Brain-migrating tumor treatment agent containing, as active ingredient, n-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7h-pyrrolo[2,3-d]pyrimidin-7-yl) bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or salt thereof

Abstract

The present invention provides a brain-migrating anti-tumor agent that exhibits brain migration ability and EGFR inhibitory activity. One embodiment of the present invention provides a brain-migrating anti-tumor agent comprising, as an active ingredient, N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl) bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof.

Description

A brain-delivering tumor therapeutic agent containing N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient

[0001] The present invention relates to a brain-delivering antitumor agent, etc., which is a compound having an inhibitory effect on epidermal growth factor receptor (EGFR).

[0002] Brain tumors are a type of brain disease and a general term for tumors that develop within the skull. Various types of tumors arise in various locations, and are divided into primary and metastatic brain tumors. Primary brain tumors arise from brain cells, nerves, or the membranes that surround the brain. Metastatic brain tumors arise when cancers such as lung cancer and breast cancer metastasize to the brain via the bloodstream. Symptomatic metastatic brain tumors are reported to occur in 8-10% of cancer patients, and autopsies of lung cancer have reported brain metastasis at a frequency of 40-50% (Non-Patent Documents 1-3). Primary tumors of metastatic brain tumors include lung cancer, breast cancer, gastrointestinal cancer (gastric cancer), malignant melanoma, and renal and urinary system cancers, with lung cancer accounting for approximately half of all cases (Non-Patent Document 2). Treatment methods for metastatic brain tumors vary depending on the patient's overall condition, tumor size, and number of metastases. Treatment methods include radiation therapy, surgery, chemotherapy, or a combination of these. Surgery is generally selected when the primary tumor is controlled, solitary, and a reasonable survival period is expected. However, tumors that metastasize to the brain are often intricately intertwined with the brain parenchyma and / or brain tissue, making it often impossible to completely remove the tumor through surgery. Two known radiotherapy methods are quantitative radiosurgery (e.g., gamma knife therapy) and whole-brain irradiation, which delivers radiation to the entire brain. Currently, most metastatic brain tumor treatments combine surgery and radiotherapy, but this does not provide sufficient therapeutic benefit (Non-Patent Documents 4 and 5). The central nervous system (CNS), including the brain, is generally protected from harmful substances by a tight junction layer of highly specialized cells called the blood-brain barrier (BBB). One of the reasons why effective drugs have not been developed for many CNS-related diseases is that almost all therapeutic molecules, including antibodies, cannot cross the BBB. Small molecular weight compounds are no exception, and it has been reported that more than 97% of small molecular weight compounds cannot cross the BBB (Non-Patent Document 6). Currently, many compounds have shown efficacy in peripheral cancers (primary tumors), but their efficacy in brain metastases is limited.One of the reasons for this is thought to be that these compounds cannot reach the brain in sufficient amounts to exert their effects, and therefore cannot exert the same effects as on primary lesions (Non-Patent Documents 7 and 8). Therefore, for CNS-related diseases and brain tumors, the development of low-molecular-weight compounds with high brain penetration and methods for their brain penetration is desired, and in particular, for the treatment of metastatic brain tumors, there is a need for drugs that are effective against primary lesions such as lung cancer, have high CNS penetration, and are also effective against brain metastatic lesions.

[0003] Many compounds have shown efficacy against primary tumors, including compounds with inhibitory activity against epidermal growth factor receptor (EGFR). EGFR is a receptor tyrosine kinase that exerts physiological functions in normal tissues by binding to its ligand, epidermal growth factor (EGF), contributing to proliferation and apoptosis inhibition in epithelial tissues (Non-Patent Document 9). EGFR is also an oncogene, and amplification of the EGFR gene and high protein expression or mutation are known in various cancer types, such as head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors (Non-Patent Document 10).

[0004] Therefore, EGFR inhibitors are thought to be useful as therapeutic agents for diseases associated with abnormal activation of this pathway.

[0005] In fact, drugs such as erlotinib, gefitinib, afatinib, and osimertinib are used in clinical settings as EGFR inhibitors, contributing to improved treatment outcomes. However, some of these drugs cause side effects by nonselectively inhibiting wild-type EGFR (WT), which is related to the occurrence of side effects. Because brain tumors often metastasize from lung cancer, research has also been conducted on the brain penetration of EGFR inhibitors used to treat these lung cancers. As a result, it has become clear that not all EGFR inhibitors can pass through the BBB (Non-Patent Documents 11, 12, and 13).

[0006] Patent Document 1 discloses a compound represented by the following general formula (1) as an EGFR inhibitor. The present invention discloses a pyrimidine compound represented by the formula (chemical name: N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide (hereinafter also referred to as "compound (1)")).

[0007] International Publication No. WO2020 / 166680 Pamphlet

[0008] Thanksgiving yes yes, The 58(20)0820008215,(20005)4000 Now it is a,five ones C14(1)S4854,(2012)SIGNIFICAN ENZY And,Shashi. 4. The 106(7)00000000000000000000000000000000000000000000000000) Knowledgeable s,s. 100%. 100%. The snowflakes. 11(4)0003222,(204)60000000000000000000000000000000 Yes,she's analytical C14(1)0162168,(2008)6B The analytical smile is,. Emotions 40(5)001481792,(108)THE SUBJECT TO YOU,. The 574(11)04420444,(2004)600 I loved it, I loved it 17 s 60126,(2015) THIS THINGS, THIS THIS THINGS 600000000000000000000000000000000000000000000000000000? And,fingers(fingers)40(5) 4200145,(2017) 66 It's a smile, a smile 100000037,(20000000000000000000000) Yes,she's analytical s27(1)0180201,202100000000000000000000000000000000 Yes, I am afraid S22000000000000000000000000000000000000000000000000000000, 10. s s, s s s LIGHTS900215236,(2010)

[0009] Thank you for watching this video Thanks for reading the snowflakes.

[0010] As a result of intensive research, the present inventors have found that a pyrimidine compound having a specific structure that selectively inhibits mutant EGFR (chemical name: N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide, hereinafter also referred to as compound (1)), or a salt thereof, is useful as a brain-delivering antitumor agent, thereby completing the present invention.

[0011] That is, the present invention includes the following embodiments.

[0012] [1] A brain-localizing antitumor agent comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient. [2] The brain-localizing antitumor agent according to [1], for treating primary or metastatic brain tumors. [3] The brain-localizing antitumor agent according to [2], wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid). [3-1] The brain-localizing antitumor agent according to [2], wherein the brain tumor has an EGFR mutation of Ex19del. [3-2] The brain-localizing antitumor agent according to [2], wherein the brain tumor has an EGFR mutation of L858R. [4] The brain-localizing antitumor agent according to [3], wherein C797X is C797S or C797G. [5] The brain-localizing antitumor agent according to [4], wherein the brain tumor further has an Ex19del EGFR mutation, preferably Del E746-A750. [5-1] The brain-localizing antitumor agent according to [4], wherein the brain tumor further has an L858R EGFR mutation. [6] The brain-localizing antitumor agent according to [5] or [5-1], wherein the brain tumor further has a T790M EGFR mutation. [7] The brain-localizing antitumor agent according to any of [1] to [6] and [5-1], for administration to a subject following osimertinib treatment. [8] A brain tumor therapeutic agent comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient. [9] The brain tumor therapeutic agent according to [8], for treating primary or metastatic brain tumors.

[10] The brain tumor therapeutic agent according to [9], wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid). [10-1] The brain tumor therapeutic agent according to [9], wherein the brain tumor has an EGFR mutation of Ex19del. [10-2] The brain tumor therapeutic agent according to [9], wherein the brain tumor has an EGFR mutation of L858R.

[11] The brain tumor therapeutic agent according to

[10] , wherein C797X is C797S or C797G.

