Pharmaceutical composition for treating tumors

Abstract

Disclosed is a pharmaceutical composition for the treatment of tumors, the pharmaceutical composition comprising (6S, 9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl) azetidin-1-yl] pyridin-2-yl} methyl)-6-(2-fluoro-4-hydroxybenzyl)-4, 7-dioxo-2-(propyl-2-en-1-yl) hexahydro-2H-pyrazino [2, 1-c] [1, 2, 3] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [1, 2, 4] triazolo [ The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof and administered in combination with a MEK inhibitor.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition for treating a tumor. BACKGROUND

[0002] The mitogen-activated protein kinase (MAPK) pathway is a signaling pathway highly conserved from yeast to mammals, and regulates various cellular functions such as cell proliferation, survival, and differentiation. The RAS-RAF-MEK-ERK signaling pathway, which is one of the main MAPK pathways, is known to be constitutively activated in many tumors and contributes to cancer cell proliferation and the like, and drug discovery research has been conducted using its constituent molecules as a target candidate for cancer treatment (Non-Patent Literature 1).

[0003] As one of the agents targeting the RAS-RAF-MEK-ERK signaling pathway, a MEK inhibitor is known. For example, trametinib, which was approved as the first MEK inhibitor in the world in 2013, is an orally administrable molecular targeted drug, and is used for treating unresectable or metastatic malignant melanoma positive for BRAF gene mutation, alone or in combination with dabrafenib (a BRAF inhibitor).

[0004] On the other hand, the Wnt / β-catenin signaling pathway is a signaling pathway highly conserved in the evolution of animals, and regulates gene expression related to cell proliferation and differentiation, formation of body axis and organs, and the like. It has been reported that the Wnt / β-catenin signaling pathway and the RAS-RAF-MEK-ERK signaling pathway form a positive feedback loop through cross-talk, thereby contributing to cancer cell proliferation, and that simultaneous inhibition of both pathways is important for anti-tumor effects (Non-Patent Literature 2).

[0005] Regarding the anti-tumor effects produced by inhibiting the Wnt / β-catenin signaling pathway and the RAS-RAF-MEK-ERK signaling pathway, Non-Patent Literature 3 describes that in a mouse model subcutaneously transplanted with a human colorectal cancer cell line HT-29 in which the MAPK pathway is activated by a BRAF V600E-mutant, the anti-tumor effect is enhanced when ICG001, which is a Wnt / β-catenin signaling pathway inhibitor, is administered in combination with vemurafenib (a BRAF inhibitor) (i), or in combination with both vemurafenib and trametinib (ii), as compared to single administration. In addition, Non-Patent Literature 4 describes that in PDX model mice produced by subcutaneously transplanting patient-derived colorectal cancer organoids, the anti-tumor effect is enhanced when ICG001 is administered in combination with trametinib, as compared to single administration.

[0006] Among them, as a compound having a Wnt pathway modulating action, (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide represented by the following formula (X) (Patent Literature 1), (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (X) (Patent Literature 2), and E7386 represented by the following formula (I) (Non-Patent Literature 5) are known.

[0007]

[0008] Both (6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide disclosed in Patent Literature 1 and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide disclosed in Patent Literature 2 are represented by the compound represented by formula (I) in IUPAC nomenclature.

[0009]

[0010] The symbol method of the chemical bond in the structural formula of formula (X) and formula (I) is different, but they represent the same stereochemistry. Therefore, in the present specification, formula (I) is used as the structural formula, and (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide is used as the chemical name.

[0011] Bibliographic List

[0012] Patent Literature

[0013] Patent Document 1: WO 2015 / 098853 A

[0014] Patent Document 2: WO 2016 / 208576 A

[0015] Non-patent literature

[0016] Non-patent document 1: Nobuya Ishii, “Progress of research and development of MAPK pathway inhibitors.”, Folia Pharmacol. Jpn. 141, 15 to 21 (2013).

[0017] Non-patent document 2: D. Kim et al., “A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK pathway.”, Oncogene 26, 4571-9 (2007).

[0018] Non-patent document 3: Chen G. et al. “Wnt / β-Catenin Pathway Activation Mediates Adaptive Resistance to BRAF Inhibition in Colorectal Cancer.” Mol. Cancer Ther. 17(4), 806-813 (2018).

[0019] Non-patent document 4: Zhan T. et al., “MEK inhibitors activate Wnt signaling and induce stem cell plasticity in colorectal cancer,” Nat. Commun. 10, 2197 (2019).

[0020] Non-patent document 5: Kazuhiro Yamada et al., "E7386, a Selective Inhibitor of the Interaction between β-Catenin and CBP, Exerts Antitumor Activity in Tumor Models with Activated Canonical Wnt Signaling", Cancer Res. 81(4), 1052-1062 (2021). SUMMARY

[0021] PROBLEMS TO BE SOLVED BY THE INVENTION

[0022] Although the combination use of ICG001 and a MEK inhibitor has been reported to inhibit tumor growth so far, the inhibitory effect of the combination is not sufficient. In addition, there is no known combination therapy using a compound represented by formula (I) and a MEK inhibitor.

[0023] An object of the present application is to provide a novel pharmaceutical composition for treating a tumor.

[0024] SOLUTION TO PROBLEM

[0025] As a result of intensive studies, the present inventors have found that the combined administration of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide (hereinafter also referred to as a compound represented by formula (I)) or a pharmaceutically acceptable salt thereof and a MEK inhibitor shows a high antitumor effect, and the present application has been completed.

[0026] That is, the present disclosure relates to the following.

[0027] [1] A pharmaceutical composition or a tumor therapeutic agent for treating a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0028]

[0029] or a pharmaceutically acceptable salt thereof,

[0030] wherein the composition or the agent is administered in combination with a MEK inhibitor.

[0031] [2] A pharmaceutical composition or a tumor therapeutic agent for treating a tumor, comprising a MEK inhibitor,

[0032] wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0033]

[0034] or a pharmaceutically acceptable salt thereof.

[0035] [3] A method of treating a tumor, wherein

[0036] an effective amount of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0037]

[0038] or a pharmaceutically acceptable salt thereof and an effective amount of a MEK inhibitor are administered to a patient in combination.

[0039] [4] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0040]

[0041] or a pharmaceutically acceptable salt thereof

[0042] use of a MEK inhibitor in the manufacture of a pharmaceutical composition or a tumor therapeutic agent for treating a tumor,

[0043] wherein the composition or the agent is administered in combination with a MEK inhibitor.

[0044] [5] Use of a MEK inhibitor in the manufacture of a pharmaceutical composition or a tumor therapeutic agent for treating a tumor, wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0045]

[0046] or a pharmaceutically acceptable salt thereof.

[0047] [6] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0048]

[0049] or a pharmaceutically acceptable salt thereof for treating a tumor in combination with a MEK inhibitor.

[0050] [7] A MEK inhibitor for use in treating a tumor in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0051]

[0052] or a pharmaceutically acceptable salt thereof.

[0053] [8] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0054]

[0055] or a pharmaceutically acceptable salt thereof, and a MEK inhibitor for use in the treatment of a tumor.

[0056] [9] A pharmaceutical composition or a tumor therapeutic agent for use in the treatment of a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0057]

[0058] or a pharmaceutically acceptable salt thereof,

[0059] wherein the composition or the agent is administered in combination with a MEK inhibitor and a RAS inhibitor.

[0060]

[10] A pharmaceutical composition or a tumor therapeutic agent for use in the treatment of a tumor, comprising a MEK inhibitor,

[0061] wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0062]

[0063] or a pharmaceutically acceptable salt thereof, and a RAS inhibitor.

[0064]

[11] A method of treating a tumor, wherein

[0065] an effective amount of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0066]

[0067] or a pharmaceutically acceptable salt thereof, an effective amount of a MEK inhibitor, and an effective amount of a RAS inhibitor.

[0068]

[12] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0069]

[0070] or a pharmaceutically acceptable salt thereof

[0071] use in the manufacture of a pharmaceutical composition for treating a tumor or a tumor therapeutic agent, wherein the composition or the agent is administered in combination with a MEK inhibitor and a RAS inhibitor.

[0072]

[13] use of a MEK inhibitor in the manufacture of a pharmaceutical composition for treating a tumor or a tumor therapeutic agent, wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0073]

[0074] or a pharmaceutically acceptable salt thereof and a RAS inhibitor.

[0075]

[14] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0076]

[0077] or a pharmaceutically acceptable salt thereof in combination with a MEK inhibitor and a RAS inhibitor for use in the treatment of a tumor.

[0078]

[15] A MEK inhibitor in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I) for use in the treatment of a tumor

[0079]

[0080] or a pharmaceutically acceptable salt thereof and a RAS inhibitor.

[0081]

[16] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0082]

[0083] or a pharmaceutically acceptable salt thereof in combination with a MEK inhibitor and a RAS inhibitor for use in the treatment of a tumor.

[0084]

[17] A pharmaceutical composition or a tumor therapeutic agent for use in the treatment of a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0085]

[0086] or a pharmaceutically acceptable salt thereof,

[0087] wherein the composition or the agent is administered in combination with a MEK inhibitor and a BRAF inhibitor.

[0088]

[18] A pharmaceutical composition or a tumor therapeutic agent for treating a tumor, comprising a MEK inhibitor,

[0089] wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0090]

[0091] or a pharmaceutically acceptable salt thereof and a BRAF inhibitor.

[0092]

[19] A method for treating a tumor, wherein

[0093] an effective amount of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0094]

[0095] or a pharmaceutically acceptable salt thereof, an effective amount of a MEK inhibitor, and an effective amount of a BRAF inhibitor are administered to a patient in combination.

[0096]

[20] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0097]

[0098] or a pharmaceutically acceptable salt thereof

[0099] Use of a MEK inhibitor in the manufacture of a pharmaceutical composition or a tumor therapeutic agent for treating a tumor,

[0100] wherein the composition or the agent is administered in combination with a MEK inhibitor and a BRAF inhibitor.

[0101]

[21] Use of a MEK inhibitor in the manufacture of a pharmaceutical composition or a tumor therapeutic agent for treating a tumor,

[0102] wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0103]

[0104] or a pharmaceutically acceptable salt thereof and a BRAF inhibitor.

[0105]

[22] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0106]

[0107] or a pharmaceutically acceptable salt thereof for use in treating a tumor in combination with a MEK inhibitor and a BRAF inhibitor.

[0108]

[23] A MEK inhibitor for use in treating a tumor in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0109]

[0110] or a pharmaceutically acceptable salt thereof and a BRAF inhibitor.

[0111]

[24] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I) or a pharmaceutically acceptable salt thereof, a MEK inhibitor, and a BRAF inhibitor combination for treating a tumor.

[0112]

[0113] or a pharmaceutically acceptable salt thereof, a MEK inhibitor, and a BRAF inhibitor combination for treating a tumor.

