A brain-pervading tumor treatment agent containing a condensed pyrimidine compound as its active ingredient.

Abstract

The present invention addresses the problem of providing a brain-migrating antitumor agent that exhibits excellent brain migration properties and RET inhibitory activity. The present invention provides a brain-migrating antitumor agent that contains a compound represented by general formula (I) (wherein R1, R2 and R3 are as described in the specification) or a salt thereof as an active ingredient.

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to Japanese Patent Application No. 2020-193073, filed on November 20, 2020 (the entire disclosure thereof is incorporated herein by reference). The present invention relates to an antitumor agent. [Background technology]

[0002] Brain tumors are a type of brain disease, specifically tumors that develop in the intracranial tissues. Brain tumors are divided into primary brain tumors, which originate from brain cells, and metastatic brain tumors, which develop when cancers such as lung cancer or breast cancer metastasize to the brain. Symptomatic metastatic brain tumors are reported to occur in 8-10% of cancer patients, and some reports indicate that brain metastases occur in 40-50% of lung cancer cases at autopsy (Non-Patent Literature 1-3). Primary sites of metastatic brain tumors include lung cancer, breast cancer, gastrointestinal cancers (stomach cancer), malignant melanoma, and renal / urinary tract cancers, with lung cancer accounting for approximately half of all cases (Non-Patent Literature 2). Treatment for metastatic brain tumors varies depending on the patient's overall condition, tumor size, and number of metastases. Treatment options include radiation therapy, surgery, chemotherapy, or a combination of these. Generally, surgery is chosen when the primary tumor is controlled, is solitary, and a reasonable survival period is expected. However, tumors that have metastasized into the brain are often intricately intertwined with brain parenchyma and / or nerve tissue, making it difficult to completely remove the tumor surgically. Two types of radiation therapy are known: quantitative radiosurgery (such as gamma knife therapy) and whole-brain irradiation, which irradiates the entire brain. Currently, most treatments for metastatic brain tumors involve a combination of surgery and radiation therapy, but it is difficult to say that these treatments are sufficiently effective (Non-Patent Literature 4, 5). Generally, the central nervous system (CNS), including the brain, is protected from harmful substances by a highly specialized layer of tight junctions called the blood-brain barrier (BBB). One reason why effective drugs have not been developed for many CNS-related diseases is that almost all therapeutic molecules, including antibodies, cannot pass through the BBB. Small molecule compounds are no exception, and some reports indicate that more than 98% of small molecule compounds cannot pass through the BBB (Non-Patent Literature 6). Currently, many compounds have shown efficacy in peripheral cancers (primary tumors), but their efficacy in brain metastases of these cancers is limited. One reason for this is thought to be that these compounds cannot reach the brain in sufficient quantities to exert their effects, and therefore cannot produce the same effect as in the primary tumor (Non-Patent Documents 7, 8).Therefore, in CNS-related diseases and brain tumors, there is a need for the development of small molecule compounds with high brain penetration and methods for their brain penetration. In particular, in the treatment of metastatic brain tumors, there is a demand for drugs that show effective efficacy against primary tumors such as lung cancer, and also show high CNS penetration and efficacy against brain metastases. For example, there are many compounds that have shown efficacy in primary tumors, including compounds with RET inhibitory activity. Here, RET is a receptor tyrosine kinase identified as one of the proto-oncogenes, and it exerts physiological functions via intracellular phosphorylation signaling by binding to glial cell line-derived neurotrophic factor (GDNF) and the GDNF receptor and forming a complex (Non-Patent Literature 9). In normal tissues, it has been reported to contribute to kidney and neurogenesis during the embryonic stage (Non-Patent Literature 10). Furthermore, in lung cancer, thyroid cancer, breast cancer, pancreatic cancer, prostate cancer, etc., it has been reported that RET is translocated, mutated, and overexpressed, leading to increased activation and contributing to cell proliferation, tumor formation, or tissue invasion (Non-Patent Literature 11-16). In addition, it has been reported that RET translocation and increased activation levels in these cancers are inversely correlated with prognosis (Non-Patent Literature 17-19), and RET is also known as a poor prognostic factor for cancer.

[0003] Therefore, inhibitors that can control RET activity are considered useful as therapeutic agents for diseases associated with abnormal hyperactivity of the RET signaling pathway.

[0004] For example, in cancers where RET is translocated, mutated, or overexpressed and activated, it is expected that administering a drug that specifically inhibits RET will selectively and intensively suppress the proliferation of cancer cells, which is expected to contribute to the treatment, survival, and improvement of quality of life of cancer patients.

[0005] While several compounds are known to possess RET inhibitory activity, PP1 (Non-Patent Literature 20) is one example. PP1 has a structure in which a p-toluyl group is attached to a fused pyrimidine skeleton. PP1 is known to exhibit high inhibitory activity not only against RET but also against Src (Non-Patent Literature 21), c-Kit, Bcr-Abl (Non-Patent Literature 22, 23), etc. For example, inhibition of Src may cause abnormal bone formation as a side effect, and inhibition of Lck may cause T cell suppression as a side effect (Non-Patent Literature 24, 25). Thus, since multi-kinase inhibitors suppress cell proliferation by inhibiting various signaling pathways in addition to RET, various side effects are a concern. If dose reduction and / or drug-free periods are necessary due to side effects, the RET inhibitory activity may not be fully exerted. From the perspective of reducing side effects, there is a need for an RET inhibitor that has high inhibitory activity against RET while having low inhibitory activity against other kinases. However, to date, no drug has been reported that exhibits strong RET inhibitory effect and good brain penetration. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Qingbei Zeng,J Med Chem.22;58(20):8200-15,(2015). [Non-Patent Document 2] Lakshmi Nayak,Curr Oncol Rep;14(1):48-54,(2012) [Non-Patent Document 3] Brunilde Gril,Eur J Cancer.;46(7):1204-10,(2010) [Non-Patent Document 4] Taofeek K. Owonikoko, Nat Rev Clin Oncol.;11(4):203-22,(2014) [Non-Patent Document 5] Chien-Hung Gow, Clin Cancer Res.1;14(1):162-8,(2008)

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Summary of the Invention

Problems to be Solved by the Invention

[0007] The object of the present invention is to provide a brain-penetrating antitumor agent exhibiting excellent brain penetration and RET inhibitory activity. Another object of the present invention is to provide the use of a compound or salt thereof for producing a brain-penetrating antitumor agent exhibiting excellent brain penetration, RET inhibition, and antitumor effects, or for the treatment of tumors using a brain-penetrating antitumor agent. Furthermore, an object of the present invention is to provide a method for treating tumors, particularly brain tumors, characterized by administering a brain-penetrating antitumor agent containing a compound or salt thereof having RET inhibitory activity. [Means for solving the problem]

[0008] As a result of diligent research to solve the aforementioned problems, the present inventors have found that a condensed pyrimidine compound or a salt thereof having a specific structure that selectively inhibits RET is useful as a brain-penetrating antitumor agent, and have completed the present invention.

[0009] In other words, the present invention includes the following embodiments.

