HK40098704A - Brain-migrating tumor therapeutic agent containing fused pyrimidine compound as active ingredient - Google Patents

Description

Brain transitional tumor therapeutic agents containing fused pyrimidine compounds as active ingredients

Technical Field

Cross-references to related applications

This application claims priority to Japanese Patent Application No. 2020-193073, filed on November 20, 2020, the entire contents of which are incorporated herein by reference.

This invention relates to an antitumor agent.

Background Technology

Brain tumors are a type of brain disease, referring to tumors that occur in the intracranial tissue. Brain tumors can be divided into primary brain tumors, which originate from brain cells, and metastatic brain tumors, which are cancers such as lung cancer or breast cancer that have spread to the brain. It has been reported that symptomatic metastatic brain tumors occur in 8–10% of cancer patients, and other reports indicate that, based on autopsy results, the frequency of brain metastasis in lung cancer is 40–50% (Non-Patent Literature 1–3). Known primary sites for metastatic brain tumors include lung cancer, breast cancer, gastrointestinal cancer (stomach cancer), malignant melanoma, kidney cancer, and urinary tract cancer, among others, with lung cancer accounting for approximately half of brain metastases (Non-Patent Literature 2). Treatment methods for metastatic brain tumors vary depending on the patient's overall condition, tumor size, and number of metastatic lesions. Treatment methods include radiotherapy, surgery, drug therapy, or combinations thereof. For example, surgery is usually chosen in cases where the primary site is under control, the brain tumor to be treated is solitary, and a certain survival rate is expected. However, tumors that metastasize to the brain are often intricately intertwined with the brain parenchyma and/or cranial nerve tissue, making complete surgical removal of the tumor often impossible. For radiotherapy, two treatment methods are known: quantitative radiosurgery (e.g., Gamma Knife therapy) and whole-brain irradiation, which involves irradiating the entire brain with radiation. Currently, in most cases, the treatment of metastatic brain tumors is a combination of surgery and radiotherapy, but it is difficult to say that sufficient therapeutic efficacy is achieved (Non-Patent Literature 4 and 5). Generally, the central nervous system (CNS), including the brain, is protected by a highly specialized layer of tightly bound cells known as the blood-brain barrier (BBB), which prevents harmful substances from entering. Many diseases associated with the CNS have yet to have effective drugs, partly because almost all therapeutic molecules, including antibodies, cannot cross the BBB. Low molecular weight compounds are no exception; in fact, it has been reported that over 98% of low molecular weight compounds cannot cross the BBB (Non-Patent Literature 6). Currently, while many compounds have shown efficacy against peripheral carcinomas (primary lesions), their efficacy against brain metastases is limited. One possible reason is that these compounds cannot reach the brain in sufficient quantities to exert their effects, thus failing to achieve the same efficacy as the primary lesion (Non-Patent Literature 7 and 8). Therefore, in CNS-related diseases and brain tumors, there is a desire to develop low-molecular-weight compounds with high brain penetration and methods for achieving this penetration. In particular, in the treatment of metastatic brain tumors, there is a need to develop drugs that show efficacy against the primary site (e.g., lung cancer) and high CNS penetration, thereby also showing efficacy against brain metastases.

For example, numerous compounds have shown therapeutic effects at the primary lesion site, one example being compounds with RET inhibitory activity. Here, RET is a receptor tyrosine kinase identified as one of the proto-oncogenes. RET binds to glial cell line-derived neurotrophic factor (GDNF) and its receptor to form a complex, enabling RET to exert its physiological functions through intracellular phosphorylation signaling (Non-Patent Literature 9). One study reported that in normal tissues, RET contributes to kidney development and neurogenesis during fetal development (Non-Patent Literature 10). Some studies have shown that in cancers such as lung cancer, thyroid cancer, breast cancer, pancreatic cancer, and prostate cancer, RET translocation, mutation, and overexpression enhance its activation, thereby promoting cell growth, tumor formation, or tissue invasion (Non-Patent Literature 11–16). In addition, RET is known to be a factor of poor cancer prognosis. As has been reported, the degree of RET translocation and enhanced activation in cancer caused by this is inversely proportional to the prognosis of the cancer (Non-Patent Literature 17-19).

Therefore, inhibitors that can suppress RET activity are considered useful therapeutic agents for diseases associated with abnormal enhancement of the RET signaling pathway.

For example, it is anticipated that in cancers involving RET translocation, mutation, and overexpression, the administration of drugs that specifically inhibit RET could selectively and strongly suppress the proliferation of cancer cells, thus contributing to the treatment, life extension, and improved quality of life for cancer patients.

As compounds exhibiting RET inhibitory activity, well-known compounds have been provided, such as the known PP1 (Non-Patent Literature 20). In PP1, a p-tolyl group is bonded to a fused-ring pyrimidine backbone. 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 Literatures 22 and 23). For example, side effects resulting from Src inhibition may lead to abnormally enhanced bone formation, and side effects resulting from Lck inhibition may lead to T cell suppression (Non-Patent Literatures 24 and 25). Since multi-kinase inhibitors inhibit not only RET but also various signaling pathways, thereby inhibiting cell growth and other functions, there is concern about the potential for various side effects requiring dose reduction and/or discontinuation, which may result in insufficient RET inhibitory activity. From the perspective of reducing side effects, there is a desire for RET inhibitors that have high inhibitory activity against RET while simultaneously exhibiting low inhibitory activity against other kinases. However, to date, no agents demonstrating strong RET inhibitory effects and good brain penetration have been reported.

Reference List

Non-patent literature

[Non-patent literature 1] Qingbei Zeng, J Med Chem. 22; 58(20):8200-15, (2015).

[Non-Patent Literature 2] Lakshmi Nayak, Curr Oncol Rep; 14(1):48-54, (2012)

[Non-Patent Literature 3] Brunilde Gril, Eur J Cancer.；46(7):1204-10,(2010)

[Non-Patent Literature 4] Taofeek K. Owonikoko, Nat Rev Clin Oncol.；11(4):203-22,(2014)

[Non-Patent Literature 5] Chien-Hung Gow, Clin Cancer Res. 1; 14(1):162-8, (2008)

[Non-Patent Literature 6] William M. Pardridge, J Neurochem. 70(5):1781-92, (1998)

[Non-Patent Literature 7] Ted W. Johnson, J Med Chem. 12; 57(11):4720-44, (2014)

[Non-Patent Literature 8] Victor A. Levin, Neuro Oncol.; 17Suppl 6:vi1-26 (2015)

[Non-Patent Literature 9] Lois M. Mulligan, Nature Rev., 14(3):pp173-186, (2014)

[Non-Patent Literature 10] Carlos F. Ibanez, Cold Spring Harb Perspect Biol., 5(2):pp1-10, (2013)

[Non-patent literature 11] Takashi Kohno, Nature Med., 18(3):pp375-377, (2012)

[Non-Patent Literature 12] Massimo Santoro, Eur J Endocrinol., 155:pp645-653, (2006)

[Non-Patent Literature 13] Marjan Zarif Yeganeh, Asian Pac J Cancer Prev., 16(6):pp2107-2117, (2015)

[Non-Patent Literature 14] Albana Gattelli, EMBO Mol Med., 5: pp1335-1350, (2013)

[Non-Patent Literature 15] Yoshinori Ito, Surgery, 138:pp788-794, (2005)

[Non-Patent Literature 16] Dawn M. Dawson, J Natl Cancer Inst., 90:pp519-523, (1998)

[Non-Patent Literature 17] Weijing Cai, Cancer, 119:pp1486-1494, (2013)

