A brain metastatic 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 effective ingredient

Abstract

The present application provides a brain metastatic antitumor agent exhibiting brain metastatic and EGFR inhibitory activities. According to one embodiment of the present application, there is provided a brain metastatic 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 effective ingredient.

Description

Technical Field

[0001] This invention relates to brain metastasis antitumor agents, etc., of compounds that have epidermal growth factor receptor (EGFR) inhibitory activity. Background Technology

[0002] Brain tumors are a type of brain disease, a general term for tumors occurring within the skull. These tumors arise from various locations and are classified into primary brain tumors and metastatic brain tumors. Primary brain tumors originate from brain cells, nerves, and the meninges surrounding the brain, while metastatic brain tumors are those formed when cancers such as lung cancer or breast cancer spread to the brain via the bloodstream. It has been reported that 8-10% of cancer patients develop symptomatic metastatic brain tumors, and brain metastases have been found in 40-50% of lung cancer cases in autopsies (Non-Patent Literature 1-3). Known primary sites for metastatic brain tumors include lung cancer, breast cancer, digestive system cancers (stomach cancer), malignant melanoma, kidney cancer, and urinary system cancer, with lung cancer accounting for approximately half (Non-Patent Literature 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, drug therapy, or a combination of these. Generally, surgery is chosen when the primary tumor is under control, is solitary, and a certain survival rate is expected. However, tumors that metastasize to the brain are often intricately intertwined with brain parenchyma and / or brain tissue, making complete surgical removal often impossible. In radiotherapy, two treatment methods are known: quantitative radiosurgery (such as Gamma Knife therapy) and whole-brain irradiation. Currently, most treatments for metastatic brain tumors combine surgery and radiotherapy, but it's difficult to say that they achieve sufficient therapeutic efficacy (Non-Patent Literature 4 and 5). Typically, the central nervous system (CNS), including the brain, is protected from harmful substances by a highly specialized layer of tight junctions between cells called the blood-brain barrier (BBB). One reason why effective agents for many CNS-related diseases have not yet been developed is that almost all therapeutic molecules, including antibodies, cannot cross the BBB. Low-molecular-weight compounds are no exception; it has been reported that over 97% of low-molecular-weight compounds cannot cross the BBB (Non-Patent Literature 6). Currently, many compounds have shown effectiveness against peripheral cancer (primary lesions), but their efficacy in brain metastases of the same cancer is limited. One reason for this is believed to be that these compounds cannot reach sufficient levels in the brain to exert their effects, thus failing to achieve the same efficacy as in the primary lesion (Non-Patent Literature 7 and 8). Therefore, there is a desire to develop low-molecular-weight compounds with high brain metastatic potential in CNS-related diseases and brain tumors, as well as methods for their brain metastasis, particularly agents that demonstrate efficacy against primary lesions such as lung cancer in the treatment of metastatic brain tumors, exhibit high CNS metastatic potential, and show efficacy against brain metastases.

[0003] Many compounds have shown effectiveness at the primary tumor site, such as those exhibiting inhibitory activity against the epidermal growth factor receptor (EGFR). EGFR is a receptor-type tyrosine kinase that binds to epidermal growth factor (EGF) as a ligand in normal tissues to exert its physiological functions, participating in epithelial tissue proliferation and inhibiting apoptosis (Non-Patent Literature 9). Furthermore, EGFR is an oncogene, and amplification of the EGFR gene, high protein expression, or mutations are known in various cancers, such as head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, skin cancer, and brain tumors (Non-Patent Literature 10).

[0004] Therefore, EGFR inhibitors are considered as therapeutic agents for diseases associated with abnormal hyperactivity of this pathway.

[0005] In practice, pharmaceuticals such as erlotinib, gefitinib, afatinib, and osimertinib are used as EGFR inhibitors in clinical settings to improve treatment efficacy. However, these drugs, due to their non-selective inhibition of wild-type EGFR (WT), which is associated with side effects, can lead to adverse reactions. Since brain tumors often originate from metastases of lung cancer, studies have also been conducted on the brain metastasis of EGFR inhibitors used in the treatment of these lung cancers. The results indicate that not all EGFR inhibitors can pass the BBB (non-patent literature 11, 12, and 13).

[0006] In Patent Document 1, a pyrimidine compound of the following general formula (1) was disclosed as a compound that inhibits EGFR (chemical name: N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide (hereinafter also referred to as "compound (1)")). Existing technical documents Patent documents Patent Document 1: International Publication No. WO2020 / 166680 Non-patent literature Non-patent literature 1: Qingbei Zeng et al., J. Med. Chem.; 58(20): p.8200-8215, (2015) Non-patent literature 2: Lakshmi Nayak et al., Curr Oncol Rep; 14(1): p.48-54, (2012) Non-patent literature 3: Brunilde Gril et al., Eur. J. Cancer; 46(7): p.1204-1210, (2010) Non-patent literature 4: Taofeek K. Owonikoko et al., Nat. Rev. Clin. Oncol. ; 11(4): p.203-222, (2014) Non-patent literature 5: Chien-Hung Gow et al., Clin Cancer Res; 14(1): p.162-168, (2008) Non-patent literature 6: William M. Pardridge et al., J. Neurochem.; 70(5): p.1781-1792, (1998) Non-patent literature 7: Ted W. Johnson et al., J. Med. Chem.; 57(11): p.4720-4744, (2004) Non-patent literature 8: Victor A. Levin et al., Neuro Oncology; 17 Suppl 6: vi1-26, (2015) Non-patent literature 9: Mario E. Lacouture, Nature Rev. Cancer; 6: pp. 803-812, (2006) Non-patent literature 10: Ping Wee et al., Cancers (Basel); 9(5); 52: p.1–45, (2017) Non-patent literature 11: Chee-Seng Tan et al., Lung Cancer; 108: p.29-37, (2017) Non-patent literature 12: Nicola Colclough et al., Clin Cancer Res; 27(1): p.189–201, (2021) Non-patent literature 13: Peter Ballard et al., Clin Cancer Res; 22(20): p.5130-5140, (2016) Non-patent literature 14: Giacomini KM. et al., Nat Rev Drug Discov; 9: p.215-236, (2010) Summary of the Invention

[0007] The problem that the invention aims to solve In the context described above, there is a need for an antitumor agent for brain metastases that exhibits both brain metastatic and EGFR inhibitory activity.

[0008] Technical solutions for solving the problem The inventors of this invention conducted in-depth research and discovered that pyrimidine compounds with specific structures that selectively inhibit mutant EGFR (chemical name: N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide, hereinafter also referred to as compound (1)) or their salts are useful as antitumor agents against brain metastases, thus completing this invention.

[0009] That is, the present invention includes the following embodiments.

[0010] [1] A brain metastasis antitumor agent comprising N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as the active ingredient.

[0011] [2] The brain metastatic antitumor agent described in [1] is used to treat primary or metastatic brain tumors.

[0012] [3] The brain metastatic antitumor agent as described in [2], wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid).

[0013] [3-1] The brain metastatic antitumor agent as described in [2], wherein the brain tumor has an EGFR mutation of Ex19del.

[0014] [3-2] The brain metastatic antitumor agent as described in [2], wherein the brain tumor has an EGFR mutation of L858R.

[0015] [4] As described in [3], the brain metastasis antitumor agent, wherein C797X is C797S or C797G.

[0016] [5] The brain metastatic antitumor agent as described in [4], wherein the brain tumor also has an EGFR mutation of Ex19del, preferably also has Del E746-A750.

[0017] [5-1] The brain metastatic antitumor agent described in [4], wherein the brain tumor also has an L858R EGFR mutation.

[0018] [6] Brain metastatic antitumor agents as described in [5] or [5-1], wherein the brain tumor also has an EGFR mutation of T790M.

[0019] [7] The brain metastatic antitumor agent as described in any one of [1] to [6] and [5-1], which is used to administer to a subject after osimertinib treatment.

[0020] [8] A brain tumor therapeutic agent comprising N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as the active ingredient.

[0021] [9] The brain tumor treatment agent described in [8] is used to treat primary or metastatic brain tumors.

[0022]

[10] The brain tumor therapeutic agent as described in [9], wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid).

[0023] [10-1] The brain tumor therapeutic agent as described in [9], wherein the brain tumor has an EGFR mutation of Ex19del.

