JP2016155776A - Antitumor effect enhancer and antitumor agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide antitumor effect enhancers that can enhance the antitumor effect of MEK inhibitors and/or c-Met inhibitors, and to provide antitumor agents that exert excellent antitumor effect to various kinds of cancers.SOLUTION: The antitumor effect enhancer according to the present invention contains a coumarin derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and can enhance the antitumor effect of MEK inhibitors and/or c-Met inhibitors.SELECTED DRAWING: Figure 17

Description

  The present invention relates to an antitumor effect potentiator and an antitumor agent.

  Malignant pleural mesothelioma is a highly malignant cancer associated with exposure to asbestos, and no adequate treatment has been established, with a life expectancy after diagnosis of 9-12 months. The number of deaths due to malignant pleural mesothelioma in Japan is expected to rise to 100,000 in the next 40 years, and the incidence is expected to increase worldwide over the next 10 years (for example, Non-Patent Document 1). .

  Malignant pleural mesothelioma is highly resistant to the currently used aggressive multimodality therapy consisting of surgical therapy, cytotoxic chemotherapy, and radiation therapy. Until now, a drug combining peplatexed, which is an antifolate agent having many targets, with cisplatin has been approved as a first-line drug for the treatment of malignant pleural mesothelioma (Non-patent Documents 2 and 3).

  Here, the mitogen-activated protein (MAP) kinase (MAPK) pathway is known to play an important role in cell proliferation, growth, differentiation and survival. The deregulation of the MAPK pathway is involved in the formation of many human tumors including malignant pleural mesothelioma. MAP kinase / extracellular signal-regulated kinase (ERK) kinase (hereinafter referred to as MEK), a component of the MAPK pathway, has been identified as a promising target for new therapies and several MEK inhibitors have been developed Some of them have been confirmed to have clinical effects.

  Trametinib is a potent and selective allosteric inhibitor of MEK1 and MEK2 and has been shown to enable survival beyond cytotoxic chemotherapy for patients with metastatic melanoma with the V600 BRAF mutation, It is a drug approved for use in the patient (Patent Document 1, Non-Patent Document 4).

  Trametinib is administered orally and has a longer circulation half-life than previously tested MEK inhibitors. Furthermore, trametinib inhibits not only phosphorylation of ERK by MEK but also activation of MEK1 and MEK2 by inhibiting phosphorylation of MEK by Raf.

  On the other hand, the expression level is increased in most human cancers, and hyaluronic acid is known as a substance associated with poor prognosis. Hyaluronic acid is a linear high-molecular glycosaminoglycan, is composed of N-acetylglucosamine and glucuronic acid disaccharide repeating units, and is synthesized by hyaluronic acid synthase (HAS) 1, HAS2, and HAS3.

  Synthesized hyaluronic acid molecules bind to cell surface receptors such as CD44, CD168 / RHAMM, LYVE-1, HARE / stabillin-2, and Toll-like receptors 2 and 4. The interaction of hyaluronic acid with these receptors regulates intracellular signaling pathways, cell proliferation, cell motility, and tumor cell invasiveness (eg, Non-Patent Document 5).

  In malignant pleural mesothelioma, hyaluronic acid is produced not only by mesothelioma cells but also by surrounding normal mesothelial cells and fibroblasts. Elevated hyaluronic acid levels are associated with increased malignancy of malignant pleural mesothelioma cells. CD44, a cell surface receptor for hyaluronic acid, is frequently expressed in cells of any cancer, including malignant pleural mesothelioma, but not in normal mesothelial cells.

  4-Methylumbelliferone (4-MU) is known as a hyaluronic acid synthesis inhibitor, and is due to cellular uridine diphosphate glucuronic acid (UDP) -glucuronic acid depletion and decreased expression of HAS2 and HAS3. Inhibits hyaluronic acid synthesis (Non-patent Document 6). 4-MU is a drug that has been used for many years as an oral bile secretion drug and anticonvulsant, and has already been established for safety when administered to humans.

  In recent years, studies have shown that 4-MU inhibits the growth of several types of tumor cells including melanoma, osteosarcoma, esophageal squamous cell carcinoma, breast cancer, prostate cancer, hepatocellular carcinoma and leukemia. (For example, nonpatent literature 7-15).

  There is also a document that discloses that a pharmaceutical composition comprising 4-MU in combination with an antitumor substance such as gemcitabine can be used for the treatment of pancreatic cancer and the like (Patent Document 2).

  On the other hand, CD44 is known to interact with signal receptors such as c-Met. For example, it is known to function as a co-receptor by physically binding to the receptor and to promote the association of intracellular mediators of signaling in the process.

  Furthermore, in recent years, lymphocytes (regulatory cells) that suppress immune reactions and / or inflammatory reactions and CTLA-4 antigens and PD-1 / PD-L1 antigens, which are antigens expressed on macrophages, are targeted to the lymphocytes ( Antibodies that reduce (suppressing lymphocytes) have been put into practical use in clinical practice (Patent Documents 3 and 4).

WO 2005/121142 (published on December 22, 2005) Japanese Patent Laying-Open No. 2006-289892 (published on November 2, 2006) International Publication No. 2004/004771 (published on January 15, 2004) Special table 2004-512005 publication (April 22, 2004 publication)

Robinson BW et. Al. Lancet. 2005; 366 (9483): 397-408. Vogelzang NJ, et.al.Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2003; 21 (14): 2636-44. Tsao AS et.al.Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2009; 27 (12): 2081-90. Flaherty KT, et al. The New England journal of medicine. 2012; 367 (2): 107-14. Toole BP. Clinical cancer research: an official journal of the American Association for Cancer Research. 2009; 15 (24): 7462-8. Kultti A, et al. Experimental cell research. 2009; 315 (11): 1914-23. Edward M, et al. The British journal of dermatology. 2010; 162 (6): 1224-32. Arai E, et al. British journal of cancer. 2011; 105 (12): 1839-49. Twarock S, et al. Molecular cancer. 2011; 10:30. Urakawa H, et al. International journal of cancer Journal international du cancer. 2012; 130 (2): 454-66. Lokeshwar VB, et al. Cancer research. 2010; 70 (7): 2613-23. Piccioni F, et al. Glycobiology. 2012; 22 (3): 400-10. Hiraga T, et al. Cancer research. 2013; 73 (13): 4112-22. Lompardia SL, et al. Glycobiology. 2013; 23 (12): 1463-76. Uchakina ON, et al. Leukemia research. 2013; 37 (10): 1294-301.

  However, Non-Patent Documents 2 and 3 describe that the medical condition of the patient administered with the first-line drug progressed within one year from the treatment. That is, the present condition is that the therapeutic agent of malignant pleural mesothelioma with sufficient therapeutic effect has not yet been found. In addition, there is no knowledge about the relationship between the above-mentioned 4-MU, trametinib and hyaluronic acid and the treatment of malignant pleural mesothelioma. Furthermore, the mechanism of 4-MU tumor cell growth inhibition described above is unknown.

  Patent Document 2 discloses a treatment of cancer by a combination of 4-MU and an antitumor substance, but how 4-MU acts on a MEK inhibitor or a c-Met inhibitor. Nothing is disclosed or suggested in any document.

  On the other hand, in view of the fact that the number of deaths due to malignant pleural mesothelioma is expected to increase all over the world as described above, it can be said that the development of a highly effective therapeutic drug is an urgent issue. In addition, the therapeutic agent desirably exhibits an antitumor effect not only against malignant pleural mesothelioma but also against other cancers.

  Furthermore, for example, the antibodies disclosed in Patent Documents 1 and 2 have been proved to be effective against malignant tumors such as melanoma that have been difficult to treat by conventional treatment methods, It is expected to expand the application to tumors. If the response rate of these antibodies can be further improved, it is considered that a therapeutic agent having a very high therapeutic effect against various cancers can be provided.

  The present invention has been made in view of such problems, and an object thereof is an antitumor effect potentiator that can enhance the antitumor effect of a MEK inhibitor and / or a c-Met inhibitor, a malignant pleura It is to provide an antitumor agent exhibiting an excellent antitumor effect against various cancers including mesothelioma, and an antitumor agent using the antitumor agent in combination with an anti-PD-1 antibody or the like. .

  Mesothelioma is thought to contribute to proliferation by producing a large amount of hyaluronic acid in pleural effusion, and that hyaluronic acid becomes a ligand for CD44. In addition, CD44 is known to be a cancer stem cell marker in solid cancers such as breast cancer and colorectal cancer, and there is a finding that the prognosis worsens in cancer patients expressing CD44. Furthermore, as mentioned above, hyaluronic acid has an increased expression level in most human cancers and is associated with poor prognosis.

  Therefore, the present inventor first focused on 4-MU that competitively inhibits hyaluronic acid, inhibited synthesis of hyaluronic acid using 4-MU, and reduced the expression of CD44 with hyaluronic acid as a ligand. We thought that a tumor effect could be obtained.

  However, as shown in the Examples described later, the expression level of CD44 did not decrease much even when 4-MU was administered alone. On the other hand, the present inventor has found that the expression of CD44 decreases due to the decrease in the expression of Fra-1 based on the inhibition of ERK phosphorylation by the MEK inhibitor, and the MEK inhibitor is combined with the MEK inhibitor and 4-MU. It was found that the antitumor effect of can be further enhanced.

  Furthermore, the present inventor can synergistically enhance the antitumor effect of a c-Met inhibitor by using 4-MU together with a c-Met inhibitor, and a combined use of a MEK inhibitor and 4-MU. Thus, it was found that the expression of PD-L1 and the like can be enhanced, and the present invention has been completed.

  That is, in order to solve the above-mentioned problems, the antitumor effect potentiator according to the present invention is a coumarin derivative or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as “coumarin derivative etc.”) as an active ingredient. And is characterized by being able to enhance the antitumor effect of MEK inhibitors and / or c-Met inhibitors.

  The antitumor effect potentiator according to the present invention is one or more compounds selected from the group consisting of compounds wherein the coumarin derivative is represented by the following general formula [IV]:

(In the formula, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, a hydroxyl group or a C _1-6 alkyl group. R ²⁰ , R ²¹ , R ²² and R ²³ each independently represent a hydrogen atom or a hydroxyl group. And the hydrogen atom of the hydroxyl group may be substituted with a C _1-6 alkyl group or a β-D-glucopyranosyl group)
It is preferable that

  Furthermore, in the antitumor effect potentiator according to the present invention, the coumarin derivative is preferably 4-methylumbelliferone.

  In the examples described below, 4-MU is shown to enhance the antitumor effect of MEK inhibitors and the antitumor effect of c-Met inhibitors. Since the coumarin derivative and the compound represented by the general formula [IV] have a basic skeleton in common with 4-MU, the antitumor effect enhancer according to the present invention containing these as an active ingredient is 4- As in the case of using MU, it is expected that the effect of enhancing the antitumor effect of the MEK inhibitor and / or c-Met inhibitor is exerted.

  In addition, 4-MU has been used as a bile agent in the past, but is no longer being sold. According to the said structure, it is useful also at the point which can provide the new use as an anti-tumor effect enhancer about the compound which 4-MU and 4-MU and a basic skeleton have in common.

  The antitumor agent according to the present invention is characterized by containing a MEK inhibitor and / or a c-Met inhibitor and the antitumor effect potentiator according to the present invention as active ingredients.

  According to the above configuration, since the expression of CD44 is suppressed by the MEK inhibitor and the synthesis of hyaluronic acid is inhibited by coumarin derivatives such as 4-MU, the binding between hyaluronic acid and CD44 is greatly increased. It is suppressed. As a result, a synergistic antitumor effect can be obtained as compared with the case where a MEK inhibitor or a coumarin derivative or the like is used alone.

  Furthermore, from the results shown in the examples described later, according to the above configuration, the antitumor effect of the c-Met inhibitor is further enhanced, and compared with the case where the c-Met inhibitor or the coumarin derivative is used alone, synergistically. It is understood that a typical anti-tumor effect can be obtained.

  Therefore, according to the said structure, the antitumor agent which has the outstanding therapeutic effect with respect to various cancer can be provided.

  In the antitumor agent according to the present invention, the MEK inhibitor is one or more compounds selected from the group consisting of compounds represented by the following general formulas [I] to [III], or a pharmaceutically acceptable agent. The salt thereof is preferred.

  The compound represented by the general formula [I] is:

[Wherein, X ¹ and X ² are the same or different and each represents a carbon atom or a nitrogen atom,

Part,

And
R ¹ ′, R ² ′ and R ⁶ are the same or different,
A C _1-6 alkyl group,
A C _2-6 alkenyl group,
(Here, the C _1-6 alkyl group and the C _2-6 alkenyl group may be substituted with 1 to 3 substituents selected from Group A below), or

{M is 0 or an integer of 1 to 4, and the ring Cy is a C _3-12 carbocyclic group or a heterocyclic group.
(Here, the heterocyclic group is a saturated or unsaturated ring having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom. The C _3-12 carbocyclic group and the heterocyclic group may be substituted with 1 to 5 substituents selected from the following group B)):
R ³ , R ⁴ , and R ⁵ are the same or different,
Hydrogen atom,
A hydroxy group,
A C _1-6 alkyl group,
A C _2-6 alkenyl group,
(Here, the C _1-6 alkyl group and the C _2-6 alkenyl group may be substituted with 1 to 3 substituents selected from Group A below),
A C _3-12 carbocyclic group, or
A heterocyclic group,
(Here, the heterocyclic group is a saturated or unsaturated ring group having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom, The C _3-12 carbocyclic group and heterocyclic group may be substituted with 1 to 5 substituents selected from the following group B.) Or R ^{2 ′} and R ³ are combined. ^May form a C _1-4 alkylene group, or R ⁴ and R ⁵ together may form a C _1-4 alkylene group.
{Where Group A is
1) a halogen atom,
2) Nitro group,
3) a cyano group,
4) C _1-4 alkyl group,
5) —OR ^A1 (wherein R ^A1 is a hydrogen atom or a C _1-4 alkyl group),
6) —SR ^A2 (wherein R ^A2 is a hydrogen atom or a C _1-4 alkyl group),
7) —NR ^A3 R ^A4 (wherein R ^A3 and R ^A4 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group),
8) —COOR ^A5 (wherein R ^A5 is a hydrogen atom or a C _1-4 alkyl group),
9) —NR ^A6 COR ^A7 (wherein R ^A6 is a hydrogen atom or a C _1-4 alkyl group, and R ^A7 is a C _1-4 alkyl group, a C _3-12 carbocyclic group, or a heterocycle A cyclic group),
10) —NR ^A8 COOR ^A9 (wherein R ^A8 and R ^A9 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group);
11) a C _3-12 carbocyclic group, and
12) a group consisting of heterocyclic groups,
(Here, the heterocyclic group is a saturated or unsaturated ring group having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom,
The C _1-4 alkyl groups of the above 4), R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^A7 , R ^A8 , and R ^A9 are each selected from the following group C Or it may be substituted with 1 to 3 different substituents,
In addition, the C _3-12 carbocyclic group of 11) and R ^A7 , and the heterocyclic group of 12) and R ^A7 are each substituted with the same or different 1 to 5 substituents selected from Group C below. May be. )
Group B
1) a halogen atom,
2) Nitro group,
3) a cyano group,
4) a C _1-8 alkyl group,
5) a _C2-4 alkenyl group,
6) a _C2-4 alkynyl group,
7) —OR ^B1 (where R ^B1 is a hydrogen atom or a C _1-4 alkyl group),
8) —SR ^B2 (wherein R ^B2 is a hydrogen atom or a C _1-4 alkyl group),
9) —NR ^B3 R ^B4 (where R ^B3 is a hydrogen atom, a C _1-4 alkyl group, a C _3-12 carbocyclic group, or a heterocyclic group, and R ^B4 is a hydrogen atom or C _1-4 alkyl group).
10) —NR ^B5 COR ^B6 (wherein R ^B5 is a hydrogen atom or a C _1-4 alkyl group, and R ^B6 is a hydrogen atom, a C _1-4 alkyl group, a C _3-12 carbocyclic group, Or a heterocyclic group).
11) —NR ^B7 COOR ^B8 (wherein R ^B7 and R ^B8 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group),
12) -NR ^B9 CONR ^B10 R ^B11 (wherein R ^B9 , R ^B10 and R ^B11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group),
13) -NR ^B12 CONR ^B13 OR ^B14 (wherein R ^B12 , R ^B13 and R ^B14 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group),
14) —NR ^B15 SO ₂ R ^B16 (wherein R ^B15 is a hydrogen atom or a C1-4 alkyl group, and R ^B16 is a _C1-4 alkyl group, a C _3-12 carbocyclic group, or A heterocyclic group),
15) —SO ₂ —R ^B17 (wherein R ^B17 is a C _1-4 alkyl group or a heterocyclic group),
16) —SO ₂ NR ^B18 R ^B19 (wherein R ^B18 and R ^B19 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group);
17) -P (= O) (R ^B20 ) (R ^B21 ) (wherein R ^B20 and R ^B21 are the same or different and each represents a C _1-4 alkyl group);
18) -COOR ^B22 (wherein R ^B22 is a hydrogen atom or a C _1-4 alkyl group),
19) -CONR ^B23 R ^B24 (wherein R ^B23 and R ^B24 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group),
20) -NR ^B25 SO ₂ NR ^B26 R ^B27 (wherein R ^B25 , R ^B26 and R ^B27 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group);
21) —NR ^B28 SO ₂ NR ^B29 CONR ^B30 R ^B31 (wherein R ^B28 , R ^B29 , R ^B30 and R ^B31 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group). ),
22) a C _3-12 carbocyclic group, and
23) a group consisting of heterocyclic groups,
(Wherein the “C _1-8 alkyl group” in 4) and the C _1-4 alkyl group in R ^{B1 to} R ^B31 are the same or different 1 to 3 substituents selected from the group A, respectively. May be replaced with
The C _2-4 alkenyl group of 5) and the C _2-4 alkynyl group of 6) may each be substituted with the same or different 1 to 3 substituents selected from the group A,
The heterocyclic group is a saturated or unsaturated ring group having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom,
The 22), C _3-12 carbocyclic group of R ^B3 , R ^B6 , and R ^B16 , the above 23), the heterocyclic group of R ^B3 , R ^B6 , R ^B16 , and R ^B17 are respectively It may be substituted with the same or different 1 to 5 substituents selected from the following group C. )
Group C
1) a halogen atom,
2) a cyano group,
3) a C _1-4 alkyl group,
4) —OR ^C1 (wherein R ^C1 is a hydrogen atom or a C _1-4 alkyl group),
5) —NR ^C2 R ^C3 (wherein R ^C2 and R ^C3 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group),
6) -COOR ^C4 (wherein R ^C4 is a hydrogen atom or a C _1-4 alkyl group.)
as well as,
7) A group consisting of oxo groups. },
(However,

Part is

When, as a condition,
R ^{2 ′} is not a methyl group,
When R ^{2 ′} is a phenyl group, R ^{1 ′} is not a phenyl group. )]
The compound represented by the general formula [II] is

[Where:
R ⁷ , R ⁸ , and R ¹⁵ are hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —OR ⁹ , —C (O) R ⁹ , —C (O) OR ⁹ , NR ¹⁰ C (O) OR ¹² , —OC (O) R ⁹ , —NR ¹⁰ SO ₂ R ¹² , —SO ₂ NR ⁹ R ¹⁰ , —NR ¹⁰ C (O) R ⁹ , —C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (NCN) NR ⁹ R ¹⁰ , —NR ⁹ R ¹⁰ , and C _{1 to} C ₁₀ alkyl, C _{2 to} C ₁₀ alkenyl, C ₂ -C _{10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10 cycloalkylalkyl, -S (O) j (C} 1 ~C 6 ^{_{alkyl), - S (O) j}} (CR 10 R 11 ) _m - aryl, Reel, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, _{^{heterocyclylalkyl, -O (CR 10 R 11)}} m - ^{aryl, -NR 10 (CR 10 R 11} ) m - aryl, -O ^(CR 10 ^{R 11)} _m - ^{heteroaryl, _{-NR 10 (CR 10 R 11)}} m - _{^{heteroaryl, -O (CR 10 R 11)}} m - heterocyclyl, and _{^{-NR 10 (CR 10 R 11)}} m - are each independently selected from heterocyclyl Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety may be oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ¹⁰ SO ₂ R ¹² , -SO ^{NR 9 R 10, -C (O} ) R 9, -C (O) OR 9, -OC (O) R 9, -NR 10 C (O) OR 12, -NR 10 C (O) R 9, - C (O) NR ⁹ R ¹⁰ , —NR ⁹ R ¹⁰ , —NR ¹¹ C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (NCN) NR ⁹ R ¹⁰ , —OR ⁹ , aryl, heteroaryl, arylalkyl Optionally substituted by 1 to 5 groups each independently selected from: heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R ⁹ is hydrogen, trifluoromethyl, and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl alkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoro Methyl, difluoromethoxy, trifluoromethoxy, azide, —NR′SO ₂ R ″ ″, —SO ₂ NR′R ″, —C (O) R ′, —C (O) OR ′, —OC (O) R ', -NR'C (O) OR "", -NR'C (O) R ", -C (O) NR'R ", -SR"", - S (O) R"", - SO 2 R ', - NR'R", - NR'C (O) NR "R"', - NR'C (NCN) NR " Optionally substituted by 1 to 5 groups, each independently selected from R ″ ′, —OR ′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R ′, R ″, and R ″ ′ are each independently selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, aryl, and arylalkyl;
R ″ ″ is selected from C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, aryl, and arylalkyl; or any of R ′, R ″, R ″ ′, or R ″ ″ The two together with the bonding partner atom may form a 4- to 10-membered carbocycle, heteroaryl ring, or heterocycle, each of which is halogen, cyano, nitro, trifluoro Optionally substituted by 1 to 3 groups, each independently selected from methyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl ; or R ⁹ and ^{R 10,} together with the binding partner of atoms, 4 to 10 membered carbocyclic, heteroaryl ring, also It may form a heterocyclic ring, each of these rings are halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{azido, -NR'SO 2 R "", -} SO 2 NR'R " , -C (O) R ', -C (O) OR', -OC (O) R ', -NR'C (O) OR "", -NR'C (O) R ", -C (O _{) NR'R ", - SO 2 R} "", - NR'R", - NR'C (O) NR "R"', - NR'C (NCN) NR "R"', - OR ', aryl Optionally substituted by 1 to 3 groups each independently selected from: heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R ¹⁰ and R ¹¹ are each independently represents hydrogen or _C 1 -C ₆ alkyl; one Alternatively, R ¹⁰ and R ¹¹ may form a 4- to 10-membered carbon ring, heteroaryl ring, or heterocyclic ring together with the bonding partner atom, and each of these rings may be halogen, cyano, , Nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR′SO ₂ R ″ ″, —SO ₂ NR′R ″, —C (O) R ′, —C (O) OR ′, — OC (O) R ', - NR'C (O) OR "", - NR'C (O) R ", - C (O) NR'R", - SO 2 R "", - NR'R " , -NR'C (O) NR "R"',-NR'C (NCN) NR "R"', -OR ', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, respectively Optionally with one to three groups selected independently It is conversion;
R ¹² is selected from trifluoromethyl and C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each alkyl, cycloalkyl , aryl, heteroaryl, and heterocyclyl moiety, oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{azido, -NR'SO 2 R "", -} SO 2 NR'R ", - C (O) R ', -C (O) OR', -OC (O) R ', -NR'C (O) OR "", -NR'C (O) R ", -C (O) NR 'R', -SO ₂ R "", -NR'R ', -NR'C (O) NR "R"', -NR'C (NCN) NR "R"',-OR', aryl, heteroa Optionally substituted with 1 to 5 groups each independently selected from reel, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R ¹³ is C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, Selected from heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoro Methoxy, azide, —NR ¹⁰ SO ₂ R ¹² , —SO ₂ NR ⁹ R ¹⁰ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ¹⁰ C (O ^{) OR 12, -NR 10 C (} O) R 9, -C (O) N _{^{9 R 10, -SO 2 R 12}} , -NR 9 R 10, -NR 11 C (O) NR 9 R 10, -NR 11 C (NCN) NR 9 R 10, -OR 9, aryl, heteroaryl, aryl Optionally substituted with 1 to 5 groups each independently selected from alkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
A is selected from OR ⁹ or NR ¹⁰ OR ⁹ ;
R ¹⁴ is hydrogen, —SCF ₃ , —Cl, —Br, —F, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —OR ⁹ , —C (O) R ⁹ , —C ^{(O) OR 9, -NR 10} C (O) OR 12, -OC (O) R 9, -NR 10 SO 2 R 12, -SO 2 NR 9 R 10, -NR 10 C (O) R 9, ^{-C (O) NR 9 R 10} , -NR 11 C (O) NR 9 R 10, -NR 9 R 10, and _C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10} alkynyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10 cycloalkylalkyl, -S (O) j (C} 1 ~C 6 ^{alkyl), - S (O) j} (CR 10 R 11) m - , aryl, Arylalkyl, hetero Reel, heteroarylalkyl, heterocyclyl, _{^{heterocyclylalkyl, -O (CR 10 R 11)}} m - ^{aryl, -NR 10 (CR 10 R 11} ) m - _{^{aryl, -O (CR 10 R 11)}} m - heteroaryl, - _{^{NR 10 (CR 10 R 11)}} m - _{^{heteroaryl, -O (CR 10 R 11)}} m - heterocyclyl, and _{^{-NR 10 (CR 10 R 11)}} m - is selected from heterocyclyl, each alkyl, alkenyl, alkynyl, cycloalkyl The alkyl, aryl, heteroaryl, and heterocyclyl moieties are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ¹⁰ SO ₂ R ¹² , —SO ₂ NR ⁹ R ¹⁰ , — C (O) R ⁹ , —C (O) O ^{R 9, -OC (O) R} 9, -NR 10 C (O) OR 12, -NR 10 C (O) R 9, -C (O) NR 9 R 10, -NR 9 R 10, -NR 11 1 independently selected from C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (NCN) NR ⁹ R ¹⁰ , —OR ⁹ , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Optionally substituted with from 5 to 5 groups;
m is 0, 1, 2, 3, 4, or 5;
j is 1 or 2.]
The compound represented by the general formula [III] is