[Non-Patent Literature 18] Rossella Elisei, J Clin Endocrinol Metab., 93(3):pp682-687, (2008)

[Non-Patent Literature 19] Q ZENG, J.Int.Med.Res., 36:pp656-664, (2008)

[Non-Patent Literature 20] Francesca Carlomagno, Cancer Res., 62(4):pp1077-1082, (2002)

[Non-patent literature 21] Johannes Waltenberger, Circ Res., 85(1):pp12-22, (1999)

[Non-Patent Literature 22] Louise Tatton, J Biol Chem., 278(7):pp4847-4853, (2003)

[Non-Patent Literature 23] Markus Warmuth, Blood. 101(2):pp664-672, (2003)

[Non-Patent Literature 24] Carolyn Lowe, Proc Natl Acad Sci U S A, 90(10):pp4485-9, (1993)

[Non-Patent Literature 25] Thierry Molina, Nature, 357(6374):pp161-4, (1992)

Summary of the Invention

Technical issues

One 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 a salt thereof for manufacturing a brain-penetrating antitumor agent exhibiting excellent brain penetration, RET inhibitory activity, and antitumor activity, or the use of a compound or a salt thereof for treating tumors by using a brain-penetrating antitumor agent. Yet another object of the present invention is to provide a method for treating tumors, particularly brain tumors, comprising administering a brain-penetrating antitumor agent comprising a compound or a salt thereof having RET inhibitory activity.

Problem Solution

The inventors have conducted extensive research to achieve the above objectives and have thus discovered that a fused pyrimidine compound or its salt having a specific structure and capable of selectively inhibiting RET is useful as a brain-penetrating antitumor agent. Therefore, the present invention is complete.

Specifically, the present invention includes the following embodiments.

[1] A brain-penetrating antitumor agent comprising a compound or a salt thereof represented by the following formula (I) as an active ingredient:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl groups, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[2] The brain-penetrating antitumor agent according to [1] wherein the substituted or unsubstituted C3-C5 cycloalkyl group represented by ^R2 is substituted with (1-1)C1-C2 alkyl group.

[3] The brain-penetrating antitumor agent according to [1] or [2], wherein ^R2 is a C3-C4 cycloalkyl group optionally substituted with methyl.

[4] A brain-penetrating antitumor agent according to any one of [1] to [3], wherein the substituted or unsubstituted C2-C6 alkynyl group represented by ^R3 is substituted with the following:

(2-1) Substituted or unsubstituted amino groups;

(2-2) Substituted or unsubstituted C1-C6 alkyl groups;

(2-3) Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted, 4- to 10-membered monocyclic saturated heterocyclic groups; or

(2-4) Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted 4 to 10 member monocyclic unsaturated heterocyclic groups.

[5] A brain-penetrating antitumor agent according to any one of [1] to [4], wherein the substituted or unsubstituted C1-C6 alkoxy group represented by ^R3 is substituted with the following:

(3-1)amino;

(3-2) Optionally, a C1-C6 alkyl group having 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, optionally substituted with at least one selected from methyl, ethyl, and amino groups; or

(3-4) Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with at least one selected from methyl, ethyl and amino groups, which are 4 to 10 membered monocyclic unsaturated heterocyclic groups.

[6] The brain-penetrating antitumor agent according to any one of [1] to [5], wherein,

^R1 is a C1-C6 alkoxy-C1-C6 alkyl group.

^R2 is a C3-C5 cycloalkyl group optionally substituted with a C1-C2 alkyl group, and

^R3 is

Substituted or unsubstituted C2-C6 ynyl group; or

Substituted or unsubstituted C1-C6 alkoxy groups,

Wherein, the substituted or unsubstituted C2-C6 ynyl group represented by R ³ is substituted by the following:

amino;

Optionally substituted with at least one C1-C6 alkyl group selected from hydroxyl, amino and cyano groups;

A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with at least one selected from C1-C6 alkyl, hydroxyl, amino, and cyano groups; or

Containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with at least one selected from C1-C6 alkyl, hydroxyl, amino, and cyano groups, a 4- to 10-membered monocyclic unsaturated heterocyclic group, and

R ³ represents the substituted or unsubstituted C1-C6 alkoxy group, which is substituted by the following:

amino;

C1-C6 alkyl groups optionally having hydroxyl groups;

A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with at least one selected from methyl, ethyl, and amino groups; or

It contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with at least one selected from methyl, ethyl and amino groups, forming a 4 to 10 member monocyclic unsaturated heterocyclic group.

[7] A brain-penetrating antitumor agent according to any one of [1] to [6], wherein the compound represented by formula (I) or a salt thereof is any one of the following or a salt thereof:

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-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-morpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(3) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidin-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(4) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-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-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-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-imidazol-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-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(12) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolid-1-yl)prop-1-yn-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-methylpent-1-yn-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)prop-1-yn-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(16) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(17) 4-amino-6-[(6-aminopyridin-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; and

(18) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

[8] A brain-penetrating antitumor agent according to any one of [1] to [7], wherein the compound represented by formula (I) or a salt thereof is any one of the following or a salt thereof:

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-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-morpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(4) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-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-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-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-(pyrrolid-1-yl)prop-1-yn-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; and

(16) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

[9] The brain-penetrating antitumor agent according to any one of [1] to [8] is used to treat primary or metastatic brain tumors.

[10] Use of compounds represented by the following formula (I) or salts thereof in the preparation of brain-penetrating antitumor agents:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[11] A method of treating a subject with a tumor, comprising administering to the subject in need of treatment a brain-penetrating antitumor agent comprising an effective amount of a compound represented by formula (I) below or a salt thereof:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[12] A compound or a salt thereof represented by the following formula (I) is used to treat tumors by means of a brain-penetrating antitumor agent:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[13] Use of a compound represented by the following formula (I) or a salt thereof for the treatment of tumors via the use of a brain-penetrating antitumor agent:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[14] A commercial packaging comprising:

The following formula (I) represents the compound or its salt as the active ingredient:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups; and

The instructions for use of this brain-penetrating antitumor agent for treating tumors in subjects.

[15] A brain-penetrating antitumor agent for treating tumors with enhanced RET activation state, comprising a compound or a salt thereof represented by formula (I) as an active ingredient:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[16] Use of the compound represented by the following formula (I) or a salt thereof in the preparation of a brain-penetrating antitumor agent for the treatment of tumors with enhanced RET activation state:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[17] A method of treating a subject with a tumor exhibiting enhanced RET activation, comprising administering to the subject a brain-penetrating antitumor agent comprising an effective amount of a compound or a salt thereof represented by formula (I) below:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[18] The compounds represented by the following formula (I) or salts thereof are used to treat tumors with enhanced RET activation state by the use of brain-penetrating antitumor agents:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[19] Use of compounds represented by the following formula (I) or salts thereof for the treatment of tumors with enhanced RET activation state by means of brain-penetrating antitumor agents:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups.

[20] A commercial packaging comprising:

The following formula (I) represents a compound or its salt as an active ingredient:

In the formula

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and

^R3 is hydrogen.

Substituted or unsubstituted C2-C6 ynyl group, or

Substituted or unsubstituted C1-C6 alkoxy groups; and

Instructions for use of this brain-penetrating antitumor agent for the treatment of tumors with enhanced RET activation in subjects.

Invention Effects

This invention provides a brain-penetrating antitumor agent. A preferred embodiment of the invention provides a novel therapeutic agent with RET inhibitory activity that is effective in treating brain tumors. Furthermore, the brain-penetrating antitumor agent of this invention exhibits highly selective inhibition of RET, which is expected to reduce toxicity caused by inhibition of any other kinases and is expected to have a higher therapeutic effect, thus making it useful.