[0024] [10-2] The brain tumor therapeutic agent as described in [9], wherein the brain tumor has an L858R EGFR mutation.

[0025]

[11] The brain tumor treatment agent as described in

[10] , wherein C797X is C797S or C797G.

[0026]

[12] The brain tumor therapeutic agent as described in

[11] , wherein the brain tumor also has an EGFR mutation of Ex19del, preferably also has Del E746-A750.

[0027] [12-1] The brain tumor therapeutic agent as described in

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

[0028]

[13] Brain tumor therapeutic agents as described in

[12] or [12-1], wherein the brain tumor also has an EGFR mutation of T790M.

[0029]

[14] The brain tumor treatment agent as described in any one of [8] to

[13] and [12-1] is used to administer osimertinib to a subject who has been treated with osimertinib.

[0030]

[15] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or its salts used for the treatment of brain tumors.

[0031]

[16] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof, as described in

[15] , is used to treat primary or metastatic brain tumors.

[0032]

[17] As described in

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

[0033] [17-1] As described in

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

[0034] [17-2] As described in

[16] , N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof, wherein the brain tumor described above has an L858R EGFR mutation.

[0035]

[18] As described in

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

[0036]

[19] As described in

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

[0037] [19-1] As described in

[18] , N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof, wherein the brain tumor also has an L858R EGFR mutation.

[0038]

[20] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in

[19] or [19-1], wherein the brain tumor also has an EGFR mutation of T790M.

[0039] [twenty one] N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof, as described in any one of

[15] to

[20] and [19-1], is used to administer to a subject after osimertinib treatment.

[0040] [twenty two] Use of N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof in the manufacture of a pharmaceutical for the treatment of brain tumors.

[0041] [twenty three] As described in

[22] , it is used to treat primary or metastatic brain tumors.

[0042] [twenty four] As described in

[23] , the brain tumor has an EGFR mutation of C797X (where X represents any amino acid).

[0043] [24-1] As described in

[23] , wherein the brain tumor has an EGFR mutation of Ex19del.

[0044] [24-2] As described in

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

[0045]

[25] As described in

[24] , where C797X is C797S or C797G.

[0046]

[26] The use as described in

[25] , wherein the brain tumor also has an EGFR mutation of Ex19del, preferably also has DelE746-A750.

[0047] [26-1] The use as described in

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

[0048]

[27] The use as described in

[26] or [26-1], wherein the brain tumor also has an EGFR mutation of T790M.

[0049]

[28] The use as described in any one of

[22] to

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

[0050]

[29] Use of N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or salts thereof in the treatment of brain tumors.

[0051]

[30] A treatment method for a subject suffering from a brain tumor includes the step of administering N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof to the subject in need of treatment.

[0052]

[31] The treatment method described in

[30] is used to treat primary or metastatic brain tumors.

[0053]

[32] The treatment method described in

[31] involves a brain tumor having an EGFR mutation of C797X (where X represents any amino acid).

[0054] [32-1] The treatment method described in

[31] , wherein the brain tumor has an EGFR mutation of Ex19del.

[0055] [32-2] The treatment method described in

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

[0056]

[33] The treatment method described in

[32] , wherein C797X is C797S or C797G.

[0057]

[34] The treatment method described in

[33] includes a brain tumor that also has an EGFR mutation of Ex19del, preferably also has Del E746-A750.

[0058] [34-1] The treatment method described in

[33] also includes a brain tumor with an L858R EGFR mutation.

[0059]

[35] The treatment methods described in

[34] or [34-1], wherein the brain tumor also has an EGFR mutation of T790M.

[0060]

[36] The treatment method described in any one of

[30] to

[35] and [34-1] is used to administer osimertinib to a subject after treatment with osimertinib.

[0061]

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

[0062]

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

[0063]

[39] Anti-brain tumor agents as described in

[38] are used to treat primary or metastatic brain tumors.

[0064]

[40] The anti-brain tumor agent as described in

[39] , wherein the brain tumor has an EGFR mutation of C797X (X represents any amino acid).

[0065] [40-1] The anti-brain tumor agent as described in

[39] , wherein the brain tumor has an EGFR mutation of Ex19del.

[0066] [40-2] The anti-brain tumor agent as described in

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

[0067]

[41] As described in

[40] , the anti-brain tumor agent, wherein C797X is C797S or C797G.

[0068]

[42] The anti-brain tumor agent as described in

[41] , wherein the brain tumor also has an EGFR mutation of Ex19del, preferably also has Del E746-A750.

[0069] [42-1] The anti-brain tumor agent as described in

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

[0070]

[43] Anti-brain tumor agents as described in

[42] or [42-1], wherein the brain tumor also has an EGFR mutation of T790M.

[0071]

[44] The anti-brain tumor agent as described in any one of

[38] to

[43] and [42-1] is used to administer to a subject who has been treated with osimertinib.

[0072]

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

[0073]

[46] As described in

[45] , a brain metastatic mutant EGFR inhibitor is used to treat primary or metastatic brain tumors.

[0074]

[47] As described in

[46] , the brain metastatic mutant EGFR inhibitor has a C797X (X represents any amino acid) EGFR mutation.

[0075] [47-1] As described in

[46] , the brain metastatic mutant EGFR inhibitor has an Ex19del EGFR mutation.

[0076] [47-2] As described in

[46] , the brain metastatic mutant EGFR inhibitor has an L858R EGFR mutation.

[0077]

[48] The brain metastatic mutant EGFR inhibitor described in

[47] , wherein C797X is C797S or C797G.

[0078]

[49] The brain metastatic mutant EGFR inhibitor described in

[48] , wherein the brain tumor also has an EGFR mutation of Ex19del, preferably also has Del E746-A750.

[0079] [49-1] As described in

[48] , the brain metastatic mutant EGFR inhibitors, wherein the brain tumors also have an L858R EGFR mutation.

[0080]

[50] Brain metastatic mutant EGFR inhibitors as described in

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

[0081]

[51] The brain metastatic mutant EGFR inhibitor as described in any one of

[45] to

[50] and [49-1] is used to administer to a subject who has been treated with osimertinib.

[0082] Invention Effects According to one aspect of the present invention, an antitumor agent capable of causing brain metastases can be provided. Additionally, according to another aspect of the present invention, an anti-brain tumor agent can be provided. Furthermore, according to yet another aspect of the present invention, a brain tumor therapeutic agent or a brain metastatic mutant EGFR inhibitor can be provided. Attached Figure Description

[0083] Figure 1 The results (luminescence amount) of the efficacy evaluation test of compound (1) and brigatinib in the mouse brain transplantation model in Experiment Example 4 are shown.

[0084] Figure 2 The results (survival curves) of the efficacy evaluation test of compound (1) and brigatinib in the mouse brain transplantation model in Experiment Example 4 are shown.

[0085] Figure 3 The results of the efficacy evaluation test of compound (1) in the mouse subcutaneous transplantation model in Experiment Example 5 are presented.

[0086] Figure 4 This indicates the efficacy evaluation results of brigatinib in the mouse subcutaneous transplantation model in Experiment Example 6. Detailed Implementation

[0087] One aspect of the present invention relates to a brain metastasis antitumor agent, wherein the active ingredient is N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof, as shown in formula (1).

[0088] The following formula (1) According to one embodiment of the present invention, a brain metastatic antitumor agent comprising compound (1) or a salt thereof is provided, which exhibits inhibitory effect on mutant EGFR and shows effective therapeutic effect on brain tumors.

[0089] According to another embodiment of the invention, the use of compound (1) or a salt thereof is provided in the manufacture of an antitumor agent exhibiting brain metastasis, inhibitory activity against mutant EGFR and / or antitumor effects.

[0090] According to one embodiment of the present invention, a compound (1) or a salt thereof is provided for treating tumors, particularly brain tumors, exhibiting brain metastasis, inhibitory activity against mutant EGFR and / or antitumor effects.

[0091] According to another embodiment of the present invention, a treatment method for tumors, particularly brain tumors, is provided, comprising the step of administering an antitumor agent comprising a compound (1) or a salt thereof having brain metastatic and / or inhibitory activity against mutant EGFR.