[Where:
X ₁ is CR ₆ ;
X ₅ is CR ₆ ;
R ₃ is hydrogen, hydroxy, unsubstituted or alkoxy substituted with one or more groups selected from group A ′, unsubstituted or hydroxyalkoxy substituted with one or more groups selected from group A ′, Aryloxy substituted or substituted with one or more groups selected from group A ′, unsubstituted or heteroaryloxy substituted with one or more groups selected from group A ′, amino, unsubstituted or group A ′ (C _1-10 ) alkylamino substituted with one or more groups selected from: unsubstituted, arylamino substituted with one or more groups selected from group A ′, unsubstituted or selected from group A ′ 1 or more hetero arylamino substituted by a group, substituted with one or more groups selected from unsubstituted or group a '(C _-10) alkyl, substituted with one or more groups selected from unsubstituted or group A 'halo substituted with one or more groups selected from (C _1-10) alkyl, unsubstituted or group A' One or more groups selected from hydroxy (C _1-10 ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′, unsubstituted (C _1-10 ) alkyl, unsubstituted or group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, substituted with at least one hetero (C _3-12 ) cycloalkyl (C ₁ ) substituted with one or more groups selected from group A ′ _-5) alkyl, one selected from an unsubstituted or group a 'aryl substituted with one or more groups selected (C _1-10) alkyl, unsubstituted or group a' Group heteroaryl _{(C 1-5)} alkyl substituted with the above, substituted with one or more groups selected from unsubstituted or group A _{'(C 9-12)} bicycloaryl _{(C 1-5)} alkyl One or more groups selected from hetero (C _8-12 ) bicycloaryl (C _1-5 ) alkyl, unsubstituted or group A ′, unsubstituted or substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl, unsubstituted or substituted with one or more groups selected from group A ′, or hetero (C _3-12 ) cycloalkyl, unsubstituted or selected from group A ′ (C _9-12 ) bicycloalkyl substituted with one or more groups, unsubstituted or hetero (C _3-12 ) bicyclo substituted with one or more groups selected from group A ′ Hetero (C ₁ ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′ (C _4-12 ) aryl, unsubstituted or substituted with one or more groups selected from group A ′ _-10 ) aryl, unsubstituted or substituted with one or more groups selected from group A '( _C9-12 ) bicycloaryl and unsubstituted or substituted with one or more groups selected from group A' Selected from the group consisting of hetero (C _4-12 ) bicycloaryl;
R ₅ is hydrogen, hydroxy, unsubstituted or alkoxy substituted with one or more groups selected from group A ′, unsubstituted or aryloxy substituted with one or more groups selected from group A ′, Heteroaryloxy, amino substituted with one or more groups selected from substituted or group A ′, (C _1-10 ) alkylamino unsubstituted or substituted with one or more groups selected from group A ′, From unsubstituted or substituted arylamino with one or more groups selected from group A ′, unsubstituted or substituted heteroarylamino with one or more groups selected from group A ′, unsubstituted or from group A ′ (C _1-10 ) alkyl substituted with one or more selected groups, unsubstituted or substituted with one or more groups selected from group A ′ B (C _1-10 ) alkyl, unsubstituted or one or more groups selected from amino (C _1-10 ) alkyl, unsubstituted or group A ′, substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, substituted with at least one hetero (C _3-12 ) cycloalkyl (C ₁ ) substituted with one or more groups selected from group A ′ _-5 ) alkyl, unsubstituted or substituted by one or more groups selected from group A ′, aryl (C _1-10 ) alkyl, unsubstituted or substituted by one or more groups selected from group A ′ heteroaryl _{(C 1-5)} alkyl, substituted with one or more groups selected from unsubstituted or group a _{'(C 9-12)} bicycloaryl _{(C 1-5)} alkyl, unsubstituted Properly it is substituted with one or more groups selected from the group A 'heteroaryl substituted with one or more groups selected from (C _8-12) bicycloaryl (C _1-5) alkyl, unsubstituted or group A' (C _3-12 ) cycloalkyl, unsubstituted or substituted with one or more groups selected from group A ′, hetero (C _3-12 ) cycloalkyl, unsubstituted or one selected from group A ′ (C _9-12 ) bicycloalkyl substituted with one or more groups, unsubstituted or hetero (C _3-12 ) bicycloalkyl substituted with one or more groups selected from group A ′, unsubstituted or group A ′ from substituted with one or more groups selected (C _4-12) aryl, heteroaryl substituted with one or more groups selected from unsubstituted or group a '(C _1-10) Reel, heteroaryl substituted with one or more groups selected from the 'substituted with one or more groups selected from (C _9-12) bicycloaryl and unsubstituted or group A' unsubstituted or group A (C _4-12 ) selected from the group consisting of bicycloaryl;
Each R ₆ is independently selected from hydrogen, halo, cyano, unsubstituted or heteroaryloxy substituted with one or more groups selected from group A ′, aminocarbonyl, unsubstituted or group A ′. (C _1-10 ) alkylaminocarbonyl substituted with one or more groups, unsubstituted or arylaminocarbonyl substituted with one or more groups selected from group A ′, unsubstituted or selected from group A ′ Heteroarylaminocarbonyl substituted with one or more groups, amino, unsubstituted or selected from (C _1-10 ) alkylamino, unsubstituted or group A ′ substituted with one or more groups selected from group A ′ Arylamino substituted with one or more groups selected from, unsubstituted or substituted with one or more groups selected from group A ′ Terrorism arylamino, unsubstituted or 'substituted with one or more groups selected from (C _1-10) alkyl, unsubstituted or group A' Group A halo substituted with one or more groups selected from ( C _1-10 ) alkyl, unsubstituted or substituted with one or more groups selected from amino (C _1-10 ) alkyl, unsubstituted or group A ′ selected from group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) Alkyl, unsubstituted or substituted with one or more groups selected from group A ′ (C _1-10 ) alkyl, unsubstituted or one or more groups selected from group A ′ Substituted heteroaryl (C _1-5 ) alkyl, unsubstituted or (C _9-12 ) bicycloaryl (C _1-5 ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′ Hetero (C _8-12 ) bicycloaryl (C _1-5 ) alkyl substituted with one or more groups selected from group A ′, unsubstituted or substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl, unsubstituted or substituted with one or more groups selected from group A ′ hetero (C _3-12 ) cycloalkyl, unsubstituted or selected from group A ′ substituted by a group (C _9-12) bicycloalkyl, hetero substituted with one or more groups selected from unsubstituted or group a '(C _3-12) bicycloalkyl 'Substituted with one or more groups selected from (C _4-12) aryl, unsubstituted or group A' unsubstituted or group A is substituted with one or more groups selected from hetero (C _1-10 ) Aryl, unsubstituted or substituted with one or more groups selected from group A ′ (C _9-12 ) Bicycloaryl and heterocycles substituted with one or more groups selected from unsubstituted or group A ′ ( C _4-12 ) selected from the group consisting of bicycloaryl;
R _14a , R _14b , R _14c , R _14d and R _14e are each independently alkoxy, unsubstituted or substituted with one or more groups selected from hydrogen, halo, cyano, unsubstituted or group A ′ From (C _1-3 ) alkyl substituted with one or more groups selected from group A ′ and hydroxy (C _1-3 ) alkyl unsubstituted or substituted with one or more groups selected from group A ′ Selected from the group consisting of:
Group A ′ may be substituted with a group selected from halo, nitro, cyano, hydroxy, group B ′ (C _1-10 ) alkoxy, group selected from group B ′ ( C _4-12 ) aryloxy, _optionally substituted with a group selected from group B ′ hetero (C _1-10 ) aryloxy, aminocarbonyl, optionally substituted with a group selected from group B ′ ( C _1-10 ) alkylaminocarbonyl, arylaminocarbonyl optionally substituted with a group selected from group B ′, heteroarylaminocarbonyl optionally substituted with a group selected from group B ′, amino, group B (C _1-10 ) alkylamino optionally substituted with a group selected from ', substituted with a group selected from group B' From arylamino, optionally substituted heteroarylamino optionally substituted with a group selected from group B ′, (C _1-10 ) alkyl _optionally substituted with a group selected from group B ′, from group B ′ A halo (C _1-10 ) alkyl _optionally substituted with a selected group, a hydroxy (C _1-10 ) alkyl _optionally substituted with a group selected from Group B ′, and a group selected from Group B ′ Optionally substituted (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, hetero (C _3-12 ) cycloalkyl (C _1-10 ) _optionally substituted with a group selected from group B ′ ) Alkyl, aryl (C _1-10 ) alkyl _optionally substituted with a group selected from group B ′, hetero (C1) optionally substituted with a group selected from group B ′ _1-10 ) aryl (C _1-5 ) alkyl, a group selected from (C _9-12 ) bicycloaryl (C _1-5 ) alkyl, group B ′ optionally substituted with a group selected from group B ′ (C _3-12 ) cycloalkyl, group B ′ _optionally substituted with a group selected from hetero (C _8-12 ) bicycloaryl (C _1-5 ) alkyl, group B ′. Hetero (C _3-12 ) cycloalkyl _optionally substituted with a group selected from: (C _9-12 ) Bicycloalkyl _optionally substituted with a group selected from group B ′: selected from group B ′ optionally substituted hetero (C _3-12) even though bicycloalkyl in groups, 'optionally substituted by a group selected from (C _4-12) aryl, group B' group B from Optionally substituted with a group selected from optionally substituted a barrel group hetero (C _1-10) aryl, the group B 'may be substituted by a group selected from (C _9-12) bicycloaryl and group B' Hetero (C _4-12 ) bicycloaryl, which may be _substituted ;
Group B ′ includes halo, nitro, cyano, hydroxy, (C _1-10 ) alkoxy, (C _4-12 ) aryloxy, hetero (C _1-10 ) aryloxy, aminocarbonyl, amino, (C _1-10 ) Alkylamino, (C _1-10 ) alkyl, halo (C _1-10 ) alkyl, hydroxy (C _1-10 ) alkyl, (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, hetero (C _{3) -12)} cycloalkyl _{(C 1-10)} alkyl, aryl _{(C 1-10)} alkyl, hetero _{(C 1-10)} aryl _{(C 1-5) alkyl, (C 9-12)} bicycloaryl _{(C 1- 5)} alkyl, hetero _{(C 8-12)} bicycloaryl _{(C 1-5) alkyl, (C 3-12)} cycloalkyl, hetero _{(C 3-12)} cycloalkyl _{Alkyl, (C 9-12)} bicycloaryl alkyl, hetero _{(C 3-12) bicycloalkyl, (C 4-12)} aryl, hetero _{(C 1-10) aryl, (C 9-12)} bicycloaryl and hetero (C _4-12 ) Bicycloaryl. ].

  According to the above-described configuration, a compound having a basic skeleton in common with trametinib, selmethinib, or TAK-733, which has been confirmed to have an antitumor effect in Examples described later, and a compound having a basic skeleton in common with 4-MU are used in combination. It will be. Therefore, an excellent antitumor effect against various cancers can be exhibited.

  In the antitumor agent according to the present invention, the c-Met inhibitor is preferably one or more compounds selected from the group consisting of crizotinib, cabozantinib and cabozantinib s-malate.

  According to the above-described configuration, crizotinib, cabozantinib s-malate, which can inhibit the binding between c-Met and CD44, as well as crizotinib and crizotinib, which have been confirmed to have an antitumor effect in the examples described below, and 4-MU. And a compound having a common basic skeleton. Therefore, an excellent antitumor effect can be exhibited against various cancers.

  The antitumor agent according to the present invention is a group in which one or more compounds selected from the group consisting of compounds represented by the general formulas [I] to [III] are composed of trametinib, selmethinib, and TAK-733. It is preferable that it is 1 type, or 2 or more types of compounds chosen from more.

  The compound is a MEK inhibitor that exhibits an excellent antitumor effect even when used alone, as shown in the Examples described later. Therefore, according to the said structure, by using together with a coumarin derivative etc., there can exist a further superior anti-tumor effect than the case where the said compound is used independently.

  The antitumor agent according to the present invention includes the antitumor agent according to the present invention, an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-PD-L2 antibody, an anti-CTLA-4 antibody, an anti-CD25 antibody, and an anti-CD33 antibody. And at least one antibody selected from the group consisting of anti-CD52 antibodies as an active ingredient.

  From the results shown in Examples described later, it is considered that the antitumor agent can enhance the expression of the antigen of the antibody in tumor cells. Therefore, it is considered that the response rate of the antibody can be improved. Therefore, it is expected that an antitumor agent that further enhances the therapeutic effect of the antibody can be provided.

  The present invention can exhibit an excellent antitumor effect against various cancers including malignant pleural mesothelioma for which no effective treatment has been established. Therefore, there is an effect that it is possible to provide a drug showing a high therapeutic effect against various cancers.

It is a graph which shows the relationship between the concentration of trametinib and cell viability when NCI-H226 cells, NCI-H2452 cells, NCI-H2052 cells and MSTO-211H cells are used as cell lines of malignant pleural mesothelioma. . It is a graph which shows the relationship between the density | concentration of 4-MU and a cell survival rate at the time of using the same cell line as FIG. It is a figure which shows the western blot analysis result of NCI-H226 cell processed for 72 hours with 0-10000 nM trametinib. It is a figure which shows the relationship between the density | concentration of trametinib, and inhibition of the phosphorylation of ERK in NCI-H226 cell ((a) of FIG. 4), and the protein level of CD44 ((b) of FIG. 4). It is a figure which shows the result of having analyzed the time-dependent change at the time of processing NCI-H226 cell for 0 to 72 hours with 20 micromol trametinib by Western blot. It is a figure which shows the relationship between the treatment time with trametinib and inhibition of phosphorylation of ERK in NCI-H226 cells (FIG. 6 (a)) and the relationship with the protein level of CD44 (FIG. 6 (b)). . It is a figure which shows the western blot analysis result of the MSTO-211H cell processed for 72 hours with 0-1000 nM trametinib. FIG. 9 is a graph showing the relationship between the concentration of trametinib and inhibition of ERK phosphorylation in MSTO-211H cells (FIG. 8 (a)) and the relationship with the protein level of CD44 (FIG. 8 (b)). It is a figure which shows the result of having analyzed the time-dependent change at the time of processing a MSTO-211H cell for 0 to 72 hours by 1 micromol trametinib by Western blotting. It is a figure which shows the relationship between the treatment time with trametinib and inhibition of ERK phosphorylation in MSTO-211H cells (FIG. 10 (a)) and the relationship with the protein level of CD44 (FIG. 10 (b)). . It is a figure which shows the western blot analysis result of NCI-H226 cell processed for 72 hours with 10 nM-100 micromol 4-MU. The figure which shows the relationship between the density | concentration of 4-MU, and the inhibition of the phosphorylation of ERK in NCI-H226 cell (FIG. 12 (a)), and the protein level of CD44 (FIG. 12 (b)). is there. It is a figure which shows the Western blot analysis result showing the relationship between the expression of Fra-1, and the treatment by trametinib and / or 4-MU. It is a figure which shows the relationship between the usage-amount of trametinib and / or 4-MU, and the expression of phosphorylated ERK. It is a figure which shows the relationship between the usage-amount of trametinib and / or 4-MU, and the expression of CD44. It is a figure which shows the relationship between the usage-amount of trametinib and / or 4-MU, and the expression of Fra-1. It is a figure which shows the result of having observed the anti-tumor effect over time when trametinib and / or 4-MU are administered to a mouse xenograft model. It is a figure which shows the result of having used the NCI-H226 tumor tissue collect | recovered 4 hours after the last administration of the chemical | medical agent to a western blot. It is a figure which shows the result of having used the NCI-H226 tumor tissue collect | recovered 4 days after the last administration of a chemical | medical agent to a western blot. It is the figure which confirmed the result of the immunohistochemistry about NCI-H226 tumor tissue collect | recovered 4 hours after the last administration of a chemical | medical agent, and the NCI-H226 tumor tissue collect | recovered 4 days after the last administration of a pharmaceutical by 40 time magnification. . It is the figure which confirmed the result of the immunohistochemical staining about NCI-H226 tumor tissue collect | recovered 4 hours after the last administration of a chemical | medical agent, and NCI-H226 tumor tissue collect | recovered 4 days after the last administration of a chemical | medical agent by 200 time magnification. . The figure which shows the result of having compared the ratio of the phosphorylated ERK positive cell expressed in the structure | tissue of NCI-H226 tumor in the nude mouse which orally administered trametinib, 4-MU, or the combination of trametinib and 4-MU compared with the control | contrast. It is. It is a graph which shows the relationship between the density | concentration of TAK-733 and a cell viability at the time of processing NCI-H226 cell by TAK-733. It is a graph which shows the relationship between the density | concentration of a cermetinib, and a cell viability at the time of processing NCI-H28 cell by a selumetinib. It is a graph which shows the relationship between the density | concentration of a cermetinib, and a cell survival rate at the time of processing a MSTO-211H cell by a selumetinib. It is a graph which shows the relationship between the density | concentration of a cermetinib, and a cell survival rate at the time of processing NCI-H226 cell by a selumetinib. It is a graph which shows the relationship between the density | concentration of a cermetinib, and a cell viability at the time of processing NCI-H2052 cell by a selumetinib. It is a figure which shows the result at the time of processing NCI-H2452 cell by a selumetinib. It is a figure which shows the cell survival rate at the time of using NCI-H2052 cell as a malignant pleural mesothelioma cell, and processing by crizotinib and / or 4-MU. It is a figure which shows the cell survival rate at the time of using NCI-H2452 cell as a malignant pleural mesothelioma cell, and processing by crizotinib and / or 4-MU. It is a figure which shows the cell survival rate at the time of using NCI-H226 cell as a malignant pleural mesothelioma cell, and processing by crizotinib and / or 4-MU. It is a figure which shows the cell survival rate at the time of using NCI-H28 as a malignant pleural mesothelioma cell, and processing by crizotinib and / or 4-MU. It is a figure which shows the result of the immunohistochemical staining which observed the expression of PD-1, PD-L1, CTLA-4 about the NCI-H226 tumor tissue collect | recovered 4 hours after the last administration of the chemical | medical agent.

  Hereinafter, embodiments of the present invention will be described in detail. A description such as “A to B” indicating a range indicates that the range is A or more and B or less. In addition, all the patent documents and nonpatent literatures described in this specification are used as reference in this specification.

[Embodiment 1: Antitumor effect enhancer]
The antitumor effect potentiator according to the present invention contains a coumarin derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and can enhance the antitumor effect of a MEK inhibitor and / or c-Met inhibitor.

  The “coumarin derivative” is a compound generated by a chemical change of a small part in the coumarin molecule, and may be a coumarin substitution product or an adduct. As the coumarin derivative, for example, one or more compounds selected from the group consisting of compounds represented by the following general formula [IV] can be suitably used.

(In the formula, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, a hydroxyl group or a C _1-6 alkyl group. R ²⁰ , R ²¹ , R ²² and R ²³ each independently represent a hydrogen atom or a hydroxyl group. And the hydrogen atom of the hydroxyl group may be substituted with a C _1-6 alkyl group or a β-D-glucopyranosyl group)
Examples of the compound represented by the general formula [IV] include 4-hydroxycoumarin, 4-methylumbelliferone (4-MU), 7-hydroxycoumarin (umbelliferone), and 7,8-dihydroxycoumarin (daphnetin). , 6,7-dihydroxycoumarin (esculetin), 4-methyl-6,7-dihydroxycoumarin (4-methylesculetin), esculin, isoscopoletin, scopalone, 5,7-dihydroxy-4-methyl-coumarin, etc. be able to. When two or more compounds are used, they can be used in combination at any ratio.

  In Examples described later, 4-MU is used in combination with a MEK inhibitor or a c-Met inhibitor, whereby the anti-tumor effect of the MEK inhibitor and the anti-tumor effect of the c-Met inhibitor are enhanced. It has been shown that an anti-tumor effect can be obtained. That is, it can be said that 4-MU can further enhance the antitumor effects of MEK inhibitors and c-Met inhibitors.

  As mentioned above, 4-MU was once used as a bile agent. However, because of the development of better antibacterial agents, it has now been discontinued and has become a so-called past drug that has not found particularly useful applications. The finding that such 4-MU can enhance the anti-tumor effects of MEK inhibitors and c-Met inhibitors has been found for the first time by the present invention, and new usefulness of 4-MU. It can be said that it is very meaningful in that it can provide a use.

  As used herein, the term “antitumor effect potentiator” means an agent that can enhance the antitumor effect of a MEK inhibitor and / or c-Met inhibitor. “The anti-tumor effect of a MEK inhibitor and / or c-Met inhibitor can be enhanced” means that the anti-tumor effect superior to the anti-tumor effect exerted by using a MEK inhibitor and / or a c-Met inhibitor. It means that a tumor effect is obtained. “Anti-tumor effect” refers to an effect of suppressing and attenuating tumor growth.

  From the matter described above, it is understood that 4-MU can be used as an active ingredient of the antitumor effect enhancer according to the present invention. On the other hand, the active ingredient is not limited to 4-MU. For example, a coumarin derivative typified by a compound represented by the general formula [IV] has different substituents but is similar in structure to 4-MU, and therefore one or more compounds selected from the group consisting of the above compounds Can be used as the active ingredient as well as 4-MU.

  The antitumor effect potentiator according to the present invention is usually a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, etc., which are generally known per se, in addition to the coumarin derivative and the like. Agents, emulsifiers, fragrances, colorants, sweeteners, thickeners, flavoring agents, solubilizers, other additives, specifically water, vegetable oils, alcohols (eg, ethanol, benzyl alcohol, etc.), polyethylene glycol, Glycerol triacetate, gelatin, carbohydrates (eg, lactose, starch, etc.), magnesium stearate, talc, lanolin, petrolatum and the like can be contained.