Attached Figure Description

Figure 1 shows the antitumor effect of the compounds of the present invention in a brain transplantation model animal (NIH/3T3_CCDC6-RET brain transplantation model).

Figure 2 shows the rate of change in body weight of the compound of the present invention in a brain transplantation model animal (NIH/3T3_CCDC6-RET brain transplantation model).

Detailed Implementation

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

In this invention, the compound represented by formula (I) is sometimes simply referred to as compound (I).

In this invention, the term "brain-penetrating antitumor agent" refers to an antitumor agent designed to allow at least a portion of its active ingredient to penetrate into the brain to achieve a therapeutic effect.

In this specification, unless otherwise stated, examples of "substituents" include deuterium, halogens, 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 (which may have at least one selected from C1-C6 alkyl, hydroxyl, amino, and cyano groups as substituents), aromatic hydrocarbons, etc. When the above substituents are present, their number is not limited, but is typically one, two, or three. In this specification, when several substituents are present, unless otherwise stated, the substituents may be the same or different.

In this specification, when there are multiple choices of substituents for each group defined in formula (I), each group may have the same or different types of substituents unless otherwise stated. For example, unless otherwise stated, "alkyl group substituted with halogen or hydroxyl group" includes not only alkyl groups substituted with halogen alone and hydrocarbon groups substituted with hydroxyl alone, but also alkyl groups substituted with both halogen and hydroxyl groups. Furthermore, "alkyl group substituted with halogen or hydroxyl group" includes, for example, alkyl groups substituted with two or more halogen atoms (e.g., fluorine and chlorine).

In this specification, examples of "halogen" include fluorine, chlorine, bromine, and iodine.

In this specification, "alkyl" refers to a straight-chain or branched saturated hydrocarbon. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, tert-pentyl, pentyl-3-yl, n-hexyl, 1,1-dimethylpropyl, 1,1,2,2-tetramethylethyl, n-heptyl, 1,1,2,2-tetramethylpropyl, n-octyl, n-nonyl, n-decyl, etc.; and specifically includes C1-C10 alkyl, C3-C10 alkyl, C1-C6 alkyl, C1-C4 alkyl, C3-C8 alkyl, C3-C6 alkyl, etc.

In this specification, "alkoxy" refers to an oxygen group bonded to the aforementioned alkyl group. Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butanol, n-pentoxy, isopentoxy, and n-hexyloxy, and specifically include C1-C6 alkoxy and C1-C4 alkoxy.

In this specification, "alkoxyalkyl" refers to an alkyl group having one or more (e.g., 1 to 5, preferably 1 to 3, more preferably 1) of the above-mentioned alkoxy groups. Examples include methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-methoxyethyl, 1-methoxyn-propyl, 3-methoxyn-propyl, 2-ethoxyn-butyl, 4-methoxyn-butyl, 5-methoxyn-pentyl, 6-methoxyn-hexyl, etc.; and specifically includes C1-C6 alkoxyC1-C6 alkyl, C1-C4 alkoxyC1-C6 alkyl, C1-C4 alkoxyC1-C4 alkyl, etc.

In this specification, "C1-C6 alkoxyalkyl" refers to an alkyl group bonded to the aforementioned C1-C6 alkoxy groups. Examples include methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-methoxyethyl, 1-methoxyn-propyl, 3-methoxyn-propyl, 2-ethoxyn-butyl, 4-methoxyn-butyl, 5-methoxyn-pentyl, 6-methoxyn-hexyl, 8-methoxyn-octyl, etc.

In this specification, “cycloalkyl” means a monocyclic or polycyclic (e.g., bicyclic or tricyclic) saturated hydrocarbon. Examples include monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl; polycyclic cycloalkyl, such as spiro[3.3]heptyl, spiro[3.4]octyl, and dispiro[5.1.78.26]heptadecyl; and specifically includes C3-C7 cycloalkyl, C3-C5 cycloalkyl, etc.

In this specification, "aromatic hydrocarbon" refers to a cyclic substituent consisting of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) ring of carbon and hydrogen with unsaturated bonds, and including 4e+2 electrons (e being an integer greater than 1) in the cyclic π-electron system. Examples include phenyl, naphthyl, anthraceneyl, phenanthryl, fluorenyl, tetrahydronaphthyl, etc.; and specifically includes C6-C14, C6-C10, and C8-C14 aromatic hydrocarbons.

In this specification, "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon having at least one (e.g., 1 or 2, or 1) double bond. Examples include vinyl, allyl, 1-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl, 3-methyl-3-butenyl, etc.; and specifically includes C2-C6 alkenyl, C2-C4 alkenyl, etc.

In this specification, "alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon having at least one (e.g., 1 or 2, or 1) triple bond. Examples include ethynyl, 1- or 2-propynyl, 1-, 2- or 3-butynyl, 1-methyl-2-propynyl, etc.; and specifically includes C2-C6 alkynyl, C2-C4 alkynyl, etc.

In this specification, "saturated heterocyclic group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) saturated heterocyclic group having one or more (e.g., 1 to 3) identical or different heteroatoms selected from nitrogen, oxygen, and sulfur. Examples include morpholino, 1-pyrrolidinyl, 3-pyrrolidinyl, piperidinyl, piperazinyl, 4-methyl-1-piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, thiazolyl, oxazolidinyl, thiomorpholino, 7-azabicyclo[2.2.1]hept-2-yl, 2,6-dioxabicyclo[3.2.1]oct-7-yl, 7-oxabicyclo[2.2.1]heptane, etc.; and specifically includes 4- to 6-membered, 4- to 10-membered, 8- to 14-membered, and 8- to 10-membered saturated heterocyclic groups.

In this specification, "unsaturated heterocyclic group" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) heterocyclic group having one or more (e.g., 1 to 3) identical or different heteroatoms selected from nitrogen, oxygen and sulfur that are fully or partially unsaturated. Examples include imidazole, thiophene, furanyl, pyrrole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isindolyl, indolyl, triazolopyridinyl, benzimidazole, benzoxazolyl, benzothiazolyl, benzothiophene, benzofuranyl, purine, quinolinyl, isoquinolinyl, quinazolinyl, quinoxolinyl, methylenedioxyphenyl, ethyldioxyphenyl, dihydrobenzofuranyl, dihydrothiazolyl, benzothiaphene, etc., and specifically include 4-6, 4-10, 8-14, and 8-10 unsaturated heterocyclic groups.

In the description of substituents in this specification, the term "Ca-Cb" indicates a substituent having a to b carbon atoms. For example, "C1-C6 alkyl" refers to an alkyl group having 1 to 6 carbon atoms, while "C6-C14 aromatic hydrocarbon oxy" refers to an oxygen group bonded to an aromatic hydrocarbon having 6 to 14 carbon atoms. Furthermore, the term "a to b-membered" indicates that the number of atoms constituting the ring (ring members) is a to b. For example, "4 to 10-membered saturated heterocyclic group" refers to a saturated heterocyclic group having a 4 to 10-membered ring.

Specific examples of compounds used as the active ingredient in the brain-penetrating antitumor agent of the present invention include, but are not limited to, those described below. The following specific descriptions represent substituents in the formula (I), such as ^R1 , ^R2 , and ^R3 . In the description of substituents, unless otherwise stated, substituents such as ^R1 , ^R2 , and ^R3 refer to those substituents in formula (I).

^R1 is a C1-C6 alkoxyalkyl group.

Examples of “C1-C6 alkoxyalkyl” represented by R ¹ include those mentioned above, preferably C1-C4 alkoxyalkyl, and more preferably methoxymethyl.