[0092] According to one embodiment of the present invention, an anti-brain tumor agent comprising compound (1) or a salt thereof is provided, which exhibits brain metastasis and / or inhibition of mutant EGFR, and shows effective therapeutic effect on brain tumors.

[0093] According to other embodiments of the invention, the use of compound (1) or a salt thereof is provided in the manufacture of an anti-brain tumor agent exhibiting brain metastasis and / or inhibitory activity against mutant EGFR and / or anti-tumor effects.

[0094] According to one embodiment of the invention, a compound (1) or a salt thereof is provided for treating tumors, particularly brain tumors, using an anti-brain tumor agent that exhibits brain metastatic and / or mutant EGFR inhibitory activity and / or anti-brain tumor effects.

[0095] According to another embodiment of the present invention, a treatment method for tumors, particularly brain tumors, is provided, comprising the step of administering an anti-brain tumor agent comprising a compound (1) or a salt thereof having brain metastatic and / or mutant EGFR inhibitory activity.

[0096] According to one embodiment of the present invention, a brain tumor therapeutic agent comprising compound (1) or a salt thereof is provided, which exhibits brain metastasis and / or inhibitory effects on mutant EGFR, and shows effective therapeutic effects on brain tumors.

[0097] According to one embodiment of the invention, the use of compound (1) or a salt thereof is provided in the manufacture of a brain tumor therapeutic agent exhibiting brain metastasis, mutant EGFR inhibitory activity and / or antitumor effects.

[0098] According to one embodiment of the invention, a compound (1) or a salt thereof is provided for treating tumors, particularly brain tumors, using a brain tumor therapeutic agent that exhibits brain metastasis, mutant EGFR inhibitory activity and / or anti-brain tumor effects.

[0099] According to another embodiment of the present invention, a treatment method for tumors, particularly brain tumors, is provided, comprising the step of administering a brain tumor therapeutic agent containing a compound (1) or a salt thereof that exhibits brain metastatic, mutant EGFR inhibitory activity and / or antitumor effects.

[0100] According to one embodiment of the present invention, a brain metastatic EGFR inhibitor comprising compound (1) or a salt thereof that exhibits antitumor effects is provided.

[0101] According to one embodiment of the invention, the use of compound (1) or a salt thereof in the manufacture of a brain metastatic EGFR inhibitor exhibiting mutant EGFR inhibitory activity and / or antitumor effects is provided.

[0102] According to one embodiment of the invention, a compound (1) or a salt thereof is provided for treating tumors, particularly brain tumors, using a brain metastatic EGFR inhibitor that exhibits mutant EGFR inhibitory activity and / or anti-brain tumor effects.

[0103] According to another embodiment of the present invention, a treatment method for tumors, particularly brain tumors, is provided, comprising the step of administering a brain metastatic EGFR inhibitor containing a compound (1) or a salt thereof that exhibits mutant EGFR inhibitory activity and / or antitumor effects.

[0104] In this specification, a brain metastatic antitumor agent refers to an antitumor agent that transfers at least a portion of its active ingredient to the brain and shows therapeutic effect against primary brain tumors and / or metastatic brain tumors.

[0105] In this specification, an anti-brain tumor agent refers to an anti-tumor agent that transfers at least a portion of its active ingredient to the brain and shows therapeutic effects against primary and / or metastatic brain tumors.

[0106] In this specification, a brain tumor therapeutic agent refers to a therapeutic agent that transfers at least a portion of the active ingredient to the brain and demonstrates a therapeutic effect on primary brain tumors and / or metastatic brain tumors.

[0107] In this specification, a brain metastatic EGFR inhibitor refers to an EGFR inhibitor that causes at least a portion of the active ingredient to be transferred to the brain and shows therapeutic efficacy against primary brain tumors and / or metastatic brain tumors.

[0108] In this specification, the compound represented by formula (1) is sometimes simply referred to as compound (1).

[0109] Compound (1) and its salt can be manufactured by known organic synthesis methods. For example, they can be manufactured according to the methods described in Patent Document 1, etc.

[0110] In the case where compound (1) has isomers such as optical isomers, stereoisomers, rotational isomers, and tautomers, any isomer or mixture thereof is included in compound (1) unless otherwise specified. For example, in the case where compound (1) has optical isomers, racemic mixtures and optical isomers obtained from the separation of racemic mixtures are also included in compound (1) unless otherwise specified.

[0111] The salt of compound (1) refers to a pharmaceutically acceptable salt, which can be listed as a base addition salt or an acid addition salt.

[0112] Specifically, such salts can be listed as: 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, p-toluenesulfonic 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.

[0113] "Pharmaceutical acceptable salt" refers to a salt of a compound that has ideal pharmacological activity, prepared from a pharmaceutically acceptable nontoxic base or acid, including inorganic or organic bases and inorganic or organic acids.

[0114] Compound (1) or its salts also include its prodrugs. A prodrug is a compound that is converted into compound (1) or its salts under physiological conditions in an organism through reactions using enzymes or gastric acid, i.e., a compound that is converted into compound (1) or its salts through enzyme-catalyzed oxidation, reduction, hydrolysis, etc. In addition, a prodrug can also be a compound that is converted into compound (1) or its salts under physiological conditions as described in the 1990 publication of Hirokawa Shoten, Volume 7, Molecular Design, pages 163 to 198.

[0115] Compound (1) or its salts may be amorphous (non-crystalline) or crystalline, and may be a single crystal form or a polycrystalline mixture, both of which are included in compound (1) or its salts. Crystals can be produced by crystallization using known crystallization methods. Compound (1) or its salts may be solvates (e.g., hydrates) or solvates-free compounds, both of which are included in compound (1) or its salts. Using isotopes (e.g., 3 H, 14 C 35 S, 125Compounds labeled with I, etc. are also included in compound (1) or its salts. Sometimes multiple crystals (polymorphs) with different spatial atomic arrangements and physicochemical properties are formed, but the salts of the compounds used in this invention can be any type of these polymorphs, or a mixture of two or more polymorphs, or a mixture of crystalline and amorphous materials.

[0116] In this specification, the term “effective amount” of compound (1) means the amount of compound (1) that causes a biological or medical response in the subject, such as a reduction or inhibition of enzyme or protein activity, or improves symptoms, alleviates the condition, slows or delays the progression of the disease, or prevents the disease, etc. (therapeutic effective amount).

[0117] In this specification, "treatment" includes: postoperative adjuvant chemotherapy to prevent recurrence after surgical removal of a tumor, and preoperative adjuvant chemotherapy prior to surgical removal of a tumor.

[0118] In this specification, the term "object" includes both mammals and non-mammals. In one embodiment, the object is a person, which may be a person diagnosed with a condition requiring treatment for the symptoms, symptoms, or diseases disclosed in this specification.

[0119] There is no particular age limitation for the subjects to whom the brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastatic EGFR inhibitor of one embodiment of the present invention is administered. The brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastatic EGFR inhibitor of one embodiment of the present invention can be used not only in adults, but also in the elderly or children.

[0120] Compound (1) or its salts, or a brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastatic EGFR inhibitor comprising a salt thereof in one embodiment of the present invention, exhibits excellent EGFR inhibitory activity. It also exhibits excellent selectivity for EGFR. Therefore, compound (1) or its salts, or a brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastatic EGFR inhibitor comprising a salt thereof in one embodiment of the present invention, is useful as an antitumor agent for malignant tumors with EGFR overexpression, EGFR gene amplification, EGFR mutation, etc.

[0121] In this specification, "wild-type EGFR" refers, for example, to the epidermal growth factor receptor represented by the amino acid sequence (Sequence No. 1) of GenBank accession number NP_005219.2.

[0122] In this specification, "exon 18" refers to the region 688-728 in the amino acid sequence of wild-type EGFR (e.g., GenBank accession number: NP_005219.2).

[0123] In this specification, "exon 19" refers to the region 729-760 in the amino acid sequence of wild-type EGFR (e.g., GenBank accession number: NP_005219.2).

[0124] In this specification, "exon 20" refers to the region 761-823 in the amino acid sequence of wild-type EGFR (e.g., GenBank accession number: NP_005219.2).

[0125] In this specification, "exon 21" refers to the region 824-875 in the amino acid sequence of wild-type EGFR (e.g., GenBank accession number: NP_005219.2).

