WO2022163843A1

WO2022163843A1 - Pim2 inhibitor

Info

Publication number: WO2022163843A1
Application number: PCT/JP2022/003446
Authority: WO
Inventors: 順平寺町; 允泰中尾; 茂樹佐野; 正博安倍; 武志原田; 英樹藤猪; 圭史村上
Original assignee: 国立大学法人徳島大学
Priority date: 2021-02-01
Filing date: 2022-01-28
Publication date: 2022-08-04
Also published as: JPWO2022163843A1

Abstract

Provided are a compound having high PIM2 inhibitory activity, and a PIM2 inhibitor and a pharmaceutical composition that contain the compound. This PIM2 inhibitor contains a compound represented by formula (1) (in the formula, A is a benzene ring optionally having one or more substituents; when the benzene ring has two substituents mutually located at the ortho position, the two substituents may form a ring together with the carbon atoms of the benzene ring to which the substituents bond; X11-X13 each independently represent an oxygen atom or a sulfur atom, and at least one of X12 and X13 represents a sulfur atom) or a pharmacologically acceptable salt thereof.

Description

PIM2 inhibitor

The present invention relates to a compound having a PIM2 inhibitory action, a PIM2 inhibitor containing the compound, a pharmaceutical composition, and the like.

PIM is a serine threonine kinase that is induced and functions in response to growth factors and cytokines, and plays an important role in cell survival and proliferation, as well as cell functions and metabolism such as sugar and amino acid transport and energy production. Overexpression of PIM is found in many human malignancies. PIM2 is highly expressed in hematopoietic malignancies, and is constitutively highly expressed in myeloma cells among hematopoietic malignancies. PIM2 may be a candidate therapeutic target molecule with high specificity in myeloma cells. The formula below:

It has been reported that a PIM inhibitor with relatively high PIM2 selectivity, represented by, suppresses myeloma growth (Non-Patent Document 1).

The main object of the present invention is to provide compounds with high PIM2 inhibitory activity, PIM2 inhibitors and pharmaceutical compositions containing the compounds.

The present inventors have made intensive studies to solve the above problems, and found the following formula (1):

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X ¹¹ to X ¹³ are each independently an oxygen atom or a sulfur atom, and at least one of X ¹² and X ¹³ is a sulfur atom)
It was found that the compound represented by or a pharmaceutically acceptable salt thereof has high PIM2 inhibitory activity and is useful for the prevention or treatment of PIM2-related diseases. The present invention has been completed through further studies based on these findings.

The present invention includes the following aspects.
Item 1.
Formula (1) below:

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X ¹¹ to X ¹³ are each independently an oxygen atom or a sulfur atom, and at least one of X ¹² and X ¹³ is a sulfur atom)
PIM2 inhibitor containing a compound represented by or a salt thereof.
Item 2.
Item 2. The ^PIM2 inhibitor according to Item 1, wherein X11 is a sulfur atom.
Item 3.
Item 3. The ^PIM2 inhibitor according to

Item

1 or 2, wherein X13 is a sulfur atom.
Item 4.
4. The ^PIM2 inhibitor according to any one of items ¹ to 3, wherein X12 and X13 are sulfur atoms.
Item 5.
A is the following formula (2):

(In the formula,
R ¹¹ to R ¹⁵ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
R ¹¹ and R ¹² , R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ form a ring together with the carbon atoms of the benzene ring to which they are attached)
The PIM2 inhibitor according to any one of items 1 to 4, which is a group represented by
Item 6.
6. The PIM2 inhibitor of paragraph 5, wherein ^R12 is a haloalkyl group.
Item 7.
A pharmaceutical composition for preventing or treating multiple myeloma,
Formula (1) below:

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X ¹¹ to X ¹³ are each independently an oxygen atom or a sulfur atom, and at least one of X ¹² and X ¹³ is a sulfur atom)
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof.
Item 8.
Item 8. The pharmaceutical composition according to Item ⁷ , wherein X11 is a sulfur atom.
Item 9.
Item 9. The pharmaceutical composition according to

Item

7 or 8, wherein ^X13 is a sulfur atom.
Item 10.
10. The pharmaceutical composition according to any one of items 7 to ⁹ , wherein X12 and ^X13 are sulfur atoms.
Item 11.
A is the following formula (2):

(In the formula,
R ¹¹ to R ¹⁵ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
R ¹¹ and R ¹² , R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ form a ring together with the carbon atoms of the benzene ring to which they are attached)
Item 11. The pharmaceutical composition according to any one of items 7 to 10, which is a group represented by
Item 12.
^12. A pharmaceutical composition according to paragraph 11, wherein R12 is a haloalkyl group.
Item 13.
Item 13. The pharmaceutical composition according to any one of Items 7 to 12, which is a pharmaceutical composition for preventing or treating a disease selected from the group consisting of hypercalcemia, renal failure, anemia, and bone lesions.
Item 14.
Formulas (1B) to (1E) below:

(In the formula,
^R2 is a hydroxyl group, an alkyl group, or a haloalkyl group;
n is an integer from 1 to 5;
R3 is an alkyl group or a haloalkyl group ^,
^R4 is a halogen atom or a haloalkyl group,
m is an integer from 1 to 5,
^R5 is a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
p is an integer from 0 to 5)
A compound or a salt thereof represented by any one of
Item 15.
Formula (1) below:

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X ¹¹ to X ¹³ are each independently an oxygen atom or a sulfur atom, and at least one of X ¹² and X ¹³ is a sulfur atom)
A compound represented by or an antibacterial agent containing a salt thereof.
Item 16.
Item 16. The antibacterial agent according to Item ¹⁵ , wherein X11 is an oxygen atom.
Item 17.
Item 17. The antibacterial agent according to Item 15 or 16, wherein ^X13 is a sulfur atom.
Item 18.
Item 18. The antibacterial agent according to any one of Items 15 to ¹⁷ , wherein X12 and ^X13 are sulfur atoms.
Item 19.
A is the following formula (2):

(In the formula,
R ¹¹ to R ¹⁵ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
R ¹¹ and R ¹² , R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ form a ring together with the carbon atoms of the benzene ring to which they are attached)
Item 19. The antibacterial agent according to any one of Items 15 to 18, which is a group represented by
Item 20.
Item 20. The antibacterial agent according to Item 19, wherein ^R12 and ^R14 are halogen atoms.
Item 21.
Item 21. The antibacterial agent according to any one of Items 15 to 20, which is an antifungal agent.
Item 22.
Item 22. The antibacterial agent according to any one of Items 15 to 21, which is an antibacterial agent against Candida, Aspergillus, or Rhizopus.