[12] The brain tumor therapeutic agent according to

[11] , wherein the brain tumor further has an Ex19del EGFR mutation, preferably Del E746-A750. [12-1] The brain tumor therapeutic agent according to

[11] , wherein the brain tumor further has an L858R EGFR mutation.

[13] The brain tumor therapeutic agent according to

[12] or [12-1], wherein the brain tumor further has a T790M EGFR mutation.

[14] The brain tumor therapeutic agent according to any of [8] to

[13] and [12-1], for administration to a subject after osimertinib treatment.

[15] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof for use in treating brain tumors.

[16] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[15] for treating primary or metastatic brain tumors.

[17] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[16] , wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid). [17-1] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[16] , wherein the brain tumor has an EGFR mutation of Ex19del. [17-2] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[16] , wherein the brain tumor has an L858R EGFR mutation.

[18] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[17] , wherein C797X is C797S or C797G.

[19] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[18] , wherein the brain tumor further has an Ex19del EGFR mutation, preferably Del E746-A750. [19-1] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[18] , wherein the brain tumor further has an L858R EGFR mutation.

[20] The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to

[19] or [19-1], wherein the brain tumor further has a T790M EGFR mutation.

[21] N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to any of

[15] to

[20] and [19-1], for administration to a subject after osimertinib treatment.

[22] Use of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof for the manufacture of a medicament for treating brain tumors.

[23] The use according to

[22] , for treating primary or metastatic brain tumors.

[24] The brain tumor is C797X (X represents any amino acid).The use according to

[23] , wherein the brain tumor has an Ex19del EGFR mutation. [24-1] The use according to

[23] , wherein the brain tumor has an Ex19del EGFR mutation. [24-2] The use according to

[23] , wherein the brain tumor has an L858R EGFR mutation.

[25] The use according to

[24] , wherein C797X is C797S or C797G.

[26] The use according to

[25] , wherein the brain tumor further has an Ex19del EGFR mutation, preferably Del E746-A750. [26-1] The use according to

[25] , wherein the brain tumor further has an L858R EGFR mutation.

[27] The use according to

[26] or [26-1], wherein the brain tumor further has a T790M EGFR mutation.

[28] The use according to any one of

[22] to

[27] and [26-1], for administration to a subject after osimertinib treatment.

[29] Use of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof for treating brain tumors.

[30] A method for treating a subject with a brain tumor, comprising administering N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof to a subject in need of treatment.

[31] The therapeutic method according to

[30] , for treating primary or metastatic brain tumors.

[32] The therapeutic method according to

[31] , wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid). [32-1] The therapeutic method according to

[31] , wherein the brain tumor has an EGFR mutation of Ex19del. [32-2] The therapeutic method according to

[31] , wherein the brain tumor has an EGFR mutation of L858R.

[33] The therapeutic method according to

[32] , wherein C797X is C797S or C797G.

[34] The therapeutic method according to

[33] , wherein the brain tumor further has an EGFR mutation of Ex19del, preferably Del E746-A750.[34-1] The treatment method according to

[33] , wherein the brain tumor further has an L858R EGFR mutation.

[35] The treatment method according to

[34] or [34-1], wherein the brain tumor further has a T790M EGFR mutation.

[36] The treatment method according to any of

[30] to

[35] and [34-1], which is for administration to a subject after osimertinib treatment.

[37] A pharmaceutical composition for treating a brain tumor, comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.

[38] An anti-brain tumor agent comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient.

[39] The anti-brain tumor agent according to

[38] , for treating primary or metastatic brain tumors.

[40] The anti-brain tumor agent according to

[39] , wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid). [40-1] The anti-brain tumor agent according to

[39] , wherein the brain tumor has an EGFR mutation of Ex19del. [40-2] The anti-brain tumor agent according to

[39] , wherein the brain tumor has an EGFR mutation of L858R.

[41] The anti-brain tumor agent according to

[40] , wherein C797X is C797S or C797G.

[42] The anti-brain tumor agent according to

[41] , wherein the brain tumor further has an Ex19del EGFR mutation, preferably Del E746-A750. [42-1] The anti-brain tumor agent according to

[41] , wherein the brain tumor further has an L858R EGFR mutation.

[43] The anti-brain tumor agent according to

[42] or [42-1], wherein the brain tumor further has a T790M EGFR mutation.

[44] The anti-brain tumor agent according to any of

[38] to

[43] and [42-1], for administration to a subject following osimertinib treatment.

[45] A brain-localizing mutant EGFR inhibitor comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient.

[46] The brain-localizing mutant EGFR inhibitor according to

[45] , for treating primary or metastatic brain tumors.

[47] The brain-localizing mutant EGFR inhibitor according to

[46] , wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid). [47-1] The brain-localizing mutant EGFR inhibitor according to

[46] , wherein the brain tumor has an EGFR mutation of Ex19del. [47-2] The brain-localizing mutant EGFR inhibitor according to

[46] , wherein the brain tumor has an L858R EGFR mutation.

[48] The brain-localizing mutant EGFR inhibitor according to

[47] , wherein C797X is C797S or C797G.

[49] The brain-localizing mutant EGFR inhibitor according to

[48] , wherein the brain tumor further has an Ex19del EGFR mutation, preferably Del E746-A750. [49-1] The brain-localizing mutant EGFR inhibitor according to

[48] , wherein the brain tumor further has an L858R EGFR mutation.

[50] The brain-localizing mutant EGFR inhibitor according to

[49] or [49-1], wherein the brain tumor further has a T790M EGFR mutation.

[51] The brain-localizing mutant EGFR inhibitor according to any one of

[45] to

[50] and [49-1], for administration to a subject after osimertinib treatment.

[0013] According to one aspect of the present invention, there is provided an antitumor agent having brain-localizing ability. According to another aspect of the present invention, there is provided an anti-brain tumor agent. According to yet another aspect of the present invention, there is provided a brain tumor therapeutic agent or a brain-localizing mutant EGFR inhibitor.

[0014]

[0039] Figure 1 shows the results of a drug efficacy evaluation test (luminescence amount) of compound (1) and brigutinib in a mouse brain transplant model in Test Example 4.

[0040] Figure 2 shows the results of a drug efficacy evaluation test (survival curve) of compound (1) and brigutinib in a mouse brain transplant model in Test Example 4.

[0050] Figure 3 shows the results of a drug efficacy evaluation test of compound (1) in a mouse subcutaneous transplant model in Test Example 5.

[0051] Figure 4 shows the results of a drug efficacy evaluation test of brigutinib in a mouse subcutaneous transplant model in Test Example 6.

[0015] One aspect of the present invention relates to a brain-delivering antitumor agent containing, as an active ingredient, N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide represented by the following formula (1), or a salt thereof:

[0016] According to one embodiment of the present invention, there is provided an antitumor agent having brain-delivering ability, comprising compound (1) or a salt thereof, which exhibits an inhibitory effect on mutant EGFR and exhibits an effective therapeutic effect against brain tumors.

[0017] Another embodiment of the present invention provides use of compound (1) or a salt thereof for producing an antitumor agent exhibiting brain-localizing activity, EGFR inhibitory activity against mutant forms, and / or antitumor effect.

[0018] According to one embodiment of the present invention, there is provided compound (1) or a salt thereof, which exhibits brain-transmitting activity, EGFR inhibitory activity against mutant forms, and / or antitumor effect, for treating tumors, particularly brain tumors.

[0019] According to yet another embodiment of the present invention, there is provided a method for treating tumors, particularly brain tumors, comprising administering an antitumor agent containing compound (1) or a salt thereof, which has brain-localizing and / or mutant EGFR inhibitory activity.

[0020] According to one embodiment of the present invention, there is provided an anti-brain tumor agent comprising compound (1) or a salt thereof, which exhibits brain-localizing and / or mutated EGFR inhibitory activity and exhibits effective therapeutic effects against brain tumors.

