data, guided by recommendations from a Bayesian logistic regression model (BLRM). When the Safety Review Committee (SRC) determined that the 80 mg BID cohort in Arm A was safe based on the evaluation of two subjects, the SRC decided to start Arm B at 40 mg BID. Importantly, at the start of Arm B, enrollment was limited to patients with specific genetic abnormalities in both Arms A and B. Therefore, the SRC decided to continue Arm A at 80 mg BID and start Arm B at 40 mg BID for patients with specific genetic abnormalities. These specific genetic abnormalities are genetic abnormalities, such as MLLr and NPM1m, that indicate the compound may be effective. Narrowing the population to subjects more likely to respond to the compound allows for a more accurate assessment of potential toxicity in the target population. Dose escalation was determined after all subjects in each dose-level cohort had completed at least Cycle 1. All available data, along with BLRM predictions of the probability of toxicity at the potential next dose level, were presented, and the SRC then determined the dose for the next cohort. [Table 1]

[0233] Example 1: Safety evaluation of the present compound At the time of data cutoff, no DLTs occurred among the 24 subjects enrolled in this clinical trial (Table 2). All 24 subjects experienced at least one treatment-emergent adverse event (TEAE). The proportion of subjects who experienced grade 3 or grade 4 TEAEs was similar: 5 (35.7%) and 4 (28.6%) in Group A, and 3 (30.0%) and 2 (20.0%) in Group B. Three subjects in Group B experienced treatment-related grade 3 TEAEs (increased aspartate aminotransferase, leukocytosis, and hypertriglyceridemia), all of which were transient and resolved. Serious TEAEs were reported in 9 (64.3%) subjects in Group A and 6 (60.0%) in Group B. Only one serious TEAE was considered treatment-related by the investigator (two cases of differentiation syndrome confirmed in one subject in Group A). Details of serious TEAEs are shown in Table 6. During the study, 5 patients (35.7%) in Group A and 3 patients (30.0%) in Group B died due to TEAEs, all of which were ruled out as being related to the treatment. Additionally, 2 of 5 patients in Group A and 2 of 3 patients in Group B died due to progression of the disease under study (see Table 5). 1 patient in Group A and 2 patients in Group B experienced a TEAE related to the compound that led to treatment interruption. No treatment-related TEAEs leading to treatment discontinuation or dose reduction were reported at the time. Adverse events (AEs) observed to date were consistent with those observed in patients with relapsed / refractory AML on other therapies (e.g., anemia, hypokalemia, nausea, fatigue, headache, etc.). The AE profile was generally consistent between Groups A and B. Most TEAEs considered to be related to the compound were grade 1 or grade 2. Table 4 shows TEAEs occurring in 20% or more of patients in either Group A or B, regardless of causality to the compound, and all TEAEs considered to be related to the 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 complications commonly observed in AML patients, and all were determined to be unrelated to the compound, except for two SAEs of differentiation syndrome that occurred in one patient (assessed by the investigator as related to the compound). The patient with potential differentiation syndrome was a 63-year-old woman with TP53 mutation-positive AML. She was enrolled in Arm A and received 80 mg twice daily. The diagnosis of differentiation syndrome was based on the observation of an increase in white blood cell count with a decrease in blast percentage associated with the administration of the compound late in Cycle 1 and early in Cycle 2. However, the evaluation of this patient was complicated by AML disease progression (bone marrow blasts increased from 11% at baseline to 53% on Day 28 of Cycle 1), transfusion adverse reactions, and pneumonia due to a potential fungal infection. Although the differentiation syndrome resolved, the patient died shortly thereafter from intracranial hemorrhage secondary to AML disease progression (the platelet count was 20,000 / μL the day before the onset of intracranial hemorrhage, suggesting AML disease progression). The investigator noted that differentiation syndrome was not the cause of the subject's death. To date, no other cases have developed differentiation syndrome, even in patients with MLLr or NPM1m positivity. Fatal SAEs occurred in eight patients (five in Group A and three in Group B), all of which were assessed by the investigator and sponsor as unrelated to the compound and likely secondary to AML disease progression or AML-related complications. Overall, the types and frequencies of TEAEs observed in Groups A and B were similar. The only SAE considered to be related was differentiation syndrome, which occurred in one patient in Group A, as described above. Other SAEs, including those resulting in death, were related to complications due to AML recurrence or disease progression. At this time, no safety findings specific to subjects in Group B were observed, and no clear differences were observed in the safety profile of this compound between Groups A and B. [Table 2] TIFF2026502548000004.tif146166 [Table 3] TIFF2026502548000006.tif230158 [Table 4] [Table 5] TIFF2026502548000009.tif181166

