JP2019014683A - Inhibitor for teratoma formation from pluripotent stem cell and use therefor - Google Patents

Abstract

To provide a means whereby, after a pluripotent stem cell-derived cell or its structure is transplanted, it is possible to substantially prevent a tumor from occurring in the cell or its structure.SOLUTION: A composition contains a compound represented by formula (I). [L is C1-C6 alkylene carbonyl or the like; A is -NRR; Rand R4 form, together with a nitrogen atom to which they bond, 4-7 membered heterocycloalkyl or heterocycloalkenyl containing one or more hetero atom selected from N, S and O].SELECTED DRAWING: None

Description

  The present invention relates to a teratoma formation inhibitor from pluripotent stem cells and use thereof.

  Regenerative medicine using pluripotent stem cells such as induced pluripotent stem cells (hereinafter also referred to as “iPS cells”) and embryonic stem cells (hereinafter also referred to as “ES cells”) Is expected to be effective against diseases for which there has been no cure. For example, in Japan, clinical studies using autologous iPS cell-derived retinal pigment epithelial cells for age-related macular degeneration are currently ongoing.

  When a pluripotent stem cell is transplanted to a subject as it is, the differentiation and proliferation of the cell proceeds in a disorderly manner, and a tumor called a teratoma (hereinafter also referred to as “teratoma”) is formed. The teratoma in the early stage of formation is a benign tumor, but eventually changes to a teratocarcinoma having metastatic potential (hereinafter also referred to as “teratocarcinoma”) to become a malignant tumor or cancer. Therefore, when stem cells remain in cells derived from pluripotent stem cells or structures thereof, formation of teratomas is feared after transplantation.

  In regenerative medicine using pluripotent stem cells, no effective method has been established as a treatment when a tumor is formed other than surgically removing the tumor. Therefore, there is a need for techniques for preventing or treating teratoma and / or teratocarcinoma formation.

  For example, Patent Document 1 describes a method for removing tumor cells using a suicide gene. In the method described in this document, first, a suicide gene is introduced into a pluripotent stem cell together with a promoter whose expression is induced by administration of a drug such as doxycycline. When a tumor is formed after transplantation, the administration of doxycycline induces suicide gene expression and induces cell death in transplanted cells including tumor cells.

  In addition, development of methods for removing pluripotent stem cells that are the source of tumor cells before transplantation is underway. For example, a method using a small molecule inhibitor that specifically induces cell death in pluripotent stem cells, or a method using a compound obtained by adding a toxin to a lectin that specifically binds to pluripotent stem cells has been developed. (Non-Patent Documents 1 and 2).

  Recently, in teratomas generated from iPS cells, no gene mutation was observed, and changes in gene expression due to changes in DNA methylation level were reported (Non-patent Document 3). This report suggests that teratoma formation depends not on gene mutation but on gene expression changes, so-called epigenetic levels.

Special Table 2015-504678

Tateno H et al., Stem Cell Rep, Volume 4, p. 811-820, 2015 Lee MO et al., Proc Natl Acad Sci, U.S.A, 110, E3281, 2013 Ohnishi K et al., Cell, 156, p. 663-677, 2014

  There have been several problems with the known techniques for preventing or treating the formation of tumors derived from pluripotent stem cells. For example, in the case of the method described in Patent Document 1, since a suicide gene is incorporated in all transplanted cells, it is difficult in principle to remove only tumor cells. In addition, this method cannot be used not only for preventing tumor formation, but also has a possibility of new tumor formation accompanying foreign gene transfer.

  In the case of the methods described in Non-Patent Documents 1 and 2, it is difficult to prevent tumor formation or remove the formed tumor after transplantation.

  Thus, in regenerative medicine using pluripotent stem cells, an effective method for preventing tumor formation after transplantation and removing the formed tumor has not been established at present. For this reason, in regenerative medicine using pluripotent stem cells, the safety of the patient after transplantation may not be sufficiently ensured. In addition, a great deal of labor and cost are required for production of functional cells from pluripotent stem cells, establishment of isolation techniques, and strict quality control of cells before transplantation. These points are major bottlenecks in the advancement of regenerative medicine and ensuring safety.

  Therefore, an object of the present invention is to provide a means capable of substantially preventing tumor formation in a cell or a structure thereof after transplanting a cell derived from a pluripotent stem cell or a structure thereof. .

  The present inventors have studied various means for solving the above problems. The present inventors have found that a specific novel compound having inhibitory activity against lysine-specific demethylase 1 (hereinafter also referred to as “LSD1”), an enzyme involved in epigenetic regulation, causes teratoma formation. It was found that it can be suppressed. Based on the above findings, the present inventors have completed the present invention.

That is, the gist of the present invention is as follows.
(1) Formula (I):
[Where:
L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or substituted or unsubstituted C ₂ -C ₆ alkynylene -CO- (However, L is bonded to A at the carbon atom position of -CO-),
A is -NR ³ R ⁴ , or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. ]
The teratoma formation inhibitor which contains the compound represented by these, its stereoisomer or those salts, or those solvates as an active ingredient.
(2) R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are bonded contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having R ⁸ and one or more R ⁹ ,
R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls, or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted 5-9 membered heteroaryl, and substituted or unsubstituted a C ₁ -C ₆ monovalent radical independently selected from the group consisting of alkyl,
R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O), Or
R ¹⁰ is one or more selected from substituted or unsubstituted C _{3 to} C ₇ cycloalkyl, N, S and O, together with one or two carbon or nitrogen atoms to which they are attached. includes hetero atoms as ring atoms, and substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or substituted or heteroaryl 5 or 6 membered unsubstituted Forming,
R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl, Or
R ¹² and R ^13, form together with the carbon atom or a nitrogen atom to which they are attached a substituted or unsubstituted C ₄ -C ₇ cycloalkyl or substituted or unsubstituted 4-7 membered heterocycloalkyl And
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl.
The teratoma formation inhibitor according to the embodiment (1).
(3) R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ ,- COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or 1 Is a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with one or more halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ Or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or substituted or unsubstituted C ₅ -C ₆ aryl;
R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl A monovalent group independently selected from the group consisting of:
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens. Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl,
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl.
The teratoma formation inhibitor according to the embodiment (2).
(4) The teratoma formation inhibitor according to any one of the above embodiments (1) to (3), wherein L is substituted or unsubstituted C _{1 to} C ₆ alkylene-CO—.
(5) L is methylene-CO-,
A is -NR ³ R ⁴
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperazinyl having one R ⁸ and one R ⁹
R ⁸ is methyl;
R ⁹ is hydrogen,
The teratoma formation inhibitor according to any one of the embodiments (1) to (4).
(6) Formula (I):
[Where:
L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or substituted or unsubstituted C ₂ -C ₆ alkynylene -CO- (However, L is bonded to A at the carbon atom position of -CO-),
A is -NR ³ R ⁴ , or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. ]
Or a salt thereof, or a solvate thereof as an active ingredient, for use in inhibiting teratoma formation.
(7) R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are bonded contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having R ⁸ and one or more R ⁹ ,
R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls, or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted 5-9 membered heteroaryl, and substituted or unsubstituted a C ₁ -C ₆ monovalent radical independently selected from the group consisting of alkyl,
R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O), Or
R ¹⁰ is one or more selected from substituted or unsubstituted C _{3 to} C ₇ cycloalkyl, N, S and O, together with one or two carbon or nitrogen atoms to which they are attached. includes hetero atoms as ring atoms, and substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or substituted or heteroaryl 5 or 6 membered unsubstituted Forming,
R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl, Or
R ¹² and R ^13, form together with the carbon atom or a nitrogen atom to which they are attached a substituted or unsubstituted C ₄ -C ₇ cycloalkyl or substituted or unsubstituted 4-7 membered heterocycloalkyl And
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl.
The medicament according to embodiment (6).
(8) R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ ,- COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or 1 Is a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with one or more halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ Or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or substituted or unsubstituted C ₅ -C ₆ aryl;
R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl A monovalent group independently selected from the group consisting of:
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens. Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl,
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl.
The medicament according to the embodiment (7).
(9) L is a substituted or C ₁ unsubstituted -C ₆ alkylene -CO-, medicament according to any one of the embodiments (6) to (8).
(10) L is methylene-CO-,
A is -NR ³ R ⁴
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperazinyl having one R ⁸ and one R ⁹
R ⁸ is methyl;
R ⁹ is hydrogen,
The medicament according to any one of the embodiments (6) to (9).
(11) The medicament according to any one of the above embodiments (6) to (10) for use in the prevention or treatment of malignant tumors in cells derived from pluripotent stem cells or structures thereof.
(12) Formula (I):
[Where:
L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or substituted or unsubstituted C ₂ -C ₆ alkynylene -CO- (However, L is bonded to A at the carbon atom position of -CO-),
A is -NR ³ R ⁴ , or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. ]
Or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers, and a pharmaceutical composition for use in inhibiting teratoma formation.

  According to the present invention, it is possible to provide means capable of substantially preventing tumor formation in a cell or a structure thereof after transplanting a cell derived from a pluripotent stem cell or a structure thereof.

  Problems, configurations, and effects other than those described above will be clarified by the following description of embodiments.

Fig. 1 shows that fibroblasts (fibroblasts) derived from healthy individuals, peripheral blood T-lymphocytes (T-cells), induced pluripotent stem cells (hiPSC) 201B and 201B were transplanted subcutaneously into immunodeficient mice. The result of having analyzed the protein expression level in the teratoma, malignant tumor cell line K562, HeLa cell line, and HEK293 cell line which formed after a week by the immunoblot is shown. A: As a result of immunoblotting, B: Relative value of each signal intensity when fibroblast value is 1.0. Fig. 2 shows teratoma, malignant tumor cell line K562, HeLa cell line, and HEK293 cell line that were formed 3 weeks after transplanting subcutaneously into immunodeficient mice with fibroblasts, T-cells, hiPSC 201B, 201B derived from healthy individuals The result of having analyzed the gene expression level in by quantitative PCR method is shown. FIG. 3 shows the results of HE staining of teratoma tissue sections and fluorescence immunostaining using a specific antibody against HDAC1, HDAC6 or LSD1 and an Alexa-488-labeled secondary antibody. In the figure, green indicates a signal from HDAC1, HDAC6 or LSD1, and blue indicates a cell nucleus by DAPI staining. FIG. 4 shows the results of quantitative PCR analysis of LSD1 gene expression in three clone substrains (E7, F6 and H12) in which the LSD1 gene was strongly expressed in the ChiPS17 strain. FIG. 5 shows the results of immunoblotting analysis of protein expression levels in three clone substrains (E7, F6 and H12) in which the LSD1 gene was strongly expressed in the ChiPS17 strain. A: As a result of immunoblotting, B: Relative value of each protein expression level when the protein expression level of the sub-strain (mock) into which only the vector is introduced is 1.0. FIG. 6 shows photographs of teratomas collected on the 22nd and 49th days after transplantation of cells of ChiPS17 substrain (H12 strain) subcutaneously into 6-8 week-old immunodeficient mice. A: Results on day 22 after transplantation, B: Results on day 49 after transplantation. Figure 7 shows the weight of teratoma (mean ± standard deviation value) collected 22 days and 49 days after transplantation of ChiPS17 substrain (H12 strain) cells subcutaneously into 6-8 week-old immunodeficient mice. Show. A: Results on day 22 after transplantation, B: Results on day 49 after transplantation. * Indicates that the p-value for mock calculated by Student's t-test is 0.05 or less. FIG. 8 shows HE staining results of teratoma sections taken on the 22nd and 49th days after transplantation of cells of ChiPS17 substrain (H12 strain) into 6-8 week-old immunodeficient mice subcutaneously. A: Results on day 22 after transplantation, B: Results on day 49 after transplantation. FIG. 9 shows photographs of teratomas collected 56 days after transplantation in administration groups and control groups in which known enzyme inhibitors were administered to 6-8 week-old immunodeficient mice subcutaneously transplanted with ChiPS17 cells. . A: Control group, B: Tubastatin A administration group, C: Bortezomib administration group. FIG. 10 shows the measurement results of luciferase activity on the 8th and 40th days after transplantation in mice of the synthetic compound 1 administration group and the control group. FIG. 11 shows the mean value ± standard deviation value of luciferase activity on the 8th and 40th day after transplantation in mice of the synthetic compound 1 administration group and the control group. * Indicates that the p value with respect to the value of the control group, calculated by Student's T test, was 0.05 or less. FIG. 12 shows a photograph of a teratoma collected 40 days after transplantation. FIG. 13 shows the weight (average value ± standard deviation value) of teratomas collected 40 days after transplantation. * Indicates that the p value with respect to the value of the control group calculated by Student's t-test is 0.05 or less. FIG. 14 shows the results of HE staining of a teratoma section collected 40 days after transplantation. FIG. 15 shows the results of fluorescent immunostaining of a frozen section of teratoma. In order from the top, fluorescent immunostaining with anti-activated caspase-3 (active-casp.3) antibody (red) and DAPI (blue) results in fluorescence immunization with anti-c-myc antibody (red) and DAPI (blue) As a result of staining, results of fluorescent immunostaining with anti-H3K4me2 antibody (green) and DAPI (blue), and results of fluorescent immunostaining with anti-H3K9me2 antibody (green) and DAPI (blue).

  Hereinafter, preferred embodiments of the present invention will be described in detail.

<1. Definition>
As used herein, “alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing the specified number of carbon atoms. For example, “C ₁ -C ₅ alkyl” means a straight or branched chain saturated aliphatic hydrocarbon group containing at least 1 and at most 5 carbon atoms. Suitable alkyls include, but are not limited to, linear or branched C, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and n-pentyl. it can be mentioned ₁ -C ₅ alkyl.

In the present specification, “alkenyl” means a group in which one or more CC single bonds of the alkyl are substituted with double bonds. Suitable alkenyls include, but are not limited to, vinyl, 1-propenyl, allyl, 1-methylethenyl (isopropenyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2 - methyl-2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 3-methylbut-2-en-1-yl and linear or branched 1-pentenyl C ₂ ~ mention may be made of the C ₅ alkenyl.

In the present specification, “alkynyl” means a group in which one or more CC single bonds of the alkyl are substituted with triple bonds. Suitable alkynyls include, but are not limited to, straight chain such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 1-pentynyl. or it can be given C ₂ -C ₅ alkynyl branched.

As used herein, “cycloalkyl” means an alicyclic alkyl containing the specified number of carbon atoms. For example, “C ₃ -C ₆ cycloalkyl” means a cyclic hydrocarbon group containing at least 3 and at most 6 carbon atoms. Suitable cycloalkyls include, but are not limited to, C ₃ -C ₆ cycloalkyls such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In the present specification, “cycloalkenyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with double bonds. Suitable cycloalkenyl includes, but is not limited to, C ₄ -C ₆ cycloalkenyl such as cyclobutenyl, cyclopentenyl, and cyclohexenyl.

In the present specification, “cycloalkynyl” means a group in which one or more CC single bonds of the cycloalkyl are substituted with triple bonds. Suitable cycloalkynyl includes, but is not limited to, C ₄ -C ₆ cycloalkynyl such as cyclobutynyl, cyclopentynyl and cyclohexynyl.

  In the present specification, “heterocycloalkyl” means that one or more carbon atoms of the cycloalkyl, cycloalkenyl or cycloalkynyl are each independently selected from nitrogen (N), sulfur (S) and oxygen (O). Means a group substituted with one or more heteroatoms. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heterocycloalkyl include, but are not limited to, eg, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Mention may be made of ˜6-membered heterocycloalkyl. Suitable heterocycloalkenyls include, but are not limited to, 5- or 6-membered heterocycloalkenyls such as dihydropyrrole and tetrahydropyridine.

In the present specification, “cycloalkylalkyl” means a group in which one of the hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkylalkyl, but are not limited to, may be, for example, a C ₇ -C ₁₁ cycloalkylalkyl such as cyclohexylmethyl and cyclohexenyl methyl.

As used herein, “heterocycloalkylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms has been replaced with the heterocycloalkyl. Suitable heterocycloalkylalkyls include, but are not limited to, 3-6 membered heterocycloalkyl-C ₁ -C ₅ alkyl.

In the present specification, “alkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the alkyl, alkenyl or alkynyl. Suitable alkoxy includes, but is not limited to, C ₁ -C ₅ alkoxy such as methoxy, ethoxy, propoxy, butoxy and pentoxy.

In the present specification, “cycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the above cycloalkyl, cycloalkenyl or cycloalkynyl. Suitable cycloalkoxy includes, but is not limited to, C ₃ -C ₆ cycloalkoxy such as cyclopropoxy, cyclobutoxy and cyclopentoxy.

  In the present specification, “heterocycloalkoxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heterocycloalkyl. Suitable cycloalkoxy includes, but is not limited to, for example, 3-6 membered heterocycloalkoxy.

In the present specification, “aryl” means an aromatic ring group. Suitable aryls include, but are not limited to, C ₆ -C ₁₈ aryls such as phenyl, biphenyl, terphenyl, naphthyl and anthracenyl.

In the present specification, “arylalkyl” means a group in which one of hydrogen atoms of the alkyl, alkenyl or alkynyl is substituted with the aryl. Preferred arylalkyl include, but are not limited to, for example, benzyl, 1-phenethyl, 2-phenethyl, biphenylmethyl, can be exemplified terphenyl methyl and C ₇ -C ₂₀ arylalkyl styryl like.

