Dihydrochromene-derivative-containing therapeutic agent for cancer

Abstract

The present invention relates to a medicinally useful dihydrochromene derivative and pharmacologically acceptable salts thereof, and a suitable usage method, dose, and application of a pharmaceutical composition containing the same.

Description

Cancer treatment agents containing dihydrochromene derivatives

[0001] The present invention relates to suitable methods, dosages and uses of dihydrochromene derivatives and pharmaceutically acceptable salts thereof which are useful as pharmaceuticals, as well as pharmaceutical compositions containing them.

[0002] Recently, a dihydrochromene derivative targeting cancer stem cells (hereinafter, sometimes referred to as "CSCs"), which are thought to be importantly involved in the sustained growth of malignant tumors, cancer metastasis, recurrence, and resistance to antitumor drugs, was reported in Patent Document 1.

[0003] International Publication No. 2019 / 181939

[0004] The objective of the present disclosure is to provide an invention relating to the dosage regimen of a dihydrochromene derivative that exhibits excellent anti-cancer activity by inhibiting emopamil-binding protein (EBP), and to provide a useful therapeutic agent and treatment method for tumors using the derivative and a combination drug.

[0005] More specifically, the present inventors have discovered that (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (hereinafter, also referred to as "the present compound" or "the compound of the present disclosure") or a pharmaceutically acceptable salt thereof inhibits EBP, suppresses de novo cholesterol biosynthesis, and activates liver X receptors (LXR) by accumulating zymosterol, a substrate of EBP, thereby depleting intracellular cholesterol, and thereby exhibits cytotoxic activity against cancer cells.

[0006] As a result of extensive research, the present inventors have found that a pharmaceutical comprising (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, exhibits excellent anticancer activity together with high safety when administered at a specific dosage. Furthermore, the present inventors have found that the anticancer activity can be further enhanced by using a concomitant drug in addition to the pharmaceutical, leading to the completion of the present disclosure.

[0007] That is, the present invention is as follows.

[0008] [Item 1] A pharmaceutical for treating or preventing cancer, comprising (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (hereinafter also referred to as "the compound"), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient, wherein the pharmaceutical is orally administered to a subject.

[0009] [Item 2] The medicine according to Item 1, wherein the active ingredient is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] diphosphate, or a hydrate or solvate thereof.

[0010] [Item 3] The pharmaceutical composition according to Item 1, wherein the active ingredient is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] diphosphate (referred to as "Compound 1").

[0011] [Item 4] The pharmaceutical composition according to any one of Items 1 to 3, which is orally administered to a subject once a day.

[0012] [Item 5] The pharmaceutical composition according to any one of Items 1 to 3, which is orally administered to a subject twice a day.

[0013] [Item 6] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 20 mg in terms of the compound.

[0014] [Item 7] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 40 mg in terms of the compound.

[0015] [Item 8] The pharmaceutical agent according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 60 mg in terms of the compound.

[0016] [Item 9] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 80 mg in terms of the compound.

[0017] [Item 10] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 100 mg in terms of the compound.

[0018] [Item 11] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 120 mg in terms of the compound.

[0019] [Item 12] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 140 mg in terms of the compound.

[0020] [Item 13] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 160 mg in terms of the compound.

[0021] [Item 14] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 180 mg in terms of the compound.

[0022] [Item 15] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 200 mg in terms of the compound.

[0023] [Item 16] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 220 mg in terms of the compound.

[0024] [Item 17] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 240 mg in terms of the compound.

[0025] [Item 18] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 260 mg in terms of the compound.

[0026] [Item 19] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 280 mg in terms of the compound.

[0027] [Item 20] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 300 mg in terms of the compound.

[0028] [Item 21] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 320 mg in terms of the compound.

[0029] [Item 22] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 340 mg in terms of the compound.

[0030] [Item 23] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 360 mg in terms of the compound.

[0031] [Item 24] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 380 mg in terms of the compound.

[0032] [Item 25] The medicine according to any one of Items 1 to 5, wherein the single dose of the active ingredient is 400 mg in terms of the compound.

[0033] [Item 26] The medicament according to any one of Items 1 to 25, which is used in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more 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, enzyme inhibitors, cholesterol absorption inhibitors, and other antitumor agents.

[0034] [Item 27] ​​The medicament according to any one of Items 1 to 25, which is used in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more selected from the group consisting of antitumor alkylating agents, antitumor monoclonal antibodies, immune checkpoint inhibitors, enzyme inhibitors, cholesterol absorption inhibitors, and other antitumor agents.

[0035] [Item 28] The pharmaceutical agent according to Item 26 or 27, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0036] [Item 29] The medicine according to Item 28, wherein the anti-PD-1 antibody or anti-PD-L1 antibody is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab, dostallimab, toripalimab, or tislelizumab.

[0037] [Item 30] The pharmaceutical agent according to Item 26 or 27, wherein the antitumor monoclonal antibody is bevacizumab or ipilimumab.

[0038] [Item 31] The medicine according to Item 26 or 27, wherein the antitumor alkylating agent is temozolomide.

[0039] [Item 32] The pharmaceutical agent according to Item 26 or 27, wherein the enzyme inhibitor is an IDH inhibitor.

[0040] [Item 33] The medicine according to Item 32, wherein the IDH inhibitor is ivosidenib, vorasidenib, ortasidenib, or enasidenib.

[0041] [Item 34] The pharmaceutical agent according to Item 26 or 27, wherein the enzyme inhibitor is an IDH1 inhibitor.

[0042] [Item 35] The pharmaceutical agent according to Item 34, wherein the IDH1 inhibitor is ivosidenib, vorasidenib, or ortasidenib.

[0043] [Item 36] The medicine according to Item 26 or 27, wherein the cholesterol absorption inhibitor is ezetimibe.

[0044] [Item 37] The pharmaceutical agent according to any one of Items 1 to 25, which is used in combination with a concomitant drug or a pharmaceutically acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one or more selected from the group consisting of: (1) bevacizumab, (2) ipilimumab, (3) temozolomide, (4) ivosidenib, (5) vorasidenib, and (6) ezetimibe.

[0045] [Item 38] The pharmaceutical agent according to any one of Items 1 to 37, which is used in combination with a cellular pharmaceutical agent.

[0046] [Item 39] The medicine according to Item 38, wherein the cell medicine is a chimeric antigen receptor T cell (CAR-T cell).

[0047] [Item 40] The pharmaceutical agent according to any one of Items 1 to 39, which is used in combination with radiotherapy.

[0048] [Item 41] The pharmaceutical agent according to any one of Items 1 to 40, wherein the cancer is a cancer resistant to an anti-PD-1 antibody drug.

[0049] [Item 42] The pharmaceutical agent according to any one of Items 1 to 41, wherein the cancer is glioma.

[0050] [Item 43] The pharmaceutical agent according to Item 42, wherein the glioma is a malignant glioma.

[0051] [Item 44] The pharmaceutical agent according to Item 43, wherein the malignant glioma is a recurrent malignant glioma.

[0052] [Item 45] The pharmaceutical agent according to any one of Items 42 to 44, wherein the glioma is diffuse glioma, pediatric diffuse low-grade glioma, pediatric diffuse high-grade glioma, focal astrocytic glioma, glioneuronal and neuronal tumor, or ependymal tumor.

[0053] [Item 46] The pharmaceutical agent according to Item 45, wherein the glioma is diffuse glioma.

[0054] [Item 47] The pharmaceutical agent according to Item 45 or 46, wherein the diffuse glioma is astrocytoma, oligodendroglioma, or glioblastoma.

[0055] [Item 48] The pharmaceutical agent according to any one of Items 45 to 47, wherein the diffuse glioma is glioblastoma.

[0056] [Item 49] The pharmaceutical agent according to Item 47 or 48, wherein the glioblastoma is secondary glioblastoma.

[0057] [Item 50] The pharmaceutical agent according to Item 45 or 46, wherein the diffuse glioma is astrocytoma or oligodendroglioma.

[0058] [Item 51] The pharmaceutical agent according to Item 45 or 46, wherein the diffuse glioma is anaplastic oligodendroglioma or anaplastic astrocytoma.

[0059] [Item 52] The pharmaceutical agent according to Item 45 or 46, wherein the diffuse glioma is pilocytic astrocytoma.

[0060] [Item 53] The pharmaceutical agent according to Item 42, wherein the glioma is grade I or II according to the WHO 2016 Brain Tumor Classification.

[0061] [Item 54] The pharmaceutical agent according to Item 42, wherein the glioma is grade II or III according to the WHO 2016 Brain Tumor Classification.

[0062] [Item 55] The pharmaceutical agent according to Item 42, wherein the glioma is grade III or IV according to the WHO 2016 Brain Tumor Classification.

[0063] [Item 56] The pharmaceutical agent according to Item 42, wherein the glioma is of grade I to III according to the WHO 2016 Brain Tumor Classification.

[0064] [Item 57] The pharmaceutical agent according to any one of Items 1 to 56, wherein the cancer is a cancer in which emopamil-binding protein is expressed at a higher level than in healthy individuals.

[0065] [Item 58] The pharmaceutical agent according to any one of Items 1 to 57, wherein the cancer is a cancer accompanied by an IDH mutation.

[0066] [Item 59] The pharmaceutical agent according to any one of Items 1 to 40, which is administered to a subject having an IDH mutation.

[0067] [Item 60] The pharmaceutical according to Item 59, wherein the subject having an IDH mutation is determined by a process comprising: (1) detecting an IDH mutation in cancer cells obtained from the subject; and (2) making a determination based on the presence or absence of the IDH mutation detected in (1).

[0068] [Item 1A] A method for treating and / or preventing cancer, comprising orally administering to a subject a therapeutically effective amount of (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (hereinafter also referred to as "the compound"), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient.

[0069] [Item 2A] The method according to Item 1A, wherein the active ingredient is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] diphosphate, or a hydrate or solvate thereof.

[0070] [Item 3A] The method according to Item 1A, wherein the active ingredient is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] diphosphate (referred to as "Compound 1").

[0071] [Item 4A] The method according to any one of Items 1A to 3A, wherein the active ingredient is orally administered to the subject once a day.

[0072] [Item 5A] The method according to any one of Items 1A to 3A, wherein the medicament is orally administered to the subject twice a day.

[0073] [Item 6A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 20 mg in terms of the compound.

[0074] [Item 7A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 40 mg in terms of the compound.

[0075] [Item 8A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 60 mg in terms of the compound.

[0076] [Item 9A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 80 mg in terms of the compound.

[0077] [Item 10A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 100 mg in terms of the compound.

[0078] [Item 11A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 120 mg in terms of the compound.

[0079] [Item 12A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 140 mg in terms of the compound.

[0080] [Item 13A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 160 mg in terms of the compound.

[0081] [Item 14A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 180 mg in terms of the compound.

[0082] [Item 15A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 200 mg in terms of the compound.

[0083] [Item 16A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 220 mg in terms of the compound.

[0084] [Item 17A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 240 mg in terms of the compound.

[0085] [Item 18A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 260 mg in terms of the compound.

[0086] [Item 19A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 280 mg in terms of the compound.

[0087] [Item 20A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 300 mg in terms of the compound.

[0088] [Item 21A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 320 mg in terms of the compound.

[0089] [Item 22A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 340 mg in terms of the compound.

[0090] [Item 23A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 360 mg in terms of the compound.

[0091] [Item 24A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 380 mg in terms of the compound.

[0092] [Item 25A] The method according to any one of Items 1A to 5A, wherein the single dose of the active ingredient is 400 mg in terms of the compound.

[0093] [Item 26A] The method according to any one of Items 1A to 25A for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is at least one or more 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, enzyme inhibitors, cholesterol absorption inhibitors, and other antitumor agents.

[0094] [Item 27A] The method according to any one of Items 1A to 25A, for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is at least one or more selected from the group consisting of antitumor alkylating agents, antitumor monoclonal antibodies, immune checkpoint inhibitors, enzyme inhibitors, cholesterol absorption inhibitors, and other antitumor agents.

[0095] [Item 28A] The method according to Item 26A or 27A, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0096] [Item 29A] The method according to Item 28A, wherein the anti-PD-1 antibody or anti-PD-L1 antibody is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab, dostallimab, toripalimab, or tislelizumab.

[0097] [Item 30A] The method according to Item 26A or 27A, wherein the anti-tumor monoclonal antibody is bevacizumab or ipilimumab.

[0098] [Item 31A] The method according to Item 26A or Item 27A, wherein the antitumor alkylating agent is temozolomide.