[0126] In this specification, "Ex19del" indicates a mutation in which one or more amino acids are deleted from exon 19 of wild-type EGFR. In addition to deletions in this region, mutations that insert one or more arbitrary amino acids are also included. Examples of exon 19 deletion mutations include the deletion of 5 amino acids from glutamic acid at position 746 to alanine at position 750 in exon 19 (Del E746-A750 (or also called d746-750)), the deletion of 7 amino acids from leucine at position 747 to proline at position 753 in exon 19 followed by the insertion of serine (Del L747-P753insS), the deletion of 5 amino acids from leucine at position 747 to threonine at position 751 in exon 19 (Del L747-T751), and the deletion of 4 amino acids from leucine at position 747 to alanine at position 750 in exon 19 followed by the insertion of proline (Del L747-A750insP). Mutations that delete five amino acids from glutamate at position 746 to alanine at position 750 in exon 19 (Del E746-A750) are preferred, but not limited to these.

[0127] In this specification, "L718X" indicates a point mutation in which the leucine encoded by codon 718 of exon 18 of wild-type EGFR is replaced by any amino acid. Examples of amino acids that can be replaced by leucine include, but are not limited to, glutamine (L718Q) and valine (L718V).

[0128] In this specification, "G724X" indicates a point mutation in which the glycine encoded by codon 724 of exon 18 of the wild-type EGFR is replaced by any amino acid. Examples of amino acids that can be replaced by glycine include, but are not limited to, serine (G724S).

[0129] In this specification, "T790X" indicates a point mutation in which the threonine residue encoded by codon 790 of exon 20 of wild-type EGFR is replaced by any amino acid. Examples of amino acids resulting from the threonine substitution include, but are not limited to, methionine (T790M). T790X includes any amino acid mutation resulting from a de novo mutation or the use of first- or second-generation EGFR inhibitors. Examples of first- and second-generation EGFR inhibitors include, but are not limited to, gefitinib, erlotinib, and afatinib.

[0130] In this specification, "L792X" indicates a point mutation in which the leucine encoded by codon 792 of exon 20 of the wild-type EGFR is replaced by any amino acid. Examples of amino acids that can be replaced by leucine include, but are not limited to, phenylalanine (L792F), histidine (L792H), tyrosine (L792Y), valine (L792V), and proline (L792P).

[0131] In this specification, "G796X" indicates a point mutation in which the glycine encoded by codon 796 of exon 20 of wild-type EGFR is replaced by any amino acid. Examples of amino acids that can be replaced by glycine include, but are not limited to, arginine (G796R), serine (G796S), and cysteine ​​(G796C).

[0132] In this specification, "C797X" represents a point mutation in which the cysteine ​​residue encoded by codon 797 of exon 20 of wild-type EGFR is replaced by any amino acid. Examples of amino acids resulting from the cysteine ​​substitution include, but are not limited to, serine (C797S) and glycine (C797G). C797X includes any amino acid mutation resulting from the use of an EGFR inhibitor covalently bonded to C797 (e.g., second-generation and / or third-generation EGFR inhibitors). 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.

[0133] In this specification, "T854X" indicates a point mutation in which threonine is replaced by any amino acid at codon 854 of exon 21 of wild-type EGFR. Examples of amino acids that can be replaced by threonine include, but are not limited to, alanine (T854A) and isoleucine (T854I).

[0134] In this specification, "L858X" indicates a point mutation in which leucine is replaced by any amino acid at codon 858 of exon 21 of wild-type EGFR. Examples of amino acids that can be replaced by leucine include, but are not limited to, arginine (L858R) and methionine (L858M).

[0135] In this specification, mutant EGFR refers to the EGFR described herein. In one embodiment of the invention, compound (1) has an inhibitory effect on “Ex19del”, “L718X”, “G724X”, “T790X”, “L792X”, “G796X”, “C797X”, “T854X”, and “L858X” (X represents any amino acid), and has a therapeutic effect on tumors having one or more of the mutant EGFRs, but the types of mutations are not limited to these.

[0136] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit is Ex19del. Among Ex19del, it is preferably selected from at least one of Del E746-A750, Del L747-P753insS, Del L747-T751 and Del L747-A750insP, but is not limited to these.

[0137] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit is C797X (X represents any amino acid). Among C797X, at least one selected from C797S and C797G is preferred, and C797S is particularly preferred, but not limited to these.

[0138] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit is L718X (X represents any amino acid). Among L718X, it is preferably selected from at least one of L718Q and L718V, but is not limited to these.

[0139] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit is G724X (where X represents any amino acid), preferably G724S, but not limited to these.

[0140] In one embodiment of the present invention, the mutant EGFR that compound (1) can inhibit is L792X (X represents any amino acid), preferably selected from at least one of L792F, L792H, L792Y, L792V and L792P, but not limited to these.

[0141] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit is G796X (X represents any amino acid), preferably selected from at least one of G796R, G796S and G796C, but not limited to these.

[0142] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit is T854X (X represents any amino acid), preferably at least one selected from T854A and T854I, but not limited to these.

[0143] In one embodiment of the invention, the mutant EGFR that compound (1) can inhibit may have at least one mutation selected from Ex19del, T790M, and L858X (X represents any amino acid) in addition to the mutations described above. Among L858X, at least one selected from L858R and L858M is preferred, particularly L858R, but not limited to these.

[0144] In one embodiment of the present invention, the mutant EGFR that compound (1) can inhibit is preferably a mutation that has one or more of the EGFR mutations selected from Ex19del, L858R and T790M in addition to C797S.

[0145] In this specification, "point mutation" means a mutation that results in the substitution, insertion or deletion of one or more (e.g., 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.

[0146] In addition, the brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent and / or brain metastatic EGFR inhibitor of an embodiment of the present invention containing the compound (1) or its salt has the advantage of excellent selectivity for mutant EGFR and fewer side effects than wild-type EGFR and other kinases.

[0147] Furthermore, the brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent and / or brain metastatic EGFR inhibitor of an embodiment of the present invention containing the compound (1) or its salt has the advantage of being applicable to subjects with mutations resulting from the use of third-generation EGFR inhibitors (e.g., subjects who show osimertinib resistance after osimertinib treatment or subjects who show lazatinib resistance after lazatinib treatment, etc.).

[0148] In this product information, "osimertinib resistance" refers to the disappearance or attenuation of the therapeutic effect of osimertinib observed in subjects treated with osimertinib for EGFR mutation-positive tumors (peripheral cancer (primary), primary brain tumors, and / or metastatic brain tumors). Similarly, "lazaitinib resistance" refers to the disappearance or attenuation of the therapeutic effect of lazaitinib observed in subjects treated with lazaitinib for EGFR mutation-positive tumors (peripheral cancer (primary), primary brain tumors, and / or metastatic brain tumors).

[0149] In this product information, "after osimertinib treatment" means administration after osimertinib administration. Similarly, "after lazatinib treatment" means administration after lazatinib administration.

[0150] Compound (1) or its salts, or brain metastatic antitumor agents, anti-brain tumor agents, brain tumor therapeutic agents and / or brain metastatic EGFR inhibitors of an embodiment of the present invention containing compound (1) or its salts, are useful as pharmaceuticals for the prevention or treatment of EGFR-involved diseases due to their excellent EGFR inhibitory activity.

[0151] One embodiment of the present invention provides an EGFR inhibitor comprising compound (1) or a salt thereof. Another embodiment of the present invention provides an EGFR inhibitor comprising compound (1) or a salt thereof for use after osimertinib treatment. Additionally, another embodiment of the present invention provides an EGFR inhibitor comprising compound (1) or a salt thereof for use after lazatinib treatment.

[0152] Another embodiment of the present invention provides an antitumor agent, an anti-brain tumor agent, and / or a brain tumor therapeutic agent comprising compound (1) or a salt thereof for use after osimertinib treatment. Additionally, another embodiment of the present invention provides an antitumor agent, an anti-brain tumor agent, and / or a brain tumor therapeutic agent comprising compound (1) or a salt thereof for use after lazatinib treatment.

[0153] Additionally, one embodiment of the present invention provides a treatment method for tumors, particularly brain tumors, comprising the step of administering an effective amount of compound (1) or a salt thereof to a subject requiring treatment after osimertinib treatment. Furthermore, one embodiment of the present invention provides a treatment method for tumors, particularly brain tumors, comprising the step of administering an effective amount of compound (1) or a salt thereof to a subject requiring treatment after lazatinib treatment.