[0021] Another embodiment of the present invention provides use of compound (1) or a salt thereof for producing an anti-brain tumor agent exhibiting brain-localizing activity and / or EGFR inhibitory activity against mutant forms and / or anti-tumor effect.

[0022] According to one embodiment of the present invention, there is provided compound (1) or a salt thereof for treating tumors, particularly brain tumors, using an anti-brain tumor agent that exhibits brain-localizing activity and / or mutant EGFR inhibitory activity and / or anti-brain tumor effect.

[0023] According to yet another embodiment of the present invention, there is provided a method for treating tumors, particularly brain tumors, comprising administering an anti-brain tumor agent containing compound (1) or a salt thereof having brain-localizing activity and / or mutant EGFR inhibitory activity.

[0024] According to one embodiment of the present invention, there is provided a brain tumor therapeutic agent comprising compound (1) or a salt thereof, which exhibits brain-localizing and / or mutated EGFR inhibitory activity and exhibits effective therapeutic effects against brain tumors.

[0025] According to one embodiment of the present invention, there is provided use of compound (1) or a salt thereof for producing a brain tumor therapeutic agent that exhibits brain-delivery ability, mutant EGFR inhibitory activity, and / or antitumor effect.

[0026] According to one embodiment of the present invention, there is provided compound (1) or a salt thereof for treating tumors, particularly brain tumors, using a brain tumor therapeutic agent that exhibits brain-delivery ability, mutant EGFR inhibitory activity, and / or anti-brain tumor effect.

[0027] According to yet another embodiment of the present invention, there is provided a method for treating tumors, particularly brain tumors, comprising administering a brain tumor therapeutic agent containing compound (1) or a salt thereof, which exhibits brain-localizing activity, mutant EGFR inhibitory activity, and / or antitumor effect.

[0028] According to one embodiment of the present invention, there is provided a brain-localizing EGFR inhibitor comprising compound (1) or a salt thereof that exhibits an antitumor effect.

[0029] According to one embodiment of the present invention, there is provided use of compound (1) or a salt thereof for producing a brain-localizing EGFR inhibitor that exhibits mutant EGFR inhibitory activity and / or antitumor effect.

[0030] According to one embodiment of the present invention, there is provided compound (1) or a salt thereof for treating tumors, particularly brain tumors, using a brain-localizing EGFR inhibitor that exhibits mutant EGFR inhibitory activity and / or anti-brain tumor effect.

[0031] According to yet another embodiment of the present invention, there is provided a method for treating tumors, particularly brain tumors, comprising administering a brain-localizing EGFR inhibitor comprising compound (1) or a salt thereof that exhibits mutant EGFR inhibitory activity and / or antitumor effect.

[0032] As used herein, a brain-localizing antitumor agent refers to an antitumor agent that allows at least a portion of its active ingredient to migrate to the brain and exhibits a therapeutic effect against primary brain tumors and / or metastatic brain tumors.

[0033] As used herein, an anti-brain tumor agent refers to an anti-tumor agent that delivers at least a portion of its active ingredient to the brain and exhibits a therapeutic effect against primary brain tumors and / or metastatic brain tumors.

[0034] As used herein, a therapeutic agent for brain tumors means a therapeutic agent that delivers at least a portion of its active ingredient to the brain and exhibits a therapeutic effect against primary brain tumors and / or metastatic brain tumors.

[0035] As used herein, a brain-localizing EGFR inhibitor refers to an EGFR inhibitor that allows at least a portion of the active ingredient to migrate to the brain and exhibits a therapeutic effect against primary brain tumors and / or metastatic brain tumors.

[0036] In this specification, the compound represented by formula (1) may be simply referred to as compound (1).

[0037] Compound (1) and salts thereof can be produced by known organic synthesis methods, for example, in accordance with the method described in Patent Document 1.

[0038] When compound (1) has isomers such as optical isomers, stereoisomers, rotamers, tautomers, etc., all isomers and mixtures thereof are encompassed in compound (1) unless otherwise specified. For example, when compound (1) has optical isomers, the racemate and optical isomers resolved from the racemate are also encompassed in compound (1) unless otherwise specified.

[0039] The salt of compound (1) means a pharmaceutically acceptable salt, and may be a base addition salt or an acid addition salt.

[0040] Specific examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, paratoluenesulfonic acid, glutamic acid, and sorbic acid; base addition salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; base addition salts with organic bases such as methylamine, ethylamine, meglumine, and ethanolamine; or salts with basic amino acids such as lysine, arginine, and ornithine; and ammonium salts.

[0041] "Pharmaceutically acceptable salts" means salts that possess the desired pharmacological activity of a compound and that are prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.

[0042] Compound (1) or a salt thereof also includes a prodrug thereof. A prodrug is a compound that is converted into compound (1) or a salt thereof by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is converted into compound (1) or a salt thereof by enzymatic oxidation, reduction, hydrolysis, or the like. It may also be a compound that is converted into compound (1) or a salt thereof under physiological conditions as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, Hirokawa Shoten, 1990.

[0043] Compound (1) or a salt thereof may be amorphous (non-crystalline) or crystalline, and whether the crystalline form is a single one or a polymorphic mixture, it is included in Compound (1) or a salt thereof. Crystals can be produced by crystallization using a known crystallization method. Compound (1) or a salt thereof may be a solvate (e.g., hydrate, etc.) or a non-solvate, and both are included in Compound (1) or a salt thereof. Isotopes (e.g., ３ H.１４ C. ３５ S. １２５ Compounds labeled with, for example, CI are also encompassed in compound (1) or a salt thereof. A plurality of crystals (crystal polymorphs) having different spatially regular atomic arrangements and physicochemical properties may be produced, and the salt of the compound used in the present invention may be any of these crystal polymorphs, or may be a mixture of two or more crystal polymorphs, or may even be a mixture of a crystal and an amorphous form.

[0044] As used herein, the term "effective amount" of compound (1) refers to an amount of compound (1) that induces a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease (a therapeutically effective amount).

[0045] As used herein, "treatment" includes postoperative adjuvant chemotherapy, which is performed to prevent recurrence after surgical removal of a tumor, and neoadjuvant chemotherapy, which is performed prior to surgical removal of a tumor.

[0046] As used herein, the term "subject" includes mammals and non-mammals. In one embodiment, the subject is a human, and may be a human diagnosed as needing treatment for a symptom, condition, or disease disclosed herein.

[0047] The age of a subject to be administered the brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention is not particularly limited. The brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention can be used not only for adults, but also for elderly people and children.

[0048] Compound (1) or a salt thereof, or a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention, comprising the compound (1) or a salt thereof, has excellent EGFR inhibitory activity and also has excellent selectivity for EGFR. Therefore, compound (1) or a salt thereof, or a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention, comprising the compound (1) or a salt thereof, is useful as an antitumor agent against malignant tumors with EGFR overexpression, EGFR gene amplification, EGFR mutation, or the like.

[0049] As used herein, "wild-type EGFR" refers to, for example, the amino acid sequence (SEQ ID NO: 1) of GenBank Accession No. NP_005219.2. As used herein, "exon 18" refers to the region from 688 to 728 in the amino acid sequence of wild-type EGFR (e.g., GenBank Accession No. NP_005219.2). As used herein, "exon 19" refers to the region from 729 to 760 in the amino acid sequence of wild-type EGFR (e.g., GenBank Accession No. NP_005219.2). As used herein, "exon 20" refers to the region from 761 to 823 in the amino acid sequence of wild-type EGFR (e.g., GenBank Accession No. NP_005219.2). As used herein, "exon 21" refers to the region from 824 to 875 in the amino acid sequence of wild-type EGFR (for example, GenBank accession number: NP_005219.2).