[0114]

[25] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or MEK inhibitor for use according to any one of [1] to

[24] , wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

[0115]

[26] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to

[25] , wherein the MEK inhibitor is at least one selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0116]

[27] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to

[25] , wherein the MEK inhibitor is selected from the group consisting of trametinib, binimetinib, selumetinib, cobimetinib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0117]

[28] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to

[25] , wherein the MEK inhibitor is selected from the group consisting of trametinib, binimetinib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0118]

[29] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to

[25] , wherein the MEK inhibitor is trametinib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0119]

[30] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to

[25] , wherein the MEK inhibitor is trametinib-dimethylsulfoxide.

[0120]

[31] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [9] to

[16] and

[25] to

[30] , wherein the RAS inhibitor is a KRAS inhibitor.

[0121]

[32] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[31] , wherein the KRAS inhibitor is at least one selected from the group consisting of sotorasib, adagrasib, MRTX1133, BI-3406, BI 1701963, RG6330, LY3537982, JDQ443, RMC-6291, RMC-6236, LUNA18, ARS-1620, JNJ-74699157, GDC-6036, iExosomes, mRNA-5671, JAB-21822, BI 1823911, MK-1084, ELI-002, SDGR5, JAB-22000, ASP3082, G12Si-1, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0122]

[33] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[31] , wherein the KRAS inhibitor is selected from the group consisting of sotorasib, adagrasib, MRTX1133, BI-3406, BI 1701963, RG6330, LY3537982, JDQ443, RMC-6291, RMC-6236, LUNA18, ARS-1620, JNJ-74699157, GDC-6036, iExosomes, mRNA-5671, JAB-21822, BI1823911, MK-1084, ELI-002, SDGR5, JAB-22000, ASP3082, G12Si-1, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0123]

[34] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[31] , wherein the KRAS inhibitor is selected from the group consisting of sotorasib, adagrasib, BI 1701963, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0124]

[35] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[31] , wherein the KRAS inhibitor is a KRAS G12C inhibitor.

[0125]

[36] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[35] , wherein the KRAS G12C inhibitor is selected from the group consisting of sotorasib, adagrasib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0126]

[37] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[35] , wherein the KRAS G12C inhibitor is sotorasib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0127]

[38] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[35] , wherein the KRAS G12C inhibitor is adagrasib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0128]

[39] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[35] , wherein the MEK inhibitor is trametinib-dimethylsulfoxide, and the KRAS G12C inhibitor is sotorasib.

[0129]

[40] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[35] , wherein the MEK inhibitor is trametinib-dimethylsulfoxide, and the KRAS G12C inhibitor is adagrasib.

[0130]

[41] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of

[17] to

[30] , wherein the BRAF inhibitor is at least one selected from the group consisting of dabrafenib, encorafenib, vemurafenib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0131]

[42] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of

[17] to

[30] , wherein the BRAF inhibitor is selected from the group consisting of dabrafenib, encorafenib, vemurafenib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0132]

[43] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of

[17] to

[30] , wherein the BRAF inhibitor is dabrafenib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0133]

[44] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of

[17] to

[30] , wherein the BRAF inhibitor is dabrafenib mesylate or encorafenib.

[0134]

[45] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[44] , wherein the MEK inhibitor is trametinib-dimethylsulfoxide, and the BRAF inhibitor is dabrafenib mesylate.

[0135]

[46] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to

[44] , wherein the MEK inhibitor is binimetinib, and the BRAF inhibitor is encorafenib.

[0136]

[47] The pharmaceutical composition, therapeutic agent, or use according to any one of [1], [4], [9],

[12] ,

[17] ,

[20] , and

[25] to

[46] , wherein the pharmaceutical composition or the therapeutic agent comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0137]

[48] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [2], [3], [5] to [8],

[10] ,

[11] ,

[13] to

[16] ,

[18] ,

[19] ,

[21] to

[24] , and

[25] to

[46] , wherein the (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide, or a pharmaceutically acceptable salt thereof, is administered orally.

[0138]

[49] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to

[48] , wherein the tumor is at least one selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer, mesothelioma, uterine cancer, ovarian cancer, bladder cancer, cholangiocarcinoma, gastric cancer, breast cancer, small cell lung cancer, testicular cancer, small intestine cancer, appendix cancer, neuroendocrine tumor, melanoma, and head and neck cancer.

[0139]

[50] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use according to any one of [1] to [8],

[25] to

[30] ,

[47] , and

[48] , wherein the tumor is at least one selected from non-small cell lung cancer, colorectal cancer, and melanoma.

[0140]

[51] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use of any one of [9] to

[16] ,

[25] to

[40] ,

[47] , and

[48] , wherein the tumor is at least one selected from non-small cell lung cancer, colorectal cancer, and pancreatic cancer.

[0141]

[52] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use of any one of

[17] to

[30] and

[41] to

[48] , wherein the tumor is at least one selected from colorectal cancer and melanoma.

[0142]

[53] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use of any one of [1] to

[48] , wherein the tumor is non-small cell lung cancer.

[0143]

[54] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use of any one of [1] to

[48] , wherein the tumor is colorectal cancer.

[0144]

[55] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or MEK inhibitor for use of any one of [1] to

[48] , wherein the tumor is melanoma.

[0145] [A1] A pharmaceutical composition or tumor therapeutic agent for use in the treatment of a tumor comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0146]

[0147] or a pharmaceutically acceptable salt thereof, wherein the composition or the agent is administered in combination with a BRAF inhibitor.

[0148] [A2] A pharmaceutical composition or a tumor therapeutic agent for treating a tumor, comprising a BRAF inhibitor, wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0149]

[0150] or a pharmaceutically acceptable salt thereof.

[0151] [A3] A method of treating a tumor, wherein

[0152] an effective amount of (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0153]

[0154] or a pharmaceutically acceptable salt thereof and an effective amount of a BRAF inhibitor are administered to a patient in combination.

[0155] [A4] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0156]

[0157] or a pharmaceutically acceptable salt thereof

[0158] use in the manufacture of a pharmaceutical composition or a tumor therapeutic agent for treating a tumor,

[0159] wherein the composition or the agent is administered in combination with a BRAF inhibitor.

[0160] [A5] Use of a BRAF inhibitor in the manufacture of a pharmaceutical composition or a tumor therapeutic agent for treating a tumor, wherein the composition or the agent is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0161]

[0162] or a pharmaceutically acceptable salt thereof.

[0163] [A6] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0164]

[0165] or a pharmaceutically acceptable salt thereof in combination with a BRAF inhibitor for treating a tumor.

[0166] [A7] A BRAF inhibitor in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I) for treating a tumor

[0167]

[0168] or a pharmaceutically acceptable salt thereof.

[0169] [A8] (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I)

[0170]

[0171] or a pharmaceutically acceptable salt thereof, in combination with a BRAF inhibitor for use in the treatment of a tumor.

[0172] [A9] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or BRAF inhibitor for use of any one of [A1] to [A8], wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

[0173] [A10] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or BRAF inhibitor for use of any one of [A1] to [A9], wherein the BRAF inhibitor is selected from the group consisting of dabrafenib, encorafenib, pharmaceutically acceptable salts thereof, and solvates thereof.

[0174] [A11] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or BRAF inhibitor for use of any one of [A1] to [A9], wherein the BRAF inhibitor is selected from the group consisting of dabrafenib mesylate and encorafenib.

[0175] [A12] The pharmaceutical composition, therapeutic agent, or use of any one of [A1], [A4], and [A9] to [A11], wherein the pharmaceutical composition or the therapeutic agent comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide or a pharmaceutically acceptable salt thereof is administered orally.

[0176] [A13] The pharmaceutical composition, therapeutic agent, method, use, combination for use, compound for use, or pharmaceutically acceptable salt thereof, or BRAF inhibitor for use according to any one of [A2], [A3], [A5] to [A7], and [A9] to [Al l], wherein the (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin- 1 -yl)azetidin- 1 -yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en- 1 -yl)hexahydro-2H-pyrazino[2, 1 -c][ 1,2,4]triazine- 1 (6H)-carboxamide or a pharmaceutically acceptable salt thereof is administered orally.

[0177] [A14] The pharmaceutical composition, therapeutic agent, method, use, compound for use, or pharmaceutically acceptable salt thereof, or BRAF inhibitor for use according to any one of [Al] to [A13], wherein the tumor is at least one selected from the group consisting of non-small cell lung cancer, colorectal cancer, and melanoma.

[0178] Advantages of the Invention

[0179] According to the present application, it is possible to provide a novel pharmaceutical composition for treating a tumor that exhibits a high antitumor effect. BRIEF DESCRIPTION OF DRAWINGS

[0180] Figure 1 is a graph showing the antitumor effect of a combination administration of a compound represented by formula (I) (abbreviated as E7386 in the figure) and trametinib in a transplanted model mouse having human colorectal cancer cell line Colo205 cells.

[0181] Figure 2 is a graph showing the antitumor effect of a combination administration of a compound represented by formula (I) (abbreviated as E7386 in the figure) and trametinib in a transplanted model mouse having human colorectal cancer cell line Colo205 cells.

[0182] Figure 3 is a graph showing the antitumor effect of a combination administration of ICG001 and trametinib in a transplanted model mouse having human colorectal cancer cell line Colo205 cells.

[0183] Figure 4 is a graph showing the antitumor effect of a combination administration of a compound represented by formula (I) (abbreviated as E7386 in the figure) and trametinib or a combination administration of ICG001 and trametinib in a transplanted model mouse having human colorectal cancer cell line Colo205 cells.

[0184] Figure 5is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure), trametinib, and adagrasyl in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0185] Figure 6 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure), trametinib, and adagrasyl in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0186] Figure 7 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure) and trametinib in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0187] Figure 8 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure), trametinib, and adagrasyl in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0188] Figure 9 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure), trametinib, and adagrasyl in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0189] Figure 10 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure) and trametinib in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0190] Figure 11 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure), trametinib, and adagrasyl in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0191] Figure 12 is a graph showing the anti-tumor effect of the combination administration of the compound represented by Formula (I) (abbreviated as E7386 in the figure), trametinib, and adagrasyl in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells.

[0192] Figure 13is a graph showing the antitumor effect of the combination administration of a compound represented by formula (I) (abbreviated as E7386 in the figure) and trametinib in a transplanted model mouse having human melanoma cell line A375 cells.

[0193] Figure 14 is a graph showing the antitumor effect of the combination administration of a compound represented by formula (I) (abbreviated as E7386 in the figure), trametinib, and dabrafenib in a transplanted model mouse having human melanoma cell line A375 cells.

[0194] Figure 15 is a graph showing the antitumor effect of the combination administration of a compound represented by formula (I) (abbreviated as E7386 in the figure), trametinib, and dabrafenib in a transplanted model mouse having human melanoma cell line A375 cells. DETAILED DESCRIPTION

[0195] Hereinafter, embodiments of the present disclosure will be described. The following embodiments are examples of the present disclosure, and are not intended to limit the present disclosure only to these embodiments. The present disclosure can be implemented in various forms without departing from the gist of the present disclosure. Note that documents, publications, patent publications, and other patent documents cited in the present specification are incorporated herein by reference.

[0196] In the present disclosure, a "pharmaceutically acceptable salt" is not particularly limited, provided that it forms a salt with a compound, and examples thereof include inorganic acid salts, organic acid salts, inorganic base salts, organic base salts, and acidic or basic amino acid salts.