[0234] Example 2: Pharmacokinetic evaluation of the compound In this study of this compound, PK samples were collected from up to 24 subjects dosed at 40, 80, 100, and 120 mg BID in Group A and 40 and 60 mg BID in Group B (Table 6). Large inter-patient variability in preliminary PK was observed. In Group A, a dose-dependent trend in increasing exposure was observed at the dose levels evaluated so far (40 mg, 80 mg, 100 mg, and 120 mg BID). In Group B, current data for assessing dose-dependent drug exposure were from 40 mg to 60 mg BID. mean plasma t 1 / 2 (where available) ranged from 2.82 to 5.64 hours in Group A and 2.61 to 7.29 hours in Group B. Absorption was relatively rapid, with T max Minimal or no drug accumulation was observed with repeated dosing when comparing exposure on Day 1 of Cycle 2 with exposure on Day 1 of Cycle 1. The effect of concomitant administration of azole antifungals on the exposure of this compound was evaluated. As shown in Table 6, the exposure of Group B at 40 mg BID (C max and AUC last) was similar to that observed in Arm A at 40 mg BID, and Arm B at 60 mg BID was closer to that observed in Arm A at 40 mg BID. The high variability in exposure and small sample sizes at each dose level limited the ability to draw conclusions at this point in the study. However, comparison of Arms A and B with the available PK data to date suggests that the azole does not have a large or dramatic effect on the exposure of this compound. [Table 6]

[0235] Example 3: Evaluation of efficacy of the present compound In this study, clinical signals were observed, including reduction and normalization of bone marrow blasts, disappearance of peripheral blood blasts, and responses based on the European LeukemiaNet 2017 Response Criteria. One MLLr-positive patient enrolled in Arm A at 120 mg BID achieved morphologic leukemia-free status (MLFS), while one MLLr-positive patient enrolled in Arm B at 60 mg BID achieved complete remission with partial hematologic recovery (CRh) and complete remission with incomplete hematologic recovery (CRi). 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 Enrollment (1) As of the data cutoff date, a total of 43 patients with acute leukemia were enrolled in the phase 1 dose-escalation part of this study at dose levels of 40–200 mg BID (n=23) in Arm A and 40–200 mg BID (n=20) in Arm B. Baseline characteristics are shown in Table 7. [Table 7] TIFF2026502548000012.tif57156

[0237] (2) As of the data cutoff date, a total of 57 patients with acute leukemia were enrolled in the phase 1 dose-escalation part of this study at dose levels of 40–300 mg BID (n=27) in Arm A and 40–300 mg BID (n=30) in Arm B. Baseline characteristics are shown in Table 8. [Table 8] TIFF2026502548000014.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 prior therapies was 3 (range, 1-9). Twenty-three patients (28.4%) had received prior allogeneic stem cell transplantation, 63 patients (77.8%) had received prior venetoclax, and 5 patients (6.2%) had received prior 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 present compound (1) No DLTs were observed at any dose level between 40 and 200 mg. The majority of TEAEs were Grade 1 or Grade 2 and were managed with supportive care. No drug-related AEs led to permanent discontinuation of treatment, and no treatment-related deaths were observed in this study. TEAEs in 20% or more patients, regardless of causality, are tabulated in Table 9, and all TEAEs associated with the compound in two or more patients are tabulated in Table 10. No treatment-related QT interval prolongation events were reported. One case of suspected differentiation syndrome has been reported in association with the compounds of the present invention in a patient with a TP-53 mutation, but no cases of suspected differentiation syndrome have been reported in patients with MLLr or NPM1m. [Table 9] [Table 10]