[0050] As used herein, "Ex19del" refers to a mutation in which one or more amino acids are deleted in the exon 19 region of wild-type EGFR. It also encompasses mutations in which one or more arbitrary amino acids are inserted in addition to the deletion of the region. Examples of exon 19 deletion mutations include a mutation in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750 (also referred to as d746-750)), a mutation in which seven amino acids from leucine at position 747 to proline at position 753 in the exon 19 region are deleted followed by an insertion of serine (Del L747-P753insS), a mutation in which five amino acids from leucine at position 747 to threonine at position 751 in the exon 19 region are deleted (Del L747-T751), and a mutation in which four amino acids from leucine at position 747 to alanine at position 750 in the exon 19 region are deleted followed by an insertion of proline (Del L747-A750insP). A preferred example is a mutation in which five amino acids from glutamic acid at position 746 to alanine at position 750 in the exon 19 region are deleted (Del E746-A750), but this is not limited to this.

[0051] As used herein, "L718X" refers to a point mutation in which leucine encoded by codon 718 in exon 18 of wild-type EGFR is substituted with any amino acid. Examples of the amino acid substituted for leucine include, but are not limited to, glutamine (L718Q) and valine (L718V).

[0052] As used herein, "G724X" refers to a point mutation in which glycine encoded by codon 724 in exon 18 of wild-type EGFR is substituted with any amino acid. Examples of the amino acid substituted for glycine include, but are not limited to, serine (G724S).

[0053] As used herein, "T790X" refers to a point mutation in which the threonine encoded by codon 790 in exon 20 of wild-type EGFR is substituted with any amino acid. Examples of the amino acid substituted for threonine include, but are not limited to, methionine (T790M). T790X encompasses any amino acid mutation that occurs due to a de novo mutation or the use of a first- or second-generation EGFR inhibitor. Examples of first- and second-generation EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, and afatinib.

[0054] As used herein, "L792X" refers to a point mutation in which the leucine encoded by codon 792 in exon 20 of wild-type EGFR is substituted with any amino acid. Examples of the amino acid substituted for the leucine include, but are not limited to, phenylalanine (L792F), histidine (L792H), tyrosine (L792Y), valine (L792V), and proline (L792P).

[0055] As used herein, "G796X" refers to a point mutation in which glycine encoded by codon 796 in exon 20 of wild-type EGFR is substituted with any amino acid. Examples of the amino acid substituted for glycine include, but are not limited to, arginine (G796R), serine (G796S), and cysteine ​​(G796C).

[0056] As used herein, "C797X" refers to a point mutation in which the cysteine ​​encoded by codon 797 in exon 20 of wild-type EGFR is substituted with any amino acid. Examples of amino acids substituted for cysteine ​​include, but are not limited to, serine (C797S) and glycine (C797G). C797X encompasses any amino acid mutation that occurs through the use of an EGFR inhibitor (e.g., a second-generation EGFR inhibitor and / or a third-generation EGFR inhibitor) that covalently binds to C797. Examples of second-generation EGFR inhibitors include, but are not limited to, afatinib. Examples of third-generation EGFR inhibitors include, but are not limited to, osimertinib and lazertinib.

[0057] As used herein, "T854X" refers to a point mutation in which threonine is substituted with any amino acid at codon 854 in exon 21 of wild-type EGFR. Examples of the amino acid substituted for threonine include, but are not limited to, alanine (T854A) and isoleucine (T854I).

[0058] As used herein, "L858X" refers to a point mutation in which leucine is substituted with any amino acid at codon 858 in exon 21 of wild-type EGFR. Examples of the amino acid substituted for leucine include, but are not limited to, arginine (L858R) and methionine (L858M).

[0059] In this specification, mutant EGFR refers to the EGFR described in this specification. In one embodiment of the present invention, compound (1) has an inhibitory effect against "Ex19del," "L718X," "G724X," "T790X," "L792X," "G796X," "C797X," "T854X," and "L858X" (X represents any amino acid), and has a therapeutic effect against tumors having one or more of these mutant EGFRs, although the types of mutations are not limited to these.

[0060] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is Ex19del, and the Ex19del is preferably at least one selected from Del E746-A750, Del L747-P753insS, Del L747-T751, and Del L747-A750insP, but is not limited thereto.

[0061] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is C797X (X represents any amino acid). Of C797X, at least one selected from C797S and C797G is preferred, with C797S being particularly preferred, but not limited thereto.

[0062] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is L718X (X represents any amino acid). L718X is preferably at least one selected from L718Q and L718V, but is not limited thereto.

[0063] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is G724X (X represents any amino acid), preferably G724S, but is not limited thereto.

[0064] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is L792X (X represents any amino acid), preferably at least one selected from L792F, L792H, L792Y, L792V, and L792P, but is not limited thereto.

[0065] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is G796X (X represents any amino acid), preferably at least one selected from G796R, G796S, and G796C, but is not limited thereto.

[0066] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is T854X (X represents any amino acid), preferably at least one selected from T854A and T854I, but is not limited thereto.

[0067] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) may have, in addition to the above mutations, at least one mutation selected from Ex19del, T790M, and L858X (X represents any amino acid). Of L858X, at least one mutation selected from L858R and L858M is preferred, and L858R is particularly preferred, but is not limited to these.

[0068] In one embodiment of the present invention, the mutant EGFR that can be inhibited by compound (1) is preferably a mutation having, in addition to C797S, one or more mutations selected from the EGFR mutations consisting of Ex19del, L858R, and T790M.

[0069] As used herein, the term "point mutation" refers to a mutation that results in the substitution, insertion, or deletion of one or more (for example, about 1 to 10, preferably about 1 to 5, more preferably about 1, 2, or 3) amino acid residues, and may also include in-frame insertion and / or deletion mutations as nucleic acids.

[0070] Furthermore, compound (1) or a salt thereof, or a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention comprising them has excellent selectivity for mutant EGFR and has the advantage of causing fewer side effects due to wild-type EGFR and other kinases.

[0071] Furthermore, compound (1) or a salt thereof, or a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention comprising them has the advantage that it can be used in subjects with mutations that occur due to the use of third-generation EGFR inhibitors (e.g., subjects who exhibit osimertinib resistance after osimertinib treatment, or subjects who exhibit lazertinib resistance after lazertinib treatment, etc.).

[0072] As used herein, "osimertinib resistance" refers to a state in which a subject who has been treated with EGFR gene mutation-positive tumors (peripheral cancers (primary lesions), primary brain tumors, and / or metastatic brain tumors) with osimertinib has experienced a loss or attenuation of the therapeutic effect of osimertinib. Additionally, "lasertinib resistance" refers to a state in which a subject who has been treated with EGFR gene mutation-positive tumors (peripheral cancers (primary lesions), primary brain tumors, and / or metastatic brain tumors) with lazertinib has experienced a loss or attenuation of the therapeutic effect of lazertinib.

[0073] As used herein, "after osimertinib treatment" refers to administration after administration of osimertinib, and "after lazertinib treatment" refers to administration after administration of lazertinib.

[0074] Compound (1) or a salt thereof, or a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention comprising them, is useful as a pharmaceutical for preventing or treating diseases involving EGFR due to its excellent EGFR inhibitory activity.

[0075] One embodiment of the present invention provides an EGFR inhibitor comprising compound (1) or a salt thereof. One embodiment of the present invention provides an EGFR inhibitor comprising compound (1) or a salt thereof for use after osimertinib treatment. Another embodiment of the present invention provides an EGFR inhibitor comprising compound (1) or a salt thereof for use after lazertinib treatment.

[0076] Another embodiment of the present invention provides an antitumor agent, anti-brain tumor agent, and / or brain tumor therapeutic agent comprising compound (1) or a salt thereof for use after osimertinib treatment. Another embodiment of the present invention provides an antitumor agent, anti-brain tumor agent, and / or brain tumor therapeutic agent comprising compound (1) or a salt thereof for use after lazertinib treatment.