  The antitumor effect enhancer is mixed with the excipients and the like, and is prepared by a conventional method, such as tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, troches, aerosols, By taking the form of elixir, suspension, emulsion, syrup, etc., it can be administered systemically or locally, orally or parenterally.

  The “pharmaceutically acceptable salt thereof” may be any salt as long as it forms a non-toxic salt with the coumarin derivative. For example, inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbine Acids, organic acids such as methanesulfonic acid, benzenesulfonic acid; inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine , Tris (hydroxymethyl) methylamine, guanidine, choline, cinchonine and other organic bases; or lysine, arginine, alanine and other amino acids. In addition, in this invention, the hydrate or hydrate and solvate of each compound are also included.

  Since the antitumor effect enhancer according to the present invention can further enhance the antitumor effect of the MEK inhibitor and the antitumor effect of the c-Met inhibitor, respectively, in combination with the MEK inhibitor and the c-Met inhibitor, respectively. , And can be used as an antitumor agent (referred to herein as “antitumor agent (A)”). Therefore, the antitumor agent (A) according to the present invention will be described next.

[Embodiment 2: Antitumor agent (A)]
(1) Active ingredient The antitumor agent (A) which concerns on this invention contains a MEK inhibitor and / or c-Met inhibitor, and the antitumor effect enhancer which concerns on this invention as an active ingredient. The antitumor effect potentiator is as described in the first embodiment. Therefore, hereinafter, the MEK inhibitor and the c-Met inhibitor will be described first, and then the antitumor agent (A) will be described.

(1-1) MEK inhibitor A MEK inhibitor inhibits cell growth by inhibiting the action of phosphorylase MEK present in the cell proliferation signaling pathway (MAPK pathway) (blocking cell proliferation signaling). A drug. Activation of cell proliferation signaling pathways leading to Ras, Raf, MEK, ERK has been observed in many carcinomas, and MEK inhibitors block cell proliferation signaling by inhibiting phosphorylation of ERK by MEK. To do.

  The MEK inhibitor can attenuate the expression of CD44, as shown in Examples described later. And since the said coumarin derivative etc. inhibit the synthesis | combination of a hyaluronic acid, the coupling | bonding of a hyaluronic acid and CD44 becomes difficult to produce. Therefore, it is considered that by using the MEK inhibitor and the coumarin derivative or the like as active ingredients, an antitumor effect that is synergistically superior to the case of using the MEK inhibitor or the coumarin derivative or the like alone can be obtained. It is done.

  As the MEK inhibitor, for example, one or more compounds selected from the group consisting of the compounds represented by the aforementioned general formulas [I] to [III] or pharmaceutically acceptable salts thereof are suitable. Can be used.

  The “pharmaceutically acceptable salt thereof” may be any salt as long as it forms a non-toxic salt with the MEK inhibitor. The c-Met inhibitor described below may be any salt as long as it forms a non-toxic salt with the c-Met inhibitor.

  Examples of the salt include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid; oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, Organic acids such as gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid; inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; methylamine, diethylamine, triethylamine, triethylamine It can be obtained by reacting with an organic base such as ethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine, choline and cinchonine; or an amino acid such as lysine, arginine and alanine. In addition, in this invention, the hydrate or hydrate and solvate of each compound are also included.

(1-1-1) Compound represented by general formula [I] The compound represented by general formula [I] is described in Japanese Patent No. 4163737. In the above general formula [I], the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. An atom, more preferably a fluorine atom as 1) of group A, more preferably a fluorine atom or a bromine atom as 1) of group C, and preferably a fluorine atom or an iodine atom as 1) of group B .

The “C _1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, 2,2-dimethylpropyl group. Group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like.

R ^{1 ′} , R ^{2 ′} and R ⁶ are preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a 2,2-dimethylpropyl group, a butyl group or an isobutyl group, and more preferably a methyl group or an ethyl group. And particularly preferably a methyl group. R ³ , R ⁴ , and R ⁵ are preferably a methyl group, an ethyl group, a propyl group, and an isobutyl group, and more preferably a methyl group.

The “C _1-4 alkyl group” is a linear or branched alkyl group having 1 to 4 carbon atoms, specifically a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, A sec-butyl group, a tert-butyl group, etc. are mentioned.

As group A 4) and group C 3), preferred are a methyl group and an ethyl group, and more preferred is a methyl group. R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^A7 , R ^A8 and R ^A9 are preferably a methyl group, an ethyl group and a butyl group, and more preferably a methyl group.

R ^{B1 to} R ^B31 are preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group, and more preferably a methyl group, an ethyl group, and a propyl group. R ^C1 , R ^C2 , R ^C3 , R ^C4 and R ^C5 are preferably a methyl group or an ethyl group, and more preferably a methyl group.

The “C _1-8 alkyl group” is a linear or branched alkyl group having 1 to 8 carbon atoms, specifically a methyl group, an ethyl group, a propyl group, an isopropyl group, or 1-ethyl-1- Examples include propyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, 3-methylbutyl group, 1-propyl-1-butyl group, pentyl group, isopentyl group, hexyl group, heptyl group, octyl group and the like. It is done.

  The group B 2) is preferably a methyl group, an ethyl group, a propyl group, an isopentyl group, a 1-ethyl-1-propyl group, a 3-methylbutyl group, or a 1-propyl-1-butyl group, more preferably a methyl group. Group, an ethyl group.

The “C _2-6 alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, and specifically includes a vinyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group, 1-pentenyl Group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1,2-dimethyl-1-propenyl group, 1,2-dimethyl-2-propenyl group, 1-ethyl-1-propenyl group, 1- Ethyl-2-propenyl group, 1-methyl-1-butenyl group, 1-methyl-2-butenyl group, 2-methyl-1-butenyl group, 1-isopropylvinyl group, 2,4-pentadienyl group, 1-hex Examples include a senyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 5-hexenyl group, a 2,4-hexadienyl group, and a 1-methyl-1-pentenyl group.

R ^{1 ′} , R ^{2 ′} , R ³ , R ⁴ , R ⁵ and R ⁶ are preferably a vinyl group, 1-propenyl group and 2-propenyl group, and more preferably a 2-propenyl group.

The “C _2-4 alkenyl group” is a linear or branched alkenyl group having 2 to 4 carbon atoms, and specifically includes a vinyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, 1 -Butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-ethylvinyl group and the like can be mentioned.

  Group B 5) is preferably a vinyl group or 1-propenyl group, and more preferably a vinyl group.

The “C _2-4 alkynyl group” is a linear or branched alkynyl group having 2 to 4 carbon atoms, specifically, an ethynyl group, 1-propynyl group, 2-propynyl group, isopropynyl group, 1- Examples include butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-1-propynyl group, 1-methyl-2-propynyl group, 2-methyl-2-propynyl group, and 1-ethylethynyl group.

Group B 6) is preferably an ethynyl group, a 1-propynyl group, or a 1-butynyl group, and more preferably an ethynyl group.

R 2 ^'and R ³ and is may be a "C _1-4 alkylene group" and R ⁴ may be formed together with R ⁵ to form together "C _1-4 alkylene group" Represents a linear or branched alkylene group having 1 to 4 carbon atoms, and specifically includes a methylene group, an ethylene group, a trimethylene group, a 2-methyltrimethylene group, a tetramethylene group, and the like.

The “C _1-4 alkylene group” that R ² ′ and R ³ may form together is preferably a methylene group, an ethylene group, or a trimethylene group, and more preferably a trimethylene group.

The “C _1-4 alkylene group” that R ⁴ and R ⁵ may form together is preferably a methylene group, an ethylene group, or a trimethylene group, and more preferably an ethylene group.

  m is preferably 0, or an integer of 1 or 2, and more preferably 0.

The “C _3-12 carbocyclic group” is a saturated or unsaturated cyclic hydrocarbon group having 3 to 12 carbon atoms, and includes a phenyl group, a naphthyl group, a C _3-8 cycloalkyl group, or a C _3-8. It means a condensed ring group of cycloalkyl and benzene.

The “C _3-8 cycloalkyl group” is a saturated cyclic hydrocarbon group having 3 to 8 carbon atoms, specifically, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, A cyclooctyl group, a norbornanyl group, etc. are mentioned, Preferably they are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

Specific examples of the “condensed cyclic group of C _3-8 cycloalkyl and benzene” include an indanyl group, 1,2,3,4-tetrahydronaphthyl group (1,2,3,4-tetrahydro-2-naphthyl). Group, 5,6,7,8-tetrahydro-2-naphthyl group and the like, preferably an indanyl group, 1,2,3,4-tetrahydronaphthyl group and the like, more preferably an indanyl group. is there.

R ¹ ′, R ² ′, R ³ , R ⁴ , R ⁵ and R ⁶ are preferably a phenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, more preferably a phenyl group and a cyclopropyl group. It is. R ¹ ′ is particularly preferably a cyclopropyl group, and R ² ′ and R ⁶ are particularly preferably a phenyl group. Group A 11), R ^A7 , Group B 22), R ^B3 , R ^B6 and R ^B16 are preferably a phenyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group, more preferably a phenyl group. , A cyclopropyl group.

The “heterocyclic group” includes 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to carbon atoms as atoms constituting the ring, and 5 or 6 A saturated monocyclic ring having an atom constituting the ring, an unsaturated monocyclic ring, a condensed ring of the monocyclic ring and a benzene ring, or the monocyclic or condensed ring and the C _3-12 A spiro ring group with a carbocycle, each of which may have 1 to 4, preferably 1 or 2 oxo groups.

  Examples of the “heterocyclic group” which is a monocyclic saturated ring include pyrrolidinyl group, tetrahydrofuryl group, tetrahydrothienyl group, imidazolidinyl group, 2-oxoimidazolidinyl group, 2,4-dioxoimidazolidinyl group, pyrazolidinyl group 1,3-dioxolanyl group, 1,3-oxathiolanyl group, oxazolidinyl group, 2-oxooxazolidinyl group, thiazolidinyl group, piperidinyl group, piperazinyl group, 2-oxopiperazinyl group, tetrahydropyranyl group, tetrahydro Thiopyranyl group, dioxanyl group, morpholinyl group, thiomorpholinyl group, 2-oxopyrrolidinyl group, 2-oxopiperidinyl group, 4-oxopiperidinyl group, 2,6-dioxopiperidinyl group, thiadiazo Lysinyl groups (eg 1,1-dioxo-1,2,5-thiadi Zorijin-2-yl group). Preferable examples include pyrrolidinyl group, piperidinyl group, piperazinyl group and morpholinyl group.

  Examples of the “heterocyclic group” that is a monocyclic unsaturated ring include a pyrrolyl group (for example, 2-pyrrolyl group), a furyl group, a thienyl group, an imidazolyl group (for example, 4-imidazolyl group, etc.), 1,2- Dihydro-2-oxoimidazolyl group, pyrazolyl group (for example, 5-pyrazolyl group, etc.), diazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, 1,2,4-triazolyl group, 1,2,3- Triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, furazanyl group, pyridyl group (for example, 3-pyridyl group, etc.), pyrimidinyl group, 3,4-dihydro-4-oxopyrimidinyl group, pyridazinyl group, pyrazinyl group, 1, , 5-triazinyl group, imidazolinyl group (for example, 2-imidazolinyl group, etc.), pyrazolinyl group, oxazolinyl group (2-oxazolinyl group, 3-oxazolinyl group, 4-oxazolinyl group), isoxazolinyl group, thiophenyl group, thiazolinyl Group, isothiazolinyl group, pyranyl group, 2-oxopyranyl group, 2-oxo-2,5-dihydrofuranyl group, 1,1-dioxo-1H-isothiazolyl group and the like. Preferable examples include pyrrolyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiophenyl group, thiazolyl group, isothiazolyl group and pyridyl group.

  Examples of the “heterocyclic group” that is a condensed ring of a single ring and a benzene ring include an indolyl group (for example, 4-indolyl group, 5-indolyl group, 6-indolyl group, 7-indolyl group, etc.), isoindolyl group, 1 , 3-dihydro-1,3-dioxoisoindolyl group, benzofuranyl group (for example, 4-benzofuranyl group, 7-benzofuranyl group, etc.), indazolyl group, isobenzofuranyl group, benzothiophenyl group (for example, 4 -Benzothiophenyl group, 5-benzothiophenyl group, 7-benzothiophenyl group, etc.), benzoxazolyl group (for example, 4-benzoxazolyl group, 7-benzoxazolyl group, etc.), benzimidazolyl Groups (for example, 4-benzimidazolyl group, 5-benzimidazolyl group, 7-benzimidazolyl group, etc.), benzothiazolyl groups (examples) 4-benzothiazolyl group, 7-benzothiazolyl group, etc.), quinolyl group, isoquinolyl group, 1,2-dihydro-2-oxoquinolyl group, quinazolinyl group, quinoxalinyl group, cinnolinyl group, phthalazinyl group, 2,3-dihydroindolyl Group, isoindolinyl group, 1,2,3,4-tetrahydroquinolyl group, 2-oxo-1,2,3,4-tetrahydroquinolyl group, benzo [1,3] dioxolyl group, chromanyl group, isochromanyl group,

Etc.

Examples of the spiro ring of the single ring or condensed ring and the C _3-12 carbocycle include groups represented by the following formulae.

  Preferably, it is a condensed ring group of a monocyclic 5-membered or 6-membered heterocyclic ring and a benzene ring, and specifically includes an indolyl group, an indazolyl group, a benzothiophenyl group, a benzimidazolyl group, 2,3-dihydro Indolyl group, 1,2,3,4-tetrahydroquinolyl group, benzo [1,3] dioxolyl group and the like.

R ¹ ′, R ² ′, R ³ , R ⁴ , R ⁵ and R ⁶ are preferably pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, thiophenyl, thiazolyl, indolyl, indazolyl, Benzothiophenyl group, benzimidazolyl group, 2,3-dihydroindolyl group, 1,2,3,4-tetrahydroquinolyl group and benzo [1,3] dioxolyl group, more preferably piperidinyl group, pyridinyl group Thiophenyl group, thiazolyl group, indolyl group, indazolyl group, benzothiophenyl group, benzimidazolyl group, 2,3-dihydroindolyl group, 1,2,3,4-tetrahydroquinolyl group, benzo [1,3] Dioxolyl group. Group A 12), RA7 and Group B 23), RB3, RB6, RB16 and RB17 are preferably a pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group, pyridyl group and oxazolinyl group, more preferably a pyrrolidinyl group. , Piperidinyl group, piperazinyl group and morpholinyl group.

“C _1-6 alkyl group” and “C _2-6 alkenyl group” of R ¹ ′, R ² ′ and R ⁶ and R ³ , R ⁴ and R ⁵ are 1 to 3 substituents selected from group A It may be substituted with a group. That is, "C _1-6 alkyl group" and "C _2-6 alkenyl group" defined above may be substituted with 1 to 3 substituents selected from group A, unsubstituted "C _{1- 6} alkyl group "and unsubstituted" C _2-6 alkenyl group ".

The “C _1-8 alkyl group” in the above definition in group B 4) and the “C _1-4 alkyl group” in the above definitions in R ^{B1 to} R ^B31 are the same or different from each other. It may be substituted with 1 to 3 substituents.

“Group A” means 1) “halogen atom” as defined above, 2) nitro group, 3) cyano group, 4) “C1-4 alkyl group” as defined above, 5) “—OR ^A1 ”, 6) “—SR ^A2 ”, 7) “—NR ^A3 R ^A4 ”, 8) “—COOR ^A5 ”, 9) “—NR ^A6 COR ^A7 ”,
10) “—NR ^A8 COOR ^A9 ”, 11) “C _3-12 carbocyclic group” as defined above and 12) “heterocyclic group” as defined above, wherein R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^A8 and R ^A9 are the same or different and each represents a hydrogen atom or the above-defined “C _1-4 alkyl group”, and R ^A7 represents the above The “C _1-4 alkyl group” defined above, the “C _3-12 carbocyclic group” defined above, or the “heterocyclic group” defined above are shown.

Specific examples of the “—OR ^A1 ” include a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropyloxy group, a tert-butoxy group, and the like.

Specific examples of the “—SR ^A2 ” include a mercapto group, a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, and a tert-butylsulfanyl group.

Examples of the “—NR ^A3 R ^A4 ” include amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methyl. Specific examples include an amino group, an N-methyl-N-propylamino group, and an N-isopropyl-N-methylamino group.

Specific examples of the “—COOR ^A5 ” include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, and the like.

Specific examples of “—NR ^A6 COR ^A7 ” include acetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, N-acetyl-N-methylamino group, butylcarbonylamino group and the like. It is done.

Specific examples of “—NR ^A8 COOR ^A9 ” include a carboxyamino group, a carboxymethylamino group, a carboxyethylamino group, a methoxycarbonylamino group, and a methoxycarbonylmethylamino group.

  “Group A” is preferably fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, propyl group, hydroxy group, methoxy group, ethoxy group, propoxy group, amino group, methylamino group, ethylamino group, dimethyl group. Examples include an amino group, a diethylamino group, a carboxyamino group, a butylcarbonylamino group, a carboxy group, a phenyl group, a 4-morpholinyl group, a 1-pyrrolidinyl group, a 1-piperidinyl group, and a 1-piperazinyl group.

  Particularly preferably as group A, fluorine atom, chlorine atom, methyl group, hydroxy group, methoxy group, amino group, dimethylamino group, diethylamino group, carboxyamino group, butylcarbonylamino group, carboxy group, phenyl group, 4-morpholinyl Group, 1-pyrrolidinyl group, 1-piperidinyl group and 1-piperazinyl group.

  The number of the preferred substituents is 1, and the substituents may be used anywhere as long as they can be substituted.

_{"C 3-12} carbon ring group" and "heterocyclic group" as well as ^R 3, _{"C 3-12} carbon ring group" of ^{R 4} or ^{R 5} and "heterocyclic group" as ring Cy is selected from the group B May be substituted with 1 to 5 substituents. That is, the above-defined “C _3-12 carbocyclic group” and “heterocyclic group” may be substituted with 1 to 5 substituents selected from Group B, and may be substituted with an unsubstituted “C _3-12 carbon”. A "ring group" and an unsubstituted "heterocyclic group".

“Group B” means 1) “halogen atom” as defined above, 2) nitro group, 3) cyano group, 4) “C _1-8 alkyl group” as defined above, and 5) “C _{2− as} defined above”. ₄ alkenyl group ”, 6)“ C _2-4 alkynyl group ”as defined above, 7)“ —OR ^B1 ”, 8)“ —SR ^B2 ”, 9)“ —NR ^B3 R ^B4 ”, 10)“ —NR ^B5 COR ^B6 ", 11)" ^- NR B7 COOR ^B8 ", 12)" ^- NR ^{B9 CONR} B10 ^{R B11} ", 13)" ^- NR ^{B12 CONR} B13 ^{OR B14} ", 14)" ^- NR _B15 SO ^{2 R B16} " 15) “—SO ₂ —R ^B17 ”, 16) “—SO ₂ NR ^B18 R ^B19 ”, 17) “—P (═O) (R ^B20 ) (R ^B21 )”, 18) “—COOR ^B22 ” 19) "-CONR ^B23 R ^B24 ”, 20)“ —NR ^B25 SO ₂ NR ^B26 R ^B27 ”, 21)“ —NR ^B28 SO ₂ NR ^B29 CONR ^B30 R ^B31 ”, 22)“ C _3-12 carbocyclic group ”and 23) as defined above. A group consisting of “heterocyclic group” as defined above, wherein R ^B1 , R ^B2 , R ^B4 , R ^B5 , R ^B7 , R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 , R ^B14 , R ^B15 , R ^B18 , R ^B19 , R ^B22 , R ^B23 , R ^B24 , R ^B25 , R ^B26 , R ^B27 , R ^B28 , R ^B29 , R ^B30 and R ^B31 are the same or different, respectively. A hydrogen atom or a “C _1-4 alkyl group” as defined above; R ^B3 and R ^B6 are each a hydrogen atom, a “C _1-4 alkyl group” as defined above, “C _3-12 carbocyclic group” as defined above, or “heterocyclic group” as defined above, and R ^B16 represents “C _1-4 alkyl group” as defined above, “C _{3-12 as} defined above”. Carbocyclic group ”or“ heterocyclic group ”as defined above, and R ^B17 represents“ C _1-4 alkyl group ”as defined above or“ heterocyclic group ”as defined above, and R ^B20 and R ^B21 is the same or different and each represents a “C _1-4 alkyl group” as defined above.

Specific examples of “—OR ^B1 ” include hydroxy group, methoxy group, ethoxy group, propoxy group, isopropyloxy group, tert-butoxy group and the like.

Specific examples of “—SR ^B2 ” include a mercapto group, a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a tert-butylsulfanyl group, and the like.

“—NR ^B3 R ^B4 ” includes amino group, methylamino group, ethylamino group, 2-aminoethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, diethylamino group, N Specific examples include -ethyl-N-methylamino group, N-methyl-N-propylamino group, N-isopropyl-N-methylamino group, N- (imidazolin-2-yl) amino group and the like.

“—NR ^B5 COR ^B6 ” includes amino group, formylamino group, acetylamino group, hydroxyacetylamino group, propionylamino group, butyrylamino group, isobutyrylamino group, pivaloylamino group, N-acetyl-N-methylamino. Group, 3-aminopropionylamino group, 3- (pentanoylamino) propionylamino group, 4-imidazolylcarbonylamino group, (1-methylpyrrol-2-yl) carbonylamino group, 4-pyrazolylcarbonylamino group, etc. For example.

Specific examples of “—NR ^B7 COOR ^B8 ” include a carboxyamino group, a carboxymethylamino group, a carboxyethylamino group, a methoxycarbonylamino group, a methoxycarbonylmethylamino group, and the like.

“—NR ^B9 CONR ^B10 R ^B11 ” includes an aminocarbonylamino group, a methylaminocarbonylamino group, a dimethylaminocarbonylamino group, a (methylaminocarbonyl) (methyl) amino group, and a (dimethylaminocarbonyl) (methyl) amino group. , [(2-hydroxyethyl) carbamoyl] amino and the like.

Specific examples of “—NR ^B12 CONR ^B13 OR ^B14 ” include a methoxyaminocarbonylamino group, (methylmethoxyaminocarbonyl) (methyl) amino group, (methylmethoxyaminocarbonyl) amino group, and the like.

Examples of “—NR ^B15 SO ₂ R ^B16 ” include sulfonylamino group, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, N-methyl-N-sulfonylamino group, N-methyl-N-methylsulfonylamino. Group, N-ethyl-N-sulfonylamino group, N-ethyl-N-methylsulfonylamino group, 3-pyridylsulfonylamino group, morpholinosulfonylamino group, piperidinomorpholinosulfonylamino group, 2-morpholinoethylsulfonylamino group Etc. are specifically mentioned.

Specific examples of “—SO ₂ —R ^B17 ” include a sulfonyl group, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, a butylsulfonyl group, and the like.

Specific examples of “—SO ₂ NR ^B18 R ^B19 ” include an aminosulfonyl group, a methylaminosulfonyl group, a dimethylaminosulfonyl group, and an ethylmethylaminosulfonyl group.

Specific examples of “—P (═O) (R ^B20 ) (R ^B21 )” include a phosphinoyl group, a methylphosphinoyl group, a dimethylphosphinoyl group, an ethylphosphinoyl group, and a diethylphosphinoyl group. Can be mentioned.

Specific examples of “—COOR ^B22 ” include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, and the like.

Specific examples of “—CONR ^B23 R ^B24 ” include carbamoyl, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl, propylcarbamoyl, butylcarbamoyl and the like.

Specific examples of “—NR ^B25 SO ₂ NR ^B26 R ^B27 ” include a sulfamoylamino group and a dimethylsulfamoylamino group.