  In the present specification, “heteroaryl” means a group in which one or more carbon atoms of the aryl are each independently substituted with one or more heteroatoms selected from N, S and O. In this case, substitution with N or S includes substitution with N-oxide or S oxide or dioxide, respectively. Suitable heteroaryl include, but are not limited to, furanyl, thienyl (thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrazinyl, Mention may be made of 5- to 15-membered heteroaryl such as pyrimidinyl, quinolinyl, isoquinolinyl and indolyl.

In the present specification, “heteroarylalkyl” means a group in which one of the alkyl, alkenyl or alkynyl hydrogen atoms is substituted with the heteroaryl. Suitable heteroarylalkyl includes, but is not limited to, 5- to 15-membered heteroaryl-C ₁ -C ₅ alkyl such as pyridylmethyl.

In the present specification, “aryloxy” means a group in which a hydroxyl hydrogen atom is substituted with the aryl. Suitable aryloxy include, but are not limited to, e.g., phenoxy, biphenyloxy, mention may be made of C ₆ -C ₁₅ aryloxy such as naphthyloxy or anthryloxy (anthracenyloxy).

In the present specification, “arylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the arylalkyl. Preferred arylalkyloxy include, without limitation, may include, for example, benzyloxy, 1-phenethyloxy, a C ₇ -C ₂₀ arylalkyloxy and 2-phenethyloxy and styryloxy.

  In the present specification, “heteroaryloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroaryl. Suitable heteroaryloxy include, but are not limited to, furanyloxy, thienyloxy (thiophenyloxy), pyrrolyloxy, imidazolyloxy, pyrazolyloxy, triazolyloxy, tetrazolyloxy, thiazolyloxy, oxazolyloxy, iso 5-15 such as oxazolyloxy, oxadiazolyloxy, thiadiazolyloxy, isothiazolyloxy, pyridyloxy, pyridazinyloxy, pyrazinyloxy, pyrimidinyloxy, quinolinyloxy, isoquinolinyloxy and indolyloxy Mention may be made of member heteroaryloxy.

In the present specification, “heteroarylalkyloxy” means a group in which a hydrogen atom of hydroxyl is substituted with the heteroarylalkyl. Preferred heteroarylalkyloxy include, without limitation, mention may be made of heteroaryl -C ₁ -C ₅ alkyloxy, for example 5 to 15 members.

In the present specification, “acyl” means a group in which a monovalent group selected from the groups described above and carbonyl are linked. Suitable acyls include, but are not limited to, C ₁ -C ₂₀ acyls, including, for example, C ₁ -C ₅ aliphatic acyls such as formyl, acetyl and propionyl, and C ₇ -C ₁₂₀ aromatic acyls such as benzoyl. Can be mentioned.

  The groups described above are each independently unsubstituted or can be further substituted with one or more of the monovalent groups described above.

  In the present specification, “halogen” or “halo” means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

<2. Teratoma formation inhibitor>
In the present specification, “epigenetics” means a regulatory mechanism of gene expression through chemical and / or structural modification of chromatin composed of genomic DNA and histone proteins. The N-terminal region of the core histone can undergo various modifications such as acetylation, methylation, phosphorylation and ubiquitination. Along with this, the chromatin structure changes and affects gene expression. These chemical and / or structural modifications involved in epigenetic regulation are diverse in terms of the site of chromatin and the position of the lysine residue subject to modification. Therefore, epigenetic control has the characteristics that it is highly plastic and can change in space and time.

  Lysine-specific demethylase (hereinafter also referred to as “LSD”) is an enzyme involved in epigenetic regulation in eukaryotes. For example, LSD1 and LSD2 isozymes are known in mammals (Karytinos A, et al., The Journal of biological chemistry, Vol. 284, p. 17775-82, 2009). Among them, LSD1 demethylates a mono- or dimethyl group added to the fourth lysine residue (H3K4) or the ninth lysine residue (H3K9) of histone H3 (Shi Y, et al., Cell 119). Volume, p. 941-53, 2004). In histone H3, methylation of the enhancer region to H3K4 serves as transcriptional activation, and methylation to H3K9 serves as transcriptional repression. Therefore, LSD1 can be involved in both transcriptional activation and transcriptional repression.

  In the present specification, “teratomas” or “teratomas” mean tumors in which inner, middle, and outer trilobular tissues are mixed, and “teratocarcinoma” or “teratocarcinoma” means teratomas or teratomas. Means a malignant tumor or cancer having stem cells having metastatic potential. Teratoma and teratocarcinoma are formed not only in germ cells but also in cells derived from pluripotent stem cells such as iPS cells and ES cells or structures thereof. In the present specification, the “cell structure” is not only a cell mass composed of a plurality of cells but not having a specific function, as well as an arbitrary tissue composed of a plurality of cells and having a specific function, and Also means organ. In each aspect of the present invention, teratomas usually formed in the pluripotent stem cell-derived cells or structures thereof exemplified above are particularly targeted, and in particular, formed in iPS cell-derived cells or structures thereof. Targets teratomas. By administering a compound having LSD1 inhibitory activity to a pluripotent stem cell-derived cell or a structure thereof, or a drug containing the compound as an active ingredient, the formation of teratoma in the cell or the structure is substantially reduced. Can be suppressed.

  In each aspect of the present invention, the teratoma is usually a human or non-human mammal (eg, pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon or chimpanzee). It is a teratoma formed in a cell derived from a pluripotent stem cell of a blood animal) or a structure thereof, and particularly a teratoma formed in a cell derived from a human pluripotent stem cell or a structure thereof.

  In each aspect of the present invention, the teratoma formation inhibitory effect of the compound represented by formula (I) used as an active ingredient, particularly the compound represented by formula (Ib) described below is not limited. For example, by culturing pluripotent stem cells in the presence of the target compound and measuring the number of cells showing differentiation and / or proliferation, the ratio of the number of cells showing differentiation and / or proliferation to the total number of cells ( %) Can be evaluated. In the case of this evaluation method, if the ratio of the number of cells showing differentiation and / or proliferation is less than 100%, it can be evaluated as having a teratoma formation inhibitory effect. Alternatively, pluripotent stem cells are implanted subcutaneously in an experimental animal (eg, an immunodeficient mouse) and then the subject compound is administered to the animal. After administration of the compound for a predetermined period, the teratoma formation inhibitory effect of the target compound is evaluated by confirming the formation of teratoma at the transplant site. In this case, confirmation of the formation of the teratoma at the transplant site can be carried out, for example, by observing the formed teratoma as it is or with the naked eye or a microscope. Alternatively, pluripotent stem cells into which a reporter gene such as a luciferase gene has been introduced may be used for transplantation, and the expression of the reporter gene in the formed teratomas may be detected by ordinary means.

One aspect of the present invention is a compound of formula (I):
And a stereoisomer or salt thereof, or a solvate thereof as an active ingredient.

  The inventors of the 2-phenylcyclopropan-1-ylamine skeleton have a structure represented by the formula (I) having a structure having a specific group in the phenyl ring and a specific group in the amino group. It has been found that a compound having a high inhibitory activity against LSD1, which is an enzyme involved in epigenetic regulation. The present inventors have also found that some novel compounds having the above characteristics have high selectivity for LSD1 inhibition. Furthermore, the present inventors have found that a specific novel compound having the above characteristics can remarkably suppress teratoma formation.

  It is known that some compounds having a 2-phenylcyclopropan-1-ylamine skeleton have LSD1 inhibitory activity (eg, WO 2010/043721; WO 2012/013727; WO 2013/057322; WO 2012/135113; Lee MG et al., Chem Biol, Vol. 13, p. 563-7, 2006; and Schmidt DM et al., Biochemistry, vol. 46, p. 4408-16, 2007). However, the relationship between the position and type of substituents on the phenyl ring and the combination of the types of substituents on the amino group and the LSD1 inhibitory activity of the resulting compound was not clear.

  The compound represented by the formula (I) has benzyloxy at the 2-position on the phenyl ring, fluorine at the 3- and 5-positions, and the amino group is substituted with a specific group. By having such a novel structural feature, the compound represented by the formula (I) has a high LSD1 inhibitory activity, a high selectivity for LSD1 inhibition, and / or a useful therapeutic effect on various diseases. Can do.

  The inventors of the present invention have a compound represented by the formula (I) having an inhibitory activity against LSD1, which is an enzyme involved in epigenetic regulation, particularly a compound represented by the formula (Ib) described below. It has been found that teratoma formation can be substantially suppressed. In addition to LSD1, histone deacetylase (HDAC) is known as an enzyme involved in epigenetic regulation. It has been suggested that epigenetic mutation is involved when teratoma is formed in cells derived from pluripotent stem cells or structures thereof (for example, Non-Patent Document 3). However, it has not been known which of the various enzymes involved in epigenetic regulation is involved in teratoma formation. Among the enzymes involved in epigenetic regulation, LSD1 is a novel finding found by the present inventors that it is involved in teratoma formation in pluripotent stem cell-derived cells or structures thereof.

  In each embodiment of the present invention, the compound represented by the formula (I), particularly the compound represented by the formula (Ib) described below preferably has a specific inhibitory activity against LSD1. It is more preferable to have a specific inhibitory activity against LSD1 derived from the same eukaryotic organism as the cell or its structure in which the teratoma can be formed, and a human or non-human mammal (for example, pig, dog, cow) It is more preferable to have a specific inhibitory activity against LSD1 derived from rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon or chimpanzee). It is particularly preferable to have specific inhibitory activity. A compound represented by the formula (I) having the above-described characteristics with respect to a cell derived from a pluripotent stem cell or a structure thereof, particularly a compound represented by the formula (Ib) described below, or the compound as an active ingredient By administering a pharmaceutical or the like containing it, it is possible to substantially suppress the formation of teratoma in the cell or its structure.

  In each embodiment of the present invention, the LSD1 inhibitory activity of the compound represented by formula (I) used as an active ingredient, particularly the compound represented by formula (Ib) described below is not limited. For example, by using a 20-residue synthetic peptide (H3K4me2 peptide) obtained by dimethylating the 4th lysine residue (K4) of histone H3 as a substrate, demethylation reaction is performed by LSD1 in the presence of the target compound. The hydrogen peroxide produced as can be evaluated by quantitatively measuring with a known peroxidase assay. LSD1 releases hydrogen peroxide as a reaction byproduct along with the demethylation reaction. In the peroxidase assay, peroxidase is produced by using 4-hydrogenantipyrine (4-AA) as a coupling agent and N-ethyl-N- (2- Oxidative condensation with hydroxy-3-sulfopropyl) -3-methoxyaniline (new Trinder reagent). In this reaction, a purple color having an absorption maximum wavelength of 555 nm is shown in a dose-dependent manner. By measuring this purple color development with an absorbance at 562 nm, hydrogen peroxide can be quantified. LSD1 is an enzyme protein prepared from cells of human or non-human mammals (eg, warm-blooded animals such as pigs, dogs, cows, rats, mice, guinea pigs, rabbits, chickens, sheep, cats, monkeys, baboons or chimpanzees). It may be a recombinant enzyme protein prepared from cultured cells in which LSD1 of the human or non-human mammal is highly expressed.

  The selective inhibitory activity against LSD1 of the compound represented by formula (I) used as an active ingredient, particularly the compound represented by formula (Ib) described below, is LSD1 inhibitory activity and monoamine oxidase inhibitory activity of the compound. Can be determined by comparing. Monoamine oxidase A (hereinafter also referred to as “MAO-A”) and monoamine oxidase B (hereinafter also referred to as “MAO-B”) are known as enzymes having a catalytic reaction mechanism similar to that of LSD1. Both MAO-A and MAO-B have the activity of oxidizing low molecular amines in vivo such as dopamine and serotonin using flavin adenine dinucleotide (FAD) as a coenzyme. A compound having an inhibitory activity against LSD1 may inhibit MAO-A and / or MAO-B depending on its structure because of its similarity to the reaction of FAD as a coenzyme and oxidation of amine. For example, one of the known LSD1 inhibitors, tranylcypromine (2-PCPA), was originally known as an inhibitor against MAO-A and MAO-B, but it was later reported that LSD1 can also be inhibited. (Lee et al., Chemistry & Biology Vol. 13, p. 563, 2006). Therefore, in compounds having inhibitory activity against LSD1, selectivity against LSD1 can be evaluated by comparing the inhibitory activity against LSD1 with the inhibitory activity against MAO-A and / or MAO-B (Mimasu et al., Biochemistry). 49, p. 6494, 2010; Mohammad et al., Cancer Cell 28, p. 57, 2015).

The selective inhibitory activity against LSD1 of the compound represented by formula (I) used as an active ingredient, particularly the compound represented by formula (Ib) described below, is not limited, but, for example, LSD1 activity Concentration of the compound that inhibits 50% (IC ₅₀ against LSD1) and concentration of the compound that inhibits MAO-A and / or MAO-B activity by 50% (IC ₅₀ against MAO-A and / or MAO-B) And selectivity for LSD1 inhibition can be determined by calculating based on the following equation.
Selectivity for LSD1 inhibition =
(IC ₅₀ for MAO-A and / or MAO-B) / (IC ₅₀ for LSD1)

In each embodiment of the present invention, the compound represented by the formula (I) used as an active ingredient, particularly the compound represented by the formula (Ib) described below, has an IC _{50 of} LSD1 inhibitory activity determined by the above procedure. The value is usually 10 μM or less, typically 3 μM or less, in particular 1 μM or less. In addition, the compound represented by the formula (I) used as an active ingredient, particularly the compound represented by the formula (Ib) described below, usually has a selectivity value for LSD1 inhibition determined by the above procedure. The value is greater than 1, typically 1.2 or greater, especially 10 or greater. When having an IC ₅₀ value in the above range, the compound represented by the formula (I) used as an active ingredient, particularly the compound represented by the formula (Ib) described below, substantially forms teratoma. Can be suppressed.

In the formula (I), L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or a substituted or unsubstituted C ₂ -C ₆ Alkynylene-CO-. However, L is bonded to A at the carbon atom position of -CO-. L is preferably substituted or unsubstituted C ₁ -C ₆ alkylene-CO—, more preferably substituted or unsubstituted C ₁ -C ₂ alkylene-CO—, and methylene-CO—. More preferably. When L is a group exemplified above, the compound represented by the formula (I) can substantially suppress teratoma formation in cells derived from pluripotent stem cells or structures thereof.

In the formula (I), A is —NR ³ R ⁴ or —CHR ³ R ⁴ . A is preferably —NR ³ R ⁴ .

R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R It is preferred to form 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ , together with the carbon or nitrogen atom to which they are attached, N, S and O Forming a 5- to 6-membered heterocycloalkyl or heterocycloalkenyl containing one or more R ⁸ and one or more R ⁹ as a ring atom containing one or more heteroatoms selected from More preferably, together with the nitrogen atom to which they are attached, piperazinyl, piperidinyl, pyrrolidinyl or 1,2,3,6-tetrahydropyridyl having 1 or 2 R ⁸ and 1 or more R ⁹ More preferably, it is formed.

R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls. In this case, R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ ,- COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or 1 It is a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with one or more halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ It is preferably hydrogen, halogen, C ₄ -C ₆ cycloalkyl, unsubstituted or C ₁ substituted with one or more hydroxyl -C ₃ alkoxy -C ₁ -C ₃ alkyl, -COR ^13, -COOR ^13, - CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more halogens , Hi Dorokishiru, phenyl, dimethylamino, N- pyrrolidino, N- morpholino, be monovalent group independently selected from the group consisting of C ₁ -C ₃ alkyl substituted with -COOR ¹² or -CONR ¹² R ¹³ Is more preferable, hydrogen, cyclohexyl, cyclopropyl, -COCH ₃ , -COC ₆ H ₅ , -COOCH ₂ CH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N (CH ₃ ) ₂ , -NHCOCH ₃ , -NHCOOCH ₃ , -NHCONHCH ₃ , -NHSO ₂ CH ₃ , methyl, 2-methoxy-1-ethyl, 3-methoxy-2-hydroxypropan-1-yl, 1-chloro-3-hydroxypropane -2-yl, 3-dimethylaminopropan-1-yl, 2-hydroxy-2-methylpropan-1-yl, 2-oxo-2- (piperidin-1-yl) ethyl, diphenylmethyl, carboxymethyl, 2 -(Dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl, 2- (carboxy) ethyl, and 2,3- Still more preferably a monovalent group independently selected from the group consisting of hydroxy propyl.

Alternatively, R ⁸ is C ₃ -C ₇ cycloalkyl, unsubstituted or substituted with one or more R ¹⁰ , taken together with 1 or 2 carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, unsubstituted C ₅ -C ₆ containing one or more heteroatoms selected from S and O as ring atoms and unsubstituted or substituted with one or more R ¹⁰ Forms an aryl, or a 5-9 membered heteroaryl that is unsubstituted or substituted with one or more R ¹¹ . In this case, R ⁸ is a C ₃ -C ₇ cycloalkyl, unsubstituted or substituted with one or more R ¹⁰ , together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from S, O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C It is preferred to form _6- aryl, or 5- or 9-membered heteroaryl which is unsubstituted or substituted with one or more R ¹¹ , together with 1 or 2 carbon or nitrogen atoms to which they are attached. Te, includes unsubstituted or 1 or more C ₄ substituted with R ¹⁰ -C ₆ cycloalkyl, N, one or more hetero atoms selected from S and O as ring atoms, and unsubstituted or 1 or a plurality of 4-6 membered heterocycloalkyl substituted with R ^10, an unsubstituted C ₅ -C ₆ Reel, or 5-9 membered it is more preferable to form a heteroaryl substituted with unsubstituted or 1 or more R ^11, together with 1 or 2 carbon atoms or a nitrogen atom they are attached Can form phenyl, triazolyl, imidazolyl, 3-methylpyrazolyl, isobenzofuranyl, 2-pyrrolidonyl, pyrrolidinyl, N-methylpyrrolidinyl, 2,3-dimethylimidazolyl, or substituted or unsubstituted indolyl Further preferred.