[0197] Examples of the inorganic acid salts include hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, and examples of the organic acid salts include carboxylic acid salts such as acetate, succinate, fumarate, maleate, tartrate, citrate, lactate, stearate, benzoate, or mandelate, and sulfonic acid salts such as methanesulfonate, ethanesulfonate, p-toluenesulfonate, or benzenesulfonate.

[0198] Examples of the inorganic base salts include alkali metal salts such as sodium salt or potassium salt, alkaline earth metal salts such as calcium salt or magnesium salt, aluminum salt, and ammonium salt, and examples of the organic base salts include diethylamine salt, diethanolamine salt, meglumine salt, and N,N'-dibenzylethylenediamine salt.

[0199] Examples of the acidic amino acid salts include aspartate and glutamate, and examples of the basic amino acid salts include arginate, lysinate, and ornithinate.

[0200] In the present disclosure, a solvate refers to a solid formed by a compound or a pharmaceutically acceptable salt thereof and a solvent molecule, and the solid may be a crystal. Solvates also include hydrates formed by a compound or a pharmaceutically acceptable salt thereof and water molecules. The solvent molecules contained in the solvate are not particularly limited, provided that it forms a solvate with the compound or its pharmaceutically acceptable salt, and examples thereof include: ketone-based solvents such as acetone, 2-butanone, or cyclohexanone; ester-based solvents such as methyl acetate or ethyl acetate; ether-based solvents such as 1,2-dimethoxyethane or tert-butyl methyl ether; alcohol-based solvents such as methanol, ethanol, 1-propanol, or isopropanol; and polar solvents such as N-methyl-2-pyrrolidone, N N-dimethylformamide, or dimethyl sulfoxide. The number of solvent molecules for the compound or its pharmaceutically acceptable salt is not particularly limited, and may be, for example, one molecule or two molecules.

[0201] The compound represented by formula (I) is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide. The compound represented by formula (I) is also referred to as "(6S,9aS)-N-benzyl-8-((6-(3-(4-ethylpiperazin-1-yl)azetidin-1-yl)pyridin-2-yl)methyl)-6-((2-fluoro-4-hydroxyphenyl)methyl)-4,7-dioxo-2-(prop-2-en-1-yl)-octahydro-1H-pyrazino[2,1-c][1,2,4]triazine-1-carboxamide" or "E7386".

[0202]

[0203] The compound represented by formula (I) can be produced by the method described in US Pat. No. 9,174,998 or US Pat. No. 1,025,9817, and has pharmacological activities including antitumor activity.

[0204] In the present disclosure, “the compound represented by formula (I) or a pharmaceutically acceptable salt thereof” may be an acid anhydride or a solvate such as a hydrate, and as an example, is, for example, a compound represented by formula (I), i.e., (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

[0205] A "pharmaceutical composition" or "therapeutic agent" in the present disclosure is understood to mean a substance that exhibits a desired effect in a tissue, animal, mammal, human, or other subject.

[0206] In the present disclosure, "treat" and derivatives thereof mean a therapeutic treatment. With respect to a particular disorder, treat means (1) to ameliorate the disorder or one or more biological signs of the disorder, (2) to interfere with (a) one or more points in a biological cascade leading to or causing the disorder or (b) one or more biological signs of the disorder, (3) to alleviate one or more symptoms, effects, or side effects associated with the disorder, or one or more symptoms, effects, or side effects associated with the disorder or treatment thereof, or (4) to delay progression of the disorder or one or more biological signs of the disorder.

[0207] In the present disclosure, "effective amount" means an amount effective to elicit a desired biological or medicinal response in a tissue system, animal, or human. In one embodiment, an effective amount means an amount effective to achieve a desired therapeutic result when administered at a necessary dosage and for a necessary period of time (e.g., to ameliorate or prevent symptoms or to prolong survival). In one embodiment, an effective amount is an amount that is no more than a maximum tolerated dose. When one component is administered in combination with another component to exhibit a desired therapeutic effect, in one embodiment, an effective amount is equivalent to an effective amount when the one component is administered as a single agent, and in another embodiment, an effective amount is a dose that is less than an effective amount when the one component is administered as a single agent.

[0208] In the present disclosure, "patient" refers to a mammal, particularly a human, who has or is suspected of having a tumor. Mammal refers to a mammalian animal such as a guinea pig, mouse, rat, hamster, cat, rabbit, dog, cow, goat, sheep, horse, monkey, chimpanzee, or human. In one embodiment, the patient is a human. The pharmaceutical compositions, therapeutic agents, or methods of the present disclosure are particularly useful for treating a human patient having a tumor.

[0209] The terms "a," "an," "the" and similar referents used in the context of the present disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0210] The pharmaceutical composition or therapeutic agent according to the present disclosure can be formulated by, for example, a method described in Japanese Pharmacopoeia 18 (JP), United States Pharmacopeia (USP), or European Pharmacopoeia (EP). In one embodiment, the pharmaceutical composition or therapeutic agent according to the present disclosure can further contain a pharmaceutically acceptable carrier. Examples of the pharmaceutically acceptable carrier include liquid or solid fillers, diluents, excipients, manufacturing aids, and solvent encapsulating materials.

[0211] In the present disclosure, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof or a therapeutic agent thereof can be administered by injection, oral administration, nasal administration, transdermal administration, pulmonary administration, ocular administration, etc. Examples of injection include intravenous injection, subcutaneous injection, intradermal injection, intra-arterial injection, and injection such as local injection into a target cell or organ. In the case of oral administration, examples of the dosage form of the pharmaceutical composition or the therapeutic agent include tablets, powders, granules, syrups, capsules, and internal liquid preparations. In the case of parenteral administration, examples of the dosage form of the pharmaceutical composition or the therapeutic agent include injections, drops, eye drops, ointments, suppositories, suspensions, pastes, lotions, aerosols, and plasters, and in one embodiment, the dosage form is an injection or a drop.

[0212] In one embodiment of the present disclosure, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is administered orally to a patient. In another embodiment, a pharmaceutical composition or a therapeutic agent comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used for oral administration.

[0213] In the present disclosure, the administration form of the two or three components administered in combination selected from the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, a MEK inhibitor, a RAS inhibitor, and a BRAF inhibitor is not particularly limited. For example, the two or three components administered in combination are administered simultaneously, separately, sequentially, or with a time interval. Here, "simultaneously" means that the components are administered within the same period of time or exactly simultaneously. "Separately" means that the components are administered with different dosing intervals or frequencies. "Sequentially" means that the components are administered in any order over a period of time. "With a time interval" means that each component is administered with an interval at each administration thereof. Examples of the administration route of each component include injection, oral administration, nasal administration, transdermal administration, pulmonary administration, and ocular administration. The case where the two or three components are administered in combination includes the case where the components are administered as one preparation and the case where the components are administered as two or more separate preparations.

[0214] The dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt when applied as a single agent varies significantly according to the type of disease to be targeted, the age, sex and weight of the patient, the degree of symptoms, etc. When the compound represented by formula (I) or its pharmaceutically acceptable salt is orally applied to an adult (body weight: 60 kg) or a child, the dosage of the compound represented by formula (I) or its pharmaceutically acceptable salt is not particularly limited, but is generally 0.1 to 5000 mg, 0.5 to 3000 mg or 1.0 to 1000 mg per day in the form of a compound represented by formula (I) and 100 mg to 300 mg in one embodiment. The compound represented by formula (I) or its pharmaceutically acceptable salt can usually be applied every day or multiple days once or every day with 2 to 6 portions at this dosage. When using one or more other chemotherapeutic agents, dosage and dosage regimen can be changed. Dosage regimen can be determined by the physician treating a particular patient. As an example, for example, the compound represented by formula (I) is orally administered to a human subject at a dose of 80 mg to 120 mg / dose twice a day. Taking into account the type of disease to be targeted, the age, sex and weight of the patient, the degree of symptoms, other agents to be administered in combination, etc., the specific dose, administration route, administration frequency, administration cycle, etc. of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof are appropriately determined.

[0215] The MEK inhibitor in the present disclosure is a substance that inhibits the action of the phosphorylase MEK (mitogen-activated protein (MAP) kinase / extracellular signal-regulated kinase (ERK)) present in the Raf / MEK / ERK signaling pathway (MAPK pathway), thereby blocking the MAPK pathway.

[0216] In the present disclosure, examples of MEK inhibitors include trametinib, selumetinib, bemetinib, cobimetinib, and pharmaceutically acceptable salts and solvates thereof.

[0217] Trametinib (trametinib: GSK1120212, also known as JTP-74057) has the following structure:

[0218]

[0219] and refers to the compound whose chemical name is N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide. Trametinib is typically administered as a dimethyl sulfoxide solvate having the following structure:

[0220]

[0221] Trametinib (GSK1120212) is disclosed as Example 4-1 in U.S. Patent No. 7,378,423. The method for manufacturing trametinib is described in column 177, line 1 to column 213, line 14, which is incorporated herein by reference.

[0222] The dose of trametinib, or a pharmaceutically acceptable salt thereof, or a solvate thereof, when administered as a single agent varies significantly depending on the type of disease to be targeted, the age, sex, and body weight of the patient, the degree of symptoms, and the like. When trametinib, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is administered orally to an adult (body weight: 60 kg) or a child, the dose of trametinib, or a pharmaceutically acceptable salt thereof, or a solvate thereof, is not particularly limited, but is generally 0.1 to 10 mg, in the form of trametinib, per day, 0.5 mg to 2 mg in one embodiment, and 2 mg, 1.5 mg, 1 mg, or 0.5 mg in another embodiment, per day. Trametinib, or a pharmaceutically acceptable salt thereof, or a solvate thereof, can generally be administered once a day on an empty stomach at this dose, for example, one or more hours before a meal or two or more hours after a meal. The dose and the dosage regimen can be changed when one or more additional chemotherapeutic agents are used. The dosage regimen can be determined by a physician who treats a particular patient. As one embodiment, for example, trametinib is administered orally to a human subject once a day at a dose of 0.5 mg to 2 mg per dose. The specific dose of trametinib, or a pharmaceutically acceptable salt thereof, or a solvate thereof, the route of administration, the frequency of administration, the cycle of administration, and the like are appropriately determined in consideration of the type of disease to be targeted, the age, sex, and body weight of the patient, the degree of symptoms, other agents to be administered in combination, and the like.

[0223] Sunitinib has the following structure:

[0224]

[0225] and means a compound whose chemical name is 5-[(4-bromo-2-chlorophenyl)amino]-4- fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide. Sunitinib is typically administered in the form of a sulfate salt. Sunitinib is disclosed in Example 10 in WO 03 / 077914A. The method for manufacturing sunitinib is also described in Example 10, which is incorporated herein by reference.

[0226] Bemarinib has the following structure:

[0227]

[0228] and means the compound whose chemical name is 5-[(4-bromo-2-fluorophenyl)amino]-4- fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide. Binimetinib is disclosed as Example 18, page 29111, in U.S. Patent No. 7,777,050. Methods for making binimetinib are also described in Example 18, which is incorporated herein by reference.