Specific examples of “—NR ^B28 SO ₂ NR ^B29 CONR ^B30 R ^B31 ” include a {[(2-hydroxyethyl) carbamoyl] (2-hydroxyethyl) sulfamoyl} amino group.

  “Group B” is preferably a fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, isopentyl group, Hexyl, 1-ethylpropyl, 1-propylbutyl, vinyl, 1-propenyl, ethynyl, 1-propynyl, 1-butynyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy Group, methylthio group, ethylthio group, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, ethylmethylamino group, methylcarbonylamino group, ethylcarbonylamino group, propylcarbonylamino group, isopropylcarbonylamino group , (Methylcarbonyl) (methyl) Mino group, ethoxycarbonylamino group, methylaminocarbonylamino group, dimethylaminocarbonylamino group, methoxyaminocarbonylamino group, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, isopropylsulfonylamino group, phenylsulfonylamino group , (Methylsulfonyl) (methyl) amino group, methylsulfonyl group, piperazin-1-ylsulfonyl group, morpholin-4-ylsulfonyl group, piperidin-4-ylsulfonyl group, pyrrolidin-4-ylsulfonyl group, aminosulfonyl group Methylaminosulfonyl group, ethylaminosulfonyl group, dimethylaminosulfonyl group, dimethylphosphinoyl group, carboxy group, methoxycarbonyl group, carbamoyl group, methylaminocarbonyl group Boniru group, ethylaminocarbonyl group, a dimethylamino sulfonyl group, a cyclopropyl group, a cyclohexyl group, a phenyl group, a piperidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group and morpholinyl group.

  Particularly preferably as "Group B", fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, cyano group, methyl group, ethyl group, propyl group, isopropyl group, butyl group, 1-ethylpropyl group, 1- Propylbutyl, butyl, isobutyl, isopentyl, vinyl, ethynyl, 1-propynyl, 1-butynyl, hydroxy, methoxy, propoxy, isopropoxy, methylthio, amino, methylamino Group, ethylamino group, dimethylamino group, diethylamino group, ethylmethylamino group, methylcarbonylamino group, ethylcarbonylamino group, propylcarbonylamino group, isopropylcarbonylamino group, (methylcarbonyl) (methyl) amino group, ethoxycarbonyl Amino group, methylaminocal Nylamino group, dimethylaminocarbonylamino group, methoxyaminocarbonylamino group, methylsulfonylamino group, ethylsulfonylamino group, propylsulfonylamino group, isopropylsulfonylamino group, phenylsulfonylamino group, (methylsulfonyl) (methyl) amino group, Methylsulfonyl group, piperazin-1-ylsulfonyl group, morpholin-4-ylsulfonyl group, piperidin-4-ylsulfonyl group, pyrrolidin-4-ylsulfonyl group, aminosulfonyl group, methylaminosulfonyl group, ethylaminosulfonyl group, Dimethylaminosulfonyl group, dimethylphosphinoyl group, carboxy group, methoxycarbonyl group, carbamoyl group, methylaminocarbonyl group, ethylaminocarbonylamino group, dimethylamine Roh sulfonylamino group, a cyclopropyl group, a phenyl group, a piperidinyl group, pyrrolidinyl group, piperidinyl group, piperazinyl group and morpholinyl group.

The number of preferred substituents is 1 or 2, and when “C _3-12 carbocyclic group” is a phenyl group, ring Cy is preferably 2-position mono-substituted, 3-position mono-substituted, 4-position mono-substituted, , 3-position di-substitution, 2,4-position di-substitution, 2,5-position di-substitution or 2,6-position di-substitution, particularly preferably 4-position mono-substitution or 2,4-position di-substitution, and R ^{2 ′} is More preferably, it is mono-substituted at the 3-position, and R ⁶ is more preferably di-substituted at the 2,4-position.

The definition of “C _1-4 alkyl group” in the above definition in 4) of group A in the above definition, R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^A7 , R ^A8 or R ^A9 The “C _1-4 alkyl group” may be substituted with the same or different 1 to 3 substituents selected from “Group C” defined below.

The “C _3-12 carbocyclic group” defined in 11) and R ^A7 of Group A and the “heterocyclic group” defined in 12) and R ^A7 are each selected from “Group C” defined below. The same or different 1 to 5 substituents may be substituted.

Group B above 22), “C _3-12 carbocyclic group” of the above definition of R ^B3 , R ^B6 and R ^B16 , and 23) of the above definition of R ^B3 , R ^B6 , R ^B16 and R ^B17 Each “heterocyclic group” may be substituted with the same or different 1 to 5 substituents selected from “Group C” defined below.

“Group C” means 1) “halogen atom” as defined above, 2) cyano group, 3) “C _1-4 alkyl group” as defined above, 4) “—OR ^C1 ”, 5) “—NR ^C2 R ^C3 ”, 6)“ —COOR ^C4 ”and 7) an oxo group, wherein R ^C1 , R ^C2 , R ^C3 and R ^C4 are the same or different and are each a hydrogen atom or The “C _1-4 alkyl group” defined above is shown.

Specific examples of “—OR ^C1 ” include hydroxy group, methoxy group, ethoxy group, propoxy group, isopropoxy group, tert-butoxy group and the like.

“—NR ^C2 R ^C3 ” includes amino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, tert-butylamino group, dimethylamino group, diethylamino group, N-ethyl-N-methylamino. Specific examples include a group, an N-methyl-N-propylamino group, and an N-isopropyl-N-methylamino group.

Specific examples of “—COOR ^C4 ” include a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropyloxycarbonyl group, a tert-butoxycarbonyl group, and the like.

As the “group C”, 1) “halogen atom” as defined above, 2) cyano group, 3) “C _1-4 alkyl group” as defined above, 4) “—OR ^C1 ”, 5) “—NR” ^C2 R ^C3 ”and 6)“ —COOR ^C4 ”, specifically, fluorine atom, chlorine atom, bromine atom, cyano group, methyl group, ethyl group, propyl group, hydroxy group, methoxy Group, ethoxy group, amino group, dimethylamino group, diethylamino group, carboxyl group and methoxycarbonyl group.

  Particularly preferred as “Group C” is a methyl group. The number of the preferred substituents is 1, and the substituents may be used anywhere as long as they can be substituted.

R ^{1 ′} is preferably a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from group A), or

(Each symbol is as described above.).

Here, m is preferably 0, ring Cy is preferably a C _3-12 carbocyclic group, and carbocyclic group is preferably a cycloalkyl group (here, “C _3-12 The “carbocyclic group” and “cycloalkyl group” may be substituted with 1 to 5 substituents selected from group B).

Specifically, as “R ^{1 ′} ”, methyl group, ethyl group, 2,2,2-trifluoroethyl group, propyl group, isopropyl group, butyl group, 2-propenyl group, cyclopropyl group, 2-propyl group, Methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 4-methoxyphenyl group, thiophene A -3-yl group, cyclopropylmethyl group, 2-methoxyethyl, carboxymethyl, 2-hydroxyethyl, 2- (dimethylamino) ethyl and benzyl groups are preferred.

  More preferably, methyl group, ethyl group, 2,2,2-trifluoroethyl group, propyl group, isopropyl group, butyl group, cyclopropyl group, 2-methylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, Phenyl group, 4-chlorophenyl group, 4-fluorophenyl group, o-tolyl group, m-tolyl group, p-tolyl group, 4-methoxyphenyl group, thiophen-3-yl group, 2-methoxyethyl, carboxymethyl, 2-hydroxyethyl and 2- (dimethylamino) ethyl are mentioned, and a methyl group or a cyclopropyl group is particularly preferred.

“R ^{2 ′} ” is preferably

(Each symbol is as described above.) Here, m is preferably 0, “ring Cy” is preferably a C _3-12 carbocyclic group, and “carbocyclic group” is preferably a phenyl group (here, “C _{3 The “-12} carbocyclic group” and the “phenyl group” may be substituted with 1 to 5 substituents selected from Group B. As “Group B”, “—NR ^B3 R ^B4 ”, “— NR ^B5 COR ^B6 "," ^- NR B7 COOR ^B8 "," ^- NR ^{B9 CONR} B10 ^{R B11} "," ^- NR ^{B12 CONR} B13 ^{OR B14} "," ^- NR _B15 SO ^{2 R B16} "," ^{- NR} B25 SO ₂ NR ^B26 R ^B27 ”and“ —NR ^B28 SO ₂ NR ^B29 CONR ^B30 R ^B31 ”).

Specifically, as “R ^{2 ′} ”, hydrogen atom, methyl group, ethyl group, 2,2,2-trifluoroethyl group, isopropyl group, butyl group, isobutyl group, 2-propenyl group, cyclopropyl group , Cyclobutyl group, cyclopentyl group, phenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2,6-difluorophenyl group, o-tolyl group, m-tolyl group , P-tolyl group, 2,6-dimethylphenyl group, 2-ethylphenyl group, 3- (3-hydroxypropyl) phenyl group, 3- (2-carboxyethyl) phenyl group, 3- (3-morpholine-4 -Ylpropyl) phenyl group, 3-dimethylaminopropylphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxy Phenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-dimethylaminoethoxyphenyl group, 3-carboxymethoxyphenyl group, 3- (3-dimethylaminopropoxy) phenyl group, 3- (2-morpholine-4 -Ylethoxy) phenyl group, 3- (2-pyrrolidin-1-ylethoxy) phenyl group, 3- (2-piperidin-1-ylethoxy) phenyl group, 3- (2-diethylaminoethoxy) phenyl group, 3- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl group, 3-aminophenyl group, 3-methylaminophenyl group, 3-dimethylaminophenyl group, 3- (methanesulfonyl) methylaminophenyl group, 3-methylcarbonyl Aminophenyl group, 3-methanesulfonylaminophenyl group, 4-chloro 3-methanesulfonylaminophenyl group, 3-ethanesulfonylaminophenyl group, 3- (propane-1-sulfonylamino) phenyl group, 3- (propane-2-sulfonylamino) phenyl group, 3-chloromethanesulfonylaminophenyl group 3-trifluoromethanesulfonylaminophenyl group, 3- (2,2,2-trifluoroethanesulfonylamino) phenyl group, 3- (2-methoxyethyl) methylaminophenyl group, 3-methylcarbonylaminophenyl group, 3 -Ethylcarbonylaminophenyl group, 3-propylcarbonylaminophenyl group, 3-isopropylcarbonylaminophenyl group, 3-ethoxycarbonylaminophenyl group, 3- (hydroxymethylcarbonyl) aminophenyl group, 3- (2-hydroxyethyl carbonate) Rubonylamino) phenyl group, 3-ethylaminocarbonylaminophenyl group, 3- (2-dimethylaminoethylcarbonylamino) phenyl group, 3- (3-dimethylaminopropylcarbonylamino) phenyl group, 3- (methoxymethylcarbonylamino) ) Phenyl group, 3- (butylcarbonylaminomethylcarbonylamino) phenyl group, 3- (2-butylcarbonylaminoethylcarbonylamino) phenyl group, 3-methylaminocarbonylaminophenyl group, 3-methoxyaminocarbonylaminophenyl group, 3-dimethylaminocarbonylaminophenyl group, 3- (dimethylaminomethylcarbonylamino) phenyl group, 3- (2-morpholin-4-ylethylamino) phenyl group, 3- (2-benzyloxycarbonylamino group) L) sulfonylaminophenyl group, 3- (2-aminoethyl) sulfonylaminophenyl group, 3- (2-butylcarbonylaminoethyl) sulfonylaminophenyl group, 3-dimethylaminosulfonylaminophenyl group, 3-carboxyphenyl group, 3-carbamoylphenyl group, 3-methanesulfonylphenyl group, 4-methanesulfonylphenyl group, 3-ethanesulfonylphenyl group, 3-methylaminosulfonylphenyl group, 3-ethylaminosulfonylphenyl group, 3-benzenesulfonylaminophenyl group 3-aminosulfonylphenyl group, 3-dimethylaminosulfonylphenyl group, 4-dimethylaminosulfonylphenyl group, 3- (4-methylpiperazine-1-sulfonyl) phenyl group, 3- (morpholine-4-sulfonyl) Phenyl group, 3- (piperidine-1-sulfonyl) phenyl group, 3- (pyrrolidin-1-sulfonyl) phenyl group, 3-methylaminocarbonylphenyl group, 3-morpholin-4-ylphenyl group, 3-pyrrolidine-1 -Ylphenyl group, 3-piperidin-1-ylphenyl group, 3- (4-methylpiperazin-1-yl) phenyl group, 3- (2-oxopyrrolidin-1-yl) phenyl group, 3- (3- Oxomorpholin-4-yl) phenyl group, thiophen-3-yl group, pyridin-3-yl group, benzyl group and the following groups:

Is preferred,
More preferably, phenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 4-bromophenyl group, 2,6-difluorophenyl group, o-tolyl group, m-tolyl group, p- Tolyl group, 2,6-dimethylphenyl group, 2-ethylphenyl group, 3- (3-hydroxypropyl) phenyl group, 3- (2-carboxyethyl) phenyl group, 3- (3-morpholin-4-ylpropyl) ) Phenyl group, 3-dimethylaminopropylphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 3-dimethylaminoethoxyphenyl group, 3-carboxymethoxyphenyl group, 3- (3-dimethylaminopropoxy) phenyl group, 3- (2 Morpholin-4-ylethoxy) phenyl group, 3- (2-pyrrolidin-1-ylethoxy) phenyl group, 3- (2-piperidin-1-ylethoxy) phenyl group, 3- (2-diethylaminoethoxy) phenyl group, 3- [3- (4-Methylpiperazin-1-yl) propoxy] phenyl group, 3-aminophenyl group, 3-methylaminophenyl group, 3-dimethylaminophenyl group, 3- (methanesulfonyl) methylaminophenyl group, 3 -Methylcarbonylaminophenyl group, 3-methanesulfonylaminophenyl group, 4-chloro-3-methanesulfonylaminophenyl group, 3-ethanesulfonylaminophenyl group, 3- (propane-1-sulfonylamino) phenyl group, 3- (Propane-2-sulfonylamino) phenyl group, 3-chloromethyl Sulfonylaminophenyl group, 3-trifluoromethanesulfonylaminophenyl group, 3- (2,2,2-trifluoroethanesulfonylamino) phenyl group, 3- (2-methoxyethyl) methylaminophenyl group, 3-methylcarbonyl Aminophenyl group, 3-ethylcarbonylaminophenyl group, 3-propylcarbonylaminophenyl group, 3-isopropylcarbonylaminophenyl group, 3-ethoxycarbonylaminophenyl group, 3- (hydroxymethylcarbonyl) aminophenyl group, 3- ( 2-hydroxyethylcarbonylamino) phenyl group, 3-ethylaminocarbonylaminophenyl group, 3- (2-dimethylaminoethylcarbonylamino) phenyl group, 3- (3-dimethylaminopropylcarbonylamino) phenyl Group, 3- (methoxymethylcarbonylamino) phenyl group, 3- (butylcarbonylaminomethylcarbonylamino) phenyl group, 3- (2-butylcarbonylaminoethylcarbonylamino) phenyl group, 3-methylaminocarbonylaminophenyl group, 3-methoxyaminocarbonylaminophenyl group, 3-dimethylaminocarbonylaminophenyl group, 3- (dimethylaminomethylcarbonylamino) phenyl group, 3- (2-morpholin-4-ylethylamino) phenyl group, 3- (2 -Benzyloxycarbonylaminoethyl) sulfonylaminophenyl group, 3- (2-aminoethyl) sulfonylaminophenyl group, 3- (2-butylcarbonylaminoethyl) sulfonylaminophenyl group, 3-dimethylaminosulfonylaminophenyl Nyl group, 3-carboxyphenyl group, 3-carbamoylphenyl group, 3-methanesulfonylphenyl group, 4-methanesulfonylphenyl group, 3-ethanesulfonylphenyl group, 3-methylaminosulfonylphenyl group, 3-ethylaminosulfonylphenyl Group, 3-benzenesulfonylaminophenyl group, 3-aminosulfonylphenyl group, 3-dimethylaminosulfonylphenyl group, 4-dimethylaminosulfonylphenyl group, 3- (4-methylpiperazine-1-sulfonyl) phenyl group, 3- (Morpholine-4-sulfonyl) phenyl group, 3- (piperidine-1-sulfonyl) phenyl group, 3- (pyrrolidine-1-sulfonyl) phenyl group, 3-methylaminocarbonylphenyl group, 3-morpholin-4-ylphenyl Group, 3-Pylori N-1-ylphenyl group, 3-piperidin-1-ylphenyl group, 3- (4-methylpiperazin-1-yl) phenyl group, 3- (2-oxopyrrolidin-1-yl) phenyl group and 3- (3-oxomorpholin-4-yl) phenyl group may be mentioned.

“R ⁶ ” is preferably

(Each symbol is as described above.) Here, m is preferably 0, “ring Cy” is preferably a C _3-12 carbocyclic group, and “carbocyclic group” is preferably a phenyl group (here, “C _{3 The “-12} carbocyclic group” and the “phenyl group” may be substituted with 1 to 5 substituents selected from Group B, wherein Group B is preferably “halogen atom” as defined above, “C _1-8 alkyl group” as defined and “C _2-4 alkynyl group” as defined above.)

Specifically, “R ⁶ ” includes 2-methoxyethyl group, 2,2-dimethylpropyl group, 3-dimethylaminopropyl group, cyclopropyl group, cyclohexyl group, phenyl group, 2-chlorophenyl group, 3- Chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 4-bromophenyl group, 2-fluorophenyl group, 4-fluorophenyl group, 4-iodophenyl group, o-tolyl group P-tolyl group, 2-ethylphenyl group, 4-ethylphenyl group, 2-propylphenyl group, 2-isopropylphenyl group, 4-isopropylphenyl group, 2-butylphenyl group, 4-butylphenyl group, 2- Isobutylphenyl group, 4-tert-butylphenyl group, 2- (3-methylbutyl) phenyl group, 4 Trifluoromethylphenyl group, 4- (2-fluoroethyl) phenyl group, 4- (2,2-difluoroethyl) phenyl group, 4- (2,2,2-trifluoroethyl) phenyl group, 4- (1 -Ethylpropyl) phenyl group, 4- (1-propylbutyl) phenyl group, 4-ethynylphenyl group, 2,4-difluorophenyl group, 2,6-difluorophenyl group, 2,4-dichlorophenyl group, 4-bromo 2-fluorophenyl group, 4-bromo-3-fluorophenyl group, 4-bromo-2-chlorophenyl group, 4-chloro-2-fluorophenyl group, 2-fluoro-4-iodophenyl group, 2-chloro- 4-methylphenyl group, 4-chloro-2-methylphenyl group, 4-bromo-2-methylphenyl group, 4-bromo-3-methylphenyl group, 2 -Fluoro-4-methylphenyl group, 2-fluoro-4-trifluoromethylphenyl group, 4-bromo-2-ethylphenyl group, 4-ethyl-2-fluorophenyl group, 4- (2-carboxyethyl)- 2-fluorophenyl group, 2-fluoro-4-propylphenyl group, 2-fluoro-4-vinylphenyl group, 4- (2-carboxyvinyl) -2-fluorophenyl group, 4-ethynyl-2-fluorophenyl group 2-fluoro-4- (prop-1-ynyl) phenyl group, 2-fluoro-4- (3-hydroxyprop-1-ynyl) phenyl group, 2-fluoro-4
-(3-methoxyprop-1-ynyl) phenyl group, 4-cyclopropyl-2-fluorophenyl group, 2-fluoro-4- (3-hydroxy-3-methylbut-1-ynyl) phenyl group, 4- ( 3-dimethylaminoprop-1-ynyl) -2-fluorophenyl group, 4-chloro-2-dimethylaminomethylphenyl group, 4-dimethylamino-2-methylphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl Group, 4-methoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-isopropoxyphenyl group, 2,4-dimethoxyphenyl group, 4-methoxy-2-methylphenyl group, 2-fluoro-4-methoxyphenyl group 4-bromo-2-hydroxyphenyl group, 4-bromo-2-methoxyphenyl group, 2-bromo-4-meth Siphenyl group, 4-methylthiophenyl group, 4-trifluoromethylthiophenyl group, 2-fluoro-4-methylthiophenyl group, 4-aminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenyl group, 3-dimethyl Aminophenyl group, 4-dimethylaminophenyl group, 4-ethylaminophenyl group, 4-diethylaminophenyl group, 4-ethylmethylamino-2-fluorophenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 6- Aminopyridin-3-yl group, 6-dimethylaminopyridin-3-yl group, 6-chloropyridin-2-yl group, 4-chloropyridin-3-yl group, 4-carboxyphenyl group, 4-methoxycarbonylphenyl Group, 4-ethylaminophenyl group, 4- (methylcarbonyl) methyla Nophenyl group, 4-methanesulfonylphenyl group, 4-trifluoromethanesulfonylphenyl group, 4-dimethylamino-2-methylphenyl group, 4-dimethylamino-3-methylphenyl group, 4-dimethylamino-3-trifluoromethyl Phenyl group, 4-dimethylamino-2-propylphenyl group, 4-dimethylamino-2-fluorophenyl group, 4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoylphenyl group, benzo [1,3 ] Dioxol-5-yl group, 1,1'-biphenyl-4-yl group, 4- (piperidin-1-yl) phenyl group, 4-benzylphenyl group, 4- (morpholin-4-yl) phenyl group, 1-methylpiperidin-4-yl group, 1-isopropylpiperidin-4-yl group, thiazole-2 Yl group, 2-dimethylaminothiazol-4-yl group, 1-methyl-1,2,3,4-tetrahydroquinolin-6-yl group, 1H-indol-5-yl group, 1-methyl-1H-indole -5-yl group, 1-ethyl-1H-indol-5-yl group, 1-methyl-1H-indol-6-yl group, 1-methyl-1H-indol-7-yl group, 1,2-dimethyl -1H-indol-5-yl group, 1,2,3-trimethyl-1H-indol-5-yl group, 6-fluoro-1H-indol-5-yl group, 1-methyl-1H-benzimidazole-5 -Yl group, 1-methyl-1H-indazol-5-yl group, 1-methyl-2,3-dihydro-1H-indol-5-yl group, benzo [b] thiophen-5-yl group, 4-chloro Benzyl group 2-bromobenzyl group, 3-bromobenzyl group, 4-bromobenzyl group, 5-bromo-2-fluorobenzyl group, 2-morpholin-4-ylethyl group and pyridin-3-ylmethyl group are preferable.