[0154] One embodiment of the present invention provides the use of compound (1) or a salt thereof in the manufacture of an antitumor agent, an anti-brain tumor agent, and / or a brain tumor therapeutic agent for use after osimertinib treatment. Furthermore, one embodiment of the present invention provides the use of compound (1) or a salt thereof in the manufacture of an antitumor agent, an anti-brain tumor agent, and / or a brain tumor therapeutic agent for use after lazatinib treatment.

[0155] One embodiment of the present invention provides a compound (1) or a salt thereof for treating tumors, particularly brain tumors, after osimertinib treatment. Furthermore, one embodiment of the present invention provides a compound (1) or a salt thereof for treating tumors, particularly brain tumors, after lazatinib treatment.

[0156] Compound (1) or its salts are useful as pharmaceuticals for the prevention or treatment of diseases involving mutant EGFR due to their excellent inhibitory activity against mutant EGFR.

[0157] "Diseases involving mutant EGFR" can include diseases that reduce incidence, alleviate symptoms, mitigate symptoms, and / or completely cure symptoms by deleting, inhibiting, and / or impairing EGFR function. Examples of such diseases include, but are not limited to, malignant tumors. Among malignant tumors, those with enhanced EGFR activation are preferred, and more preferably those with enhanced EGFR activation, such as head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, gastric cancer (digestive system cancer), duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, 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, endometrial cancer, etc.), kidney cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, testicular tumors, leukemia, malignant lymphoma, multiple myeloma, bone and soft tissue tumors, skin cancer, malignant melanoma, adrenal tumors, and brain tumors. Preferred cancer types include 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. More preferably, these cancer types include salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, leukemia, skin cancer, malignant melanoma, and brain tumors. Even more preferably, these cancer types include salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumors. Particularly preferred are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumors.

[0158] Enhanced EGFR activation refers to the enhanced activation state caused by EGFR gene translocation, mutation (including point mutations, deletion mutations, and insertion mutations), and overexpression (including increased EGFR gene copy number, EGFR messenger RNA overexpression, increased EGFR protein, and constitutive activation of EGFR protein).

[0159] There are no particular restrictions on the types of cancers and tumors that can be included. Examples include epithelial cancers (respiratory system cancers, digestive system cancers, reproductive system cancers, endocrine system cancers, etc.), sarcomas, hematopoietic cell tumors, central nervous system tumors, peripheral nerve tumors, etc.

[0160] Specific types of cancer include: head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, stomach cancer (digestive system cancer), duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, 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, endometrial cancer, etc.), kidney cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, testicular tumors, leukemia, malignant lymphoma, multiple myeloma, bone and soft tissue tumors, skin cancer, malignant melanoma, adrenal tumors, and brain tumors. 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 are preferred. Preferred cancer types include 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. More preferred cancer types include salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumors. Particularly preferred cancer types include non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumors.

[0161] In a typical embodiment of the present invention, the target tumor for exerting its effect by allowing compound (1) to pass through the BBB is a brain tumor. In this specification, brain tumors include primary brain tumors and metastatic brain tumors. Primary tumors are not limited to the following types, but may include gliomas, primary malignant lymphomas of the central nervous system, meningiomas, pituitary adenomas, schwannomas, craniopharyngiomas, etc. Furthermore, in metastatic brain tumors, the type of tumor that forms the primary site is not limited.

[0162] In the case of metastatic brain tumors, the type of tumor as the primary lesion is not limited. Specific types of cancer that can be listed include: head and neck cancer, digestive tract cancers (esophageal cancer, stomach cancer, duodenal cancer, liver cancer, biliary tract cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon 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.)), breast cancer, reproductive organ cancers (ovarian cancer, vulvar cancer, uterine cancer (cervical cancer, endometrial cancer, etc.)), urinary organ cancers (kidney cancer, bladder cancer, prostate cancer, testicular tumors, urothelial carcinoma, renal pelvis cancer, urethral cancer, etc.), hematopoietic system tumors (leukemia, malignant lymphoma, multiple myeloma, etc.), bone and soft tissue tumors, rhabdomyosarcoma, skin cancer, malignant schwannomas, neuroendocrine tumors, thyroid cancer, etc. The preferred cancers are head and neck cancer, breast cancer, colorectal cancer, esophageal cancer, pancreatic cancer, lung cancer, ovarian cancer, kidney cancer, bladder cancer, and skin cancer, with lung cancer being particularly preferred.

[0163] Even drugs that cross the brain's blood-brain barrier (BBB) ​​can sometimes be actively expelled into the bloodstream due to transporters such as P-glycoprotein (hereinafter, P-gp) or breast cancer resistance protein (hereinafter, BCRP), which are locally present on the vascular side of brain capillary endothelial cells, making it difficult to maintain an effective concentration. To demonstrate efficacy against primary and / or metastatic brain tumors, it is preferable to avoid becoming a substrate of these transporters. Whether a drug is a substrate of these transporters can be confirmed by transcellular transport assays using cells expressing transporters such as P-gp or BCRP, as described in Example 7 of the embodiments. According to Non-Patent Literature 14, if the efflux ratio (which in this specification is synonymous with the apparent permeability (Papp) ratio) is less than 2, it can be determined that the drug is not a substrate of these transporters.

[0164] Regarding the brain transferability of compound (1), it 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 transferability evaluation, if the Kp value is 0.1 or higher when 0.1 is used as the cutoff value, it is considered to have brain transferability. In this invention, the preferred Kp value is 0.1 or higher. In addition, the Kp,uu value is correlated with brain transferability. If it is 0.3 or higher, it is judged to have good brain transferability. The higher the Kp,uu value, the higher the brain transferability, which is a better value. The Kp,uu value is preferably 0.4 or higher, and more preferably 0.5 or higher.

[0165] Compound (1) has an inhibitory effect on mutant EGFR, and therefore can inhibit mutant EGFR in tumors (primary or metastatic) occurring in brain tissue, and can be used for tumor growth inhibition. In addition, compound (1) has high selectivity, and is therefore particularly useful for the treatment of brain tumors (primary or metastatic) with EGFR mutations and cancer cell proliferation.

[0166] Compound (1) or its salts, or brain metastatic antitumor agents, anti-brain tumor agents, brain tumor therapeutic agents, and / or brain metastatic EGFR inhibitors comprising compounds (1) or their salts according to one embodiment of the present invention, can also be used preventively for the occurrence of brain tumors. Since compound (1) can cross the BBB, it can be used to prevent the metastasis and colonization of EGFR-mutant cancer cells to the brain. That is, in one embodiment of the present invention, compound (1) can also be used to prevent the occurrence of metastatic brain tumors. Furthermore, in one embodiment of the present invention, compound (1) exhibits excellent brain metastasis, and therefore can simultaneously treat peripheral cancer (primary lesion) with EGFR mutations and brain tumors with EGFR mutations.

[0167] One embodiment of the present invention provides a brain metastasis antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastasis EGFR inhibitor that can be provided alone as an active ingredient. Furthermore, one embodiment of the present invention provides a brain metastasis antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastasis EGFR inhibitor that, in addition to compound (1) or its salt as an active ingredient, can also be combined with a pharmaceutically acceptable carrier, etc., as needed. Thus, one embodiment of the present invention provides a brain metastasis antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastasis EGFR inhibitor that can be prepared as a pharmaceutical composition consisting of one component or containing two or more components. One aspect of the present invention provides a pharmaceutical composition comprising compound (1) or its salt. One embodiment of the present invention provides a pharmaceutical composition comprising compound (1) or its salt and a pharmaceutically acceptable carrier. Furthermore, one embodiment of the present invention provides the use of compound (1) or its salt in the manufacture of a brain metastasis antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastasis EGFR inhibitor or pharmaceutical composition. Another embodiment of the present invention provides a compound (1) or a salt thereof for use as an antitumor agent for brain metastasis, an antitumor agent for brain tumors, a therapeutic agent for brain tumors and / or an EGFR inhibitor for brain metastasis or a pharmaceutical product.