The compounds of the present invention have high PIM2 inhibitory activity and are useful for the prevention or treatment of PIM2-related diseases.

1 is a ¹ H-NMR spectrum chart of the compound of Example 1. FIG. 2 is a ¹ H-NMR spectrum chart of the compound of Example 2. FIG. 3 is a ¹ H-NMR spectrum chart of the compound of Example 3. FIG. 4 is a ¹ H-NMR spectrum chart of the compound of Example 4. FIG. 5 is a ¹ H-NMR spectrum chart of the compound of Example 5. FIG. 6 is a ¹ H-NMR spectrum chart of the compound of Example 6. FIG. 7 is a ¹ H-NMR spectrum chart of the compound of Example 7. FIG. 8 is a ¹ H-NMR spectrum chart of the compound of Example 8. FIG. 9 is a ¹ H-NMR spectrum chart of the compound of Example 9. FIG. 10 is a ¹ H-NMR spectrum chart of the compound of Example 10. FIG. 11 is a ¹ H-NMR spectrum chart of the compound of Example 11. FIG. 12 is a ¹ H-NMR spectrum chart of the compound of Example 12. FIG. 13 is a ¹ H-NMR spectrum chart of the compound of Example 13. FIG. FIG. 14A is a graph showing the results of PIM2 expression suppression by the compounds of the present invention on human multiple myeloma cell line RPMI 8226. FIG. FIG. 14B is a graph showing the results of PIM2 expression suppression by the compounds of the present invention on human multiple myeloma cell line KMS11. FIG. 14C is a graph showing the results of PIM2 expression suppression by the compounds of the present invention on human multiple myeloma cell line MM.1S. FIG. 14D is a graph showing the results of PIM2 expression suppression against human multiple myeloma cell line INA-6 by the compounds of the present invention. FIG. 15 is a graph showing the results of suppressing the expression of phosphorylated 4E-BP1 on human multiple myeloma cell line RPMI 8226 by the compounds of the present invention. Figure 16A is a graph showing the anticancer activity of compounds of the invention against the human multiple myeloma cell line U266-B1. Figure 16B is a graph showing the anticancer activity of compounds of the invention against the human multiple myeloma cell line RPMI 8226. FIG. 17A is a graph showing the suppression of anti-apoptotic factor expression by the compounds of the present invention on various human multiple myeloma cell lines INA-6. Figure 17B is a graph showing the suppression of anti-apoptotic factor expression by the compounds of the present invention on various human multiple myeloma cell lines RPMI 8226; Figure 18 shows the osteoblast differentiation promoting activity of the compounds of the present invention. Figure 19A shows the anticancer activity of compounds of the present invention in mice. Figure 19B shows the anticancer activity of compounds of the present invention in mice. Figure 20A shows the anticancer activity of the compounds of the present invention against the human adult T-cell leukemia cell line KK1. Figure 20B is a diagram showing the anticancer activity of the compounds of the present invention against the human adult T-cell leukemia cell line Su9T01. FIG. 21 is a diagram showing the bactericidal action of the compounds of the present invention on Candida albicans CAD1 strain.

1. Definition In the present specification, "C _ab " means that the number of carbon atoms in question is an integer of a or more and b or less.

As used herein, the term "halogen atom" is a concept that includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

As used herein, the term "alkyl group" is a concept that includes linear alkyl groups and branched chain alkyl groups. Alkyl groups include, for example, straight-chain C _{1- 20} alkyl groups; branched _C3-20 alkyl groups such as isopropyl, isobutyl, s-butyl, t-butyl, isopentyl, neopentyl, isohexyl, isoheptyl, isooctyl and 2-ethylhexyl.

As used herein, the term "haloalkyl group" means the above "alkyl group" substituted with one or more halogen atoms. When two or more halogen atoms substitute an alkyl group, the types of each halogen atom may be the same or different. For example, one or more fluorine atoms and one or more chlorine atoms may substitute the alkyl group. The number of halogen atoms to be substituted can be selected, for example, from the range of 1 to the maximum number that can be substituted.

Haloalkyl groups include, for example, monofluoromethyl, difluoromethyl, trifluoromethyl (perfluoromethyl), 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2 and fluoro- _C1-10 alkyl groups such as ,2-tetrafluoroethyl, pentafluoroethyl (perfluoroethyl) and the like.

As used herein, a "hydroxyalkyl group" means the above "alkyl group" substituted with one or more hydroxyl groups. The number of hydroxyl groups to be substituted can be selected, for example, from the range of 1 to the maximum number that can be substituted.

Hydroxyalkyl groups include, for example, _hydroxyC1-10 alkyl groups such as hydroxymethyl, 1-hydroxyethyl and 2-hydroxyethyl.

As used herein, a "mercaptoalkyl group" means the above-mentioned "alkyl group" substituted with one or more mercapto groups. The number of mercapto groups to be substituted can be selected, for example, from the range of 1 to the maximum number that can be substituted.

Mercaptoalkyl groups include, for example, mercaptoC _1-10 alkyl groups such as mercaptomethyl, 1-mercaptoethyl and 2-mercaptoethyl.

As used herein, an "aminoalkyl group" means the above-mentioned "alkyl group" substituted with one or more amino groups. The number of amino groups to be substituted can be selected, for example, from the range of 1 to the maximum possible number of substitutions.

Aminoalkyl groups include, for example, amino _C1-10 alkyl groups such as aminomethyl, 1-aminoethyl and 2-aminoethyl.

As used herein, the term "alkoxy group" refers to a group represented by the formula: R ^A O- (wherein R ^A is an alkyl group). Alkoxy groups include, for example, C _1-10 alkoxy groups such as methoxy, ethoxy, propoxy (n-propoxy, isopropoxy), butoxy (n-butoxy, isobutoxy, s-butoxy, t-butoxy).

As used herein, the term "alkylthio group" refers to a group represented by the formula: R ^B S- (wherein R ^B is an alkyl group). The alkylthio group includes, for example, C _1-10 alkylthio groups such as methylthio, ethylthio, propylthio (n-propylthio, isopropylthio), butylthio (n-butylthio, isobutylthio, s-butylthio, t-butylthio).

As used herein, an "N-monoalkylamino group" refers to a group represented by the formula: R ^C -NH- (wherein R ^C is an alkyl group). Monoalkylamino groups include, for example, monoC _1-10 alkylamino groups such as monomethylamino, monoethylamino, monopropylamino (mono n-propylamino, monoisopropylamino).