[0240] The above test (1) was further continued and the following results were obtained. (2) No DLTs were observed at any dose level between 40 and 300 mg BID. TEAEs assessed as compound-related in ≥10% of patients were vomiting (15.5%) and nausea (12.1%). Grade >3 TEAEs assessed as unrelated to the study drug included pneumonia (17.2%), sepsis and febrile neutropenia (15.5% each), anemia (13.8%), and decreased platelet count (12.1%). Possible differentiation syndrome (DS) was documented in three patients. Two patients discontinued treatment, but no patients discontinued, and no deaths were attributed to DS. One patient reported asymptomatic grade 3 QT prolongation in the presence of other QT-prolonging drugs, which required temporary interruption and subsequent dose reduction without recurrence.

[0241] (3) No DLTs were observed in 57 patients at any dose level between 40 and 300 mg. No drug-related AEs led to permanent discontinuation of treatment, and no treatment-related deaths were observed in this study. Table 11 lists treatment-related TEAEs in ≥10% of patients. Tables 12 and 13 show non-hematological or hematological TEAEs in ≥10% of patients, regardless of causality. Table 14 lists non-hematological laboratory changes in ≥10% of patients. Differentiation syndrome (DS) was reported in three patients, none of which led to permanent discontinuation of treatment. No DS prophylaxis was used at the start of treatment. Some patients showed hematologic differentiation without significant systemic symptoms, and these were not evaluated as DS. [Table 11] [Table 12] [Table 13] [Table 14]

[0242] (4) At the data cutoff, the dose level was increased from 40 mg BID to 300 mg BID (n=81), with no DLTs. TEAEs assessed as compound-related in ≥10% of patients were vomiting (14.8%) and nausea (12.3%). Grade 3 nausea and vomiting was reported in one patient. TEAEs occurring in ≥20% of patients, regardless of relatedness, included nausea (37.0%), vomiting (29.6%), febrile neutropenia (22.2%), decreased appetite, diarrhea, and hypokalemia (21.0% each). No grade ≥3 QTc prolongation was reported in association with the compound. Grade 1 QTc prolongation was reported in two patients (2.4%), and grade 2 QTc prolongation was reported in two patients (2.4%). Possible differentiation syndrome was reported in nine patients (11.1%).

[0243] Example 6: Pharmacokinetic evaluation of the present compound (1) In this study, PK samples were collected from up to 42 patients receiving doses of 40, 80, 100, 120, 140, and 200 mg BID in Group A and 40, 60, 100, and 200 mg BID in Group B (Table 15). The mean apparent half-lives ranged from approximately 2 to 5 hours in Group A and approximately 3 to 7 hours in Group B. Absorption was rapid, reaching maximum concentrations within 2 hours after administration. A dose-dependent increase in exposure was observed, with little drug accumulation with repeated dosing. Data to date suggest that azoles do not significantly affect the exposure of this compound (Figures 2 and 3). [Table 15]

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

[0245] (3) Figures 4A to 4D show the pharmacokinetic data at the data cutoff time. Mean t 1 / 2 The mean pharmacokinetic (PDR) response time ranged from 2 to 6 hours in group A (without azole) and from 3 to 7 hours in group B (with azole). A dose-related increase in exposure was observed at doses of 140 mg BID and above, with little accumulation with repeated dosing. No significant drug-drug interactions (>2-fold) with azoles were identified in the pharmacokinetic data to date.

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

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

[0248] Example 8: Clinical activity evaluation of the compound (1) Of the 43 patients enrolled, 17 had MLLr and 9 had NPM1m, and 19 were evaluable at the time of data extraction. Five responded to ELN2017 (Figure 7A). In Group B, 200 mg BID, four evaluable patients had MLLr or NPM1m (n = 1 and 3, respectively), with one achieving CRh / CRi, one achieving CRi, and one achieving MLFS. Two additional MLLr patients also achieved responses (CRh / CRi and MLFS) with ELN2017 at lower dose levels.