Examples of "substituents" in "substituted or unsubstituted C3-C5 cycloalkyl" represented by R ² (in this specification, "substituents" in "substituted or unsubstituted C3-C5 cycloalkyl" represented by R ² are sometimes also referred to as "substituent ^RA ") include examples of those "substituents" mentioned above, preferably C1-C6 alkyl, more preferably C1-C3 alkyl, and even more preferably methyl.

Examples of “substituted or unsubstituted C3-C5 cycloalkyl” represented by R ² include C3-C5 cycloalkyl with or without substituent ^RA , preferably C3-C4 cycloalkyl, more preferably propyl.

Examples of “C2-C6 alkynyl” in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ include those mentioned above;

Preferably C2-C4 acetylene; and

More preferably, it is acetylene or propyne.

The number of triple bonds in the "C2-C6 alkynyl group" of "substituted or unsubstituted C2-C6 alkynyl group" is preferably 1, and the position of the triple bond is preferably set between the carbon atom bonded to the 7H-pyrrolo[2,3-d]pyrimidine skeleton and the carbon atom adjacent to that carbon atom.

Preferred examples of "substituents" in "substituted or unsubstituted C2-C6 ynylene" represented by R ³ (in this specification, "substituents" in "substituted or unsubstituted C2-C6 ynylene" represented by R ³ are sometimes also referred to as "substituent ^RB ") include:

Substituted or unsubstituted amino groups;

Substituted or unsubstituted C1-C6 alkyl groups;

It contains 4- to 10-membered monocyclic saturated heterocyclic groups with 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, whether substituted or unsubstituted.

Containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted 4 to 10 membered monocyclic unsaturated heterocyclic groups;

wait.

"Substituent ^RB " is more preferably

amino,

Substituted or unsubstituted straight-chain or branched C1-C6 alkyl groups,

Containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted, 4- to 10-membered monocyclic saturated heterocyclic groups, or

Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted, 4- to 10-membered monocyclic or polycyclic unsaturated heterocyclic groups.

Even better

amino;

Optionally substituted with at least one C1-C6 alkyl group selected from hydroxyl, amino and cyano groups;

A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with at least one selected from C1-C6 alkyl, hydroxyl, amino, and cyano groups; or

It contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with at least one selected from C1-C6 alkyl, hydroxyl, amino and cyano groups, which are 4 to 10 membered monocyclic unsaturated heterocyclic groups.

"Substituent ^RB " is even more preferred as

C1-C6 alkyl groups optionally substituted with hydroxyl groups;

A 5- or 6-membered monocyclic saturated heterocyclic group containing one or two nitrogen atoms and optionally substituted with C1-C6 alkyl groups; or

It contains one or two identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with at least one of C1-C6 alkyl and amino groups, which are 5- or 6-membered monocyclic unsaturated heterocyclic groups.

As an example of a substituent (substituent R ^B ) in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ , preferred examples of “substituent” in the above-mentioned “substituted or unsubstituted amino” include C1-C6 alkyl, hydroxyl, etc.

As an example of a substituent (substituent R ^B ) in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ , preferred examples of “substituent” in the above-mentioned “substituted or unsubstituted C1-C6 alkyl” include hydroxyl, C1-C6 alkoxy, and oxo, and hydroxyl is preferred.

As an example of a substituent (substituent R ^B ) in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ , in the above-mentioned “substituted or unsubstituted straight-chain or branched C1-C6 alkyl”, “C1-C6 alkyl” is preferably branched C1-C6 alkyl, and more preferably branched C3-C6 alkyl.

As an example of a substituent (substituent R ^B ) in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ , the above-mentioned example of “substituted or unsubstituted C1-C6 alkyl” preferably includes hydroxybutyl.

As an example of a substituent (substituent R ^B ) in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ , a preferred example of the “substituent” in the above-mentioned “substituent containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur substituted or unsubstituted 4 to 10 membered monocyclic saturated heterocyclic groups” includes C1-C6 alkyl, hydroxyl, amino and cyano, preferably C1-C6 alkyl, more preferably methyl.

As an example of a substituent (substituent R ^B ) in "substituted or unsubstituted C2-C6 ynyl group" represented by R ³ , the above-mentioned "substituted or unsubstituted 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur":

Preferably, it contains "4-6 membered monocyclic saturated heterocyclic groups, which are substituted or unsubstituted, and contain 1-2 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur".

More preferably, it is "a substituted or unsubstituted 4- to 6-membered monocyclic saturated heterocyclic group containing 1 to 2 nitrogen atoms" (when the group has a substituent, the substituent is methyl).

Even more preferred are substituted or unsubstituted morpholino, tetrahydrofurano, tetrahydropyrano, piperazine, pyrrolidinyl, piperidinyl, thiomorpholino, or oxecyclobutane (when the group has a substituent, the substituent is methyl, ethyl, or amino).

Furthermore, it is more preferably substituted or unsubstituted morpholino, tetrahydrofurano, tetrahydropyrano, piperazine, pyrrolidinyl, piperidinyl, or thiomorpholino (when the group has a substituent, the substituent is preferably methyl or ethyl, more preferably methyl).

As an example of the substituent ^RB , in the above-mentioned "4-10 member monocyclic saturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, whether substituted or unsubstituted", the number of substituents is not particularly limited, but is preferably 0 to 3, and more preferably 0 to 2.

As an example of a substituent (substituent R ^B ) in “substituted or unsubstituted C2-C6 alkynyl” represented by R ³ , a preferred example of the “substituent” in the above-mentioned “substituent containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur substituted or unsubstituted 4 to 10-membered monocyclic unsaturated heterocyclic groups” includes C1-C6 alkyl, amino, hydroxyl and cyano, preferably C1-C6 alkyl or amino, and more preferably methyl or amino.

The phrase "containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted, 4- to 10-membered monocyclic unsaturated heterocyclic groups" refers to:

Preferably, it contains "4-10 membered monocyclic unsaturated heterocyclic groups, either substituted or unsubstituted, consisting of 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur" (the substituents being C1-C6 alkyl, C1-C6 alkoxy, or amino groups).

More preferably, it is "a substituted or unsubstituted 4-6 membered monocyclic unsaturated heterocyclic group containing 1-3 nitrogen heteroatoms" (the substituent being a C1-C6 alkyl or amino group).

Even more preferred are substituted or unsubstituted pyrazolyl, imidazo[1,2-b]pyridazinyl, imidazoyl, pyridinyl, thiazolyl, or furano[3,2-b]pyridinyl (with substituents being methyl, ethyl, or amino).

More preferably, it is a substituted or unsubstituted pyrazolyl, imidazole or pyridyl group (the substituent is methyl, ethyl or amino, preferably methyl or amino).

As an example of the substituent ^RB , in the above-mentioned "4-10 member monocyclic unsaturated heterocyclic groups containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, whether substituted or unsubstituted", the number of substituents is not particularly limited, but is preferably 0 to 3, more preferably 0 to 2.

In this specification, the "substituent" in "substituted or unsubstituted C1-C6 alkoxy" represented by R ³ is sometimes referred to as "substituent R ^C ".

R ³ indicates "substituted or unsubstituted C1-C6 alkoxy group":

Preferably, the C1-C6 alkoxy group optionally has "1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with at least one of methyl, ethyl and amino" as a substituent R ^C , and

More preferably, a C1-C6 alkoxy group is selected as a substituent R ^C having "1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur".