R ⁹ is hydrogen, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted 5-9 membered heteroaryl, and substituted or unsubstituted A monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl. R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, aryl, substituted or unsubstituted 5- to 9-membered heteroaryl, and non- substituted or one or more oxetanyl, tetrahydrofuranyl, aryl, or be 5-9 membered independently from the group consisting of C ₁ -C ₆ alkyl substituted with a heteroaryl is a monovalent radical selected preferably, Hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl, and unsubstituted Or one or more oxetanyl, tetrahydrofuranyl, or more preferably a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with phenyl, hydrogen, oxetane-3-yl, 1-methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo [d] imidazol-1-yl, 2-hydroxy-1H-benzo [d] imidazol-1-yl More preferably, it is a monovalent group independently selected from the group consisting of pyridine-2-yl, pyrazin-2-yl, methyl, and benzyl.

R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O). In this case, R ¹⁰ is preferably a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, and consists of hydrogen, oxo, and methyl. More preferably, it is a monovalent group selected independently from the group.

Alternatively, R ¹⁰ is one or more selected from substituted or unsubstituted C ₃ -C ₇ cycloalkyl, N, S and O, together with 1 or 2 carbon or nitrogen atoms to which they are attached. of including a hetero atom as a ring atom, and a substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or a substituted or unsubstituted 5-membered or 6-membered heteroaryl Form. R ^10, together with one or two carbon atoms to which they are attached, a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or to form a substituted or unsubstituted C ₅ -C ₆ aryl Are preferred, and more preferably together with 1 or 2 carbon atoms to which they are attached, form a phenyl.

R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl. R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen or hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl It is preferably a monovalent group independently selected from the group consisting of hydrogen, methyl, ethyl, hydroxymethyl, trifluoromethyl, carboxymethyl, 2- (dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl More preferably, the monovalent group is independently selected from the group consisting of 2- (N-morpholino) ethyl, 2- (carboxy) ethyl, and 2,3-dihydroxypropyl.

R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl. R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens. Preferably, it is a monovalent group independently selected from the group consisting of hydrogen, phenyl, methyl, and ethyl.

Alternatively, R ¹² and R ¹³ together with the carbon atom or nitrogen atom to which they are attached are substituted or unsubstituted C _{4 to} C ₇ cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl. Form. R ¹² and R ¹³ are preferably taken together with the carbon atom or nitrogen atom to which they are attached to form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl, More preferably, together with the carbon or nitrogen atom to which is attached, piperidin-1-yl is formed.

R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl. R ¹⁴ is preferably a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl, more preferably hydrogen.

When each of the groups exemplified above is substituted, unless otherwise specified, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted. Alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted Or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, Replacement or non- Substituted alkoxy, substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted Substituted heteroarylalkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, substituted Or one or more monovalent or divalent groups selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. Preferred, halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or heteroaryl -C ₁ ~ unsubstituted 5-15 membered C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or C ₃ -C ₆ cycloalkoxy unsubstituted, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ ~ C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, heteroaryl -C ₁ -C 5-15 membered substituted or unsubstituted ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ ~ C ₂₀ acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted More preferably, it is at least one monovalent group or divalent group selected from the group consisting of substituted carbonyldiimino, carboxyl, and oxo, and includes halogen (fluorine, chlorine, bromine or iodine), hydroxyl, 2- Hydroxy-3-methoxypropyl, 1-chloro-3-hydroxypropan-2-yl, 3- (dimethylamino) propyl, 2-hydroxy-2-methylpropyl, 2-methoxyethyl, 2-oxo-2- (piperidine -1-yl) ethyl, methoxymethyl, hydroxymethyl, trifluoromethyl, diphenylmethyl, carboxymethyl, methyl, 2- (dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl 2- (carboxy) ethyl, 2,3-dihydroxypropyl, cyclopropyl, oxetan-3-yl, 1-methylpiperidin-4-yl, pyrazin-2-yl, Pyridin-2-yl, 3-methoxyphenyl, 4-chlorophenyl, 4- (dimethylamino) phenyl, ethoxycarbonyl, aminocarbonyl (carbamoyl), methylcarbamoyl, acetyl, benzoyl, amino, methylamino, dimethylamino, acetylamino, More preferably, it is at least one monovalent group or divalent group selected from the group consisting of methoxycarbonylamino, methylsulfonamide, N-methylcarbonyldiimino, carboxyl, and oxo. When the monovalent group is substituted, the substituent can be further selected from the monovalent group or the divalent group.

Preferably, the compound represented by formula (I) is:
L is a C ₁ -C ₆ alkylene -CO- substituted or unsubstituted,
A is -NR ³ R ⁴ or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ ,
R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls, or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted or unsubstituted 5 to 9 membered heteroaryl, and substituted or unsubstituted a C ₁ -C ₆ monovalent radical independently selected from the group consisting of alkyl,
R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O), Or
R ¹⁰ is one or more selected from substituted or unsubstituted C _{3 to} C ₇ cycloalkyl, N, S and O, together with 1 or 2 carbon or nitrogen atoms to which they are attached. includes hetero atoms as ring atoms, and substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or substituted or heteroaryl 5 or 6 membered unsubstituted Forming,
R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl, Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form a substituted or unsubstituted C _{4 to} C ₇ cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl And
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl;
When the group is substituted, unless otherwise stated, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5 substituted or unsubstituted 15-membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy Substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 member heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, Wakashi substituted Is at least one monovalent or divalent group selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. When a valent group is substituted, the substituent may be further selected from the monovalent group or divalent group.

More preferably, the compound represented by formula (I) is:
L is a C ₁ -C ₆ alkylene -CO- substituted or unsubstituted,
A is -NR ³ R ⁴ or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ ,
R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more A monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ , or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or substituted or unsubstituted C ₅ -C ₆ aryl;
R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl A monovalent group independently selected from the group consisting of:
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl;
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl;
When the group is substituted, unless otherwise stated, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5 substituted or unsubstituted 15-membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy Substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 member heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, Wakashi substituted Is at least one monovalent or divalent group selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. When a valent group is substituted, the substituent may be further selected from the monovalent group or divalent group.

More preferably, the compound represented by formula (I) is:
L is a C ₁ -C ₆ alkylene -CO- substituted or unsubstituted,
A is -NR ³ R ⁴ or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 5 and 6-membered heterocycloalkyl or heterocycloalkenyl having ⁸ and one or more R ⁹ ;
R ⁸ is hydrogen, halogen, C ₄ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more A monovalent group independently selected from the group consisting of C ₁ -C ₃ alkyl substituted with halogen, hydroxyl, phenyl, dimethylamino, N-pyrrolidino, N-morpholino, —COOR ¹² or —CONR ¹² R ¹³ ; Is or
R ⁸ is C ₄ -C ₆ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ , together with one or two carbon or nitrogen atoms to which they are attached. 4- to 6-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, oxo, and methyl, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a phenyl;
R ¹¹ is hydrogen, methyl, ethyl, hydroxymethyl, trifluoromethyl, carboxymethyl, 2- (dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl, 2- (carboxy ) A monovalent group independently selected from the group consisting of ethyl and 2,3-dihydroxypropyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, phenyl, methyl, and ethyl, or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form piperidin-1-yl;
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl;
When the group is substituted, unless otherwise stated, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5 substituted or unsubstituted 15-membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy Substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 member heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, Wakashi substituted Is at least one monovalent or divalent group selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. When a valent group is substituted, the substituent may be further selected from the monovalent group or divalent group.

Particularly preferably, the compound represented by the formula (I) is
L is methylene-CO-
A is -NR ³ R ⁴
R ³ and R ⁴ , together with the nitrogen atom to which they are attached, have one or two R ⁸ and one or more R ⁹ piperazinyl, piperidinyl, pyrrolidinyl or 1,2,3,6- Form tetrahydropyridinyl,
R ⁸ is hydrogen, cyclohexyl, cyclopropyl, -COCH ₃ , -COC ₆ H ₅ , -COOCH ₂ CH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N (CH ₃ ) ₂ , -NHCOCH ₃ , -NHCOOCH ₃ , -NHCONHCH ₃ , -NHSO ₂ CH ₃ , methyl, 2-methoxy-1-ethyl, 3-methoxy-2-hydroxypropan-1-yl, 1-chloro-3-hydroxypropane -2-yl, 3-dimethylaminopropan-1-yl, 2-hydroxy-2-methylpropan-1-yl, 2-oxo-2- (piperidin-1-yl) ethyl, diphenylmethyl, carboxymethyl, 2 One independently selected from the group consisting of-(dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl, 2- (carboxy) ethyl, and 2,3-dihydroxypropyl; A valent group, or
R ⁸ together with one or two carbon or nitrogen atoms to which they are attached, phenyl, triazolyl, imidazolyl, 3-methylpyrazolyl, isobenzofuranyl, 2-pyrrolidonyl, pyrrolidinyl, N-methylpyrrole Form dinyl, 2,3-dimethylimidazolyl, or substituted or unsubstituted indolyl;
R ⁹ is hydrogen, oxetane-3-yl, 1-methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo [d] imidazol-1-yl, 2-hydroxy A monovalent group independently selected from the group consisting of -1H-benzo [d] imidazol-1-yl, pyridin-2-yl, pyrazin-2-yl, methyl, and benzyl.

In one embodiment of each aspect of the present invention, the compound represented by formula (I) is represented by formula (Ib):
It is preferable that it is a compound represented by these, its stereoisomer, those salts, or those solvates.

In the formula (Ib), A ^b is, -CHR ³ R ^4, or -NR ³ R ^4. A ^b is preferably an -NR ³ R ^4.

In the formula (Ib), R ³ and R ⁴ are as defined above.

In one preferred embodiment, A ^b is preferably substituted or unsubstituted C _{4 to} C ₁₁ cycloalkyl, or substituted or unsubstituted 4 to 15 membered heterocycloalkyl or heterocycloalkenyl, and is preferably substituted or unsubstituted. C ₄ -C ₇ cycloalkyl substituted, or substituted or more preferably heterocycloalkyl or heterocycloalkenyl unsubstituted 4-7 membered, substituted or unsubstituted C ₅ -C ₆ cycloalkyl, or substituted Or more preferably an unsubstituted 5 to 6-membered heterocycloalkyl or heterocycloalkenyl, and a substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or 1,2,3,6-tetrahydropyridinyl. Is particularly preferred.

If each group of the illustrated A ^b at the is substituted, the substituent are each independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted alkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted Substituted cycloalkylalkyl, substituted or unsubstituted heterocycloalkylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, substituted or Unsubstituted alkoxy Substituted or unsubstituted cycloalkoxy, substituted or unsubstituted heterocycloalkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted heteroaryl Alkyloxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted cycloalkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, substituted or unsubstituted It is preferably one or more monovalent or divalent groups selected from the group consisting of amino, substituted or unsubstituted sulfonamido, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. (Fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, a substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or 3-6 membered unsubstituted heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted Or unsubstituted C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkoxy substituted or unsubstituted, substituted or 3-6 membered heterocycloalkyl alkoxy unsubstituted, substituted or unsubstituted C ₆ -C ₁₅ aryloxy, substituted or unsubstituted C ₇ -C ₂₀ arylalkyloxy, substituted or unsubstituted 5-15 membered heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, substituted or unsubstituted C ₁ -C ₂₀ acyloxy, substituted or unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyl More preferably, it is at least one monovalent or divalent group selected from the group consisting of diimino, carboxyl, and oxo, such as halogen (fluorine, chlorine, bromine or iodine), hydroxyl, 2-hydroxy-3- Methoxypropyl, 1-chloro-3-hydroxypropan-2-yl, 3- (dimethylamino) propyl, 2-hydroxy-2-methylpropyl, 2-methoxyethyl, 2-oxo-2- (piperidin-1-yl ) Ethyl, methoxymethyl, hydroxymethyl, trifluoromethyl, diphenylmethyl, carboxymethyl, methyl, 2- (dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl, 2- ( Carboxy) ethyl, 2,3-dihydroxypropyl, cyclopropyl, oxetan-3-yl, 1-methylpiperidin-4-yl, pyrazin-2-yl, pyridin-2-yl, 3-methoxyphenyl, 4-chlorophenyl, 4- (dimethylamino) phenyl, ethoxycarbonyl, aminocarbonyl (carbamoyl), methylcarbamoyl, acetyl, benzoyl, amino, methylamino, dimethylamino, acetylamino, methoxycarbonylamino, methylsulfone More preferably, it is at least one monovalent group or divalent group selected from the group consisting of amide, N-methylcarbonyldiimino, carboxyl, and oxo. When the monovalent group is substituted, the substituent can be further selected from the monovalent group or the divalent group.

If each group of the illustrated A ^b at the is substituted with one or more groups, the substituents, together with the carbon atoms to which they are attached, a substituted or unsubstituted C ₄ -C ₇ cycloalkyl alkyl, substituted or unsubstituted C ₄ -C ₇ aryl, N, 4 to 7 membered heterocycloalkyl or heterocycloalkenyl containing one or more heteroatoms selected from S and O as ring atoms, or N, A 4- to 7-membered heteroaryl containing one or more heteroatoms selected from S and O as ring atoms may be formed. In this case, A ^b is a substituted or unsubstituted bridged ring is preferably a polycyclic fused ring or spiro ring, substituted or unsubstituted 5,6-dihydro - [1,2,4] triazolo [4 , 3-a] pyrazin-7 (8H) -yl, 5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H) -yl, 6,7-dihydropyrazolo [1,5-a] Pyrazin-5 (4H) -yl, 3H-spiro [isobenzofuran-1,4'-piperidin] -1'-yl, 2,7-diazaspiro [4.4] nonan-1-one, 2,7-diazaspiro [4.4 ] Nonan-2-yl, 5,6-dihydroimidazo [1,5-a] pyrazin-7 (8H) -yl, 1,7-diazaspiro [4.4] nonane-7-yl, 1,8-diazaspiro [4.5 ] Decan-8-yl, 1,3,8-triazaspiro [4.5] decane-2,4-dione, 2,7-diazaspiro [4.4] nonan-3-one, 1,8-diazaspiro [4.5] decane-2 -One, 1,3,7-triazaspiro [4.4] nonane-2,4-dione, 3,8-diazabicyclo [3.2.1] octan-3-yl, 3,8-diazabicyclo [3. 2.1] octane-8-yl, 3,8-diazabicyclo [3.2.1] octane-3-yl, or 3,4-dihydro-1H-pyrido [3,4-b] indol-2 (9H) -yl More preferably. If the multi-ring is substituted, the substituent is preferably selected from the substituents exemplified A ^b above.

Preferably, the compound represented by the formula (Ib) is
A ^b is -CHR ³ R ⁴ or -NR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ ,
R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls, or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, substituted or unsubstituted 4 to 7 membered heterocycloalkyl, substituted or unsubstituted C _{6 to} C ₁₅ aryl, substituted or unsubstituted 5 to 9 membered heteroaryl, and substituted or unsubstituted a C ₁ -C ₆ monovalent radical independently selected from the group consisting of alkyl,
R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O), Or
R ¹⁰ is one or more selected from substituted or unsubstituted C _{3 to} C ₇ cycloalkyl, N, S and O, together with 1 or 2 carbon or nitrogen atoms to which they are attached. includes hetero atoms as ring atoms, and substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or substituted or heteroaryl 5 or 6 membered unsubstituted Forming,
R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl, Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form a substituted or unsubstituted C _{4 to} C ₇ cycloalkyl or substituted or unsubstituted 4 to 7 membered heterocycloalkyl And
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl;
When the group is substituted, unless otherwise stated, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5 substituted or unsubstituted 15-membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy Substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 member heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, Wakashi substituted Is at least one monovalent or divalent group selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. When a valent group is substituted, the substituent may be further selected from the monovalent group or divalent group.

More preferably, the compound represented by the formula (Ib) is:
A ^b is -CHR ³ R ⁴ or -NR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ ,
R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more A monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ , or
R ⁸ is C ₄ -C ₆ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ , together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or substituted or unsubstituted C ₅ -C ₆ aryl;
R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl A monovalent group independently selected from the group consisting of:
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl;
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl;
When the group is substituted, unless otherwise stated, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5 substituted or unsubstituted 15-membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy Substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 member heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, Wakashi substituted Is at least one monovalent or divalent group selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. When a valent group is substituted, the substituent may be further selected from the monovalent group or divalent group.