[0249] The above test (1) was further continued and the following results were obtained. (2) Of the 58 patients, 26 had MLLr and 14 had NPM1m. Among all patients (n=22) with MLLr or NPM1m treated at 140 mg BID or higher who had completed one cycle and were menin inhibitor-naïve, the ORR (CR+CRi+MLFS) was 45% (10 / 22), and the CR+CRh rate was 23% (5 / 22). Across all dose levels (40 mg BID to 300 mg BID) in menin inhibitor-naïve patients with MLLr or NPM1m who completed one cycle, the ORR and CR+CRh rates were 32% (12 / 38) and 16% (6 / 38), respectively (Figure 7B).

[0250] (3) Bone marrow blast reduction was observed in patients with MLLr or NPM1m (Figure 8). Among patients enrolled in ≥140 mg BID, 12 MLLr patients and 9 NPM1m patients were evaluable at the data cutoff. Table 17 shows response according to the ELN2017 criteria. In MLLr patients, CR+CRh was 17% (2 / 12 patients), and the objective response rate (ORR; CR+CRh+CRi+MLFS) was 67% (8 / 12 patients). In NPM1m patients, CR+CRh was 33% (3 / 9 patients), and the ORR was 44% (4 / 9 patients). [Table 17] (4) At the time of data cutoff, 35 patients with MLLr or NPM1m who had not previously received a menin inhibitor were treated with an effective dose of the compound (≥140 mg BID in Arm A or Arm B). Among 22 patients with MLLr (20 AML, 2 ALL), 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). Among 13 patients with NPM1m AML, 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 a CR. Overall, the median time to objective response and time to CR+CRh were 1.0 month and 1.0 month, respectively.

[0251] Example 9: Evaluation test of combined drug efficacy on cell proliferation MOLM-13 and OCI-AML3 cells were obtained from DSMZ (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH). MOLM-13 cells were cultured in RPMI 1640 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 in a 96-well plate at 1,600 cells per well, and the compound was added to a final concentration of 7.8 to 250 nmol / L. Venetoclax, azacitidine, cytarabine, daunorubicin, or gilteritinib were then added to final concentrations of 3.9 to 125 nmol / L, 313 to 10,000 nmol / L, 7.8 to 250 nmol / L, 0.78 to 25 nmol / L, or 3.9 to 125 nmol / L, respectively, and the cells were cultured for 7 days. OCI-AML3 cells were seeded in a 96-well plate at 1,600 cells per well, and the compound was added to a final concentration of 7.8 to 250 nmol / L. Venetoclax, azacitidine, cytarabine, or daunorubicin was then added to a final concentration of 156 to 5,000 nmol / L, 313 to 10,000 nmol / L, 313 to 10,000 nmol / L, or 0.78 to 25 nmol / L, respectively, and the cells were cultured for 7 days. After the culture was completed, 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 a combination drug efficacy evaluation study on cell proliferation, this compound demonstrated superior cell proliferation inhibitory effects in combination with venetoclax, azacitidine, cytarabine, daunorubicin, or gilteritinib in MOLM-13 cells.In OCI-AML3 cells, this compound demonstrated superior cell proliferation inhibitory effects in combination with venetoclax, azacitidine, or cytarabine.

[0253] Example 10: Evaluation of combined 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 compound concentrations of 20 mg / mL and 10 mg / mL. Venetoclax was weighed and suspended in Phosal 50 propylene glycol (60%) / polyethylene glycol-400 (30%) / ethanol (10%) mixed solution to compound concentrations of 5 mg / mL. Azacitidine was weighed and dissolved in saline to compound concentrations of 0.3 mg / mL. Five-week-old NOD.CB17-Prkdc SCID / J mice (female, Jackson Laboratory Japan) were inoculated with 1 × 10 MOLM-13 cells (DSMZ). 6 The tumors were intradermally transplanted into the ventral region of the mice at a concentration of 100 or 200 mg / kg, with venetoclax administered at a dose of 50 mg / kg once daily for 15 days. Azacitidine was administered intraperitoneally at a dose of 3 mg / kg once daily for 5 days. Tumor volume was measured over time from the start of administration, and the effect of compound administration on tumor volume reduction was evaluated. Tumor volume was calculated using the following formula, using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm 3 ]=0.5×(minor diameter [mm]) 2 × major diameter [mm] The control group administered with only the solvent was compared with the test substance administration group, and the T / C was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (tumor volume at the end of administration in the test substance administration group - tumor volume at the start of administration in the test substance administration group) / (tumor volume at the end of administration in the control administration group - tumor volume at the start of administration in the control administration group) × 100 Table 27 shows the T / C (%) of tumor-bearing mice transplanted with MOLM-13 cells in each test. [Table 27]