[0010] [1] General formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or A brain-penetrating antitumor agent comprising a compound represented by (which may have substituents, a C1-C6 alkoxy group) or a salt thereof as an active ingredient. [2]R 2 A substituent of a C3-C5 cycloalkyl group which may have substituents shown by (1-1)C1-C2 alkyl group The brain-penetrating antitumor agent described in [1]. [3]R 2The brain metastatic anti-tumor agent according to [1] or [2], which is a C3-C4 cycloalkyl group that may have a methyl group as a substituent. [4]R 3 The substituent of the C2-C6 alkynyl group that may have a substituent represented by (2-1) An amino group that may have a substituent; (2-2) A C1-C6 alkyl group that may have a substituent; (2-3) A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms that may have a substituent; or, (2-4) A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms that may have a substituent The brain metastatic anti-tumor agent according to any one of [1] to [3]. [5]R 3 The substituent of the C1-C6 alkoxy group that may have a substituent represented by (3-1) An amino group; (3-2) A C1-C6 alkyl group that may have a hydroxyl group; (3-3) A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms that may have at least one substituent selected from the group consisting of a methyl group, an ethyl group, and an amino group; or (3-4) A 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur atoms that may have at least one substituent selected from the group consisting of a methyl group, an ethyl group, and an amino group The brain metastatic anti-tumor agent according to any one of [1] to [4]. [6]R 1 is a C1-C6 alkoxy C1-C6 alkyl group R 2 is a C3-C5 cycloalkyl group that may have a C1-C2 alkyl group as a substituent, R 3 is A C2-C6 alkynyl group which may have substituents; or C1-C6 alkoxy groups which may have substituents The antitumor agent described in any one of the items [1] to [5]. (R 3 A substituent of a C2-C6 alkynyl group which may have substituents shown by, amino group; A C1-C6 alkyl group may have at least one substituent selected from the group consisting of a hydroxyl group, an amino group, and a cyano group; A 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups; or, The substituent may be at least one selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups, and is a 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. R 3 A substituent of a C1-C6 alkoxy group which may have substituents shown by, amino group; A C1-C6 alkyl group that may have a hydroxyl group; A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups; or A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups. (That is the case.) [7] A compound represented by general formula (I) or a salt thereof, (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethinyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidine-4-yl)ethinyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (7)(R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazole-5-yl)ethinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (14) 4-amino-6-(4-hydroxy-4-methylpentin-1-tin-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)propyl-1-pin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (17) 4-Amino-6-[(6-aminopyridine-3-yl)ethinyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide or a salt thereof, the brain-penetrating antitumor agent described in any one of items [1] to [6]. [8] A compound represented by general formula (I) or a salt thereof, (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethinyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide A brain-penetrating antitumor agent as described in any one of items [1] to [7], or a salt thereof. [9] A brain-penetrating antitumor agent according to any one of the items [1] to [8] for the treatment of primary or metastatic brain tumors.

[10] For manufacturing brain-penetrating antitumor agents, the following general formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) Use of a compound represented by or a salt thereof.

[11] General formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or A method for treating a subject having a tumor, comprising administering a brain-penetrating antitumor agent containing an effective amount of a compound represented by (which may have substituents, a C1-C6 alkoxy group) or a salt thereof to the subject in need of treatment.

[12] For use in the treatment of tumors with brain-penetrating antitumor agents, the following general formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or A compound represented by the following general formula (I) for the treatment of tumors by a brain-penetrating antitumor agent: [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) Use of a compound represented by or a salt thereof.

[14] The following general formula (I) as an active ingredient [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) A commercial package comprising a compound represented by or a salt thereof, along with instructions for its use in treating tumors in a subject with a brain-penetrating antitumor agent.

[15] General formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) A brain-penetrating antitumor agent for treating tumors in which the RET activation state is enhanced, comprising a compound represented by or a salt thereof as an active ingredient.

[16] For manufacturing a brain-penetrating antitumor agent for treating tumors in which the RET is in an enhanced state of activation, the following general formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) Use of a compound represented by or a salt thereof.

[17] For subjects with tumors in which the activation state of RET is elevated, an effective dose of the following general formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) A method for treating the subject, comprising administering a brain-penetrating antitumor agent containing a compound represented by or a salt thereof.

[18] For use in the treatment of tumors in which the RET is activated by brain-penetrating antitumor agents, the following general formula (I) [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) A compound represented by or a salt thereof.

[19] The following general formula (I) for treating tumors in which the RET activation state is enhanced by brain-penetrating antitumor agents: [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) Use of a compound represented by or a salt thereof.

[20] The following general formula (I) as the active ingredient [ka] (In the formula, R 1 It is a C1-C6 alkoxyalkyl group, R 2 This is a C3-C5 cycloalkyl group which may have substituents. R 3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) A commercial package comprising a compound represented by or a salt thereof, along with instructions for its use in treating tumors in which the RET activation state is elevated in a subject with a brain-penetrating antitumor agent. [Effects of the Invention]

[0011] The present invention provides an antitumor agent that has brain penetration. In a preferred embodiment of the present invention, a novel therapeutic agent having RET inhibitory activity that has an effective therapeutic effect against brain tumors is provided. Furthermore, since the brain-penetrating antitumor agent of the present invention has a highly selective inhibitory activity against RET, it is expected to reduce toxicity by inhibiting other kinases and thus be useful because it can be expected to have a high therapeutic effect. [Brief explanation of the drawing]

[0012] [Figure 1] The antitumor effect of the compound of the present invention is demonstrated in a brain transplantation model animal (NIH / 3T3_CCDC6-RET brain transplantation model). [Figure 2]This shows the percentage change in body weight of the compound of the present invention in an animal brain transplant model (NIH / 3T3_CCDC6-RET brain transplant model). [Modes for carrying out the invention]

[0013] One embodiment of the present invention relates to a brain-penetrating antitumor agent comprising a compound represented by the following general formula (I) or a salt thereof as an active ingredient. [ka]

[0014] In this invention, a compound represented by general formula (I) may be simply referred to as compound (I).

[0015] In the present invention, a brain-penetrating antitumor agent means an antitumor agent intended to exert a therapeutic effect by having at least a portion of its active ingredient penetrate the brain.

[0016] In this specification, unless otherwise explicitly stated, "substituents" include, for example, deuterium atoms, halogen atoms, hydroxyl groups, alkyl groups, alkoxy groups, alkoxyalkyl groups, cycloalkyl groups, cycloalkyl-alkyl groups, alkenyl groups, alkynyl groups, amino groups, mono- or dialkylamino groups, oxo groups, saturated or unsaturated heterocyclic groups (the saturated or unsaturated heterocyclic groups may have at least one substituent selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups), aromatic hydrocarbon groups, and the like. If such substituents are present, their number is not limited, but is typically one, two, or three. In this specification, if multiple substituents are present, they may be the same or different unless otherwise explicitly stated.

[0017] In this specification, if there are multiple options for substituents that each group defined in the general formula (I) may have, unless otherwise specified, the substituents for each group may be of the same type or different types. For example, unless otherwise specified, "alkyl group having a halogen atom or a hydroxyl group as a substituent" includes not only alkyl groups having only a halogen atom or only a hydroxyl group, but also alkyl groups having both a halogen atom and a hydroxyl group. Furthermore, "alkyl group having a halogen atom or a hydroxyl group as a substituent" also includes, for example, alkyl groups having two or more types of halogen atoms (e.g., a fluorine atom and a chlorine atom).

[0018] In this specification, "halogen atoms" include fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms.