[0099] [Item 32A] The method according to Item 26A or 27A, wherein the enzyme inhibitor is an IDH inhibitor.

[0100] [Item 33A] The method according to Item 32A, wherein the IDH inhibitor is ivosidenib, vorasidenib, ortasidenib, or enasidenib.

[0101] [Item 34A] The method according to Item 26A or 27A, wherein the enzyme inhibitor is an IDH1 inhibitor.

[0102] [Item 35A] The method according to Item 34A, wherein the IDH1 inhibitor is ivosidenib, vorasidenib, or ortasidenib.

[0103] [Item 36A] The method according to Item 26A or Item 27A, wherein the cholesterol absorption inhibitor is ezetimibe.

[0104] [Item 37A] The method according to any one of Items 1A to 25A for treating cancer in combination with a concomitant drug or a pharmaceutically acceptable salt thereof, wherein the concomitant drug is at least one or more selected from the group consisting of: (1) bevacizumab, (2) ipilimumab, (3) temozolomide, (4) ivosidenib, (5) vorasidenib, and (6) ezetimibe.

[0105] [Item 38A] The method according to any one of Items 1A to 37A, which is used in combination with a cellular medicine.

[0106] [Item 39A] The method according to Item 38A, wherein the cellular medicine is a chimeric antigen receptor T cell (CAR-T cell).

[0107] [Item 40A] The method according to any one of Items 1A to 39A, which is used in combination with radiation therapy.

[0108] [Item 41A] The method according to any one of Items 1A to 40A, wherein the cancer is a cancer resistant to an anti-PD-1 antibody drug.

[0109] [Item 42A] The method according to any one of Items 1A to 41A, wherein the cancer is glioma.

[0110] [Item 43A] The method according to Item 42A, wherein the glioma is a malignant glioma.

[0111] [Item 44A] The method according to Item 43A, wherein the malignant glioma is a recurrent malignant glioma.

[0112] [Item 45A] The method according to any one of Items 42A to 44A, wherein the glioma is a diffuse glioma, pediatric diffuse low-grade glioma, pediatric diffuse high-grade glioma, focal astrocytic glioma, glioneuronal and neuronal tumor, or ependymal tumor.

[0113] [Item 46A] The method according to Item 45A, wherein the glioma is a diffuse glioma.

[0114] [Item 47A] The method according to Item 45A or Item 46A, wherein the diffuse glioma is astrocytoma, oligodendroglioma, or glioblastoma.

[0115] [Item 48A] The method according to any one of Items 45A to 47A, wherein the diffuse glioma is glioblastoma.

[0116] [Item 49A] The method according to Item 47A or Item 48A, wherein the glioblastoma is secondary glioblastoma.

[0117] [Item 50A] The method according to Item 45A or Item 46A, wherein the diffuse glioma is an astrocytoma or an oligodendroglioma.

[0118] [Item 51A] The method according to Item 45A or Item 46A, wherein the diffuse glioma is anaplastic oligodendroglioma or anaplastic astrocytoma.

[0119] [Item 52A] The method according to Item 45A or Item 46A, wherein the diffuse glioma is pilocytic astrocytoma.

[0120] [Item 53A] The method according to Item 42A, wherein the glioma is grade I or II according to the WHO 2016 Brain Tumor Classification.

[0121] [Item 54A] The method according to Item 42A, wherein the glioma is grade II or III according to the WHO 2016 Brain Tumor Classification.

[0122] [Item 55A] The method according to Item 42A, wherein the glioma is grade III or IV according to the WHO 2016 Brain Tumor Classification.

[0123] [Item 56A] The method according to Item 42A, wherein the glioma is grade I to III according to the WHO 2016 brain tumor classification.

[0124] [Item 57A] The method according to any one of Items 1A to 56A, wherein the cancer is a cancer in which emopamil-binding protein is expressed at a higher level compared to healthy individuals.

[0125] [Item 58A] The method of any one of Items 1A to 57A, wherein the cancer is a cancer associated with an IDH mutation.

[0126] [Item 59A] The method of any one of Items 1A to 40A, wherein the method is administered to a subject having an IDH mutation.

[0127] [Item 60A] The method according to Item 59A, characterized in that the subject having an IDH mutation is determined by a process comprising: (1) detecting an IDH mutation in cancer cells obtained from the subject; and (2) determining the presence or absence of the IDH mutation detected in (1).

[0128] The technology of the present disclosure is useful as a therapeutic and / or preventive agent for glioma by using the compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, in the dosage regimen provided herein, and exhibits excellent anticancer activity against cancer. Using the technology of the present disclosure, the compound can be administered at a dose that has been confirmed or is expected to be tolerable to humans, and used as various therapeutic and / or preventive agents. Furthermore, the anticancer activity can be further enhanced by using the compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, in combination with a drug.

[0129] The object of the present disclosure is to provide an invention relating to the dosage regimen of a dihydrochromene derivative that exhibits excellent anticancer activity by inhibiting binding to emopamil-binding protein (EBP), and to provide a useful therapeutic agent and treatment method for tumors in combination with other anticancer agents.

[0130] More specifically, the present inventors provide a technology related to a medicine comprising (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0131] The clinical trial design for the clinical trial using Compound 1 in patients with recurrent WHO grade III or IV malignant glioma is shown. The patient selection criteria for the clinical trial using Compound 1 in patients with recurrent WHO grade III or IV malignant glioma are shown (Baseline Characteristics). The results of dose-limiting toxicity in the clinical trial using Compound 1 in patients with recurrent WHO grade III or IV malignant glioma (dose-escalation part) are shown (Data Cut-off: September 22, 2023). The safety data in the clinical trial using Compound 1 in patients with recurrent WHO grade III or IV malignant glioma (dose-escalation part) are shown (Data Cut-off: September 22, 2023). The lathosterol / zymostenol (L / Z) ratio in the clinical trial using Compound 1 in patients with recurrent WHO grade III or IV malignant glioma (dose-escalation part) is shown (Data Cut-off: September 2023). This figure shows the relationship between treatment duration and treatment effect in a clinical trial (dose-escalation part) using compound 1 in patients with recurrent WHO grade III or IV malignant glioma (Data Cut-off: September 22, 2023). This figure shows the preliminary antitumor effect in a clinical trial (dose-escalation part) using compound 1 in patients with recurrent WHO grade III or IV malignant glioma (Data Cut-off: September 11, 2023). This figure shows an MRI image of the brain of a patient with anaplastic astrocytoma who was enrolled in a 120 mg QD dose and achieved a complete response in a clinical trial (dose-escalation part) using compound 1 in patients with recurrent WHO grade III or IV malignant glioma. This figure shows the preliminary antitumor effect in a clinical trial (dose-escalation part) using compound 1 in patients with recurrent WHO grade III or IV malignant glioma (Data Cut-off: April 22, 2024).The lathosterol / zymostenol (L / Z) ratio is shown in the dose-escalation part of a clinical trial using compound 1 in patients with recurrent malignant glioma of WHO classification grade III or IV (as of April 2024). The mean plasma concentration-time curves are shown for compound 1 administered at doses of 20 mg once daily to 240 mg once daily in a clinical trial in patients with recurrent malignant glioma of WHO classification grade III or IV (Data Cut-off: April 2023). The mean plasma concentration-time curves are shown for compound 1 administered at doses of 20 mg once daily to 240 mg twice daily in a clinical trial in patients with recurrent malignant glioma of WHO classification grade III or IV (Data Cut-off: March 2024). 1 shows the blood L / Z ratio relative to the blood exposure of compound 1 in each dose group in a clinical trial (dose escalation study part) using compound 1 in patients with recurrent malignant glioma of WHO classification grade III or IV. 2 shows the clinical trial design for a clinical trial in patients with recurrent malignant glioma of WHO classification grade II, III, or IV. 3 shows the antitumor effect in a combined efficacy evaluation test of compound 1 and bevacizumab in mice bearing luciferase-expressing U-87 cells. 4 shows the antitumor effect in a combined efficacy evaluation test of compound 1 and ipilimumab in mice bearing MC38 cells. 5 shows the antitumor effect in a combined efficacy evaluation test of compound 1 and ipilimumab in mice bearing B16 cells. 6 shows the antitumor effect in a single-agent efficacy evaluation test of compound 1 in mice bearing B16 cells, a cancer model resistant to anti-PD-1 antibodies.

[0033] Figure 1 shows the cytotoxicity of Compound 1 in an in vitro sphere culture test using IDH1R132H mutant U-87 cells supplemented with low-density lipoprotein (LDL). Figure 2 shows the results of an evaluation of the cytotoxicity of a combination of Compound 1 and ezetimibe against U-87 cells (IDH1 wild-type) in an in vitro sphere culture supplemented with low-density lipoprotein (LDL). Figure 3 shows the estimated metabolic pathway of this compound. Figure 4 shows the results of an evaluation test of cytotoxicity using metabolites in an in vitro sphere culture.1 shows the results of evaluating the cytotoxicity of Compound 1 in sphere culture with low-density lipoprotein (LDL) added using BT142 cells, a cell line derived from low-grade glioma.

[0132] Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, 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 the case of conflict, the present specification (including definitions) will control.

[0133] (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]diphosphate (Compound 1) has the following structure: In addition, the term "hydrate or solvate thereof" in "the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof" refers to a hydrate or solvate of the present compound, and a hydrate or solvate of a pharmaceutically acceptable salt of the present compound.

[0134] The compound refers to (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and refers to a compound in its free form without forming a salt. Compound 1 refers to (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]diphosphate.

[0135] "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. Furthermore, 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.

[0136] The compounds provided herein can include various stereochemical forms.The compounds of the present disclosure include not only optical isomers but also diastereomers, for example, mixtures of enantiomers, including racemic mixtures, as well as individual enantiomers and diastereomers that result from 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.

[0137] The present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof also includes various hydrates, solvates, and crystalline polymorphs. Furthermore, the compounds of the present disclosure 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 disclosure.

[0138] 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 substituted with an alkanoyloxymethylamino group, or compounds in which the amino group is hydroxylamine.

[0139] The terms used in this specification are explained below.

[0140] In some embodiments, the "subject" treated by the above methods is a mammal. The present disclosure can be used with mammals, and the term "mammal" is used herein in its normal biological sense, and thus specifically includes humans, cows, horses, dogs, cats, rats, and mice, but also many other species. In some further embodiments, the subject is a human.

[0141] When a pharmaceutically acceptable salt of the present compound is to be obtained, if the 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.

[0142] In the present invention, the term "concomitant drug" refers to an antitumor agent that can be used in combination with the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 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, angiogenesis inhibitors, immune checkpoint inhibitors, epigenetics-related molecule inhibitors, protein post-translational modification inhibitors, proteasome inhibitors, enzyme inhibitors, cholesterol absorption 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 Paribu, sorafenib, vemurafenib, dabrafenib, trametinib, palbociclib, bortezomib, carfilzomib, rituximab, cetuximab, trastuzumab, bevacizumab, panitumumab, nivolumab, atezolizumab, mogamulizumab, alemtuzumab, ofatumumab, ipilimumab, ramucirumab, brentuximab Examples include vedotin, gemtuzumab ozogamicin, inotuzumab ozogamicin, venetoclax, gilteritinib, vorasidenib, ivosidenib, oltasidenib, enasidenib, pembrolizumab, durvalumab, avelumab, cemiplimab, dostallimab, toripalimab, tislelizumab, and ezetimibe.

[0143] Cellular medicines are drugs that are expected to have a therapeutic effect when administered as cells themselves, regardless of the origin of the cells or the degree of processing. Examples include chimeric antigen receptor T cells (CAR-T cells), TCR-T, or NK cells. Preferably, chimeric antigen receptor T cells (CAR-T cells) are used. Specific examples include idecactagen bicleucel, lisocabtagene maraleucel, siltacabtadine autoleucel, tisagenlecleucel, and axicabtagene ciloreucel.

[0144] Radiation therapy is a treatment that uses high-energy x-rays or other radiation to damage tumor cells, both internally and externally.

[0145] "U-87 cells" are a cell line of human malignant glioma derived from epithelial tissue, and have properties similar to glioblastoma. To observe tumor growth in brain tissue, luciferase-expressing U-87 cells were established by forcibly expressing luciferase, a luminescent enzyme.

[0146] "MC38 cells" are a methylcholanthrene-induced colon adenocarcinoma cell line derived from C57BL / 6 mice, and are considered to be relatively highly immunogenic.

[0147] "B16 cells" are a malignant melanoma cell line that spontaneously develops in C57BL / 6 mice.