More preferably, the compound represented by the formula (Ib) is:
A ^b is -CHR ³ R ⁴ or -NR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 5 and 6-membered heterocycloalkyl or heterocycloalkenyl having ⁸ and one or more R ⁹ ;
R ⁸ is hydrogen, halogen, C ₄ -C ₆ cycloalkyl, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more A monovalent group independently selected from the group consisting of C ₁ -C ₃ alkyl substituted with halogen, hydroxyl, phenyl, dimethylamino, N-pyrrolidino, N-morpholino, —COOR ¹² or —CONR ¹² R ¹³ ; Is or
R ⁸ is C ₄ -C ₆ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ , together with one or two carbon or nitrogen atoms to which they are attached. 4- to 6-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, oxo, and methyl, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a phenyl;
R ¹¹ is hydrogen, methyl, ethyl, hydroxymethyl, trifluoromethyl, carboxymethyl, 2- (dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl, 2- (carboxy ) A monovalent group independently selected from the group consisting of ethyl and 2,3-dihydroxypropyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, phenyl, methyl, and ethyl, or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form piperidin-1-yl;
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl;
When the group is substituted, unless otherwise stated, each substituent is independently halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, hydroxyl, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, substituted or unsubstituted C ₂ -C ₅ alkynyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted C ₃ -C ₆ cycloalkenyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C ₇ -C ₁₁ cycloalkylalkyl, substituted or unsubstituted 3 6-membered heterocycloalkyl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted C ₇ -C ₂₀ arylalkyl, 5 substituted or unsubstituted 15-membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₃ -C ₆ cycloalkoxy Substituted or unsubstituted 3 to 6 membered heterocycloalkoxy, substituted or unsubstituted C _{6 to} C ₁₅ aryloxy, substituted or unsubstituted C _{7 to} C ₂₀ arylalkyloxy, substituted or unsubstituted 5 to 15 member heteroaryloxy, substituted or unsubstituted 5-15 membered heteroaryl -C ₁ -C ₅ alkyloxy, substituted or unsubstituted C ₁ -C ₆ alkoxycarbonyl, substituted or unsubstituted C ₃ -C ₆ cycloalkyl alkoxycarbonyl, substituted or unsubstituted aminocarbonyl (carbamoyl), substituted or unsubstituted C ₁ -C ₂₀ acyl, a substituted or unsubstituted C ₁ -C ₂₀ acyloxy, Wakashi substituted Is at least one monovalent or divalent group selected from the group consisting of unsubstituted amino, substituted or unsubstituted sulfonamide, substituted or unsubstituted carbonyldiimino, carboxyl, and oxo. When a valent group is substituted, the substituent may be further selected from the monovalent group or divalent group.

Particularly preferably, the compound represented by the formula (Ib) is:
A ^b is -NR ³ R ⁴
R ³ and R ⁴ , together with the nitrogen atom to which they are attached, have one or two R ⁸ and one or more R ⁹ piperazinyl, piperidinyl, pyrrolidinyl or 1,2,3,6- Form tetrahydropyridinyl,
R ⁸ is hydrogen, cyclohexyl, cyclopropyl, -COCH ₃ , -COC ₆ H ₅ , -COOCH ₂ CH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N (CH ₃ ) ₂ , -NHCOCH ₃ , -NHCOOCH ₃ , -NHCONHCH ₃ , -NHSO ₂ CH ₃ , methyl, 2-methoxy-1-ethyl, 3-methoxy-2-hydroxypropan-1-yl, 1-chloro-3-hydroxypropane -2-yl, 3-dimethylaminopropan-1-yl, 2-hydroxy-2-methylpropan-1-yl, 2-oxo-2- (piperidin-1-yl) ethyl, diphenylmethyl, carboxymethyl, 2 One independently selected from the group consisting of-(dimethylamino) ethyl, 2- (N-pyrrolidino) ethyl, 2- (N-morpholino) ethyl, 2- (carboxy) ethyl, and 2,3-dihydroxypropyl; A valent group, or
R ⁸ together with one or two carbon or nitrogen atoms to which they are attached, phenyl, triazolyl, imidazolyl, 3-methylpyrazolyl, isobenzofuranyl, 2-pyrrolidonyl, pyrrolidinyl, N-methylpyrrole Form dinyl, 2,3-dimethylimidazolyl, or substituted or unsubstituted indolyl;
R ⁹ is hydrogen, oxetane-3-yl, 1-methylpiperidin-4-yl, 3-methoxyphenyl, 4-chlorophenyl, 4-carboxyphenyl, 1H-benzo [d] imidazol-1-yl, 2-hydroxy A monovalent group independently selected from the group consisting of -1H-benzo [d] imidazol-1-yl, pyridin-2-yl, pyrazin-2-yl, methyl, and benzyl.

Particularly preferably, the compounds of the formulas (I) and (Ib) are selected from the group consisting of the following compounds:

In a particularly preferred embodiment, the compound of formula (I) is
L is methylene-CO-
A is -NR ³ R ⁴
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperazinyl having one R ⁸ and one R ⁹
R ⁸ is methyl;
R ⁹ is hydrogen.

In another particularly preferred embodiment, the compound of formula (Ib) is
A ^b is a 4-methylpiperazin-1-yl or -NR ³ R ^4,
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperazinyl having one R ⁸ and one R ⁹
R ⁸ is methyl;
R ⁹ is hydrogen.

In the above particularly preferred embodiments, the compounds of the formulas (I) and (Ib) are
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (4-methylpiperazin-1-yl) ethanone hydrochloride (Synthetic compound 1);
It is.

  The compounds represented by formulas (I) and (I-b) having the above characteristics can particularly strongly suppress the formation of teratomas in cells derived from pluripotent stem cells or structures thereof.

  In each embodiment of the present invention, the compounds represented by formulas (I) and (I-b) include not only the compounds themselves but also their salts. Examples of salts of the compounds represented by formulas (I) and (Ib) include, but are not limited to, sodium ions, potassium ions, calcium ions, magnesium ions, or substituted or unsubstituted ammonium ions. Salts with cations, or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid or phosphoric acid, or formic acid, acetic acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, lactic acid, succinic acid, bis Methylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, malic acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, Benzenesulfonic acid, cyclohexylsulfamic acid, methanesulfonic acid, Tan sulfonic acid, a salt with an organic acid anion such as isethionic acid, p- toluenesulfonic acid or naphthalenesulfonic acid. When the compound represented by the formula (I) or (I-b) is in the form of the salt, the compound can be used without substantially reducing the effect of inhibiting teratoma formation.

  In each embodiment of the present invention, the compounds represented by the formulas (I) and (I-b) include not only the compounds themselves but also solvates of the compounds or salts thereof. Examples of the solvent that can form a solvate with the compound represented by the formula (I) or (Ib) or a salt thereof include, but are not limited to, for example, water, or a lower alcohol (for example, methanol, ethanol). Or alcohol having 1 to 6 carbon atoms such as 2-propanol (isopropyl alcohol), higher alcohol (for example, alcohol having 7 or more carbon atoms such as 1-heptanol or 1-octanol), dimethyl Organic solvents such as sulfoxide (DMSO), acetic acid, ethanolamine or ethyl acetate are preferred. When the compound represented by the formula (I) or (Ib) or a salt thereof is in the form of a solvate with the above solvent, the compound is used without substantially reducing the teratoma formation inhibitory effect. can do.

  In each embodiment of the present invention, the compounds represented by formulas (I) and (I-b) include not only the compounds themselves but also their protected forms. In the present specification, the “protected form” means a form in which a protecting group is introduced into one or a plurality of functional groups (for example, a hydroxyl group or an amino group). In this specification, the protected form of the compound may be referred to as a protected derivative of the compound. In the present specification, a “protecting group” is a group introduced into a specific functional group in order to prevent an undesirable reaction from progressing, and is quantitatively removed under specific reaction conditions. In other reaction conditions, it means a group that is substantially stable, that is, reaction-inactive. The protecting group capable of forming a protected form of the compound is not limited. For example, in the case of a protecting group for a hydroxyl group, silyl (for example, t-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS) Or tert-butyldiphenylsilyl (TBDPS)) or alkoxy (for example, methoxymethoxy (MOM) or methoxy (Me)) is an amino-protecting group, t-butoxycarbonyl (Boc), 2-bromobenzyloxy Carbonyl (BrZ) or 9-fluorenylmethoxycarbonyl (Fmoc) is preferred respectively. Protection and deprotection by the protecting group can be appropriately performed by those skilled in the art based on known reaction conditions. Even when the compound represented by the formula (I) or (Ib) is a protected form by the above-mentioned protecting group, the compound can be used without substantially reducing the teratoma formation inhibitory effect. There is a case.

  In each embodiment of the present invention, when the compound represented by the formula (I) or (Ib) has one or more tautomers, the compounds are in the form of individual tautomers of the compounds. Is also included.

  In each embodiment of the present invention, when the compound represented by the formula (I) or (Ib) has one or more stereocenters (chiral centers), the compound includes the individual enantiomers of the compound and Also included are stereoisomers of the compounds, including diastereomers as well as mixtures thereof, such as racemates.

  By having the above characteristics, the compounds represented by the formulas (I) and (I-b) can exhibit a high inhibitory effect on teratoma formation.

<3. Pharmaceutical use>
As already described, by administering the compound represented by the formula (I) or (Ib) to a pluripotent stem cell-derived cell or a structure thereof, formation of teratoma in the cell or the structure thereof is achieved. It can be substantially suppressed. Therefore, another aspect of the present invention provides a teratoma formation comprising a compound represented by the formula (I) or (Ib), a stereoisomer or a salt thereof, or a solvate thereof as an active ingredient. It relates to a medicament for use in inhibition.

  When the compounds represented by formula (I) or (Ib) are applied for pharmaceutical use, these compounds are not only the compounds themselves, but also the stereoisomers of the compounds, their pharmaceutically acceptable salts, and These pharmaceutically acceptable solvates are also included. Examples of the pharmaceutically acceptable salt of the compound represented by the formula (I) or (Ib) or a stereoisomer thereof and pharmaceutically acceptable solvates thereof include, but are not limited to, The salt or solvate exemplified in the above is preferable. When the compound represented by the formula (I) or (Ib) or a stereoisomer thereof is in the form of the above-mentioned salt or solvate, the compound is desired without substantially reducing the teratoma formation inhibitory effect. It can be applied for pharmaceutical use.

  When the compounds represented by the formula (I) or (I-b) are applied for pharmaceutical use, these compounds include not only the compounds themselves but also prodrug forms of the compounds. As used herein, “prodrug” means a compound that is converted into the parent drug in vivo. Examples of the prodrug form of the compound include, but are not limited to, for example, when a hydroxyl group is present, an ester of the hydroxyl group and an arbitrary carboxylic acid, an amide of the hydroxyl group and an arbitrary amine, and the like. Can be mentioned. For example, when an amino group is present, an amide of the amino group and an arbitrary carboxylic acid can be exemplified. When the compound represented by formula (I) or (Ib) is in the above-mentioned prodrug form, the teratoma formation inhibitory effect of the compound represented by formula (I) or (Ib) as the parent drug is substantially reduced. The pharmacokinetics during administration of the prodrug form to the subject can be improved.

  When the compound represented by formula (I) or (Ib) is applied for pharmaceutical use, the compound may be used alone or in combination with one or more pharmaceutically acceptable ingredients. . The medicament of this embodiment can be formulated into various dosage forms commonly used in the art depending on the desired administration method. Therefore, the medicament of this embodiment also includes a compound represented by formula (I) or (Ib), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Can be provided in the form of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers. In addition to the above components, the pharmaceutical composition of this embodiment comprises one or more pharmaceutically acceptable media (for example, a solvent such as sterile water or a solution such as physiological saline), an excipient, a binder, Vehicles, solubilizers, preservatives, stabilizers, bulking agents, lubricants, surfactants, emulsifiers, oily liquids (eg vegetable oils), suspending agents, buffering agents, soothing agents, antioxidants, sweeteners and A flavoring agent etc. may be included.

  The pharmaceutical agent of this embodiment comprising a compound represented by the formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient. The form is not particularly limited, and may be a preparation for use in parenteral administration or a preparation for use in oral administration. In addition, the pharmaceutical dosage form of this embodiment may be a unit dosage form or a multiple dosage form. Examples of preparations for parenteral administration include injections such as sterile solutions or suspensions with water or other pharmaceutically acceptable media, lotions, ointments, eye drops, and suppositories. Can be mentioned. Ingredients that can be mixed with injections include, but are not limited to, for example, saline, glucose or other adjuvants (eg, D-sorbitol, D-mannitol, D-mannose or sodium chloride). Vehicles such as isotonic solutions, solubilizing agents such as alcohols (eg ethanol or benzyl alcohol), polyalcohols (eg propylene glycol or polyethylene glycol) or esters (eg benzyl benzoate), polysorbate 80 ™ or poly Nonionic surfactants such as oxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, benzalkonium chloride or procaine hydrochloride A soothing agent, human serum albumin or Stabilizers such as polyethylene glycol, may be mentioned preservatives, and antioxidants, and the like. The prepared injection is usually filled in an appropriate vial (for example, an ampoule) and stored in an appropriate environment until use.

  Examples of preparations for use in oral administration include tablets, pills, powders, granules, powders, capsules, microcapsules, elixirs, solutions, syrups, slurries and suspensions. Can do. The tablet may be formulated as a sugar-coated tablet with a sugar coating or a soluble coating, a gelatin-encapsulated tablet, an enteric-coated tablet, or a film-coated tablet, if desired, or as a dosage form of a double tablet or a multilayer tablet It may be formulated.

  Ingredients that can be mixed into tablets or capsules are not limited, but for example, water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, Binders such as gelatin, corn starch, gum tragacanth or gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin or silicic acid; dried starch, sodium alginate , Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch or lactose; white sugar, stearin cacao Disintegration inhibitors such as water or hydrogenated oils; absorption enhancers such as quaternary ammonium salts or sodium lauryl sulfate; humectants such as glycerin or starch; starch, lactose, kaolin, bentonite or colloidal silicic acid Adsorbents such as; refined talc, stearates (eg magnesium stearate), lubricants such as boric acid powder or polyethylene glycol; sweeteners such as sucrose, lactose or saccharin; and peppermint, red oil or cherry And the like. When the preparation is a capsule, it may further contain a liquid carrier such as fats and oils.

  The medicament of this embodiment can also be formulated as a depot preparation. In this case, the medicament of this embodiment in the form of a depot preparation can be administered, for example, subcutaneously or intramuscularly, or administered by intramuscular injection. By applying the medicament of this embodiment to a depot preparation, the teratoma formation inhibitory effect of the compound represented by formula (I) or (I-b) can be continuously expressed over a long period of time.

  The medicament of this embodiment comprising a compound represented by formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient, It can also be used in combination with one or more other drugs useful as pharmaceuticals. In the pharmaceutical of this embodiment, the other drug used in combination with the compound represented by the formula (I) or (Ib) is not limited, and examples thereof include an anticancer drug, a steroidal anti-inflammatory drug, thalidomide, and lenalidomide. Can be mentioned. Among these, examples of the anticancer agent include alkylating agents such as cyclophosphamide and melphalan, HDAC inhibitors such as vorinostat, panobinostat, romidepsin, phenylbutyric acids, Tubastatin A, and Tubacin. it can. Examples of steroidal anti-inflammatory agents include cortisol, prednisolone, triamcinolone, dexamethasone and betamethasone. In this case, the medicament of this embodiment includes a compound represented by the formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, It is in the form of a combination drug containing one or more other drugs. The combination drug includes a compound represented by the formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, and one or more kinds thereof. It may be in the form of a pharmaceutical composition in combination with the other drug, the compound represented by the formula (I) or (Ib), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or It may be in the form of a pharmaceutical composition used in combination with one or more of the other drugs, including a pharmaceutically acceptable solvate. When the medicament of this embodiment is in the form of a combined medicament as described above, the compound represented by formula (I) or (Ib), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof It may be provided in the form of a single formulation comprising an acceptable solvate and one or more other drugs, and multiple formulations formulated separately with one or more other drugs. It may be provided in the form of a pharmaceutical combination or kit comprising. When in the form of a pharmaceutical combination or kit, the respective formulations can be administered simultaneously or separately (eg sequentially).

  The medicament of this embodiment comprising a compound represented by formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient, Various diseases, symptoms and / or disorders involving teratoma formation can be similarly prevented or treated. Examples of the diseases, symptoms and / or disorders include, but are not limited to, malignant tumors in pluripotent stem cell-derived cells or structures thereof. In each aspect of the invention, malignant tumors include hematopoietic tumors, epithelial cell-derived cancers, and non-epithelial cell-derived sarcomas. Hematopoietic tumors include, but are not limited to, leukemia, malignant lymphoma and multiple myeloma. Examples of cancer include, but are not limited to, lung cancer, breast cancer, stomach cancer, liver cancer, pancreatic cancer, colon cancer, uterine cancer, ovarian cancer, prostate cancer, kidney cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer and tongue. Mention can be made of cancer. Examples of sarcoma include, but are not limited to, osteosarcoma and soft tissue sarcoma. The malignant tumor in pluripotent stem cell-derived cells or structures thereof is one or more malignant tumors selected from the group consisting of hematopoietic tumors, epithelial cell-derived cancers, and non-epithelial cell-derived sarcomas. Is preferred. By administering the medicament of this embodiment to a subject in need of prevention or treatment of the disease, symptom or disorder, the disease, symptom or disorder involving teratoma formation, for example, a cell derived from pluripotent stem cells or the structure thereof A malignant tumor in the body can be prevented or treated.

  The medicament of this embodiment comprising a compound represented by formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient, It can be applied to various subjects in need of prevention or treatment of the symptoms, diseases and / or disorders associated with teratoma formation. The subject is a subject or patient of a human or non-human mammal (eg, a warm-blooded animal such as a pig, dog, cow, rat, mouse, guinea pig, rabbit, chicken, sheep, cat, monkey, baboon or chimpanzee). Preferably there is. By administering the medicament of this embodiment to the subject, the disease, symptom and / or disorder associated with teratoma formation of the subject can be prevented or treated.