[0019] In this specification, "alkyl group" refers to a linear or branched saturated hydrocarbon group, and examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, 1-methylpropyl group, n-pentyl group, isopentyl group, tert-pentyl group, pentan-3-yl group, n-hexyl group, 1,1-dimethylpropyl group, 1,1,2,2-tetramethylethyl group, n-heptyl group, 1,1,2,2-tetramethylpropyl group, n-octyl group, n-nonyl group, n-decyl group, etc., and includes C1-C10 alkyl groups, C3-C10 alkyl groups, C1-C6 alkyl groups, C1-C4 alkyl groups, C3-C8 alkyl groups, C3-C6 alkyl groups, etc.

[0020] In this specification, "alkoxy group" refers to an oxy group to which the aforementioned alkyl group is attached, and examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, n-hexyloxy group, etc., and also includes C1-C6 alkoxy groups, C1-C4 alkoxy groups, etc.

[0021] In this specification, "alkoxyalkyl group" refers to the alkyl group having one or more alkoxy groups (for example, 1 to 5, preferably 1 to 3, more preferably 1), and examples include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, n-butoxymethyl group, 2-methoxyethyl group, 1-methoxy-n-propyl group, 3-methoxy-n-propyl group, 2-ethoxy-n-butyl group, 4-methoxy-n-butyl group, 5-methoxy-n-pentyl group, 6-methoxy-n-hexyl group, etc., and includes C1-C6 alkoxyC1-C6 alkyl group, C1-C4 alkoxyC1-C6 alkyl group, C1-C4 alkoxyC1-C4 alkyl group, etc.

[0022] In this specification, "C1-C6 alkoxyalkyl group" refers to an alkyl group to which the C1-C6 alkoxy group is bonded, and examples include methoxymethyl group, ethoxymethyl group, n-propoxymethyl group, n-butoxymethyl group, 2-methoxyethyl group, 1-methoxy-n-propyl group, 3-methoxy-n-propyl group, 2-ethoxy-n-butyl group, 4-methoxy-n-butyl group, 5-methoxy-n-pentyl group, 6-methoxy-n-hexyl group, 8-methoxy-n-octyl group, and the like.

[0023] In this specification, "cycloalkyl group" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) saturated hydrocarbon group, and includes monocyclic cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group, as well as polycyclic cycloalkyl groups such as spiro[3.3]heptyl group, spiro[3.4]octyl group, and dispiro[5.1.78.26]heptadecanyl group, and also includes C3-C7 cycloalkyl groups and C3-C5 cycloalkyl groups.

[0024] In this specification, "aromatic hydrocarbon group" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) cyclic substituent consisting of carbon and hydrogen atoms having unsaturated bonds, wherein the cyclic π-electron system contains 4e+2 electrons (where e is an integer of 1 or more). Examples include phenyl group, naphthyl group, anthracenyl group, phenanthryl group, fluorenyl group, tetrahydronaphthyl group, etc., and includes aromatic hydrocarbon groups such as C6-C14, C6-C10, and C8-C14.

[0025] In this specification, "alkenyl group" refers to a linear or branched unsaturated hydrocarbon group containing at least one double bond (e.g., 1-2, 1, etc.), and examples include vinyl group, allyl group, 1-propenyl group, 2-methyl-2-propenyl group, isopropenyl group, 1-, 2- or 3-butenyl group, 2-, 3- or 4-pentenyl group, 2-methyl-2-butenyl group, 3-methyl-2-butenyl group, 5-hexenyl group, 3-methyl-3-butenyl group, etc., and also includes C2-C6 alkenyl groups, C2-C4 alkenyl groups, etc.

[0026] In this specification, "alkynyl group" refers to a linear or branched unsaturated hydrocarbon group containing at least one triple bond (e.g., 1-2 bonds, 1 bond, etc.), and includes, for example, an ethynyl group, a 1- or 2-propynyl group, a 1-, 2- or 3-butynyl group, a 1-methyl-2-propynyl group, etc., and also includes C2-C6 alkynyl groups, C2-C4 alkynyl groups, etc.

[0027] In this specification, "saturated heterocyclic group" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) saturated heterocyclic group containing one or more heteroatoms (e.g., 1 to 3) of the same or different type selected from nitrogen, oxygen, and sulfur atoms, such as morpholino group, 1-pyrrolidinyl group, 3-pyrrolidinyl group, piperidino group, piperazinyl group, 4-methyl-1-piperazinyl group, tetrahydrof Examples include lanyl groups, tetrahydropyranyl groups, tetrahydrothiophenyl groups, thiazolidinyl groups, oxazolidinyl groups, thiomorphonyl groups, 7-azabicyclo[2.2.1]hepto-2-yl groups, 2,6-dioxabicyclo[3.2.1]octo-7-yl groups, and 7-oxabicyclo[2.2.1]heptane groups, and include saturated heterocyclic groups with 4-6 members, 4-10 members, 8-14 members, and 8-10 members.

[0028] In this specification, "unsaturated heterocyclic group" refers to a monocyclic or polycyclic (e.g., bicyclic, tricyclic) fully unsaturated or partially unsaturated heterocyclic group containing one or more (e.g., 1 to 3) homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, such as imidazolyl, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazyl, pyrimidinyl, and pyridinyl groups. Examples include ridazinyl group, indolyl group, isoindolyl group, indazolyl group, triazolopyridinyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, benzothienyl group, benzofuranyl group, prinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, dihydrobenzofuranyl group, dihydrothiazolyl group, and benzothiophenyl group, and include unsaturated heterocyclic groups with 4-6 members, 4-10 members, 8-14 members, and 8-10 members.

[0029] In this specification, "Ca-Cb" indicates a substituent having a to b carbon atoms. For example, "C1-C6 alkyl group" refers to an alkyl group having 1 to 6 carbon atoms, and "C6-C14 aromatic hydrocarbon oxy group" refers to an oxy group to which an aromatic hydrocarbon group having 6 to 14 carbon atoms is bonded. Also, "a to b member" indicates that the number of atoms constituting the ring (number of ring members) is a to b. For example, "4 to 10 member saturated heterocyclic group" means a saturated heterocyclic group with 4 to 10 ring members.

[0030] Specific compounds that can be used as the active ingredient of the brain-penetrating antitumor agent of the present invention include, but are not limited to, the following. Hereinafter, the R in the general formula representing compound (I) 1 , R 2 , R 3 The substituents such as R will be described in detail. When describing the substituents, unless otherwise specified, 1 , R 2 , R 3 These substituents represent the substituents in general formula (I).

[0031] R 1 It is a C1-C6 alkoxyalkyl group.

[0032] R 1 The "C1-C6 alkoxyalkyl group" shown is one of the above, but is preferably a C1-C4 alkoxyalkyl group, and more preferably a methoxymethyl group.

[0033] R 2 In the "C3-C5 cycloalkyl group which may have substituents" shown as, the "substituent" (in this specification, R 2 In the "C3-C5 cycloalkyl group which may have substituents" shown, the "substituent" is referred to as "substituent R A Examples of "substituents" (sometimes referred to as "substituents") include those mentioned above, but preferably they are C1-C6 alkyl groups, more preferably C1-C3 alkyl groups, and even more preferably methyl groups.

[0034] R 2 The "C3-C5 cycloalkyl group which may have substituents" shown is the substituent R A Examples of C3-C5 cycloalkyl groups that may or may not have a propyl group include, but are preferably C3-C4 cycloalkyl groups, and more preferably propyl groups.