[0148] Examples of gliomas include diffuse gliomas, pediatric diffuse low-grade gliomas, pediatric diffuse high-grade gliomas, focal astrocytic gliomas, glioneuronal and neuronal tumors, and ependymal tumors. Examples of diffuse gliomas include astrocytomas with IDH mutations, oligodendroglioma with IDH mutations and 1p / 19q codeletion, and glioblastomas. Regarding the classification of gliomas, Volume 6 of the "WHO Classification Series, 5th Edition" was referenced.

[0149] Gliomas are classified into grades I to IV based on the WHO 2016 new classification (4th revised edition), which is a diagnostic standard that combines morphological diagnosis and molecular diagnosis.

[0150] There are two subsets of glioblastoma: secondary glioblastoma, which arises from the malignant transformation of benign astrocytoma, and de novo glioblastoma, which arises without any precursor lesion.

[0151] Malignant gliomas are gliomas that grow rapidly, infiltrate adjacent normal tissue, and have unclear boundaries. They are classified as grades III and IV of the four WHO classifications, determined by pathological examination. Low-grade gliomas are gliomas classified as grades I or II. For example, oligodendrogliomas are classified as grade II, but those that transform to grade III are called anaplastic oligodendrogliomas. Astrocytomas are classified as grade II, but those that transform to grade III are called anaplastic astrocytomas. Pilocytic astrocytomas are classified as grade I.

[0152] It has been reported that IDH1 or IDH2 mutations are primarily found in the majority of grade II or grade III gliomas based on the WHO 2016 classification (4th revised edition) and in secondary glioblastomas arising from these precursors (N. Engl. J. Med. 360, 765-773 (2009)).

[0153] Recurrence is when cancer that was previously confirmed to have disappeared through treatment reappears. This includes not only cases where the cancer reappears in the area where the primary tumor was located or in its vicinity, but also cases where the cancer is found as a "metastasis" in another organ.

[0154] The frequency of oral administration of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can be once a day, twice a day, three times a day, or four times a day, preferably once a day or twice a day, more preferably once a day. In another preferred embodiment, it is twice a day.

[0155] "In terms of this compound" means administering a dose containing the same number of moles of this compound. For example, the dose of Compound 1 is calculated using the following formula: Dose of Compound 1 = (Dose of this compound) x (Molecular weight of Compound 1 (611.94) / Molecular weight of this compound (415.95)) Specifically, "20 mg of Compound 1 in terms of this compound" is: Dose of Compound 1 = 20 x (Molecular weight of Compound 1 (611.94) / Molecular weight of this compound (415.95)) = 29.4, which corresponds to 29.4 mg. Similar calculations can be made for other forms such as salts, hydrates, or solvates.

[0156] A single oral dose of a medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, 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, 83 mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440m g, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 610mg, 620mg, 630mg, 640mg, 650mg, 660mg, 670mg, 680mg, 690mg, 700mg, 710mg, 720mg, 730mg, 740mg, 750mg, 760mg, 770mg, 780mg, 7 90mg, 800mg, 810mg, 820mg, 830mg, 840mg, 850mg, 860mg, 870mg, 880mg, 890mg, 900mg, 910mg, 920mg, 930mg, 940mg, 950mg, 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, or 1200 mg, and also includes a range between any two of these doses.

[0157] A single oral dose of a medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof 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, or 460 mg, calculated as the present compound. , 480 mg, 500 mg, 520 mg, 540 mg, 560 mg, 580 mg, 600 mg, 620 mg, 640 mg, 660 mg, 680 mg, 700 mg, 720 mg, 740 mg, 760 mg, 780 mg, 800 mg, 820 mg, 840 mg, 860 mg, 880 mg, 900 mg, 920 mg, 940 mg, 960 mg, 980 mg, or 1000 mg, as well as ranges between any two of these doses.

[0158] More preferred examples of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, calculated as the present compound, include 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, or 600 mg, and also include a range between any two of these dosage amounts selected arbitrarily.

[0159] More preferred examples of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, calculated as the present compound, include 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, or 500 mg, and also include a range between any two of these dosage amounts selected arbitrarily.

[0160] A single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, converted into the present compound, is most 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, or 400 mg, and also includes a range between any two of these doses selected arbitrarily.

[0161] Another preferred embodiment of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, or 380 mg, calculated as the present compound, and also includes a range between any two of these dosage amounts selected arbitrarily.

[0162] Another preferred embodiment of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, or 360 mg, calculated as the present compound, and also includes a range between any two of these dosage amounts.

[0163] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 20 mg, 40 mg, 60 mg, 80 mg, 120 mg, 180 mg, 240 mg, or 360 mg of the present compound, and also include a range between any two of these doses.

[0164] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 120 mg, 180 mg, 240 mg, or 360 mg, calculated as the present compound, and also include a range between any two of these doses.

[0165] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 20 mg, 40 mg, 60 mg, or 80 mg, calculated as the present compound, and also include a range between any two of these doses.

[0166] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, or 280 mg, calculated as the present compound, and also include a range between any two of these doses.

[0167] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, or 260 mg, calculated as the present compound, and also include a range between any two of these doses.

[0168] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, or 260 mg, calculated as the present compound, and also include a range between any two of these doses.

[0169] Other preferred embodiments of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof include 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, or 240 mg, calculated as the present compound, and also include a range between any two of these doses.

[0170] Another more preferred embodiment of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 160 mg, 180 mg, 200 mg, 220 mg, or 240 mg, calculated as the present compound, and also includes a range between any two of these doses selected arbitrarily.

[0171] Another more preferred embodiment of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 160 mg, 180 mg, 200 mg, or 220 mg, calculated as the present compound, and also includes a range between any two of these doses selected arbitrarily.

[0172] Another most preferred embodiment of a single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, is 160 mg, 180 mg, or 200 mg, calculated as the present compound, and also includes a range between any two of these doses selected arbitrarily.

[0173] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 20 mg, calculated as the present compound.

[0174] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 40 mg, calculated as the present compound.

[0175] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 60 mg, calculated as the present compound.

[0176] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 80 mg, calculated as the present compound.

[0177] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 120 mg, calculated as the present compound.

[0178] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 160 mg, calculated as the present compound.

[0179] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 180 mg, calculated as the present compound.

[0180] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 200 mg, calculated as the present compound.

[0181] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 240 mg, calculated as the present compound.

[0182] Another most preferred embodiment of the single oral dose of a medicament containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is 360 mg, calculated as the present compound.

[0183] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and the single dose, converted into the present compound, is preferably 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, and also includes a range between any two of these doses.

[0184] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and the single dose more preferably includes, in terms of the present compound, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, or 300 mg, and also includes a range between any two of these doses.

[0185] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and the single dose is more preferably 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, or 280 mg, calculated as the present compound, and also includes a range between any two of these doses.

[0186] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and the single dose is most preferably 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, or 260 mg, calculated as the present compound, and also includes a range between any two of these doses.

[0187] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and other preferred embodiments of the single dose, calculated as the present compound, include 160 mg, 180 mg, 200 mg, 220 mg, or 240 mg, as well as a range between any two of these doses.

[0188] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 20 mg, calculated as the present compound.

[0189] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 40 mg, calculated as the present compound.

[0190] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 60 mg, calculated as the present compound.

[0191] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 80 mg, calculated as the present compound.

[0192] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 120 mg, calculated as the present compound.

[0193] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 160 mg, calculated as the present compound.

[0194] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 180 mg, calculated as the present compound.

[0195] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 200 mg, calculated as the present compound.

[0196] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 240 mg, calculated as the present compound.

[0197] A medicine containing the present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof is preferably orally administered once a day, and another more preferred embodiment of the single dose is 360 mg, calculated as the present compound.

[0198] The present compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof can be administered orally or parenterally, either directly or after being formulated in an appropriate dosage form. A more preferred embodiment is oral administration, either directly or after being formulated in an appropriate dosage form.

[0199] Examples of dosage forms include, but are not limited to, tablets, capsules, powders, granules, liquids, suspensions, injections, patches, poultices, etc. The preparations are produced by known methods using pharmaceutically acceptable additives.

[0200] 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. Specific examples of additives include lactose, mannitol, crystalline cellulose, low-substituted hydroxypropyl cellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, etc.

[0201] The metabolites used in the following examples were prepared in the following reference examples.

[0202] The following abbreviations may be used in this specification: Hex: hexane IPA: isopropyl alcohol THF: tetrahydrofuran TFA: trifluoroacetic acid NaBH(OAc) ３ : Sodium triacetoxyborohydride DMF: N,N-dimethylformamide MeCN: Acetonitrile WSCI·HCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride HOBt·H ２ O: 1-hydroxybenzotriazole monohydrate Me: methyl Et: ethyl Boc: tert-butoxycarbonyl

[0203] The NMR data used for compound identification was acquired using a JEOL JNM-AL series AL400. The symbols used in NMR are s, d, dd, t, q, m, br, br, brs, brm, br, and J, respectively.

[0204] The LC / MS analysis conditions used for compound identification were as follows: The observed mass spectrometry value [MS (m / z)] was expressed as [M+H] ＋ or [M+2H] ２＋ and retention time is indicated as Rt (min).

[0205] LC / MS measurement method: Detector: ACQUITY (registered trademark) SQ detector (Waters) HPLC: ACQUITY UPLC (registered trademark) system Column: Waters ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, 2.1 mm × 30 mm) Solvent: Solution A: 0.06% formic acid / H ２ O, B solution: 0.06% formic acid / MeCN Gradient condition: 0.0-1.3min Linear gradient from B 2% to 96% Flow rate: 0.8mL / min UV: 220nm and 254nm

[0206] The optically active compounds of the compounds of the Reference Examples described herein and their synthetic intermediates were analyzed under the following conditions.

[0207] HPLC evaluation system for optical resolution: Pump: LC-20AD (Shimadzu Corporation) Detector: SPD-20A (Shimadzu Corporation) Pump: SIL-20A (Shimadzu Corporation) Condition A Column: CHIRALPAK IE Size: 0.46 cm ID x 25 cmL Mobile phase: n-Hex / EtOH / i-PrNH ２ =90 / 10 / 0.1<v / v> Flow rate: 1.0 mL / min Temperature: 40°C Wavelength: 287 nm

[0208] Condition B Column: CHIRALPAK IE Size: 0.46cmI. D. x 25cmL Mobile phase: n-Hex / IPA / i-PrNH ２ =80 / 20 / 0.1<v / v> Flow rate: 1.0mL / min Temperature: 40°C Wavelength: 285nm

[0209] Condition C Column: CHIRALPAK IE Size: 0.46cmI. D. x 25 cmL Mobile phase: MeOH / i-PrNH ２=100 / 0.1<v / v> Flow rate: 1.0mL / min Temperature: 40°C Wavelength: 280nm

[0210] Condition D Column: CHIRALPAK AD-H Size: 0.46cmI. D. x 25 cmL Mobile phase: n-Hex / IPA / EtOH / i-PrNH ２ =85 / 5 / 10 / 0.1<v / v> Flow rate: 1.0 mL / min Temperature: 40°C Wavelength: 280 nm

[0211] Reference Example 1 tert-butyl 4-(hydroxymethyl)-4-(3-methylbut-2-en-1-yl)piperidine-1-carboxylate

[0212] a) Preparation of 1-tert-butyl 4-methyl 4-(3-methylbut-2-en-1-yl)piperidine-1,4-dicarboxylate To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (69.0 g) in tetrahydrofuran (700 mL) was added dropwise 1 mol / L sodium bis(trimethylsilyl)amide (326 mL) at −78° C., and the mixture was stirred at the same temperature for 1 hour. The temperature was raised to −20° C. and the mixture was stirred for 1 hour, and then 1-bromo-3-methyl-2-butene (42.6 mL) was added dropwise at −78° C. The mixture was heated to −20° C. and stirred for 3 hours, and then stirred overnight while warming to room temperature. After completion of the reaction, an aqueous ammonium chloride solution was added, followed by addition of water and ethyl acetate. The mixture was subjected to liquid separation and extraction with ethyl acetate and water, and the resulting organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (69.0 g). １H-NMR (400 MHz, CDCl3): 5.01 (1H, t, J = 7.5 Hz), 3.87-3.72 (2H, m), 3.68 (3H, s), 2.86 (2H, dd, J = 2.7, 11.4 Hz), 2.21 (2H, d, J = 7.3 Hz), 2.06 (2H, d, J = 14.2 Hz), 1.69 (3H, s), 1.58 (3H, s), 1.44 (9H, s), 1.43-1.34 (2H, m). LC-MS; [M+H] ＋ 312.3 / Rt (min) 1.24