  As used herein, “prevention” means substantially preventing the occurrence (onset or onset) of symptoms, diseases and / or disorders. In the present specification, “treatment” means to suppress (e.g., suppress progression), relieve, repair, and / or cure a symptom, disease, and / or disorder that has occurred (onset or onset).

  The compound represented by the formula (I) or (Ib) is used in a subject having the symptoms, diseases and / or disorders described above (for example, malignant tumor in cells derived from pluripotent stem cells or structures thereof). It can be used for the prevention or treatment of symptoms, diseases and / or disorders. Therefore, the medicament of this embodiment is a medicament for use in the prevention or treatment of the symptoms, diseases and / or disorders described above (for example, malignant tumors in cells derived from pluripotent stem cells or structures thereof). Preferably, the prevention of one or more malignant tumors selected from the group consisting of hematopoietic tumors, epithelial cell-derived cancers, and non-epithelial cell-derived sarcomas in pluripotent stem cell-derived cells or structures thereof Or it is more preferable that it is a pharmaceutical for use in treatment. By using the medicament of this embodiment for the prevention or treatment of the symptoms, diseases and / or disorders associated with teratoma formation, via the teratoma formation inhibitory effect of the compound represented by formula (I) or (Ib), The symptoms, diseases and / or disorders can be prevented or treated.

  The compound represented by the formula (I) or (Ib) is used in a subject having the symptoms, diseases and / or disorders described above (for example, malignant tumor in cells derived from pluripotent stem cells or structures thereof). It can be used for the prevention or treatment of symptoms, diseases and / or disorders. Therefore, another aspect of the present invention is a subject in need of prevention or treatment of the symptoms, diseases and / or disorders described above (eg, malignant tumors in pluripotent stem cell-derived cells or structures thereof). The administration of an effective amount of a compound represented by formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. A method for preventing or treating the disease or symptom involving teratoma formation. The symptom, disease and / or disorder is one selected from the group consisting of hematopoietic tumor, epithelial cell-derived cancer, and non-epithelial cell-derived sarcoma in pluripotent stem cell-derived cells or structures thereof The above malignant tumor is preferable. By administering a compound represented by the formula (I) or (Ib) to a subject in need of prevention or treatment of the symptom, disease and / or disorder associated with teratoma formation, the formula (I) or (Ib The symptom, disease and / or disorder can be prevented or treated through the teratoma formation inhibitory effect of the compound represented by

  Another aspect of the present invention provides a formula (for use in the prevention or treatment of the symptoms, diseases and / or disorders described above (for example, malignant tumors in cells derived from pluripotent stem cells or structures thereof) A compound represented by I) or (Ib), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. Another aspect of the present invention relates to the manufacture of a medicament for use in the prevention or treatment of the symptoms, diseases and / or disorders described above (for example, malignant tumors in cells derived from pluripotent stem cells or structures thereof). For the use of a compound of formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. The symptom, disease and / or disorder is one selected from the group consisting of hematopoietic tumor, epithelial cell-derived cancer, and non-epithelial cell-derived sarcoma in pluripotent stem cell-derived cells or structures thereof The above malignant tumor is preferable. By using the compound represented by the formula (I) or (Ib) or the medicament of this embodiment for the prevention or treatment of the above-mentioned symptoms, diseases and / or disorders in which teratoma formation is involved, the formula (I) or ( The symptom, disease and / or disorder can be prevented or treated through the teratoma formation inhibitory effect of the compound represented by Ib).

  A medicament comprising a compound represented by the formula (I) or (Ib), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof as an active ingredient, particularly When administered to a human patient, the exact dosage and usage (eg, dosage, frequency of administration, and / or route of administration) should be such that the subject's age, sex, symptoms to be prevented or treated, disease and / or disorder are accurate. In view of many factors such as the condition (for example, severity) and the route of administration, the attending physician should make a final decision in view of the therapeutically effective dose, number of doses, route of administration, and the like. Therefore, in the medicament of this embodiment, the compound represented by the formula (I) or (I-b) which is an active ingredient is administered to a subject in a therapeutically effective amount and frequency. For example, when the pharmaceutical of this embodiment is administered to a human patient, the dose of the compound represented by the formula (I) or (Ib) as the active ingredient is usually 0.001 to 100 mg / kg per administration. The range of body weight, typically in the range of 0.01 to 10 mg / kg body weight per dose, in particular in the range of 0.1 to 10 mg / kg body weight per dose. In addition, the number of administrations of the medicament of this embodiment can be, for example, once a day or a plurality of times (for example, 2 or 3 times), or once every several days. In addition, the administration route of the medicament of this embodiment is not particularly limited, and may be administered orally, and parenterally (for example, rectal, radial mucosa, intestine, intramuscular, subcutaneous, intramedullary, intrathecal). May be administered directly or intra-ventricularly, intravenously, intravitreally, intraperitoneally, intranasally, or intraocularly). By using the medicament of this embodiment in the above-mentioned dosage and usage, the above-mentioned symptoms, diseases and / or diseases involving teratoma formation via the teratoma formation inhibitory effect of the compound represented by formula (I) or (Ib) Or a disorder can be prevented or treated.

<4. Production method of new compound>
The method for producing the compounds represented by the formulas (I) and (Ib), which are the active ingredients of each aspect of the present invention, will be described.

  The production method of the present disclosure can be carried out based on various known compound synthesis methods unless otherwise specified. In each step of the production method of the present disclosure described below, functional groups can be protected and deprotected as necessary. The protection and deprotection of the functional group is not limited, but is known, for example, the method described in “Protective Groups in Organic Synthesis”, 4th edition, by Greene and Wuts. This can be implemented by applying the protection and deprotection methods.

  In the production method of the present disclosure, the compounds represented by formulas (I) and (I-b) can be produced by the same or similar method as the production method 1 exemplified below.

  In the production method of the present disclosure, the compound obtained in each step described below can be used for the reaction in the next step as the reaction mixture after completion of the reaction or in the state of a crude product. Alternatively, the compound obtained in each step is used for the reaction in the next step in the state isolated or purified from the reaction mixture based on the organic compound isolation or purification means usually used in the art, or It can also be obtained as a final product. In this case, the isolation or purification means of the compound that can be used is not limited, and examples thereof include concentration, extraction, filtration, centrifugation, adsorption, recrystallization, distillation, and various chromatography. it can.

  In the production method of the present disclosure, when the compound obtained in each step described below is in the form of a mixture of stereoisomers, the compound can be used in the reaction in the next step as it is. Alternatively, a compound that is in the form of a mixture of stereoisomers is optically resolved, i.e., substantially optically pure, by known means such as chiral column chromatography, optical resolution or diastereomeric derivatization. It can be used in the reaction of the next step or can be obtained as a final product.

[4-1. Manufacturing method 1]
For example, the production method of the present disclosure can be carried out by a method including steps 1-1 and 1-2 exemplified below (hereinafter also referred to as “production method 1”). According to production method 1, the compounds represented by formulas (I) and (Ib) can be produced.

Manufacturing method 1
Formula (II):
A compound represented by formula (III):
R ^L1 -L-OR ^L2 (III)
Is reacted with a compound represented by formula (IV):
A step of obtaining a compound represented by formula (step 1-1), a compound represented by formula (IV), and formula (V):
R ^A1 -A (V)
Reacting with a compound represented by formula (I) to obtain a compound represented by formula (I) (step 1-2),
It can implement by the method of including.

In the production method 1, when the compound represented by the formula (Ib) is produced, in the compound represented by the formula (III), L is methylene-CO—. In this case, the compound represented by the formula (III) is represented by the formula (III ′):
R ^L1 -CH ₂ -CO-OR ^L2 (III ')
It is preferable that it is a compound represented by these.

In addition, in the production method 1, when the compound represented by the formula (Ib) is produced, the compound represented by the formula (V) is represented by the formula (V ′):
R ^A1 -A ^b (V ')
It is preferable that it is a compound represented by these.

In formulas (II) and (IV), PG ^N1 is hydrogen or a protecting group. The protecting group is preferably a protecting group for the amino group exemplified above.

In the formulas (III), (IV), (V) and (V ′), L, A and ^Ab are as defined above.

In the formulas (III) and (III ′), R ^L1 is halogen. R ^L1 is preferably F, Cl, Br or I, and more preferably Cl or Br.

In formulas (III), (III ′) and (IV), R ^L2 is hydrogen, substituted or unsubstituted C ₁ -C ₅ alkyl, substituted or unsubstituted C ₂ -C ₅ alkenyl, or substituted or unsubstituted C ₂ -C ₅ alkynyl. R ^L2 is preferably methyl, ethyl or propyl.

In the formulas (V) and (V ′), R ^A1 is hydrogen.

  Step 1-1 can be carried out by reacting the compound represented by formula (II) with the compound represented by formula (III) in the presence of a base.

  In the production method 1, the compound represented by the formula (II) may be prepared by purchasing the compound prepared in advance, etc., and known literature (Mimasu, S et al., Biochemistry, Vol. 49 (30), p. 6494-6503; 2010).

  In step 1-1, the compound represented by formula (III) may be prepared by purchasing the compound prepared in advance.

  In Step 1-1, the compound represented by the formula (III) is usually used in an amount ranging from 1 to 10 molar equivalents relative to the compound represented by the formula (II).

  In step 1-1, the base used is not limited, and examples thereof include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, cesium carbonate, potassium Examples thereof include tert-butoxide, sodium hydroxide, potassium hydroxide, lithium hexamethyldisilazane, sodium hexamethyldisilazane, and NaH. The base used in this step is preferably lithium hexamethyldisilazane or NaH.

  In Step 1-1, the base is usually used in an amount of 1 molar equivalent or more with respect to the compound represented by the formula (II).

  In Step 1-1, this reaction is usually carried out in an inert solvent. Examples of the solvent used in this step include, but are not limited to, tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, and the like. . Two or more kinds of these solvents may be mixed and used in an arbitrary ratio.

  In step 1-1, the reaction temperature of this reaction is usually in the range of 0 to 100 ° C. The reaction time of this reaction is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 24 hours.

In step 1-1, after completion of the reaction, the reaction product is preferably hydrolyzed under basic conditions. The hydrolysis is usually carried out by mixing the reaction product and a basic aqueous solution in a water-soluble solvent. Thereby, the compound represented by Formula (IV) whose R ^L2 is hydrogen can be obtained.

  In the hydrolysis, the basic aqueous solution used is not limited, and examples thereof include a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, a lithium hydroxide aqueous solution, and a barium hydroxide aqueous solution. The base used for the hydrolysis is usually used in an amount of 1 molar equivalent or more with respect to the compound represented by the formula (II).

  In the hydrolysis, the water-soluble solvent used is not limited, and examples thereof include methanol, ethanol, tetrahydrofuran, 1,4-dioxane, dimethoxyethane and the like.

  The reaction temperature for the hydrolysis is usually in the range of 0-100 ° C. The reaction time for hydrolysis is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 24 hours.

  Step 1-2 can be performed by reacting the compound represented by formula (IV) with the compound represented by formula (V) in the presence of a condensing agent.

  In step 1-2, the compound represented by the formula (V) may be prepared by purchasing the compound prepared in advance, and may be prepared by publicly known literature (Bonnet, PA et al., Journal of Chemical Research, Synopses, No. 1). 2, p. 28; 1984).

  In step 1-2, the compound represented by the formula (V) is usually used in an amount ranging from 1 to 10 molar equivalents relative to the compound represented by the formula (IV).

  In step 1-2, the condensing agent used is not limited, and examples thereof include 1-ethyl-1- (3-methylaminopropyl) carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide, and diethyl cyanophosphate. , Diphenylphosphoryl azide, 1,1′-carbonyldiimidazole, benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, o- (benzotriazol-1-yl) -N, N, N ′, N-tetramethyluronium hexafluorophosphate, o- (7-azabenzotriazol1-1yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, etc. it can. Alternatively, in this step, if desired, a condensing agent bound to a porous resin, such as PS-carbodiimide resin (manufactured by Biotage) can be used.

  In Step 1-2, the condensing agent is usually used in an amount ranging from 1 to 10 molar equivalents relative to the compound represented by Formula (V).

  In step 1-2, in addition to the condensing agent, if desired, one or more condensing accelerators may be used. In this case, examples of the condensation accelerator include, but are not limited to, 1-hydroxybenzotriazole, N-hydroxysuccinimide, N, N-dimethyl-4-aminopyridine, and the like. Alternatively, in this step, a condensation accelerator bonded to the porous resin, for example, PS-HOBt resin (manufactured by Biotage) can be used as desired.

  In step 1-2, when a condensation accelerator is used, the condensation accelerator is usually used in an amount in the range of 0.1 to 10 molar equivalents relative to the compound represented by formula (IV).

  In Step 1-2, this reaction is preferably carried out in the presence of a base such as triethylamine, diisopropylethylamine, or 1,8-diazabicyclo [5.4.0] undec-7-ene. In this case, the base is usually used in an amount ranging from 0.1 to 10 molar equivalents relative to the compound represented by formula (V).

  In step 1-2, this reaction is usually carried out in an inert solvent. Examples of the solvent used in this step include, but are not limited to, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, 1,4-dioxane, N, N-dimethylacetamide, acetonitrile, and the like. Two or more kinds of these solvents may be mixed and used in an arbitrary ratio.

  In step 1-2, the reaction temperature of this reaction is usually in the range of 0 to 150 ° C. The reaction time of this reaction is not particularly limited, but is usually in the range of 0.1 to 100 hours, preferably in the range of 0.5 to 72 hours.

In the present embodiment, when PG ^N1 is a protecting group, the production method 1 preferably further includes a step 1-3 for deprotecting PG ^N1 from the reaction product of the step 1-2.

In step 1-3, the reaction conditions for deprotecting ^PGN1 can be appropriately set by those skilled in the art based on the type of protecting group used. For example, when PG ^N1 is t-butoxycarbonyl (Boc), the deprotection reaction can usually be carried out in the presence of an acid, in an inert solvent, or in an excess of acid. In this case, examples of the acid used include, but are not limited to, hydrochloric acid, trifluoroacetic acid, hydrobromic acid, sulfuric acid, and hydrofluoric acid. The acid used is preferably hydrochloric acid or trifluoroacetic acid. For example, when hydrochloric acid is used, the compound represented by the formula (I) or (Ib) obtained by the production method 1 can be obtained in the form of a hydrochloride thereof. Alternatively, when trifluoroacetic acid is used, the compound represented by the formula (I) or (Ib) obtained by the production method 1 can be obtained in the form of their trifluoroacetate. If desired, such a salt form compound can be converted to a free form by means such as treatment with amino silica gel chromatography or an ion exchange resin, or washing with a basic aqueous solution.

  In Step 1-3, when the deprotection reaction is carried out by acid treatment, the acid is usually used in an amount ranging from 1 to 1000 molar equivalents relative to the reaction product of Step 1-2.

  In the production method 1, a compound represented by formulas (I) and (Ib) and any compound selected from the group consisting of reaction intermediates thereof are subjected to a known functional group introduction reaction or conversion reaction. It may further include a functional group introduction or conversion step that is performed to obtain a new compound represented by the formula (I) or (Ib).

  In the functional group introduction or conversion step, the functional group conversion reaction is not limited, but includes, for example, substitution of primary or secondary amine, reduction of nitro group to amine, amine to amide, sulfone. Conversion to amide, sulfamide, carbamate or urea, palladium-catalyzed cross coupling of amine and aryl halide, conversion to carboxy group by hydrolysis of ester, conversion to carbamoyl group by amidation of carboxyl group, conversion of carboxyl group Conversion to hydroxymethyl group by reduction, conversion to alcohol form by reduction or alkylation of carbonyl group, reductive amination of carbonyl group, oximation of carbonyl group, conversion to carboxyl group by hydrolysis of cyano group, cyano Reduction of the group to an aminomethyl group, Conversion to the amine body according kill reduction, and can be given conversion or the like to a carbamoyl group by the addition of water.

  By the production method 1 of the present disclosure, the compounds represented by the formulas (I) and (I-b) can be produced.

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the technical scope of the present invention is not limited to these examples.

  Unless otherwise stated, in all example compounds disclosed herein, the stereochemical configuration is relative to the respective compound, even if the depicted structure may represent a more specific configuration. Defined by the chemical name shown.

  In all the compounds prepared in the examples, the relative configuration of the adjacent substituent bonded to the cyclopropyl ring is “trans”, and a mixture of the absolute configurations of both (1R, 2S) and (1S, 2R) It is. This is because the starting material, phenylcyclopropanecarboxylic acid, is a racemic mixture whose configuration is “trans”. Starting materials in the “cis” configuration, as well as the individual diastereomers / enantiomers, can be prepared by similar procedures if available by purchasing or synthesizing their raw materials.

  Thus, each aspect of the invention pertains to all stereoisomers of the compounds described and defined herein. That is, each aspect of the invention encompasses not only the compounds described in the Examples as defined by their chemical names, but also all stereoisomers arising from the depicted structures.

  In the following examples, the term “room temperature” usually indicates a temperature in the range of 10 to 35 ° C. The value in% unit indicates a value in% by weight unless otherwise specified.

  CambridgeSoft ChemDraw Ultra (Ver.12.0.2) was used to generate IUPAC names corresponding to the structural formulas of the example compounds shown below.

¹ H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR. ACD / Spectrus Processor 2015 Pack2 was used for the analysis. Proton peaks such as hydroxyl groups and amino groups that exhibit very gentle shapes are not shown.