[0035] R 3 The "C2-C6 alkynyl group" in the "C2-C6 alkynyl group which may have substituents" shown above is an example of the "C2-C6 alkynyl group", but is preferably a C2-C4 alkynyl group, and more preferably an ethynyl group or a propynyl group.

[0036] In the "C2-C6 alkynyl group which may have substituents," the number of triple bonds in the "C2-C6 alkynyl group" is preferably one, and its position is preferably between the carbon atom bonded to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to that carbon atom.

[0037] R 3 In the "C2-C6 alkynyl group which may have substituents" shown as, the "substituents" (in this specification, R 3 In the "C2-C6 alkynyl group which may have substituents" shown, the "substituent" is referred to as "substituent R B (Sometimes this is indicated as ") Preferably, An amino group which may have a substituent; C1-C6 alkyl groups that may have substituents; A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents; or A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents. These are some examples. "Substituent R B "More preferably, amino group Linear or branched C1-C6 alkyl groups which may have substituents, A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents, or A 4-10 member monocyclic or polycyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents. More preferably, amino group; A C1-C6 alkyl group may have at least one substituent selected from the group consisting of a hydroxyl group, an amino group, and a cyano group; A 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups; or, The substituent may be at least one selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups, and is a 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. Even more preferably, amino group; A C1-C6 alkyl group which may have a hydroxyl group as a substituent; The substituent may have a C1-C6 alkyl group, and may be a 5-6 member monocyclic saturated heterocyclic group containing 1-2 nitrogen heteroatoms; or, The substituent may be selected from the group consisting of C1-C6 alkyl groups and amino groups, and the monocyclic unsaturated heterocyclic group has 5-6 members and may contain 1-2 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms. That is the case.

[0038] R 3 The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in BAs an example of the aforementioned "amino group which may have substituents," preferred examples of the "substituents" include, for example, C1-C6 alkyl groups, hydroxyl groups, and so on.

[0039] R 3 The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in B As an example of the aforementioned "C1-C6 alkyl group which may have substituents," preferred examples of the "substituent" include, for example, a hydroxyl group, a C1-C6 alkoxy group, or an oxo group, with a hydroxyl group being preferred.

[0040] R 3 The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in B As an example, in the aforementioned "linear or branched C1-C6 alkyl group which may have substituents," the "C1-C6 alkyl group" is preferably a branched C1-C6 alkyl group, and more preferably a branched C3-C6 alkyl group.

[0041] R 3 The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in B As an example of the aforementioned "C1-C6 alkyl group which may have substituents," a hydroxybutyl group is a preferred example.

[0042] R 3 The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in B As an example of the aforementioned "4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents", preferred examples of the "substituents" include C1-C6 alkyl groups, hydroxyl groups, amino groups, or cyano groups, preferably C1-C6 alkyl groups, and more preferably methyl groups.

[0043] R 3The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in B As an example, the aforementioned "4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents" is preferably "4-6 member monocyclic saturated heterocyclic group containing 1-2 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents," More preferably, it is a "4-6 membered monocyclic saturated heterocyclic group containing 1-2 heteroatoms of a nitrogen atom which may have substituents" (if substituents are present, the substituents represent methyl groups), More preferably, the group may have substituents: a morpholino group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperazinyl group, a pyrrolidinyl group, a piperidinyl group, a thiomorphonillyl group, or an oxetanyl group (if substituents are present, the substituents represent a methyl group, an ethyl group, or an amino group). More preferably, the group may have substituents: morpholino group, tetrahydrofuranyl group, tetrahydropyranyl group, piperazinyl group, pyrrolidinyl group, piperidinyl group, or thiomorphonillyl group (if substituents are present, the substituent is preferably a methyl group or an ethyl group, more preferably a methyl group).

[0044] Substituent R B As an example, in the aforementioned "4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents," the number of substituents is not particularly limited, but is preferably 0-3, and more preferably 0-2.

[0045] R 3 The substituent (substituent R) in the "C2-C6 alkynyl group which may have substituents" shown in BAs an example of the aforementioned "4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents", preferred examples of the "substituents" include C1-C6 alkyl groups, amino groups, hydroxyl groups, or cyano groups, preferably C1-C6 alkyl groups or amino groups, and more preferably methyl groups or amino groups.

[0046] The "4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents" is, Preferably, it is a "4-10 membered monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents" (the substituents represent C1-C6 alkyl groups, C1-C6 alkoxy groups, or amino groups). More preferably, it is a "4-6 member monocyclic unsaturated heterocyclic group containing 1-3 heteroatoms of nitrogen atoms which may have substituents" (the substituents represent C1-C6 alkyl groups or amino groups), More preferably, the group may have a substituent, such as a pyrazolyl group, an imidazo[1,2-b]pyridazinyl group, an imidazolyl group, a pyridinyl group, a thiazolyl group, or a flu[3,2-b]pyridinyl group (the substituent being a methyl group, an ethyl group, or an amino group). More preferably, the substituent is a pyrazolyl group, imidazolyl group, or pyridinyl group (the substituent being a methyl group, an ethyl group, or an amino group, preferably a methyl group or an amino group), which may have a substituent.

[0047] Substituent R B As an example, in the aforementioned "4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents," the number of substituents is not particularly limited, but is preferably 0-3, and more preferably 0-2.

[0048] In this specification, R 3 In the "C1-C6 alkoxy group which may have substituents" shown, the "substituent" is referred to as "substituent R C They sometimes indicate this as "." R 3 The "C1-C6 alkoxy group which may have substituents" shown is, Preferably, substituent R C The C1-C6 alkoxy group may have "a 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups," and more preferably, Substituent R C It is a C1-C6 alkoxy group which may have "a 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms." Substituent R C As an example, the aforementioned "4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms" is preferably a "4-6 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms," more preferably a "4-6 member monocyclic saturated heterocyclic group containing 1 oxygen atom," and even more preferably a "5 member monocyclic saturated heterocyclic group containing 1 oxygen atom."

[0049] R 3 The "C1-C6 alkoxy group which may have substituents" shown is preferably a substituent R C A C1-C6 alkoxy group which may have "a 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms", More preferably, substituent R CIt may be a C1-C4 alkoxy group having a "4- to 6-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom", More preferably, the substituent R C It may be a C1-C4 alkoxy group having a "4- to 6-membered monocyclic saturated heterocyclic group containing 1 oxygen atom", More preferably, it is a methoxy group, an ethoxy group, a tetrahydrofuranylmethoxy group, a tetrahydropyranylmethoxy group, a tetrahydrofuranylethoxy group, or a tetrahydropyranylethoxy group. More preferably, it is an ethoxy group or a tetrahydrofuranylmethoxy group.

[0050] The number of substituents is not particularly limited, but is preferably 0 to 3, and more preferably 0 to 2. R 3 Examples of the "substituent" when each group represented by has a substituent include those described above, and the number thereof is typically 1, 2, or 3.

[0051] R 3 Examples of the "C1-C6 alkoxy group which may have a substituent" represented by include those described above, Preferably, it is a C1-C4 alkoxy group, More preferably, it is a methoxy group or an ethoxy group.