[0077] One embodiment of the present invention also provides a method for treating tumors, particularly brain tumors, comprising administering to a subject in need thereof an effective amount of compound (1) or a salt thereof after osimertinib treatment.One embodiment of the present invention also provides a method for treating tumors, particularly brain tumors, comprising administering to a subject in need thereof an effective amount of compound (1) or a salt thereof after lazertinib treatment.

[0078] One embodiment of the present invention provides use of compound (1) or a salt thereof for producing an antitumor agent, anti-brain tumor agent and / or brain tumor therapeutic agent for use after osimertinib treatment. Another embodiment of the present invention provides use of compound (1) or a salt thereof for producing an antitumor agent, anti-brain tumor agent and / or brain tumor therapeutic agent for use after lazertinib treatment.

[0079] One embodiment of the present invention provides compound (1) or a salt thereof for treating tumors, particularly brain tumors, after osimertinib treatment. Another embodiment of the present invention provides compound (1) or a salt thereof for treating tumors, particularly brain tumors, after lazertinib treatment.

[0080] Due to its excellent mutant EGFR inhibitory activity, compound (1) or a salt thereof is useful as a pharmaceutical for preventing or treating diseases associated with mutant EGFR.

[0081] "Diseases associated with mutant EGFR" include diseases whose incidence rate is reduced, symptoms are alleviated, mitigated, and / or cured by deleting, suppressing, and / or inhibiting the function of EGFR. Examples of such diseases include, but are not limited to, malignant tumors. The malignant tumor is preferably a malignant tumor in which the activation state of EGFR is increased, and more preferably includes head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, gastric cancer (digestive system cancer), duodenal cancer, liver cancer, biliary tract cancer (gallbladder and bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), kidney cancer, renal pelvis and ureter cancer, bladder cancer, prostate cancer, testicular tumor, leukemia, malignant lymphoma, multiple myeloma, bone and soft tissue tumor, skin cancer, malignant melanoma, adrenal tumor, brain tumor, etc., in which the activation state of EGFR is increased. Preferred are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, leukemia, skin cancer, malignant melanoma, and brain tumors. Preferred are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, pancreatic cancer, leukemia, skin cancer, malignant melanoma, and brain tumors, and more preferred are salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumors. Even more preferred are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumors.

[0082] The term "enhanced activation of EGFR" refers to an enhanced activation state of the EGFR gene due to translocation, mutation (including point mutation, deletion mutation, and insertion mutation), and overexpression (including an increase in the copy number of the EGFR gene, excessive expression of EGFR messenger RNA, an increase in EGFR protein, and a state in which the EGFR protein is constitutively activated), etc.

[0083] The target cancers and tumors are not particularly limited, but examples include epithelial cancers (respiratory system cancer, digestive system cancer, reproductive system cancer, endocrine system cancer, etc.), sarcoma, hematopoietic cell tumors, central nervous system tumors, peripheral nerve tumors, etc.

[0084] Specific cancer types include head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, gastric cancer (digestive system cancer), duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, uterine body cancer, etc.), kidney cancer, renal pelvis / ureter cancer, bladder cancer, prostate cancer, testicular tumor, leukemia, malignant lymphoma, multiple myeloma, bone and soft tissue tumor, skin cancer, malignant melanoma, adrenal tumor, brain tumor, etc. Preferred are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, leukemia, skin cancer, malignant melanoma, and brain tumor. Preferable are salivary gland cancer, lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), colorectal cancer (colon cancer, rectal cancer, etc.), thyroid cancer, breast cancer, pancreatic cancer, leukemia, skin cancer, malignant melanoma, and brain tumor, more preferable are salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumor, and even more preferable are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumor.

[0085] In a typical embodiment of the present invention, the tumor targeted by compound (1) for its effect through the BBB is a brain tumor. In this specification, brain tumors include primary brain tumors and metastatic brain tumors. Primary tumors include, but are not limited to, glioma, primary central nervous system malignant lymphoma, meningioma, pituitary adenoma, schwannoma, craniopharyngioma, etc. Furthermore, for metastatic brain tumors, the type of tumor that serves as the primary focus is not important. In the case of metastatic brain tumors, the type of tumor that serves as the primary focus is not limited, but specific carcinomas include head and neck cancer, digestive cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder / bile duct cancer, etc.), pancreatic cancer, colon cancer (colorectal cancer, colon cancer, rectal cancer, anal cancer, etc.)), lung cancer (non-small cell lung cancer, small cell lung cancer), mesothelioma (pleural mesothelioma, peritoneal mesothelioma, pericardial mesothelioma, testicular mesothelioma, etc.), and the like. Examples of cancers that can be cured include breast cancer, reproductive cancers (ovarian cancer, vulvar cancer, uterine cancer (cervical cancer, uterine corpus cancer, endometrial cancer, etc.)), urinary cancers (kidney cancer, bladder cancer, prostate cancer, testicular tumor, urothelial cancer, renal pelvis cancer, urethral cancer, etc.), hematopoietic tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, malignant neurilemmoma, neuroendocrine tumor, thyroid cancer, etc. Preferred are head and neck cancer, breast cancer, colon cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, and skin cancer, with lung cancer being particularly preferred.

[0086] Even drugs that have crossed the BBB may be actively excreted into the bloodstream by transporters such as P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), which are localized on the vascular side of brain capillary endothelial cells, making it difficult to maintain a concentration that exerts therapeutic efficacy. To demonstrate therapeutic efficacy against primary and / or metastatic brain tumors, it is preferable to avoid becoming a substrate for these transporters. Whether a drug is a substrate for these transporters can be confirmed by transcytosis tests using cells expressing transporters such as P-gp or BCRP, as in Test Example 7 in the Examples. According to Non-Patent Document 14, if the efflux ratio (synonymous with the "ratio of apparent permeability coefficients (Papp)" in this specification) is less than 2, it can be determined that the drug is not a substrate for these transporters.

[0087] The brain penetration of compound (1) can be evaluated using the brain-to-plasma drug concentration ratio (Kp value) and / or the brain-to-plasma unbound drug concentration ratio (Kp,uu value). In mouse brain penetration evaluation, a Kp value of 0.1 or greater is considered to have brain penetration, with 0.1 as the cutoff value. In the present invention, the Kp value is preferably 0.1 or greater. There is also a correlation between the Kp,uu value and brain penetration, and a value of 0.3 or greater can be considered to have good brain penetration. The higher the Kp,uu value, the higher the brain penetration, which is a preferred value. The Kp,uu value is preferably 0.4 or greater, more preferably 0.5 or greater.

[0088] Compound (1) has an inhibitory effect on mutant EGFR and can therefore be used to inhibit mutant EGFR in tumors (primary or metastatic) occurring in brain tissue and suppress tumor growth. Furthermore, compound (1) is highly selective and therefore particularly useful for the treatment of brain tumors (primary or metastatic) in which EGFR mutations are involved in cancer cell proliferation.

[0089] Compound (1) or a salt thereof, or a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor according to one embodiment of the present invention, can also be used to prevent the development of brain tumors. Because compound (1) can cross the BBB, it can be used to prevent the metastasis and establishment of cancer cells with EGFR mutations in the brain. That is, in one embodiment of the present invention, compound (1) can also be used to prevent the development of metastatic brain tumors. Furthermore, in one embodiment of the present invention, compound (1) exhibits excellent brain-localizing properties, making it possible to simultaneously treat peripheral cancers (primary lesions) with EGFR mutations and brain tumors with EGFR mutations.

[0090] In one embodiment of the present invention, the brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor can be provided as a single active ingredient. Furthermore, in one embodiment of the present invention, the brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor can also be formulated with a pharmaceutically acceptable carrier, etc., as needed, in addition to the active ingredient, compound (1) or a salt thereof. Thus, the brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor in one embodiment of the present invention can be prepared as a pharmaceutical composition consisting of a single ingredient or containing two or more ingredients. One aspect of the present invention provides a pharmaceutical composition comprising compound (1) or a salt thereof. One embodiment of the pharmaceutical composition comprises compound (1) or a salt thereof and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides use of compound (1) or a salt thereof for producing a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor or pharmaceutical composition. Another embodiment of the present invention provides compound (1) or a salt thereof for use as a brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent and / or brain-localizing EGFR inhibitor or pharmaceutical.