MS (mass spectrum) was measured by LC / MS (liquid chromatograph mass spectrometer). As an ionization method, ESI (ElectroSprey Ionization) method was used, and measurement was performed in a positive mode (ESI ⁺ ) and a negative mode (ESI ⁻ ). The data described the actual measurement (Found). In MS under the above conditions, a molecular ion peak is usually observed. However, an ion peak to which protons (H ⁺ ) or sodium ions (Na ⁺ ) are added may be observed. In the case of a compound having a tert-butoxycarbonyl group, a peak in which the tert-butoxycarbonyl group or tert-butyl group is eliminated may be observed as a fragment ion.

For preparative thin-layer chromatography, Merck PLC glass plate silica gel 60 _F254 , 0.5 mm was used.

  As the PS-carbodiimide resin, No. 800369 (1.34 mmol / g) manufactured by Biotage was used. As the PS-isocyanate resin, No. 800261 (1.48 mmol / g) manufactured by Biotage was used. As the phase separation filter, Phase Separator (6 mL) manufactured by Biotage was used.

The following abbreviations are used in the following examples.
EDCI: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
TBTU: O-benzotriazolyl-N, N, N ', N'-tetramethyluronium
LHMDS: Lithium hexamethyldisilazane
¹ H NMR: proton nuclear magnetic resonance; s: singlet, d: doublet, t: triplet, m: multiplet, br s: wide singlet
CDCl ₃ : Deuterated chloroform
DMSO-d ₆ : Heavy dimethyl sulfoxide
CD ₃ OD: Deuterated methanol
LC / MS: Liquid chromatograph mass spectrometer
MS: Mass spectrometry using electrospray ionization by LC / MS
[M + H] ⁺ , [M + Na] ⁺ : Molecular ion peak
M: Molar concentration
N: Normality

<I. Synthesis of compounds>
[Synthetic compound 1]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (4-methylpiperazin-1-yl) ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- (4-methylpiperazin-1-yl) -2-oxoethyl] carbamate
To a solution of 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (1.51 g) in anhydrous dichloromethane (30 mL), 1 -Methylpiperazine (0.5 mL) and EDCI (863 mg) were added and stirred for 1.5 hours. The mixture was diluted with dichloromethane (100 mL), washed with water (50 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by amino silica gel column chromatography (ethyl acetate / hexane) to obtain the title compound (490 mg).

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (4-methylpiperazin-1-yl) ethanone hydrochloride
tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- (4-methylpiperazin-1-yl) -2-oxoethyl] carbamate (490 mg) , Dissolved in 1,4-dioxane solution (10 mL). To the resulting solution was added 4N hydrochloric acid / 1,4-dioxane solution (10 mL). The mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure to give the title compound (460 mg) as a colorless powder.

MS (ESI ⁺ ): [M + H] ⁺ 416.4
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.24 (1H, m), 1.59 (1H, m), 2.60 (1H, m), 2.75 (3H, s), 2.80-3.52 (7H, m ), 3.76 (1H, m), 4.00-4.50 (3H, m), 5.00 (1H, ABq A, J = 10.8 Hz), 5.12 (1H, ABq B, J = 10.8 Hz), 6.73 (1H, d, J = 9.7 Hz), 7.20 (1H, m), 7.38-7.45 (3H, m), 7.54 (2H, m), 9.72 (2H, br s), 11.55 (1H, br s).

[Synthetic compound 2]
1-((S) -3-Aminopyrrolidin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2-{(S) -3-[(tert-butoxycarbonyl) amino] pyrrolidine- 1-yl} -2-oxoethyl} carbamate 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert- The title compound (937 mg) was obtained from butoxycarbonyl) amino} acetic acid (1.19 g) and (S) -tert-butylpyrrolidin-3-ylcarbamate (652 mg).

(B) 1-((S) -3-Aminopyrrolidin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} ethanone Hydrochloric acid Salt In the same manner as in Step B of synthetic compound 1, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2-{(S) -3-[( The title compound (717 mg) was obtained as a colorless powder from tert-butoxycarbonyl) amino] pyrrolidin-1-yl} -2-oxoethyl} carbamate (930 mg).

MS (ESI ⁺ ): [M + H] ⁺ 402.4
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.29 (1H, m), 1.59 (1H, m), 1.95-2.30 (2H, m), 2.60 (1H, m), 2.89 (1H, m ), 3.07 (1H, m), 3.30-4.10 (7H, m), 4.99 (1H, Abq A, J = 10.8 Hz), 5.14 (1H, ABq B, J = 10.8 Hz), 6.73 (1H, m), 7.24 (1H, m), 7.33-7.42 (3H, m), 7.54 (2H, m), 8.52 (3H, br s), 9.71 (2H, br s).

[Synthetic compound 3]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (5,6-dihydro- [1,2,4] triazolo [4,3 -a] pyrazin-7 (8H) -yl) ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- (5,6-dihydro- [1,2,4] triazolo [4, 3-a] pyrazin-7 (8H) -yl) -2-oxoethyl} carbamate
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (217 mg) was dissolved in anhydrous DMF (5 mL). . The resulting solution was charged with 5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazine hydrochloride (93 mg), diisopropylethylamine (383 μL) and TBTU at room temperature. (186 mg) was added. The mixture was stirred for 24 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (153 mg).

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (5,6-dihydro- [1,2,4] triazolo [ 4,3-a] pyrazin-7 (8H) -yl) ethanone hydrochloride In the same manner as in Synthesis Compound 1, Step B, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluoro Phenyl] cyclopropyl} [2- (5,6-dihydro- [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl) -2-oxoethyl} carbamate (504 mg) The title compound (488 mg) was obtained as a colorless powder.

MS (ESI ⁺ ): [M + H] ⁺ 440.4
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.26 (1H, m), 1.62 (1H, m), 2.94 (1H, m), 3.08 (1H, m), 3.71-4.50 (6H, m ), 4.87-4.93 (2H, m), 5.00 (1H, ABq A, J = 10.8 Hz), 5.13 (1H, ABq B, J = 10.8 Hz), 6.74 (1H, d, J = 10.8 Hz) , 7.24 (1H, m), 7.36-7.44 (3H, m), 7.55 (2H, m), 9.09 (1H, s), 9.83 (2H, br s).

[Synthetic compound 4]
1- [4- (1H-Benzo [d] imidazol-1-yl) piperidin-1-yl] -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl } Amino} ethanone hydrochloride

(A) tert-butyl {2- [4- (1H-benzo [d] imidazol-1-yl) piperidin-1-yl] -2-oxoethyl} {trans-2- [2- (benzyloxy) -3 , 5-Difluorophenyl] cyclopropyl} carbamate
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (217 mg) in anhydrous dichloromethane (5 mL) -Piperidin-4-yl-1H-benzimidazole hydrochloride (206 mg), triethylamine (311 μL) and EDCI (144 mg) were added at 0 ° C., and the mixture was stirred for 1.5 hours. The mixture was diluted with dichloromethane (15 mL), washed with water (15 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (114 mg).

(B) 1- [4- (1H-Benzo [d] imidazol-1-yl) piperidin-1-yl] -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl ] Cyclopropyl} amino} ethanone hydrochloride In the same manner as in Synthesis Compound 1, Step B, tert-butyl {2- [4- (1H-benzo [d] imidazol-1-yl) piperidin-1-yl] -2 The title compound (345 mg) was obtained as a colorless powder from -oxoethyl} {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} carbamate (356 mg).

MS (ESI ⁺ ): [M + H] ⁺ 517.5
¹ H-NMR (DMSO-d ₆ , 270 MHz) δ: 1.29 (1H, m), 1.65 (1H, m), 1.85-2.30 (4H, m), 2.93-4.24 (8H, m), 4.59 (1H , br d, J = 13.5 Hz), 5.01 (1H, Abq A, J = 10.8 Hz), 5.07 (1H, m), 5.14 (1H, ABq B, J = 10.8 Hz), 6.76 (1H, d , J = 10.8 Hz), 7.24 (1H, m), 7.37 (3H, m), 7.54-7.66 (4 H, m), 7.90 (1H, m), 8.16 (1H, m), 9.76 (1H, s ), 9.55-9.95 (2H, br m).

[Synthetic compound 5]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- [4- (2-methoxyethyl) piperidin-1-yl] ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- [4- (2-methoxyethyl) piperazin-1-yl] -2- Oxoethyl} carbamate
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (15 mg) in chloroform solution (500 μL) A chloroform solution (223 μL) of (2-methoxyethyl) piperazine (7.5 mg) and a chloroform solution (500 μL) of EDCI (9.95 mg) were added, and the mixture was stirred at room temperature for 16 hours. Water (1 mL) was added to the mixture and stirred. The mixture was passed through a phase separation filter, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (chloroform / methanol) to obtain the title compound (12 mg).

MS (ESI ⁺ ): [M + H] ⁺ 560.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- [4- (2-methoxyethyl) piperidin-1-yl] ethanone Hydrochloride
tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- [4- (2-methoxyethyl) piperazin-1-yl] -2-oxoethyl} carbamate (12 mg) was dissolved in 1,4-dioxane (1 mL). 4N HCl / 1,4-dioxane (0.5 mL) was added to the resulting solution, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure to obtain the title compound (9.4 mg).

MS (ESI ⁺ ): [M + H] ⁺ 460.4
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.22-1.45 (1H, m), 1.46-1.71 (1H, m), 2.61-2.90 (1H, m), 2.90-3.89 (14H, m), 3.42 (3H, s), 4.04-4.68 (2H, m), 5.07 (1H, d, J = 10.8 Hz), 5.20 (1H, d, J = 10.8 Hz), 6.60 (1H, d, J = 8.9 Hz) ), 6.88-7.04 (1H, m), 7.31-7.60 (5H, m).

[Synthetic compound 6]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (5,6-dihydroimidazo [1,2-a] pyrazine-7 (8H ) -Yl) ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- (5,6-dihydroimidazo [1,2-a] pyrazine-7 ( 8H) -yl) -2-oxoethyl] carbamate In analogy to step A of synthetic compound 5, 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert The title compound (10 mg) was obtained from -butoxycarbonyl) amino} acetic acid (15 mg) and 5,6,7,8-tetrahydroimidazo [1,2-a] pyrazine (6.4 mg).

MS (ESI ⁺ ): [M + H] ⁺ 539.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (5,6-dihydroimidazo [1,2-a] pyrazine- 7 (8H) -yl) ethanone hydrochloride In the same manner as in Synthesis Compound 5, Step B, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- The title compound (7.4 mg) was obtained from (5,6-dihydroimidazo [1,2-a] pyrazin-7 (8H) -yl] -2-oxoethyl] carbamate (10 mg).

MS (ESI ⁺ ): [M + H] ⁺ 439.3
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.25-1.45 (1H, m), 1.45-1.72 (1H, m), 2.69-2.91 (1H, m), 2.93-3.18 (1H, m), 3.54-3.93 (2H, m), 3.98-4.62 (3H, m), 4.08-5.14 (3H, m), 5.20 (1H, d, J = 10.9 Hz), 6.60 (1H, d, J = 8.9 Hz) , 6.91-7.03 (1H, m), 7.28-7.65 (7H, m).

[Synthetic compound 7]
1- (4-acetylpiperazin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} ethanone hydrochloride

(A) tert-butyl [2- (4-acetylpiperazin-1-yl) -2-oxoethyl] {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} carbamate synthetic compound 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (15 mg) and 1 as in step A of 5. The title compound (10 mg) was obtained from-(piperazin-1-yl) ethanone (6.7 mg).

MS (ESI ⁺ ): [M + Na] ⁺ 566.4.

(B) 1- (4-Acetylpiperazin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} ethanone hydrochloride Synthetic compound 5 In the same manner as in Step B, tert-butyl [2- (4-acetylpiperazin-1-yl) -2-oxoethyl] {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclo The title compound (8.1 mg) was obtained from propyl} carbamate (10 mg).

MS (ESI ⁺ ): [M + H] ⁺ 444.3
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.30-1.46 (1H, m), 1.48-1.65 (1H, m), 2.12 (3H, s), 2.66-2.82 (1H, m), 2.89- 3.04 (1H, m), 3.05-3.38 (2H, m), 3.38-3.84 (7H, m), 4.04-4.35 (2H, m), 5.07 (1H, d, J = 11.0 Hz), 5.20 (1H, d, J = 11.0 Hz), 6.54-6.66 (1H, m), 6.90-7.03 (1H, m), 7.31-7.60 (5H, m).

[Synthetic compound 8]
1- (4-Amino-4-methylpiperidin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyll} amino} ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- {4-[(tert-butoxycarbonyl) amino] -4-methylpiperidine- 1-yl} -2-oxoethyl} carbamate 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert- The title compound (10 mg) was obtained from butoxycarbonyl) amino} acetic acid (15 mg) and tert-butyl (4-methylpiperidin-4-yl) carbamate (11.1 mg).

MS (ESI ⁺ ): [M + H] ⁺ 630.5.

(B) 1- (4-Amino-4-methylpiperidin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyll} amino} ethanone Hydrochloride In the same manner as in Synthesis Compound 5, Step B, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- {4-[(tert-butoxy The title compound (7.9 mg) was obtained from (carbonyl) amino] -4-methylpiperidin-1-yl} -2-oxoethyl} carbamate (10 mg).

MS (ESI ⁺ ): [M + H] ⁺ 430.4.
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.30-1.65 (2H, m), 1.44 (3H, s), 2.65-2.82 (1H, m), 2.87-3.82 (11H, m), 3.94- 4.43 (3H, m), 5.08 (1H, d, J = 11.0 Hz), 5.19 (1H, d, J = 11.0 Hz), 6.54-6.67 (1H, m), 6.90-7.05 (1H, m), 7.32 -7.65 (5H, m).

[Synthetic compound 9]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (2-methyl-6,7-dihydropyrazolo [1,5-a] Pyrazine-5 (4H) -yl) ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- (2-methyl-6,7-dihydropyrazolo [1,5-a ] Pyrazin-5 (4H) -yl) -2-oxoethyl] carbamate In the same manner as in Synthesis Compound 5, Step A, 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] From cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (15 mg) and 2-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine dihydrochloride (10.9 mg), the title Compound (9.1 mg) was obtained.

MS (ESI ⁺ ): [M + H] ⁺ 553.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (2-methyl-6,7-dihydropyrazolo [1,5 -a] pyrazin-5 (4H) -yl) ethanone hydrochloride In the same manner as in Synthesis Compound 5, Step B, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclo Propyl} [2- (2-methyl-6,7-dihydropyrazolo [1,5-a] pyrazin-5 (4H) -yl) -2-oxoethyl] carbamate (9.1 mg) gave the title compound (7.8 mg )

MS (ESI ⁺ ): [M + H] ⁺ 453.3
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.31-1.48 (1H, m), 1.48-1.65 (1H, m), 2.38 (3H, s), 2.67-2.84 (1H, m), 2.90- 3.11 (1H, m), 3.47-3.89 (7H, m), 4.01-4.42 (2H, m), 5.06 (1H, d, J = 10.8 Hz), 5.20 (1H, d, J = 10.8 Hz), 6.33 (1H, s), 6.60 (1H, d, J = 7.9 Hz), 6.91-7.04 (1H, m), 7.27-7.58 (5H, m).

[Synthetic compound 10]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (3H-spiro [isobenzofuran-1,4'-piperidine] -1'- Il) Ethanone hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2-oxo-2- (3H-spiro [isobenzofuran-1,4'-piperidine ] -1′-yl) ethyl] carbamate In analogy to step A of synthetic compound 5, 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert- The title compound (11.6 mg) was obtained from butoxycarbonyl) amino} acetic acid (15 mg) and 3H-spiro [isobenzofuran-1,4′-piperidine] (9.8 mg).

MS (ESI ⁺ ): [M + H] ⁺ 605.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (3H-spiro [isobenzofuran-1,4'-piperidine]- 1′-yl) ethanone hydrochloride In the same manner as in Synthesis Compound 5, Step B, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2-oxo- The title compound (9.8 mg) was obtained from 2- (3H-spiro [isobenzofuran-1,4′-piperidin] -1′-yl) ethyl] carbamate (11.6 mg).

MS (ESI ⁺ ): [M + H] ⁺ 505.4
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.31-1.48 (1H, m), 1.48-1.65 (1H, m), 2.66-2.88 (1H, m), 2.88-3.17 (1H, m), 3.32-3.89 (8H, m), 4.01-4.53 (3H, m), 5.01-5.14 (3H, m), 5.19 (1H, d, J = 10.8 Hz), 6.55-6.67 (1H, m), 6.91- 7.05 (1H, m), 7.06-7.62 (9H, m).

[Synthetic compound 11]
1- {2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} acetyl} piperidine-4-carboxamide hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- (4-carbamoylpiperidin-1-yl) -2-oxoethyl} carbamate synthetic compound 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (15 mg) and piperidine as in step A of 5. The title compound (17.5 mg) was obtained from -4-carboxamide (6.7 mg).

MS (ESI ⁺ ): [M + H] ⁺ 544.4.

(B) 1- {2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} acetyl} piperidine-4-carboxamide hydrochloride Step B of Synthetic Compound 5 and Similarly, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- (4-carbamoylpiperidin-1-yl) -2-oxoethyl} carbamate ( The title compound (9.2 mg) was obtained from 17.5 mg).