[0168] The brain metastatic antitumor agent, anti-brain tumor agent, brain tumor therapeutic agent, and / or brain metastatic EGFR inhibitor of one embodiment of the present invention can be manufactured into various drug delivery formulations by known methods using pharmaceutically acceptable carriers as needed. The form of administration can be any form, either oral or non-oral. There are no particular limitations on such formulation forms, and examples include oral dosage forms such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspending agents, emulsions, and non-oral dosage forms such as injections, suppositories, and inhalations.

[0169] As pharmaceutically acceptable carriers, various conventional organic or inorganic carrier substances can be used as raw materials for formulations. In solid formulations, excipients, binders, disintegrants, lubricants, and coating agents can be included, while in liquid formulations, they can be used as solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics. Additionally, formulation additives such as preservatives, antioxidants, colorants, sweeteners, and stabilizers can be used as needed.

[0170] Examples of excipients include starches, sugars, polysaccharides, and inorganic compounds. Examples of starches include potato starch, corn starch, rice starch, and partially α-adapted starch. Examples of sugars include monosaccharides, disaccharides, trisaccharides, and sugar alcohols. Examples include lactose, white sugar, trehalose, D-mannitol, raffinose, xylitol, and erythritol. Examples of polysaccharides include cellulose and dextran. Examples include crystalline cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Examples of inorganic compounds include silicates, such as light anhydrous silicic acid and calcium silicate.

[0171] Examples of adhesives include hydroxypropyl cellulose, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, malt syrup powder, and hydroxypropyl methylcellulose.

[0172] Examples of disintegrants include sodium starch glycolate, calcium carboxymethyl cellulose, croscarmellose sodium carboxymethyl cellulose, cross-linked polyvinyl chloride, low-substituted hydroxypropyl cellulose, and partially α-substituted starch.

[0173] Examples of lubricants include talc, magnesium stearate, sucrose fatty acid esters, stearic acid, and sodium stearate fumarate.

[0174] Examples of coating agents include ethyl cellulose, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose, and white sugar.

[0175] Examples of solvents include water, propylene glycol, and physiological saline.

[0176] Examples of solubilizers include alcohols such as polyethylene glycol and ethanol, cyclodextrins, cyclodextrin derivatives, ionic surfactants, and nonionic surfactants. Examples of solubilizers include sorbitan fatty acid esters such as polysorbate 80, sucrose fatty acid esters, and sodium dodecyl sulfate.

[0177] Examples of suspending agents include carrageenan, crystalline cellulose-sodium carboxymethyl cellulose, polyoxyethylene hydrogenated castor oil, gum arabic, and sodium alginate.

[0178] Examples of isotonic agents include sodium chloride, glycerol, and potassium chloride.

[0179] Examples of pH adjusters and buffers include sodium citrate, hydrochloric acid, lactic acid, phosphoric acid, and sodium dihydrogen phosphate.

[0180] Examples of analgesics include procaine hydrochloride and lidocaine.

[0181] Examples of preservatives include ethylparaben, cresol, and benzalkonium chloride.

[0182] Examples of antioxidants include sodium sulfite, ascorbic acid, and natural vitamin E.

[0183] Examples of colorants include titanium dioxide, ferric oxide, food blue No. 1, and copper chlorophyll.

[0184] As a flavoring and odor-correcting agent, examples include aspartame, saccharin, sucralose, L-menthol, and peppermint flavoring agents.

[0185] Examples of stabilizers include sodium metabisulfite, sodium ethylenediaminetetraacetate, isoascorbic acid, magnesium oxide, and butylated hydroxytoluene.

[0186] In the case of preparing oral solid dosage forms, excipients, binders as needed, disintegrants, lubricants, colorants, flavoring / odorants, etc. can be added to compound (1) and then tablets, coated tablets, granules, powders, capsules, etc. can be manufactured by conventional methods.

[0187] In the preparation of injectables, pH adjusters, buffers, stabilizers, isotonic agents, local anesthetics, etc. can be added to compound (1) to manufacture subcutaneous, intramuscular or intravenous injectables by conventional methods.

[0188] The amount of compound (1) to be incorporated in each dosing unit varies depending on the symptoms of the patient to whom it is intended or on the dosage form, etc. Generally, in each dosing unit, compound (1) is preferably 0.05 to 1000 mg in oral formulations, about 0.1 to 500 mg in injectable formulations, and about 1 to 1000 mg in suppositories or topical formulations.

[0189] In addition, the daily dosage of compound (1) in various forms of administration varies depending on the patient's symptoms, weight, age, gender, etc., and cannot be generalized. Generally, the daily dosage of compound (1) for an adult (weight 50kg) is set at about 0.05 to 5000mg, preferably 0.1 to 1000mg.

[0190] Example The present invention will be described in more detail below with reference to specific embodiments, but the invention is not limited thereto. The invention has been fully illustrated by these embodiments, but it should be understood that various changes and / or modifications can be made by those skilled in the art. Therefore, all such changes and / or modifications are included in the invention as long as they do not depart from its scope.

[0191] In the following examples of compounds, unless otherwise specified, % indicates weight percentage.

[0192] Unless otherwise specified, all reagents used in the examples are commercially available products, products synthesized using methods described in patent documents or known methods.

[0193] In addition, the meanings of the abbreviations are as follows.

[0194] PBS: Phosphate-buffered saline HPMC: Hydroxypropyl Methylcellulose HP-β-CD: Hydroxypropyl-β-cyclodextrin 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 a REDdevice system. PBS was added to the recipient side of the system, and after incubation for 8 hours in a 5% CO2 incubator, the compound concentrations on both the donor and recipient sides were determined by LC-MS / MS. The non-binding rate of the compound to plasma proteins was calculated from the ratio of the compound concentration on the recipient side to the donor side. The non-binding rate to plasma proteins was 0.0008.

[0195] Instead of mouse plasma, compound (1) was added to mouse brain homogenate to a final concentration of 5000 nmol / g. The dilution factor was taken into account when calculating the non-binding rate. Otherwise, the non-binding rate of the compound to mouse brain proteins was calculated in the same manner as described above. The mouse brain homogenate used here was obtained by adding PBS containing 3 times the amount of 50 mmol / L sodium fluoride to mouse brains. The non-binding rate of brain proteins was 0.0017.

[0196] Experimental Example 2: Evaluation of Brain Metastasis in Mice Compound (1) was added as a solvent to a 20% HP-β-CD and 0.1 mol / L hydrochloric acid solution, and then ground using an agate mortar to prepare a drug formulation. BALB / cAJcl-nu / nu mice (Clea Co., Ltd., Japan) were administered orally at doses of 20, 40, and 80 mg / kg. Following oral administration, blood was collected from the inferior vena cava under isoflurane anesthesia at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. The mice were euthanized by exsanguination, and the brain was removed. The obtained blood samples were centrifuged to obtain plasma samples. Three times the volume of PBS was added to the obtained brain samples, and the samples were homogenized using a beaded homogenizer to obtain brain homogenate.

[0197] The concentrations of compounds in plasma and brain homogenate were determined by LC-MS / MS. The concentration of compounds in the brain was calculated using a standard curve that accounted for the dilution ratio of the brain homogenate, and the AUC was calculated based on the concentrations in plasma and brain. 0－24 AUC from brain / plasma 0－24 The Kp value was calculated. Additionally, based on the plasma protein non-binding rate and brain protein non-binding rate obtained in Experiment Example 1, the AUC of plasma and brain non-binding proteins was calculated. 0－24 According to the non-binding AUC of brain / plasma 0－24 The Kp,uu values ​​were calculated. The results are shown in Table 1. The Kp values ​​ranged from 0.319 to 0.691, and the Kp,uu values ​​ranged from 0.68 to 1.47. Based on these results, compound (1) showed good brain metastasis.

[0198] [Table 1] Experimental Example 3 Next, as comparative compound 1, a compound having the structure of the following formula (2) was used, and the Kp value at 0.5 hours after administration was calculated. Furthermore, comparative compound 1 was prepared by the method described in Patent Document 1. After a single oral administration at a dose of 40 mg / kg, the brain was removed 0.5 hours later. Three times the volume of water was added to the brain sample, and homogenization was performed using an ultrasonic homogenizer. Otherwise, the test was conducted under the same conditions as in Test Example 2. The results are recorded in Table 2. In the case of compound (1), the Kp value at 0.5 hours after administration was 0.832, but in the case of comparative compound 1, the Kp value was 0.0214.