  More preferably, a phenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 4-bromophenyl group, 2-fluorophenyl group, 4- Fluorophenyl group, 4-iodophenyl group, o-tolyl group, p-tolyl group, 2-ethylphenyl group, 4-ethylphenyl group, 2-propylphenyl group, 2-isopropylphenyl group, 4-isopropylphenyl group, 2-butylphenyl group, 4-butylphenyl group, 2-isobutylphenyl group, 4-tert-butylphenyl group, 2- (3-methylbutyl) phenyl group, 4-trifluoromethylphenyl group, 4- (2-fluoro Ethyl) phenyl group, 4- (2,2-difluoroethyl) phenyl group, 4- (2,2,2- (Rifluoroethyl) phenyl group, 4- (1-ethylpropyl) phenyl group, 4- (1-propylbutyl) phenyl group, 4-ethynylphenyl group, 2,4-difluorophenyl group, 2,6-difluorophenyl group 2,4-dichlorophenyl group, 4-bromo-2-fluorophenyl group, 4-bromo-3-fluorophenyl group, 4-bromo-2-chlorophenyl group, 4-chloro-2-fluorophenyl group, 2-fluoro -4-iodophenyl group, 2-chloro-4-methylphenyl group, 4-chloro-2-methylphenyl group, 4-bromo-2-methylphenyl group, 4-bromo-3-methylphenyl group, 2-fluoro -4-methylphenyl group, 2-fluoro-4-trifluoromethylphenyl group, 4-bromo-2-ethylphenyl group, 4-ethyl-2 Fluorophenyl group, 4- (2-carboxyethyl) -2-fluorophenyl group, 2-fluoro-4-propylphenyl group, 2-fluoro-4-vinylphenyl group, 4- (2-carboxyvinyl) -2- Fluorophenyl group, 4-ethynyl-2-fluorophenyl group, 2-fluoro-4- (prop-1-ynyl) phenyl group, 2-fluoro-4- (3-hydroxyprop-1-ynyl) phenyl group, 2 -Fluoro-4- (3-methoxyprop-1-ynyl) phenyl group, 4-cyclopropyl-2-fluorophenyl group, 2-fluoro-4- (3-hydroxy-3-methylbut-1-ynyl) phenyl group 4- (3-dimethylaminoprop-1-ynyl) -2-fluorophenyl group, 4-chloro-2-dimethylaminomethylphenyl group, 4-di Tilamino-2-methylphenyl group, 4-hydroxyphenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-trifluoromethoxyphenyl group, 4-isopropoxyphenyl group, 2,4-dimethoxyphenyl group, 4 -Methoxy-2-methylphenyl group, 2-fluoro-4-methoxyphenyl group, 4-bromo-2-hydroxyphenyl group, 4-bromo-2-methoxyphenyl group, 2-bromo-4-methoxyphenyl group, 4 -Methylthiophenyl group, 4-trifluoromethylthiophenyl group, 2-fluoro-4-methylthiophenyl group, 4-aminophenyl group, 4-methylaminophenyl group, 2-dimethylaminophenyl group, 3-dimethylaminophenyl group, 4-dimethylaminophenyl group, 4-ethylaminophenyl group, 4-di Ethylaminophenyl group, 4-ethylmethylamino-2-fluorophenyl group, 4-nitrophenyl group, 4-cyanophenyl group, 6-aminopyridin-3-yl group, 6-dimethylaminopyridin-3-yl group, 6-chloropyridin-2-yl group, 4-chloropyridin-3-yl group, 4-carboxyphenyl group, 4-methoxycarbonylphenyl group, 4-ethylaminophenyl group, 4- (methylcarbonyl) methylaminophenyl group 4-methanesulfonylphenyl group, 4-trifluoromethanesulfonylphenyl group, 4-dimethylamino-2-methylphenyl group, 4-dimethylamino-3-methylphenyl group, 4-dimethylamino-3-trifluoromethylphenyl group 4-dimethylamino-2-propylphenyl group, 4-dimethylamino- -Fluorophenyl group, 4-dimethylamino-3-fluorophenyl group, 4-dimethylphosphinoylphenyl group, 1,1'-biphenyl-4-yl group, 4- (piperidin-1-yl) phenyl group, 4 -Benzylphenyl group and 4- (morpholin-4-yl) phenyl group are mentioned.

“R ³ ” is preferably a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from group A). .

  Specifically, a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isobutyl group, a 2-methoxyethyl group, a cyclopropyl group, a 2-dimethylaminoethyl group, and a 2-propenyl group are preferable, and a methyl group is particularly preferable.

“R ⁴ ” is preferably a C _1-6 alkyl group (wherein the C _1-6 alkyl group may be substituted with 1 to 3 substituents selected from group A). .

  Specifically, a hydrogen atom, a methyl group, a propyl group, and a hydroxy group are preferable, and a methyl group is particularly preferable.

As “R ⁵ ”, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is particularly preferable.

  The compound represented by the general formula (I) can be produced, for example, according to the method described in Japanese Patent No. 4163737.

  As the compound represented by the general formula (I), for example, trametinib can be particularly preferably used. Trametinib is a compound represented by the following structural formula.

  Trametinib is a MEK inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, and is the first in the world to be approved as a MEK inhibitor It is a medicinal product. A combination of Raf inhibitor and trametinib is also approved for malignant melanoma.

(1-1-2) Compound Represented by General Formula [II] The compound represented by General Formula [II] is described in Japanese Patent No. 4093966. The symbols in the formula of the compound represented by the general formula [II] are as described above. As the compound, R ¹³ is C _{1 to} C ₁₀ alkyl, C _{3 to} C ₇ cycloalkyl, or C _3. -C ₇ cycloalkylalkyl, they are each oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{^{azido, -NR 10 SO 2 R 12,}} -SO 2 NR 9 R 10, _{^{-C (O) R 9, -C}} (O) OR 9, -OC (O) R 9, -SO 2 R 9, -NR 10 C (O) OR 12, -NR 10 C (O) R 9, ^{-C (O) NR 9 R 10} , -NR 9 R 10, -NR 11 C (O) NR 9 R 10, -NR 11 C (NCN) NR 9 R 10, -OR 9, aryl, heteroaryl Arylalkyl, heteroarylalkyl, heterocyclyl, and it may be optionally substituted with one to three groups selected independently from heterocyclylalkyl.

The compound represented by the general formula ^{[II], R 14} is -OCF _3, is -Br, or -Cl, ^{R 8} is hydrogen, compound wherein ^{R 7} is lower alkyl or halogen; R A compound wherein ¹⁵ is hydrogen or halogen; or a compound wherein R ⁹ is hydrogen or lower alkyl when A is —OR ⁹ and R ¹⁰ is hydrogen when A is —NR ¹⁰ OR ^9; Also good.

In the compound represented by the general formula [II], R ⁷ , R ¹³ , R ¹⁴ , and R ¹⁵ are as defined above for the general formula [II], and A is —OR ⁹ or —NR ¹⁰ OR ^9. And R ⁹ and R ¹⁰ may be a compound represented by the following general formula [II] a, as defined above for general formula [II].

In the compound represented by the general formula [II] a, R ¹³ is C _{1 to} C ₁₀ alkyl, C _{3 to} C ₇ cycloalkyl, or C _{3 to} C ₇ cycloalkylalkyl, which are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{^{azido, -NR 10 SO 2 R 12,}} -SO 2 NR 9 R 10, -C (O) R 9, -C (O) OR 9, - _{^{OC (O) R 9, -SO}} 2 R 9, -NR 10 C (O) OR 12, -NR 10 C (O) R 9, -C (O) NR 9 R 10, -NR 9 R 10, - ^{NR 11 C (O) NR 9} R 10, -NR 11 C (NCN) NR 9 R 10, -OR 9, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, By one to three groups selected independently from fine heterocyclylalkyl may be optionally substituted.

The compound represented by the general formula [II] a is a compound in which R ¹⁴ is —OCF ₃ , —Br, or —Cl, R ⁷ is lower alkyl or halogen; and R ¹⁵ is fluoro or chloro. Or a compound in which R ⁹ is hydrogen or lower alkyl when A is —OR ⁹ , and R ¹⁰ is hydrogen when A is —NR ¹⁰ OR ⁹ ;

Regarding the symbols in general formula [II] and general formula [II] a, the terms “C ₁ -C ₁₀ alkyl”, “alkyl” and “lower alkyl” are methyl, ethyl, propyl, isopropyl, n-butyl, linear having 1 to 10 carbon atoms, such as s-butyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl, octyl or the like It means a molecular chain alkyl group. Preferred alkyl groups are C ₁ -C ₆ alkyl, and more preferred alkyl groups are C ₁ -C ₃ alkyl.

The terms “C ₂ -C ₁₀ alkenyl”, “lower alkenyl”, and “alkenyl” are linear and molecular hydrocarbons having 2 to 10 carbon atoms and at least one double bond. Means a group, including ethenyl, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl, and the like. Most preferred is lower alkenyl having 3 to 5 carbon atoms.

“C ₂ -C ₁₀ alkynyl”, “lower alkynyl”, and “alkynyl” mean linear and branched hydrocarbon groups having 2 to 10 carbon atoms and at least one triple bond. This includes ethynyl, propynyl, butynyl, pentyn-2-yl and the like. More preferred is alkynyl having 3 to 5 carbon atoms.

  Regarding the symbols in the general formula [II] and the general formula [II] a, the term “halogen” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom as in the general formula [I].

  “Aryl” also means that at least one is aromatic, optionally mono-, di-, or tri-substituted, for example by halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl, and hydroxy. It means an aromatic carbocyclic group having a certain monocycle (eg phenyl), polycycle (eg biphenyl), or condensed polycycle (eg 1,2,3,4-tetrahydronaphthyl, naphthyl).

  The term “heteroaryl” means one or more aromatic ring systems consisting of 5, 6 or 7 membered rings, including at least one and at most selected from nitrogen, oxygen or sulfur A fused ring system of 5 to 10 atoms containing 4 heteroatoms, at least one of which is aromatic. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, Indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and phlopyridinyl. Spiro moieties are also included within the scope of the present invention. A heteroaryl group is optionally mono-, di-, or tri-substituted, for example by halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.

With respect to the symbols in general formula [II] and general formula [II] a, the terms “carbocycle”, “carbocyclyl”, “cycloalkyl” or “C ₃ -C ₁₀ cycloalkyl” are 3 to 10 A saturated carbocyclic group having a carbon atom. Cycloalkyls may be monocyclic or polycyclic fused systems and may be fused to an aromatic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups are unsubstituted herein or are substituted with various groups at one or more substitutable positions as specified. For example, such cycloalkyl groups include, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C _{6) alkylamino,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 1 -C ₆ haloalkoxy, amino _(C 1 -C ₆₎ alkyl, mono (C _It may be optionally substituted with ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl or di (C ₁ -C ₆ ) alkylamino (C ₁ -C ₆ ) alkyl.

  With respect to the symbols in general formula [II] and general formula [II] a, the term “carbocycle” or “heterocyclyl” means one or more carbocyclic ring systems consisting of 5, 6 or 7-membered rings, This includes at least one and at most 4 heteroatoms selected from nitrogen, oxygen, or sulfur, provided that the ring of the group does not contain 2 adjacent O or S atoms. Included are fused ring systems of 10 atoms. The condensed system may be a heterocycle fused to an aromatic group.

  Preferred heterocycles include pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, Homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl , Pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazoli Nyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3H-indolyl, and quinolidinyl. .

  Spiro parts are also included in the scope of this rule. As long as it is possible, the aforementioned group may be bonded to C or N, as long as it is derived from that group listed above. For example, a group derived from pyrrole may be pyrrol-1-yl (N-bonded) or pyrrol-3-yl (C-bonded). Further, the group derived from imidazole may be imidazol-1-yl (N-bonded type) or imidazol-3-yl (C-bonded type). An example of a heterocyclic group wherein 2 ring carbon atoms are substituted with oxo (═O) moieties is 1,1-dioxo-thiomorpholinyl. The heterocyclic group is unsubstituted in the compounds represented by the general formulas [II] and [II] a, or one or more substitutable positions are substituted with various groups as specified. Has been.

For example, such heterocyclic groups include, for example, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C _{6) alkylamino,} C 2 -C _{6 alkenyl,} C 2 -C _{6 alkynyl,} C 1 -C _{6 haloalkyl,} C 1 -C ₆ haloalkoxy, amino _(C 1 -C ₆₎ alkyl, mono _{(C 1} -C ₆₎ alkylamino _(C 1 ~C ₆₎ alkyl, or di _(C 1 ~C ₆₎ may optionally be substituted by alkylamino _(C 1 ~C ₆₎ alkyl.

The term “arylalkyl” means an alkyl moiety (as also defined above) substituted with one or more aryl moieties (as defined above). More preferred arylalkyl groups are aryl-C ₁ -C ₃ -alkyl. For example, benzyl, phenylethyl and the like are included.

The term “heteroarylalkyl” means an alkyl moiety (as also defined above) substituted with a heteroaryl moiety (as defined above). More preferred heteroarylalkyl groups are 5 or 6 membered heteroaryl-C ₁ -C ₃ -alkyl. For example, oxazolylmethyl, pyridylethyl and the like are included.

The term “heterocyclylalkyl” means an alkyl moiety (as also defined above) substituted with a heterocyclyl moiety (as defined above). More preferred heterocyclylalkyl groups are 5 or 6 membered heterocyclyl-C ₁ -C ₃ -alkyl. For example, tetrahydropyranylmethyl is included.

The term “cycloalkylalkyl” means an alkyl moiety (as also defined above) substituted with a cycloalkyl moiety (as defined above). More preferred heterocyclyl groups are 5 or 6 membered cycloalkyl-C ₁ -C ₃ -alkyl. For example, cyclopropylmethyl is included.

  The compounds represented by general formula [II] and general formula [II] a can be produced, for example, according to the method described in Japanese Patent No. 4093966.

  As the compound represented by the general formula [II] and the general formula [II] a, for example, selmethinib can be particularly preferably used. Cermetinib is a compound represented by the following structural formula.

  It is described in the above publication that selmethinib is useful for the treatment of hyperproliferative diseases and can be used for the treatment of cancer. It is also known that iodine uptake can be restored in iodine-refractory advanced thyroid cancer (N. Engl. Med. 2013; 368: 623-632).

(1-1-3) Compound represented by general formula [III] The compound represented by general formula [III] is described in Japanese Patent No. 5513127. The symbols in the formula of the compound represented by the general formula [III] are as described above.

With respect to the symbols in the formula of the compound represented by the general formula [III], “substituted or unsubstituted” means that a predetermined part may consist only of hydrogen substituents over available valences. (Unsubstituted) or may further include (substituted) one or more non-hydrogen substituents (not otherwise specified by the name of the given moiety) over the available valences . For example, isopropyl is an example of an ethylene moiety that is substituted by -CH _3.

With respect to the symbols in the formula of the compound represented by the general formula [III], “alkyl” represented alone means a linear or branched, saturated, aliphatic group having a carbon atom chain. . (C _X ) alkyl and (C _XY ) alkyl are typically used where X and Y indicate the number of carbon atoms in the chain. For example, (C _1-6 ) alkyl includes alkyl having a chain of 1 to 6 carbons (eg, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, etc.). .

Alkyl represented with another group (eg, in the case of arylalkyl, heteroarylalkyl, etc.) is a straight or branched, saturated, aliphatic, divalent group having the indicated number of atoms. Or a bond when no atom is indicated (eg, (C _6-10 ) aryl (C _1-3 ) alkyl includes benzyl, phenethyl, 1-phenylethyl, 3- Including phenylpropyl).

Examples of the compound represented by the general formula [III] include a compound selected from the group consisting of the following:
5- (2-Fluoro-4-iodophenylamino) -3,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluoro-4-iodophenyl) Amino) -3- (2-hydroxyethyl) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluoro-4-iodophenylamino) -3 , 6,8-trimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (S) -3- (2,3-dihydroxypropyl) -5- (2-fluoro- 4-iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -3- (2,3-dihydroxypropyl) -5- (2- Fluoro-4-iodophenylamino) 8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (S) -6-chloro-3- (2,3-dihydroxypropyl) -5- (2-fluoro-4 -Iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -3- (2,3-dihydroxypropyl) -5- (2-fluoro -4-iodophenylamino) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (S) -5- (4-bromo-2-fluorophenylamino) -3- (2,3-dihydroxypropyl) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -5- (4-bromo-2- Fluorophenylamino) -3- (2,3- Hydroxypropyl) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (4-bromo-2-fluorophenylamino) -3- (2-hydroxyethyl) ) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluoro-4-iodophenylamino) -6,8-dimethylpyrido [2,3 -D] pyrimidine-4,7 (3H, 8H) -dione; (S) -3- (2,3-dihydroxypropyl) -5- (2-fluoro-4-iodophenylamino) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluoro-4-iodophenylamino) -3- (2-hydroxyethyl) -6,8-dimethylpyrido [2 , 3-d Pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluorophenylamino) -3- (2-hydroxyethyl) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 6-fluoro-5- (2-fluoro-4-iodophenylamino) -3- (2-hydroxyethyl) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -3- (2,3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d ] Pyrimidine-4,7 (3H, 8H) -dione; (S) -3- (2,3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3- ] Pyrimidine-4,7 (3H, 8H) -dione; (R) -5- (4-bromo-2-fluorophenylamino) -3- (2,3-dihydroxypropyl) -6-fluoro-8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 3- (1,3-dihydroxypropan-2-yl) -5- (2-fluoro-4-iodophenylamino) -8- Methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 3- (1,3-dihydroxypropan-2-yl) -6-fluoro-5- (2-fluoro-4-iodophenyl) Amino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluoro-4-iodophenylamino) -3- (2-hydroxyethoxy) -8 -Methylpyri [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -3- (2,3-dihydroxypropoxy) -5- (2-fluoro-4-iodophenylamino) -8 -Methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -3- (2,3-dihydroxypropoxy) -6-fluoro-5- (2-fluoro-4-) Iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; (R) -5- (4-bromo-2-fluorophenylamino) -6-chloro- 3- (2,3-dihydroxypropyl) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 6-chloro-5- (2-fluoro-4-iodophenylamino) ) -3- (2-Hydroxye) Til) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (2-fluoro-4-iodophenylamino) -3- (3-hydroxypropyl) -8 -Methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 6-chloro-5- (2-fluoro-4-iodophenylamino) -3- (3-hydroxypropyl) -8 -Methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (4-bromo-2-fluorophenylamino) -3- (3-hydroxypropyl) -8-methylpyrido [2 , 3-d] pyrimidine-4,7 (3H, 8H) -dione; 5- (4-bromo-2-fluorophenylamino) -6-chloro-3- (3-hydroxypropyl) -8-methylpyrido [2 , 3- ] Pyrimidine-4,7 (3H, 8H) -dione; 5- (4-bromo-2-chlorophenylamino) -3- (3-hydroxypropyl) -8-methylpyrido [2,3-d] pyrimidine-4, 7 (3H, 8H) -dione; 5- (4-bromo-2-chlorophenylamino) -6-chloro-3- (3-hydroxypropyl) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 3- (2- (dimethylamino) ethyl) -5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 ( 3H, 8H) -dione; 5- (2-fluoro-4-iodophenylamino) -3- (2-hydroxypropyl) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -Dione (S) -3- (2,4-dihydroxybutyl) -5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H)- Dione; 6-chloro-5- (2-fluoro-4-iodophenylamino) -3- (2-hydroxypropyl) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H)- Dione; (S) -5- (4-bromo-2-fluorophenylamino) -3- (2,3-dihydroxypropyl) -6-fluoro-8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; 3-benzyl-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione; and 3- (1,3-Dighi Droxypropan-2-yl) -5- (2-fluoro-4-iodophenylamino) -6,8-dimethylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione.

  As a compound represented by general formula [III], 1 type may be used among the compounds illustrated above, for example, and 2 or more types may be used. When using 2 or more types, the use ratio of each compound may be arbitrary. The compound represented by the general formula [III] can be produced, for example, by the method described in Japanese Patent No. 5513127, and a commercially available product may be used.

  Among them, (R) -3- (2,3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d] pyrimidine-4,7 (3H, 8H) -dione (TAK-733) can be used particularly preferably. SETAK-733 is a compound represented by the following structural formula.

(1-2) c-Met inhibitor c-Met is a receptor tyrosine kinase that exists mainly in epithelial cells and is highly expressed in the liver and kidney. c-Met has an action of transmitting signals such as proliferation, movement, and organ formation by hepatocyte growth factor (HGF) in these organs and cells. In addition, c-Met is not expressed when cells mature, but is reactivated in cancerous cells and is involved in the proliferation, invasion and metastasis of cancer cells. Furthermore, as described above, it is known that CD44 interacts by binding to c-Met.

  A c-Met inhibitor is an agent that suppresses cell proliferation signals by inhibiting the kinase activity of c-Met. The inhibition also inhibits the binding between CD44 and c-Met, so it is thought that the expression of CD44 is also attenuated.

  As shown in Examples described later, crizotinib or 4-MU alone is treated by treating malignant pleural mesothelioma cells in combination with c-Met inhibitor crizotinib and coumarin derivative 4-MU. The survival rate of the cells was remarkably reduced as compared with the case used in the above. This result is thought to be due to the fact that the expression of CD44 was attenuated as described above, and the binding of hyaluronic acid and CD44 became difficult to occur due to inhibition of hyaluronic acid synthesis by 4-MU. Therefore, by using a c-Met inhibitor and the coumarin derivative or the like as active ingredients, an antitumor effect that is synergistically superior to that obtained when the c-Met inhibitor or the coumarin derivative or the like is used alone is obtained. It is thought that you can.

  The c-Met inhibitor is not particularly limited, and one or more compounds selected from the group consisting of crizotinib, cabozantinib and cabozantinib s-malate can be used particularly preferably. Crizotinib is a compound represented by the following structural formula.

  Cabozantinib is a compound represented by the following structural formula.

  Furthermore, cabozantinib s-malate is a compound represented by the following structural formula.

  The ratio of each compound used in the case of using two or more c-Met inhibitors is arbitrary. Crizotinib can be produced, for example, by the method described in Japanese Patent No. 4167295, and a commercially available product may be used. Cabozantinib and cabozantinib s-malate can be produced, for example, by the method described in EP2213661 A1, and commercially available products may be used.

(2) Antitumor agent (A)
The antitumor agent (A) according to the present invention contains a MEK inhibitor and / or c-Met inhibitor and the antitumor effect enhancer according to the present invention as active ingredients. That is, the antitumor agent (A) according to the present invention contains a MEK inhibitor and / or c-Met inhibitor and a coumarin derivative as active ingredients, and a MEK inhibitor and / or c-Met inhibitor. In combination with a coumarin derivative, etc., the antitumor effect is synergistically superior to that when the active ingredient is used alone.

  In the antitumor agent (A), the use ratio (weight ratio) of the MEK inhibitor and / or c-Met inhibitor and the coumarin derivative or the like is 1: 200 or more, 1: 225 or more, 1: It is preferably 250 or more, and the maximum ratio is preferably 1: 1500 or less and 1: 1000 or less.

  The said minimum ratio is considered suitable from the confirmation result (for example, Example 5) of the anti-tumor effect using a mouse | mouth. The maximum ratio is that the maximum approved amount of 4-MU as a drug for humans is 3 g / body / day, and that the maximum usable amount of trametinib for humans is combined with dabrafenib (BRAF inhibitor) In view of the results (Georgina V. Long et al. The New England Journal of Medicine (N Engl J Med) 2014; 371: 1877-1888), it is considered to be preferable because it is considered to be 2 mg / body / day. . In addition, as shown in FIGS. 3, 4, 7, and 8 to be described later, the blood concentration when the antitumor agent (A) is administered to a living body is preferably 10 nM or more.

  The antitumor agent (A) according to the present invention may contain only one or both of a MEK inhibitor and a c-Met inhibitor. When both are included, the use ratio of the MEK inhibitor and the c-Met inhibitor may be arbitrary, and the use ratio of the total of the MEK inhibitor and the c-Met inhibitor and the coumarin derivative or the like is within the above range. Is preferred.

  The antitumor agent (A) according to the present invention is a composition in which a MEK inhibitor and / or a c-Met inhibitor and a coumarin derivative or the like which is an active ingredient of the antitumor effect enhancer according to the present invention are mixed. It may be. On the other hand, the MEK inhibitor and / or c-Met inhibitor and the coumarin derivative and the like may be present separately without being mixed.

  That is, as long as a MEK inhibitor and / or c-Met inhibitor and a coumarin derivative or the like are used as active ingredients, the MEK inhibitor and / or c-Met inhibitor and the coumarin derivative or the like are not mixed. Are also included in the scope of the antitumor agent (A) according to the present invention.

  For example, a MEK inhibitor and / or c-Met inhibitor, a coumarin derivative, and the like are administered to a patient, and then the MEK inhibitor and / or c-Met inhibitor is administered first, and then a coumarin derivative and the like are administered. Even when administered separately, the MEK inhibitor and / or c-Met inhibitor and the coumarin derivative or the like are used in combination as active ingredients, so the MEK inhibitor and / or c-Met inhibitor And an antitumor agent (A) according to the present invention containing coumarin derivatives and the like as active ingredients. However, the order of administration is not limited thereto, and the MEK inhibitor and / or c-Met inhibitor may be administered after the coumarin derivative or the like is administered to the patient, and the MEK inhibitor and / or c- A Met inhibitor and a coumarin derivative or the like may be simultaneously administered to a patient.