As used herein, the term "N,N-dialkylamino group" is represented by the formula: R ^D R ^E N- (wherein R ^D and R ^E are each independently an alkyl group). base. The dialkylamino group includes, for example, diC _1-10 alkylamino groups such as dimethylamino, ethylmethylamino, diethylamino and propylmethylamino.

2. PIM2 Inhibitor The PIM2 inhibitor of the present invention has the following formula (1):

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X ¹¹ to X ¹³ are each independently an oxygen atom or a sulfur atom, and at least one of X ¹² and X ¹³ is a sulfur atom)
Contains a compound represented by or a salt thereof.

Examples of substituents that can be substituted on the benzene ring represented by A include halogen atoms, hydroxyl groups, mercapto groups, amino groups, alkyl groups, and combinations thereof (haloalkyl groups, hydroxyalkyl groups, mercaptoalkyl groups, alkoxy groups, alkylthio groups, N-monoalkylamino groups, N,N-dialkylamino groups, etc.), but are not limited to these. The number of such substituents can be, for example, 0, 1, 2, 3, 4, or 5. When the number of substituents is two or more, the types of each substituent may be the same or different.

A is the following formula (2):

(In the formula,
R ¹¹ to R ¹⁵ are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
R ¹¹ and R ¹² , R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ form a ring together with the carbon atoms of the benzene ring to which they are attached)
is preferably a group represented by

In one embodiment, R ¹¹ to R ¹⁵ are each independently preferably a hydrogen atom, a halogen atom, or a haloalkyl group. In one embodiment, R ¹² is preferably a halogen atom or a haloalkyl group, more preferably R ¹² is a haloalkyl group, R ¹² is a haloalkyl group, and R ¹¹ and R ¹³ to R More preferably, ¹⁵ is a hydrogen atom. The halogen atom is preferably a fluorine atom or a chlorine atom. Said haloalkyl group is preferably a fluoroalkyl group, more preferably a fluoroC _1-6 alkyl group, even more preferably a fluoroC _1-4 alkyl group.

In one embodiment, R ¹¹ to R ¹⁵ are each independently preferably a hydrogen atom, a hydroxyl group, or an alkoxy group. Also, in one embodiment, it is preferred that R ¹² is an alkoxy group and R ¹³ is a hydroxyl group, R ¹² is an alkoxy group, R ¹³ is a hydroxyl group, and R ¹¹ , R More preferably, ¹⁴ and R ¹⁵ are hydrogen atoms. Said alkoxy group is preferably a C _1-6 alkoxy group, more preferably a C _1-4 alkoxy group.

In one embodiment, R ¹¹ and R ¹⁵ are hydrogen atoms, or R ¹¹ , R ¹⁴ and R ¹⁵ are hydrogen atoms, R ¹¹ and R ¹³ to R ¹⁵ are hydrogen atoms, or R ¹¹ to R ¹⁵ are preferably hydrogen atoms.

When R ¹¹ and R ¹² , R ¹² and R ¹³ , R ¹³ and R ¹⁴ , or R ¹⁴ and R ¹⁵ form a ring together with carbon atoms of a benzene ring, the ring may be a hydrocarbon ring or a heterocyclic ring. There may be. Examples of the heterocyclic ring include rings containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The number of atoms constituting the ring is not limited, and the ring may be, for example, a 5-, 6-, or 7-membered ring. The ring may have one or more substituents. Examples of substituents include halogen atoms, hydroxyl groups, mercapto groups, amino groups, alkyl groups, and combinations thereof (haloalkyl groups, hydroxyalkyl groups, mercaptoalkyl groups, alkoxy groups, alkylthio groups, N-monoalkylamino groups, N,N-dialkylamino groups, etc.), but are not limited to these. The number of such substituents can be, for example, 0, 1, 2, 3, 4, or 5. When the number of substituents is two or more, the types of each substituent may be the same or different.

^X11 is preferably a sulfur atom.

Although X ¹² may be a sulfur atom and X ¹³ may be an oxygen atom or a sulfur atom, it is preferable that X ¹² is an oxygen atom or a sulfur atom and X ¹³ is a sulfur atom, Most preferably, both ¹² and ^X13 are sulfur atoms.

The compound represented by formula (1) preferably has the following formula (1A):

(Wherein, R ¹¹ to R ¹⁵ , X ¹¹ and X ¹² are the same as above)
It is a compound represented by

Examples of the compound represented by formula (1A) include compounds represented by the following formulas (1B) to (1E):

(In the formula,
^R2 is a hydroxyl group, an alkyl group, or a haloalkyl group;
n is an integer from 1 to 5;
R3 is an alkyl group or a haloalkyl group ^,
^R4 is a halogen atom or a haloalkyl group,
m is an integer from 1 to 5,
^R5 is a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
p is an integer from 0 to 5).

R ² is preferably a haloalkyl group, more preferably a fluoroalkyl group, still more preferably a fluoroC _1-6 alkyl group, particularly preferably a fluoroC _1-4 alkyl group.

n is preferably 1, 2, or 3, more preferably 1 or 2, still more preferably 1.

R ³ is preferably a haloalkyl group, more preferably a fluoroalkyl group, even more preferably a fluoroC _1-6 alkyl group, particularly preferably a fluoroC _1-4 alkyl group.

R ⁴ is preferably a fluorine atom or a fluoroalkyl group, more preferably a fluorine atom or a fluoroC _1-6 alkyl group, still more preferably a fluorine atom or a fluoroC _1-4 alkyl group.

m is preferably 1, 2, or 3, more preferably 1 or 2.

R ⁵ is preferably a hydroxyl group, a fluoroalkyl group or an alkoxy group, more preferably a hydroxyl group, a fluoroC _1-6 alkyl group or a C _1-6 alkoxy group, still more preferably a hydroxyl group, a fluoro It is a C _1-4 alkyl group or a C _1-4 alkoxy group.

p is preferably 0, 1, 2, or 3, more preferably 0, 1, or 2.

When the compound represented by formula (1) is in the form of a salt, the salt may be an inorganic salt or an organic salt. Examples of the salt include inorganic acid salts such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, and phosphate; salt, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, tartrate, oxalate , organic acid salts such as maleates; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates. The salt may be a pharmaceutically acceptable salt.

The compound represented by formula (1) or a salt thereof can be prepared, for example, in step A below:

(wherein A and X ¹¹ to X ¹³ are the same as above)
It can be produced by a method comprising

More specifically, the compound represented by formula (1) or a salt thereof can be produced, for example, according to the following reaction scheme:

(wherein A, X ¹¹ and X ¹² are the same as above).