[0199] The following formula (2) [Table 2] Example 4: Efficacy evaluation of compound (1) and brigatinib in a mouse brain transplantation model. In a model where NIH / 3T3 cells expressing EGFR (serial number 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 brigatinib on intracranial tumor proliferation and mouse survival were verified. Brigatinib is used clinically for anaplastic lymphoma kinase (ALK) mutation-positive lung cancer, but it is also known to inhibit EGFR with ex19del / T790M / C797S.

[0200] The cells were prepared with PBS to a concentration of 5.0 × 10⁶. 6 Cells / mL were used to prepare cell suspensions, which were stored on ice until transplantation. Six-week-old male nude mice (BALB / cAJcl-nu / nu, Japanese Clea) were anesthetized and their heads were fixed using a positioning and fixation device. 2 μL of cell suspension was injected into the head 0.5 mm anteriorly, 2.0 mm to the right, and 3.5 mm deep from the anterior fontanelle. This resulted in the transplantation of 1.0 × 10⁶ cells per mouse. 4 Cells. Set the cell transplantation day as Day0.

[0201] On Day 8, fluorescein was administered intraperitoneally, and the luminescence intensity (photons / sec) was measured using the IVIS Lumina II Imaging System (PerkinElmer). Based on the measured luminescence intensity, the animals were divided into three groups of ten each, ensuring that the luminescence intensity in each group was the same.

[0202] Compound (1) was administered orally at 80 mg / kg / day from Day 8 to Day 56, or continuously until the applicable humanitarian endpoint or death. In the compound (1) administration group, individuals exhibiting loose stools or diarrhea during Day 50 to Day 56 were either reduced to 50 mg / kg or the administration was discontinued. A dosing solution was prepared by dissolving compound (1) at 8.0 mg / mL in a dosing solvent prepared with 0.5 w / v% HPMC and 0.1 mol / L hydrochloric acid. Brigatinib was administered orally at 50 mg / kg from Day 8 to Day 37, or continuously until the applicable humanitarian endpoint or death. A dosing solution was prepared by dissolving brigatinib in a dosing solvent prepared with 0.5 w / v% HPMC and 0.1 mol / L hydrochloric acid. A control group was established receiving the dosing solvent and administered the same dose. Based on the body weight of each mouse on the day of administration, a dose of 10 mL / kg per mouse was administered.

[0203] To evaluate intracranial tumor proliferation, luminescence levels were measured using the methods described above on Day 8, Day 14, and Day 21. Furthermore, the period until death, the applicable humanitarian endpoint for each mouse, was defined as the survival period, from which the median survival was calculated. All animal experiments were conducted in accordance with the Animal Experimentation Guidelines of Taiho Pharmaceutical Co., Ltd. (effective April 2013).

[0204] The results are expressed as Figure 1 Regarding luminescence as an indicator of intracranial tumor proliferation, in the control group, from Day 8 to Day 21, an increase in luminescence over time was confirmed, with the luminescence on Day 21 being 8.353 × 10⁻⁶. 8 ±1.608×10 8 p / s (photons / sec). In the brigatinib dosing group, the luminescence intensity on Day 21 was 4.303 × 10⁻⁶. 8 ±1.970×10 8 p / s is a value of the same magnitude. On the other hand, in the group treated with compound (1), it was 1.648 × 10 on Day 21. 6 ±8.929×10 5 p / s. A statistically significant difference was identified in the compound (1) group relative to the control group (Dunnett type multiple comparison test, p < 0.001), while no statistically significant difference was identified in the brigatinib group. Statistical analysis was performed using EXSUS (ver 10.0.) with SAS (ver 9.4).

[0205] The results are expressed as Figure 2Regarding survival in each group, a statistically significant longer survival was confirmed in the group administered compound (1) compared to the control group and the brigatinib group (p < 0.001, log-rank test). Additionally, a statistically significant longer survival was also confirmed in the brigatinib group compared to the control group (p < 0.001, log-rank test). The median survival was 24.0 days in the control group, 56.5 days in the compound (1) group, and 30.5 days in the brigatinib group. Statistical analysis was performed using the methods described above.

[0206] The results above show that in a mouse model in which NIH / 3T3 cells expressing EGFR and luciferase with the ex19del / T790M / C797S mutations were transplanted into the skull, compound (1) inhibited the proliferation of intracranial tumors and showed a superior prolongation of survival compared to brigatinib.

[0207] Experimental Example 5: Efficacy Evaluation Test of Compounds in a Mouse Subcutaneous Transplantation Model (1) In a subcutaneous model of BALB / cAJcl-nu / nu mice, NIH / 3T3 cells expressing EGFR (serial number 2) with the mutations Ex19del (Del E746-A750), T790M, and C797S (ex19del / T790M / C797S) were transplanted into erlotinib and osimertinib to verify the effect of compound (1) on tumor proliferation.

[0208] On the day of cell transplantation, the cells were placed at a rate of 2.0 × 10⁻⁶. 7 Cells / mL were suspended in PBS and then mixed with an equal volume of Matrigel (Corning Inc.) to prepare 1.0 × 10⁻⁶ cells / mL. 7 Cell suspensions of 1.0 × 10⁶ cells / mL were stored on ice until transplantation. After fixing the mice, 0.1 mL of the cell suspension was injected into the right side of each mouse's chest using a 1-mL syringe fitted with 25-G, thereby transplanting 1.0 × 10⁶ cells per mouse. 6 cell.

[0209] In mice where tumor implantation was confirmed, the major and minor diameters of the tumor were measured using electronic calipers, and the tumor volume was calculated according to the following formula.

[0210] Tumor volume (mm) 3 = Major axis (mm) × Minor axis (mm) 2 / 2 The tumor volume was selected as 91.7914500 mm. 3 Up to 135.3264660mm 3Mice were randomly assigned to groups of 5. After grouping, the mean tumor volume of each group after logarithmic transformation was not statistically significant, as confirmed by the Turkey test. Statistical analysis was performed using EXSUS (ver. 10.0.3) with SAS (ver. 9.4). The grouping day was designated as Day 1.

[0211] Compound (1), erlotinib, and osimertinib were administered orally for several consecutive days from Day 1 to Day 10. Compound (1) was dissolved in a drug solution prepared with 20 w / v % HP-β-CD and 0.1 mol / L hydrochloric acid to prepare drug solutions of 1.0 mg / mL, 2.0 mg / mL, 4.0 mg / mL, and 8.0 mg / mL. Erlotinib was suspended in a drug solution prepared with 0.5 w / v % HPMC and 0.1 w / v % Tween 80 to prepare a drug solution of 8.0 mg / mL. Osimertinib was dissolved in a drug solution prepared with 0.5 w / v % HPMC and 0.1 mol / L hydrochloric acid to prepare a drug solution of 2.5 mg / mL. Based on the body weight of each mouse on the day of administration, each mouse was administered a dose of 10 mL / kg.

[0212] To evaluate the antitumor effects of compound (1), erlotinib, and osimertinib, tumor volumes in mice on Days 1, 4, 8, and 11 were calculated using the method described above, and the average tumor volume for each group was determined. For comparison, a control group was administered the solvent for compound (1), and tumor volumes were also calculated. All animal experiments were conducted in accordance with the Animal Experimentation Guidelines of Daiho Pharmaceutical Co., Ltd. (effective April 2013).

[0213] The results are expressed as Figure 3 In the control group, the mean tumor volume increased over time, reaching 1116.1 ± 138.9 mm on the final evaluation day, Day 11. 3 The mean tumor volume in the Day 11 compound (1) administration group was 378.5 ± 19.6 mm at doses of 10, 20, 40, and 80 mg / kg / day. 3 155.1±22.9mm 3 69.7±7.5mm 3 and 34.1±3.9mm 3 The mean tumor volumes of the different dosage groups of compound (1) were 33.9%, 13.9%, 6.2%, and 3.1%, respectively, relative to the control group. The tumor volumes of all dosage groups of compound (1) were statistically significant relative to the control group, as confirmed by the Dunnett test (p < 0.001). Statistical analysis was performed using the methods described above.