  Since the dose of the active ingredient (MEK inhibitor and / or c-Met inhibitor and coumarin derivative, etc.) of the antitumor agent (A) according to the present invention varies depending on the age, symptoms, etc. of the patient, it cannot be generally stated. However, it is usually preferable to administer the MEK inhibitor and / or c-Met inhibitor three times a day so that a single dose is 400 to 1000 mg per adult. Moreover, it is preferable to administer a coumarin derivative etc. once a day so that a single dose may be 2 mg.

  From the matters described above, it can be said that a method for treating cancer by administering the antitumor agent (A) according to the present invention to a human or a mammal is also included in the scope of the present invention. The type of cancer is not particularly limited, and can be applied to, for example, various cancers described later. Among them, the antitumor agent (A) according to the present invention is very effective for the treatment of malignant pleural mesothelioma for which no effective treatment has been established.

[Embodiment 3: Antitumor agent (B)]
The antitumor agent according to the present invention (hereinafter referred to as “antitumor agent (B)”) includes the antitumor agent (A) according to the present invention, anti-PD-L1 antibody, anti-PD-1 antibody, anti-PD- One or more antibodies selected from the group consisting of L2 antibody, anti-CTLA-4 antibody, anti-CD25 antibody, anti-CD33 antibody and anti-CD52 antibody are contained as active ingredients.

The antitumor agent (A) is as described in the second embodiment. The anti-PD-L1 antibody, anti-PD-1 antibody, and anti-PD-L2 antibody are described in detail in Patent Document 3. As described in Patent Document 3, cDNA of human PD-1 is obtained from EMBL / GenBank Acc. No. MN_005018 and the mouse PD-1 cDNA is Acc. No. X67914, and its expression is recognized in thymocytes upon differentiation from CD4 ⁻ CD8 ⁻ to CD4 ⁺ CD8 ⁺ cells (Int. Immunol., 1996, Vol. 18, Vol. 18). No. 5, p.773-780, J. Exp.Med. 2000, Vol. 191, No. 5, p.

  PD-1 expression in the periphery depends on T cells, B cells (Int. Immunol., 1996, Vol. 18, No. 5, p. 765-772) activated by stimulation from antigen receptors or activated macrophages. It has been reported to be found in bone marrow cells including PD-1 is also known to transmit a signal that suppresses an antigen receptor (TCR) signal.

  PD-L1 is a ligand of PD-1, and is expressed not only in tumor cells but also in so-called antigen-presenting cells such as activated monocytes and dendritic cells (J. Exp. Med. 2000, 191st). Vol. 7, p. 1027-1034). As described in Patent Document 3, cDNA of human PD-L1 is obtained from EMBL / GenBank Acc. No. The cDNAs of AF233516 and mouse PD-L1 are composed of a base sequence represented by NM_021893.

  These cells present interacting molecules that induce various immunity-inducing signals to T lymphocytes, and PD-L1 is one of the molecules that induces inhibitory signals by PD-1. .

  That is, when PD-L1 expressed on the surface of tumor cells binds to PD-1 expressed on the surface of T cells, the activity of T cells is suppressed. Inhibitory signals from conjugate-suppressed molecules such as PD-1 are expressed by immunological tolerance and self-expression during the development or maturation of lymphocytes by a mechanism that appropriately controls positive signals by antigen receptors (TCRs) and conjugate-stimulating molecules. It is thought to control abnormal immune responses to antigens.

  As described in Patent Document 3, PD-L2 was identified as the second ligand of PD-1, but it has been reported that its expression and function are almost the same as PD-L1. The human PD-L2 cDNA was obtained from EMBL / GenBank Acc. No. The cDNA of NM_025239 and mouse PD-L2 is composed of the base sequence shown by NM_021896 (Nature Immunology, 2001, Vol. 2, No. 3, p.261-267).

  The anti-CTLA-4 antibody is described in, for example, JP-A-2007-277242. CTLA-4 is cytotoxic T lymphocyte-related antigen 4 (CD152), and as described in JP-A-2007-277242, CTLA-4 is its natural ligand, B7. When bound to 1 (CD80) and B7.2 (CD86), a negative regulatory signal is delivered to the T cell, and blocking this negative signal enhances T cell immune function and antitumor activity in animal models (Thompson). And Allison, Immunity, 7, 445-450 (1997); McCoy and LeGros, Immunol. & Cell Biol. 77: 1-10 (1999)).

  Blocking CTLA-4 using antibodies has been shown to enhance T cell-mediated tumor killing and induce anti-tumor immunity (see, eg, Leach et al. Science 271: 1734-1736 ( 1996)). The complete sequence of human CTLA-4 cDNA is described in GenBank Accession No. L15006.

  CD25 is a single-chain glycoprotein having a molecular weight of 55 kDa and is known as a surface antigen of adult T-cell leukemia cells. CD33 is known as the surface antigen of acute myeloid leukemia cells, and CD52 is known as the surface antigen of B cell chronic lymphocytic leukemia cells.

  As shown in Examples described later, after transplanting malignant pleural mesothelioma cells, the tumor tissues of mice administered with the antitumor agent (A) according to the present invention were observed. PD-1, CTLA-4, and PD-L1 expression was enhanced, and PD-L1 expression was remarkably enhanced. On the other hand, in a clinical trial of lung cancer patients, when an anti-PD-1 antibody was administered to a patient alone, the patient with strong PD-L1 expression was more anti-PD- than the patient with weak PD-L1 expression. There is a finding that the response rate of 1 antibody is high (First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status, American Society of Clinical Oncology (ASCO2014) J Clin Oncol 32: 5s, 2014 (suppl; abstr 8024)).

  In view of this finding and the result of the present Example that the antitumor agent (A) remarkably enhances the expression of PD-L1, the antitumor agent (A) significantly improves the response rate of the anti-PD-1 antibody. It can be fully expected to be improved. In addition, from the results of the Examples, it can be sufficiently expected that the antitumor agent (A) can improve the response rate of the anti-PD-L1 antibody, anti-PD-L2 antibody, and anti-CTLA-4 antibody.

  Furthermore, since the antitumor agent (A) enhanced the expression of PD-L1 and the like in malignant pleural mesothelioma cells, the antitumor agent (A) worked on tumors, tumor cell environment, immune cells, and IL-2. It affects the secretion of cytokines such as interferon gamma, which may affect antigen expression. Therefore, the anti-tumor agent (A) can sufficiently be expected to enhance the expression of CD25, CD33, and CD52, which are surface antigens of tumor cells, and therefore anti-CD25 antibody, anti-CD33 antibody, anti-CD52 antibody It can also be expected to improve the response rate.

  Therefore, it is considered that the antitumor agent (B) may effectively act for the treatment of acute myeloid leukemia, B cell chronic lymphocytic leukemia, and adult T cell leukemia.

  From the above, it consists of antitumor agent (A), anti-PD-L1 antibody, anti-PD-1 antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, anti-CD25 antibody, anti-CD33 antibody and anti-CD52 antibody. The antitumor agent (B) containing one or more antibodies selected from the group as an active ingredient improves the response rate of the antibody, and as a result, when the antitumor agent (A) and the antibody are not used in combination It is considered that the antitumor effect is synergistically superior.

  Anti-PD-L1 antibody, anti-PD-1 antibody, anti-PD-L2 antibody, anti-CTLA-4 antibody, anti-CD25 antibody, anti-CD33 antibody and anti-CD52 antibody are respectively PD-L1, PD-1, PD-L2 Any antibody such as a human-derived antibody, a mouse-derived antibody, a rat-derived antibody, a rabbit-derived antibody or a goat-derived antibody may be used as long as it inhibits an immunosuppressive signal caused by CTLA-4, CD25, CD33, and CD52. Their polyclonal or monoclonal antibodies, complete or truncated (eg, F (ab ′) 2, Fab ′, Fab or Fv fragments; these are also referred to hereinafter as “antibody fragments”) antibodies, chimerized antibodies, humanized Either an antibody or a fully human antibody may be used.

  These antibodies should be produced according to known antibody or antiserum production methods using PD-L1, PD-1, PD-L2, CTLA-4, CD25, CD33 or CD52 partial proteins in the extracellular region as antigens. Can do. Commercial products may be used. The partial protein in the extracellular region can be prepared by known protein expression and purification methods.

  Polyclonal antibodies can be produced by known methods. For example, it can be produced by immunizing a suitable animal with an antigen protein or a mixture of it and a carrier protein, collecting an antibody-containing substance against the antigen protein from the immunized animal, and performing antibody separation and purification.

  As the animal to be used, mouse, rat, sheep, goat, rabbit and guinea pig are generally mentioned. In order to enhance antibody production ability, complete Freund's adjuvant or incomplete Freund's adjuvant can be administered together with the antigen protein. Administration is generally performed about once every 2 weeks, about 3 to 10 times in total.

  Polyclonal antibodies can be collected from blood, ascites, etc. of animals immunized by the above method. The polyclonal antibody titer in the antiserum can be measured by ELISA.

  Separation and purification of polyclonal antibodies include, for example, purification methods using an antigen-binding solid phase or an active adsorbent such as protein A or protein G, salting-out method, alcohol precipitation method, isoelectric precipitation method, electrophoresis method, ion exchange It can be carried out in accordance with immunoglobulin separation and purification methods such as body adsorption / desorption, ultracentrifugation, and gel filtration.

  As said antibody, a monoclonal antibody or its modification is more preferable. As described in Patent Document 3, monoclonal antibody-producing cells are prepared by selecting an individual having an antibody titer from an animal immunized with an antigen, and spleen or lymph nodes 2 to 5 days after the final immunization. The antibody-producing cells contained therein are collected and fused with myeloma cells of the same or different animals to produce monoclonal antibody-producing hybridomas that can be subcultured.

  The “one or more antibodies” may be any number as long as it is an antibody selected from the above group. When two or more types of antibodies are used, the ratio of the amounts used is arbitrary.

  The use ratio (weight ratio) between the antitumor agent (A) and the antibody in the antitumor agent (B) is 1 at maximum considering that the side effects of the antitumor agent (A) and the antibody do not overlap. 1 is considered preferable.

  The antitumor agent (B) according to the present invention may be a composition in which the antitumor agent (A) and the antibody are mixed. On the other hand, the antitumor agent (A) and the antibody may not be mixed and may exist separately. Further, as described above, the antitumor agent (A) may be a composition in which a MEK inhibitor and / or c-Met inhibitor and a coumarin derivative or the like are mixed, or a MEK inhibitor and The c-Met inhibitor and the coumarin derivative and the like may be present separately without being mixed.

  That is, as long as the antitumor agent (A) and the antibody are used as active ingredients, the antitumor agent (A) and the antibody are not mixed, and the MEK inhibitor and / or c-Met. Even when the inhibitor, the coumarin derivative, and the like and the antibody are not mixed, they are included in the range of the antitumor agent (B) according to the present invention.

  For example, even when a MEK inhibitor and / or c-Met inhibitor, a coumarin derivative, and the like and the antibody are administered to a patient without mixing, the MEK inhibitor and / or c-Met inhibitor And a coumarin derivative or the like and the antibody as an active ingredient, the antitumor agent (A) and the antitumor agent (B) according to the present invention containing the antibody as an active ingredient. . However, the order of administration is not limited to this.

  From the matters described above, it can be said that a method for treating cancer by administering the antitumor agent (B) according to the present invention to a human or mammal is also included in the scope of the present invention.

[Embodiment 4: Use of antitumor agent, etc.]
In the present specification, the “antitumor agent” means a compound having an antitumor effect, including an anticancer agent. Both the antitumor agent (A) and the antitumor agent (B) in the present specification are included in the “antitumor agent”. “Tumor” includes malignant tumors.

  The antitumor agent (A) according to the present invention has an effect of strongly suppressing the expression of CD44, which is a cancer stem cell marker in solid cancers such as breast cancer and colon cancer. Moreover, it is thought that an antitumor agent (B) can improve the response rate of anti-PD-1 antibody etc. in a tumor tissue.

  Therefore, the antitumor agent (A) and antitumor agent (B) according to the present invention are various tumors, specifically, mesothelioma (malignant pleural mesothelioma, etc.), brain tumor (malignant astrocytoma, poor Glioma with glioma component), esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer (colon cancer, rectal cancer, etc.), lung cancer (non-small cell lung cancer, small cell lung cancer, primary and metastatic) Squamous cell carcinoma, etc.), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, bone / soft tissue tumor, bone tumor, osteosarcoma, testicular tumor, extragonadal tumor, testicular tumor, uterine cancer (Cervical cancer, endometrial cancer, etc.), head and neck tumors (maxillary cancer, laryngeal cancer, pharyngeal cancer, tongue cancer, oral cancer, etc.), multiple myeloma, malignant lymphoma (most reticulosarcoma, lymphosarcoma, Hodgkin disease, etc.) ), Polycythemia vera, leukemia (acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.), Thyroid cancer, renal pelvic cancer, ureteral tumor, bladder tumor, gallbladder cancer, cholangiocarcinoma, choriocarcinoma, malignant melanoma, childhood tumor (Ewing sarcoma family, Wilms tumor, rhabdomyosarcoma, hemangiosarcoma, testicular fetal cancer, (Neurodematosis, retinal atheroma, hepatoblastoma, nephroblastoma, etc.) and the like.

  The antitumor agent (A) and antitumor agent (B) according to the present invention are generally known pharmaceutically acceptable carriers, excipients, diluents, extenders, disintegrating agents, in addition to the above active ingredients, Stabilizer, preservative, buffer, emulsifier, fragrance, colorant, sweetener, thickener, corrigent, solubilizer, other additives, specifically water, vegetable oil, alcohol (eg, ethanol, benzyl) Alcohol, etc.), polyethylene glycol, glycerol triacetate, gelatin, carbohydrates (eg, lactose, starch, etc.), magnesium stearate, talc, lanolin, petrolatum and the like.

  In addition, the antitumor agent (A) and antitumor agent (B) according to the present invention are mixed with the above-mentioned excipients and the like, and tablet, pill, powder, granule, suppository, injection, ophthalmic solution by conventional methods. It can be administered systemically or locally, orally or parenterally, in the form of an agent, solution, capsule, troche, aerosol, elixir, suspension, emulsion, syrup and the like. The administration mode of the antitumor agent may be appropriately determined using a conventionally known method (for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. 15th Edition, 1975, etc.).

  Examples of the administration form of the antitumor agent (A) and antitumor agent (B) according to the present invention include intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, and buccal. Administration via intranasal, liposome, via inhalation, vaginal, intraocular, via local delivery (eg, by catheter or stent), subcutaneous, intrafacial, intraarticular, or intrathecal.

  The present invention is not limited to the above-described embodiments, and various modifications are possible within the scope shown in the claims, and embodiments obtained by appropriately combining technical means disclosed in different embodiments. Is also included in the technical scope of the present invention.

  Hereinafter, the present invention will be described in more detail with reference to examples. The present invention is not limited to the following examples.

  First, materials used in the examples and experimental methods will be described.

〔Materials and methods〕
(1) Cell Line NCI-H226, NCI-H2452, NCI-H2052, MSTO-211H, NCI-H28 (obtained from American Type Culture Collection) were used as cell lines for malignant pleural mesothelioma. Cells were grown and stored in a manner according to the teachings of the American Type Culture Collection. The cells were cultured in RPMI-1640 medium (manufactured by Sigma-Aldrich) containing 10% fetal bovine serum (manufactured by Cell Culture Bioscience) at 37 ° C. in a 5% CO ₂ atmosphere.

(2) Reagents Trametinib was purchased from LC Laboratories, and 4-MU was purchased from Sigma-Aldrich. Trametinib and 4-MU stocks were prepared in DMSO (Wako Pure Chemical Industries). All antibodies used in this example were purchased from Cell Signaling Technology. Rabbit monoclonal antibodies include phospho-MEK1 / 2 (Ser221) (# 2338), phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (# 4370), phospho-Akt (Ser473) (# 4060) , antibodies against phospho-Stat3 (Se ^r27 27) (# 9134), phospho-B-Raf (Ser445) (# 2696) and β-Actin (# 4970) were used. Mouse monoclonal antibodies include MEK1 / 2 (# 4694), p44 / 42 MAP Kinase (# 4696), Akt (pan) (# 2920), Stat3 (# 9139), FRA1 (# 5281) and CD44 (# 3570) An antibody against was used. The numbers such as “(# 2338)” are code numbers of Cell Signaling Technology.

(3) Cell Viability Assay Malignant pleural mesothelioma cells (5 × 10 ³ cells / well) were seeded in a 96-well microplate and cultured at 37 ° C. in a 5% CO ₂ atmosphere. The cells were treated for 72 hours by adding trametinib (0-100 μM) and 4-MU (0-1 mM) to the microplate. Cell viability was determined using the WST-8 assay (Cell Counting kit-8, Dojindo Molecular Technologies) according to the manufacturer's protocol. Absorbance was measured at 450 nm using SpectraMax Plus 384 (Molecular Devices).

(4) Western blot analysis Cell lysates were prepared using RIPA buffer (Nacalai Tesque) containing a phosphatase inhibitor (Nacalai Tesque). Western blot analysis was performed according to standard protocols. Chemiluminescence based on peroxidase was generated by adding ECL (manufactured by GE Healthcare Life Sciences). Protein bands were detected using ImageQuant LAS 4010 (GE Healthcare Life Science) and quantified using ImageQuant TL (GE Healthcare Life Science).

(5) Examination of tumor xenotransplantation 4-5 weeks old female nude mice (BALB / cA Jci-nu / nu) were obtained from Clea Japan. The research protocol was approved by the Animal Experiment Committee of Hyogo College of Medicine. NCI-H226 cells (5 × 10 ⁶ cells / 0.1 mL) were injected subcutaneously into the dorsum of the nude mice and grown as tumor xenografts. The administration of the drug was started 7 days after transplantation (the day when the tumor was transplanted as day 0, 7 days after that), the day when the tumor was detected to grow to a diameter of about 100 to 200 mm ³ .

  Trametinib and 4-MU were dissolved in a 0.5 w / v% methylcellulose 400 solution (manufactured by Wako Pure Chemical Industries). 1 mg or 3 mg (1 mg or 3 mg / kg / day) of trametinib orally once daily is administered orally once a day to give 225 mg per kg of body weight (225 mg / kg / day). Oral administration of MU twice daily continued for 32 days.

  When trametinib and 4-MU were used in combination, the dose of trametinib was 1 mg / kg / day and the dose of 4-MU was 225 mg / kg / day. The first oral administration of trametinib and 4-MU was performed almost simultaneously, and the second oral administration of 4-MU was performed 6-8 hours after the first oral administration. When 4-MU is administered alone or when trametinib and 4-MU are used in combination, the first oral dose of 4-MU is 112.5 mg / kg, and the second oral dose is 112. 0.5 mg / kg so that the total was 225 mg / kg / day.

Results were determined as the average volume of tumors in a population of 4-5 mice. Tumors were measured twice a week using calipers and the approximate volume was calculated using Equation 1 below.
Tumor volume (mm ³ ) = [tumor length × (tumor width) ² ] × 0.5 (1)
Statistical analysis was performed by Tukey test using GraphPad Prism 6 software for Windows (registered trademark), Version 6.03 (GraphPad Software).

  The expression of phosphorylated ERK in xenografted NCI-H226 tumor tissue was determined by Western blot using the phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (# 4370) according to the manufacturer's protocol. Confirmed by analysis and immunohistochemical staining. Xenografted NCI-H226 tumor tissue was harvested 4 hours, 1 day, and 4 days after the last dose of trametinib and / or 4-MU. The dissected tumor tissue was dissolved in RIPA buffer containing a phosphatase inhibitor and subjected to Western blot analysis. Tumor tissues were fixed in 10% formalin for 24 hours and transferred to ethanol before paraffin embedding prior to immunohistochemical staining. Phosphorylated ERK positive cells were observed and counted at a magnification of 400 in 10 random fields per tumor, and expressed as a percentage of the total number of phosphorylated ERK positive cells observed in each tumor. Statistical analysis was performed by one-way analysis of variance using GraphPad Prism 6 software for Windows (registered trademark), Version 6.03 (GraphPad Software).

[Example 1: Inhibition of cell survival of malignant pleural mesothelioma cells by trametinib and 4-MU]
As described in “(3) Cell Viability Assay”, as a result of treating malignant pleural mesothelioma cells with trametinib, the number of surviving cells decreased depending on the concentration of trametinib. IC ₅₀ values ranged from 0.15 μM to 12.7 μM.

  FIG. 1 shows the relationship between trametinib concentration and cell viability when NCI-H226 cells, NCI-H2452 cells, NCI-H2052 cells and MSTO-211H cells are used as cell lines for malignant pleural mesothelioma. It is a graph to show. In FIG. 1, the horizontal axis represents the concentration of trametinib, and the vertical axis represents the cell viability. In the examples of the present application, the cell survival rate is expressed as a ratio of the number of cells before treatment with a drug (in this case, trametinib) to 1.0 and the number of cells after treatment with the drug.

IC ₅₀ is 11.5 μM for NCI-H226 cells, 11.2 μM for NCI-H2452 cells, 12.7 μM for NCI-H2052 cells, 0.15 μM for MSTO-211H cells, The decrease in the number of viable cells induced by trametinib was more marked than the cell line.

  FIG. 2 is a graph showing the relationship between the 4-MU concentration and the cell viability when the same cell line as in FIG. 1 is used.

IC ₅₀ showed values from 186 μM to 1.52 mM in NCI-H2452, NCI-H2052 and NCI-H226. On the other hand, as shown in FIG. 2 (d), MSTO-211 cells were not subject to survival inhibition by 4-MU at the concentration tested in this Example.

Example 2: Blocking of ERK phosphorylation by trametinib and inhibition of CD44 expression
To examine the effect of trametinib alone on intracellular signaling, Western blot analysis of malignant pleural mesothelioma cells was performed. That is, NCI-H226 cells and MSTO-211H cells cultured as described in (3) of [Materials and Methods] were treated with various concentrations of trametinib for 72 hours to obtain the Raf-MEK-ERK and Pl3K-Akt pathways. The state of phosphorylation was analyzed. Furthermore, NCI-H226 cells and MSTO-211H cells were treated with 20 μM and 1 μM trametinib, respectively, and subjected to analysis of changes with time.

  FIG. 3 shows the results of Western blot analysis of NCI-H226 cells treated with 0 to 10000 nM trametinib for 72 hours. FIG. 4 shows the relationship between the trametinib concentration and the inhibition of phosphorylation of ERK in the NCI-H226 cells (FIG. 4 (a)), and the relationship between the trametinib concentration and the protein level of CD44 (FIG. 4). FIG. 4B is a diagram illustrating (b)). In FIG. 4, the horizontal axis represents the concentration of trametinib, and the vertical axis (Volume) represents the band volume in the western blotting membrane. Hereinafter, the vertical axes of FIGS. 6, 8, 10, 12, 14 to 16, 18 (b) and 19 (b) are the same.

  As shown in FIGS. 3 and 4, it can be seen that ERK phosphorylation is already suppressed from the case where the concentration of trametinib is 1 nM, and is almost completely suppressed when the concentration is 10 nM or more. It can also be seen that the expression of CD44 also decreases depending on the concentration of trametinib.

  FIG. 5 shows the results of Western blot analysis of changes over time when NCI-H226 cells were treated with 20 μM trametinib for 0 to 72 hours. FIG. 6 shows the relationship between the treatment time with trametinib and the inhibition of ERK phosphorylation in the NCI-H226 cells (FIG. 6 (a)), and the relationship with the protein level of CD44 (FIG. 6 (b)). )). The horizontal axis in FIG. 6 represents the processing time with 20 μM trametinib.