[0213] b) Preparation of tert-butyl 4-(hydroxymethyl)-4-(3-methylbut-2-en-1-yl)piperidine-1-carboxylate (Reference Example 1) A solution of the obtained 1-tert-butyl 4-methyl 4-(3-methylbut-2-en-1-yl)piperidine-1,4-dicarboxylate (69.0 g) in tetrahydrofuran (300 mL) was added dropwise to a solution of lithium aluminum hydride (9.25 g) in tetrahydrofuran (700 mL) at −78°C. The mixture was stirred at the same temperature for 1 hour and then stirred at −20°C under a nitrogen atmosphere for 5 hours. After completion of the reaction, a saturated aqueous sodium sulfate solution was added at 0°C. After stirring at room temperature for 1 hour, magnesium sulfate was added to the reaction solution for drying. The reaction solution was filtered through Celite, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give Reference Example 1 (58.0 g). １ H-NMR (400 MHz, CDCl3): 5.17 (1H, t, J = 7.8 Hz), 3.48-3.41 (2H, m), 3.46 (2H, s), 3.38-3.31 (2H, m), 2.09 (2H, d, J = 7.8 Hz), 1.73 (3H, s), 1.65 (3H, s), 1.51-1.37 (4H, m), 1.46 (9H, s). LC-MS; [M+H] ＋ 284.3 / Rt (min) 1.08

[0214] Reference Example 2 Racemate of (4'aR,10'bR)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] and (4'aS,10'bS)-9'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] To a solution of Reference Example 1 (69.0 g) in dichloromethane (1000 mL) were added 5-chloro-2-hydroxybenzaldehyde (48.0 g), trimethyl orthoformate (100 mL), and para-toluenesulfonic acid hydrate (1.90 g) in that order at 0°C, and the mixture was stirred at 0°C under a nitrogen atmosphere for 5 hours. The solvent was distilled off under reduced pressure, and to the residue obtained, a 4 mol / L hydrochloric acid / ethyl acetate solution (300 mL) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. The solvent was distilled off under reduced pressure, and the residue obtained was purified by amine silica gel column chromatography (chloroform / methanol) to give the racemic Reference Example 2 (61.5 g). １ H-NMR (400 MHz, CDCl3): 7.38 (1H, s), 7.11 (1H, d, J = 8.6 Hz), 6.70 (1H, d, J = 8.6 Hz), 4.12 (1H, d, J = 11.4 Hz), 4.08 (1H, d, J = 10.9 Hz), 3.31 (1H, d, J = 10.9 Hz), 2.90-2.86 (3H, m), 2.81-2.77 (1H, m), 1.91-1.80 (3H, m), 1.57-1.53 ​​(1H, m), 1.39-1.37 (2H, m), 1.38 (3H, s), 1.17 (3H, s), 1.11-1.05 (1H, m). LC-MS; [M+H] ＋ 322.2 / Rt (min) 0.77

[0215] The obtained Reference Example 2 was subjected to optical resolution to obtain Reference Examples 3 and 4, which are optically active forms of Reference Example 2. Reference Example 3: Condition A; Rt (min) = 10.35 LC-MS; [M+H] ＋322.2 / Rt (min) 0.77 Reference example 4: Condition A; Rt (min) = 12.07 LC-MS; [M+H] ＋ 322.2 / Rt (min) 0.77

[0216] Reference Examples 5 to 15 The compounds of Reference Examples 5 to 15 shown in the table below were obtained by the same method as in Reference Example 2 using the corresponding starting compounds.

[0217] The NMR data for the compound of Reference Example 7 in the above table are shown below. １ H-NMR (400 MHz, CDCl3): 7.33 (1H, d, J = 9.2 Hz), 6.88 (1H, d, J = 8.4 Hz), 6.80 (1H, s), 4.14-4.07 (2H, m), 3.32 (1H, d, J = 11.6 Hz), 2.90-2.80 (4H, m), 1.93-1.82 (2H, m), 1.58-1.51 (1H, m), 1.38-1.34 (1H, m), 1.36 (3H, s), 1.27-1.19 (2H, m), 1.24 (3H, s), 1.12-1.06 (1H, m).

[0218] Synthesis of tert-butyl {2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl}carbamate (Reference Example 16)

[0219] To a solution of Reference Example 9 (6.42 g), which is metabolite M4, in acetonitrile (100 mL) were added triethylamine (2.8 mL), potassium carbonate (2.76 g), and tert-butyl(2-bromoethyl)carbamate (4.92 g), and the mixture was stirred for 5 hours at 85° C. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol=1 / 0 to 25 / 1) to give Reference Example 16 (9.10 g). １H-NMR (400 MHz, CDCl3): 7.32 (1H, dd, J = 8.8, 0.8 Hz), 6.86 (1H, dd, J = 8.4, 2.0 Hz), 6.78 (1H, d, J = 2.0 Hz), 4.95 (1H, bs), 4.08-4.02 (2H, m), 3.30 (1H, d, J = 11.2 Hz), 3.22-3.20 (2H, m), 2.46-2.38 (5H, m), 2.31-2.27 (1H, m), 1.89-1.82 (3H, m), 1.62 (2H, m), 1.45 (9H, s), 1.43-1.39 (1H, m), 1.36 (3H, s), 1.17 (3H, s), 1.11-1.03 (1H, m). (NMR model: Bruker-400)

[0220] Reference Example 18 N-2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethyl-N ２ -Synthesis of formylglycinamide (metabolite M2) a) To a solution of Reference Example 16 (9.10 g) in chloroform (100 mL), 4 M hydrogen chloride / cyclopentyl methyl ether solution (48.4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was removed by evaporation under reduced pressure, and chloroform (100 mL) was added to the residue. The solvent was again removed by evaporation under reduced pressure (repeated twice in total) to obtain Reference Example 17 (9.76 g), which was used directly in the next reaction. b) To a solution of Reference Example 17 (9.76 g, assumed to be 19.6 mmol) in dehydrated chloroform (100 mL), N-formylglycine (2.42 g), 1-hydroxybenzotriazole (3.17 g), N-methylmorpholine (10.3 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.62 g) were added at 0°C, and the mixture was warmed to room temperature and stirred for 15 hours. The organic layer was diluted with chloroform, washed with saturated aqueous sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol=1 / 0 to 6.25 / 1) and further purified by aminosilica gel column chromatography (chloroform / methanol=1 / 0 to 50 / 1) to give Reference Example 18 (7.32 g). １ H-NMR (400 MHz, DMSO-d6): 8.24-8.18 (1H, m), 8.05 (1H, s), 7.82-7.76 (1H, m), 7.29 (1H, d, J = 7.8 Hz), 6.88 (1H, dd, J = 8.0, 2.0 Hz), 6.78 (1H, d, J = 2.0 Hz), 4.12 (1H, d, J = 11.0 Hz), 3.89 (1H, d, J = 11.0 Hz), 3.68 (2H, d, J = 6.0 Hz),3.31-3.28 (1H, m), 3.15 (2H, q, J = 6.4 Hz), 2.40-2.24 (6H, m), 1.76-1.48 (4H, m), 1.36-1.30 (2H, m), 1.32 (3H, s), 1.13 (3H, s), 1.16-1.06 (1H, m). (JEOL JNM-AL series AL400)

[0221] Reference Example 19 Synthesis of 2-[(4'aR,10'bR)-8'-chloro-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran]-1-yl]ethan-1-ol (Metabolite M) Potassium carbonate (3.99 g) and 2-bromoethanol (0.821 mL) were added to a solution of metabolite M4 (3.1 g) in acetonitrile (60 mL), and the mixture was stirred for 2 hours at 50° C. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was purified by aminosilica gel column chromatography (ethyl acetate) to give Reference Example 19 (3.05 g). １ H-NMR (400 MHz, DMSO-d6): 7.29 (1H, d, J = 8.0 Hz), 6.88 (1H, dd, J = 8.4, 2.4 Hz), 6.78 (1H, d, J = 2.4 Hz), 4.31 (1H, t, J = 5.6 Hz), 4.11 (1H, d, J = 10.4 Hz), 3.88 (1H, d, J = 10.8 Hz), 3.45 (2H, q, J = 6.4 Hz), 3.31-3.27 (1H, m), 2.41-2.24 (6H, m), 1.76-1.47 (4H, m), 1.36-1.29 (2H, m), 1.32 (3H, s), 1.13 (3H, s), 1.13-1.06 (1H, m). (JEOL JNM-AL series AL400)

[0222] The present invention will be described in more detail below with reference to examples, but is not limited thereto. The dosages (mg) in "1. Clinical trial in patients with WHO classification grade III or IV recurrent malignant glioma," "2. Clinical trial in patients with WHO classification grade II, III, or IV recurrent malignant glioma," and Examples 1 to 15 below are all dosages (mg) converted to the present compound (free form). For example, "Compound 1 was provided in a 20 mg capsule" means "Compound 1 was provided in a capsule containing 20 mg of active ingredient, converted to the present compound," and the capsule contains 29.4 mg of Compound 1. For example, "initial starting dose 20 mg / day" means "initial starting dose 20 mg / day, converted to the present compound," meaning that the initial starting dose of Compound 1 was 29.4 mg / day. For example, "20 mg QD" means "20 mg QD, converted to the present compound," meaning that 29.4 mg QD of Compound 1 was administered.

[0223] 1. Clinical Trial in Patients with WHO Classification Grade III or IV Recurrent Malignant Gliomas (1) Clinical Trial Design Overview This clinical trial is a Phase 1 dose-escalation study with a dose-expansion portion designed to evaluate the safety, PK, PD, and preliminary antitumor activity of oral administration of Compound 1 in patients with WHO Classification Grade III or IV recurrent malignant gliomas. Compound 1 was administered orally daily in this study. Safety and treatment response were assessed over 28-day cycles. Subjects were administered the drug until unacceptable toxicity, consent withdrawal, loss to follow-up, or discontinuation by the investigator and / or sponsor. The overall design of the clinical trial is outlined in Figure 1. This trial consists of two parts: a dose-escalation part (Part 1) and a dose-expansion part (Part 2). In the dose-escalation portion, Compound 1 was dose-escalated in patients with WHO grade III or IV malignant glioma to determine the maximum tolerated dose (MTD) and / or a recommended dose (RDE) below the MTD that is appropriate for the dose expansion portion. Compound 1 was provided in 20 mg and 60 mg capsules, equivalent to the compound. Once the MTD and / or RDE were established, the dose expansion portion of the study will begin. Approximately 20-40 patients with WHO grade IV recurrent glioblastoma (GBM) will be enrolled in the dose expansion portion to evaluate the preliminary clinical activity, safety, and tolerability of Compound 1. A Bayesian approach will be used to (a) estimate the posterior probability of achieving a response rate (ORR) of 15% or greater after reaching 10 ORR-evaluable subjects, and (b) guide enrollment in the dose expansion portion. At the end of the dose expansion portion, the dose selected by the sponsor in consultation with the investigators will be determined as the RP2D (recommended phase 2 dose) based on the safety, clinical activity, PK, and PD data collected during the study. Approximately 30-40 subjects were enrolled in the dose escalation portion of the study, and approximately 20-40 subjects will be enrolled in the dose expansion portion.

[0224] (2) Overall Clinical Trial Design: The initial dose of 20 mg / day was determined in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 guidance. Based on a 4-week mouse toxicity study conducted in accordance with Good Laboratory Practice (GLP), the dose at which severe toxicity occurred in 10% of test animals (STD10) was set at 50 mg / kg. Applying a safety factor of 10 and interspecies scaling, the starting dose for this first-in-human (FIH) study was calculated to be 0.4 mg / kg, resulting in a fixed dose of 24 mg for a 60 kg human. In a 4-week non-human primate toxicity study conducted in accordance with GLP, the maximum non-severe toxicity dose (HNSTD) was determined to be 7.5 mg / kg. Applying a safety factor of 6 and interspecies scaling, the starting dose in humans was estimated to be 0.4 mg / kg and a fixed dose of 24 mg. The final recommended starting dose for the FIH study was rounded to 20 mg / day. This recommended starting dose exceeds the minimum pharmacologically active dose in humans of 15 mg (3 mg / kg human equivalent dose (HED) that demonstrated consistent tumor regression in mice xenografted with U-87 GBM cells). Tentative dose levels are shown in Table 2. Alternative dosing schedules, e.g., twice-daily (BID), were initiated at a total daily dose of 480 mg to reduce pill burden (see the provisional dose levels table for details). Changing the dosing schedule from QD to BID is not expected to affect mean steady-state exposure relative to the total daily dose.