[0254] In a combination efficacy evaluation test using tumor-bearing mice, it was revealed that this compound showed excellent antitumor effects when combined with venetoclax and azacitidine.

[0255] Example 11: Evaluation of combined 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 compound concentrations of 20 mg / mL and 10 mg / mL. Cytarabine (Kiloside Injection 200 mg / 10 mL, Nippon Shinyaku Co., Ltd.) was diluted with saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to 8 mg / mL. Daunorubicin (Daunomycin for Intravenous Injection 20 mg, Meiji Seika Pharma Co., Ltd.) was dissolved in saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to 0.2 mg / mL. 1 × 10 MOLM-13 cells (DSMZ) were inoculated into 8-week-old NOD.CB17-Prkdc SCID / J mice (female, Jackson Laboratory Japan). 6 The tumors were intradermally transplanted into the ventral region at a concentration of 100 or 200 mg / kg cells per mouse. Six days after transplantation, MOLM-13 cell engraftment was confirmed, and the compound was then orally administered to the mice at a dose of 100 or 200 mg / kg once daily for 17 days. Cytarabine was administered intraperitoneally to the mice at a dose of 80 mg / kg once daily for 5 days. Daunorubicin was administered intravenously to the mice at a dose of 1 mg / kg once daily for 3 days. Tumor volume was measured over time from the start of administration, and the effect of compound administration on tumor volume reduction was evaluated. Tumor volume was calculated using the following formula, using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm 3 ]=0.5×(minor diameter [mm]) 2 × major diameter [mm] The control group administered with only the solvent was compared with the test substance administration group, and the T / C was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (tumor volume at the end of administration in the test substance administration group - tumor volume at the start of administration in the test substance administration group) / (tumor volume at the end of administration in the control administration group - tumor volume at the start of administration in the control administration group) × 100 Table 28 shows the T / C (%) of tumor-bearing mice transplanted with MOLM-13 cells in each test. [Table 28]

[0256] In a combined efficacy evaluation test using tumor-bearing mice, it was revealed that this compound exhibited excellent antitumor effects when combined with cytarabine and daunorubicin.

[0257] Example 12: Evaluation of combined 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 give compound concentrations of 20 mg / mL and 10 mg / mL. Gilteritinib was weighed and suspended in 0.5 w / v% methylcellulose 400 solution to give a compound concentration of 3 mg / mL. Five-week-old NOD.CB17-Prkdc SCID / J mice (female, Jackson Laboratory Japan) were inoculated with 1 × 10 MOLM-13 cells (DSMZ). 6 The cells were intradermally transplanted into the ventral region of the mice so that MOLM-13 cells per mouse were used. Six days after transplantation, the engraftment of MOLM-13 cells was confirmed. The compound was then orally administered to the mice at a dose of 100 mg / kg or 200 mg / kg, and gilteritinib at a dose of 30 mg / kg, once daily for 18 days. The tumor volume was measured over time from the start of administration, and the effect of compound administration on tumor volume reduction was evaluated. Tumor volume was calculated using the following formula, using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm 3 ]=0.5×(minor diameter [mm]) 2 × major diameter [mm] The control group administered with only the solvent was compared with the test substance administration group, and the T / C was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (tumor volume at the end of administration in the test substance administration group - tumor volume at the start of administration in the test substance administration group) / (tumor volume at the end of administration in the control administration group - tumor volume at the start of administration in the control administration group) × 100 Table 29 shows the T / C (%) of tumor-bearing mice transplanted with MOLM-13 cells in each test. [Table 29]

[0258] In a combined efficacy evaluation test using tumor-bearing mice, it was revealed that this compound exhibited excellent antitumor effects when combined with gilteritinib.