  As shown in FIGS. 5 and 6, (a), it can be seen that phosphorylation of ERK is suppressed to an almost undetectable level within 1 hour from the start of treatment with trametinib. In addition, inhibition of ERK phosphorylation by trametinib followed by inhibition of CD44 expression is shown in the results 48 to 72 hours after the start of treatment with trametinib (FIG. 6 (b)).

  FIG. 7 shows the results of Western blot analysis of MSTO-211H cells treated with 0 to 1000 nM trametinib for 72 hours. FIG. 8 shows the relationship between the concentration of trametinib and the inhibition of ERK phosphorylation in the MSTO-211H cells (FIG. 8 (a)) and the relationship with the protein level of CD44 (FIG. 8 (b)). ). In FIG. 8, the horizontal axis represents the concentration of trametinib.

  As shown in FIGS. 7 and 8, phosphorylation of ERK tended to be suppressed depending on the concentration of trametinib even when MSTO-211H cells were used, and the expression of CD44 also depended on the concentration of trametinib. It can be seen that it is decreasing.

  FIG. 9 shows the results of Western blot analysis of changes over time when MSTO-211H cells were treated with 1 μM trametinib for 0 to 72 hours. FIG. 10 shows the relationship between the treatment time with trametinib and the inhibition of phosphorylation of ERK in the MSTO-211H cells (FIG. 10 (a)), and the relationship with the protein level of CD44 (FIG. 10 (b)). )). The horizontal axis of FIG. 10 represents the processing time with 1 μM trametinib.

  As shown in FIG. 9 and FIG. 10 (a), even when MSTO-211H cells were used, phosphorylation of ERK was suppressed to an almost undetectable level within 1 hour from the start of treatment with trametinib. I understand that. In addition, inhibition of ERK phosphorylation by trametinib is followed by inhibition of CD44 expression as shown in the results 48 to 72 hours after the start of trametinib treatment (FIG. 10 (b)).

[Example 3: Effect of 4-MU on intracellular signal pathway]
To examine the effect of 4-MU alone on the intracellular signaling pathway, Western blot analysis of malignant pleural mesothelioma cells was performed. That is, NCI-H226 cells cultured as described in (3) of [Materials and Methods] are treated with 4-MU of 10 nM to 100 μM for 72 hours, and phosphorylation of Raf-MEK-ERK and Pl3K-Akt pathways The state of was analyzed.

  FIG. 11 shows the results of Western blot analysis of NCI-H226 cells treated with 4-MU of 10 nM to 100 μM for 72 hours. FIG. 12 shows the relationship between the concentration of 4-MU and the inhibition of ERK phosphorylation in the NCI-H226 cells (FIG. 12 (a)), and the relationship between the protein level of CD44 (FIG. 12 ( It is a figure which shows b)). In FIG. 12, the horizontal axis represents the concentration of 4-MU.

  In several types of tumor cells, it is known that the interaction between hyaluronic acid and the hyaluronic acid receptor activates various downstream signaling pathways, including the MAPK and Pl3K-Akt pathways (eg, non-patent literature). 5).

  However, as shown in FIGS. 11 and 12 (a), in this example, phosphorylation of ERK was only slightly inhibited when 4-MU was at a high concentration. Further, as shown in FIGS. 11 and 12 (a), when the concentration of 4-MU was as low as 100 nM, the phosphorylation of ERK tended to increase. Furthermore, as shown in FIGS. 11 and 12 (b), the result that no significant decrease in the protein expression level of CD44 was observed by the 4-MU treatment was obtained.

[Example 4: Relationship between CD44 expression and ERK-dependent Fra-1 expression]
Activator protein 1 (AP-1), a transcription factor, is a major target of the signal transduction pathway induced by asbestos. Ramos-Nino ME et al. Show that in rat pleural mesothelioma cells, the expression of Fra-1, the main component of AP-1, is dependent on the activation of ERK, and the induction of CD44 is Fra-1. (Ramos-Nino ME, et. Al. Cancer research. 2002; 62 (21): 6065-9., Ramos-Nino ME, et. Al. Cancer research. 2003; 63 (13): 3539-45.). In addition, Ramos-Nino ME et al. Also report that Fra-1 is regulated by ERK, Srk, and P13K pathways in human malignant mesothelioma cells (Ramos-Nino ME, et. Al. Molecular cancer. 2007; 6: 81.).

  In this example, Fra-1 expression was analyzed to examine the relationship between phosphorylated ERK expression and CD44. That is, NCI-H226 cells cultured as described in (3) of [Materials and Methods] were transformed into trametinib at the concentrations shown in FIGS. 13 to 16; 4-MU; or a combination of trametinib and 4-MU. After 72 hours of treatment, ERK phosphorylation, Fra-1 expression, CD44 expression and the like were examined.

  FIG. 13 shows the results of Western blot analysis showing the relationship between the expression of Fra-1 and the treatment with trametinib and / or 4-MU.

  FIG. 14 is a graph showing the relationship between the amount of trametinib and / or 4-MU used and the expression of phosphorylated ERK. FIG. 15 shows the amount of trametinib and / or 4-MU used and the expression of CD44. FIG. 16 is a diagram showing the relationship between the amount of trametinib and / or 4-MU used and the expression of Fra-1.

  14 to 16 correspond to the results shown in “pERK”, “CD44”, and “Fra-1” in FIG. 13, respectively. 14 to 16, “T” represents trametinib, “M” represents 4-MU, and the number represents the concentration (μM), which corresponds to the concentration illustrated in FIG. “(−)” Indicates that administration is not performed.

  13-16, consistent with the tendency for phosphorylated ERK and CD44 expression to be inhibited, Fra-1 expression was also observed for trametinib alone, 4-MU alone, and a combination of trametinib and 4-MU. It can be seen that the concentration was inhibited depending on the concentration of these drugs. The results shown in FIGS. 13-16 suggest that CD44 expression correlates with ERK-dependent Fra-1 expression in malignant pleural mesothelioma cells. That is, it is suggested that the expression of Fra-1 is attenuated as the expression of phosphorylated ERK is attenuated by the drug, and the expression of CD44 is attenuated as the expression of Fra-1 is attenuated.

[Example 5: Antitumor effect of trametinib and 4-MU in a mouse xenograft model]
In this example, the antitumor effect of trametinib and / or 4-MU in a mouse xenograft model transplanted with NCI-H226 cells was examined. The method is as shown in (5) of [Materials and Methods]. FIG. 17 is a diagram showing the results of observing the antitumor effect over time when trametinib and / or 4-MU was administered to the mouse xenograft model. The horizontal axis indicates the number of days from the day of transplanting NCI-H226 cells. For example, “day7” indicates that the day of transplantation is taken as day 0 and that 7 days after that date. The vertical axis shows the volume of transplanted NCI-H226 cells.

  As shown in FIG. 17, tumor growth was significantly greater when trametinib was administered at 1 mg / kg / day and when 4-MU was administered at 225 mg / kg / day compared to controls where no drug was administered. Was suppressed.

  Further, when trametinib (1 mg / kg / day) and 4-MU (225 mg / kg / day) were administered in combination (Combination treatment in the figure), compared to the case where trametinib was administered at 1 mg / kg / day. P <0.01 and 4-MU showed a significant difference at P <0.0001 compared to 225 mg / kg / day and P <0.0001 compared to the control, respectively.

  That is, it has been found that obviously synergistic anti-tumor effects can be obtained by administering trametinib or 4-MU in combination rather than administering alone.

  Next, the effect of trametinib, 4-MU, and combinations thereof on ERK activation in vivo was examined. FIG. 18 shows the results of subjecting NCI-H226 tumor tissue collected 4 hours after the final administration of the drug to Western blotting. FIG. 18 (a) shows the Western blot analysis results, and FIG. 18 (b) shows the relationship between treatment with trametinib, 4-MU, or a combination thereof and inhibition of ERK phosphorylation in NCI-H226 cells. Each is shown.

  In FIG. 18A, “ERK” indicates the total expression of phosphorylated ERK and non-phosphorylated ERK, and “pERK” indicates the expression of phosphorylated ERK. In FIGS. 18A and 18B, “CTRL day 0” indicates the result of analyzing the tumor tissue of NCI-H226 on the day when the administration of the drug was started.

  As shown in FIG. 18, when trametinib was administered, phosphorylation of ERK was strongly inhibited regardless of whether the dose was 1 mg / kg / day or 3 mg / kg / day. Further, when trametinib and 4-MU were administered in combination, results similar to those obtained when trametinib was administered alone were obtained.

  FIG. 19 shows the results of subjecting NCI-H226 tumor tissue collected 4 days after the final administration of the drug to Western blotting. FIG. 19 (a) shows the results of Western blot analysis, and FIG. 19 (b) shows the relationship between treatment with trametinib, 4-MU, or a combination thereof and inhibition of ERK phosphorylation in NCI-H226 cells. Each is shown.

  Comparing FIG. 19 with FIG. 18, ERK phosphorylation, which was inhibited by drug administration, was recovered both when trametinib was administered and when trametinib and 4-MU were administered in combination. I understand.

  20 and 21 show the tumor tissue of NCI-H226 collected 4 hours after the final administration of the drug (in the figure, described as “Immediately after cessation of treatment”), and the NCI− collected 4 days after the final administration of the drug. It is the figure which confirmed the result of the immunohistochemical dyeing | staining about the tumor tissue of H226 (it describes as "4 days after cessation of treatment" in a figure) by magnification 40 times and 200 times, respectively. FIG. 22 compares the percentage of phosphorylated ERK-positive cells expressed in tumor tissue of NCI-H226 in the nude mice that were orally dosed with trametinib, 4-MU, or a combination of trametinib and 4-MU. It is a figure which shows the result.

  20 and 21, when trametinib (1 mg / kg / day) and 4-MU (225 mg / kg / day) were administered in combination ("combination treatment" in the figure), they were stained brown It has been shown that there are few cells, ie phosphorylated ERK positive cells.

  As shown in FIG. 22, when trametinib 1 mg / kg / day was administered, when trametinib 3 mg / kg / day was administered, and when 4-MU225 mg / kg / day was administered, all were significant compared to the control Inhibited ERK phosphorylation (P <0.0001, P <0.0001, P <0.001 respectively).

  When trametinib (1 mg / kg / day) and 4-MU (225 mg / kg / day) were administered in combination (“combination treatment” in the figure), trametinib (1 mg / kg / day) was administered P <0.01, P <0.05 compared to when trametinib (3 mg / kg / day) was administered, and P <0 against 4-MU (225 mg / kg / day). .0001, P <0.0001 vs. control, each significantly inhibited ERK phosphorylation.

[Example 6: Inhibition of cell survival of malignant pleural mesothelioma cells when TAK-733, cermethinib is used as a MEK inhibitor]
In this example, as a MEK inhibitor, TAK-733 (# S2617, Selleck Chemicals) or selmetinib (# S-4490, LC Laboratories) was used in an amount of 0 to 1000 μM instead of trametinib used in Examples 1-5. A cell viability of malignant pleural mesothelioma cells was examined by the same method as in Example 1 except that NCI-H28 was further used as a cell line for pleural mesothelioma.

  23 to 28 are graphs showing the relationship between the concentration of the tested MEK inhibitor and the cell viability. When NCI-H226 cells were treated with TAK-733 (FIG. 23), respectively, NCI- When H28 cells were treated (FIG. 24), MSTO-211H cells were treated with selumetinib (FIG. 25), NCI-H226 cells were treated with selumetinib (FIG. 26), and NCI-H2052 cells were treated with selmethinib. In the case (FIG. 27), it is a figure which shows the result when a NCI-H2452 cell is processed by a selumetinib (FIG. 28).

  In each figure, the horizontal axis represents the concentration of the MEK inhibitor, and the vertical axis represents the cell viability. As shown in FIGS. 23 to 28, it was revealed that each MEK inhibitor has a remarkable growth inhibitory effect on malignant pleural mesothelioma cells at a concentration of 100 μM to 1000 μM.

[Example 7: Enhancement of antitumor effect of crizotinib by 4-MU]
In this example, c-Met inhibitor crizotinib was used instead of MEK inhibitor, and the cell viability of malignant pleural mesothelioma cells when treated with crizotinib and / or 4-MU was examined.

  That is, using various concentrations of crizotinib; 4-MU; or a combination of crizotinib and 4-MU (the respective concentrations are shown in FIGS. 29 to 32 (a) to (c)), [Materials and Methods] Malignant pleural mesothelioma cells were treated by the method described in (3).

  Figures 29-32 show cell viability when treated with crizotinib and / or 4-MU, respectively, using NCI-H2052, NCI-H2452, NCI-H226, NCI-H28 as malignant pleural mesothelioma cells FIG.

  29 to 32, (a) to (c) are the results of processing with crizotinib, processing with 4-MU, and processing with a combination of crizotinib and 4-MU, respectively. The vertical axis shows cell viability, and the horizontal axis shows the concentration of crizotinib and / or 4-MU. In the (c), the horizontal axis indicates the concentration of 4-MU on the top and the concentration of crizotinib on the bottom.

  As can be seen from FIGS. 29 to 32, the survival rate of malignant pleural mesothelioma cells decreases depending on the concentration of crizotinib or 4-MU, depending on the cell line, and crizotinib and 4-MU are combined. In the case of crizotinib or 4-MU, the survival rate was significantly reduced. That is, it was shown that the antitumor effect of crizotinib could be remarkably improved by using together with 4-MU.

[About the results of Examples 1 to 7]
As described above, the antitumor agent according to the present invention is a combination of an MEK inhibitor and / or c-Met inhibitor and a coumarin derivative or the like as active ingredients. As shown in Examples 1, 5, 6, and 7, when trametinib, selmethinib, TAK-733 or crizotinib was used alone (without the above combination), or when 4-MU was used alone, Although antitumor effects against malignant pleural mesothelioma cells have been obtained, synergistic antitumor effects can be obtained when the above combination is performed, which is significantly better than when the combination is not performed. (FIG. 17, 29-32).

  Trametinib, selmethinib, TAK-733 or crizotinib inhibited the survival of malignant pleural mesothelioma cells in a concentration-dependent manner (FIGS. 1, 23-28, 29-32). Western blots showed that trametinib strongly inhibited ERK phosphorylation in NCI-H226 and MSTO-211H cells (FIGS. 3-10). In a mouse xenograft model, trametinib was shown to significantly suppress tumor growth and strongly inhibit ERK phosphorylation (FIGS. 17 and 18).

  Furthermore, the results of Example 2 also showed that CD44 expression was inhibited by trametinib (FIGS. 3 to 10). On the other hand, as shown in Example 3 (FIG. 11, FIG. 12, (b)), the 4-MU treatment did not show a significant decrease in the protein expression level of CD44.

  Hyaluronic acid activates various downstream signaling pathways by binding to cell surface receptors such as CD44, resulting in enhanced cell proliferation, survival, motility, invasiveness and chemical resistance (Edward M, et al. The British journal of dermatology. 2010; 162 (6): 1224-32. Etc.).

  Since overexpression of hyaluronic acid is seen in many cases of malignant pleural mesothelioma, the inventor believed that the expression of CD44 was suppressed by using hyaluronic acid synthesis inhibitor 4-MU From the results of Examples 3 and 4, the expression of Fra-1 is attenuated as the expression of phosphorylated ERK is attenuated by the antitumor agent according to the present invention, and the expression of Fra-1 is attenuated. This suggests that CD44 expression is attenuated. And, since the binding of hyaluronic acid and CD44 is further suppressed by the attenuation of CD44 expression and the inhibition of hyaluronic acid synthesis by 4-MU, compared to the case of using trametinib alone, Example 5 It is considered that a synergistic antitumor effect as shown in FIG.

  In Example 6, TAK-733 and selmethinib alone were shown to act on malignant pleural mesothelioma cells, but both TAK-733 and selmethinib are MEK inhibitors, as is trametinib. ERK phosphorylation, Fra-1 expression, and CD44 expression can be attenuated. When used in combination with 4-MU, the antitumor effect is superior to that obtained when TAK-733 and selmethinib are used alone. It is considered possible.

  In view of structural similarity, not only trametinib, selmethinib and TAK-733, but also one or more compounds selected from the group consisting of compounds represented by the general formulas [I] to [III] When used, and when not only 4-MU but also one or more compounds selected from the group consisting of compounds represented by the general formula [IV] are used, and the MEK inhibitor and the coumarin Even when a derivative or the like is used, it is considered that the antitumor effect can be exhibited.

  As shown in Example 7, when crizotinib, which is a c-Met inhibitor, was used, a synergistic antitumor effect was obtained by using 4-MU together. In view of the results of Example 7, instead of crizotinib, c-Met inhibitor cabozantinib, cabozantinib s-malate or pharmaceutically acceptable salts thereof was used; instead of 4-MU Also, it is considered that the antitumor effect as shown in Example 7 can be exhibited even when one or more compounds selected from the group consisting of compounds represented by the general formula [IV] are used. . Furthermore, not only the combination of crizotinib and 4-MU, but if a c-Met inhibitor and the coumarin derivative are used, an antitumor effect as shown in Example 7 can be achieved. Conceivable.

  In addition, as shown in FIG. 17, 4-MU can enhance the antitumor effect of MEK inhibitor and c-Met inhibitor, and therefore, an antitumor effect enhancer for MEK inhibitor and c-Met inhibitor. It can be used as an active ingredient. In view of the similarity of the structure with 4-MU, one or more compounds selected from the group consisting of compounds represented by the general formula [IV], the coumarin derivative, and the like are also the active ingredients. It can be used as

[Example 8: Enhanced expression of PD-1, PD-L1 and CTLA-4 by 4-MU and trametinib]
Instead of confirming the expression of phosphorylated ERK in the tissue of NCI-H226 tumor, the above [Materials and Methods] except that the expression of PD-1, PD-L1 and CTLA-4 in the tissue was confirmed. Immunohistochemical staining was performed according to the method described in (5) of the section. As an antibody, instead of phospho-p44 / 42 MAPK (Erk1 / 2) (Thr202 / Tyr204) (# 4370), an anti-PD-1 antibody (R and D systems: AF1086), an anti-PD-L1 antibody (Cell Signaling Technology: 13684) and anti-CTLA-4 antibody (Santa Cruz: sc-376016) were used.

  FIG. 33 is a diagram showing the results of immunohistochemical staining in which expression of PD-1, PD-L1, and CTLA-4 was observed for NCI-H226 tumor tissue collected 4 hours after the final administration of the drug. The magnification is 200 times. (A)-(c) of FIG. 33 shows the result of having observed the expression of PD-1, PD-L1, and CTLA-4, respectively. In addition, what is necessary is just to observe and count in the visual field of 400 times magnification, when counting the said expression positive cell quantitatively.

  In FIG. 33, “Control” is a control, “4-MU” is 4-MU when 225 mg / kg / day is administered, “Trametinib 1 mg / kg / day” is “Trametinib 1 mg / kg / day”, “Trametinib “3 mg / kg / day” when trametinib 3 mg / kg / day was administered, “Combination treatment” when trametinib (1 mg / kg / day) and 4-MU (225 mg / kg / day) were administered in combination Results are shown.

  As shown in “Combination treatment” in FIG. 33, cells stained brown, that is, cells expressing PD-1 in (a), PD-L1 in (b), and HTLA-4 in (c), It was observed more frequently when 4-MU and trametinib were administered in combination than when 4-MU or trametinib was administered alone. With the combination, PD-1 and CTLA-4 were enhanced to moderate expression, and PD-L1 was markedly enhanced, although both were weakly expressed in the control.

  From this result, it was revealed that the expression of PD-1, PD-L1, and CTLA-4 can be enhanced by administering 4-MU in combination with trametinib. In view of this result, it is presumed that the response rate of the anti-PD-1 antibody, the anti-PD-L1 antibody, and the anti-CTLA-4 antibody can be increased by enhancing the expression.

  The present invention can be effectively used for the treatment of various cancers. Therefore, it can be widely used in medicine and related fields.

Claims (8)