[0229] Cobimetinib has the following structure:

[0230]

[0231] and its chemical name is l-[{3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl}carbonyl]-3- [(2S)-piperidin-2-yl]azetidin-3-ol. Cobimetinib is disclosed as compound number 28 in U.S. Patent No. 7,803,839. General methods for making cobimetinib are described in columns 221-237, and methods for making compounds thereof are described in Example 22(b) of columns 300-305, which are incorporated herein by reference.

[0232] In the present disclosure, examples of MEK inhibitors include trametinib, selumetinib, binimetinib, cobimetinib, and pharmaceutically acceptable salts thereof, and solvates thereof. These can be used alone or in combination of two or more thereof. In one embodiment, the MEK inhibitor is selected from the group consisting of trametinib, selumetinib, binimetinib, cobimetinib, and pharmaceutically acceptable salts thereof, and solvates thereof. In another embodiment, the MEK inhibitor is selected from the group consisting of trametinib, binimetinib, and pharmaceutically acceptable salts thereof, and solvates thereof. In a particular embodiment, the MEK inhibitor is trametinib-dimethylsulfoxide or binimetinib.

[0233] The BRAF inhibitor in the present disclosure is a substance that targets, reduces, or inhibits the activity of the serine / threonine protein kinase BRAF. For example, the BRAF inhibitor also includes a substance that inhibits signal transduction downstream of BRAF, particularly a substance that specifically inhibits signal transduction caused by a mutant BRAF having a functional gain of enhanced serine threonine kinase activity.

[0234] In the present disclosure, examples of BRAF inhibitors include dabrafenib, encorafenib, vemurafenib, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0235] Dabrafenib has the following structure:

[0236]

[0237] and its chemical name is N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3- thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide. The structure of this compound and methods for making this compound are disclosed as U.S. Patent No. 8415345, which is incorporated herein by reference.

[0238] Encorafenib has the following structure:

[0239]

[0240] and its chemical name is N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(methylsulfonamido)phenyl]-1- (propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl}methy lcarbamate. The structure of this compound is disclosed as Compound 32 in U.S. Patent No. 8501758, and methods for making this compound are also disclosed, which is incorporated herein by reference.

[0241] Vemurafenib (also known as ZELBORAF (registered trademark)) has the following structure:

[0242]

[0243] and its chemical name is N-{3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4- difluorophenyl}propane-1-sulfonamide. The structure of this compound is disclosed as P-1261 in U.S. Patent No. 8143271, and methods for making this compound are disclosed in U.S. Patent No. 8741920, which are incorporated herein by reference.

[0244] In the present disclosure, examples of embodiments of the BRAF inhibitor include encorafenib, dabrafenib, and pharmaceutically acceptable salts thereof, and solvates thereof. Embodiments of the BRAF inhibitor are selected from the group consisting of encorafenib, dabrafenib, vemurafenib, and pharmaceutically acceptable salts thereof, and solvates thereof. Particular embodiments of the BRAF inhibitor are selected from the group consisting of encorafenib and dabrafenib mesylate.

[0245] When the BRAF inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof is orally administered to an adult (body weight: 60 kg) or a child, the dose of the BRAF inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof is not particularly limited, but is usually 0.1 to 5000 mg, 0.5 to 3000 mg, or 1.0 to 1000 mg per day. The BRAF inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof can usually be administered once a day or more or 2 to 6 times a day in this dose. When one or more additional chemotherapeutic agents are used, the dose and the dosage regimen can be changed. The dosage regimen can be determined by a physician who treats a particular patient. When dabrafenib is administered alone as a BRAF inhibitor, for example, dabrafenib is orally administered at a dose selected from the group consisting of 300 mg, 200 mg, 150 mg, 125 mg, 100 mg, 75 mg, and 50 mg per day. The specific dose of the BRAF inhibitor, the route of administration, the frequency of administration, the cycle of administration, and the like are appropriately determined in consideration of the type of disease to be targeted, the age, sex, and body weight of the patient, the degree of symptoms, other agents to be administered in combination, and the like.

[0246] The RAS inhibitor in the present disclosure can contain any compound or biological molecule that (a) binds to and inhibits the function of a biological molecule (e.g., a protein or a nucleic acid) having RAS, (b) binds to and degrades a biological molecule (e.g., a protein or a nucleic acid) having RAS, (c) inhibits the expression of a biological molecule (e.g., a protein or a nucleic acid) having RAS, inhibits the GDP-GTP exchange reaction of RAS by inhibiting the protein-protein interaction between RAS and a guanine nucleotide exchange factor (e.g., SOS1 or SOS2), or (e) acts as a vaccine to stimulate immunity against mutant RAS.

[0247] In the present disclosure, examples of embodiments of the RAS inhibitor include sorafenib (AMG 510), adagrasyl (MRTX849), MRTX1133, BI-3406, BI 1701963, RG6330, LY3537982, JDQ443, RMC-6291, RMC-6236, LUNA18, ARS-1620, JNJ-74699157, GDC-6036, iExosomes, D-1553, mRNA-5671, BI2852, SCH-54292, TLN-4601, salirasib, detadacin, JAB-21822, BI 1823911, MK-1084, ELI-002, SDGR5, JAB-22000, ASP3082, and G12Si-1.

[0248] Sorafenib (also known as AMG 510) has the following structure:

[0249]

[0250] and means the compound whose chemical name is 6-fluoro-7-(2-fluoro-6- hydroxyphenyl)-l-(4-methyl-2-(2-propanyl)-3-pyridinyl)-4-((2S)-2-methyl-4-(2- propenoyl)-l-piperazinyl)pyrido[2,3-d]pyrimidin-2(lH)-one. The structural formula of sotorasib (AMG 510) and methods for making sotorasib are described in U.S. Patent No. 10519146 at column 411, line 10 to column 415, line 19, which is incorporated herein by reference.

[0251] Adagrasib (also known as MRTX 849) has the following structure:

[0252]

[0253] and means the compound whose chemical name is 2-[(2S)-4-[7-(8-chloro-l- naphthalenyl)-2-[[(2S)-l-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H- pyrido[3,4-d]pyrimidin-4-yl]-l-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile. The structural formula of adagrasib (MRTX 849) and methods for making adagrasib are described in U.S. Patent No. 10689377 at column 1286, line 32 to column 1288, line 17, which is incorporated herein by reference.

[0254] MRTX1133 has the following structure:

[0255]

[0256] and means the compound whose chemical name is 4-(4-((lR,5S)-3,8- diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-lH- pyrrol-7a-yl)methoxy)pyrrolo[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen- 2-ol. The structural formula of MRTX1133 and methods for making MRTX1133 are described in WO2021041671 A.

[0257] The structural formula of BI-3406 and methods for making BI-3406 are described in U.S. Patent No. 10898487, which is incorporated by reference herein.

[0258] The pharmacological activity of BI 1701963 is reported in AACR Annual Meeting [American Association for Cancer Research] 2021 #CT210; April 10-15 and May 17-21 (Abstract https: / / doi.org / 10.1158 / 1538-7445.AM2021-CT210).

[0259] RG6330 is the same compound as GDC-6036. The structural formula of RG6330 and methods for making RG6330 are described in U.S. Patent No. 11236068, which is incorporated herein by reference.

[0260] The pharmacological activity of LY3537982 is reported in AACR Annual Meeting [American Association for Cancer Research] 2021 #1259; April 10-15 and May 17-21 (Abstract https: / / doi.org / 10.1158 / 1538-7445.AM2021-1259).

[0261] The structural formula of JDQ443 and methods for making JDQ443 are described in WO 2021124222A.

[0262] The structural formula of ARS-1620 and methods for making ARS-1620 are described in U.S. Patent No. 10370386, which is incorporated herein by reference.

[0263] The pharmacological activity of iExosomes is reported in Nature [Nature] Volume 546, Pages 498-503 (2017).

[0264] The structural formula of D-1553 and methods for making D-1553 are described in U.S. Patent No. 11091481, which is incorporated herein by reference.

[0265] The structural formula of BI 2852 and methods for making BI 2852 are described in WO 2020 / 173935A.

[0266] The structural formula of SCH-54292 and methods for making SCH-54292 are reported in Bioorganic & Medicinal Chemistry, Volume 5, Issue 1, January 1997, Pages 125-133.

[0267] The structural formula of TLN-4601 and methods for making TLN-4601 are described in U.S. Patent No. 7101872, which is incorporated herein by reference.

[0268] The structural formula of salinomycin and methods for making salinomycin are described in U.S. Reissued Patent No. 39,682, which is incorporated herein by reference.

[0269] The structural formula of detalisib and methods for making detalisib are described in U.S. Patent No. 9,861,623, which is incorporated herein by reference.

[0270] The pharmacological activity of JAB-21822 is reported in Journal of Clinical Oncology 40, no. 16 Supplement (June 01, 2022) 3089-3089 (DOI: 10.1200 / JCO.2022.40.16_suppl.3089).

[0271] The pharmacological activity of ELI-002 is reported in Journal of Clinical Oncology 40, no. 16 Supplement (June 01, 2022) TPS2701-TPS2701 (DOI: 10.1200 / JCO.2022.40.16_suppl.TPS2701).

[0272] The pharmacological activity of G12Si-1 is reported in Nat Chem Biol 18, 1177-1183 (2022) (DOI: 10.1038 / s41589-022-01065-9).

[0273] In the present disclosure, examples of RAS inhibitors include sotorasib (AMG 510), adagrasib (MRTX849), MRTX1133, BI-3406, BI 1701963, RG6330, LY3537982, JDQ443, RMC-6291, RMC-6236, LUNA18, ARS-1620, JNJ-74699157, GDC-6036, iExosomes, D-1553, mRNA-5671, JAB-21822, BI 1823911, MK-1084, ELI-002, SDGR5, JAB-22000, BI 2852, SCH-54292, TLN-4601, salirasib, datagliptin, ASP3082, and G12Si-1, and these can be used alone or in combination of two or more thereof. In one embodiment, the RAS inhibitor is selected from sotorasib, adagrasib, MRTX1133, BI-3406, BI 1701963, RG6330, LY3537982, JDQ443, RMC-6291, RMC-6236, LUNA18, ARS-1620, JNJ-74699157, GDC-6036, iExosomes, mRNA-5671, JAB-21822, BI 1823911, MK-1084, ELI-002, SDGR5, JAB-22000, ASP3082, G12Si-1, and pharmaceutically acceptable salts thereof, and solvates thereof. In a specific embodiment, the RAS inhibitor is selected from sotorasib (AMG 510), adagrasib (MRTX849), BI 1701963, and pharmaceutically acceptable salts thereof, and solvates thereof. In another embodiment, the RAS inhibitor is sotorasib. In another embodiment, the RAS inhibitor is adagrasib.

[0274] In one embodiment of the present disclosure, the RAS inhibitor is a KRAS inhibitor, a NRAS inhibitor, or a HRAS inhibitor. In another embodiment of the present disclosure, the RAS inhibitor is a KRAS inhibitor.

[0275] In the present disclosure, a KRAS inhibitor means an inhibitor that (i) blocks downstream signaling by RAS through binding to KRAS or (ii) inhibits the protein-protein interaction between KRAS and a guanine nucleotide exchange factor (e.g., SOS1 or SOS2). In (i) above, an inhibitor that binds to a GTP-bound mutant KRAS protein is a RAS-on inhibitor, and an inhibitor that binds to a GDP-bound mutant KRAS protein is a RAS-off inhibitor.