[0259] Example 13: Evaluation of combined drug efficacy 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 compound concentrations of 20 mg / mL and 10 mg / mL. Venetoclax was weighed and suspended in Phosal 50 propylene glycol (60%) / polyethylene glycol-400 (30%) / ethanol (10%) mixed solution to compound concentrations of 5 mg / mL. Azacitidine was weighed and dissolved in saline to compound concentrations of 0.3 mg / mL. Six-week-old NOD.CB17-Prkdc SCID / J mice (female, Jackson Laboratory Japan) were inoculated with 1 × 10 OCI-AML3 cells (DSMZ). 6 The tumors were intradermally transplanted into the ventral region at 100 mg / kg or 200 mg / kg, with venetoclax at 50 mg / kg, once daily for 21 days. Azacitidine was intraperitoneally administered at 3 mg / kg once daily for 5 days. Tumor volume was measured over time from the start of administration, and the effect of compound administration on tumor volume reduction was evaluated. Tumor volume was calculated using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo) using the following formula: Tumor volume [mm 3 ]=0.5×(minor diameter [mm]) 2 × major diameter [mm] The control group administered with only the solvent was compared with the test substance administration group, and the T / C was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (tumor volume at the end of administration in the test substance administration group - tumor volume at the start of administration in the test substance administration group) / (tumor volume at the end of administration in the control administration group - tumor volume at the start of administration in the control administration group) × 100 Table 30 shows the T / C (%) of tumor-bearing mice transplanted with OCI-AML3 cells in each test. [Table 30]

[0260] In a combination efficacy evaluation test using tumor-bearing mice, it was revealed that this compound showed excellent antitumor effects when combined with venetoclax and azacitidine.

[0261] Example 14: Evaluation of combined drug efficacy 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 compound concentrations of 20 mg / mL and 10 mg / mL. Cytarabine (Kiloside Injection 200 mg / 10 mL, Nippon Shinyaku Co., Ltd.) was diluted with saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to 8 mg / mL. Daunorubicin (Daunomycin for Intravenous Injection 20 mg, Meiji Seika Pharma Co., Ltd.) was dissolved in saline (Otsuka Saline Injection, Otsuka Pharmaceutical Factory Co., Ltd.) to 0.2 mg / mL. Seven-week-old NOD.CB17-Prkdc SCID / J mice (female, Jackson Laboratory Japan) were inoculated with 1 × 10 OCI-AML3 cells (DSMZ). 6The tumors were intradermally transplanted into the ventral region at a ratio of 100 to 200 mg / kg per mouse. Eleven days after transplantation, engraftment of OCI-AML3 cells was confirmed. The compounds were then orally administered to the mice at a dose of 100 mg / kg or 200 mg / kg once daily for 21 days. Cytarabine was administered intraperitoneally to the mice at a dose of 80 mg / kg once daily for 5 days. Daunorubicin was administered intravenously to the mice at a dose of 1 mg / kg once daily for 3 days. Tumor volume was measured over time from the start of administration, and the effect of compound administration on tumor volume reduction was evaluated. Tumor volume was calculated using the following formula, using the short and long diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm 3 ]=0.5×(minor diameter [mm]) 2 × major diameter [mm] The control group administered with only the solvent was compared with the test substance administration group, and the T / C was calculated using the following formula to evaluate the antitumor effect. T / C (%) = (tumor volume at the end of administration in the test substance administration group - tumor volume at the start of administration in the test substance administration group) / (tumor volume at the end of administration in the control administration group - tumor volume at the start of administration in the control administration group) × 100 Table 31 shows the T / C (%) of tumor-bearing mice transplanted with OCI-AML3 cells in each test. [Table 31]

[0262] In a combined efficacy evaluation test using tumor-bearing mice, it was revealed that this compound exhibited excellent antitumor effects when combined with cytarabine and daunorubicin.

[0263] The above Examples 1 to 8 may be carried out at a dose of 400 mg / BID, 500 mg / BID, 600 mg / BID, or 700 mg / BID calculated as the free form of the present compound.