As an example of the substituent R ^C , the above-mentioned example of "4-10 member monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur" preferably includes "4-6 member monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur", more preferably includes "4-6 member monocyclic saturated heterocyclic group containing 1 oxygen atom", and even more preferably includes "5 member monocyclic saturated heterocyclic group containing 1 oxygen atom".

The "substituted or unsubstituted C1-C6 alkoxy group" represented by ^R3 is preferably a C1-C6 alkoxy group optionally having "1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur" as substituent R ^C.

More preferably, a C1-C4 alkoxy group optionally having "one to three identical or different heteroatoms selected from nitrogen, oxygen, and sulfur" as a substituent R ^C ,

Even more preferably, a C1-C4 alkoxy group with a "4-6 membered monocyclic saturated heterocyclic group containing one oxygen atom" as a substituent R ^C ,

More preferably, it is methoxy, ethoxy, tetrahydrofuranylmethoxy, tetrahydropyranylmethoxy, tetrahydrofuranylethoxy, or tetrahydropyranylethoxy, and

Even more preferably, it is ethoxy or tetrahydrofuranylmethoxy.

There is no particular limitation on the number of substituents, but it is preferred to have 0 to 3, and more preferably 0 to 2.

When each group represented by R ³ has a substituent, examples of "substituents" include those mentioned above, and the number of them is usually one, two, or three.

Examples of “C1-C6 alkoxy” in “substituted or unsubstituted C1-C6 alkoxy” represented by R ³ include those mentioned above;

Preferably, it is a C1-C4 alkoxy group; and

More preferably, it is methoxy or ethoxy.

In one embodiment, the compound represented by formula (I) or a salt thereof is as follows:

^R1 is a C1-C6 alkoxyalkyl group.

^R2 is an optional C3-C5 cycloalkyl group having a substituent ^RA , and

^R3 is

hydrogen,

C2-C6 alkynyl groups with substituent ^RB can be selected, or

C1-C6 alkoxy groups with substituents R ^C are optional.

In one embodiment, the compound represented by formula (I) or a salt thereof is as follows:

^R1 is a C1-C3 alkoxyalkyl group.

^R2 is an optional C3 cycloalkyl group having a substituent ^RA , and

^R3 is

C2-C3 alkynyl groups with substituent ^RB can be selected, or

C1-C2 alkoxy groups with substituents R ^C are optional.

In one embodiment, the compound represented by formula (I) or a salt thereof is as follows:

^R1 is methoxymethyl.

^R2 is methylcyclopropyl, and

^R3 is hydrogen.

The propynyl group may be optionally substituted with morpholino, dimethylamino, piperidinyl, pyrrolyl, branched propanol, or 3-thiomorpholino.

The acetylene group may be optionally substituted with 1,3-dimethylpyrazolyl, 1-methylpiperidinyl, 1-methylpyrazolyl, 1-methylimidazolyl, pyridinyl, or 6-aminopyridinyl.

ethoxy, or

Tetrahydrofuranylmethoxy

In one embodiment, the compound represented by formula (I) or a salt thereof is as follows:

^R1 is methoxymethyl.

^R2 is methylcyclopropyl, and

^R3 is a propynyl group optionally substituted with morpholino, dimethylamino, piperidinyl, pyrrolidinyl, branched propanol, 3-thiomorpholino, or tetrahydropyranyl.

The acetylene group may be optionally substituted with 1,3-dimethylpyrazolyl, 1-methylpiperidinyl, 1-methylpyrazolyl, 1-methylimidazolyl, pyridyl, 6-aminopyridyl, or tetrahydropyranyl.

ethoxy, or

Tetrahydrofuranylmethoxy

In one embodiment, the compound represented by formula (I) or a salt thereof is as follows:

^R1 is methoxymethyl.

^R2 is methylcyclopropyl, and

^R3 is a propynyl group that may be optionally substituted with morpholino, dimethylamino, or pyrrolidinyl.

The ethynyl group may be optionally substituted with 1,3-dimethylpyrazolyl, 1-methylpyrazolyl, pyridyl, or tetrahydropyranyl, or

Ethoxy group.

In one embodiment, the compound represented by formula (I) or a salt thereof is any one of the following or a salt thereof:

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-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-morpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(3) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidin-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(4) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-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-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-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-imidazol-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-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(12) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolid-1-yl)prop-1-yn-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-methylpent-1-yn-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)prop-1-yn-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(16) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(17) 4-amino-6-[(6-aminopyridin-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; and

(18) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

In one embodiment, the compound represented by formula (I) or a salt thereof is any one of the following or a salt thereof:

(1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-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-morpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(4) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-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-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide;

(6) 4-amino-6-[3-(dimethylamino)prop-1-yn-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-(pyrrolid-1-yl)prop-1-yn-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-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide.

The present invention also provides: a RET inhibitor comprising a compound (I) or a salt thereof (e.g., a compound or a salt thereof as an active ingredient of a brain-penetrating antitumor agent according to any one of items [1] to [9] above. The same applies below); a method of treating a subject with a tumor, the method comprising administering to the subject requiring treatment a brain-penetrating antitumor agent comprising an effective amount of a compound (I) or a salt thereof; a commercial package comprising a compound (I) or a salt thereof as an active ingredient and instructions for use for treating the tumor of the subject by using the brain-penetrating antitumor agent; a brain-penetrating antitumor agent for treating a tumor with enhanced RET activation state, comprising a compound (I) or a salt thereof as an active ingredient; a method of treating a subject with a tumor with enhanced RET activation state, comprising administering to the subject a brain-penetrating antitumor agent comprising an effective amount of a compound (I) or a salt thereof; a commercial package comprising a compound or a salt thereof as an active ingredient and instructions for use for treating a tumor with enhanced RET activation state in the subject by using the brain-penetrating antitumor agent; and so on.

Compound (I) and its salts can be prepared by known organic synthetic methods. For example, compound (I) and its salts can be prepared by the methods described in international publication number WO2017/146116, etc.

When compound (I) has isomers, such as optical isomers, stereoisomers, rotational isomers, and tautomers, mixtures of any isomers are included in the scope of compound (I) unless otherwise stated. For example, when compound (I) has optical isomers, optical isomers separated from racemic mixtures are also included in the scope of compound (I) unless otherwise stated.

Salts of compound (I) are pharmaceutically acceptable salts. Examples of such salts include base addition salts and acid addition salts.

The term "pharmaceutically acceptable salt" refers to a salt of a compound that has the desired pharmacological activity, prepared from any pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids.

Examples of such salts specifically 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; salts with basic amino acids such as lysine, arginine, and ornithine; and ammonium salts.

Compound (I) or its salts also include its prodrugs. A prodrug is a compound that can be converted into compound (I) or its salts under physiological conditions in the body through reaction with enzymes, gastric acid, etc., that is, a compound that can be converted into compound (I) or its salts through enzymatic oxidation, reduction, hydrolysis, etc.; or a compound that can be converted into compound (I) or its salts through hydrolysis with gastric acid, etc. In addition, a prodrug can be a compound that can be converted into compound (I) or its salts under physiological conditions, as described in "Iyakuhin no Kaihatsu [Development of Pharmaceuticals]", Vol. 7, Molecular Design, published by Hirokawa Shoten Co. in 1990, pp. 163-198.