Steps A, C, and D are steps of reacting the compounds represented by formulas (3), (3B), and (3C) with the compound represented by formula (4), respectively. The amount of the compound represented by formula (3), (3B), or (3C) to be used is, for example, 1 to 1.5 mol, preferably 1 to 1.2 mol, per 1 mol of the compound represented by formula (4). Mole.

Steps A, C, and D are preferably carried out in the presence of a base. Examples of bases include nitrogen-containing heterocycles such as piperidine and pyridine. The base may be used singly or in combination of two or more. The amount of the base to be used is, for example, 0.1-1 mol, preferably 0.1-0.5 mol, per 1 mol of the compound represented by formula (4).

It is preferable to perform steps A, C, and D in the presence of a solvent. Examples of solvents include aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; alcohols such as ethanol; and ethers such as diethyl ether, dioxane and tetrahydrofuran. The solvent may be a single solvent or a mixed solvent of two or more.

In steps A, C, and D, the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 0 to 110°C, preferably 50 to 110°C. The reaction time is, for example, 1 to 26 hours, preferably 1 to 12 hours.

Step B is a step of reacting the compound represented by formula (3A) with a thiocarbonylating agent. Thiocarbonylating agents include, for example, diphosphorus pentasulfide, Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide), 2, 4-bis(4-phenoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 2,4-bis(methylthio)-1,3-dithia-2,4-diphosphetane-2 ,4-disulfide, 2,4-bis(ethylthio)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 2,4-bis(isopropylthio)-1,3-dithia-2, 4-diphosphetane-2,4-disulfide, 2,4-bis(phenylthio)-1,3-dithia-2,4-diphosphetane-2,4-disulfide, 2,4-bis(benzylthio)-1,3- Examples include, but are not limited to, dithia-2,4-diphosphetane-2,4-disulfide. Thiocarbonylating agents may be used singly or in combination of two or more. The amount of the thiocarbonylating agent to be used is, for example, 0.5-1 mol, preferably 0.8-1 mol, per 1 mol of the compound represented by formula (3A).

It is preferable to perform step B in the presence of a solvent. Examples of the solvent include the same solvents as those exemplified in steps A, C, and D.

In step B, the reaction temperature and reaction time are not particularly limited as long as the reaction proceeds. The reaction temperature is, for example, 25 to 110°C, preferably 50 to 110°C. The reaction time is, for example, 0.5 to 20 hours, preferably 0.5 to 12 hours.

Step E is a step of reacting the compound represented by formula (1G) with a thiocarbonylating agent. Step E can be carried out in the same manner as Step B.

The PIM2 inhibitor of the present invention can be suitably used for prevention or treatment of PIM2-related diseases. Here, "PIM2-related disease" includes all diseases directly or indirectly related to the expression and/or activity of PIM2. PIM2-related diseases include, for example, solid cancers such as head and neck cancer, thyroid cancer, lung cancer, breast cancer, stomach cancer, kidney cancer, liver cancer, pancreatic cancer, colon cancer, colon cancer, uterine cancer, ovarian cancer, and prostate cancer; hematologic cancers such as leukemia (multiple myeloma, etc.), lymphoma (non-Hodgkin's lymphoma, etc.), leukemia (acute lymphocytic leukemia, chronic lymphocytic leukemia, etc.). PIM2-related diseases also include, for example, hypercalcemia, renal failure, anemia, and bone lesions.

3. Antibacterial agent The antibacterial agent of the present invention contains the compound represented by formula (1) or a salt thereof.

In formula (1), A is preferably a group represented by formula (2). In formula (2), R ¹¹ to R ¹⁵ are each independently preferably a hydrogen atom, a halogen atom, or a haloalkyl group, more preferably a hydrogen atom, a fluorine atom, or a fluoroalkyl group, More preferably, it is a hydrogen atom, a fluorine atom, or a fluoro- _C1-6 alkyl group. ^In one embodiment, ^R12 and R14 are preferably halogen atoms, more preferably ^R12 and ^R14 are fluorine atoms.

^X11 is preferably an oxygen atom.

The antibacterial agent of the present invention is useful for inhibiting or delaying the growth of bacteria, reducing the number of bacteria, or killing bacteria. The antimicrobial agent of the present invention is preferably an antifungal agent.

Examples of fungi include Absidia, Alternaria, Aspergillus, Bipolaris, Blastomyces, Candida, Cladophialophora, Cladosporium, Coccidioides, Cryptococcus, Cunninghamella, Epidermophyton, Exophiala, Fonsecaea, Fusarium, Geotrichum, Histoplasma, Malassezia, Microsporum, Mucor, Penicillium, Phialophora, Pseudallescheria, Rhizopus bacteria, Saccharomyces, Scedosporium, Sporothrix, Trichophyton, Trichosporon, etc., but not limited thereto. Among these, at least one selected from the genus Candida, the genus Aspergillus, and the genus Rhizopus is preferred.

Examples of the Candida genus include, but are not limited to, Candida albicans, Candida auris, Candida famata, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida utilis, and the like. . Among these, Candida albicans is preferred.

Examples of Aspergillus genus bacteria include, but are not limited to, Aspergillus fumigatus, Aspergillus flavus, Aspergillus nidulans, Aspergillus niger, Aspergillus terreus, Aspergillus ochraceus, and Aspergillus versicolor. Among these, Aspergillus fumigatus or Aspergillus niger are preferred.

Examples of Rhizopus bacteria include, but are not limited to, Rhizopus microsporus, Rhizopus oryzae, and the like. Among these, Rhizopus oryzae is preferred.

4. Pharmaceutical Composition The pharmaceutical composition of the present invention contains the compound represented by formula (1) or a pharmaceutically acceptable salt thereof (hereinafter referred to as "active ingredient"). The compounds represented by formula (1) may be used singly or in combination of two or more.

From the viewpoint of activity, the lower limit of the content of the active ingredient is, for example, 0.001% by mass, preferably 0.01% by mass, more preferably 0.05% by mass, relative to the total mass of the pharmaceutical composition. The upper limit of the content of the active ingredient is not particularly limited, but is, for example, 99% by mass, 95% by mass, or 90% by mass with respect to the total mass of the pharmaceutical composition. You may select the content of an active ingredient from the range which combined the said lower limit and upper limit arbitrarily.

The pharmaceutical composition of the present invention may further contain pharmaceutically acceptable additives. Additives can be appropriately selected according to the form of the pharmaceutical composition. Forms of pharmaceutical compositions include, for example, solid formulations such as granules, powders, tablets, capsules, and dry syrups; semi-solid formulations such as creams, ointments, and gels; and liquid formulations such as injections. .