[0276] In an embodiment of the disclosure, the KRAS inhibitor is selected from the group consisting of Sotorasib, Adagrasib, MRTX1133, BI-3406, BI 1701963, RG6330, LY3537982, JDQ443, RMC-6291, RMC-6236, LUNA18, ARS-1620, JNJ-74699157, GDC-6036, iExosomes, mRNA-5671, JAB-21822, BI 1823911, MK-1084, ELI-002, SDGR5, JAB-22000, ASP3082, G12Si-1, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0277] In an embodiment of the disclosure, the RAS-on inhibitor is selected from the group consisting of MRTX1133, RMC-6291, RMC-6236, and pharmaceutically acceptable salts thereof, and solvates thereof. In an embodiment of the disclosure, the RAS-off inhibitor is selected from the group consisting of Sotorasib, Adagrasib, MRTX1133, RG6330, LY3537982, JDQ443, ARS-1620, JNJ-74699157, JAB-21822, BI 1823911, MK-1084, JAB-22000, G12Si-1, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0278] Examples of useful KRAS inhibitors include KRAS G12C inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, and pan-KRAS inhibitors, and in one embodiment, the useful KRAS inhibitor is, for example, a KRAS G12C inhibitor. Here, KRAS G12C inhibitor means an inhibitor that binds to a mutant (e.g., protein or nucleic acid) of KRAS that has a mutation in which the 12th Gly of KRAS is replaced with Cys and blocks downstream signaling caused by the mutant KRAS, and KRAS G12D inhibitor means an inhibitor that binds to a mutant (e.g., protein or nucleic acid) of KRAS that has a mutation in which the 12th Gly of KRAS is replaced with Asp and blocks downstream signaling caused by the mutant KRAS. KRAS G12S inhibitor means an inhibitor that binds to a mutant (e.g., protein or nucleic acid) of KRAS that has a mutation in which the 12th Gly of KRAS is replaced with Ser and blocks downstream signaling caused by the mutant KRAS. Pan-KRAS inhibitor means an inhibitor that (a) binds to KRAS (e.g., protein or nucleic acid) and blocks downstream signaling caused by RAS, regardless of the presence or absence of mutations, mutation locations, and mutated amino acids, or (b) blocks downstream signaling caused by RAS by binding to a guanine nucleotide exchange factor (e.g., SOS1 or SOS2) of KRAS and inhibiting protein-protein interaction between KRAS and the guanine nucleotide exchange factor.

[0279] In one embodiment, the KRAS G12C inhibitor is selected from sotorasib (AMG 510), adagrasib (MRTX849), RG6330, LY3537982, JDQ443, RMC-6291, JAB-21822, BI 1823911, MK-1084, and pharmaceutically acceptable salts thereof, and solvates thereof. In another embodiment, the KRAS G12C inhibitor is selected from sotorasib (AMG 510), adagrasib (MRTX849), and pharmaceutically acceptable salts thereof, and solvates thereof. In another embodiment, the KRAS G12C inhibitor is MK-1084. In another embodiment, the KRAS G12C inhibitor is sotorasib or a pharmaceutically acceptable salt thereof, or a solvate thereof. In another embodiment, the KRAS G12C inhibitor is adagrasib or a pharmaceutically acceptable salt thereof, or a solvate thereof. In a specific embodiment, the KRAS G12C inhibitor is sotorasib (AMG 510). In another specific embodiment, the KRAS G12C inhibitor is adagrasib (MRTX849). In one embodiment, the KRAS G12D inhibitor is selected from MRTX1133, JAB-22000, and pharmaceutically acceptable salts thereof, and solvates thereof. In one embodiment, the KRAS G12S inhibitor is G12Si-1 or a pharmaceutically acceptable salt thereof, or a solvate thereof. In one embodiment, the pan-KRAS inhibitor is selected from BI-3406, BI 1701963, LUNA18, SDGR5, RMC-6236, and pharmaceutically acceptable salts thereof, and solvates thereof.

[0280] The dose of the RAS inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof is not particularly limited when the RAS inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof is orally administered to an adult (body weight: 60 kg) or a child, but is generally 0.1 to 5000 mg, 0.5 to 3000 mg, or 1.0 to 1000 mg per day. The RAS inhibitor or a pharmaceutically acceptable salt thereof or a solvate thereof can generally be administered once a day or more or 2 to 6 times a day in this dose. The dose and the dosage regimen can be changed when one or more additional chemotherapeutic agents are used. The dosage regimen can be determined by a physician who treats a particular patient. When sorafenib is administered alone as a RAS inhibitor, for example, sorafenib is orally administered at a dose selected from the group consisting of 960 mg, 480 mg, 240 mg, and 120 mg per day. When adagrasyl is administered alone as a RAS inhibitor, for example, adagrasyl is orally administered at a dose selected from the group consisting of 1200 mg, 800 mg, 600 mg, 400 mg, and 200 mg per day. The specific dose of the RAS inhibitor, the route of administration, the frequency of administration, the cycle of administration, and the like are appropriately determined in consideration of the type of disease to be targeted, the age, sex, and body weight of the patient, the degree of symptoms, other agents to be administered in combination, and the like.

[0281] The MEK inhibitor, the RAS inhibitor, and the BRAF inhibitor according to the present disclosure can each be administered by injection, oral administration, nasal administration, transdermal administration, pulmonary administration, ocular administration, or the like. Examples of injection include intravenous injection, subcutaneous injection, intradermal injection, intra-arterial injection, and injection such as local injection into a target cell or organ. In the case of oral administration, examples of the dosage form include tablets, powders, granules, syrups, capsules, and internal liquid preparations. In the case of parenteral administration, examples of the dosage form include injections, drops, eye drops, ointments, suppositories, suspensions, pastes, lotions, aerosols, and plasters, and in one embodiment, the dosage form is an injection or a drop. The MEK inhibitor, the RAS inhibitor, and the BRAF inhibitor according to the present disclosure can be formulated by, for example, a method described in Japanese Pharmacopoeia 18 (JP), United States Pharmacopoeia (USP), or European Pharmacopoeia (EP).

[0282] The tumor to be treated in the present disclosure is, for example, a solid cancer. Examples of the solid cancer in the tumor to be treated include non-small cell lung cancer, colorectal cancer, pancreatic cancer, mesothelioma, uterine cancer (e.g., cervical cancer or corpus uteri cancer), ovarian cancer, bladder cancer, cholangiocarcinoma, gastric cancer, breast cancer, small cell lung cancer, testicular cancer, small intestine cancer, appendix cancer, neuroendocrine tumor, melanoma, and head and neck cancer. Examples of the melanoma include BRAF V600 mutant melanoma. Examples of the non-small cell lung cancer include KRAS mutation-positive non-small cell lung cancer. The colorectal cancer also includes KRAS mutation-positive colorectal cancer. In a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to one embodiment and administered in combination with a MEK inhibitor or a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a MEK inhibitor and administered in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the tumor to be treated can be non-small cell lung cancer, colorectal cancer, or melanoma, can be non-small cell lung cancer or colorectal cancer, can be non-small cell lung cancer or melanoma, or can be colorectal cancer or melanoma. In a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to one embodiment and administered in combination with a MEK inhibitor and a RAS inhibitor or a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a MEK inhibitor and administered in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a RAS inhibitor, the tumor to be treated can be non-small cell lung cancer, colorectal cancer, or pancreatic cancer, or can be non-small cell lung cancer. In a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to one embodiment and administered in combination with a MEK inhibitor and a BRAF inhibitor or a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a MEK inhibitor and administered in combination with a compound represented by formula (I) or a pharmaceutically acceptable salt thereof and a BRAF inhibitor, the tumor to be treated can be melanoma, or can be BRAF V600 mutant melanoma.

[0283] Examples of one embodiment of the present disclosure include a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a compound represented by formula (I) and administered in combination with trametinib-dimethyl sulfoxide and sorafenib, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0284] Examples of one embodiment of the present disclosure include a pharmaceutical composition for treating a tumor (or a tumor therapeutic agent) containing a compound represented by formula (I) and administered in combination with trametinib-dimethyl sulfoxide and adagrasyl, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0285] An example of one embodiment of the present disclosure includes a pharmaceutical composition (or a tumor therapeutic) for treating a tumor containing a compound represented by Formula (I) and administered in combination with trametinib-dimethyl sulfoxide, and the tumor to be treated is at least one selected from the group consisting of non-small cell lung cancer, colorectal cancer, and melanoma.

[0286] An example of one embodiment of the present disclosure includes a pharmaceutical composition (or a tumor therapeutic) for treating a tumor containing a compound represented by Formula (I) and administered in combination with trametinib-dimethyl sulfoxide and MK-1084, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0287] An example of one embodiment of the present disclosure includes a pharmaceutical composition (or a tumor therapeutic) for treating a tumor containing a compound represented by Formula (I) and administered in combination with trametinib-dimethyl sulfoxide and MK-1084, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0288] An example of one embodiment of the present disclosure includes a pharmaceutical composition (or a tumor therapeutic) for treating a tumor containing a compound represented by Formula (I) and administered in combination with trametinib-dimethyl sulfoxide and MK-1084, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0289] An example of one embodiment of the present disclosure includes a pharmaceutical composition (or a tumor therapeutic) for treating a tumor containing a compound represented by Formula (I) and administered in combination with trametinib-dimethyl sulfoxide and MK-1084, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0290] An example of one embodiment of the present disclosure includes a pharmaceutical composition (or a tumor therapeutic) for treating a tumor containing a compound represented by Formula (I) and administered in combination with trametinib-dimethyl sulfoxide and MK-1084, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0291] In one embodiment of the present disclosure, there is provided a method of treating a tumor, wherein a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof and a MEK inhibitor are administered in combination, and in another embodiment, there is provided a method of treating a tumor, wherein a BRAF inhibitor is further administered in combination. In another embodiment, there is provided a method of treating a tumor, wherein a RAS inhibitor is further administered in combination. In one embodiment of the present disclosure, the compound represented by Formula (I) or a pharmaceutically acceptable salt thereof is administered orally.

[0292] In addition, in one embodiment of the disclosure, there is provided a method of treating a tumor, wherein a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, and a MEK inhibitor are administered in combination and orally administered to a patient in an effective amount.

[0293] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I), trametinib-dimethylsulfoxide, and sorafenib are combined and orally administered to a patient in an effective amount, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0294] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I), trametinib-dimethylsulfoxide, and adagrasyl are combined and orally administered to a patient in an effective amount, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0295] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I) and trametinib-dimethylsulfoxide are combined and orally administered to a patient in an effective amount, and the tumor to be treated is at least one selected from the group consisting of non-small cell lung cancer, colorectal cancer, and melanoma.