[0052] In one embodiment, the compound represented by the general formula (I) or a salt thereof is R 1 is a C1-C6 alkoxyalkyl group, R 2 is a C3-C5 cycloalkyl group which may have a substituent R A and R 3 is hydrogen, a C2-C6 alkynyl group which may have a substituent R B or a C2-C6 alkynyl group which may have a substituent R CThis is a C1-C6 alkoxy group that may have a .

[0053] In one embodiment, a compound represented by general formula (I) or a salt thereof is, R 1 However, it is a C1-C3 alkoxyalkyl group, R 2 However, substituent R A A C3 cycloalkyl group which may have, R 3 but, Substituent R B A C2-C3 alkynyl group which may have, Substituent R C It is a C1-C2 alkoxy group which may have a .

[0054] In one embodiment, a compound represented by general formula (I) or a salt thereof is R 1 However, it is a methoxymethyl group, R 2 However, it is a methylcyclopropyl group, R 3 However, hydrogen, A propynyl group which may be substituted with a morpholino group, a dimethylamino group, a piperidinyl group, a pyrrolidinyl group, a branched propanol group, or a 3-thiomorphonyl group. Ethynyl groups which may be substituted with 1,3-dimethylpyrazolyl group, 1-methylpiperidinyl group, 1-methylpyrazolyl group, 1-methylimidazolyl group, pyridinyl group, or 6-aminopyridinyl group. Ethoxy group, or Tetrahydrofuranylmethoxy group That is the case.

[0055] In one embodiment, a compound represented by general formula (I) or a salt thereof is, R 1 However, it is a methoxymethyl group, R 2 However, it is a methylcyclopropyl group, R 3 but, A propynyl group which may be substituted with a morpholino group, a dimethylamino group, a piperidinyl group, a pyrrolidinyl group, a branched propanol group, a 3-thiomorpholino group, or a tetrahydropyranyl group. Ethynyl group which may be substituted with a 1,3-dimethylpyrazolyl group, a 1-methylpiperidinyl group, a 1-methylpyrazolyl group, a 1-methylimidazolyl group, a pyridinyl group, a 6-aminopyridinyl group, or a tetrahydropyranyl group. Ethoxy group, or Tetrahydrofuranylmethoxy group That is the case.

[0056] In one embodiment, a compound represented by general formula (I) or a salt thereof is, R 1 However, it is a methoxymethyl group, R 2 However, it is a methylcyclopropyl group, R 3 but, A propynyl group which may be substituted with a morpholino group, a dimethylamino group, or a pyrrolidinyl group. Ethynyl group which may be substituted with a 1,3-dimethylpyrazolyl group, a 1-methylpyrazolyl group, a pyridinyl group, or a tetrahydropyranyl group. Ethoxy group That is the case.

[0057] In one embodiment, a compound represented by general formula (I) or a salt thereof is: (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethinyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidine-4-yl)ethinyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (7)(R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazole-5-yl)ethinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (14) 4-amino-6-(4-hydroxy-4-methylpentin-1-tin-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)propyl-1-pin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (17) 4-Amino-6-[(6-aminopyridine-3-yl)ethinyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide Or its salt.

[0058] In one embodiment, a compound represented by general formula (I) or a salt thereof is: (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethinyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethinyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethinyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide Or its salt.

[0059] Furthermore, the present invention relates to a method for treating a subject having a tumor, comprising administering a RET inhibitor containing compound (I) or a salt thereof (for example, a compound or a salt thereof described as an active ingredient of any of the brain-penetrating antitumor agents described in any of [1] to [9] above; the same applies hereinafter) as an active ingredient, or a brain-penetrating antitumor agent containing an effective amount of compound (I) or a salt thereof, to a subject in need of treatment; and a commercial package containing compound (I) or a salt thereof as an active ingredient, together with instructions for its use in treating a tumor in a subject with the brain-penetrating antitumor agent. ; A brain-penetrating antitumor agent for treating tumors with enhanced RET activation, comprising compound (I) or a salt thereof as an active ingredient; a method for treating a subject having a tumor with enhanced RET activation, comprising administering an effective amount of a brain-penetrating antitumor agent containing compound (I) or a salt thereof to the subject; a commercial package, etc., containing a compound or a salt represented by compound (I) or a salt thereof as an active ingredient, along with instructions for use in treating tumors with enhanced RET activation in a subject with a brain-penetrating antitumor agent. To provide.

[0060] Compound (I) and its salts can be prepared by known organic synthesis methods. For example, they can be prepared in accordance with the method described in International Publication WO2017 / 146116, etc.

[0061] If compound (I) has isomers such as optical isomers, stereoisomers, rotational isomers, or tautomers, then unless otherwise specified, all isomers and mixtures thereof are included in compound (I). For example, if compound (I) has optical isomers, then unless otherwise specified, the racemate and the optical isomers separated from the racemate are also included in compound (I).

[0062] A salt of compound (I) refers to a pharmaceutically acceptable salt, and may include a base addition salt or an acid addition salt.

[0063] "Pharmacologically acceptable salt" means a salt of a compound that has the desired pharmacological activity and is prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids.

[0064] 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, p-toluenesulfonic acid, and glutamic acid; salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; 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.

[0065] Compound (I) or its salts also include its prodrugs. A prodrug is a compound that is converted to compound (I) or its salts by reactions with enzymes, gastric acid, etc., under physiological conditions in the body; that is, a compound that changes to compound (I) or its salts by enzymatic oxidation, reduction, hydrolysis, etc., or a compound that changes to compound (I) or its salts by hydrolysis, etc., due to gastric acid, etc. It may also be a compound that changes to compound (I) or its salts under physiological conditions as described on pages 163 to 198 of Volume 7, Molecular Design, of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0066] Compound (I) or its salt may be amorphous (non-crystalline) or crystalline, and its crystalline form may be single or polymorphic mixture, both of which are included in Compound (I) or its salt. Crystals can be produced by crystallization using known crystallization methods. Compound (I) or its salt may be a solvate (e.g., hydrate) or a solvate, both of which are included in Compound (I) or its salt. Isotopes (e.g., 3 H, 14 C, 35 S, 125Compounds labeled with (I, etc.) are also included in compound (I) or its salt. Multiple crystals (crystalline polymorphs) with spatially regular atomic arrangements and different physicochemical properties may be formed, but the salt according to the present invention may be any of these crystalline polymorphs, a mixture of two or more crystalline polymorphs, or even a mixture of crystals and amorphous materials.

[0067] In this specification, the term “effective amount” of compound (I) means the amount of compound (I) that is therapeutically effective in causing a target biological or medical response, such as a decrease or inhibition of enzyme or other protein activity, or improving symptoms, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease. In this specification, “treatment” includes adjuvant chemotherapy administered after surgical removal of a tumor to prevent recurrence, and adjuvant chemotherapy administered prior to surgical removal of a tumor.

[0068] In this specification, the term “subject” encompasses both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish, and reptiles. In one embodiment, the subject may be a mammal, particularly a human, who has been diagnosed as requiring treatment for one of the symptoms, conditions, or diseases disclosed herein. The age of the person to whom the therapeutic agent of the present invention is administered is not particularly limited. The therapeutic agent of the present invention can be used not only in adults, but also in the elderly or children.