Compound (I) or its salts can be amorphous or crystalline. Single crystals and polycrystalline mixtures are both included in the scope of compound (I) or its salts. Such crystals can be produced by crystallization according to known crystallization methods. Compound (I) or its salts can be solvates (e.g., hydrates) or non-solvents. Any such form is included in the scope of compound (I) or its salts. Compounds labeled with isotopes (e.g., ^3H , ^14C , ^35S , ^125I , etc.) are also included in the scope of compound (I) or its salts. Multiple crystals (crystalline polymorphs) with spatially regular atomic arrangements and physicochemical properties that differ from each other can be generated, and the salts according to the invention can be any one of these crystalline polymorphs, or a mixture of two or more crystalline polymorphs, or even a mixture of crystalline and amorphous forms.

In this specification, the term "effective amount" of compound (I) means the amount of compound (I) that can induce a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity; improving symptoms; alleviating condition; slowing or delaying the progression of disease; or preventing disease (therapeutic effective amount).

In this specification, "treatment" includes postoperative adjuvant chemotherapy to prevent recurrence after surgical removal of the tumor, and preoperative adjuvant chemotherapy administered in advance for surgical removal of the tumor.

In this specification, the term "subject" includes 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, guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, reptiles, etc. In one embodiment, the subject is a mammal, particularly a human, and may be a human diagnosed with a condition requiring treatment for the symptoms, conditions, or diseases disclosed in this specification.

There is no particular age limit for the subjects who receive the therapeutic agent of the present invention. The therapeutic agent of the present invention can be used not only for adults, but also for the elderly or children.

Compound (I) or its salt, which possesses excellent RET inhibitory activity, may be used as a pharmaceutical preparation for the prevention and/or treatment of RET-related diseases. Examples of “RET-related diseases” include diseases whose incidence can be reduced and whose symptoms can be relieved, alleviated, and/or completely cured by eliminating, inhibiting, and/or blocking RET function. Examples of such diseases include, but are not limited to, malignant tumors. Malignant tumors are preferably malignant tumors with enhanced RET activation; 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, or brain tumors with enhanced RET activation; even more preferably, salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, or brain tumors; particularly preferably, non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, or brain tumors.

The phrase “enhanced RET activation” means that the activation state of RET is enhanced due to, for example, RET gene translocations and mutations (including point mutations, deletion mutations, and insertion mutations) and overexpression (including RET gene copy number increase, RET messenger RNA overexpression, RET protein increase, and constitutive activation of RET protein).

There are no particular limitations on the types of cancers and tumors that can be treated with the compounds of the present invention or their salts. Examples include epithelial cancers (respiratory organ cancers, digestive organ cancers, reproductive organ cancers, endocrine organ cancers, etc.), sarcomas, hematopoietic system tumors, central nervous system tumors, and peripheral nerve tumors.

Specific examples of cancer types include head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, stomach cancer (cancer of digestive organs), duodenal cancer, liver cancer, bile duct cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), kidney cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, testicular tumors, leukemia, malignant lymphoma, multiple myeloma, osteosarcoma, soft tissue sarcoma, skin cancer, malignant melanoma, adrenal tumors, brain tumors, etc. The target cancers are 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, or brain tumors; 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, or brain tumors; even more preferably salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, or brain tumors; particularly preferably non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, or brain tumors.

In a typical embodiment of the invention, the tumor to which compound (I) exerts its effect by crossing the BBB is a brain tumor. In this invention, brain tumors include primary brain tumors and metastatic brain tumors. Examples of primary tumors include, but are not particularly limited to, gliomas, primary central nervous system lymphomas, meningiomas, pituitary adenomas, schwannomas, craniopharyngiomas, etc. Furthermore, the type of tumor that serves as the primary site for metastatic brain tumors is not limited.

In the case of metastatic brain tumors, the type of tumor at the primary site is not restricted. Specific examples of cancer types include head and neck cancer, thyroid cancer, salivary gland cancer, esophageal cancer, stomach cancer (digestive organ cancer), duodenal cancer, liver cancer, bile duct cancer (gallbladder cancer, bile duct cancer, etc.), pancreatic cancer, colorectal cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, mesothelioma, etc.), breast cancer, ovarian cancer, uterine cancer (cervical cancer, endometrial cancer, etc.), kidney cancer, renal pelvis-ureter cancer, bladder cancer, prostate cancer, testicular tumors, leukemia, malignant lymphoma, multiple myeloma, osteosarcoma, soft tissue sarcoma, skin cancer, malignant melanoma, adrenal tumors, etc. The target cancer is 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, or brain tumor; more preferably salivary gland cancer, lung cancer, breast cancer, pancreatic cancer, colorectal cancer, ovarian cancer, thyroid cancer, skin cancer, malignant melanoma, or brain tumor; particularly preferably non-small cell lung cancer, breast cancer, colorectal cancer, thyroid cancer, or brain tumor.

The active ingredient can be provided alone as the therapeutic agent of the present invention. Furthermore, in addition to the compound (I) or its salt used as the active ingredient, the therapeutic agent of the present invention may, as needed, incorporate a pharmaceutically acceptable carrier or the like. Therefore, the therapeutic agent of the present invention can be prepared as a pharmaceutical composition containing one or more ingredients. One aspect of the present invention provides a pharmaceutical composition containing compound (I) or its salt. A pharmaceutical composition according to one embodiment of the present invention comprises compound (I) or its salt and a pharmaceutically acceptable carrier. Furthermore, one embodiment of the present invention provides the use of compound (I) or its salt in the preparation of a therapeutic agent or pharmaceutical composition. Another embodiment of the present invention provides the use of compound (I) or its salt in the preparation of a therapeutic agent or pharmaceutical formulation.

The therapeutic agents of the present invention can be prepared into any of a variety of formulations for administration using known methods and, as needed, a pharmaceutically acceptable carrier. The dosage form can be either oral or parenteral. There are no particular limitations on the form of these formulations, and examples include: oral formulations such as tablets, coated tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions; parenteral formulations such as injections, suppositories, and inhalers; and so on.

Examples of pharmaceutically acceptable carriers that can be used when formulated into tablet form include: excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silica; binders such as water, ethanol, propanol, corn starch, monosaccharide syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; and binders such as dry starch and alginate. Disintegrants such as sodium, agar powder, brown algae starch, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, glyceryl monostearate, and lactose; disintegrant inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oils; absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silica; and lubricants such as refined talc, stearates, boric acid powder, and polyethylene glycol. Furthermore, tablets can be formulated as needed into tablets undergoing typical coating processes, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, bilayer tablets, or multilayer tablets.

When formed into pills, examples of pharmaceutically acceptable carriers that can be used include excipients such as 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 algae starch and agar. Capsules are prepared according to conventional methods by mixing the compound or its salts with any of the pharmaceutically acceptable carriers exemplified above, and filling the mixture into hard gelatin capsules, soft capsules, etc.

When forming oral liquid formulations, oral liquids, syrups, elixirs, etc., can be prepared using conventional methods by using pharmaceutically acceptable carriers such as sweeteners, buffers, and stabilizers. Examples of such sweeteners include sucrose, orange peel, citric acid, and tartaric acid; buffers such as sodium citrate; and stabilizers such as gum arabic, gum arabic, and gelatin.

When formed into suppositories, examples of pharmaceutically acceptable carriers that may be used include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides, etc.

When forming injectable formulations, solutions, emulsions, and suspensions are preferably sterilized and isotonic with blood. Furthermore, in forming these forms, diluents can be used as pharmaceutically acceptable carriers, and examples of such diluents include water, aqueous lactic acid solutions, ethanol, propylene glycol, polyethylene glycol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, and polyoxyethylene sorbitol fatty acid esters.

In this case, an amount of sodium chloride, glucose, or glycerol sufficient to prepare an isotonic solution can be incorporated into the pharmaceutical preparation, and general solubilizers, buffers, soothing agents, etc., can be added.