[0296] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I), trametinib-dimethylsulfoxide, and MK-1084 are combined and orally administered to a patient in an effective amount, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0297] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I), trametinib-dimethylsulfoxide, and sorafenib are combined and orally administered to a patient in an effective amount, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0298] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I), trametinib-dimethylsulfoxide, and sorafenib are combined and orally administered to a patient in an effective amount, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0299] One embodiment of the disclosure is a method of treating a tumor, wherein a compound represented by Formula (I), trametinib-dimethylsulfoxide, and sorafenib are combined and orally administered to a patient in an effective amount, and the tumor to be treated is colorectal cancer or non-small cell lung cancer.

[0300] As used herein, the terms "comprising" or "including," or "having" are intended to be open-ended and allow for the inclusion of additional, unrecited features, unless specifically stated otherwise, and are to be construed as encompassing those features that are described in the specification, as well as those that are equivalent thereto.

[0301] Unless otherwise defined, all terms (technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Each of the terms used herein is to be interpreted in the same way as its meaning consistent with the meaning thereof in the specification and related art, and should not be interpreted in an idealized or overly formal sense, unless a different definition is explicitly stated.

[0302] Examples

[0303] [Example 1: Antitumor effects of combination administration of a MEK inhibitor and a compound represented by formula (I) or ICG001 or ICG001 in a transplanted model mouse having human colorectal cancer cell line Colo205 cells]

[0304] Colo205 cells, which are a human colorectal cancer-derived cell line (provided by ATCC), were suspended in Hanks' Balanced Salt Solution (HBSS) (manufactured by FUJIFILM Wako Chemicals) at 5 x 10 7 cells / mL. 0.1 mL of the obtained cell suspension was transplanted subcutaneously into the right breastbone of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by Charles River Laboratories Japan, Inc.). Ten days after the transplantation, the long axis and the short axis of the tumor produced in each mouse were measured with a digital caliper (manufactured by Mitutoyo Corp.), and the mice were grouped into six mice each so that the average tumor volume was approximately equal. The tumor volume was calculated according to the following formula.

[0305] Tumor volume (mm 3 ) = Tumor long axis (mm) x Tumor short axis (mm) / 2 2 2

[0306] From ten days after the transplantation, the compound represented by formula (I) (12.5 mg / kg or 25 mg / kg, once a day for 14 days, oral administration), trametinib (0.3 mg / kg, once a day for 14 days, oral administration), and ICG001 (100 mg / kg, once a day for 14 days, intraperitoneal administration) were administered alone or in combination to the mice in the single administration group or the combination administration group. Note that none of the above agents were administered to the control group.​​

[0307] Note that, at the time of administration, the compound represented by formula (I) was dissolved in 0.1M hydrochloric acid at 1.25 mg / mL or 2.50 mg / mL, trametinib (manufactured by Amadis Chemical Co., Ltd.) was dissolved in distilled water (pH 8.0) (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.5 w / v% of hydroxypropyl methylcellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) and 0.2 w / v% of Tween 80 (manufactured by Sigma) at 0.03 mg / mL, and ICG001 (manufactured by WuXi App Tec) was dissolved in physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 3.5 w / v% of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.) and 6.5 w / v% of Tween 80 at 10 mg / mL.

[0308] The day on which administration was started was defined as day 1, and the long axis and the short axis of the tumor produced in each mouse were measured on day 5, day 8, day 12, and day 15, and the tumor volume was calculated by a method similar to the above-described method. Figure 1 The change in tumor volume was demonstrated in the case where 12.5 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinib were administered alone or in combination. Figure 2 The change in tumor volume was demonstrated in the case where 25.0 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinib were administered alone or in combination. Figure 3 The change in tumor volume was demonstrated in the case where 100 mg / kg of ICG001 and 0.3 mg / kg of trametinib were administered alone or in combination. Figure 4 The change in tumor volume was demonstrated in the case where 12.5 mg / kg or 25.0 mg / kg of the compound represented by formula (I) or 100 mg / kg of ICG001 and 0.3 mg / kg of trametinib were administered in combination. Note that, in the figure, the compound represented by formula (I) is described as E7386. Furthermore, the measurement results of the tumor volume of each group are expressed as the mean ± standard error (SEM).

[0309] Thus, compared to the case where the compound represented by formula (I) or trametinib was administered alone, the compound represented by formula (I) exhibited a significant enhancement of the anti-tumor effect by being used in combination with trametinib, and inhibited the proliferation of tumors in a statistically significant manner Figure 1 and 2). This significant enhancement of the anti-tumor effect was not observed in the combination use of ICG001 and trametinib Figure 3 ). In addition, the combination administration of the compound represented by formula (I) and trametinib inhibited tumor proliferation in a statistically significant manner compared to the combination administration of ICG001 and trametinib Figure 4 Figures 1 to 4 *, **, *** and **** in the above table mean p < 0.05, p < 0.01, p < 0.001 and p < 0.0001, respectively, relative to the control group (repeated measures ANOVA followed by Dunnett-type multiple comparison). Figures 1 to 4 #, ##, ### and #### in the above table mean p < 0.05, p < 0.01, p < 0.001 and p < 0.0001, respectively, relative to the single agent administration group; repeated measures ANOVA followed by Dunnett-type multiple comparison).

[0310] [Example 2: Anti-tumor effects of combination administration of MEK inhibitor and compound represented by formula (I), and combination administration of MEK inhibitor, compound represented by formula (I) and KRAS inhibitor in transplanted model mice with human colorectal cancer cell line SW1463 cells]

[0311] Human colorectal cancer cell line SW1463 cells (provided by ATCC) were suspended in Hanks' Balanced Salt Solution (HBSS) (manufactured by Fuji Photo Film and Optical Co., Ltd.) and Matrigel Basement Membrane Matrix (manufactured by Corning International) (1:1 mixture) at 2 x 10 8 cells / mL. 0.1 mL of the obtained cell suspension was transplanted subcutaneously into the right sternum of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by CLEA Japan, Inc.). Seven days after the transplantation, the long axis and the short axis of the tumor produced in each mouse were measured with a digital caliper (manufactured by Mitutoyo Corporation), and the mice were grouped so that each group included six mice and the average tumor volume was approximately equal. The tumor volume was calculated according to the following formula.

[0312] Tumor volume (mm 3 ) = Tumor long axis (mm) x Tumor short axis (mm) / 2 2 2

[0313] ​​​From nine days after the transplantation, the compound represented by formula (I) (25.0 mg / kg, once a day, 14 days, oral administration), trametinib (0.3 mg / kg, once a day, 14 days, oral administration), and adagrasyl (10 mg / kg, once a day, 14 days, oral administration) were administered to the mice in the single administration group or the combined administration group, alone or in combination. Note that none of the above agents were administered to the control group.

[0314] Note that, at the time of administration, the compound represented by formula (I) was dissolved in 0.1 M hydrochloric acid at 1.25 mg / mL or 2.50 mg / mL, trametinib (manufactured by Amadis Chemical Co., Ltd.) was dissolved in distilled water (pH 8.0) (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.5 w / v% of hydroxypropyl methylcellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) and 0.2 w / v% of Tween 80 (manufactured by Sigma-Aldrich Co. LLC) at 0.03 mg / mL, and adagrasyl (manufactured by Amadis Chemical Co., Ltd.) was dissolved in an aqueous solution of 3.5 w / v% of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.5 w / v% of hydroxypropyl methylcellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) containing 6.5 w / v% of Tween 80 at 1.0 mg / mL.

[0315] The day on which administration was started was defined as day 1, and the long axis and the short axis of the tumor produced in each mouse were measured on day 5, day 8, day 12, and day 15, and the tumor volume was calculated by a method similar to the above-described method. Figure 5 The change in tumor volume was demonstrated in the case where 25.0 mg / kg of the compound represented by formula (I) was administered alone, in the case where 0.3 mg / kg of trametinib and 10 mg / kg of adagrasyl were administered in combination, or in the case where 25.0 mg / kg of the compound represented by formula (I), 0.3 mg / kg of trametinib, and 10 mg / kg of adagrasyl were administered in a three-agent combination. Figure 6 The change in tumor volume was demonstrated in the case where 10 mg / kg of adagrasyl was administered alone, in the case where 25.0 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinib were administered in combination, or in the case where 10 mg / kg of adagrasyl, 25.0 mg / kg of the compound represented by formula (I), and 0.3 mg / kg of trametinib were administered in a three-agent combination. Note that, in the figures, the compound represented by formula (I) is described as E7386. Furthermore, the measurement results of the tumor volume of each group are expressed as the mean ± standard error (SEM).

[0316] Therefore, triple-drug combination administration of a compound represented by formula (I), trametinib, and adagracib inhibited tumor proliferation in a statistically significant manner compared to the case where the compound represented by formula (I) was administered alone or the case where trametinib and adagracib were administered in combination. Figure 5 Furthermore, triple-drug combination administration of a compound represented by formula (I), trametinib, and adagracib inhibited tumor proliferation in a statistically significant manner compared to the case where adagracib was administered alone or the case where the compound represented by formula (I) and trametinib were administered in combination ( Figure 6 ). Figure 5 and 6 *, **, *** and **** in the table mean p<0.05, p<0.01, p<0.001 and p<0.0001, respectively, relative to the control group (repeated measures ANOVA followed by Dunning's multiple comparisons). Figure 5 and 6 #, ##, ###, and #### in mean p<0.05, p<0.01, p<0.001, and p<0.0001, respectively, relative to the single-agent administration group; repeated-measures ANOVA followed by Dunning-type multiple comparisons).

[0317] [Example 3: Antitumor effect of combined administration of a MEK inhibitor, a BRAF inhibitor, and a compound represented by formula (I) in model mice transplanted with human colorectal cancer cell line Colo205 cells]

[0318] Human colorectal cancer-derived cell line Colo205 cells (provided by ATCC) were cultured at a rate of 5×10 7 Cells / mL were suspended in Hanks' balanced salt solution (HBSS) (manufactured by Fujifilm and Photochemical Co., Ltd.). 0.1 mL of the obtained cell suspension was subcutaneously transplanted into the right sternum of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by Vital River Laboratories Japan). Six days after transplantation, the long and short axes of the tumors produced in each mouse were measured with a digital caliper (manufactured by Mitutoyo Co., Ltd.), and the mice were grouped, with each group including six mice, so that the average tumor volume was roughly equal. Tumor volume was calculated according to the following formula.

[0319] Tumor volume (mm 3 ) = tumor long axis (mm) × tumor short axis 2 (mm 2 ) / 2

[0320] From six days after the transplantation, the compound represented by formula (I) (25 mg / kg, once a day, 14 days, oral administration), trametinib (0.3 mg / kg, once a day, 14 days, oral administration), and dabrafenib (30 mg / kg, once a day, 14 days, oral administration) were administered to the mice in the single administration group or the combined administration group, alone or in combination. Note that none of the above agents were administered to the control group.

[0321] Note that, at the time of administration, the compound represented by formula (I) was dissolved in 0.1M hydrochloric acid at 2.50 mg / mL, and trametinib (manufactured by Amadis Chemical Co., Ltd.) and dabrafenib (manufactured by Amadis Chemical Co., Ltd.) were dissolved in distilled water (pH 8.0) (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.5 w / v% of hydroxypropyl methylcellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) and 0.2 w / v% of Tween 80 (manufactured by Sigma-Aldrich Co. LLC.) at 0.03 mg / mL and 0.3 mg / mL, respectively.