[0091] In one embodiment of the present invention, the brain-localizing antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain-localizing EGFR inhibitor can be prepared as various dosage forms by known methods, using a pharmaceutically acceptable carrier as needed. The dosage form may be either oral or parenteral. The dosage form is not particularly limited, and examples include oral dosage forms such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions, and parenteral dosage forms such as injections, suppositories, and inhalants.

[0092] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, and include excipients, binders, disintegrants, lubricants, coating agents, etc. in solid formulations, and are incorporated as solvents, solubilizers, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, stabilizers, etc. can also be used as needed.

[0093] Examples of excipients include starches, sugars, polysaccharides, inorganic compounds, and the like. Examples of starches include potato starch, corn starch, rice starch, and partially pregelatinized starch. Examples of sugars include monosaccharides, disaccharides, trisaccharides, and sugar alcohols. Examples include lactose, sucrose, trehalose, D-mannitol, raffinose, xylitol, and erythritol. Examples of polysaccharides include cellulose and dextran. Examples include crystalline cellulose, hydroxypropyl cellulose, and hydroxypropylmethyl cellulose. Examples of inorganic compounds include silicic acids, such as light anhydrous silicic acid and calcium silicate. Examples of binders include hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, candy powder, and hypromellose. Disintegrants include sodium starch glycolate, carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and partially pregelatinized starch. Lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, and sodium stearyl fumarate. Coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hypromellose, and sucrose. Solvents include water, propylene glycol, and physiological saline. Solubilizers include polyethylene glycol, alcohols such as ethanol, cyclodextrins, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants, such as sorbitan fatty acid esters such as polysorbate 80, sucrose fatty acid esters, and sodium lauryl sulfate. Suspending agents include carrageenan, crystalline cellulose-carmellose sodium, polyoxyethylene hydrogenated castor oil, gum arabic, and sodium alginate. Examples of isotonic agents include sodium chloride, glycerin, potassium chloride, etc. Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, sodium dihydrogen phosphate, etc. Examples of soothing agents include procaine hydrochloride, lidocaine, etc.Examples of preservatives include ethyl parahydroxybenzoate, cresol, and benzalkonium chloride. Examples of antioxidants include sodium sulfite, ascorbic acid, and natural vitamin E. Examples of colorants include titanium oxide, ferric oxide, Food Blue No. 1, and copper chlorophyll. Examples of flavoring and odor correcting agents include aspartame, saccharin, sucralose, 1-menthol, and mint flavor. Examples of stabilizers include sodium metabisulfite, sodium edetate, erythorbic acid, magnesium oxide, and dibutylhydroxytoluene.

[0094] When preparing a solid oral preparation, an excipient, and if necessary, a binder, a disintegrant, a lubricant, a colorant, a flavoring / flavoring agent, etc., are added to compound (1), and tablets, coated tablets, granules, powders, capsules, etc. can be produced by conventional methods. When preparing an injection, a pH adjuster / buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. are added to compound (1), and a subcutaneous, intramuscular, or intravenous injection can be produced by conventional methods.

[0095] The amount of compound (1) to be formulated in each dosage unit form varies depending on the symptoms of the patient to which it is to be administered or on the dosage form, but it is generally desirable that the amount of compound (1) per dosage unit form be about 0.05 to 1000 mg for oral preparations, about 0.1 to 500 mg for injections, and about 1 to 1000 mg for suppositories or external preparations.

[0096] The daily dose of compound (1) for each dosage form varies depending on the symptoms, body weight, age, sex, etc. of the patient and cannot be determined in general. However, the daily dose of compound (1) for an adult (body weight 50 kg) is usually about 0.05 to 5000 mg, preferably 0.1 to 1000 mg.

[0097] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. Although the present invention has been fully explained with reference to examples, it is understood that various changes and / or modifications may be made by those skilled in the art. Therefore, as long as such changes and / or modifications do not deviate from the scope of the present invention, they are included in the present invention.

[0098] In the following compound examples, % indicates weight percent unless otherwise specified. Various reagents used in the examples were commercially available products, those described in patent documents, or those synthesized by known methods unless otherwise specified. Abbreviations have the following meanings: PBS: phosphate buffered saline HPMC: hydroxypropyl methylcellulose HP-β-CD: hydroxypropyl-beta-cyclodextrin

[0099] Test Example 1 Evaluation of Plasma Protein Binding and Brain Protein Binding Compound (1) was added to mouse plasma to a final concentration of 5 μmol / L. The resulting compound-added mouse plasma was added to the donor side of an equilibrium dialysis device (RED device system). PBS was added to the receiver side of the device, and the device was immersed in 5% CO ２ After 8 hours of incubation in an incubator, the compound concentrations on the donor and receiver sides were measured by LC-MS / MS. The non-binding rate of the compound to plasma protein was calculated from the ratio of compound concentration on the receiver side to that on the donor side. The plasma protein non-binding rate was 0.0008. Compound (1) was added to mouse brain homogenate instead of mouse plasma to a final concentration of 5000 nmol / g, and the non-binding rate of the compound to mouse brain protein was calculated in the same manner as above, except that the dilution fraction was taken into account when calculating the non-binding rate. The mouse brain homogenate used here was obtained by adding 3 times the amount of PBS containing 50 mmol / L sodium fluoride to mouse brain. The brain protein non-binding rate was 0.0017.

[0100] Test Example 2: Evaluation of brain penetration in mice. Compound (1) was mixed with 20% HP-β-CD and 0.1 mol / L hydrochloric acid solution as the administration solvent and ground in an agate mortar to prepare a dosage formulation. BALB / cAJcl-nu / nu mice (CLEA Japan, Inc.) were orally administered at single doses of 20, 40, and 80 mg / kg. At 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after oral administration, blood was collected from the inferior vena cava under isoflurane anesthesia, and the mice were euthanized by exsanguination, followed by removal of the brain. The obtained blood samples were centrifuged to obtain plasma samples. The obtained brain samples were mixed with three volumes of PBS and homogenized using a bead impact homogenizer to obtain brain homogenates. The compound concentrations in the obtained plasma and brain homogenates were measured by LC-MS / MS. The brain compound concentration was calculated using a calibration curve that took into account the dilution rate of the brain homogenate, and the AUC of each compound was calculated from the plasma concentration and the brain concentration. ０－２４ The AUC of the brain / plasma was calculated. ０－２４ The Kp value was calculated from the ratio. In addition, the plasma protein unbound rate and the brain protein unbound rate obtained in Test Example 1 were used to calculate the unbound AUC of plasma and brain. ０－２４ was calculated, and the unbound AUC of the brain / plasma ０－２４ The Kp,uu value was calculated from the ratio. The results are shown in Table 1. The Kp value was 0.319 to 0.691, and the Kp,uu value was 0.68 to 1.47. These results demonstrate that compound (1) exhibits good intracerebral transferability.