When formed into an inhaler, examples include various forms such as aerosols, powder inhalers, and liquid inhalers.

In addition, each such formulation may be mixed with colorants, preservatives, flavorings, flavorings, sweeteners, etc., and/or other drugs as pharmaceutically acceptable carriers, as needed.

In this invention, the term "daily dose" refers to the amount of active ingredient to be applied daily. In the therapeutic agents of this invention, the daily dose of compound (I) or its salt on the day of application depends on the patient's symptoms, weight, age, sex, etc., and cannot be generalized. For example, the dose of compound (I) for an adult (weight: 50 kg) is generally preferably 10 to 2000 mg/day, more preferably 20 to 1500 mg/day, and even more preferably 40 to 1200 mg/day.

Furthermore, the amount of compound (1) to be incorporated into each such dosage unit depends on the condition of the patient being administered the compound, the dosage form, etc. Generally, the amount of compound in each dosage unit is preferably 0.05 to 1000 mg in oral preparations, 0.01 to 500 mg in injectable preparations, and 1 to 1000 mg in suppositories.

The method of administration of the therapeutic agent of the present invention is appropriately determined based on the various forms of the formulation, the patient's age, sex, and other conditions, the severity of the patient's symptoms, etc. The method of drug administration of the present invention is not limited; however, since its active ingredient compound (I) or its salt exhibits excellent brain penetration, a method of administration that allows penetration to the brain via the systemic bloodstream is preferred. Examples of methods of administration of the therapeutic agent of the present invention include oral administration, intravenous administration, intra-arterial administration, intramuscular administration, intradermal administration, subcutaneous administration, intraperitoneal administration, and rectal administration. In the present invention, at least two of these methods of administration can be used in combination. For example, tablets, pills, powders, granules, capsules, liquids, suspensions, and emulsions are administered orally. Injections are administered intravenously alone or mixed with a common adjuvant (such as glucose or amino acids), or, as needed, intra-arterial, intramuscular, intradermal, subcutaneous, or intraperitoneal administration via rectal administration. Suppositories are administered rectally.

In this invention, "instruction manual" means, but is not limited to, accompanying documents provided with the drug, including instructions displayed electronically, such as instructions accessed via barcodes or QR codes used on boxes containing the drug.

The invention will now be described in more detail with reference to the embodiments. However, the invention is not limited to the embodiments.

All references and publications mentioned in this specification, regardless of their purpose, are incorporated herein by way of citation.

Furthermore, the objects, features, advantages, and concepts of the present invention will be apparent to those skilled in the art from the description herein, and those skilled in the art can readily implement the invention based on the description herein. The best mode for carrying out the invention, specific embodiments, etc., are descriptions of preferred embodiments of the invention and are shown for illustrative or descriptive purposes; the invention is not limited thereto. It will be apparent to those skilled in the art that various modifications can be made based on the description herein within the spirit and scope of the invention disclosed herein.

[Example]

In the following embodiments, unless otherwise stated, % represents a percentage by mass.

Unless otherwise stated, commercially available reagents are used in the examples.

The following are the abbreviations used and their meanings.

PBS: Phosphate-buffered saline

LC-MS/MS: Liquid Chromatography-Tandem Mass Spectrometry

HPMC: Hydroxypropyl Methylcellulose

Test Example 1: Evaluation of plasma protein binding and brain protein binding

The compounds shown in Tables 1–4 were added to mouse plasma at a final concentration of 1 μmol/L. The resulting compound-added mouse plasma was added to the supply side of an HTDialysis apparatus equipped with a balanced dialysis membrane. An equal volume of PBS was added to the receiver side of the apparatus, and after incubation in a 10% _CO2 incubator for 6 hours, the compounds on both the supply and receiver sides were detected by LC-MS/MS. The unbound ratio of each compound to plasma proteins was calculated based on the ratio of the peak area of the compound on the receiver side to the peak area of the compound on the supply side.

The calculation method for the unbound ratio of each compound to brain proteins is the same as described above, except that the compounds are added to mouse brain homogenate instead of mouse plasma; and the dilution ratio needs to be considered when calculating the unbound ratio. In this case, mouse brain tissue homogenate was obtained by adding 3 times the amount of PBS to the mouse brain and then homogenizing the mixture using an ultrasonic homogenizer.

Test Example 2: Brain Penetration Assessment

The compounds shown in Tables 1–4 were dissolved or suspended in 0.5% HPMC and 0.1N hydrochloric acid, and administered orally in a single dose to untreated or subcutaneously implanted TT cells or subcutaneously implanted BaF3/KIF5B-RET_RFP cell lines BALB/cAJcl-nu/nu mice (CLEA Japan, Inc.). One hour after oral administration, blood was collected from the inferior vena cava under isoflurane anesthesia, and the entire brain was then removed. Thus, blood and brain samples were obtained. The obtained blood samples were centrifuged to obtain plasma samples. Three times the volume of water was added to the obtained brain samples, and the mixture was homogenized using an ultrasonic homogenizer to obtain a brain tissue homogenate.

The concentrations of compounds in plasma and brain homogenates were measured using LC-MS/MS, and the concentrations in brain tissue homogenates were multiplied by a factor of 4 to calculate the concentrations in the brain. The Kp value was calculated based on the ratio of brain to plasma compound concentrations. The concentrations of unbound compounds in plasma and brain were calculated based on the plasma protein unbound ratio and brain protein unbound ratio of each compound determined in Test Example 1, and the Kp,uu value was calculated based on the ratio of brain to plasma unbound compound concentrations. Brain penetration characteristics were evaluated based on the calculated Kp and Kp,uu values (Tables 1-4). Specifically, a compound with a Kp value of 0.1 or higher was considered to have brain penetration, and a compound with a Kp,uu value of 0.3 or higher was considered to have excellent brain penetration (Varadharajan, S., et al. (2015) J Pharm Sci 104, 1197-1206). In Table 4, "N/A" in the "Kp,uu value" column indicates that this value was not measured.

The results shown in Tables 1-4 indicate that compound (I) exhibits high Kp and Kp,uu values, suggesting that it has good brain penetration.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

Test Example 3: Drug Efficacy Evaluation in a Brain Tumor Implantation Model

Antitumor effects were evaluated in a brain tumor implantation model. The compounds of Examples 2 and 4 shown in Table 1 and the compound of Example 13 shown in Table 3 were confirmed to inhibit the growth of the implanted tumor.

Growth inhibition was confirmed using NIH/3T3 cells (NIH/3T3_CCDC6-RET cells) with gene transfer involving forced expression of luciferase and the CCDC6-RET fusion protein. Six-week-old male nude mice (BALB/cAJcl-nu/nu, CLEA Japan, Inc.) were fixed on a stereotactic frame, and 2.5 × ^10⁴ cells were implanted into each mouse at a position 0.5 mm anterior to the anterior fontanelle, 2–2.2 mm to the right, and 3.5 mm deep. The implantation day was defined as day 0. On day 4, luciferin (150 mg/kg) was administered intraperitoneally, and luminescence intensity (photons/second) was measured using an IVIS imaging system (Lumina II, PerkinElmer). Based on the measured luminescence intensity, the animals were divided into four groups (N = 10) to ensure similar mean luminescence intensity across groups (only the control group was assessed as N = 9 due to the observation of one animal that died unexpectedly).

Starting from the next day (day 5), the compound was administered twice daily for 16 consecutive days. Each 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 luminescence intensity was measured every 3 or 4 days using the method described above.

The day after the last dose (day 21) was defined as the last day of measurement to confirm the inhibitory effect of the compound on tumor growth. However, because the humane endpoint of tumor growth was used in the untreated group (control group), the measurements on day 14 were used for statistical evaluation via the Dunnett trial.