[0322] The day on which administration was started was defined as day 1, and the long axis and the short axis of the tumor produced in each mouse were measured on day 4, day 8, day 11, and day 15, and the tumor volume was calculated by a method similar to the above-described method. Figure 7 The change in tumor volume is shown in the case where the compound represented by formula (I) at 25 mg / kg and trametinib at 0.3 mg / kg were administered alone or in combination. Figure 8 The change in tumor volume is shown in the case where the compound represented by formula (I) at 25.0 mg / kg was administered alone, in the case where trametinib at 0.3 mg / kg and dabrafenib at 30 mg / kg were administered in combination, or in the case where the compound represented by formula (I) at 25.0 mg / kg, trametinib at 0.3 mg / kg, and dabrafenib at 30 mg / kg were administered in combination. Figure 9 The change in tumor volume is shown in the case where dabrafenib at 30 mg / kg was administered alone, in the case where the compound represented by formula (I) at 25.0 mg / kg and trametinib at 0.3 mg / kg were administered in combination, or in the case where the compound represented by formula (I) at 25.0 mg / kg, trametinib at 0.3 mg / kg, and dabrafenib at 30 mg / kg were administered in combination. Note that, in the figure, the compound represented by formula (I) is described as E7386. Furthermore, the measurement results of the tumor volume of each group are expressed as the mean ± standard error (SEM).

[0323] Therefore, the compound represented by formula (I) exhibited a significant enhancement of anti-tumor effect by use in combination with trametinib, and inhibited tumor proliferation in a statistically significant manner compared to the case where the compound represented by formula (I) or trametinib was administered alone Figure 7 ). Furthermore, the three-agent combination administration of the compound represented by formula (I), trametinib, and dabrafenib inhibited tumor proliferation in a statistically significant manner compared to the two-agent combination administration of the compound represented by formula (I) and trametinib Figure 8 ). Furthermore, the three-agent combination administration of the compound represented by formula (I), trametinib, and dabrafenib inhibited tumor proliferation in a statistically significant manner compared to the two-agent combination administration of the compound represented by formula (I) and trametinib Figure 9 Figures 7 to 9 *, **, ***, and **** in the table mean p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively, relative to the control group (repeated measures ANOVA followed by Dunnett's multiple comparison). Figures 7 to 9 #, ##, ###, and #### in the table mean p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively, relative to the single agent administration group; repeated measures ANOVA followed by Dunnett's multiple comparison).

[0324] [Example 4: Anti-tumor effects of combination administration of MEK inhibitor and compound represented by formula (I), and combination administration of MEK inhibitor, compound represented by formula (I), and KRAS inhibitor in a transplanted model mouse having human non-small cell lung cancer cell line NCI-H358 cells]

[0325] Human non-small cell lung cancer cell line NCI-H358 cells (provided by ATCC) were suspended in Hanks' Balanced Salt Solution (HBSS) (manufactured by Fuji Photo Film and Optical Co., Ltd.) and Matrigel Basement Membrane Matrix (manufactured by Coming International Corp.) (1:1 mixture) at 8 x 10 7 cells / mL. 0.1 mL of the obtained cell suspension was transplanted subcutaneously into the right sternum of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by CLEA Japan, Inc.). Seven days after the transplantation, the long axis and the short axis of the tumor produced in each mouse were measured with a digital caliper (manufactured by Mitutoyo Corporation), and the mice were grouped so as to include six mice in each group so that the average tumor volume was approximately equal. The tumor volume was calculated according to the following formula.

[0326] Tumor volume (mm 3 ) = Tumor long axis (mm) x Tumor short axis (mm) / 2 2 2

[0327] ​​​From seven days after transplantation, the compound represented by formula (I) (25 mg / kg, once a day, 14 days, oral administration), trametinib (0.3 mg / kg, once a day, 14 days, oral administration), and adagrasyl (3 mg / kg, once a day, 14 days, oral administration) were administered to the mice in the single administration group or the combination administration group, alone or in combination. Note that none of the above agents were administered to the control group.

[0328] Note that, at the time of administration, the compound represented by formula (I) was dissolved in 0.1M hydrochloric acid at 1.25 mg / mL or 2.50 mg / mL, trametinib (manufactured by Amadis Chemical Co., Ltd.) was dissolved in distilled water (pH 8.0) (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.5 w / v% of hydroxypropylmethyl cellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) and 0.2 w / v% of Tween 80 (manufactured by Sigma-Aldrich Co. LLC) at 0.03 mg / mL, and adagrasyl (manufactured by Amadis Chemical Co., Ltd.) was dissolved in an aqueous solution containing 6.5 w / v% of Tween 80 in 3.5 w / v% of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.5 w / v% of hydroxypropylmethyl cellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) at 0.3 mg / mL.

[0329] The day on which administration was started was defined as day 1, and the long axis and the short axis of the tumor produced in each mouse were measured on day 5, day 8, day 12, and day 15, and the tumor volume was calculated by a method similar to the above-described method. Figure 10 The transition in tumor volume is shown in the case where the compound represented by formula (I) at 25.0 mg / kg and trametinib at 0.3 mg / kg were administered alone or in combination. Figure 11 The transition in tumor volume is shown in the case where the compound represented by formula (I) at 25.0 mg / kg was administered alone, in the case where trametinib at 0.3 mg / kg and adagrasyl at 3 mg / kg were administered in combination, or in the case where the compound represented by formula (I) at 25.0 mg / kg, trametinib at 0.3 mg / kg, and adagrasyl at 3 mg / kg were administered in a three-agent combination. Figure 12The transition of tumor volume is shown in the case of administration of 3 mg / kg of adagrasyl alone, in the case of administration of 25.0 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinib in combination, or in the case of administration of 3 mg / kg of adagrasyl, 25.0 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinid in a triple combination. Note that in the figure, the compound represented by formula (I) is described as E7386. Further, the measurement results of tumor volume of each group are expressed as mean ± standard error (SEM).

[0330] Thus, the compound represented by formula (I) exhibited a significant enhancement of anti-tumor effect by use in combination with trametinid, and there was a tendency to enhance anti-tumor effect compared to the case of administration of the compound represented by formula (I) or trametinid alone Figure 10 ). Further, the triple combination administration of the compound represented by formula (I), trametinid and adagrasyl inhibited tumor proliferation in a statistically significant manner compared to the case of administration of the compound represented by formula (I) alone or the case of dual combination administration of trametinid and adagrasyl Figure 11 ). Further, the triple combination administration of the compound represented by formula (I), trametinid and adagrasyl inhibited tumor proliferation in a statistically significant manner compared to the case of administration of adagrasyl alone, and exhibited an enhancing tendency compared to the case of dual combination administration of the compound represented by formula (I) and trametinid Figure 12 ). Figures 10 to 12 *, **, *** and **** in mean p<0.05, p<0.01, p<0.001 and p<0.0001, respectively, relative to the control group (repeated measures ANOVA followed by Dunnett’s type multiple comparison). Figures 10 to 12 #, ##, ### and #### in mean p<0.05, p<0.01, p<0.001 and p<0.0001, respectively, relative to the single agent administration group; repeated measures ANOVA followed by Dunnett’s type multiple comparison).

[0331] [Example 5: Anti-tumor effect of combination administration of MEK inhibitor and compound represented by formula (I), or combination administration of MEK inhibitor, compound represented by formula (I) and BRAF inhibitor in a transplanted model mouse with human melanoma cell line A375 cells]

[0332] Human melanoma cell line A375 cells (provided by Dainippon Pharma Co., Ltd.) were inoculated at 5 x 10 7The cells were suspended in Hanks' balanced salt solution (HBSS) (manufactured by Fuji Photo Film and Optical Co., Ltd.). 0.1 mL of the obtained cell suspension was subcutaneously transplanted into the right breastbone of a 6-week-old nude mouse (CAnN.Cg-Foxn1nu / CrlCrlj, manufactured by CLEA Japan, Inc.). Thirteen days after the transplantation, the long axis and the short axis of the tumor produced in each mouse were measured with a digital caliper (manufactured by Mitutoyo Corporation), and the mice were grouped so that the average tumor volume was approximately equal, with each group including six mice. The tumor volume was calculated according to the following formula.

[0333] Tumor volume (mm 3 ) = Tumor long axis (mm) x Tumor short axis 2 (mm 2 ) / 2

[0334] From thirteen days after the transplantation, the compound represented by formula (I) (25 mg / kg, once a day, 14 days, oral administration), trametinib (0.3 mg / kg, once a day, 14 days, oral administration), and dabrafenib (30 mg / kg, once a day, 14 days, oral administration) were administered to the mice in the single administration group or the combined administration group, alone or in combination. Note that none of the above agents were administered to the control group.

[0335] Note that, at the time of administration, the compound represented by formula (I) was dissolved in 0.1 M hydrochloric acid at 1.25 mg / mL or 2.50 mg / mL, trametinib (manufactured by Amadis Chemical Co., Ltd.) was dissolved in distilled water (pH 8.0) (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.5 w / v% of hydroxypropylmethyl cellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) and 0.2 w / v% of Tween 80 (manufactured by Sigma-Aldrich Japan Co., Ltd.) at 0.03 mg / mL, and dabrafenib (manufactured by Amadis Chemical Co., Ltd.) was dissolved in distilled water (pH 8.0) (manufactured by Otsuka Pharmaceutical Co., Ltd.) containing 0.5 w / v% of hydroxypropylmethyl cellulose (manufactured by Fuji Photo Film and Optical Co., Ltd.) and 0.2 w / v% of Tween 80 (manufactured by Sigma-Aldrich Japan Co., Ltd.) at 3 mg / mL.

[0336] The day on which administration was started was defined as day 1, and the long axis and the short axis of the tumor produced in each mouse were measured on day 4, day 8, day 11, and day 15, and the tumor volume was calculated by a method similar to the above-described method. Figure 13 The transition in tumor volume was demonstrated in the case where 25.0 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinib were administered alone or in combination. Figure 14Shown are transitions in tumor volume in the case of single administration of 25.0 mg / kg of the compound represented by formula (I), in the case of combined administration of 0.3 mg / kg of trametinib and 30 mg / kg of dabrafenib, or in the case of triple-drug combination administration of 25.0 mg / kg of the compound represented by formula (I), 0.3 mg / kg of trametinib, and 30 mg / kg of dabrafenib. Figure 15 The figure shows the transition of tumor volume when 30 mg / kg of dabrafenib was administered alone, when 25.0 mg / kg of the compound represented by formula (I) and 0.3 mg / kg of trametinib were administered in combination, or when a three-drug combination of 30 mg / kg of dabrafenib, 25.0 mg / kg of the compound represented by formula (I), and 0.3 mg / kg of trametinib was administered. Note that in the figure, the compound represented by formula (I) is described as E7386. In addition, the measurement results of tumor volume for each group are expressed as mean ± standard error (SEM).