MS (ESI ⁺ ): [M + H] ⁺ 444.3
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.30-1.98 (4H, m), 2.40-3.17 (3H, m), 3.26-3.87 (9H, m), 3.90-4.53 (2H, m), 5.07 (1H, d, J = 10.7 Hz), 5.20 (1H, d, J = 10.7 Hz), 6.51-6.65 (1H, m), 6.89-7.03 (1H, m), 7.30-7.55 (5H, m) .

[Synthetic compound 12]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (3-ethyl-5,6-dihydro- [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl) ethanone hydrochloride

(A) tert-butyl {2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2- (3-ethyl-5,6-dihydro- [1,2,4] triazolo [ 4,3-a] pyrazin-7 (8H) -yl) -2-oxoethyl] carbamate In the same manner as in Synthesis Compound 5, Step A, 2-{{trans-2- [2- (benzyloxy) -3, 5-Difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (15 mg) and 3-ethyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a The title compound (18.6 mg) was obtained from pyrazine (7.9 mg).

MS (ESI ⁺ ): [M + H] ⁺ 568.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- (3-ethyl-5,6-dihydro- [1,2, 4] Triazolo [4,3-a] pyrazin-7 (8H) -yl) ethanone hydrochloride In the same manner as in Synthesis Compound 5, Step B, tert-butyl {2- [2- (benzyloxy) -3,5 -Difluorophenyl] cyclopropyl} [2- (3-ethyl-5,6-dihydro- [1,2,4] triazolo [4,3-a] pyrazin-7 (8H) -yl) -2-oxoethyl] The title compound (19.3 mg) was obtained from carbamate (18.6 mg).

MS (ESI ⁺ ): [M + H] ⁺ 468.4
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.31-1.65 (2H, m), 1.45 (3H, t, J = 6.5 Hz), 2.73-2.92 (1H, m), 2.93-3.24 (2H, m), 3.50-4.03 (6H, m), 4.05-4.67 (4H, m), 5.08 (1H, d, J = 10.6 Hz), 5.20 (1H, d, J = 10.6 Hz), 6.53-6.71 (1H , m), 6.89-7.04 (1H, m), 7.31-7.69 (5H, m).

[Synthetic compound 13]
7- {2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} acetyl} -2,7-diazaspiro [4.4] nonan-1-one hydrochloride

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2-oxo-2- (6-oxo-2,7-diazaspiro [4.4] nonane 2-yl) ethyl] carbamate Similar to Step A of Synthesis Compound 5, 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl ) Amino} acetic acid (15 mg) and 2,7-diazaspiro [4.4] nonan-1-one (7.3 mg) gave the title compound (8.1 mg).

MS (ESI ⁺ ): [M + H] ⁺ 556.4.

(B) 7- {2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} acetyl} -2,7-diazaspiro [4.4] nonan-1-one Hydrochloride salt In the same manner as in Synthesis Compound 5, Step B, tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} [2-oxo-2- (6-oxo The title compound (4.8 mg) was obtained from -2,7-diazaspiro [4.4] nonan-2-yl) ethyl] carbamate (8.1 mg).

MS (ESI ⁺ ): [M + H] ⁺ 456.3
¹ H-NMR (CD ₃ OD, 270 MHz) δ: 1.31-1.65 (2H, m), 1.80-2.35 (4H, m), 2.66-2.88 (1H, m), 2.88-3.17 (1H, m), 3.35-3.87 (7H, m), 3.88-4.47 (2H, m), 5.06 (1H, ABq A, J = 10.6 Hz), 5.20 (1H, d, J = 10.6 Hz), 6.46-6.71 (1H, m), 6.81-7.11 (1H, m), 7.24-7.63 (5H, m), 8.08 (1H, s).

[Synthetic compound 14]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- [4- (oxetan-3-yl) piperazin-1-yl] ethanone

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- [4- (oxetan-3-yl) piperazin-1-yl] -2 -Oxoethyl} carbamate In the same manner as in Step A of Synthesis Compound 5, 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid The title compound (15.0 mg) was obtained from (15 mg) and 4- (oxetane-3-yl) piperazine (7.4 mg).

MS (ESI ⁺ ): [M + H] ⁺ 558.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1- [4- (oxetane-3-yl) piperazin-1-yl] Ethanon
tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2- [4- (oxetan-3-yl) piperazin-1-yl] -2-oxoethyl} Carbamate (15.0 mg) was dissolved in dichloromethane (1.2 mL). To the resulting solution was added trifluoroacetic acid (0.8 mL) at room temperature. After stirring the mixture for 1 hour, the solvent was distilled off under reduced pressure. The residue was purified by amino silica gel chromatography (chloroform / methanol) to obtain the title compound (11.2 mg).

MS (ESI ⁺ ): [M + H] ⁺ 458.3
¹ H-NMR (CDCl ₃ , 270 MHz) δ: 0.89-1.00 (1H, m), 1.10-1.22 (1H, m), 2.06-2.38 (6H, m), 3.08-3.28 (2H, m), 3.34 -3.77 (6H, m), 4.51-4.72 (4H, m), 4.95-5.12 (2H, m), 6.23 (1H, dt, J = 9.4, 3.0 Hz), 6.62-6.74 (1H, m), 7.28 -7.52 (5H, m).

[Synthetic compound 15]
1-((R) -3-Aminopyrrolidin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} ethanone hydrochloride

(A) tert-butyl {(3R) -1- {2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} acetyl} pyrrolidin-3-yl} Carbamate
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} acetic acid (15 mg) in chloroform (500 μL) ) -tert-butyl pyrrolidin-3-ylcarbamate (9.7 mg) in chloroform (500 μL) and PS-carbodiimide resin (100 mg) were added. The mixture was stirred for 24 hours with shaking at room temperature. PS-isocyanate resin (150 mg) and chloroform (500 μL) were added to the mixture, and the mixture was further stirred for 24 hours while shaking. Insoluble matter was separated by a phase separation filter and washed twice with chloroform (500 μL). The filtrate was concentrated under reduced pressure using a centrifugal evaporator to obtain the title compound (5.8 mg).

MS (ESI ⁺ ): [M + H] ⁺ 602.5.

(B) 1-((R) -3-Aminopyrrolidin-1-yl) -2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} ethanone Hydrochloric acid salt
tert-butyl {(3R) -1- {2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} acetyl} pyrrolidin-3-yl} carbamate (5.8 mg) was dissolved in 1,4-dioxane (1 mL), and 4N HCl / 1,4-dioxane (400 μL) was added. The mixture was stirred at room temperature for 14 hours. The solvent was distilled off from the mixture with a centrifugal evaporator to obtain the title compound (5.1 mg).

MS (ESI ⁺ ): [M] ⁺ 401.3.

[Synthetic compounds 16 to 45]
The compounds prepared according to the method described in synthetic compound 15 or a method analogous thereto are shown in the following table. In the table, the compound obtained in the final step is the target synthetic compound, and the compound obtained in the previous step is the precursor compound. In the table, MS indicates the actual measurement value of the produced compound.

[Synthetic compound 46]
2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1-[(S) -3- (dimethylamino) pyrrolidin-1-yl] ethanone

(A) tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2-[(S) -3- (dimethylamino) pyrrolidin-1-yl]- 2-oxoethyl} carbamate In the same manner as in Synthesis Compound 15, Step A, 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} (tert-butoxycarbonyl) amino} The title compound (11.0 mg) was obtained from acetic acid (15 mg) and (3S) -3- (dimethylamino) pyrrolidine (5.9 mg).

MS (ESI ⁺ ): [M + H] ⁺ 530.4.

(B) 2-{{trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} amino} -1-[(S) -3- (dimethylamino) pyrrolidin-1-yl ] Ethanon
tert-butyl {trans-2- [2- (benzyloxy) -3,5-difluorophenyl] cyclopropyl} {2-[(S) -3- (dimethylamino) pyrrolidin-1-yl] -2-oxoethyl } To a dichloromethane solution (1.2 mL) of carbamate (11.0 mg) was added trifluoroacetic acid (0.8 mL), and the mixture was stirred at room temperature for 1 hour. After evaporating the solvent under reduced pressure, the residue was purified by amino silica gel chromatography (chloroform / methanol) to obtain the title compound (6.7 mg).

MS (ESI ⁺ ): [M + H] ⁺ 430.3.

[Synthetic compounds 47-58]
Compounds prepared according to the method described in synthetic compound 46 or a method analogous thereto are shown in the following table. In the table, the compound obtained in the final step is the target synthetic compound, and the compound obtained in the previous step is the precursor compound. In the table, MS indicates the actual measurement value of the produced compound.

<II. Enzyme inhibitory activity of novel compounds>
[II-1. LSD1 inhibitory activity]
The LSD1 inhibitory activity of the compound produced by the above procedure was measured by the following procedure. Produced as a by-product by demethylating LSD1 in the presence of a test compound using a 20-residue synthetic peptide (H3K4me2 peptide) obtained by dimethylating the 4th lysine residue (K4) of histone H3. Hydrogen peroxide was measured quantitatively with a known peroxidase assay. LSD1 releases hydrogen peroxide as a reaction byproduct along with the demethylation reaction. In the peroxidase assay, peroxidase is produced by using 4-hydrogenantipyrine (4-AA) as a coupling agent and N-ethyl-N- (2- Oxidative condensation with hydroxy-3-sulfopropyl) -3-methoxyaniline (new Trinder reagent). In this reaction, a purple color having an absorption maximum wavelength of 555 nm is shown in a dose-dependent manner. By measuring this purple color development with an absorbance at 562 nm, hydrogen peroxide can be quantified.

In a buffer of 50 mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), pH 7.5, 0.4 mM 4-AA, 4 mM N-ethyl-N- (2-hydroxy-3- Sulfopropyl) -3-methoxyaniline, 0.04 mg / mL peroxidase and 1 μM LSD1, and a dimethyl sulfoxide (DMSO) solution of the test compound prepared to a predetermined concentration or the same volume of DMSO as a control are added for 10 minutes. Pre-warmed at room temperature. Thereafter, histone H3K4me2 peptide having a final concentration of 100 μM was added to the reaction solution to start the reaction. After a predetermined time elapsed from the start of the reaction, the absorbance of the reaction solution at a wavelength of 562 nm was measured. Based on the absorbance 30 minutes after the start of the measurement, the percentage of the absorbance of the test compound reaction solution (residual activity) relative to the absorbance of the control (DMSO) reaction solution was calculated, and the inhibition rate (%) of the test compound at each concentration Was calculated. A test that inhibits LSD1 activity by 50% by drawing a dose response curve of each test compound using Prism6 (GraphPad Software, San Diego, Calif., USA) based on the calculated inhibition rate of the test compound at each concentration The concentration of the compound (IC ₅₀ value) was calculated.

The known compounds used in the test as comparative compounds are shown below. Comparative compound A is the compound (N1-((trans) -2-phenylcyclopropyl) cyclohexane-1,4-diamine) described in Example 1 of WO 2013/057322. Comparative compound B is the compound (4-((4-((((1R, 2S) -2-phenylcyclopropyl) amino) methyl) piperidine-1 described in Example 29 of WO 2012/135113). -Yl) methyl) benzoic acid). Comparative compound C is the compound described in Example 26 of WO 2010/043721 ((2-((trans) -2- (4- (benzoyloxy) phenyl) cyclopropylamino) -1- (4 Comparative compound D is a compound (4 ′-((trans) -2-aminocyclopropyl) biphenyl described in Example 4 of WO 2012/013727). Comparative compound E is compound S2101 described in Mimasu S et al., Biochemistry, Vol. 49 (30), p. 6494-6503, 2010. Comparative compound F is published internationally. Compound described in Example 57 of No. 2010/043721 (2-((trans) -2- (5′-fluoro-2′-trifluoromethyl) biphenyl-4-yl) cyclopropylamino) -1- (4-methylpiperazin-1-yl) ethanone). Comparative compound G is compound (1-((S) -3-aminopyrrolidin-1-yl) -2-((trans) -2-phenylcyclohexane) described in Example 16 of WO 2010/043721. Propylamino) ethanone). Comparative compound H is the compound (1- (4-methylpiperazin-1-yl) -2-((trans) -2-phenylcyclopropylamino) ethanone described in Example 22 of WO 2010/043721 ).

[II-2. Monoamine oxidase inhibitory activity]
The MAO-A and MAO-B inhibitory activity of the compound produced by the above procedure was measured by the following procedure. Monoamine is used as a substrate to oxidize amines with MAO-A and MAO-B in the presence of a test compound, and hydrogen peroxide produced as a by-product is converted into a known peroxidase assay in the same manner as LSD1 inhibitory activity is measured. Was measured quantitatively.

  In a buffer of 50 mM HEPES, pH 7.5, 0.4 mM 4-AA, 4 mM N-ethyl-N- (2-hydroxy-3-sulfopropyl) -3-methoxyaniline, 0.04 mg / mL peroxidase and 0.1 Add mg / ml MAO-A or 0.2 mg / ml MAO-B and a dimethyl sulfoxide (DMSO) solution of the test compound prepared to a final concentration of 100 μM or the same volume of DMSO as a control, and continue at room temperature for 10 minutes. Preheated. Thereafter, tyramine was added to the reaction solution to a final concentration of 50 μM for the MAO-A reaction solution and 150 μM for the MAO-B reaction solution to initiate the reaction. After a predetermined time elapsed from the start of the reaction, the absorbance of the reaction solution at a wavelength of 562 nm was measured. Based on the absorbance 30 minutes after the start of the measurement, the percentage of the absorbance of the test compound reaction solution (residual activity) relative to the absorbance of the control (DMSO) reaction solution was calculated, and the inhibition rate (%) of the test compound at each concentration Was calculated.

<III. LSD1 expression pattern in normal cells derived from healthy individuals, induced pluripotent stem cells (hiPSC), hiPSC-derived teratomas and tumor cell lines>
Fibroblasts derived from healthy individuals (fibroblasts), peripheral blood T-lymphocytes (T-cells), induced pluripotent stem cells (hiPSC) 201B and 201B were transplanted subcutaneously into immunodeficient mice and formed 3 weeks later Protein lysates and total RNA were extracted from teratoma, malignant tumor cell line K562, HeLa cell line, and HEK293 cell line. Both fibroblasts and tumor cell lines were provided by Human Science Research Resource Bank, and hiPSC 201B strain was provided by Professor Yamanaka of Kyoto University. Teratomas are formed by transplanting 2 x 10 ⁶ hiPSC (201B strain) suspended in Matrigel (Corning) subcutaneously to 6-8 week old immunodeficient (NOD / SCID) mice (CLEA Japan) I let you.

  The protein expression level in each cell and teratoma was analyzed by immunoblot. Each 2.5 μg protein was reacted with specific antibodies against HDAC1, HDAC3, HDAC6, LSD1 and Oct3 / 4, followed by horseradish peroxidase (HRP) labeled secondary antibody using Simple Western System Wes (Protein Simple). Luminescence was detected with a coloring reagent. GAPDH was used as a protein amount control. The intensity of the obtained signal was corrected per protein amount using the signal intensity of each GAPDH. The relative value of each signal intensity was calculated when the fibroblast value after correction was 1.0. FIG. 1 shows the results of analyzing the protein expression level in each cell and teratoma by immunoblotting. In the figure, A shows the result of immunoblotting, and B shows the relative value of each signal intensity when the fibroblast value is 1.0.

  As shown in FIG. 1, the expression of HDAC1, HDAC3, HDAC6 and LSD1 was hardly detected in normal cells (fibroblasts and T-cells) and hiPSCs derived from healthy individuals, but the expression was strongly detected in teratomas . Although the expression levels of HDAC1 and HDAC3 in teratoma were similar to those of the tumor cell line (K562 strain), expression of HDAC6 and LSD1 was detected stronger than any cell.

  The gene expression level in each cell and teratoma was analyzed by quantitative PCR. Complementary DNA was synthesized from the extracted RNA using reverse transcriptase (TOYOBO). Using a commercially available probe for quantitative PCR (TaqManProbe) for HDAC1, HDAC3, HDAC6 and LSD1, analysis was performed by StepOnePlus real-time PCR system (Life Technology), and the gene expression level was quantified by ΔCT method. The relative value of each gene expression level when the gene expression level of fibroblast was 1.0 was calculated. The results of analyzing the gene expression level in each cell and teratoma by quantitative PCR are shown in FIG.

  As shown in FIG. 2, strong expression of HDAC1, HDAC3, HDAC6 and LSD1 in teratomas was detected at the gene expression level as well as at the protein level (FIG. 1B).

  Expression in teratoma tissue was analyzed by fluorescent immunostaining. The excised teratoma was fixed with 4% paraformaldehyde overnight and then replaced with 10% and 20% sucrose. Samples were embedded with OCT compound (Optical Cutting Temperature compound, SAKURA Finetek US). A plurality of frozen sample sections having a thickness of 7 to 10 μm were prepared using a cryostat and used as continuous sections. Cryosections were stained with hematoxylin eosin (HE). The serial sections were fluorescently immunostained with a specific antibody against HDAC1, HDAC6 or LSD1 and an Alexa-488 labeled secondary antibody. For HE staining, frozen section slides were immersed in hematoxylin solution (Carazzi) and 0.5% eosin solution to stain cytoplasm and nucleus. After that, it was dehydrated and transparent, and sealed with Canadian balsam. For fluorescent immunostaining, serial sections were reacted for 15 minutes each with fixation buffer and blocking buffer (Life Technologies). Subsequently, serial sections were incubated overnight at 4 ° C. with primary antibody diluted 1/100 in blocking buffer. On the next day, serial sections were reacted with a secondary antibody diluted to 1/1000 in blocking buffer, and sealed with ProLong Gold Antifade Reagent with DAPI (Cell Signaling) for nuclear staining. Sections were observed using a fluorescence microscope (Biorevo BZ-X710 Keyence). FIG. 3 shows the results of HE staining of a teratoma tissue section and fluorescent immunostaining using a specific antibody against HDAC1, HDAC6 or LSD1 and an Alexa-488-labeled secondary antibody. In the figure, green indicates a signal from HDAC1, HDAC6 or LSD1, and blue indicates a cell nucleus by DAPI staining.