Solid preparations, for example, mix active ingredients and additives (excipients, binders, disintegrants, lubricants, colorants, etc.), and if desired, granulate, granulate, compress and/or coat It can be manufactured by

A semi-solid preparation can be produced, for example, by mixing an active ingredient, a semi-solid carrier, and other additives as desired.

Liquid formulations include, for example, an active ingredient, a liquid carrier [aqueous carrier (e.g., purified water), an oily carrier, etc.], and optionally other additives (emulsifiers, dispersants, suspending agents, buffers, antioxidants, Surfactants, osmotic pressure regulators, chelating agents, antibacterial agents, etc.) and, if necessary, sterilization can be performed.

The administration method of the pharmaceutical composition of the present invention may be oral administration, or parenteral administration such as intravenous administration, intramuscular administration, or subcutaneous administration. Moreover, the administration method of the pharmaceutical composition of the present invention may be local administration.

The subject of administration of the pharmaceutical composition of the present invention may be humans, non-human mammals such as monkeys, sheep, dogs, mice and rats, or non-mammals.

The pharmaceutical composition of the present invention is preferably a pharmaceutical composition for preventing or treating PIM2-related diseases. Examples of PIM2-related diseases include the same diseases as exemplified for PIM2 inhibitors. The pharmaceutical composition of the present invention is a pharmaceutical composition for preventing or treating multiple myeloma, or a disease selected from the group consisting of hypercalcemia, renal failure, anemia, and bone lesions. It is preferably a pharmaceutical composition for

The pharmaceutical composition of the present invention is a pharmaceutical composition for inhibiting or delaying the growth of bacteria, reducing the number of bacteria, or killing bacteria, and a pharmaceutical composition for preventing or treating infections caused by bacteria. It is also preferable that Examples of bacteria include the same bacteria as exemplified in 3 above.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these.

[Synthesis example]
The compounds of Examples 1 to 7 were synthesized according to the following reaction schemes or methods analogous thereto.

Compound of Example 1: Synthesis of (Z)-2-thioxo-5-(3-methoxy-4-hydroxybenzylidene)thiazolidin-4-one 2-thioxothiazolidin-4-one (200 mg, 1.50 mmol) and Piperidine (14.9 μL, 0.150 mmol) was added to a solution of 4-hydroxy-3-methoxybenzaldehyde (228 mg, 1.50 mmol) in ethanol (6 mL) under an argon atmosphere, and the mixture was heated under reflux for 24 hours. The reaction solution was cooled to room temperature, and the resulting solid was filtered to obtain a crude product (260 mg). The solid was recrystallized (ethanol-n-hexane) to obtain the compound of Example 1 (yellow solid, 225 mg, 56%). A ¹ H-NMR spectrum chart of the compound of Example 1 is shown in FIG.

Compound of Example 2: Synthesis of (Z)-2-thioxo-5-(3-(trifluoromethyl)benzylidene)thiazolidin-4-one 2-thioxothiazolidin-4-one (1.50 g, 11.3 mmol) and To a toluene (45 mL) solution of 3-(trifluoromethyl)benzaldehyde (1.50 mL, 11.3 mmol) was added piperidine (112 μL, 1.13 mmol) under an argon atmosphere, and the mixture was heated under reflux for 7 hours. The reaction solution was cooled to room temperature, acetic acid (5.5 mL) and water (100 mL) were added, and extracted with chloroform (250 mL×2). The organic layer was dried over anhydrous magnesium sulfate, filtered with filter paper, and the filtrate was concentrated under reduced pressure to obtain a solid crude product (3.19 g). The solid was washed with n-hexane and then recrystallized (methanol) to obtain the compound of Example 2 (orange solid, 2.40 g, 74%). A ¹ H-NMR spectrum chart of the compound of Example 2 is shown in FIG.

Compound of Example 3: Synthesis of (Z)-4-thioxo-5-(3-(trifluoromethyl)benzylidene)thiazolidin-2-one Thiazolidin-2,4-dione (1.00 g, 8.54 mmol) in THF ( 34 mL) solution, Lawesson's reagent (3.45 g, 8.54 mmol) was added under an argon atmosphere, and the mixture was heated under reflux for 20 hours. After concentrating the reaction solution under reduced pressure, the residue was purified by dry column chromatography using silica gel (Kanto Kagaku, silica gel 60N) (eluent: n-hexane-ethyl acetate = 3:1) to obtain 4-thioxothiazolidine. -2-one (orange solid, 1.02 g, 89%) was obtained.

Piperidine (7.5 μL, 0.0752 mmol) was added, and the mixture was stirred at the same temperature for 26 hours. After the reaction solution was concentrated under reduced pressure to about 1 mL, acetic acid (0.5 mL) and water (5 mL) were added, followed by extraction with chloroform (10 mL×2). The organic layer was dried over anhydrous magnesium sulfate, filtered with filter paper, and the filtrate was concentrated under reduced pressure to obtain a solid crude product (206 mg). The solid was purified by column chromatography using silica gel (Kanto Kagaku, silica gel 60N) (eluent: chloroform-ethyl acetate = 40:1) and recrystallization (chloroform-n-hexane) to obtain the compound of Example 3 ( A red solid, 83.3 mg, 38%) was obtained. A ¹ H-NMR spectrum chart of the compound of Example 3 is shown in FIG.

Compound of Example 4: Synthesis of (Z)-5-(4-hydroxy-3-methoxybenzylidene)-4-thioxoxazolidin-2-one 4-thioxoxazolidin-2-one (116 mg, 0.993 mmol) and 4-hydroxy-3-methoxybenzaldehyde (151 mg, 0.993 mmol) in ethanol (4 mL), piperidine (9.9 μL, 0.0993 mmol) was added under an argon atmosphere, and the mixture was heated under reflux for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting solid was subjected to column chromatography (eluent: chloroform-methanol = 20:1 to 10:1) using silica gel (Kanto Kagaku, silica gel 60N) and recrystallization (ethanol-n -hexane) to obtain the compound of Example 4 (yellow solid, 81.7 mg, 33%). A ¹ H-NMR spectrum chart of the compound of Example 4 is shown in FIG.

Compound of Example 5: Synthesis of (Z)-4-thioxo-5-(3-(trifluoromethyl)benzylidene)oxazolidin-2-one 3-(trifluoromethyl ) The compound of Example 5 (yellow solid, 56.8 mg, 25%) was obtained in the same manner as for the synthesis of the compound of Example 4, except that benzaldehyde (110 μL, 0.826 mmol) was used. A ¹ H-NMR spectrum chart of the compound of Example 5 is shown in FIG.