[0214] On the other hand, the mean tumor volume on Day 11 was 810.8 ± 47.1 mm in the erlotinib 80 mg / kg / day and osimertinib 25 mg / kg / day groups. 3 and 972.9±82.3mm 3 The mean tumor volume in the erlotinib and osimertinib dose groups was 72.6% and 87.2% respectively, compared to the control group. Furthermore, no statistically significant differences relative to the control group were identified in either group. Statistical analysis was performed using the methods described above.

[0215] Based on the above results, in this model where erlotinib and osimertinib did not show efficacy, namely in the NIH / 3T3 mouse model with subcutaneous transplantation of EGFR expressing the ex19del / T790M / C797S mutation, compound (1) showed a dose-dependent antitumor effect when administered at doses ranging from 10 mg / kg to 80 mg / kg.

[0216] Experimental Example 6: Evaluation of the efficacy of brigatinib in a mouse subcutaneous transplantation model Similar to Experiment 5, the effect of brigatinib on tumor proliferation was verified in a BALB / cAJcl-nu / nu mouse model of subcutaneous transplantation of NIH / 3T3 cells expressing EGFR (serial number 2) with Ex19del (DelE746-A750), T790M and C797S mutations (ex19del / T790M / C797S).

[0217] On the day of cell transplantation, the cells were injected at a rate of 1×10⁻⁶. 8 Cells / mL were suspended in PBS and then mixed with an equal volume of Matrigel to prepare 5×10⁶ cells / mL. 7 Cell suspension per mL. After fixing the mice, 0.1 mL of cell suspension was injected into the right chest of each mouse using a 1 mL syringe fitted with a 25-G syringe, thereby transplanting 5 × 10⁶ cells per mouse. 6 cell.

[0218] In mice where tumor implantation was confirmed, the major and minor diameters of the tumor were measured using electronic calipers, and the tumor volume was calculated according to the following formula.

[0219] Tumor volume (mm) 3 = Major axis (mm) × Minor axis (mm) 2 / 2 The tumor volume was 237.995 mm. 3 up to 382.316mm 3 45 mice (Mean±SE: 308.5119±5.6413 mm) 3Five mice were randomly assigned to each group. The grouping day was designated as Day 0.

[0220] Brigatinib was administered orally for several consecutive days from Day 1 to Day 11. Brigatinib was dissolved in a drug solution prepared with 0.5 w / v % HPMC and 0.1 mol / L hydrochloric acid to prepare a 7.5 mg / mL solution. Based on the body weight of each mouse on the day of administration, each mouse was given a dose of 10 mL / kg.

[0221] To evaluate the antitumor effect of brigatinib, the tumor volume of mice on Days 0, 4, 8, and 11 was calculated using the method described above, and the average tumor volume for each group was determined. As a comparison, a control group was established that received the brigatinib-containing solvent, and the tumor volume was also calculated in the same manner. All these animal experiments were conducted in accordance with the Animal Experimentation Guidelines of Taiho Pharmaceutical Co., Ltd. (effective April 2013).

[0222] The results are expressed as Figure 4 In the control group, the mean tumor volume increased over time, reaching 1575.34 ± 134.60 mm on Day 11. 3 The mean tumor volume in the brigatinib 75 mg / kg group on Day 11 was 195.63 ± 27.54 mm. 3 The mean tumor volume in the brigatinib group was 13% compared to the control group. The tumor volume in the brigatinib group was statistically significant relative to the control group using a Student-t test (p < 0.001). Statistical analysis was performed using the methods described above.

[0223] Based on the above results, it can be concluded that in a NIH / 3T3 mouse model with subcutaneous transplantation of EGFR expressing the ex19del / T790M / C797S mutation, brigatinib at a dose of 75 mg / kg showed antitumor effects. Combining these results with those of control case 4, it can be concluded that while brigatinib is effective against subcutaneous tumors, it does not exert the same effect on the proliferation of intracranial tumors as the compound of formula (1).

[0224] Test Example 7: Substrate Confirmation Test of P-gp and BCRP The in vitro substrate properties of compound (1) with P-gp and BCRP were evaluated using Caco-2 cells. Caco-2 cells, purchased from American Type Culture Collection, were seeded into porous membrane filters and cultured for a certain period before substrate properties were evaluated by transcellular transport of the compound. The apparent permeation rates (Papp (×10⁻¹⁰)) of compound (1) from the apical side to the basal side and from the basal side to the apical side of the filter were calculated using the following formula. －6 (cm / sec). The apparent permeability is expressed as the mean ± standard deviation (n=3).

[0225] Papp = [dQt / dt] / A / C0 dQ / dt: Permeation rate (pmol / sec) A: Cell surface area (cm²) 2 ) C0: Initial concentration (pmol / mL) of compound (1) Next, calculate the apparent permeability ratio (Papp ratio) according to the following formula.

[0226] Papp ratio = Papp (base side to apex side) / Papp (apex side to base side) The results are presented in Table 3. The apparent permeability ratio (Papp ratio) of compound (1) at concentrations of 0.01, 0.1, 1 and 3 μmol / L were 1.2, 1.2, 0.9 and 0.8, respectively, all less than 2. Based on these results, compound (1) can be determined to be neither a substrate of P-gp nor BCRP.

[0227] [Table 3] Furthermore, the scope of the claims, description, and drawings of Japanese Patent Application No. 2023-210446 (filed December 13, 2023) and No. 2024-170941 (filed September 30, 2024), which form the basis for asserting priority of this application, are incorporated herein by reference.

Claims

1. A brain metastasis antitumor agent, characterized in that: It contains N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or its salt as an active ingredient.

2. The brain metastasis antitumor agent as described in claim 1, characterized in that: It is used to treat primary or metastatic brain tumors.

3. The brain metastasis antitumor agent as described in claim 2, characterized in that: The brain tumor has an EGFR mutation of C797X, where X represents any amino acid.

4. The brain metastasis antitumor agent as described in claim 3, characterized in that: C797X is either C797S or C797G.

5. The brain metastasis antitumor agent as described in claim 4, characterized in that: The brain tumor also has an EGFR mutation in Ex19del.

6. The brain metastasis antitumor agent as described in claim 5, characterized in that: The brain tumor also has an EGFR mutation, T790M.

7. The brain metastatic antitumor agent according to any one of claims 1 to 6, characterized in that: It is used to administer to subjects who have been treated with osimertinib.

8. A brain tumor therapeutic agent, characterized in that: It contains N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or its salt as an active ingredient.

9. The brain tumor therapeutic agent as described in claim 8, characterized in that: It is used to treat primary or metastatic brain tumors.

10. The brain tumor therapeutic agent as described in claim 9, characterized in that: The brain tumor has an EGFR mutation of C797X, where X represents any amino acid.

11. The brain tumor therapeutic agent as described in claim 10, characterized in that: C797X is either C797S or C797G.

12. The brain tumor therapeutic agent as described in claim 11, characterized in that: The brain tumor also has an EGFR mutation in Ex19del.

13. The brain tumor therapeutic agent as described in claim 12, characterized in that: The brain tumor also has an EGFR mutation, T790M.

14. The brain tumor therapeutic agent according to any one of claims 8 to 13, characterized in that: It is used to administer to subjects who have been treated with osimertinib.

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

16. The N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in claim 15, characterized in that: It is used to treat primary or metastatic brain tumors.

17. The N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in claim 16, characterized in that: The brain tumor has an EGFR mutation of C797X, where X represents any amino acid.

18. The N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in claim 17, characterized in that: C797X is either C797S or C797G.

19. The N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in claim 18, characterized in that: The brain tumor also has an EGFR mutation in Ex19del.

20. The N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in claim 19, characterized in that: The brain tumor also has an EGFR mutation, T790M.

21. The N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof as described in any one of claims 15 to 20, characterized in that: It is used to administer to subjects who have been treated with osimertinib.

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

23. Use of N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or salts thereof in the treatment of brain tumors.

24. A treatment method for a subject suffering from a brain tumor, characterized in that, include: The procedure of administering N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof to a subject requiring treatment.

25. A pharmaceutical composition for treating brain tumors, characterized in that: Contains N-(4-(4-amino-6-ethynyl-5-(quinoline-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)bicyclo[2.2.1]heptane-1-yl)-5-methylpyrazine-2-carboxamide or a salt thereof and a pharmaceutically acceptable carrier.

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