[0225] (3) Dose Escalation Part: An adaptive Bayesian logistic regression model (BLRM) following dose escalation with overdose control (EWOC) guided dose escalation. The MTD was estimated based on the occurrence of dose-limiting toxicity (DLT) during the DLT evaluation period (Cycle 1, 28 days after the start of study drug administration). Cohorts of 1 to 6 patients were evaluated at each dose level. In all cohorts, the first patient completed all safety evaluations on Day 8 of Cycle 1 before the second or subsequent patient was eligible for study drug administration. If a DLT was observed at a dose level, at least three patients were evaluated at that dose level. At dose level 2 of the dose escalation part, at least three patients were evaluated before escalation to a higher dose. After completion of a cohort, the MTD was estimated by updating the probability of DLT observation at each dose level in this study using the BLRM method using cumulative data from the previous cohort. The safety of each dose level was evaluated in a dose determination meeting (DDM), which consisted of representatives from the sponsor (the medical monitor, who chaired the meeting, the clinical planner, the statistician, and representatives from pharmacovigilance, clinical pharmacology, and biomarkers) and the investigators participating in the study. The primary objective of the DDM was to determine the dose and dosing schedule, as well as the number of subjects to be subsequently treated in the study. At the end of the DDM, the medical monitor, pharmacovigilance representatives, and the investigators agreed on subsequent dosing and enrollment decisions based on the protocol. The decision to escalate, decrease, or maintain the dose in the next cohort was made by reviewing the recommendation by the BLRM and other available data (PK, PD, and other clinical data such as subject demographics, medical history, history of previous cancer treatment, dose reduction / discontinuation, clinical test results, imaging test and performance status assessment results, AEs (adverse events), SAEs (serious adverse events), and whether DLTs were observed, for all subjects who received the study drug. Dose escalation within the same subject was optional and could be performed at the discretion of the investigator if a higher dose was shown to be safe and the subject might benefit from a dose increase.Intrasubject dose escalation was not permitted at any time within the first two cycles of treatment at the originally assigned dose level. To receive a higher dose of Compound 1, a subject must have tolerated the lower dose for at least two cycles of treatment (i.e., they must not have experienced CTCAE Grade 2 or higher Compound 1-related non-hematologic or hematologic toxicity at the initially assigned lower dose). Furthermore, the new higher dose a subject receives must be one that has been fully evaluated and does not exceed the MTD. There is no limit to the number of times a subject can receive an increased dose of Compound 1. For further dose escalations after the initial intrasubject dose escalation, the following rules were applied: the subject must not have experienced CTCAE Grade 2 or higher Compound 1-related non-hematologic or hematologic toxicity at the lower dose for at least the last two cycles of treatment. Furthermore, the higher dose being considered must have been fully evaluated and shown not to exceed the MTD.

[0226] (4) Dose Expansion Part: Once the MTD and / or RDE have been established, the dose expansion part will begin. Approximately 20-40 patients with WHO grade IV recurrent GBM will be enrolled in the dose expansion part to evaluate the preliminary antitumor activity of Compound 1 when administered at the MTD and / or RDE, and further evaluate safety and tolerability. At the end of the dose expansion part, the sponsor will select the dose in consultation with the investigators based on the safety, clinical activity, PK, and PD data collected during the study, and determine the RP2D. Using a Bayesian approach, (a) the posterior probability of achieving a response rate (ORR) of 15% or greater will be estimated after 10 or more subjects are evaluable for ORR, and (b) the number of subjects in the dose expansion part will be adjusted.

[0227] (5) Description of the Dose Escalation and Dose Expansion Parts Compound 1 was provided in 20 mg and 60 mg capsules. Compound 1 was administered orally daily, preferably with 200 mL or half a glass of water. Compound 1 was administered after at least 6 hours of fasting, with one hour of fasting following administration. For BID administration, for the morning dose, Compound 1 was administered after at least 6 hours of fasting, with one hour of fasting following administration. For the evening dose, Compound 1 was administered after two hours of fasting, with one hour of fasting following administration. The evening dose was administered approximately 12 hours after the morning dose. During the dose escalation part, subjects took the assigned dose until a discontinuation criterion was met. Subject compliance was monitored via patient medication diaries and / or investigational drug administration records at times specified by the sponsor. Subjects recorded their administration of Compound 1 using the patient medication diaries. In the dose expansion part, patients will receive the MTD and / or RDE determined in the dose escalation part until a discontinuation criterion is met. At the end of the dose expansion part, the sponsor will select the dose as the RP2D based on the safety, clinical activity, PK, and PD data collected during the study, in consultation with the investigator.

[0228] Example 1: Clinical Safety Evaluation of Compound 1 (1) As of the data cutoff date of April 21, 2023, 23 patients received Compound 1. The doses were 20 mg (2 patients), 40 mg (4 patients), 80 mg (3 patients), 120 mg (6 patients), 180 mg (3 patients), and 240 mg (5 patients). Twenty-one of the 23 patients (91.3%) discontinued Compound 1 at the time of the data cutoff, with the most common reason being disease progression (17 patients, 73.9%). Nine patients discontinued the study, with four due to death (all due to disease progression), two due to completion of the 12-month survival follow-up, and three due to the clinical trial termination at the study site due to investigator transfer. All 23 patients who received Compound 1 experienced new or worsening adverse events (TEAEs), most of which were reported by a single patient. TEAEs reported in more than 10% of patients are summarized in Table 3. The doses in Table 3 refer to the dose equivalent to the compound. For example, "20 mg of Compound 1" refers to 20 mg of Compound 1, meaning that 29.4 mg of Compound 1 was actually administered. Sixteen of 23 patients (69.6%) experienced TEAEs considered related to the study drug. Of these, TEAEs reported by two or more patients included nausea, increased alanine aminotransferase, increased aspartate aminotransferase, dry skin, decreased platelet count, vomiting, constipation, and decreased appetite. Grade 3 or higher TEAEs were observed in 13 patients (56.5%), the most common of which were seizures (4 patients, 17.4%), neutrophil count decreased (3 patients, 13.0%), aphasia, headache, decreased lymphocyte count, and decreased white blood cell count (2 patients, 8.7%). One patient experienced a Grade 3 or higher TEAE (dry skin) that was deemed to be related to Compound 1. Six patients (26.1%) experienced serious TEAEs (three seizures in the 20 mg, 120 mg, and 180 mg groups, one aphasia in the 120 mg group, one disease progression in the 40 mg group, and one neoplasm progression in the 240 mg group). None of these serious TEAEs were deemed to be related to Compound 1. Two patients died during the study due to TEAEs (one disease progression in the 40 mg group and one neoplasm progression in the 240 mg group).None were assessed as related to Compound 1. No dose-limiting toxicities were identified at any dose.

[0229] Example 2: Interim Report of Phase 1 First-in-Human Study of Compound 1 (1) Patient Background As of September 2023, 33 patients were enrolled. The median age was 51 years. Approximately 67% of patients had glioblastoma based on the WHO 2016 criteria, and approximately 45% had IDH1 mutations. Most patients had a history of prior treatment with total resection and radiation therapy (Figure 2).

[0230] (2) Dose Escalation and Dose-Limiting Toxicity As of September 2023, safety evaluations were completed for dose levels from 20 mg to 480 mg. No dose-limiting toxicities were reported from 20 mg to 240 mg. One patient in the 360 ​​mg cohort experienced a Grade 3 maculopapular rash, which was considered a DLT. The event resolved to Grade 1 upon discontinuation of treatment (Figure 3).

[0231] (3) Safety As of September 2023, the most common TEAEs were grade 1 or 2 nausea, vomiting, and asymptomatic ALT / AST elevations without increased bilirubin. No SAEs related to the study drug were reported. Only two grade 3 AEs related to the study drug were reported: dry skin and rash, which were manageable with dose adjustment or supportive care (Figure 4).

[0232] (4) Pharmacodynamics - Lathosterol / Zymostenol (L / Z) Ratio As of September 2023, pharmacodynamic evaluation clearly demonstrated that Compound 1 inhibited the target, at least in serum. The ratio of lathosterol to zymostenol, intermediates in EBP-mediated cholesterol biosynthesis, decreased by more than 80%, as observed in the 40 mg QD cohort (Figure 5).

[0233] (5) Treatment duration - dose escalation part (n = 33) The patients enrolled in the dose escalation part were heterogeneous, but it was notable that two patients with IDH-mutated grade III glioma (astrocytoma and oligodendroglioma, respectively) experienced shrinkage of target lesions and continued treatment for more than one year. One of these two patients achieved a complete response after one year of study treatment (Figure 6).

[0234] (6) Summary of Preliminary Antitumor Activity As of September 2023, preliminary antitumor activity of Compound 1 monotherapy was observed in four patients during the dose-escalation phase. Three of the four patients had grade III glioma with IDH mutations. All patients had received at least two prior therapies (Figure 7). The patient who achieved a complete response (CR) had grade III astrocytoma with IDH mutations and was administered 120 mg of Compound 1. This patient achieved a CR after more than one year of treatment (Figure 8).

[0235] (7) Conclusions Compound 1 is an investigational small-molecule inhibitor of EBP, a novel target that regulates cholesterol biosynthesis and modulates LXR downstream signaling pathways. Oral administration of compound 1 has been well tolerated to date, demonstrating favorable dose-dependent PK and PD responses. The most common TEAEs were grade 1 or 2 nausea, vomiting, and asymptomatic elevation of ALT / AST (bilirubin levels were within normal range). One DLT (grade 3 maculopapular rash at 360 mg QD) resolved to grade 1 with treatment interruption. Two patients with WHO grade III IDH-mutated gliomas experienced tumor shrinkage of 22% and 100%, respectively, and had been on study for 15 and 13 months, respectively, at the data cutoff. The dose-escalation portion will continue, and a dose-expansion portion for patients with IDH-mutated gliomas will begin.

[0236] Example 3: Clinical Safety Evaluation of Compound 1 (2) As of the data cutoff date of April 21, 2024, 39 patients received Compound 1. The doses were 20 mg QD (n = 2), 40 mg QD (n = 4), 80 mg QD (n = 3), 120 mg QD (n = 6), 180 mg QD (n = 6), 240 mg QD (n = 6), 360 mg QD (n = 6), and 480 mg daily (240 mg BID) (n = 6). Thirty-seven of the 39 patients (94.9%) had discontinued Compound 1 at the time of the data cutoff, with the most common reason for discontinuation being disease progression (27 patients, 69.2%). All 39 patients receiving Compound 1 experienced treatment-emergent or worsening adverse events (TEAEs). TEAEs reported in more than 10% of patients are summarized in Table 4. Here, the doses in Table 4 refer to doses converted to this compound. For example, "20 mg of Compound 1" means that "20 mg of Compound 1 converted to this compound" is included, and actually means that 29.4 mg of Compound 1 was administered. Thirty of 39 patients (76.9%) experienced TEAEs that were considered to be related to the study drug. Of these, TEAEs reported by two or more patients were nausea, increased alanine aminotransferase, vomiting, increased aspartate aminotransferase, constipation, diarrhea, dry skin, maculopapular rash, hair loss, fatigue, decreased platelet count, and decreased appetite. Grade 3 or higher TEAEs were observed in 23 patients (59.0%), the most common of which were seizures (5 patients, 12.8%), fatigue (4 patients, 10.3%), aphasia, headache, decreased lymphocyte count, and decreased neutrophil count (3 patients, 7.7%), dry skin, maculopapular rash, decreased white blood cell count, and increased alanine aminotransferase (2 patients, 5.1%). Grade 3 or higher TEAEs considered related to Compound 1 were dry skin (2 patients, 5.1%), maculopapular rash (2 patients, 5.1%), and fatigue (1 patient, 2.6%).Serious TEAEs occurred in 9 patients (23.1%) (4 patients with seizures (1 in the 20 mg QD group, 1 in the 120 mg QD group, and 2 in the 180 mg QD group), 1 patient with disease progression (40 mg QD group), 1 patient with aphasia (1 in the 120 mg QD group), 1 patient with neoplasm progression (240 mg QD group), and 1 patient each with confusional state and fatigue (480 mg daily [240 mg BID] group). Of these serious TEAEs, 9 were considered related to Compound 1. Two patients died from TEAEs during the study (1 patient with disease progression in the 40 mg QD group and 1 patient with neoplasm progression in the 240 mg QD group). Neither of these events was evaluated as related to Compound 1. No DLTs were observed from 20 mg QD to 240 mg QD. One patient at 360 mg QD reported a DLT (grade 3 maculopapular rash). This event resolved to grade 1 after treatment interruption. Two patients at 480 mg daily (240 mg BID) reported DLTs: grade 3 maculopapular rash and grade 2 nausea and vomiting. The grade 3 maculopapular rash resolved to grade 1 after discontinuation of Compound 1. The grade 2 nausea and vomiting resolved to grade 1 after dose reduction and treatment interruption. Based on these results, the MTD was determined to be 480 mg daily (240 mg BID), and dose escalation was completed.