Compound of Example 6: Synthesis of (Z)-4-thioxo-5-(3-(trifluoromethyl)benzylidene)thiazolidin-2-one 4-Hydroxy-3-instead of 3-(trifluoromethyl)benzaldehyde The compound of Example 6 (orange solid, 207 mg, 41%) was obtained in the same manner as for the synthesis of the compound of Example 3, except that methoxybenzaldehyde (286 mg, 1.88 mmol) was used. A ¹ H-NMR spectrum chart of the compound of Example 6 is shown in FIG.

Compound of Example 7: Synthesis of (Z)-5-(3-(trifluoromethyl)benzylidene)thiazolidine-2,4- dithione Compound of Example 2 (200 mg, 0.691 mmol) in xylene (7 mL) To the mixture was added Lawesson's reagent (280 mg, 0.691 mmol) under an argon atmosphere, and the mixture was heated under reflux for 40 minutes. The reaction solution was cooled to room temperature and subjected to flash column chromatography (eluent: n-hexane-ethyl acetate = 3:1) using silica gel (Fuji Silysia Chemical Ltd., silica gel PSQ60B) and recrystallization (chloroform-n-hexane). to obtain the compound of Example 7 (orange solid, 65.1 mg, 31%). A ¹ H-NMR spectrum chart of the compound of Example 7 is shown in FIG.

Compound of Example 8: Synthesis of (Z)-4-thioxo-5-(2-fluorobenzylidene)thiazolidin-2-one 2-fluorobenzaldehyde (118 μL, 1.128 mmol) instead of 3-(trifluoromethyl)benzaldehyde ) was used to obtain the compound of Example 8 (red solid, 181 mg, 67%) in the same manner as the synthesis method of the compound of Example 3. A ¹ H-NMR spectrum chart of the compound of Example 8 is shown in FIG.

Compound of Example 9: Synthesis of (Z)-4-thioxo-5-(3-fluorobenzylidene)thiazolidin-2-one 3-Fluorobenzaldehyde (79.1 μL, 0.752 mmol) instead of 3-(trifluoromethyl)benzaldehyde ) was used to obtain the compound of Example 9 (orange solid, 83.1 mg, 46%) in the same manner as the synthesis method of the compound of Example 3. A ¹ H-NMR spectrum chart of the compound of Example 9 is shown in FIG.

Compound of Example 10: Synthesis of (Z)-4-thioxo-5-(4-fluorobenzylidene)thiazolidin-2-one 4-fluorobenzaldehyde (79.1 μL, 0.752 mmol) instead of 3-(trifluoromethyl)benzaldehyde ) was used to obtain the compound of Example 10 (orange solid, 52.2 mg, 29%) in the same manner as the synthesis method of the compound of Example 3. A ¹ H-NMR spectrum chart of the compound of Example 10 is shown in FIG.

Compound of Example 11: Synthesis of (Z)-5-(3-(trifluoromethyl)benzylidene)oxazolidine-2,4- dithione 3.6 mL) solution, Lawesson's reagent (365 mg, 0.903 mmol) was added under an argon atmosphere, and the mixture was heated under reflux for 5 hours. After cooling the reaction solution to room temperature, it was purified by column chromatography (eluent: n-hexane-ethyl acetate = 3:1) using silica gel (Fuji Silysia Chemical, silica gel PSQ60B) to remove some by-products. oxazolidine-2,4-dithione (tan solid, 115 mg) containing

Piperidine (9.0 μL, 0.0903 mmol) was added to a solution of oxazolidine-2,4-dithione (115 mg) and 3-(trifluoromethyl)benzaldehyde (120 μL, 0.903 mmol) in toluene (3.6 mL) at room temperature under an argon atmosphere. The mixture was added and heated under reflux for 2 hours. After cooling the reaction solution to room temperature, acetic acid (1 mL) and water (30 mL) were added, and the mixture was extracted with chloroform (50 mL×3). The organic layer was dried over anhydrous magnesium sulfate, filtered with filter paper, and the filtrate was concentrated under reduced pressure to obtain a solid crude product (243 mg). The solid was purified by column chromatography (eluent: chloroform-ethyl acetate = 20:1) using silica gel (Fuji Silysia Chemical, silica gel PSQ60B) and recrystallization (chloroform-n-hexane) to obtain the compound of Example 11. (orange solid, 130 mg, 50% two-step yield). A ¹ H-NMR spectrum chart of the compound of Example 11 is shown in FIG.

Compound of Example 12: Synthesis of (Z)-5-(3-fluorobenzylidene)oxazolidine-2,4-dithione 2-Thioxoxazolidin-4-one (110 mg, 0.943 mmol) in toluene (4 mL) To the solution was added Lawesson's reagent (381 mg, 0.943 mmol) under an argon atmosphere, and the mixture was heated under reflux for 5 hours. After cooling the reaction solution to room temperature, it was purified by column chromatography (eluent: n-hexane-ethyl acetate = 3:1) using silica gel (Fuji Silysia Chemical, silica gel PSQ60B) to remove some by-products. oxazolidine-2,4-dithione (tan solid, 116 mg) containing

Piperidine (9.4 μL, 0.0943 mmol) was added to a toluene (4 mL) solution of oxazolidine-2,4-dithione (116 mg) and 3-fluorobenzaldehyde (100 μL, 0.943 mmol) at room temperature under an argon atmosphere for 2 hours. Heated to reflux. After cooling the reaction solution to room temperature, acetic acid (1 mL) and water (30 mL) were added, and the mixture was extracted with chloroform (50 mL×3). The organic layer was dried over anhydrous magnesium sulfate, filtered with filter paper, and the filtrate was concentrated under reduced pressure to obtain a solid crude product (223 mg). The solid was purified by column chromatography (eluent: chloroform-ethyl acetate = 20:1) using silica gel (Fuji Silysia Chemical, silica gel PSQ60B) and recrystallization (chloroform-n-hexane) to obtain the compound of Example 12. (orange solid, 101 mg, 37% two-step yield). A ¹ H-NMR spectrum chart of the compound of Example 12 is shown in FIG.