[0101]

[0102] Test Example 3 Next, the Kp value 0.5 hours after administration was calculated using a compound having the structure of the following formula (2) as comparative compound 1. Comparative compound 1 was prepared by the method described in Patent Document 1. A test was carried out under the same conditions as in Test Example 2, except that the brain was removed 0.5 hours after a single oral administration of 40 mg / kg, a three-fold amount of water was added to the brain sample, and then the sample was homogenized using an ultrasonic homogenizer. The results are shown in Table 2. The Kp value 0.5 hours after administration for compound (1) was 0.832, while for comparative compound 1 it was 0.0214. The Kp value of the following formula (2)

[0103] Test Example 4: Efficacy evaluation of compound (1) and brigutinib in a mouse brain transplant model. NIH / 3T3 cells expressing EGFR (SEQ ID NO: 2) with Ex19del (Del E746-A750), T790M, and C797S mutations (ex19del / T790M / C797S), and luciferase were transplanted into the skull of BALB / cAJcl-nu / nu mice. The effects of compound (1) and brigutinib on intracranial tumor growth and mouse survival were examined. Brigutinib is used clinically in anaplastic lymphoma kinase (ALK) mutation-positive lung cancer, but it is also known to inhibit EGFR with ex19del / T790M / C797S. The cells were cultured at 5.0 × 10 ６ The heads of 6-week-old male nude mice (BALB / cAJcl-nu / nu, CLEA Japan) were fixed under anesthesia using a stereotaxic apparatus, and 2 μL of the cell suspension was injected at a position 0.5 mm anterior and 2.0 mm right of the bregma, at a depth of 3.5 mm, resulting in a cell density of 1.0 × 10 cells per mouse. ４ The cells were transplanted. The day of cell transplantation was designated Day 0. On Day 8, luciferin was intraperitoneally administered, and the luminescence intensity (Photons / sec) was measured using an IVIS Lumina II Imaging System (PerkinElmer). Based on the measured luminescence intensity, the mice were divided into a total of 3 groups, each containing 10 mice, so that the luminescence intensity in each group was approximately the same.

[0104] Compound (1) was administered orally at 80 mg / kg / day daily from Day 8 to Day 56, or until a humane endpoint was reached or death occurred. Between Day 50 and Day 56, individuals in the compound (1) administration group who exhibited loose stools or diarrhea were reduced to 50 mg / kg or discontinued administration. Compound (1) was dissolved at 8.0 mg / mL in an administration solvent prepared with 0.5 w / v% HPMC and 0.1 mol / L hydrochloric acid to prepare an administration solution. Brigutinib was administered orally at 50 mg / kg daily from Day 8 to Day 37, or until a humane endpoint was reached or death occurred. Brigutinib was dissolved in an administration solvent prepared with 0.5 w / v% HPMC and 0.1 mol / L hydrochloric acid to prepare a 5.0 mg / mL administration solution. A control group was administered with the administration solvent in the same manner. Based on the weight measurement results of each mouse on the day of administration, the administration was performed at a dose of 10 mL / kg per mouse.

[0105] To evaluate intracranial tumor growth, luminescence intensity was measured on Days 8, 14, and 21 using the method described above. The median survival time was calculated based on the time until a humane endpoint was reached or the mouse died. All animal studies were conducted in accordance with the Taiho Pharmaceutical Co., Ltd. Animal Experiment Guidelines (enacted in April 2013).

[0106] The results are shown in Figure 1. Regarding the luminescence intensity, which is an index of intracranial tumor growth, in the control group, an increase in the luminescence intensity over time was observed from Day 8 to Day 21, and the luminescence intensity on Day 21 was 8.353 x 10 ８ ±1.608×10 ８ p / s (photon / sec). In the brigutinib-administered group, the luminescence intensity on Day 21 was 4.303 × 10 ８ ±1.970×10 ８ On the other hand, in the compound (1) administration group, the value was 1.648 × 10 ６ ±8.929 × 10 ５p / s. A statistically significant difference was observed in the compound (1) administration group compared to the control group (Dunnett type multiple comparison test, p<0.001), while no statistically significant difference was observed in the brigutinib administration group. Statistical analysis was performed using EXSUS (ver 10.0.) via SAS (ver 9.4).

[0107] The results are shown in Figure 2. The survival time of each group was statistically significantly longer in the group administered with compound (1) than in the control group and the brigutinib-administered group (p<0.001, log-rank test). Furthermore, a statistically significant extension of survival time was observed in the brigutinib-administered group compared to the control group (p<0.001, log-rank test). The median survival time was 24.0 days in the control group, 56.5 days in the compound (1)-administered group, and 30.5 days in the brigutinib-administered group. Statistical analysis was performed using the method described above. These results demonstrate that compound (1) suppresses intracranial tumor growth and demonstrates a superior survival time extension compared to brigutinib in a mouse model intracranially implanted with NIH / 3T3 expressing EGFR and luciferase carrying the ex19del / T790M / C797S mutation.

[0108] Test Example 5: Evaluation of the efficacy of compound (1) in a mouse subcutaneous transplantation model. In a model in which NIH / 3T3 cells expressing EGFR (SEQ ID NO: 2) having Ex19del (Del E746-A750), T790M, and C797S mutations (ex19del / T790M / C797S) were subcutaneously transplanted into BALB / cAJcl-nu / nu mice, the effect of compound (1) on tumor growth was examined together with erlotinib and osimertinib. On the day of cell transplantation, the cells were diluted to 2.0 × 10 in PBS. ７ After suspending at 1.0 × 10 cells / mL, the cells were mixed with an equal volume of Matrigel (Corning Inc.) and diluted to 1.0 × 10 cells / mL. ７ A cell suspension of 1.0 × 10 cells / mL was prepared and stored on ice until transplantation. After restraining the mice, 0.1 mL of the cell suspension per mouse was injected into the right side of the chest using a 1-mL syringe equipped with a 25-G. ６The cells were transplanted.

[0109] In mice in which tumor engraftment was observed, the major and minor diameters of the tumor were measured using an electronic caliper, and the tumor volume was calculated according to the following formula: Tumor volume (mm ３ ) = major axis (mm) x minor axis (mm) ２ / 2 Tumor volume was 91.7914500 mm ３ From 135.3264660mm ３ Mice were selected, and five mice were randomly assigned to each group. After grouping, the logarithmically transformed mean tumor volumes of each group were confirmed to be statistically insignificant by Turkey's test. Statistical analysis was performed using EXSUS (ver. 10.0.3) via SAS (ver. 9.4). The day of grouping was designated Day 1.

[0110] Compound (1), erlotinib, and osimertinib were orally administered daily from Day 1 to Day 10. Compound (1) was dissolved in an administration solvent prepared with 20 w / v% HP-β-CD and 0.1 mol / L hydrochloric acid to prepare administration solutions of 1.0 mg / mL, 2.0 mg / mL, 4.0 mg / mL, and 8.0 mg / mL. Erlotinib was suspended in an administration solvent prepared with 0.5 w / v% HPMC and 0.1 w / v% Tween 80 to prepare an 8.0 mg / mL administration solution. Osimertinib was dissolved in an administration solvent prepared with 0.5 w / v% HPMC and 0.1 mol / L hydrochloric acid to prepare a 2.5 mg / mL administration solution. Based on the weight measurement results of each mouse on the day of administration, a dose of 10 mL / kg per mouse was administered.

[0111] To evaluate the antitumor effects of compound (1), erlotinib, and osimertinib, the tumor volume of each mouse on days 1, 4, 8, and 11 was calculated using the method described above, and the average tumor volume for each group was determined. For comparison, a control group administered with the vehicle used for compound (1) was set up, and the tumor volume was determined in the same manner. All of these animal tests were conducted in accordance with the Taiho Pharmaceutical Co., Ltd. Animal Experiment Guidelines (enacted in April 2013).

[0112] The results are shown in Figure 3. In the control group, the average tumor volume increased over time and reached 1116.1 ± 138.9 mm on Day 11, the final evaluation day.３ The average tumor volume of the compound (1) administration group on Day 11 was 378.5±19.6 mm at doses of 10, 20, 40, and 80 mg / kg / day, respectively. ３ , 155.1±22.9mm ３ , 69.7±7.5mm ３ and 34.1±3.9 mm ３ The mean tumor volumes of the groups administered with each dose of compound (1) relative to the mean tumor volume of the control group were 33.9%, 13.9%, 6.2%, and 3.1%, respectively. The tumor volumes of the groups administered with each dose of compound (1) were all statistically significantly different from the control group by Dunnett's test (p<0.001). Statistical analysis was performed according to the method described above.