Figure 1 shows the change in luminescence intensity over time, and Figure 2 shows the change in body weight. In the control group, an increase in luminescence intensity was observed, indicating that the implanted tumor was growing. Furthermore, a decrease in body weight was also observed, possibly due to tumor growth. By day 19, all animals had lost weight and were considered unable to continue testing; therefore, a humane endpoint was adopted. On the other hand, in the compound treatment groups, there was no significant increase in luminescence intensity for any compound, indicating that tumor growth was inhibited. Statistical analysis of luminescence intensity on day 14 showed a significant difference in luminescence intensity in all compound treatment groups compared to the control group (*: p < 0.05). This indicates that compound administration has a significant inhibitory effect on tumor growth. Furthermore, all animals in the compound treatment groups were able to complete compound administration until day 22, suggesting that compound administration may also extend lifespan.

These results indicate that the application of compounds exhibiting brain-penetrating properties can significantly inhibit the growth of tumor cells implanted in the brain and may have a life-prolonging effect.

Claims (19)

1. A brain-penetrating antitumor agent comprising a compound or a salt thereof represented by formula (I) as an active ingredient: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl groups, or Substituted or unsubstituted C1-C6 alkoxy groups. 2. The brain-penetrating antitumor agent according to claim 1, wherein the substituted or unsubstituted C3-C5 cycloalkyl group represented by R ² is substituted with a (1-1)C1-C2 alkyl group. 3. The brain-penetrating antitumor agent according to claim 1 or 2, wherein ^R2 is a C3-C4 cycloalkyl group optionally substituted with methyl. 4. The brain-penetrating antitumor agent according to any one of claims 1 to 3, wherein the substituted or unsubstituted C2-C6 alkynyl group represented by R ³ is substituted with the following: (2-1) Substituted or unsubstituted amino groups; (2-2) Substituted or unsubstituted C1-C6 alkyl groups; (2-3) Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, either substituted or unsubstituted, 4- to 10-membered monocyclic saturated heterocyclic groups; or (2-4) Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, substituted or unsubstituted 4 to 10 member monocyclic unsaturated heterocyclic groups. 5. The brain-penetrating antitumor agent according to any one of claims 1 to 4, wherein the substituted or unsubstituted C1-C6 alkoxy group represented by R ³ is substituted with the following: (3-1)amino; (3-2) Optionally, a C1-C6 alkyl group having 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, optionally substituted with at least one selected from methyl, ethyl, and amino groups; or (3-4) Contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted with at least one selected from methyl, ethyl and amino groups, which are 4 to 10 membered monocyclic unsaturated heterocyclic groups. 6. The brain-penetrating antitumor agent according to any one of claims 1 to 5, wherein, ^R1 is a C1-C6 alkoxy-C1-C6 alkyl group. ^R2 is a C3-C5 cycloalkyl group optionally substituted with a C1-C2 alkyl group, and ^R3 is Substituted or unsubstituted C2-C6 ynyl group; or Substituted or unsubstituted C1-C6 alkoxy groups, Where R ³ represents a substituted or unsubstituted C2-C6 ynyl group, which is substituted by the following: amino; Optionally substituted with at least one C1-C6 alkyl group selected from hydroxyl, amino and cyano groups; A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with at least one selected from C1-C6 alkyl, hydroxyl, amino, and cyano groups; or Containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, and optionally substituted with at least one selected from C1-C6 alkyl, hydroxyl, amino, and cyano groups, a 4- to 10-membered monocyclic unsaturated heterocyclic group, and R ³ represents the substituted or unsubstituted C1-C6 alkoxy group, which is substituted by the following: amino; C1-C6 alkyl groups optionally having hydroxyl groups; A 4- to 10-membered monocyclic saturated heterocyclic group containing 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with at least one selected from methyl, ethyl, and amino groups; or It contains 1 to 3 identical or different heteroatoms selected from nitrogen, oxygen and sulfur, and optionally substituted with at least one selected from methyl, ethyl and amino groups, forming a 4 to 10 member monocyclic unsaturated heterocyclic group. 7. The brain-penetrating antitumor agent according to any one of claims 1 to 6, wherein the compound represented by formula (I) or a salt thereof is any one of the following or a salt thereof: (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-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-morpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (3) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-[(1-methylpiperidin-4-yl)ethynyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (4) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-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-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (6) 4-amino-6-[3-(dimethylamino)prop-1-yn-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-imidazol-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-(piperidin-1-yl)prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (12) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-(pyrrolid-1-yl)prop-1-yn-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-methylpent-1-yn-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)prop-1-yn-1-yl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (16) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (17) 4-amino-6-[(6-aminopyridin-3-yl)ethynyl]-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; and (18) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(3-thiomorpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. 8. The brain-penetrating antitumor agent according to any one of claims 1 to 7, wherein the compound represented by formula (I) or a salt thereof is any one of the following or a salt thereof: (1) 4-amino-6-[2-(1,3-dimethyl-1H-pyrazol-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-morpholinylprop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (4) 4-Amino-N-[4-(methoxymethyl)phenyl]-6-((1-methyl-1H-pyrazol-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-(prop-1-yn-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide; (6) 4-amino-6-[3-(dimethylamino)prop-1-yn-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-(pyrrolid-1-yl)prop-1-yn-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; and (16) 4-Amino-N-[4-(methoxymethyl)phenyl]-7-(1-methylcyclopropyl)-6-(pyridin-3-ylethynyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide. 9. The brain-penetrating antitumor agent according to any one of claims 1 to 8, used for the treatment of primary or metastatic brain tumors. 10. Use of compounds represented by formula (I) or salts thereof in the preparation of brain-penetrating antitumor agents: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 11. A method of treating a subject suffering from a tumor, comprising administering to the subject requiring treatment a brain-penetrating antitumor agent comprising an effective amount of a compound or a salt thereof represented by formula (I): In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl groups, or Substituted or unsubstituted C1-C6 alkoxy groups. 12. A compound or a salt thereof represented by formula (I) is used to treat tumors through the use of brain-penetrating antitumor agents: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 13. The use of a compound or salt thereof represented by formula (I) for the treatment of tumors through the use of brain-penetrating antitumor agents: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 14. A commercial packaging comprising: The following compounds or their salts, represented by formula (I), are used as active ingredients: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups; and The instructions for use of this brain-penetrating antitumor agent for treating tumors in subjects. 15. A brain-penetrating antitumor agent for treating tumors with enhanced RET activation state, comprising a compound or a salt thereof represented by formula (I) as the active ingredient: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 16. Use of a compound represented by formula (I) or a salt thereof in the preparation of a brain-penetrating antitumor agent for the treatment of tumors with enhanced RET activation: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 17. A method of treating a subject with a tumor exhibiting enhanced RET activation, comprising administering to the subject a brain-penetrating antitumor agent comprising an effective amount of a compound or a salt thereof represented by formula (I): In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 18. A compound or a salt thereof represented by formula (I), used to treat tumors with enhanced RET activation state by means of a brain-penetrating antitumor agent: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups. 19. Use of a compound or a salt thereof represented by formula (I) for the treatment of tumors with enhanced RET activation state via the use of brain-penetrating antitumor agents: In the formula, ^R1 is a C1-C6 alkoxyalkyl group. ^R2 is a substituted or unsubstituted C3-C5 cycloalkyl group, and ^R3 is hydrogen. Substituted or unsubstituted C2-C6 ynyl group, or Substituted or unsubstituted C1-C6 alkoxy groups.