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

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

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

[0267] (iii) Data processing LC / MS full scan data were manually processed using Metabolynx to identify metabolites, and product ion spectra were acquired by separate UPLC-HRMS / MS runs, and metabolite structures were assigned by MS / MS data interpretation.

[0268] (iv) Equipment UPLC system: Waters ACQUITY I-Class system (SN's: J14UFL436M, E14BUR170G) Mass spectrometer: 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 spectrum conditions Ionization: Positive ESI Sample cone: 30 V Capillary: 1.2 KV Source offset voltage: 80 V Source temperature: 115℃ Desolvation gas flow rate: 500 (L / Hr) Desolvation 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 to 300 mg BID (Examples 1 and 5), and clinical results suggesting efficacy have been obtained at doses of 60 mg BID in Group B, 120 mg BID in Group A (Example 3), and 140 to 300 mg BID in Group A or Group B (Example 8). Therefore, safety and efficacy can be ensured even at doses of 200 mg BID or higher. Furthermore, it has been found that this compound exhibits significant cell proliferation inhibitory effects when used in combination with venetoclax, azacitidine, cytarabine, daunorubicin, or gilteritinib (Example 9). In particular, in MOLM-13 cells, particularly significant tumor growth inhibitory effects were confirmed in the "combination of this compound, venetoclax, and azacitidine," "combination of this compound, cytarabine, and daunorubicin," and "combination of this compound and gilteritinib" (Examples 10 to 12), and in OCI-AML3 cells, particularly significant tumor growth inhibitory effects were confirmed in the "combination of this compound, venetoclax, and azacitidine" and "combination of this compound, cytarabine, and daunorubicin" (Examples 13 and 14). [Industrial Applicability]

[0272] The pharmaceuticals disclosed herein include optically active azabicyclo derivatives or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, and can be used as pharmaceuticals for treating or preventing cancer.

Claims

1. A pharmaceutical 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}pyrimidin-5-yl)oxy]-N,N-di(propan-2-yl)benzamide (hereinafter sometimes referred to as the "free form") or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient, the pharmaceutical being characterized in that it is orally administered to a subject.

2. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is orally administered to a subject once daily.

3. 2. The method of claim 1, wherein the method is administered orally to a subject twice daily.

4. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 40 mg in terms of the free form.

5. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 60 mg in terms of the free form.

6. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 80 mg in terms of the free form.

7. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 100 mg in terms of the free form.

8. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 120 mg in terms of the free form.

9. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 140 mg in terms of the free form.

10. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 180 mg in terms of the free form.

11. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 200 mg in terms of the free form.

12. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 220 mg in terms of the free form.

13. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 240 mg in terms of the free form.

14. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 260 mg in terms of the free form.

15. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 280 mg in terms of the free form.

16. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 300 mg in terms of the free form.

17. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 320 mg in terms of the free form.

18. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 340 mg in terms of the free form.

19. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 360 mg in terms of the free form.

20. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 380 mg in terms of the free form.

21. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 400 mg in terms of the free form.

22. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 500 mg in terms of the free form.

23. 4. The pharmaceutical composition according to claim 1, wherein the single dose of the active ingredient is 600 mg in terms of the free form.

24. 24. The pharmaceutical according to any one of claims 1 to 23, which is used in combination with another drug or a pharmaceutically acceptable salt thereof, wherein the other drug is at least one or more selected from 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, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, and other antitumor agents.

25. The pharmaceutical agent according to any one of claims 1 to 23, 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 The pharmaceutical agent is at least one selected from the group consisting of:

26. The pharmaceutical agent of any one of claims 1 to 23, which is administered once a day in combination with gilteritinib.

27. The pharmaceutical agent of any one of claims 1 to 23, which is administered in combination with 120 mg of gilteritinib.

28. The pharmaceutical composition of any one of claims 1 to 27, 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, gastric cancer, gallbladder / bile duct cancer, liver cancer, hepatocellular carcinoma, pancreatic cancer, colon cancer, rectal cancer, anal cancer, choriothelial carcinoma, uterine cancer, cervical cancer, ovarian cancer, bladder cancer, urothelial cancer, 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. The pharmaceutical composition of any one of claims 1 to 27, wherein the cancer is leukemia, B-cell lymphoma, neuroblastoma, or prostate cancer.