[0337] Therefore, compared with the case where the compound represented by formula (I) or trametinib was administered alone, the compound represented by formula (I) showed a significant enhancement of the antitumor effect by combined use with trametinib, and suppressed tumor proliferation in a statistically significant manner ( Figure 13 Furthermore, the triple-drug combination of a compound represented by formula (I), trametinib, and dabrafenib inhibited tumor proliferation in a statistically significant manner compared to the case where the compound represented by formula (I) was administered alone or the case where trametinib and dabrafenib were administered in combination. Figure 14 Furthermore, the triple-drug combination of a compound represented by formula (I), trametinib, and dabrafenib inhibited tumor proliferation in a statistically significant manner compared to the case where dabrafenib was administered alone or the case where the compound represented by formula (I) and trametinib were administered in combination. Figure 15 ). Figures 13 to 15 *, **, *** and **** in the table mean p<0.05, p<0.01, p<0.001 and p<0.0001, respectively, relative to the control group (repeated measures ANOVA followed by Dunning's multiple comparisons). Figures 13 to 15 #, ##, ###, and #### in mean p<0.05, p<0.01, p<0.001, and p<0.0001, respectively, relative to the single-agent administration group; repeated-measures ANOVA followed by Dunning-type multiple comparisons).

[0338] [Example A-1: ​​Antitumor effect of combined administration of a MEK inhibitor and a compound represented by formula (I) or ICG001 in transplant model mice bearing the human melanoma cell line LOX]

[0339] Human melanoma cell line LOX (obtained from ERI) was cultured at 5×10 7 Cells / mL were suspended in Hanks' balanced salt solution (HBSS) (manufactured by Fujifilm and Photochemical Co., Ltd.). 0.1 mL of the obtained cell suspension was subcutaneously transplanted into the right sternum of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by Vital River Laboratories Japan Co., Ltd.). Seven days after transplantation, the long and short axes of the tumors generated in each mouse were measured with a digital caliper (manufactured by Mitutoyo Co., Ltd.), and the mice were divided into groups, each including six mice, so that the average tumor volume was approximately equal.

[0340] Starting seven days after transplantation, mice in the single or combined administration groups were administered either alone or in combination with a compound represented by Formula (I) (12.5 mg / kg or 25 mg / kg, once daily for 14 days, orally), trametinib (0.3 mg / kg, once daily for 14 days, orally), and ICG001 (100 mg / kg, once daily for 14 days, intraperitoneally). None of the above agents were administered to the control group.

[0341] Note that the preparation of the drug solution, the method for measuring the tumor volume, and the time for measuring the tumor volume were performed in a similar manner to Example 1.

[0342] [Example B-1: Antitumor effect of combined administration of a MEK inhibitor, a compound represented by formula (I), and a RAS inhibitor in model mice transplanted with human non-small cell lung cancer cell line NCI-H2122 cells]

[0343] Human non-small cell lung cancer cell line NCI-H2122 cells (provided by ATCC) were cultured at 5×10 7 Cells / mL were suspended in Hanks' balanced salt solution (HBSS) (manufactured by Fujifilm and Photochemical Co., Ltd.). 0.1 mL of the obtained cell suspension was subcutaneously transplanted into the right sternum of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by Vital River Laboratories Japan). Ten days after transplantation, the long and short axes of the tumors generated in each mouse were measured with a digital caliper (manufactured by Mitutoyo Co., Ltd.), and the mice were divided into groups, each including six mice, so that the average tumor volume was approximately equal.

[0344] From ten days after the transplantation, the compound represented by formula (I) (12.5 mg / kg or 25 mg / kg, once a day, 14 days, oral administration), trametinib (0.3 mg / kg, once a day, 14 days, oral administration), and sorafenib (manufactured by Angene International, 100 mg / kg, once a day, 14 days, oral administration) as a RAS inhibitor were administered to the mice in the single administration group, the two-drug combination administration group, or the three-drug combination administration group, alone or in combination. None of the above agents was administered to the control group.

[0345] Note that the preparation of the compound represented by formula (I) and the trametinib drug solution, the method for measuring the tumor volume, and the timing of measuring the tumor volume were performed in a similar manner to Example 1. Note that sorafenib was dissolved in 1% Tween 80 (manufactured by Sigma) / 2% HPMC (manufactured by Fuji Photo Film and Optical Co., Ltd.) / 97% distilled water (manufactured by Otsuka Pharmaceutical Co., Ltd.).

[0346] The tumor volume proliferation inhibitory effect was confirmed for each single administration group and each combination administration group.

[0347] [Example B-2: Antitumor effect of combination administration of MEK inhibitor, compound represented by formula (I), and RAS inhibitor in transplanted model mouse having human pancreatic cancer cell line MIAPaCa-2]

[0348] The experiment was performed in a similar manner to Example B-1, except that MIAPaCa-2 (provided by ATCC) was used instead of human non-small cell lung cancer cell line NCI-H2122 cells as the cells to be transplanted into the model mice.

[0349] [Example C-1: Antitumor effect of combination administration of compound represented by formula (I), MEK inhibitor, and BRAF inhibitor in transplanted model mouse having human melanoma cell line A375]

[0350] Human melanoma cell line A375 (manufactured by ATCC) was suspended in Hanks' Balanced Salt Solution (HBSS) (manufactured by Fuji Photo Film and Optical Co., Ltd.) at 1 x 10 8 The obtained cell suspension was subcutaneously transplanted into the right breastbone of 6-week-old nude mice (CAnN.Cg-Foxn1 nu / CrlCrlj, manufactured by CLEA Japan, Inc.) at 0.1 mL. Seven days after the transplantation, the long axis and the short axis of the tumor that had developed in each mouse were measured with a digital caliper (manufactured by Mitutoyo Corporation), and the mice were grouped so that each group included six mice, with the average tumor volume being approximately equal.

[0351] From twelve days after the transplantation, the compound represented by formula (I) (12.5 mg / kg or 25 mg / kg, once a day, 14 days, oral administration), trametinib (0.3 mg / kg, once a day, 14 days, oral administration), and dabrafenib (30 mg / kg, once a day, 14 days, intraperitoneal administration) were administered to the mice in the single administration groups or the combined administration groups, alone or in combination. None of the above agents was administered to the control group.

[0352] Note that the preparation of the drug solution, the method for measuring the tumor volume, and the timing of measuring the tumor volume were performed in a similar manner to Example 1.

[0353] The tumor volume proliferation inhibitory effect was confirmed for each single administration group and each combined administration group.

Claims

1. A pharmaceutical composition for treating a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I): or a pharmaceutically acceptable salt thereof, wherein the composition is administered in combination with a MEK inhibitor.

2. A pharmaceutical composition for treating tumors, comprising a MEK inhibitor, wherein the composition is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I): or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1 or 2, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H )-carboxamide or a pharmaceutically acceptable salt thereof is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the MEK inhibitor is selected from trametinib, bemetinib, selumetinib, cobimetinib, and pharmaceutically acceptable salts and solvates thereof.

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the MEK inhibitor is trametinib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

6. A pharmaceutical composition for treating a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I): or a pharmaceutically acceptable salt thereof, wherein the composition is administered in combination with a MEK inhibitor and a RAS inhibitor.

7. A pharmaceutical composition for treating tumors, comprising a MEK inhibitor, wherein the composition is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I): or a pharmaceutically acceptable salt thereof and a RAS inhibitor.

8. The pharmaceutical composition according to claim 6 or 7, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H )-carboxamide or a pharmaceutically acceptable salt thereof is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

9. The pharmaceutical composition according to any one of claims 6 to 8, wherein the MEK inhibitor is selected from trametinib, bemetinib, selumetinib, cobimetinib, and pharmaceutically acceptable salts and solvates thereof.

10. The pharmaceutical composition according to any one of claims 6 to 8, wherein the MEK inhibitor is trametinib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

11. A pharmaceutical composition for treating a tumor, comprising (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I): or a pharmaceutically acceptable salt thereof, wherein the composition is administered in combination with a MEK inhibitor and a BRAF inhibitor.

12. A pharmaceutical composition for treating tumors, comprising a MEK inhibitor, wherein the composition is administered in combination with (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide represented by the following formula (I): or a pharmaceutically acceptable salt thereof and a BRAF inhibitor.

13. The pharmaceutical composition according to claim 11 or 12, wherein (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1( 6H)-carboxamide or a pharmaceutically acceptable salt thereof is (6S,9aS)-N-benzyl-8-({6-[3-(4-ethylpiperazin-1-yl)azetidin-1-yl]pyridin-2-yl}methyl)-6-(2-fluoro-4-hydroxybenzyl)-4,7-dioxo-2-(prop-2-en-1-yl)hexahydro-2H-pyrazino[2,1-c][1,2,4]triazine-1(6H)-carboxamide.

14. The pharmaceutical composition according to any one of claims 11 to 13, wherein the MEK inhibitor is selected from trametinib, bemetinib, selumetinib, cobimetinib, and pharmaceutically acceptable salts and solvates thereof.

15. The pharmaceutical composition according to any one of claims 11 to 13, wherein the MEK inhibitor is trametinib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

16. The pharmaceutical composition according to any one of claims 6 to 10, wherein the RAS inhibitor is a KRAS inhibitor.

17. The pharmaceutical composition according to claim 16, wherein the KRAS inhibitor is a KRAS G12C inhibitor.

18. The pharmaceutical composition according to claim 17, wherein the KRAS G12C inhibitor is sotolacib or a pharmaceutically acceptable salt or solvate thereof.

19. The pharmaceutical composition according to claim 17, wherein the KRAS G12C inhibitor is adagracib or a pharmaceutically acceptable salt or solvate thereof.

20. The pharmaceutical composition according to any one of claims 11 to 15, wherein the BRAF inhibitor is selected from dabrafenib, conefactinib, vemurafenib, and pharmaceutically acceptable salts and solvates thereof.

21. The pharmaceutical composition according to any one of claims 11 to 15, wherein the BRAF inhibitor is dabrafenib or a pharmaceutically acceptable salt thereof, or a solvate thereof.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the tumor is at least one selected from non-small cell lung cancer, colorectal cancer, pancreatic cancer, mesothelioma, uterine cancer, ovarian cancer, bladder cancer, bile duct cancer, gastric cancer, breast cancer, small cell lung cancer, testicular cancer, small intestine cancer, appendix cancer, neuroendocrine tumors, melanoma, and head and neck cancer.

23. The pharmaceutical composition according to any one of claims 1 to 5, wherein the tumor is non-small cell lung cancer.

24. The pharmaceutical composition according to any one of claims 1 to 5, wherein the tumor is colorectal cancer.

25. The pharmaceutical composition according to any one of claims 1 to 5, wherein the tumor is a melanoma.

26. The pharmaceutical composition according to any one of claims 6 to 10 and 16 to 19, wherein the tumor is at least one selected from non-small cell lung cancer, colorectal cancer, and pancreatic cancer.

27. The pharmaceutical composition according to any one of claims 6 to 10 and 16 to 19, wherein the tumor is non-small cell lung cancer.

28. The pharmaceutical composition according to any one of claims 6 to 10 and 16 to 19, wherein the tumor is colorectal cancer.

29. The pharmaceutical composition according to any one of claims 11 to 15, 20 and 21, wherein the tumor is colorectal cancer.

30. The pharmaceutical composition according to any one of claims 11 to 15, 20 and 21, wherein the tumor is a melanoma.

Images