Compound of Example 13: Synthesis of (Z)-5-(3,5-difluorobenzylidene)oxazolidine-2,4-dithione 2-Thioxoxazolidin-4-one (107 mg, 0.912 mmol) in toluene (3.8 mL) ), Lawesson's reagent (369 mg, 0.912 mmol) was added to the solution under an argon atmosphere, and the solution was heated under reflux for 5 hours. After cooling the reaction solution to room temperature, it was purified by column chromatography (eluent: n-hexane-ethyl acetate = 3:1) using silica gel (Fuji Silysia Chemical, silica gel PSQ60B) to remove some by-products. oxazolidine-2,4-dithione (orange solid, 142 mg) containing

Piperidine (9.1 μL, 0.0912 mmol) was added to a solution of oxazolidine-2,4-dithione (142 mg) and 3,5-difluorobenzaldehyde (100 μL, 0.912 mmol) in toluene (3.8 mL) at room temperature under an argon atmosphere. Heated to reflux for 2 hours. After cooling the reaction solution to room temperature, acetic acid (1 mL) and water (30 mL) were added, and the mixture was extracted with chloroform (50 mL×3). The organic layer was dried over anhydrous magnesium sulfate, filtered with filter paper, and the filtrate was concentrated under reduced pressure to obtain a solid crude product (224 mg). The solid was purified by column chromatography (eluent: chloroform-ethyl acetate = 20:1) using silica gel (Fuji Silysia Chemical, silica gel PSQ60B) and recrystallization (chloroform-n-hexane) to obtain the compound of Example 13. (orange solid, 109 mg, 46% two-step yield). A ¹ H-NMR spectrum chart of the compound of Example 13 is shown in FIG.

Test Example 1 PIM2-expressing human multiple myeloma cell lines (RPMI 8226, KMS11, MM.1S, INA-6) were placed in a 3.5 cm dish at 4 × 10 ⁵ cells/well. Seeded at density and incubated overnight at 37°C in a 5% carbon dioxide atmosphere. Separately, the compounds of Examples and Comparative Examples were dissolved in dimethyl sulfoxide and added to each well so that the final concentration of the compound was the indicated concentration (unit: μM).

Then, after culturing at 37°C for 24 hours in a 5% carbon dioxide atmosphere, the cells were harvested, a cell extract was prepared using RIPA buffer, electrophoresed by SDS-PAGE, and transferred to a PVDF membrane using a semi-dry transfer device. transcribed to.

<Antibody treatment>
Primary antibody: Anti-PIM2 #4730 Lot: 4 [CST]
Anti-β-actin A5441 Lot: 127M4866V [Sigma Aldrich]
Secondary antibody: Anti-rabbit IgG #7074 Lot: 28 [CST]
Anti-mouse IgG #7076 Lot: 34 [CST]

<Detection conditions>
Detection reagent: ECL Plus
Detection strength: Standard
Exposure time: 10 seconds Gel concentration: 4-20% gradient Protein amount: 25 μg/lane

The results are shown in Figures 14A to 14D. As is clear from FIGS. 14A to 14D, the compounds of Examples can significantly inhibit the expression of PIM2 protein compared to the compounds of Comparative Examples.

Test Example 2 Phosphorylated 4E-BP1 (P4E-BP1) Expression in Human Multiple Myeloma Cell Line RPMI 8226 Human multiple myeloma cell line RPMI 8226 was placed in a 3.5 cm dish at a density of 4 × 10 ⁵ cells/well. Inoculated and incubated overnight at 37°C in a 5% carbon dioxide atmosphere. Separately, the compounds of Examples and Comparative Examples were dissolved in dimethyl sulfoxide and added to each well so that the final concentration of the compound was the indicated concentration (unit: μM).

<Antibody treatment>
Primary antibody: Anti-P4E-BP1 #9451 Lot: 14 [CST]
Anti-4E-BP1 #9452 Lot: 10 [CST]
Anti-β-actin A5441 Lot: 127M4866V [Sigma Aldrich]
Secondary antibody: Anti-rabbit IgG #7074 Lot: 28 [CST]
Anti-mouse IgG #7076 Lot: 34 [CST]

The results are shown in Fig. 15. As is clear from FIG. 15, the compounds of Examples can remarkably suppress the phosphorylation of 4E-BP1 compared to the compounds of Comparative Examples.

Test Example 3 Anticancer activity against various human multiple myeloma cell lines Various human multiple myeloma cell lines (U266-B1, RPMI 8226) were seeded in a 96-well plate at a density of ² x 104 cells/well. , incubated overnight at 37°C in a 5% carbon dioxide atmosphere. Separately, the compounds of Examples and Comparative Examples were dissolved in dimethylsulfoxide and added to each well so that the final concentrations of the compounds were 1 μM, 10 μM and 20 μM.

Then, after culturing at 37°C for 24 hours in a 5% carbon dioxide atmosphere, an orange dye ( Formazan) absorbance (420 nm) was measured.

The results are shown in Figures 16A and 16B. As is clear from FIGS. 16A and 16B, the compounds of Examples are also superior to the compounds of Comparative Examples in terms of cell-killing action.

Test Example 4 Expression of apoptotic pathways and anti-apoptotic factors in various human multiple myeloma cell lines Various human multiple myeloma cell lines (INA-6, RPMI 8226) were placed in a 3.5 cm dish at 4 × 10 ⁵ cells/well. Seeded at density and incubated overnight at 37°C in a 5% carbon dioxide atmosphere. Separately, the compounds of Examples and Comparative Examples were dissolved in dimethylsulfoxide and added to each well so that the final concentrations of the compounds were 5 μM and 10 μM.

<Antibody treatment>
Primary antibody: Anti-PIM2 #4730 Lot: 4 [CST]
Anti-P4E-BP1 #9451 Lot: 14 [CST]
Anti-c-myc #5605 Lot: 15 [CST]
Anti-Sp1 #5931 Lot: 3 [CST]
Anti-caspase-3 #9662 Lot: 18 [CST]
Anti-caspase-8 #9746 Lot: 18 [CST]
Anti-β-actin A5441 Lot: 127M4866V [Sigma Aldrich]
Secondary antibody: Anti-rabbit IgG #7074 Lot: 28 [CST]
Anti-mouse IgG #7076 Lot: 34 [CST]

The results are shown in Figures 17A and 17B. As is clear from FIGS. 17A and 17B, the compounds of Examples are also superior to the compounds of Comparative Examples in terms of their ability to inhibit active apoptotic signals.

Test Example 5 Osteoblast Differentiation Promoting Activity Mouse osteoprogenitor cell line MC3T3-E1 was seeded in a 24-well plate at a density of 10 ⁵ cells/well, and recombinant human BMP-2 (25 ng/ml), β-glycerophosphate ( 10 mM) and ascorbic acid (50 mg/ml), the compounds of Examples and Comparative Examples were added to a final concentration of 5 μM, and cultured at 37° C. for 21 days in a 5% carbon dioxide atmosphere. . The medium was exchanged twice a week. After culturing, alkaline phosphatase staining was performed, and the stained area per well was quantified using ImageJ.

The results are shown in Fig. 18. As is clear from FIG. 18, the compounds of Examples have the same osteoblast differentiation-promoting activity as the compounds of Comparative Examples.