30. The pharmaceutical agent of any one of claims 1 to 27, wherein the cancer is leukemia.

31. The pharmaceutical agent according to any one of claims 28 to 30, wherein the leukemia is acute leukemia, chronic lymphocytic leukemia, or chronic myeloid leukemia.

32. The pharmaceutical agent of claim 31, wherein the acute leukemia is MLL acute leukemia, MLL partial tandem duplication acute leukemia, or NPM1-mutated acute leukemia.

33. The pharmaceutical agent of claim 31, wherein the acute leukemia is MLL acute leukemia or NPM1-mutated acute leukemia.

34. The pharmaceutical agent of claim 31, wherein the acute leukemia is acute myeloid leukemia with MLL rearrangement.

35. The pharmaceutical agent of claim 31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia with MLL rearrangement.

36. The pharmaceutical agent of claim 31, wherein the acute leukemia is acute lymphoblastic leukemia with MLL rearrangement.

37. The pharmaceutical agent of claim 31, wherein the acute leukemia is relapsed or refractory acute lymphoblastic leukemia with MLL rearrangement.

38. The pharmaceutical agent of claim 31, wherein the acute leukemia is acute myeloid leukemia with an NPM1 mutation.

39. The pharmaceutical agent of claim 31, wherein the acute leukemia is relapsed or refractory acute myeloid leukemia associated with an NPM1 mutation.

40. The pharmaceutical agent according to claim 31, wherein the acute leukemia is leukemia associated with high expression of the HOXa gene group or the MEIS gene group.

41. The pharmaceutical agent according to any one of claims 1 to 27, wherein the cancer is a tumor associated with a p53 gain-of-function mutation.

42. The pharmaceutical agent according to any one of claims 1 to 27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, DNMT3A gene mutation, FLT gene mutation, and MLL translocation.

43. The pharmaceutical agent according to any one of claims 1 to 27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation, FLT gene mutation, and MLL translocation.

44. The pharmaceutical agent according to any one of claims 1 to 27, wherein the cancer exhibits at least one genetic abnormality selected from NPM1 gene mutation and MLL translocation.

45. The pharmaceutical agent according to any one of claims 1 to 44, which is 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. The pharmaceutical agent of any one of claims 1 to 44, which is administered to a subject having at least one genetic abnormality selected from NPM1 gene mutation and MLL translocation.

47. The pharmaceutical agent of any one of claims 1 to 44, which is administered to a subject having an NPM1 gene mutation.

48. Subjects with NPM1 gene mutations (1) detecting an NPM1 gene mutation in cancer cells obtained from a subject; and (2) determining the presence or absence of the NPM1 gene mutation detected in step (1); The pharmaceutical of claim 47, wherein the pharmaceutical is determined based on the following:

49. The pharmaceutical agent of any one of claims 1 to 44, which is administered to a subject having an MLL translocation.

50. Subjects with MLL translocations (1) detecting an MLL translocation in cancer cells obtained from a subject; and (2) determining the presence or absence of the MLL translocation detected in step (1); The pharmaceutical of claim 49, wherein the formula is determined based on the formula:

51. The pharmaceutical agent of any one of claims 1 to 44, which is administered to a subject having a FLT gene mutation.

52. Subjects with FLT gene mutations (1) detecting a FLT gene mutation in cancer cells obtained from a subject; and (2) determining the presence or absence of the FLT gene mutation detected in step (1); The pharmaceutical of claim 51, wherein the formula is determined based on the formula:

53. The pharmaceutical agent of any one of claims 1 to 44, which is administered to a subject having a DNMT3A gene mutation.

54. Subjects with DNMT3A gene mutations (1) detecting a DNMT3A gene mutation in cancer cells obtained from a subject; and (2) determining the presence or absence of the DNMT3A gene mutation detected in step (1); The pharmaceutical of claim 53, wherein the formula is determined based on the formula:

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