[0113] On the other hand, the mean tumor volume in the erlotinib 80 mg / kg / day administration group and the osimertinib 25 mg / kg / day administration group was 810.8 ± 47.1 mm on Day 11. ３ and 972.9 ± 82.3 mm ３ The mean tumor volumes of the erlotinib and osimertinib dose groups relative to the mean tumor volume of the control group were 72.6% and 87.2%, respectively. Furthermore, no statistically significant differences were observed in any of the groups compared to the control group. Statistical analysis was performed using the method described above.

[0114] From the above results, it was revealed that in this model in which erlotinib and osimertinib are ineffective, i.e., in a mouse model in which NIH / 3T3 expressing EGFR having ex19del / T790M / C797S mutations was subcutaneously transplanted, compound (1) exhibited a dose-dependent antitumor effect when administered at doses of 10 mg / kg to 80 mg / kg.

[0115] Test Example 6: Evaluation of efficacy of brigutinib in a mouse subcutaneous transplantation model As in Test Example 5, the effect of brigutinib on tumor growth was examined in a model in which NIH / 3T3 cells expressing EGFR (SEQ ID NO: 2) having Ex19del (Del E746-A750), T790M, and C797S mutations (ex19del / T790M / C797S) were subcutaneously transplanted into BALB / cAJcl-nu / nu mice.

[0116] On the day of cell transplantation, cells were diluted to 1 × 10 in PBS. ８ After suspending at 5 × 10 cells / mL, the cells were mixed with an equal volume of Matrigel. ７ After restraining the mice, 0.1 mL of the cell suspension per mouse was injected into the right thoracic region using a 1-mL syringe equipped with a 25-G needle, resulting in a cell suspension of 5 × 10 cells / mL per mouse. ６ The cells were transplanted.

[0117] In mice in which tumor engraftment was observed, the major and minor diameters of the tumor were measured using an electronic caliper, and the tumor volume was calculated according to the following formula: Tumor volume (mm ３ ) = major axis (mm) x minor axis (mm) ２ / 2 Tumor volume was 237.995 mm ３ From 382.316 mm ３ 45 mice (Mean ± SE: 308.5119 ± 5.6413 mm ３ Five mice were randomly assigned to each group from the day of group assignment. The day of group assignment was designated as Day 0.

[0118] Brigutinib was orally administered daily from Day 1 to Day 11. Brigutinib was dissolved in an administration solvent prepared from 0.5 w / v% HPMC and 0.1 mol / L hydrochloric acid to prepare a 7.5 mg / mL administration solution. Based on the weight measurement results of each mouse on the day of administration, a dose of 10 mL / kg was administered per mouse.

[0119] To evaluate the antitumor effect of brigutinib, the tumor volume of each mouse on days 0, 4, 8, and 11 was calculated using the method described above, and the average tumor volume for each group was determined. For comparison, a control group administered with the brigutinib administration solvent was set up, and the tumor volume was determined in the same manner. All of these animal tests were conducted in accordance with the Taiho Pharmaceutical Co., Ltd. Animal Experiment Guidelines (enacted in April 2013).

[0120] The results are shown in Figure 4. In the control group, the average tumor volume increased over time and reached 1575.34 ± 134.60 mm on Day 11. ３ The mean tumor volume in the brigutinib 75 mg / kg administration group on Day 11 was 195.63 ± 27.54 mm ３ The mean tumor volume of the brigutinib-administered group relative to the mean tumor volume of the control group was 13%. The tumor volume of the brigutinib-administered group was statistically significantly different from the control group by Student's t-test (p<0.001). Statistical analysis was performed according to the method described above.

[0121] From the above results, it was revealed that brigutinib showed antitumor effects when administered at a dose of 75 mg / kg in a mouse model subcutaneously implanted with NIH / 3T3 expressing EGFR with the ex19del / T790M / C797S mutation. When these results are compared with the results of Test Example 4, it can be seen that brigutinib is effective against subcutaneous tumors, but does not have the same effect as the compound of chemical formula (1) on the growth of intracranial tumors.

[0122] Test Example 7: Test to confirm substrate activity for P-gp and BCRP The in vitro substrate activity of compound (1) for P-gp and BCRP was evaluated using Caco-2 cells. Caco-2 cells purchased from American Type Culture Collection were seeded on a porous membrane filter and cultured for a certain period of time, after which the substrate activity was evaluated by transcellular transport of the compound. The apparent permeation rate (Papp (×10) of compound (1) from the top (apical side) to the bottom (basal side) and from the bottom (basal side) to the top (apical side) of the filter was －６The apparent permeation rate was expressed as the mean ± standard deviation (n = 3). Papp = [dQt / dt] / A / C0, where dQ / dt is the permeation rate (pmol / sec) and A is the cell surface area (cm ２ C0: initial concentration of compound (1) (pmol / mL) Furthermore, the apparent permeability coefficient ratio (Papp ratio) was calculated according to the following formula: Papp ratio=Papp (basal to apical) / Papp (apical to basal)

[0123] The results are shown in Table 3. The apparent permeability coefficient ratios (Papp ratios) of compound (1) were 1.2, 1.2, 0.9, and 0.8 at concentrations of 0.01, 0.1, 1, and 3 μmol / L, respectively, all of which were less than 2. From these results, it was determined that compound (1) is not a substrate for P-gp or BCRP.

[0124] This specification incorporates by reference the claims, specifications, and disclosures of the drawings of Japanese Patent Application Nos. 2023-210446 (filed December 13, 2023) and 2024-170941 (filed September 30, 2024), which are the basis for the priority claim of this application.

Claims

1. A brain-delivering antitumor agent comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient.

2. A brain-delivering antitumor agent as described in claim 1 for treating primary or metastatic brain tumors.

3. The brain-delivering antitumor agent according to claim 2, wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid).

4. The brain-delivering antitumor agent according to claim 3, wherein C797X is C797S or C797G.

5. The brain-delivering antitumor agent according to claim 4, wherein the brain tumor further has an Ex19del EGFR mutation.

6. The brain-delivering antitumor agent according to claim 5, wherein the brain tumor further has an EGFR mutation of T790M.

7. A brain-delivering antitumor agent according to any one of claims 1 to 6, for administration to a subject following osimertinib treatment.

8. A brain tumor treatment agent comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as an active ingredient.

9. The brain tumor therapeutic agent according to claim 8 for treating primary or metastatic brain tumors.

10. The brain tumor therapeutic agent according to claim 9, wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid).

11. The brain tumor therapeutic agent according to claim 10, wherein C797X is C797S or C797G.

12. The brain tumor therapeutic agent according to claim 11, wherein the brain tumor further has an Ex19del EGFR mutation.

13. The brain tumor therapeutic agent according to claim 12, wherein the brain tumor further has an EGFR mutation of T790M.

14. A brain tumor therapeutic agent according to any one of claims 8 to 13, for administration to a subject following osimertinib treatment.

15. N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof for use in the treatment of brain tumors.

16. The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to claim 15 for use in treating primary or metastatic brain tumors.

17. The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to claim 16, wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid).

18. The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to claim 17, wherein C797X is C797S or C797G.

19. The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to claim 18, wherein the brain tumor further has an Ex19del EGFR mutation.

20. The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to claim 19, wherein the brain tumor further has an EGFR mutation of T790M.

21. The N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof according to any one of claims 15 to 20, for administration to a subject following osimertinib treatment.

22. Use of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof for the manufacture of a medicament for treating a brain tumor.

23. Use of N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof for treating a brain tumor.

24. A method for treating a subject having a brain tumor, comprising administering N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof to a subject in need of treatment.

25. A pharmaceutical composition for treating brain tumors, comprising N-(4-(4-amino-6-ethynyl-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptan-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof and a pharma- ceutically acceptable carrier.

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