[0237] Example 4: Evaluation of preliminary antitumor activity of compound 1 As of the data cutoff on April 21, 2024, of the 39 patients enrolled in the dose-escalation portion, two patients with IDH-mutated grade III astrocytomas had 22% and 100% reduction in enhancing lesions based on RANO criteria and remained on study for 15 and 20 months, respectively (Figure 9).

[0238] Example 5: Pharmacodynamic Evaluation of Compound 1 As of April 2024, pharmacodynamic evaluation of 39 patients enrolled in the dose-escalation portion demonstrated that Compound 1 inhibited the target, at least in serum. Across the entire cohort, the mean L / Z ratio rapidly decreased after administration of Compound 1. By day 2 of cycle 1 (C1D2), the L / Z ratio decreased by 70% at 20 mg QD, 85-91% at 40 mg to 120 mg QD, 95-97% at 180 mg QD and 240 mg QD, respectively, and 97.5% at 360 mg QD. By C1D8, the L / Z ratio decreased to approximately 100% at doses from 20 mg QD to 360 mg QD, and this level was maintained in subsequent cycles. A strong dose-dependent relationship was observed between 20 mg and 40 mg, but the change was more gradual between 40 mg and 360 mg. Data for 180 mg QD, 240 mg QD, and 360 mg QD were comparable. Patients at 480 mg daily (240 mg BID) did not demonstrate a greater decrease in L / Z ratio than those at the 180 mg QD through 360 mg QD dose levels (Figure 10).

[0239] Example 6: Pharmacokinetic evaluation of Compound 1 (1) Summary statistics for the pharmacokinetics of Compound 1 were obtained from preliminary data of patients in the 20 mg once-daily to 240 mg once-daily groups (Table 5). The mean plasma concentration-time curves for Compound 1 in the 20 mg once-daily to 240 mg once-daily groups are shown in Figure 11 (in Figure 11, Compound 1 is referred to as Compound 1). In this evaluation study, one cycle is 28 days, and Cycle 1 Day 1 refers to the first day of the first cycle. In all dose groups, the geometric mean values ​​of Cmax and AUC on Cycle 1 Day 1 were 4 to 145 ng / mL. 0-24 The geometric mean values ​​of Cmax and AUC on Cycle 2 Day 1 were 27.7-359 ng / mL and 27.7-359 ng / mL, respectively, and the median Tmax was 2-8 hours. 0-24 The geometric mean values ​​of Cmax and AUC were 556.5 to 6671 ng*h / mL, and the median Tmax was 2 to 7 hours. Accumulation was observed after repeated administration. 0-24The mean accumulation ratios of Compound 1 were 2.6 to 6.2 and 3.9 to 8.6, respectively. Based on these accumulation ratios, the half-life of Compound 1 was considered to be approximately 4 days. Based on currently available data, the plasma concentration reached a steady state by Day 15. On Cycle 1 Day 1 and Cycle 2 Day 1, the exposure of Compound 1 (Cmax and AUC 0-24 ) increased (Data Cut-off: April 2023). In the table, AR indicates the accumulation ratio, and NC indicates that it was not calculated.

[0240] Example 7: Pharmacokinetic Evaluation of Compound 1 (2) Preliminary summary statistics for the pharmacokinetics of Compound 1 were obtained for patients in the 20 mg QD, 40 mg QD, 80 mg QD, 120 mg QD, 180 mg QD, 240 mg QD, 360 mg QD, and 480 mg daily (240 mg BID) groups (Table 6). The mean plasma concentration-time curves for Compound 1 in the 20 mg QD to 480 mg daily (240 mg BID) groups are shown in Figure 12 (in Figure 12, Compound 1 is referred to as DSP-0390). In this evaluation study, one cycle was 28 days, and Cycle 1 Day 1 refers to Day 1 of the first cycle. Preliminary pharmacokinetic data indicated that Compound 1 exposure increased with dose escalation from 20 mg to 360 mg QD. The median Tmax ranged from 2 to 8 hours. Accumulation was observed with repeated administration, and assuming linearity based on the observed accumulation rate, the estimated elimination half-life was thought to be several days (approximately 1 to 6 days) (Data Cut-off: March 2024). [a] Median [b] AUCtau: Area under the plasma concentration-time curve during the dosing interval (tau) (tau = 24 hours for QD, 12 hours for BID); AR: Accumulation ratio

[0241] Example 8: Determination of the recommended dose for dose expansion (RDE) As described in Example 3, the MTD of Compound 1 was determined to be 480 mg daily (240 mg BID). Furthermore, with increasing dose, Grade 2 or 3 adverse events related to Compound 1 were observed more frequently, particularly in the 240 mg QD and higher dose groups compared with the 180 mg and lower dose groups, suggesting dose-dependent toxicity. Evaluation of PK / PD data showed that Compound 1 exposure increased dose-dependently from 20 mg QD to 360 mg QD. Meanwhile, the blood L / Z ratio remained at the same level from the 180 mg QD group to the 360 ​​mg QD group, suggesting a plateau (Figure 13). Preliminary antitumor efficacy evaluations demonstrated tumor shrinkage at 20 mg QD and 120 mg QD (22% and 100% reductions from baseline at 20 mg QD and 120 mg QD, respectively), and long-term stable disease was observed at 180 mg QD and 240 mg QD. However, at 360 mg QD and 480 mg daily (240 mg BID), most patients discontinued compound 1 within two months due to objective disease progression as assessed by RANO. Therefore, the clinical activity of compound 1 was observed at doses of 240 mg or less, and no dose-dependent increase in antitumor efficacy was observed. Based on all available clinical data and discussions with all clinical investigators and the sponsor, 180 mg QD was selected as the RDE dose, as it is expected to be long-term tolerable and effective.

[0242] 2. Clinical Trial in Patients with WHO Classification Grade II, III, or IV Recurrent Malignant Gliomas (1) Clinical Trial Design Overview This clinical trial is a Phase 1 dose-escalation study with a dose-expansion portion designed to evaluate the safety, PK, PD, and preliminary antitumor activity of oral administration of Compound 1 in patients with WHO Classification Grade II, III, or IV recurrent malignant gliomas. Compound 1 will be administered orally daily in this study. Safety and treatment response will be assessed over 28-day cycles. Subjects will continue treatment until unacceptable toxicity, consent withdrawal, loss to follow-up, or discontinuation by the investigator and / or sponsor. The overall design of the clinical trial is outlined in Figure 14. This clinical trial consists of two parts: a dose-escalation part (Part 1) and a dose-expansion part (Part 2). In the dose-escalation portion, the dose of Compound 1 will be titrated in patients with WHO grade II, III, or IV malignant gliomas to determine the MTD and / or a recommended dose expansion (RDE) below the MTD that is appropriate for the dose expansion portion. Once the MTD and / or RDE are established, the dose expansion portion will begin in patients with IDH-mutated WHO grade II or III non-enhancing gliomas to evaluate the preliminary clinical activity, as well as the safety and tolerability of Compound 1. Approximately 30-50 subjects will be enrolled in the dose-escalation portion of this clinical trial, and approximately 20-30 subjects will be enrolled in the dose-expansion portion. Because the number of subjects (in each cohort) dynamically changes in the Bayesian adaptive design, the exact number of subjects cannot be determined in advance.

[0243] (2) Overall Clinical Trial Design: The initial dose of 20 mg / day was determined in accordance with the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 guidance. Based on a 4-week mouse toxicity study conducted in accordance with Good Laboratory Practice (GLP), the dose at which severe toxicity occurred in 10% of test animals (STD10) was set at 50 mg / kg. Applying a safety factor of 10 and interspecies scaling, the starting dose for this first-in-human (FIH) study was calculated to be 0.4 mg / kg, resulting in a fixed dose of 24 mg for a 60 kg human. In a 4-week non-human primate toxicity study conducted in accordance with GLP, the maximum non-severe toxicity dose (HNSTD) was determined to be 7.5 mg / kg. Applying a safety factor of 6 and interspecies scaling, the starting dose in humans was estimated to be 0.4 mg / kg and a fixed dose of 24 mg. The final recommended starting dose for the FIH study was rounded to 20 mg / day. This recommended starting dose exceeds the minimum pharmacologically active dose in humans of 15 mg (3 mg / kg human equivalent dose (HED) that demonstrated consistent tumor regression in mice xenografted with U-87 GBM cells). Tentative dose levels are shown in Table 7. Alternative dosing schedules, such as twice-daily (BID) dosing, can be initiated at a total daily dose of 480 mg to reduce pill burden (see the provisional dose levels table for details). Changing the dosing schedule from QD to BID is not expected to affect average steady-state exposure relative to the total daily dose.

[0244] (3) Dose Escalation Part: An adaptive Bayesian logistic regression model (BLRM, Section 20.1) following dose escalation with overdose control (EWOC) will guide dose escalation, and the MTD will be estimated based on the occurrence of DLTs during the DLT assessment period (Cycle 1, 28 days after the start of study drug administration). Each dose level will be evaluated in a cohort consisting of approximately 1 to 6 patients. In all cohorts, the second and subsequent patients will be eligible for study drug administration after the completion of all safety evaluations on Day 8 of Cycle 1 for the first patient. If a DLT is observed at a certain dose level, at least three patients will be evaluated at that dose level. At dose level 2 of the dose escalation part, at least three patients will be evaluated before escalation to a higher dose. After completion of a cohort, the MTD will be estimated by updating the probability of DLTs observed at each dose level in this study using the BLRM method using cumulative data from the previous cohort. The safety of each dose level is evaluated in a dose determination meeting (DDM), which is comprised of representatives from the sponsor (the medical monitor, who chairs the meeting, the clinical planner, the statistician, and representatives from pharmacovigilance, clinical pharmacology, and biomarkers) and the investigators participating in the trial. External experts (e.g., ophthalmologists) may also be consulted as necessary. The primary purpose of the DDM is to determine the dose and dosing schedule and the number of subjects to be subsequently treated in the trial. Representatives from all study sites (preferably including the investigator) are invited to participate in the DDM, but participation is required only for sites with active study subjects. At the end of the DDM, the medical monitor, pharmacovigilance representative, and investigators agree on subsequent dosing and enrollment decisions in accordance with the protocol. A DDM is required if the required number of subjects completes the minimum evaluation period or a certain number of DLTs occur, as specified in the protocol.The decision to escalate, deescalate, or maintain the dose in the next cohort will be made by reviewing the BLRM recommendation and other available data (PK, PD, and other clinical data, such as demographics, medical history, prior cancer treatment history, and study drug administration data, including dose reductions / discontinuations, laboratory test results, imaging and performance status assessment results, and the presence or absence of AEs, SAEs, and DLTs, for all subjects who received the study drug). Based on the Bayesian logistic regression model (BLRM) and the principles of dose escalation with overdose control (EWOC), additional intermediate dose levels may be added during the dose escalation phase. Once a dose is evaluated and deemed safe, additional subjects may be enrolled as an enrichment cohort for that dose to obtain data to further evaluate the dose's safety and tolerability, preliminary antitumor activity, PK, and PD. Enrichment cohorts do not require a one-week waiting period between the first and subsequent subjects. Intrasubject dose escalation is optional and may be performed at the investigator's discretion if the higher dose is shown to be safe and the subject may benefit from it. Intrasubject dose escalation is not permitted at any time within the first two cycles of treatment at the originally assigned dose level. After completion of Cycle 2, individual subjects may be considered for treatment with Compound 1 at a higher dose than the originally assigned dose. To receive Compound 1 at a higher dose, a subject must have tolerated the lower dose for at least two cycles of treatment (i.e., they must not have experienced CTCAE Grade 2 or higher Compound 1-related non-hematologic or hematologic toxicity at the originally assigned lower dose). Furthermore, the new higher dose a subject receives must be one that has been fully evaluated and does not exceed the MTD. There is no limit to the number of times a subject's Compound 1 dose can be increased. The following rules apply to further dose escalations after the initial intrasubject dose escalation:That is, subjects must not have experienced Compound 1-related non-hematologic or hematologic toxicity of CTCAE Grade 2 or greater at lower doses in at least the last two cycles of treatment, and any higher doses being considered must be adequately evaluated and shown not to exceed the MTD.