  An antitumor effect potentiator comprising a coumarin derivative or a pharmaceutically acceptable salt thereof as an active ingredient and capable of enhancing the antitumor effect of a MEK inhibitor and / or c-Met inhibitor. One or more compounds selected from the group consisting of compounds wherein the coumarin derivative is represented by the following general formula [IV]:
(In the formula, R ¹⁸ and R ¹⁹ each independently represent a hydrogen atom, a hydroxyl group or a C _1-6 alkyl group. R ²⁰ , R ²¹ , R ²² and R ²³ each independently represent a hydrogen atom or a hydroxyl group. And the hydrogen atom of the hydroxyl group may be substituted with a C _1-6 alkyl group or a β-D-glucopyranosyl group)
The antitumor effect potentiator according to claim 1, wherein   The antitumor effect potentiator according to claim 2, wherein the coumarin derivative is 4-methylumbelliferone.   An antitumor agent comprising a MEK inhibitor and / or a c-Met inhibitor and the antitumor effect potentiator according to any one of claims 1 to 3 as active ingredients. The MEK inhibitor is one or more compounds selected from the group consisting of compounds represented by the following general formulas [I] to [III], or a pharmaceutically acceptable salt thereof. The antitumor agent according to claim 4:
The compound represented by the general formula [I] is:
[Wherein, X ¹ and X ² are the same or different and each represents a carbon atom or a nitrogen atom,
Part,
And
R ¹ ′, R ² ′ and R ⁶ are the same or different,
A C _1-6 alkyl group,
A C _2-6 alkenyl group,
(Here, the C _1-6 alkyl group and the C _2-6 alkenyl group may be substituted with 1 to 3 substituents selected from Group A below), or
{M is 0 or an integer of 1 to 4, and the ring Cy is a C _3-12 carbocyclic group or a heterocyclic group.
(Here, the heterocyclic group is a saturated or unsaturated ring having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom. The C _3-12 carbocyclic group and the heterocyclic group may be substituted with 1 to 5 substituents selected from the following group B)):
R ³ , R ⁴ , and R ⁵ are the same or different,
Hydrogen atom,
A hydroxy group,
A C _1-6 alkyl group,
A C _2-6 alkenyl group,
(Here, the C _1-6 alkyl group and the C _2-6 alkenyl group may be substituted with 1 to 3 substituents selected from Group A below),
A C _3-12 carbocyclic group, or
A heterocyclic group,
(Here, the heterocyclic group is a saturated or unsaturated ring group having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom, The C _3-12 carbocyclic group and heterocyclic group may be substituted with 1 to 5 substituents selected from the following group B.) Or R ² ′ and R ³ are combined. ^May form a C _1-4 alkylene group, or R ⁴ and R ⁵ together may form a C _1-4 alkylene group.
{Where Group A is
1) a halogen atom,
2) Nitro group,
3) a cyano group,
4) C _1-4 alkyl group,
5) —OR ^A1 (wherein R ^A1 is a hydrogen atom or a C _1-4 alkyl group),
6) —SR ^A2 (wherein R ^A2 is a hydrogen atom or a C _1-4 alkyl group),
7) —NR ^A3 R ^A4 (wherein R ^A3 and R ^A4 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group),
8) —COOR ^A5 (wherein R ^A5 is a hydrogen atom or a C _1-4 alkyl group),
9) —NR ^A6 COR ^A7 (wherein R ^A6 is a hydrogen atom or a C _1-4 alkyl group, and R ^A7 is a C _1-4 alkyl group, a C _3-12 carbocyclic group, or a heterocycle A cyclic group),
10) —NR ^A8 COOR ^A9 (wherein R ^A8 and R ^A9 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group);
11) a C _3-12 carbocyclic group, and
12) a group consisting of heterocyclic groups,
(Here, the heterocyclic group is a saturated or unsaturated ring group having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom,
The C _1-4 alkyl groups of the above 4), R ^A1 , R ^A2 , R ^A3 , R ^A4 , R ^A5 , R ^A6 , R ^A7 , R ^A8 , and R ^A9 are each selected from the following group C Or it may be substituted with 1 to 3 different substituents,
In addition, the C _3-12 carbocyclic group of 11) and R ^A7 , and the heterocyclic group of 12) and R ^A7 are each substituted with the same or different 1 to 5 substituents selected from Group C below. May be. )
Group B
1) a halogen atom,
2) Nitro group,
3) a cyano group,
4) a C _1-8 alkyl group,
5) a _C2-4 alkenyl group,
6) a _C2-4 alkynyl group,
7) —OR ^B1 (where R ^B1 is a hydrogen atom or a C _1-4 alkyl group),
8) —SR ^B2 (wherein R ^B2 is a hydrogen atom or a C _1-4 alkyl group),
9) —NR ^B3 R ^B4 (where R ^B3 is a hydrogen atom, a C _1-4 alkyl group, a C _3-12 carbocyclic group, or a heterocyclic group, and R ^B4 is a hydrogen atom or C _1-4 alkyl group).
10) —NR ^B5 COR ^B6 (wherein R ^B5 is a hydrogen atom or a C _1-4 alkyl group, and R ^B6 is a hydrogen atom, a C _1-4 alkyl group, a C _3-12 carbocyclic group, Or a heterocyclic group).
11) —NR ^B7 COOR ^B8 (wherein R ^B7 and R ^B8 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group),
12) -NR ^B9 CONR ^B10 R ^B11 (wherein R ^B9 , R ^B10 and R ^B11 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group),
13) -NR ^B12 CONR ^B13 OR ^B14 (wherein R ^B12 , R ^B13 and R ^B14 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group),
14) —NR ^B15 SO ₂ R ^B16 (wherein R ^B15 is a hydrogen atom or a C _1-4 alkyl group, and R ^B16 is a C _1-4 alkyl group, a C _3-12 carbocyclic group, or , A heterocyclic group),
15) —SO ₂ —R ^B17 (wherein R ^B17 is a C _1-4 alkyl group or a heterocyclic group),
16) —SO ₂ NR ^B18 R ^B19 (wherein R ^B18 and R ^B19 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group);
17) -P (= O) (R ^B20 ) (R ^B21 ) (wherein R ^B20 and R ^B21 are the same or different and each represents a C _1-4 alkyl group);
18) -COOR ^B22 (wherein R ^B22 is a hydrogen atom or a C _1-4 alkyl group),
19) -CONR ^B23 R ^B24 (wherein R ^B23 and R ^B24 are the same or different and each is a hydrogen atom or a C _1-4 alkyl group),
20) -NR ^B25 SO ₂ NR ^B26 R ^B27 (wherein R ^B25 , R ^B26 and R ^B27 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group);
21) —NR ^B28 SO ₂ NR ^B29 CONR ^B30 R ^B31 (wherein R ^B28 , R ^B29 , R ^B30 and R ^B31 are the same or different and each represents a hydrogen atom or a C _1-4 alkyl group). ),
22) a C _3-12 carbocyclic group, and
23) a group consisting of heterocyclic groups,
(Wherein the “C _1-8 alkyl group” in 4) and the C _1-4 alkyl group in R ^{B1 to} R ^B31 are the same or different 1 to 3 substituents selected from the group A, respectively. May be replaced with
The C _2-4 alkenyl group of 5) and the C _2-4 alkynyl group of 6) may each be substituted with the same or different 1 to 3 substituents selected from the group A,
The heterocyclic group is a saturated or unsaturated ring group having 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom in addition to a carbon atom,
The 22), C _3-12 carbocyclic group of R ^B3 , R ^B6 , and R ^B16 , the above 23), the heterocyclic group of R ^B3 , R ^B6 , R ^B16 , and R ^B17 are respectively It may be substituted with the same or different 1 to 5 substituents selected from the following group C. )
Group C
1) a halogen atom,
2) a cyano group,
3) a C _1-4 alkyl group,
4) —OR ^C1 (wherein R ^C1 is a hydrogen atom or a C _1-4 alkyl group),
5) —NR ^C2 R ^C3 (wherein R ^C2 and R ^C3 are the same or different and are each a hydrogen atom or a C _1-4 alkyl group),
6) -COOR ^C4 (wherein R ^C4 is a hydrogen atom or a C _1-4 alkyl group.)
as well as,
7) A group consisting of oxo groups. },
(However,
Part is
When, as a condition,
R ^{2 ′} is not a methyl group,
When R ^{2 ′} is a phenyl group, R ^{1 ′} is not a phenyl group. )]
The compound represented by the general formula [II] is
[Where:
R ⁷ , R ⁸ , and R ¹⁵ are hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —OR ⁹ , —C (O) R ⁹ , —C (O) OR ⁹ , NR ¹⁰ C (O) OR ¹² , —OC (O) R ⁹ , —NR ¹⁰ SO ₂ R ¹² , —SO ₂ NR ⁹ R ¹⁰ , —NR ¹⁰ C (O) R ⁹ , —C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (NCN) NR ⁹ R ¹⁰ , —NR ⁹ R ¹⁰ , and C _{1 to} C ₁₀ alkyl, C _{2 to} C ₁₀ alkenyl, C ₂ -C _{10 alkynyl,} C 3 _{-C 10 cycloalkyl,} C 3 _{-C 10 cycloalkylalkyl, -S (O) j (C} 1 ~C 6 ^{_{alkyl), - S (O) j}} (CR 10 R 11 ) M-aryl, a Reel, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, _{^{heterocyclylalkyl, -O (CR 10 R 11)}} m - ^{aryl, -NR 10 (CR 10 R 11} ) m - aryl, -O ^(CR 10 ^{R 11)} _m - ^{heteroaryl, _{-NR 10 (CR 10 R 11)}} m - _{^{heteroaryl, -O (CR 10 R 11)}} m - heterocyclyl, and _{^{-NR 10 (CR 10 R 11)}} m - are each independently selected from heterocyclyl Each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety may be oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ¹⁰ SO ₂ R ¹² , -SO ₂ NR ⁹ R ¹⁰ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ¹⁰ C (O) OR ¹² , —NR ¹⁰ C (O) R ⁹ , — C (O) NR ⁹ R ¹⁰ , —NR ⁹ R ¹⁰ , —NR ¹¹ C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (NCN) NR ⁹ R ¹⁰ , —OR ⁹ , aryl, heteroaryl, arylalkyl Optionally substituted by 1 to 5 groups each independently selected from: heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R ⁹ is hydrogen, trifluoromethyl, and C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkyl alkyl, aryl , Arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoro Methyl, difluoromethoxy, trifluoromethoxy, azide, —NR′SO ₂ R ″ ″, —SO ₂ NR′R ″, —C (O) R ′, —C (O) OR ′, —OC (O) R ', -NR'C (O) OR "", -NR'C (O) R ", -C (O) NR'R ", -SR"", - S (O) R"", - SO 2 R ', - NR'R", - NR'C (O) NR "R"', - NR'C (NCN) NR " Optionally substituted by 1 to 5 groups, each independently selected from R ″ ′, —OR ′, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R ′, R ″, and R ″ ′ are each independently selected from hydrogen, C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, aryl, and arylalkyl;
R ″ ″ is selected from C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, aryl, and arylalkyl; or any of R ′, R ″, R ″ ′, or R ″ ″ The two together with the bonding partner atom may form a 4- to 10-membered carbocycle, heteroaryl ring, or heterocycle, each of which is halogen, cyano, nitro, trifluoro Optionally substituted by 1 to 3 groups, each independently selected from methyl, difluoromethoxy, trifluoromethoxy, azide, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl ; or R ⁹ and ^{R 10,} together with the binding partner of atoms, 4 to 10 membered carbocyclic, heteroaryl ring, also It may form a heterocyclic ring, each of these rings are halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{azido, -NR'SO 2 R "", -} SO 2 NR'R " , -C (O) R ', -C (O) OR', -OC (O) R ', -NR'C (O) OR "", -NR'C (O) R ", -C (O _{) NR'R ", - SO 2 R} "", - NR'R", - NR'C (O) NR "R"', - NR'C (NCN) NR "R"', - OR ', aryl Optionally substituted by 1 to 3 groups each independently selected from: heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; or R ¹⁰ and R ¹¹ are each independently represents hydrogen or _C 1 -C ₆ alkyl; one Alternatively, R ¹⁰ and R ¹¹ may form a 4- to 10-membered carbon ring, heteroaryl ring, or heterocyclic ring together with the bonding partner atom, and each of these rings may be halogen, cyano, , Nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR′SO ₂ R ″ ″, —SO ₂ NR′R ″, —C (O) R ′, —C (O) OR ′, — OC (O) R ', - NR'C (O) OR "", - NR'C (O) R ", - C (O) NR'R", - SO 2 R "", - NR'R " , -NR'C (O) NR "R"',-NR'C (NCN) NR "R"', -OR ', aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, respectively Optionally with one to three groups selected independently It is conversion;
R ¹² is selected from trifluoromethyl and C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, each alkyl, cycloalkyl , aryl, heteroaryl, and heterocyclyl moiety, oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, _{azido, -NR'SO 2 R "", -} SO 2 NR'R ", - C (O) R ', -C (O) OR', -OC (O) R ', -NR'C (O) OR "", -NR'C (O) R ", -C (O) NR 'R', -SO ₂ R "", -NR'R ', -NR'C (O) NR "R"', -NR'C (NCN) NR "R"',-OR', aryl, heteroa Optionally substituted with 1 to 5 groups each independently selected from reel, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
R ¹³ is C ₁ -C ₁₀ alkyl, C ₂ -C ₁₀ alkenyl, C ₂ -C ₁₀ alkynyl, C ₃ -C ₁₀ cycloalkyl, C ₃ -C ₁₀ cycloalkylalkyl, aryl, arylalkyl, heteroaryl, Selected from heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl moiety is oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoro Methoxy, azide, —NR ¹⁰ SO ₂ R ¹² , —SO ₂ NR ⁹ R ¹⁰ , —C (O) R ⁹ , —C (O) OR ⁹ , —OC (O) R ⁹ , —NR ¹⁰ C (O ^{) OR 12, -NR 10 C (} O) R 9, -C (O) N _{^{9 R 10, -SO 2 R 12}} , -NR 9 R 10, -NR 11 C (O) NR 9 R 10, -NR 11 C (NCN) NR 9 R 10, -OR 9, aryl, heteroaryl, aryl Optionally substituted with 1 to 5 groups each independently selected from alkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
A is selected from OR ⁹ or NR ¹⁰ OR ⁹ ;
R ¹⁴ is hydrogen, —SCF ₃ , —Cl, —Br, —F, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —OR ⁹ , —C (O) R ⁹ , —C ^{(O) OR 9, -NR 10} C (O) OR 12, -OC (O) R 9, -NR 10 SO 2 R 12, -SO 2 NR 9 R 10, -NR 10 C (O) R 9, ^{-C (O) NR 9 R 10} , -NR 11 C (O) NR 9 R 10, -NR 9 R 10, and _C 1 _{-C 10 alkyl,} C 2 _{-C 10 alkenyl,} C 2 _{-C 10} alkynyl, C ₃ -C _{10 cycloalkyl,} C 3 _{-C 10 cycloalkylalkyl, -S (O) j (C} 1 ~C 6 ^{alkyl), - S (O) j} (CR 10 R 11) m - , aryl, Arylalkyl, hetero Reel, heteroarylalkyl, heterocyclyl, _{^{heterocyclylalkyl, -O (CR 10 R 11)}} m - ^{aryl, -NR 10 (CR 10 R 11} ) m - _{^{aryl, -O (CR 10 R 11)}} m - heteroaryl, - _{^{NR 10 (CR 10 R 11)}} m - _{^{heteroaryl, -O (CR 10 R 11)}} m - heterocyclyl, and _{^{-NR 10 (CR 10 R 11)}} m - is selected from heterocyclyl, each alkyl, alkenyl, alkynyl, cycloalkyl The alkyl, aryl, heteroaryl, and heterocyclyl moieties are oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azide, —NR ¹⁰ SO ₂ R ¹² , —SO ₂ NR ⁹ R ¹⁰ , — C (O) R ⁹ , —C (O) O ^{R 9, -OC (O) R} 9, -NR 10 C (O) OR 12, -NR 10 C (O) R 9, -C (O) NR 9 R 10, -NR 9 R 10, -NR 11 1 independently selected from C (O) NR ⁹ R ¹⁰ , —NR ¹¹ C (NCN) NR ⁹ R ¹⁰ , —OR ⁹ , aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl. Optionally substituted with from 5 to 5 groups;
m is 0, 1, 2, 3, 4, or 5;
j is 1 or 2.]
The compound represented by the general formula [III] is
[Where:
X ₁ is CR ₆ ;
X ₅ is CR ₆ ;
R ₃ is hydrogen, hydroxy, unsubstituted or alkoxy substituted with one or more groups selected from group A ′, unsubstituted or hydroxyalkoxy substituted with one or more groups selected from group A ′, Aryloxy substituted or substituted with one or more groups selected from group A ′, unsubstituted or heteroaryloxy substituted with one or more groups selected from group A ′, amino, unsubstituted or group A ′ (C _1-10 ) alkylamino substituted with one or more groups selected from: unsubstituted, arylamino substituted with one or more groups selected from group A ′, unsubstituted or selected from group A ′ 1 or more hetero arylamino substituted by a group, substituted with one or more groups selected from unsubstituted or group a '(C _-10) alkyl, substituted with one or more groups selected from unsubstituted or group A 'halo substituted with one or more groups selected from (C _1-10) alkyl, unsubstituted or group A' One or more groups selected from hydroxy (C _1-10 ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′, unsubstituted (C _1-10 ) alkyl, unsubstituted or group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, substituted with at least one hetero (C _3-12 ) cycloalkyl (C ₁ ) substituted with one or more groups selected from group A ′ _-5) alkyl, one selected from an unsubstituted or group a 'aryl substituted with one or more groups selected (C _1-10) alkyl, unsubstituted or group a' Group heteroaryl _{(C 1-5)} alkyl substituted with the above, substituted with one or more groups selected from unsubstituted or group A _{'(C 9-12)} bicycloaryl _{(C 1-5)} alkyl One or more groups selected from hetero (C _8-12 ) bicycloaryl (C _1-5 ) alkyl, unsubstituted or group A ′, unsubstituted or substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl, unsubstituted or substituted with one or more groups selected from group A ′, or hetero (C _3-12 ) cycloalkyl, unsubstituted or selected from group A ′ (C _9-12 ) bicycloalkyl substituted with one or more groups, unsubstituted or hetero (C _3-12 ) bicyclo substituted with one or more groups selected from group A ′ Hetero (C ₁ ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′ (C _4-12 ) aryl, unsubstituted or substituted with one or more groups selected from group A ′ _-10 ) aryl, unsubstituted or substituted with one or more groups selected from group A '( _C9-12 ) bicycloaryl and unsubstituted or substituted with one or more groups selected from group A' Selected from the group consisting of hetero (C _4-12 ) bicycloaryl;
R ₅ is hydrogen, hydroxy, unsubstituted or alkoxy substituted with one or more groups selected from group A ′, unsubstituted or aryloxy substituted with one or more groups selected from group A ′, Heteroaryloxy, amino substituted with one or more groups selected from substituted or group A ′, (C _1-10 ) alkylamino unsubstituted or substituted with one or more groups selected from group A ′, From unsubstituted or substituted arylamino with one or more groups selected from group A ′, unsubstituted or substituted heteroarylamino with one or more groups selected from group A ′, unsubstituted or from group A ′ (C _1-10 ) alkyl substituted with one or more selected groups, unsubstituted or substituted with one or more groups selected from group A ′ B (C _1-10 ) alkyl, unsubstituted or one or more groups selected from amino (C _1-10 ) alkyl, unsubstituted or group A ′, substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, substituted with at least one hetero (C _3-12 ) cycloalkyl (C ₁ ) substituted with one or more groups selected from group A ′ _-5 ) alkyl, unsubstituted or substituted by one or more groups selected from group A ′, aryl (C _1-10 ) alkyl, unsubstituted or substituted by one or more groups selected from group A ′ heteroaryl _{(C 1-5)} alkyl, substituted with one or more groups selected from unsubstituted or group a _{'(C 9-12)} bicycloaryl _{(C 1-5)} alkyl, unsubstituted Properly it is substituted with one or more groups selected from the group A 'heteroaryl substituted with one or more groups selected from (C _8-12) bicycloaryl (C _1-5) alkyl, unsubstituted or group A' (C _3-12 ) cycloalkyl, unsubstituted or substituted with one or more groups selected from group A ′, hetero (C _3-12 ) cycloalkyl, unsubstituted or one selected from group A ′ (C _9-12 ) bicycloalkyl substituted with one or more groups, unsubstituted or hetero (C _3-12 ) bicycloalkyl substituted with one or more groups selected from group A ′, unsubstituted or group A ′ from substituted with one or more groups selected (C _4-12) aryl, heteroaryl substituted with one or more groups selected from unsubstituted or group a '(C _1-10) Reel, heteroaryl substituted with one or more groups selected from the 'substituted with one or more groups selected from (C _9-12) bicycloaryl and unsubstituted or group A' unsubstituted or group A (C _4-12 ) selected from the group consisting of bicycloaryl;
Each R ₆ is independently selected from hydrogen, halo, cyano, unsubstituted or heteroaryloxy substituted with one or more groups selected from group A ′, aminocarbonyl, unsubstituted or group A ′. (C _1-10 ) alkylaminocarbonyl substituted with one or more groups, unsubstituted or arylaminocarbonyl substituted with one or more groups selected from group A ′, unsubstituted or selected from group A ′ Heteroarylaminocarbonyl substituted with one or more groups, amino, unsubstituted or selected from (C _1-10 ) alkylamino, unsubstituted or group A ′ substituted with one or more groups selected from group A ′ Arylamino substituted with one or more groups selected from, unsubstituted or substituted with one or more groups selected from group A ′ Terrorism arylamino, unsubstituted or 'substituted with one or more groups selected from (C _1-10) alkyl, unsubstituted or group A' Group A halo substituted with one or more groups selected from ( C _1-10 ) alkyl, unsubstituted or substituted with one or more groups selected from amino (C _1-10 ) alkyl, unsubstituted or group A ′ selected from group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl (C _1-5 ) Alkyl, unsubstituted or substituted with one or more groups selected from group A ′ (C _1-10 ) alkyl, unsubstituted or one or more groups selected from group A ′ Substituted heteroaryl (C _1-5 ) alkyl, unsubstituted or (C _9-12 ) bicycloaryl (C _1-5 ) alkyl, unsubstituted or substituted with one or more groups selected from group A ′ Hetero (C _8-12 ) bicycloaryl (C _1-5 ) alkyl substituted with one or more groups selected from group A ′, unsubstituted or substituted with one or more groups selected from group A ′ (C _3-12 ) cycloalkyl, unsubstituted or substituted with one or more groups selected from group A ′ hetero (C _3-12 ) cycloalkyl, unsubstituted or selected from group A ′ substituted by a group (C _9-12) bicycloalkyl, hetero substituted with one or more groups selected from unsubstituted or group a '(C _3-12) bicycloalkyl 'Substituted with one or more groups selected from (C _4-12) aryl, unsubstituted or group A' unsubstituted or group A is substituted with one or more groups selected from hetero (C _1-10 ) Aryl, unsubstituted or substituted with one or more groups selected from group A ′ (C _9-12 ) Bicycloaryl and heterocycles substituted with one or more groups selected from unsubstituted or group A ′ ( C _4-12 ) selected from the group consisting of bicycloaryl;
R _14a , R _14b , R _14c , R _14d and R _14e are each independently alkoxy, unsubstituted or substituted with one or more groups selected from hydrogen, halo, cyano, unsubstituted or group A ′ From (C _1-3 ) alkyl substituted with one or more groups selected from group A ′ and hydroxy (C _1-3 ) alkyl unsubstituted or substituted with one or more groups selected from group A ′ Selected from the group consisting of:
Group A ′ may be substituted with a group selected from halo, nitro, cyano, hydroxy, group B ′ (C _1-10 ) alkoxy, group selected from group B ′ ( C _4-12 ) aryloxy, _optionally substituted with a group selected from group B ′ hetero (C _1-10 ) aryloxy, aminocarbonyl, optionally substituted with a group selected from group B ′ ( C _1-10 ) alkylaminocarbonyl, arylaminocarbonyl optionally substituted with a group selected from group B ′, heteroarylaminocarbonyl optionally substituted with a group selected from group B ′, amino, group B (C _1-10 ) alkylamino optionally substituted with a group selected from ', substituted with a group selected from group B' From arylamino, optionally substituted heteroarylamino optionally substituted with a group selected from group B ′, (C _1-10 ) alkyl _optionally substituted with a group selected from group B ′, from group B ′ A halo (C _1-10 ) alkyl _optionally substituted with a selected group, a hydroxy (C _1-10 ) alkyl _optionally substituted with a group selected from Group B ′, and a group selected from Group B ′ Optionally substituted (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, hetero (C _3-12 ) cycloalkyl (C _1-10 ) _optionally substituted with a group selected from group B ′ ) Alkyl, aryl (C _1-10 ) alkyl _optionally substituted with a group selected from group B ′, hetero (C1) optionally substituted with a group selected from group B ′ _1-10 ) aryl (C _1-5 ) alkyl, a group selected from (C _9-12 ) bicycloaryl (C _1-5 ) alkyl, group B ′ optionally substituted with a group selected from group B ′ (C _3-12 ) cycloalkyl, group B ′ _optionally substituted with a group selected from hetero (C _8-12 ) bicycloaryl (C _1-5 ) alkyl, group B ′. Hetero (C _3-12 ) cycloalkyl _optionally substituted with a group selected from: (C _9-12 ) Bicycloalkyl _optionally substituted with a group selected from group B ′: selected from group B ′ optionally substituted hetero (C _3-12) even though bicycloalkyl in groups, 'optionally substituted by a group selected from (C _4-12) aryl, group B' group B from Optionally substituted with a group selected from optionally substituted a barrel group hetero (C _1-10) aryl, the group B 'may be substituted by a group selected from (C _9-12) bicycloaryl and group B' Hetero (C _4-12 ) bicycloaryl, which may be _substituted ;
Group B ′ includes halo, nitro, cyano, hydroxy, (C _1-10 ) alkoxy, (C _4-12 ) aryloxy, hetero (C _1-10 ) aryloxy, aminocarbonyl, amino, (C _1-10 ) Alkylamino, (C _1-10 ) alkyl, halo (C _1-10 ) alkyl, hydroxy (C _1-10 ) alkyl, (C _3-12 ) cycloalkyl (C _1-5 ) alkyl, hetero (C _{3) -12)} cycloalkyl _{(C 1-10)} alkyl, aryl _{(C 1-10)} alkyl, hetero _{(C 1-10)} aryl _{(C 1-5) alkyl, (C 9-12)} bicycloaryl _{(C 1- 5)} alkyl, hetero _{(C 8-12)} bicycloaryl _{(C 1-5) alkyl, (C 3-12)} cycloalkyl, hetero _{(C 3-12)} cycloalkyl _{Alkyl, (C 9-12)} bicycloaryl alkyl, hetero _{(C 3-12) bicycloalkyl, (C 4-12)} aryl, hetero _{(C 1-10) aryl, (C 9-12)} bicycloaryl and hetero (C _4-12 ) is bicycloaryl].   6. The antitumor agent according to claim 4 or 5, wherein the c-Met inhibitor is one or more compounds selected from the group consisting of crizotinib, cabozantinib and cabozantinib s-malate. .   One or more compounds selected from the group consisting of the compounds represented by the above general formulas [I] to [III] are one or two compounds selected from the group consisting of trametinib, selmethinib, and TAK-733. The antitumor agent according to claim 5 or 6, which is the above compound.   The antitumor agent according to any one of claims 4 to 7, an anti-PD-L1 antibody, an anti-PD-1 antibody, an anti-PD-L2 antibody, an anti-CTLA-4 antibody, an anti-CD25 antibody, an anti-CD33 antibody, and An antitumor agent comprising, as an active ingredient, one or more antibodies selected from the group consisting of anti-CD52 antibodies.