[0069] Compound (I) or its salts are useful as pharmaceuticals for the prevention and / or treatment of RET-related diseases due to their excellent RET inhibitory activity. "RET-related diseases" refer to diseases in which the incidence is reduced, symptoms are relieved, alleviated, and / or cured by the elimination, suppression, and / or inhibition of RET function. Examples of such diseases include, but are not limited to, malignant tumors. Malignant tumors are preferably malignant tumors in which the RET activation state is enhanced, and more preferably 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 in which the RET activation state is enhanced, and even more preferably salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, and brain tumors. More preferably, these are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumors.

[0070] Increased RET activation refers to a state in which the RET gene is activated due to translocation, mutation (including point mutations, deletion mutations, and insertion mutations), or overexpression (including an increase in the copy number of the RET gene, overexpression of RET messenger RNA, an increase in RET protein, or a state in which the RET protein is constitutively activated). There are no particular restrictions on the types of cancers and tumors covered, but examples include epithelial cancers (respiratory cancers, digestive cancers, reproductive cancers, endocrine cancers, etc.), sarcomas, hematopoietic cell tumors, central nervous system tumors, and peripheral nerve tumors.

[0071] 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 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, endometrial cancer, etc.), kidney cancer, renal pelvis and ureteral 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. Preferably, 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. Preferably, the cancers 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. More preferably, the cancers 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 preferably, the cancers are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumors.

[0072] In a typical embodiment of the present invention, compound (I) passes through the blood-brain barrier (BBB) ​​to exert its effect, and the target tumor is a brain tumor. In the present invention, brain tumors include primary brain tumors and metastatic brain tumors. Primary tumors are not particularly limited to the following, but include gliomas, primary central nervous system lymphomas, meningiomas, pituitary adenomas, schwannomas, craniopharyngiomas, etc. Furthermore, among metastatic brain tumors, the type of tumor that was the primary site is not limited. In the case of metastatic brain tumors, the type of primary tumor is not limited, but 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 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, endometrial cancer, etc.), kidney cancer, renal pelvis and ureteral cancer, bladder cancer, prostate cancer, testicular tumors, leukemia, malignant lymphoma, multiple myeloma, bone and soft tissue tumors, skin cancer, malignant melanoma, and adrenal tumors. Preferably, the cancers 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. More preferably, the cancers 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 preferably, the cancers are non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, and brain tumors.

[0073] The therapeutic agent of the present invention can be provided as an active ingredient alone. Furthermore, the therapeutic agent of the present invention may also contain, as necessary, a pharmaceutically acceptable carrier or the like, in addition to the active ingredient compound (I) or a salt thereof. Thus, the therapeutic agent of the present invention can be prepared as a pharmaceutical composition consisting of one component or containing two or more components. One embodiment of the present invention provides a pharmaceutical composition containing compound (I) or a salt thereof. A pharmaceutical composition of one embodiment of the present invention comprises compound (I) or a salt thereof and a pharmaceutically acceptable carrier. Another embodiment of the present invention provides the use of compound (I) or a salt thereof for producing a therapeutic agent or pharmaceutical composition. Another embodiment of the present invention provides compound (I) or a salt thereof for use as a therapeutic agent or pharmaceutical.

[0074] The therapeutic agent of the present invention can be manufactured in various dosage forms by known methods using a pharmaceutically acceptable carrier as needed. The dosage form may be either oral or parenteral. There are no particular limitations on such dosage forms, and examples include oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions, and parenteral preparations such as injections, suppositories, and inhalants.

[0075] When forming the tablets, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid are used as pharmaceutically acceptable carriers; binders such as water, ethanol, propanol, corn starch, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, and polyvinylpyrrolidone are used; and dried starch and sodium alginate are used. Disintegrants such as agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, and lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as refined talc, stearate, boric acid powder, and polyethylene glycol can be used. Furthermore, tablets can be coated with a conventional coating as needed, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multi-layer tablets.

[0076] When forming the product into pill form, pharmaceutically acceptable carriers such as excipients including glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminaran and agar can be used. Capsules are prepared by mixing the product with the various pharmaceutically acceptable carriers exemplified above according to conventional methods and filling them into hard gelatin capsules, soft capsules, etc.

[0077] When preparing an oral liquid formulation, pharmaceutically acceptable carriers such as flavoring / odorizing agents, buffers, and stabilizers can be used, and oral liquids, syrups, elixirs, etc., can be manufactured by conventional methods. Examples of flavoring / odorizing agents include sucrose, orange peel, citric acid, and tartaric acid; examples of buffers include sodium citrate; and examples of stabilizers include tragacanth, gum arabic, and gelatin.

[0078] When forming the suppository form, pharmaceutically acceptable carriers such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides can be used.

[0079] When prepared as an injectable preparation, the solution, emulsion, and suspension are preferably sterilized and isotonic with blood. Furthermore, when forming these forms, a diluent can be used as a pharmaceutically acceptable carrier. Examples of such diluents include water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, macrogol, ethoxylated isostearyl alcohol, polyoxyethylene-modified isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.

[0080] In this case, the pharmaceutical preparation may contain a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and ordinary solubilizers, buffers, analgesics, etc., may also be added.

[0081] When used as an inhalant, various forms can be used, such as aerosols, powdered inhalants, and liquid inhalants.

[0082] Furthermore, each of the above-mentioned formulations may contain, as necessary, colorants, preservatives, fragrances, flavorings, sweeteners, and / or other pharmaceuticals as pharmaceutically acceptable carriers.

[0083] In the present invention, the daily dose refers to the amount of the active ingredient administered per day. In the therapeutic agent of the present invention, the daily dose of compound (I) or its salt on the day of administration varies depending on the patient's symptoms, weight, age, sex, etc., and cannot be determined in general. For example, as compound (I), a typical adult (weight 50 kg) is preferably 10 to 2000 mg / day, more preferably 20 to 1500 mg / day, and even more preferably 40 to 1200 mg / day.

[0084] Furthermore, the amount of compound (I) to be included in each of the above-mentioned dosage units is not fixed and depends on the symptoms of the patient to whom it is administered, or on the dosage form, etc. Generally, it is desirable to include 0.05 to 1000 mg per dosage unit for oral preparations, 0.01 to 500 mg for injectable preparations, and 1 to 1000 mg for suppositories.

[0085] The method of administering the therapeutic agent of the present invention is determined appropriately according to the various formulation forms, the patient's age, sex, other conditions, the severity of the patient's symptoms, etc. The method of administering the therapeutic agent of the present invention is not limited, but because the active ingredient, compound (I) or its salt, exhibits good brain penetration, it is preferable to use an administration method that allows it to penetrate to the brain via the systemic blood flow. Examples of administration methods for the therapeutic agent of the present invention include oral administration, intravenous administration, intra-arterial, intramuscular, intradermal, subcutaneous or intraperitoneal administration, and rectal administration. Furthermore, in the present invention, at least two of these administration methods may be combined. For example, tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions are administered orally. Injectable preparations are administered intravenously alone or mixed with conventional infusion fluids such as glucose and amino acids, and further administered alone intra-arterial, intramuscular, intradermal, subcutaneous or intraperitoneal as needed. Suppositories are administered rectally.

[0086] In the present invention, "instructions" refers to, but is not particularly limited to, a package insert provided with a drug, which is an instructions document displayed electronically and includes a barcode or two-dimensional code on the box for storing the drug to access the instructions document.