  As shown in FIG. 3, HDAC1, HDAC6 or LSD1 expression (green) in the teratoma tissue was detected to the same extent at any site of the teratoma formed.

<IV. Teratoma formation promoting action of hiPSC with strong expression of LSD1>
A clone sub-strain that strongly expressed the LSD1 gene in the ChiPS17 strain was established. LSD1 gene expression in the three established substrains (E7, F6 and H12) was analyzed by quantitative PCR. When the gene expression level of the sub-strain (mock) into which only the vector was introduced was 1.0, the relative value of each gene expression level was calculated. In addition, the expression of LSD1 of three sub-strains and c-myc protein, which is a carcinogenic factor, was analyzed by immunoblotting. When the protein expression level of the sub-strain (mock) into which only the vector was introduced was 1.0, the relative value of each protein expression level was calculated. FIG. 4 shows the results of quantitative PCR analysis of LSD1 gene expression in the three sub-strains (E7, F6 and H12). Further, FIG. 5 shows the result of analyzing the protein expression level in three sub-strains (E7, F6 and H12) by immunoblotting. In the figure, A indicates the result of immunoblotting, and B indicates the relative value of the protein expression level when the protein expression level of the sub-strain (mock) into which only the vector is introduced is 1.0.

  In teratoma formation, it has been suggested that c-myc, a carcinogenic factor, is strongly expressed (Lee et al., Nat Med, Vol. 19, p. 998, 2013). In pancreatic cancer, c-myc has been shown to be regulated by LSD1 expression (Gupta et al., Prostate Cancer Prostatic Dis., Vol. 19, p. 349, 2016). As shown in FIGS. 4 and 5, among the three substrains, the H12 strain strongly expressed LSD1 and c-myc. Henceforth, the experiment was advanced using this strain.

2 × 10 ⁶ ChiPS17 substrains (H12 strains) were suspended in Matrigel and transplanted subcutaneously into 6-8 week-old immunodeficient mice. Teratomas were excised on the 22nd and 49th days after transplantation and weighed, and then frozen sections were prepared. The frozen section was stained with HE in the same manner as in III. Fig. 6 shows photographs of teratomas collected on the 22nd and 49th days after transplantation, Fig. 7 shows the weight of teratomas (mean ± standard deviation), and Fig. 8 shows HE staining results of the collected teratomas. Show. In the figure, A shows the result on the 22nd day after transplantation, and B shows the result on the 49th day after transplantation. * Indicates that the p-value for mock calculated by Student's t-test is 0.05 or less.

  As shown in FIGS. 6 and 7, a significant teratoma growth promoting effect was observed on day 22 after transplantation due to the strong expression of LSD1. In addition, as shown in FIG. 8, in the teratoma collected on the 49th day after transplantation, differentiation into three germ layers was observed in both mock and LSD1 strongly expressing sub-strains. From these results, it is speculated that LSD1 strong expression did not affect pluripotency and acted to promote teratoma formation after transplantation. Therefore, LSD1 overexpression is considered to be a driver of teratoma formation. As shown in III above, LSD1 is not expressed in normal cells and is specifically strongly expressed in teratomas (FIGS. 1 and 2). Therefore, it is presumed that a compound having LSD1 inhibitory activity does not affect normal cells and can specifically suppress teratoma formation in cells derived from pluripotent stem cells or structures thereof.

<V. Teratoma formation suppression effect by enzyme inhibitors involved in epigenetic regulation>
Using known inhibitors for enzymes involved in epigenetic regulation, the inhibitory effect of these inhibitors on teratoma formation was evaluated. Known inhibitors include panobinostat (Crisanti MC et al., Mol Cancer Ther, Vol. 8, p.2221, 2009), an HDAC inhibitor, bortezomib (Kikuchi J et al., Blood, vol. 116), a proteasome inhibitor. , p. 406, 2010) and the HDAC6 inhibitor Tubastatin A (Gradilone SA et al., Cancer Res, Vol. 73, p. 2259, 2013). Six ⁶ × ⁶ ChiPS17 strains were suspended in Matrigel and transplanted subcutaneously into 6-8 week-old immunodeficient mice. Immediately after transplantation, the transplanted mice were divided into 4 groups. In the Tubastatin A administration group, the DMSO solution of Tubastatin A was diluted with physiological saline to a final concentration of 50 mg / kg, and in the bortezomib administration group, the DMSO solution of Bortezomib was adjusted to a final concentration of 0.5 mg / kg. In the panoinostat administration group, the DMSO solution of panobinostat was diluted with physiological saline to a final concentration of 20 mg / kg, and in the control group, an equal volume of DMSO Was diluted intraperitoneally for 3 consecutive days except Sunday. The dosage of the inhibitor was referred to literatures (Woan KV et al., Mol Oncol, Vol. 9, p. 1447, 2015; Ocio EM et al., Haematologica, Vol. 95, p. 794, 2010). On day 56 after transplantation, teratomas were removed. In the panobinostat-administered group, a sample could not be obtained because significant weight loss occurred and the mouse died. A photograph of the teratoma collected 56 days after transplantation is shown in FIG. In the figure, A shows a control group, B shows a tubastatin A administration group, and C shows a bortezomib administration group. Table 8 shows the relationship between the inhibition mode of the inhibitor used in the test and the teratoma formation inhibitory effect.

  As shown in FIG. 9 and Table 8, no significant teratoma formation suppression effect was confirmed by administration of panobinostat, bortezomib and tubastatin A that inhibits HDAC.

<VI. Inhibition of teratoma formation by new compounds>
In order to observe the growth of teratoma in the mouse body, the ChiPS17 cell line (ChiPS-Luc) into which the luciferase gene was introduced was established. The ChiPS17 cell line 2 × 10 ⁶ cells were suspended in Matrigel and transplanted subcutaneously in the upper right leg of 6-8 week-old immunodeficient mice. Immediately after transplantation, the transplanted mice were divided into two groups. In the compound administration group, a DMSO solution of synthetic compound 1 was diluted with physiological saline to a final concentration of 50 mg / kg, and in the control group, a solution in which an equal amount of DMSO was diluted with physiological saline was used. Each was administered intraperitoneally for 4 consecutive weeks except Sunday. The luciferase activity was measured by injecting 200 mg of D-luciferin (Promega) into the mouse abdominal cavity and using the IVIS imaging system (Xenogen). The measurement results of luciferase activity on the 8th and 40th day after transplantation of the mice of the synthetic compound 1 administration group and the control group are shown in FIG. 10, and the average value ± standard deviation value of the luciferase activity is shown in FIG. In the figure, * indicates that the p value relative to the value of the control group, calculated by Student's T test, was 0.05 or less.

  As shown in FIGS. 10 and 11, the administration of synthetic compound 1 was observed to have a significant inhibitory effect on the expression of luciferase activity 40 days after transplantation.

  On the 40th day after transplantation, the teratoma was excised and weighed, and then frozen sections were prepared. The frozen section was stained with HE in the same manner as in III. A photograph of the teratoma collected 40 days after the transplantation is shown in FIG. 12, the weight of the teratoma (mean value ± standard deviation value) is shown in FIG. 13, and the result of HE staining of the collected teratoma section is shown in FIG. In the figure, * indicates that the p value with respect to the value of the control group calculated by Student's t-test is 0.05 or less.

  As shown in FIGS. 12 and 13, administration of the synthetic compound 1 observed a significant teratoma formation suppression effect on the 40th day after transplantation. Further, as shown in FIG. 14, in the control group, tissues differentiated into three germ layers were observed and teratomas were formed. In contrast, in the synthetic compound 1 administration group, a large number of apoptotic cells were observed, and tissues differentiated into the three germ layers were not observed.

  The frozen section of teratoma obtained by the above procedure was divided into anti-activated caspase-3 (active-casp.3) antibody or anti-c-myc antibody, and Alexa-594-labeled secondary antibody, anti-H3K4me2 antibody or anti-H3K9me2 Fluorescent immunostaining was performed using the antibody and Alexa-488-labeled secondary antibody. The frozen sections were reacted with a fixing buffer and a blocking buffer (Life Technologies) for 15 minutes each. The frozen sections were then incubated overnight at 4 ° C. with primary antibody diluted to 1/100 concentration in blocking buffer. On the next day, the frozen section was reacted with a secondary antibody diluted to a 1/1000 concentration with a blocking buffer and enclosed with a reagent for nuclear staining (ProLong Gold Antifade Reagent with DAPI, Cell Signaling). The sections were observed with a fluorescence microscope (Biorevo BZ-X710 Keyence). The results of fluorescent immunostaining of teratoma frozen sections are shown in FIG. In the figure, as a result of fluorescent immunostaining with anti-active caspase-3 (active-casp.3) antibody (red) and DAPI (blue) in order from the top, anti-c-myc antibody (red) and DAPI (blue) The results of fluorescent immunostaining with, the results of fluorescent immunostaining with anti-H3K4me2 antibody (green) and DAPI (blue), and the results of fluorescent immunostaining with anti-H3K9me2 antibody (green) and DAPI (blue) are shown, respectively.

  As shown in FIG. 15, in the synthetic compound 1 administration group, activated caspase-3, which is a marker for apoptosis induction, was observed, while the expression of c-myc was lower than that in the control group. Further, in the synthetic compound 1 administration group, enhancement of methylation of H3K4 and H3K9, which are targets of LSD1, was observed.

  In addition, this invention is not limited to an above-described Example, Various modifications are included. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Moreover, it is possible to add, delete, and / or replace another configuration with respect to a part of the configuration of each embodiment.

Claims (12)

Formula (I):
[Where:
L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or substituted or unsubstituted C ₂ -C ₆ alkynylene -CO- (However, L is bonded to A at the carbon atom position of -CO-),
A is -NR ³ R ⁴ , or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. ]
The teratoma formation inhibitor which contains the compound represented by these, its stereoisomer or those salts, or those solvates as an active ingredient. R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ ,
R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls, or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted 5-9 membered heteroaryl, and substituted or unsubstituted a C ₁ -C ₆ monovalent radical independently selected from the group consisting of alkyl,
R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O), Or
R ¹⁰ is one or more selected from substituted or unsubstituted C _{3 to} C ₇ cycloalkyl, N, S and O, together with one or two carbon or nitrogen atoms to which they are attached. includes hetero atoms as ring atoms, and substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or substituted or heteroaryl 5 or 6 membered unsubstituted Forming,
R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl, Or
R ¹² and R ^13, form together with the carbon atom or a nitrogen atom to which they are attached a substituted or unsubstituted C ₄ -C ₇ cycloalkyl or substituted or unsubstituted 4-7 membered heterocycloalkyl And
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl.
2. The teratoma formation inhibitor according to claim 1. R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more A monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ , or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or substituted or unsubstituted C ₅ -C ₆ aryl;
R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl A monovalent group independently selected from the group consisting of:
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens. Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl,
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl.
The teratoma formation inhibitor according to claim 2. L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, teratoma formation inhibitor according to any one of claims 1 to 3. L is methylene-CO-
A is -NR ³ R ⁴
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperazinyl having one R ⁸ and one R ⁹
R ⁸ is methyl;
R ⁹ is hydrogen,
The teratoma formation inhibitor according to any one of claims 1 to 4. Formula (I):
[Where:
L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or substituted or unsubstituted C ₂ -C ₆ alkynylene -CO- (However, L is bonded to A at the carbon atom position of -CO-),
A is -NR ³ R ⁴ , or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. ]
Or a salt thereof, or a solvate thereof as an active ingredient, for use in inhibiting teratoma formation. R ³ and R ⁴ together with the carbon or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, and 1 or 2 R Forming 4-7 membered heterocycloalkyl or heterocycloalkenyl having ⁸ and 1 or more R ⁹ ,
R ⁸ is hydrogen, halogen, substituted or unsubstituted C ₃ -C ₇ cycloalkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and substituted or unsubstituted C _{1 to} C A monovalent group independently selected from the group consisting of ₆ alkyls, or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, substituted or unsubstituted 4-7 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₅ aryl, substituted or unsubstituted 5-9 membered heteroaryl, and substituted or unsubstituted a C ₁ -C ₆ monovalent radical independently selected from the group consisting of alkyl,
R ¹⁰ is a monovalent or divalent group independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo (═O), Or
R ¹⁰ is one or more selected from substituted or unsubstituted C _{3 to} C ₇ cycloalkyl, N, S and O, together with one or two carbon or nitrogen atoms to which they are attached. includes hetero atoms as ring atoms, and substituted or unsubstituted 3-7 membered heterocycloalkyl, substituted or unsubstituted C ₅ -C ₆ aryl, or substituted or heteroaryl 5 or 6 membered unsubstituted Forming,
R ¹¹ is a monovalent group independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C ₁ -C ₆ alkoxy, and substituted or unsubstituted C ₁ -C ₆ alkyl;
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₆ -C ₁₅ aryl, and substituted or unsubstituted C ₁ -C ₆ alkyl, Or
R ¹² and R ^13, form together with the carbon atom or a nitrogen atom to which they are attached a substituted or unsubstituted C ₄ -C ₇ cycloalkyl or substituted or unsubstituted 4-7 membered heterocycloalkyl And
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₆ alkyl.
The medicament according to claim 6. R ⁸ is hydrogen, halogen, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl unsubstituted or substituted with one or more hydroxyl, -COR ¹³ , -COOR ¹³ , -CONR ¹² R ¹³ , -NR ¹² R ¹³ , -NR ¹² COR ¹³ , -NR ¹² CO ₂ R ¹³ , -NR ¹⁴ CONR ¹² R ¹³ , -NR ¹² SO ₂ R ¹³ , and unsubstituted or one or more A monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl substituted with halogen, hydroxyl, phenyl, substituted amino, cyclic amino, —COOR ¹² or —CONR ¹² R ¹³ , or
R ⁸ is a C _{3 to} C ₇ cycloalkyl, N, S and unsubstituted or substituted with one or more R ¹⁰ together with one or two carbon or nitrogen atoms to which they are attached. 3- to 7-membered heterocycloalkyl, which contains one or more heteroatoms selected from O as ring atoms and is unsubstituted or substituted with one or more R ¹⁰ , unsubstituted C ₅ -C ₆ aryl, Or form a 5-9 membered heteroaryl unsubstituted or substituted with one or more R ¹¹ ,
R ⁹ is hydrogen, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholyl, pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzimidazolyl, pyridinyl, pyrazinyl And a monovalent group independently selected from the group consisting of C ₁ -C ₆ alkyl unsubstituted or substituted with one or more oxetanyl, tetrahydrofuranyl, or phenyl,
R ¹⁰ is a monovalent group independently selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, —CONR ¹² R ¹³ and oxo, or
R ¹⁰ together with 1 or 2 carbon atoms to which they are attached form a substituted or unsubstituted C ₃ -C ₇ cycloalkyl, or substituted or unsubstituted C ₅ -C ₆ aryl;
R ¹¹ is hydrogen, halogen, C ₁ -C ₆ alkoxy, and unsubstituted or one or more halogen, hydroxyl, dimethylamino, N- morpholino, from C ₁ -C ₆ alkyl substituted with N- pyrrolidino or carboxyl A monovalent group independently selected from the group consisting of:
R ¹² and R ¹³ are monovalent groups independently selected from the group consisting of hydrogen, C ₆ -C ₁₅ aryl, and C ₁ -C ₆ alkyl unsubstituted or substituted with one or more halogens. Or
R ¹² and R ¹³ together with the carbon or nitrogen atom to which they are attached form an unsubstituted C ₄ -C ₇ cycloalkyl or 4-7 membered unsubstituted heterocycloalkyl,
R ¹⁴ is a monovalent group independently selected from the group consisting of hydrogen and unsubstituted C ₁ -C ₆ alkyl.
The medicament according to claim 7. L is a substituted or C ₁ -C ₆ alkylene -CO- unsubstituted medicament according to any one of claims 6-8. L is methylene-CO-
A is -NR ³ R ⁴
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a piperazinyl having one R ⁸ and one R ⁹
R ⁸ is methyl;
R ⁹ is hydrogen,
The medicament according to any one of claims 6 to 9.   The medicament according to any one of claims 6 to 10, for use in the prevention or treatment of malignant tumors in cells derived from pluripotent stem cells or structures thereof. Formula (I):
[Where:
L is a substituted or unsubstituted C ₁ -C ₆ alkylene -CO-, substituted or unsubstituted C ₂ -C ₆ alkenylene -CO-, or substituted or unsubstituted C ₂ -C ₆ alkynylene -CO- (However, L is bonded to A at the carbon atom position of -CO-),
A is -NR ³ R ⁴ , or -CHR ³ R ⁴ ,
R ³ and R ⁴ together with the carbon atom or nitrogen atom to which they are attached contain one or more heteroatoms selected from N, S and O as ring atoms, substituted or unsubstituted 4 to Forms 7-membered heterocycloalkyl or heterocycloalkenyl. ]
Or a salt thereof, or a solvate thereof, and one or more pharmaceutically acceptable carriers, and a pharmaceutical composition for use in inhibiting teratoma formation.