[0245] (4) Dose Expansion Part: Once the MTD and / or RDE have been established, the dose expansion part will begin. Approximately 20–30 patients with WHO grade II or III IDH-mutant recurrent non-enhancing glioma will be enrolled in the dose expansion part to evaluate the preliminary antitumor activity of Compound 1 at the selected dose and further evaluate safety and tolerability. A Bayesian approach may be used to assess the posterior probability of achieving ORR (complete response (CR), partial response (PR), or minor response (MR)) based on RANO-LGG. During the dose expansion part, DLT incidence will be monitored using the BLRM model and dose escalation with overdose control (EWOC). If one or more DLTs occur during dose expansion, the BLRM model will be initially fitted at the time of the first DLT. Dose expansion will be discontinued only if a lower dose is suggested by the BLRM model and jointly decided by the sponsor and investigators based on review of model estimates and evaluation of available safety, PK, PD, and other clinical data. If DLTs occur, the BLRM model will be refitted, and the decision to discontinue the dose expansion portion will be made according to the procedure described above after the first DLT occurs. Furthermore, in the dose expansion portion, which will begin after the MTD and / or RDE have been established, case enrollment will be limited to patients with specific genetic abnormalities. These specific genetic abnormalities are those for which compound 1 is expected to be effective, such as IDH. Recently, a phase 3 trial of vorasidenib, a dual inhibitor of IDH1 and IDH2 mutant enzymes, demonstrated that patients with grade 2 IDH-mutant gliomas for whom observation was considered appropriate had a longer progression-free survival compared with placebo and delayed the initiation of subsequent anticancer drug therapy. Furthermore, new evidence is accumulating regarding the relationship between IDH-mutant low-grade gliomas and cholesterol metabolism. A recent study reported that IDH mutations in gliomas increase 24(S)-hydroxycholesterol (24-OHC), thereby lowering cholesterol levels and activating LXR. As a result, IDH1-mutated glioma cells become more sensitive to atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase.Furthermore, recent bioinformatics analyses have shown that cholesterol metabolism plays an important role in immunosuppression in low-grade gliomas and serves as an independent prognostic factor for these tumors. Therefore, regulation of cholesterol biosynthesis in IDH-mutant gliomas may be a therapeutic target.

[0246] (5) Description of the Dose Escalation and Dose Expansion Parts Compound 1 is provided in 20 mg and 60 mg capsules. Compound 1 is administered orally daily, preferably with 200 mL or half a glass of water. Compound 1 is administered after at least 6 hours of fasting, with one hour of fasting following dosing. Alternative dosing regimens (e.g., BID) may be considered. For BID dosing, for the morning dose, Compound 1 is administered after at least 6 hours of fasting, with one hour of fasting following dosing. For the evening dose, Compound 1 is administered after two hours of fasting, with one hour of fasting following dosing. The evening dose is administered approximately 12 hours after the morning dose. During the dose escalation part, subjects will receive their assigned dose until a discontinuation criterion is met. Based on recommendations from the BLRM and review of safety data, intermediate dose levels may be explored rather than those listed as interim dose levels. Additionally, certain interim dose levels may be skipped, provided that the maximum dose escalation to the next cohort does not exceed 100%. Subject compliance will be monitored via patient diaries and / or investigational drug administration records at times specified by the sponsor. Subjects will record their Compound 1 dosing using patient diaries. The recommended dose for the dose expansion part will be determined based on all data obtained in the dose escalation part, including safety, PK, PD, and preliminary clinical activity. At the end of the dose expansion part, additional subjects at one or more dose levels may be considered for dose optimization based on the safety, clinical activity, PK, and PD data collected during the study.

[0247] Example 9: In vivo evaluation test of efficacy in combination with bevacizumab Luciferase-expressing U-87 cells (obtained from ATCC (American Type Culture Collection)) were established by forcibly expressing luciferase, a luminescent enzyme.６ The cells were transplanted into the brains of immunodeficient mice to form brain tumors. On day 18 after tumor cell transplantation, compound 1 was administered at 10 mg / kg (twice daily) and bevacizumab at 1 mg / kg (twice weekly). On day 30, compound 1 was administered once daily. The efficacy of each agent alone and in combination was compared by quantifying the orthotopic tumor kinetics using an IVIS Imaging System. The results are shown in Figure 15. It was revealed that compound 1 exhibited a particularly significant antitumor effect when used in combination with bevacizumab.

[0248] Example 10: In vivo evaluation of efficacy of combination therapy with ipilimumab MC38 cells 3x10 ５ The cells were intradermally transplanted into C57BL / 6j mice (n=6) to form tumors. 12 days after transplantation, Compound 1 was administered at 3 mg / kg or 30 mg / kg (once daily) and ipilimumab (anti-CTLA-4 antibody) at 5 mg / kg (once weekly), and the efficacy of each agent alone and in combination was compared. 3x10 B16 cells were transplanted intradermally into C57BL / 6j mice (n=6) to form tumors. 12 days after transplantation, Compound 1 was administered at 3 mg / kg or 30 mg / kg (once daily) and ipilimumab (anti-CTLA-4 antibody) at 5 mg / kg (once weekly), and the efficacy of each agent alone and in combination was compared. ５ The cells were intradermally transplanted into C57BL / 6j mice (n=6) to allow tumor formation. On day 12 after transplantation, administration of Compound 1 at 3 mg / kg or 10 mg / kg (once daily) and ipilimumab (anti-CTLA-4 antibody) at 5 mg / kg (once weekly) was initiated, and the efficacy of each agent alone and in combination was compared. The results for mice transplanted with MC38 cells are shown in Figure 16, and the results for mice transplanted with B16 cells are shown in Figure 17. Tumor volume was calculated using the following formula using the minor and major diameters of the tumor measured with an electronic caliper (Mitutoyo). Tumor volume [mm ３ ]=0.5×(breadth [mm]) ２ × major axis [mm] The control group administered with only the solvent was compared with the test substance administered 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 administered group - tumor volume at the start of administration in the test substance administered group) / (tumor volume at the end of administration in the control administered group - tumor volume at the start of administration in the control administered group) × 100

[0249] In a combination efficacy evaluation test using mice transplanted with MC38 cells, compound 1, when used in combination with ipilimumab, exhibited a particularly significant antitumor effect. Furthermore, compound 1 showed a more pronounced effect at higher doses, demonstrating a concentration-dependent synergistic effect. In a combination efficacy evaluation test using mice transplanted with B16 cells, compound 1, when used in combination with ipilimumab, exhibited a particularly significant antitumor effect. Furthermore, compound 1 showed a more pronounced effect at higher doses, demonstrating a concentration-dependent synergistic effect. This tumor-bearing mouse model is known as a model of ipilimumab resistance, and compound 1 is thought to contribute to improving that resistance.

[0250] Compound 1 has been shown to be safe at doses of 20 to 240 mg once daily (QD) (Example 1), and clinical results suggesting efficacy have been obtained at doses of 20 to 240 mg QD (Example 2). Therefore, safety and efficacy can be guaranteed even at doses of 240 mg QD or higher. Additional studies demonstrated the safety and efficacy of compound 1 at doses of 20 to 360 mg QD (Examples 3 and 4). Based on all available clinical data, the RDE was determined to be 180 mg QD, which is expected to be long-term tolerable and effective (Example 8). Furthermore, compound 1 demonstrated particularly significant antitumor effects in combination with bevacizumab (Example 9). Compound 1 also demonstrated particularly significant antitumor effects in combination with ipilimumab (Example 10). In particular, in B16 cell tumor-bearing mice, a model of ipilimumab resistance, Compound 1 showed a significant antitumor effect when used in combination with ipilimumab, and it was confirmed that Compound 1 contributed to improving the resistance (Example 10).

[0251] Example 11: Evaluation of efficacy in an anti-PD-1 antibody drug resistance in vivo model B16 cells (obtained from JCRB cell bank) 5 x 10 ５The cells were intradermally transplanted into C57BL / 6j mice to allow tumor formation. 12 days after transplantation, Compound 1 was administered at 10 mg / kg (once daily) or anti-PD-1 antibody (nivolumab) at 5 mg / kg (once weekly), and the efficacy of each single-agent treatment group was compared with that of the control group.

[0252] The compound 1 group showed statistically significant suppression of tumor growth in the B16 tumor-bearing model, a cancer model resistant to anti-PD-1 antibodies, compared with the nivolumab group (Figure 18). In other words, compound 1 demonstrated a tumor growth inhibitory effect as a single agent against cancer resistant to anti-PD-1 antibodies.

[0253] Example 12: Cytotoxicity test of IDH1R132H mutant U-87 cells in in vitro sphere culture with low-density lipoprotein (LDL) added. It is generally believed that the blood-brain barrier prevents the penetration of peripheral LDL into brain tumor tissue, and brain tumor cells are thought to proliferate via the endogenous cholesterol synthesis pathway. However, in recent years, it has been reported that the normality of the blood-brain barrier is not maintained due to tissue damage caused by the progression of glioma and standard treatments such as surgery, radiation therapy, and chemotherapy. In other words, it is thought that disruption of the blood-brain barrier may result in the migration of LDL from the periphery to brain tissue, increasing the LDL concentration in glioma.

[0254] This compound exerts cytotoxicity against cancer cells in a manner dependent on the intracellular cholesterol synthesis pathway. However, it has been reported that when low-density lipoprotein (LDL) is added to cells and the intracellular LDL concentration increases, the compound becomes independent of the intracellular cholesterol synthesis pathway (PLoS One. 2012; 7(6): e39445.). This suggests that the cytotoxicity of this compound due to EBP inhibition is significantly reduced because cholesterol is supplied from an alternative pathway.

[0255] It has been reported that the IDH1R132H mutation reduces LDL receptor expression levels (Oncogene (2020) 39:6340-6353). In other words, even if LDL is added to cells, the LDL concentration in cells with the mutation before addition is lower than in wild-type cells. Therefore, the contribution of cholesterol supply via the intracellular cholesterol synthesis pathway is still significant, and this compound is thought to exhibit stronger cytotoxicity through EBP inhibition in mutant cells.

[0256] U-87 cells were established with a tetracycline-IDH1R132H mutation regulatory system. The cells were cultured for 5 days in the presence of 1 μM doxycycline, a tetracycline derivative, to induce the IDH1R132H mutation. After mutation induction, the cells were transferred to sphere medium (medium containing B-27 supplement, epidermal growth factor, cell proliferation factor, insulin, and low-density lipoprotein (LDL)) and cultured for 7 days under sphere-forming conditions with the addition of 1 μM compound 1. The LDL concentration was 5 μg / ml. After culture, the ATP content of the cultured cells was quantified as an indicator of cell viability. The cell viability was calculated as the ratio of the ATP content to that under solvent alone, and the cytotoxicity of this compound under LDL-containing conditions was compared between the wild-type (doxycycline-) and mutant (doxycycline-) cells.

[0257] The cytotoxicity of Compound 1 was confirmed in an IDH1 wild-type cell line and an IDH1R132H mutant cell line, which has a lower intracellular LDL concentration compared to the IDH1 wild-type, under LDL-added conditions. As a result, as shown in Figure 19, under conditions where LDL was added at a high concentration, Compound 1 exhibited statistically significantly stronger cytotoxicity in the IDH1R132H mutant cell line compared to the wild-type cell line.

[0258] Example 13: Cytotoxicity evaluation test of U-87 cells (IDH1 wild-type) in vitro in sphere culture with low-density lipoprotein (LDL) added U-87 cells added with 3.3 / 10 / 30 μM of the cholesterol absorption inhibitor ezetimibe, U-87 cells added with 1 μM of Compound 1, and U-87 cells added with both agents were cultured for 7 days in sphere medium added with LDL to a concentration of 5 μg / ml. Cell viability was calculated in the same manner as in Example 12, and cytotoxicity when each agent was added alone was compared with when the agents were added in combination.

[0259] The cytotoxicity of a combination of Compound 1 and ezetimibe was evaluated in U-87 cells (IDH1 wild-type) under high LDL concentration conditions based on Example 13. As a result, as shown in Figure 20, each agent alone had low cytotoxicity in IDH1 wild-type cells under high LDL concentration conditions, but the combined use of Compound 1 and ezetimibe showed strong cytotoxicity.