Test Example 6 Mouse myeloma cell line 5TGM-1, which constitutively expresses anticancer activity luciferase in a mouse model , was transplanted into the bone marrow of the right tibia of a ⁶ -week-old female ICR mouse, and engraftment was confirmed 3 days later. Thereafter, mice were intraperitoneally administered every other day to a final concentration of 20 mg/kg of the compound of the example. After 20 days of administration, luciferin was intraperitoneally administered and detected by the IVIS imaging system in order to observe the proliferation of tumor cells in the body. For the compound of Example 7, the same experiment as above was repeated except that the final concentration was changed to 10 mg/kg and the administration period was changed to 21 days, and the proliferation of tumor cells in the body was observed.

The results are shown in Figures 19A and 19B. As is clear from FIGS. 19A and 19B, the compounds of Examples have excellent anticancer activity in the 5TGM-1-implanted mouse model.

Test Example 7 Anticancer activity against various human adult T-cell leukemia cell lines Various human adult T-cell leukemia cell lines (KK1, Su9T01) were seeded in a 6-well plate at a density of 4 × 10 ⁵ cells/well, and 5% Incubate overnight at 37°C in a carbon dioxide atmosphere. Separately, the compounds of Examples and Comparative Examples were dissolved in dimethylsulfoxide and added to each well so that the final concentrations of the compounds were 1.25 μM, 2.5 μM, 5 μM and 10 μM.

Then, after culturing at 37°C for 24 hours in a 5% carbon dioxide atmosphere, detection was performed by flow cytometry using an Annexin V/propidium iodide double staining reagent (MEBCYTO (trademark) Apoptosis Kit manufactured by MBL).

The results are shown in Figures 20A and 20B. As is clear from FIGS. 20A and 20B, the compounds of Examples have excellent anticancer activity against various human adult T-cell leukemia cell lines.

Test Example 8 Minimum inhibitory concentration (MIC) against Candida albicans CAD1 strain The minimum inhibitory concentration (MIC) was measured by the broth microdilution method. After preparing serial dilutions of the drug using RPMI1640/MOPS (pH 7.0) medium, about 2×10 ³ CFU/ml of bacterial solution was inoculated and cultured at 35° C. for 24 hours. After culturing, turbidity was used to determine the minimum concentration MIC (μg/ml) at which growth was inhibited by 50% or more of the control.

Table 1 shows the results.

Test Example 9 The compounds of Examples 3, 9, and 11 to 13 were added to the Candida albicans CAD1 strain adjusted to a concentration of 10 ⁶ CFU/ml in a Sabouraud medium with bactericidal activity against the Candida albicans CAD1 strain, at 10 μg/ml and 25 μg/ml. ml, and 50 µg/ml, and cultured at 37°C. Immediately before addition of the compound and 2, 4, and 6 hours after the addition of the compound, the bacterial solution was inoculated on an agar medium, cultured at 37°C for 24 hours, and the viable cell count was measured. The survival rate at each time was calculated with the number of viable cells immediately before the addition of the compound as 100%.

The results are shown in Fig. 21. As can be seen from Figure 21, the compounds of Examples 3, 9, and 11-13 are able to reduce viability, particularly at 50 µg/ml or 25 µg/ml with a viability of 0.1% after about 2 hours. It has excellent bactericidal action.

Test Example 10 Minimum Inhibitory Concentration (MIC) against Asperugillus and Rizopus The minimum inhibitory concentration (MIC) was determined by the broth microdilution method. After preparing serial dilutions of the drug using RPMI1640/MOPS (pH 7.0) medium, they were inoculated with a bacterial solution of about 1×10 ⁴ conidia/ml and cultured at 35° C. for 72 and 24 hours. After culturing, turbidity was used to determine the minimum concentration MIC (μg/ml) at which growth was inhibited by 50% or more of the control.

Table 2 shows the results.

Claims

Formula (1) below:

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X 11 to X 13 are each independently an oxygen atom or a sulfur atom, and at least one of X 12 and X 13 is a sulfur atom)
PIM2 inhibitor containing a compound represented by or a salt thereof.
2. The PIM2 inhibitor of claim 1, wherein X11 is a sulfur atom.
3. The PIM2 inhibitor according to claim 1 or 2, wherein X13 is a sulfur atom.
A PIM2 inhibitor according to any one of claims 1 to 3, wherein X 12 and X 13 are sulfur atoms.
A is the following formula (2):

(In the formula,
R 11 to R 15 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , or R 14 and R 15 form a ring together with the carbon atoms of the benzene ring to which they are attached)
PIM2 inhibitor according to any one of claims 1 to 4, which is a group represented by
6. The PIM2 inhibitor of Claim 5, wherein R12 is a haloalkyl group.
A pharmaceutical composition for preventing or treating multiple myeloma,
Formula (1) below:

(In the formula,
A is a benzene ring optionally having one or more substituents, and when the benzene ring has two substituents located at the ortho position to each other, the two substituents are may form a ring together with the carbon atoms of the benzene ring to which it is attached,
X 11 to X 13 are each independently an oxygen atom or a sulfur atom, and at least one of X 12 and X 13 is a sulfur atom)
A pharmaceutical composition containing a compound represented by or a pharmaceutically acceptable salt thereof.
8. The pharmaceutical composition according to claim 7 , wherein X11 is a sulfur atom.
9. The pharmaceutical composition according to claim 7 or 8, wherein X13 is a sulfur atom.
The pharmaceutical composition according to any one of claims 7-9, wherein X 12 and X 13 are sulfur atoms.
A is the following formula (2):

(In the formula,
R 11 to R 15 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , or R 14 and R 15 form a ring together with the carbon atoms of the benzene ring to which they are attached)
The pharmaceutical composition according to any one of claims 7 to 10, which is a group represented by
12. The pharmaceutical composition according to Claim 11, wherein R12 is a haloalkyl group.
The pharmaceutical composition according to any one of claims 7 to 12, which is a pharmaceutical composition for preventing or treating a disease selected from the group consisting of hypercalcemia, renal failure, anemia, and bone lesions.
Formulas (1B) to (1E) below:

(In the formula,
R2 is a hydroxyl group, an alkyl group, or a haloalkyl group;
n is an integer from 1 to 5,
R3 is an alkyl group or a haloalkyl group ,
R4 is a halogen atom or a haloalkyl group,
m is an integer from 1 to 5,
R5 is a hydroxyl group, an alkyl group, a haloalkyl group, or an alkoxy group;
p is an integer from 0 to 5)
A compound or a salt thereof represented by any one of