[0087] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Furthermore, all references and publications mentioned herein, regardless of their purpose, shall be incorporated herein by reference in their entirety. Furthermore, the object, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description herein, and those skilled in the art will be able to easily implement the present invention from the description herein. The best mode for carrying out the invention and specific examples are provided for illustrative or explanatory purposes only and do not limit the present invention to them. It will be apparent to those skilled in the art that various modifications can be made based on the description herein, within the intent and scope of the present invention disclosed herein. [Examples]

[0088] In the following examples, percentages (%) indicate mass percentages unless otherwise specified. Unless otherwise specified, the reagents used in the examples were commercially available products. The meanings of the abbreviations are shown below. PBS: Phosphate-buffered saline LC-MS / MS: Liquid Chromatography Tandem Mass Spectrometer HPMC: Hydroxypropylmethylcellulose

[0089] Test Example 1: Evaluation of plasma protein binding and brain protein binding The compounds shown in Tables 1-4 were added to mouse plasma to a final concentration of 1 μmol / L. The resulting compound-added mouse plasma was added to the donor side of an equilibrium dialysis device (HTDialysis) equipped with an equilibrium dialysis membrane. The same amount of PBS was added to the receiver side of the device, and after incubation for 6 hours in a 10% CO2 incubator, the compounds on both the donor and receiver sides were detected by LC-MS / MS. The non-binding rate of the compounds to plasma proteins was calculated from the ratio of the compound peak areas on the receiver side to those on the donor side. The non-binding rate of the compound to brain proteins was calculated in the same manner as described above, except that the compound was added to mouse brain homogenate instead of mouse plasma, and the dilution ratio was taken into consideration when calculating the non-binding rate. Here, the mouse brain homogenate was obtained by adding three times the amount of PBS to mouse brain and then homogenizing it using an ultrasonic homogenizer.

[0090] Test Example 2: Evaluation of Brain Transition The compounds shown in Tables 1-4 were dissolved or suspended in 0.5% HPMC and 0.1N hydrochloric acid solution and administered orally as a single dose to BALB / cAJcl-nu / nu mice (Claire Japan Co., Ltd.) that were untreated, subcutaneously transplanted with TT cells, or subcutaneously transplanted with the BaF3 / KIF5B-RET_RFP cell line. One hour after oral administration, blood was collected from the inferior vena cava under isoflurane anesthesia, and the whole brain was excised to obtain blood and brain samples. The obtained blood samples were centrifuged to obtain plasma samples. Three times the volume of water was added to the obtained brain samples, and homogenization was performed using an ultrasonic homogenizer to obtain brain homogenates. The compound concentrations in the obtained plasma and brain homogenates were measured by LC-MS / MS, and the brain compound concentration was calculated by multiplying by a coefficient of 4. The Kp value was calculated from the brain / plasma compound concentration ratio. The unbound compound concentrations in plasma and brain were calculated from the plasma protein unbound rate and brain protein unbound rate of each compound obtained in Test Example 1, and the Kp,uu values ​​were calculated from the brain / plasma unbound compound concentration ratio. Brain permeability was evaluated from the calculated Kp values ​​and Kp,uu values ​​(Tables 1-4). Specifically, a Kp value of 0.1 or higher was judged to indicate brain permeability, and a Kp,uu value of 0.3 or higher was judged to indicate good brain permeability (Varadharajan, S., et al. (2015) J Pharm Sci 104, 1197-1206). In Table 4, "N / A" for Kp,uu values ​​means that it was not measured.

[0091] The results shown in Tables 1-4 indicate that compound (I) exhibited high Kp and Kp,uu values, demonstrating good brain permeability.

[0092] [Table 1] [Table 2] [Table 3] [Table 4]

[0093] Test Example 3: Evaluation of drug efficacy in a brain tumor transplantation model. Antitumor evaluations were performed in a model in which tumors were transplanted into the brain. The compounds shown in Examples 2 and 4 (Table 1) and Example 13 (Table 3) were confirmed to have inhibitory effects on the growth of the transplanted tumors. To confirm the growth inhibitory effect, NIH / 3T3 cells (NIH / 3T3_CCDC6-RET cells) in which luciferase and CCDC6-RET fusion protein were forcibly expressed via gene transfer were used. Six-week-old male nude mice (BALB / cAJcl-nu / nu, CLEA Japan) were fixed to a stereotactic device, and 2.5 × 10⁶ cells were placed per mouse at a location 0.5 mm anterior to the bregma, 2–2.2 mm to the right, and 3.5 mm deep. 4 Individual cells were transplanted. Day 0 was designated as the transplantation day, and on Day 4, luciferin (150 mg / kg) was administered intraperitoneally. Luminescence (photons / sec) was measured using the IVIS Imaging System (Lumina II, PerkinElmer). Based on the measured luminescence, animals were assigned to four groups (N=10) so that the average luminescence in each group was similar (the Control group was evaluated as N=9 due to one accidental death). The compound was administered twice daily for 16 consecutive days starting the following day (Day 5). The compound was suspended in 0.5% HPMC / 0.1N hydrochloric acid and administered orally at a dose of 50 mg / kg / day. To confirm tumor growth, the amount of luminescence was measured at intervals of 3 or 4 days using the method described above. The tumor growth inhibitory effect of the compound was confirmed on the day following the final administration (Day 21). However, since a humane endpoint based on tumor growth was applied in the control group (no drug administration), statistical evaluation was performed using Dunnett's test with the measurements taken on Day 14.

[0094] Figure 1 shows the temporal changes in luminescence, and Figure 2 shows the changes in body weight. In the control group, an increase in luminescence was observed, suggesting that the transplanted tumor had grown. In addition, weight loss was observed, which is thought to be due to tumor growth. By Day 19, all animals had shown weight loss, and it was determined that it was impossible to continue the study, so the humanitarian endpoint was applied. On the other hand, in the compound administration groups, no significant increase in luminescence was observed with any of the compounds, suggesting that tumor growth was suppressed. Statistical analysis of luminescence at Day 14 showed a significant difference (*: p<0.05) in all compound administration groups compared to the control group. From this, it was considered that compound administration had a significant inhibitory effect on tumor growth. Furthermore, in the compound administration groups, all animals were able to complete administration until Day 22, suggesting that compound administration may also have a life-extending effect. These results suggest that administering compounds that exhibit brain penetration significantly suppresses the proliferation of tumor cells transplanted into the brain, and that a life-extending effect can also be expected.

Claims

1. The following general formula (I) 【Chemistry 1】 (In the formula, R １ It is a C1-C6 alkoxyalkyl group, R ２ This is a C3-C5 cycloalkyl group which may have substituents. R ３ is hydrogen, A C2-C6 alkynyl group which may have substituents, or A brain-penetrating antitumor agent comprising a compound represented by (which may have substituents, a C1-C6 alkoxy group) or a salt thereof as an active ingredient.

2. The following general formula (I) as the active ingredient 【Chemistry 2】 (In the formula, R1 is a C1-C6 alkoxyalkyl group, R2 is a C3-C5 cycloalkyl group which may have substituents. R3 is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) A commercial package comprising a compound represented by or a salt thereof, along with instructions for its use in treating tumors in a subject with a brain-penetrating antitumor agent.

3. R ２ A substituent of a C3-C5 cycloalkyl group which may have substituents shown by, (1-1) C1-C2 alkyl groups The brain-penetrating antitumor agent according to claim 1, or the commercial package according to claim 2.