[0260] While this compound exhibits significant cytotoxicity in cell culture systems dependent on the intracellular cholesterol synthesis pathway, as mentioned above, it may be affected by elevated LDL levels due to the breakdown of the blood-brain barrier. However, it is believed that sufficient cytotoxicity is exerted in gliomas that are less susceptible to elevated LDL levels, such as IDH1R132H mutant gliomas (Example 12). Furthermore, even in gliomas with elevated LDL levels, it is believed that the compound exhibits strong cytotoxicity when used in combination with a cholesterol absorption inhibitor, thereby exhibiting antitumor effects (Example 13).

[0261] Example 14: Cytotoxicity Test Using Active Metabolites in In Vitro Sphere Cultures. The major metabolic pathways of this compound were identified as oxidative metabolism of the imidazole ring (M2), N-dealkylation (M4), and hydroxylation (M5) in vitro (mice, rabbits, monkeys, and humans), and oxidative metabolism of the imidazole ring (M2) and N-dealkylation (M4) in vivo (mice and monkeys). Other metabolic pathways included oxidative elimination and carboxylation of imidazole (M1), N-dealkylation and oxidation (M3), oxidative metabolism of the N-ethyl-imidazole moiety (M6 and M7), and conjugation of N-acetylglucosamine (M8) (Figure 21). Metabolites detected in the human substrate were also observed in animal hepatocytes, and no human-specific metabolites were identified. There were no significant species differences in the metabolite profile of this compound.

[0262] In the following metabolite identification test, the structures of the metabolites (M2, M4, and M5) detected in mouse and monkey plasma were confirmed by comparison with the synthetic standard products of Reference Examples 18, 9, and 19. The LC / MS / MS analysis conditions used for metabolite identification were as follows:

[0263] LC / MS / MS system: Detection equipment: API5500 Qtrap LC / MS / MS (Sciex) Detection mode: MRM mode, positive ion detection mode HPLC: Nexera X2 (Shimadzu) Column: Cadenza CD-C18 (3 μm, 2.0 mm ID x 50 mm) Flow rate: 0.4 mL / min Condition 1 (for measuring compound 1, metabolites M2 and M4) Mobile phase: Solution A: 10 mM ammonium acetate aqueous solution, Solution B: methanol Gradient conditions: 0.0-0.3 min B 40%, 0.3-1.7 min B 40% to 90%, 1.7-3.7 min B 90%, 3.71-5.5 min B 40% Condition 2 (for measurement of Compound 1 and Metabolite M5) Mobile phase: Solution A: 10 mM ammonium acetate aqueous solution, Solution B: 0.1% formic acid / acetonitrile Gradient conditions: 0.0-3.0 min B 10% to 90%, 3.0-3.5 min B 90%, 3.51-5.0 min B 10%

[0264] Acetonitrile was added to the plasma of mice and monkeys administered with Compound 1 to remove proteins, and the centrifuged supernatant was used as a sample for LC / MS / MS measurement. Standard solutions of synthesized Compound 1, Reference Example 18, Reference Example 9, and Reference Example 19, prepared with acetonitrile, were added to blank plasma of mice and monkeys not administered with Compound 1 to remove proteins, and the centrifuged supernatant was used as a sample for LC / MS / MS measurement.

[0265] The LC / MS / MS measurement results are shown in the table below. Under each condition, the target ions were separated and further fragmented in Q1, and then the separated compound-specific product ions were selected and detected in Q3.

[0266] As shown in the above table, it was confirmed that the retention times of the metabolites (M2, M4, and M5) contained in the plasma of mice and monkeys administered with Compound 1 were consistent with those of the synthesized compounds of Reference Examples 18, 9, and 19. Therefore, it was demonstrated that the compound structures of metabolites M2, M4, and M5 in Figure 21 were correct.

[0267] U-87 cells were cultured in the presence of metabolites M2, M4, and M5 in Sphere medium for 7 days. After the culture, the amount of ATP in the cultured cells was quantified as an index of cell survival, and the cell viability was calculated in the same manner as in Example 12, and the cytotoxicity was compared.

[0268] As a result, as shown in Figure 22, metabolites M2, M4, and M5 exhibited cytotoxicity in sphere culture using U-87 cells. ５０ The values ​​were 3.6 μM for M2, 1.6 μM for M3, and 2.1 μM for M5.

[0269] Example 15: Cytotoxicity test of low-grade glioma-derived cell line in sphere culture U-87 cells (IDH1 wild-type) and BT142 cells (IDH1 mutant, R132H / -), derived from low-grade glioma, were cultured in LDL-supplemented sphere medium for 7 days in the presence or absence of 1 μM Compound 1. The LDL concentration was 5 μg / ml. After culture, the ATP level of the cultured cells was quantified as an indicator of cell viability, and cytotoxicity was compared.

[0270] As a result, as shown in FIG. 23, Compound 1 exhibited significant cytotoxicity in the cell line BT142 derived from low-grade glioma, even in the presence of LDL.

[0271] As described in Example 12, in glioma tissues where the blood-brain barrier may be disrupted, the intracellular LDL concentration is elevated, which may result in an effect of not depending on the intracellular cholesterol synthesis pathway. However, the results of this Example 15 suggest that in target diseases such as low-grade gliomas, where IDH1 mutations are clinically observed, the effect is reduced even under conditions of high LDL concentrations, and Compound 1 exhibits sufficient cytotoxicity. Therefore, it is thought that low-grade gliomas may be one of the indications for Compound 1.

[0272] The medicament of the present disclosure comprises a dihydrochromene derivative or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, and can be used as a medicament for treating or preventing cancer.

Claims

1. A medicine for treating or preventing cancer, comprising (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (hereinafter also referred to as "the compound"), or a pharma- ceutical acceptable salt thereof, or a hydrate or solvate thereof, as an active ingredient, wherein the medicine is orally administered to a subject.

2. The medicine according to claim 1, wherein the active ingredient is (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] diphosphate, or a hydrate or solvate thereof.

3. The medicine according to claim 1, wherein the active ingredient is the diphosphate salt of (4'aR,10'bR)-8'-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5',5'-dimethyl-4'a,10'b-dihydro-2'H,4'H,5'H-spiro[piperidine-4,3'-pyrano[3,2-c][1]benzopyran] (referred to as "Compound 1").

4. The medicine according to any one of claims 1 to 3, which is orally administered to a subject once a day.

5. The medicament according to any one of claims 1 to 3, characterized in that the medicament is orally administered to the subject twice a day.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 20 mg of the compound.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 40 mg of the compound.

8. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 60 mg of the compound.

9. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 80 mg of the compound.

10. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 100 mg of the compound.

11. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 120 mg of the compound.

12. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 140 mg of the compound.

13. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 160 mg of the compound.

14. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 180 mg of the compound.

15. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 200 mg of the compound.

16. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 220 mg of the compound.

17. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 240 mg of the compound.

18. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 260 mg of the compound.

19. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 280 mg of the compound.

20. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 300 mg of the compound.

21. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 320 mg of the compound.

22. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 340 mg of the compound.

23. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 360 mg of the compound.

24. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 380 mg of the compound.

25. The pharmaceutical composition according to any one of claims 1 to 5, wherein the single dose of the active ingredient is 400 mg of the compound.

26. The medicament according to any one of claims 1 to 25, for treating cancer in combination with a concomitant drug or a pharma- ceutical acceptable salt thereof, wherein the concomitant drug is at least one selected from the group consisting of antitumor alkylating agents, antitumor antimetabolites, antitumor antibiotics, plant-derived antitumor drugs, 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, enzyme inhibitors, cholesterol absorption inhibitors, and other antitumor agents.

27. The pharmaceutical according to any one of claims 1 to 25, for use in combination with a concomitant drug or a pharma- ceutical acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one selected from the group consisting of antitumor alkylating agents, antitumor monoclonal antibodies, immune checkpoint inhibitors, enzyme inhibitors, cholesterol absorption inhibitors, and other antitumor agents.

28. The pharmaceutical according to claim 26 or 27, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

29. The pharmaceutical composition of claim 28, wherein the anti-PD-1 antibody or anti-PD-L1 antibody is pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, cemiplimab, dostallimab, toripalimab, or tislelizumab.

30. The pharmaceutical composition according to claim 26 or 27, wherein the antitumor monoclonal antibody is bevacizumab or ipilimumab.

31. The pharmaceutical composition of claim 26 or 27, wherein the antitumor alkylating agent is temozolomide.

32. The pharmaceutical composition of claim 26 or 27, wherein the enzyme inhibitor is an IDH inhibitor.

33. The pharmaceutical agent according to claim 32, wherein the IDH inhibitor is ivosidenib, vorasidenib, ortasidenib, or enasidenib.

34. The pharmaceutical composition of claim 26 or 27, wherein the enzyme inhibitor is an IDH1 inhibitor.

35. The pharmaceutical agent according to claim 34, wherein the IDH1 inhibitor is ivosidenib, vorasidenib, or ortasidenib.

36. The pharmaceutical composition of claim 26 or 27, wherein the cholesterol absorption inhibitor is ezetimibe.

37. The pharmaceutical composition according to any one of claims 1 to 25, for use in combination with a concomitant drug or a pharma- ceutical acceptable salt thereof to treat cancer, wherein the concomitant drug is at least one selected from the group consisting of: (1) bevacizumab, (2) ipilimumab, (3) temozolomide, (4) ivosidenib, (5) vorasidenib, and (6) ezetimibe.

38. A pharmaceutical agent according to any one of claims 1 to 37, which is used in combination with a cellular medicine.

39. The pharmaceutical according to claim 38, wherein the cellular pharmaceutical is a chimeric antigen receptor T cell (CAR-T cell).

40. A pharmaceutical composition according to any one of claims 1 to 39, which is used in combination with radiation therapy.

41. The pharmaceutical agent according to any one of claims 1 to 40, wherein the cancer is a cancer resistant to an anti-PD-1 antibody drug.

42. The pharmaceutical composition according to any one of claims 1 to 41, wherein the cancer is glioma.

43. The pharmaceutical composition according to claim 42, wherein the glioma is a malignant glioma.

44. The pharmaceutical composition of claim 43, wherein the malignant glioma is a recurrent malignant glioma.

45. The pharmaceutical agent according to any one of claims 42 to 44, wherein the glioma is diffuse glioma, pediatric diffuse low-grade glioma, pediatric diffuse high-grade glioma, focal astrocytic glioma, glial neuronal and neuronal tumor, or ependymal tumor.

46. ​​The pharmaceutical composition of claim 45, wherein the glioma is a diffuse glioma.

47. The pharmaceutical composition of claim 45 or 46, wherein the diffuse glioma is astrocytoma, oligodendroglioma, or glioblastoma.

48. The pharmaceutical agent according to any one of claims 45 to 47, wherein the diffuse glioma is glioblastoma.

49. The pharmaceutical composition of claim 47 or 48, wherein the glioblastoma is secondary glioblastoma.

50. The pharmaceutical composition of claim 45 or 46, wherein the diffuse glioma is an astrocytoma or an oligodendroglioma.

51. The pharmaceutical agent according to claim 45 or 46, wherein the diffuse glioma is anaplastic oligodendroglioma or anaplastic astrocytoma.

52. The pharmaceutical agent described in claim 45 or 46, wherein the diffuse glioma is a pilocytic astrocytoma.

53. The pharmaceutical composition of claim 42, wherein the glioma is grade I or II based on the WHO 2016 brain tumor classification.

54. The pharmaceutical composition of claim 42, wherein the glioma is grade II or III based on the WHO 2016 brain tumor classification.

55. The pharmaceutical composition of claim 42, wherein the glioma is grade III or IV based on the WHO 2016 Brain Tumor Classification.

56. The pharmaceutical composition of claim 42, wherein the glioma is grade I to III based on the WHO 2016 brain tumor classification.

57. The pharmaceutical agent according to any one of claims 1 to 56, wherein the cancer is a cancer in which emopamil-binding protein is highly expressed compared to healthy individuals.

58. The pharmaceutical agent according to any one of claims 1 to 57, wherein the cancer is a cancer associated with an IDH mutation.

59. A pharmaceutical agent according to any one of claims 1 to 40, characterized in that it is administered to a subject having an IDH mutation.

60. The pharmaceutical composition according to claim 59, characterized in that the subject containing an IDH mutation is determined by a process comprising: (1) detecting an IDH mutation in cancer cells obtained from the subject; and (2) making a judgment based on the presence or absence of the IDH mutation detected in (1).