4. R ２ The brain-penetrating antitumor agent according to claim 1, the commercial package according to claim 2, or the brain-penetrating antitumor agent or commercial package according to claim 3, wherein the C3-C4 cycloalkyl group may have a methyl group as a substituent.

5. R ３ A substituent of a C2-C6 alkynyl group which may have substituents shown by, (2-1) an amino group which may have a substituent; (2-2) C1-C6 alkyl groups which may have substituents; (2-3) A 4-10 member monocyclic saturated heterocyclic group comprising 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents; or, (2-4) A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents. The brain-penetrating antitumor agent according to claim 1, the commercial package according to claim 2, or the brain-penetrating antitumor agent or commercial package according to claim 3 or 4.

6. R ３ A substituent of a C1-C6 alkoxy group which may have substituents shown in, (3-1) Amino group; (3-2) C1-C6 alkyl groups which may have a hydroxyl group; (3-3) A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups; or (3-4) A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups. The brain-penetrating antitumor agent according to claim 1, the commercial package according to claim 2, or the brain-penetrating antitumor agent or commercial package according to any one of claims 3 to 5.

7. R １ is a C1-C6 alkoxy C1-C6 alkyl group R ２ is a C3-C5 cycloalkyl group which may have a C1-C2 alkyl group as a substituent, R ３ but, A C2-C6 alkynyl group which may have substituents; or C1-C6 alkoxy groups which may have substituents The antitumor agent according to claim 1, the commercial package according to claim 2, or the brain-penetrating antitumor agent or commercial package according to any one of claims 3 to 6. (R ３ A substituent of a C2-C6 alkynyl group which may have substituents shown by, amino group; A C1-C6 alkyl group may have at least one substituent selected from the group consisting of a hydroxyl group, an amino group, and a cyano group; A 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups; or, The substituent may be at least one selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups, and is a 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. R ３ A substituent of a C1-C6 alkoxy group which may have substituents shown in, amino group; C1-C6 alkyl groups which may have hydroxyl groups; A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups; or A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups. (That is the case.)

8. A compound represented by general formula (I) or a salt thereof, (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidine-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (7) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazole-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (14) 4-amino-6-(4-hydroxy-4-methylpentin-1-tin-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)propyl-1-pin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (17) 4-amino-6-[(6-aminopyridine-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide The brain-penetrating antitumor agent according to claim 1, or a salt thereof, the commercial package according to claim 2, or the brain-penetrating antitumor agent or commercial package according to any one of claims 3 to 7.

9. A compound represented by general formula (I) or a salt thereof, (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide The brain-penetrating antitumor agent according to claim 1, or a salt thereof, the commercial package according to claim 2, or the brain-penetrating antitumor agent or commercial package according to any one of claims 3 to 8.

10. A brain-penetrating antitumor agent according to claim 1, a commercial package according to claim 2, or a brain-penetrating antitumor agent or commercial package according to any one of claims 3 to 9, for the treatment of primary or metastatic brain tumors.

11. A brain-penetrating antitumor agent according to claim 1, a commercial package according to claim 2, or a brain-penetrating antitumor agent or commercial package according to any one of claims 3 to 10, for treating a tumor in which the RET activation state is enhanced.

12. The following general formula (I) for manufacturing brain-penetrating antitumor agents 【Transformation 3】 (In the formula, R １ It is a C1-C6 alkoxyalkyl group, R ２ This is a C3-C5 cycloalkyl group which may have substituents. R ３ is hydrogen, A C2-C6 alkynyl group which may have substituents, or (This is a C1-C6 alkoxy group that may have substituents.) Use of a compound represented by or a salt thereof.

13. A substituent of a C3-C5 cycloalkyl group which may have substituents represented by R2, (1-1) C1-C2 alkyl groups The use described in claim 12.

14. The use according to claim 12 or 13, wherein R2 is a C3-C4 cycloalkyl group which may have a methyl group as a substituent.

15. A substituent of the C2-C6 alkynyl group which may have substituents represented by R3, (2-1) an amino group which may have a substituent; (2-2) C1-C6 alkyl groups which may have substituents; (2-3) A 4-10 member monocyclic saturated heterocyclic group comprising 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents; or, (2-4) A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have substituents. The use according to any one of claims 12 to 14.

16. A substituent of the C1-C6 alkoxy group which may have substituents represented by R3, (3-1) Amino group; (3-2) C1-C6 alkyl groups which may have a hydroxyl group; (3-3) A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups; or (3-4) A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups. The use according to any one of claims 12 to 15.

17. R1 is a C1-C6 alkoxy C1-C6 alkyl group R2 is a C3-C5 cycloalkyl group which may have a C1-C2 alkyl group as a substituent. R 3 is, A C2-C6 alkynyl group which may have substituents; or C1-C6 alkoxy groups which may have substituents The use according to any one of claims 12 to 16. (The substituent of the C2-C6 alkynyl group may have the substituent represented by R3, amino group; A C1-C6 alkyl group may have at least one substituent selected from the group consisting of a hydroxyl group, an amino group, and a cyano group; A 4-10 member monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups; or, The substituent may be at least one selected from the group consisting of C1-C6 alkyl groups, hydroxyl groups, amino groups, and cyano groups, and is a 4- to 10-membered monocyclic unsaturated heterocyclic group containing 1 to 3 homogeneous or heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms. A substituent of the C1-C6 alkoxy group which may have substituents represented by R3, amino group; C1-C6 alkyl groups which may have hydroxyl groups; A 4-10 membered monocyclic saturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups; or A 4-10 member monocyclic unsaturated heterocyclic group containing 1-3 homogeneous or heteroatoms selected from nitrogen, oxygen, and sulfur atoms, which may have at least one substituent selected from the group consisting of methyl, ethyl, and amino groups. (That is the case.)

18. A compound represented by general formula (I) or a salt thereof, (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (3) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidine-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (7) (R)-4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydrofuran-2-yl)methoxy)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (8) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (10) 4-amino-N-(4-(methoxymethyl)phenyl)-6-((1-methyl-1H-imidazole-5-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (11) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(piperidine-1-yl)propyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (14) 4-amino-6-(4-hydroxy-4-methylpentin-1-tin-1-yl)-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (15) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[3-(tetrahydro-2H-pyran-4-yl)propyl-1-pin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (17) 4-amino-6-[(6-aminopyridine-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (18) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide The use according to any one of claims 12 to 17, or a salt thereof.

19. A compound represented by general formula (I) or a salt thereof, (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazole-4-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (2) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-morpholinopropyl-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (4) 4-amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazole-4-yl)ethynyl)-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (5) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (6) 4-amino-6-[3-(dimethylamino)propyl-1-pin-1-yl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (9) 4-amino-6-ethoxy-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (12) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrroridine-1-yl)pro-1-pin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (13) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-((tetrahydro-2H-pyran-4-yl)ethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (16) 4-amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridine-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide The use according to any one of claims 12 to 18, or a salt thereof.

20. The use according to any one of claims 12 to 19 for producing a brain-penetrating antitumor agent for the treatment of primary or metastatic brain tumors.

21. The use according to any one of claims 12 to 20 for producing a brain-penetrating antitumor agent for treating tumors in which the RET activation state is enhanced.

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