JPWO2016039398A1 - Nitrogen-containing heterocyclic derivatives, neuroprotective agents, and pharmaceutical compositions for cancer treatment - Google Patents

Abstract

It is an object of the present invention to provide a medicament for preventing and / or treating a nervous system disease with respect to a neuroprotective agent. By using a compound having a 2-aminobenzamide structure having a substituent at the para position of the amino group and a dioxopiperazine structure, it is possible to protect nervous system cells and suppress cell death of nervous system cells. To solve.

Description

  The present invention relates to a nitrogen-containing heterocyclic derivative that suppresses both abnormal cell proliferation and induction of cell death by stopping the cell cycle and making it quiescent without inducing cell death. Moreover, this invention provides the pharmaceutical composition used for the treatment and / or prevention of the cancer containing these, and a cell growth inhibitor. Furthermore, this invention relates to the neuroprotective agent containing the said compound, and provides the pharmaceutical for the prevention and / or treatment of a nervous system disease.

  Histone deacetylase (hereinafter also referred to as HDAC) has a pocket for substrate docking, but in most cases it has divalent zinc at the bottom. Hydroxamic acid type and 2-aminobenzamide type HDAC inhibitors are compounds that bind to this pocket and form a chelate with zinc to inhibit HDAC. Recently, it has been reported that an HDAC inhibitor introduced with a phenyl group or a thienyl group at the para position of the amino group of the latter 2-aminobenzamide group selectively strongly suppresses HDAC1 and HDAC2, which are deeply involved in anticancer activity. (Non-Patent Document 1). This type of compound is presumed to have improved selectivity for HDAC1 and HDAC2 because the phenyl group or thienyl group at the para position of the amino group of the 2-aminobenzamide group fits into the internal cavity adjacent to the aforementioned pocket. ing. At present, with regard to the same type of HDAC inhibitor, drug discovery research aimed at anticancer agents has been energetically performed, and many compounds have been studied mainly with thienyl group-substituted products (Patent Documents 1 to 5). .

  The above compound group showed a tumor shrinking effect in an anti-tumor effect test using cancer-bearing mice, but side effects such as weight loss and death occurred at a relatively low dose, so the therapeutic range was narrow. (Non-Patent Document 2). Moreover, biaryl 2-aminobenzamide type HDAC inhibitors into which amino acids such as phenylglycine and phenylalanine were introduced instead of thienyl groups were synthesized, and an antitumor effect test by intraperitoneal administration was performed (Non-patent Document 3). Furthermore, a biaryl 2-aminobenzamide type HDAC inhibitor into which a phosphate ester derivative was introduced was also synthesized (Non-patent Document 4). In addition, the inventors synthesized a plurality of 2-aminobenzamide type HDAC inhibitors and reported on the HDAC isoform inhibitory action (Non-patent Document 5). It has been reported in the literature that MS-275 broadly inhibits class I HDACs (HDAC1, HDAC2 and HDAC3), and compounds 2, 8b, etc. selectively inhibit HDAC1 and HDAC2 without inhibiting HDAC3.

  On the other hand, activation of cell cycle proteins such as pRb / E2F has been reported to cause cell death in animal models and Parkinson's disease patients (Non-patent Documents 6 and 7). It has been suggested that cell death is suppressed by inhibiting the activation of and inhibiting the cell cycle.

  In the brain, HDAC1 and HDAC2 are particularly abundant among histone deacetylase (hereinafter also referred to as HDAC) class I, and inhibition of HDAC1 promotes survival of neurons (Non-patent Documents 8 and 9). In addition, it has been reported that inhibition of HDAC2 improves memory function in neurodegenerative diseases (Non-patent Document 10). In the central nervous system, not only pan-HDAC inhibitors such as trichostatin A (TSA) and Valproic acid, but also MS-275 has been reported to have neuroprotective effects in brain trauma models and the like (Non-Patent Document 11, 12, 13).

    Patent Document 6 describes a 2-aminobenzamide type HDAC inhibitor, but there is no specific description of a neuroprotective action.

International Publication No. 2005/030704 A1 International Publication No. 2005/030705 A1 International Publication No. 2007/118137 A1 International Publication No. 2008/010985 A2 International Publication No. 2009/002495 A1 Japanese National Patent Publication No. 2010-531359

O. M. Moradei, et al., J. Med. Chem. 50 (2007) 5543-5546 J. L. Methot, et al., Bioorg. Med. Chem. Lett. 18 (2008) 973-978 K. J. Wilson, et al., Bioorg. Med. Chem. Lett. 18 (2008) 1859-1863 R. W. Heidebrecht, et al., Bioorg. Med. Chem. Lett. 19 (2009) 2053-2058 Hirata Y et al. Bioorganic & Medicinal Chemistry Letters 22 (2012) 1926-1930 Hoglinger GU et.al.Proc Natl Acad Sci U S A. 2007 Feb 27; 104 (9): 3585-90 Folch J.et.al.Neurotox Res. 2012 Oct; 22 (3): 195-207 Kim D et al. Neuron. 2008 Dec 10; 60 (5): 803-17 Bardai FH et al. J Biol Chem. 2012 Oct 12; 287 (42): 35444-53 Graff J et al. Nature. 2012 Feb 29; 483 (7388): 222-6 Simonini MV et al. Proc Natl Acad Sci U S A. 2006 Jan 31; 103 (5): 1587-92 Murphy SP et al. J Neurochem. 2013 Oct 21.doi: 10.1111 / jnc.12498. Summers AR et al. J Clin Invest. 2013 Jul 1; 123 (7): 3112-23

  As described above, compounds having a 2-aminobenzamide group having no substituent and 2-aminobenzamide type compounds having a substituent of an aryl group such as a thienyl group at the para position of the amino group have been reported. . However, a compound having a 2-aminobenzamide group that does not have a substituent is highly toxic because of its low selectivity and inhibitory activity against HDAC1, 2, 3 and 8 classified as HDAC Class I. It was thought that there was a problem in the application of drugs such as anticancer drugs. Until now, HDAC inhibitors introduced with aryl groups such as thienyl groups are compounds that selectively inhibit HDAC1 and 2, but few have satisfactory antitumor effects.

  One reason for not being able to obtain satisfactory results is that the introduction of an aryl group deteriorates the physical properties such as water solubility and decreases the bioavailability.

  An object of the present invention is to provide a nitrogen-containing heterocyclic derivative having improved physical properties such as water solubility, or a pharmacologically acceptable salt thereof.

  Furthermore, activation of cancer cell-related apoptosis-related proteins under the treatment of radiation and chemotherapeutic agents leads to cancer recurrence and exacerbation, and these therapeutic effects are reduced. Therefore, the object of the present invention is to stop the cell cycle of cancer cells and suppress cell proliferation, but not induce cell death, a pharmaceutical composition for cancer treatment and / or prevention, And providing a cell growth inhibitor and the like.

  Further, as described above, although there is a report that an HDAC inhibitor exhibits a neuroprotective action, a substance having an HDAC inhibitory effect does not necessarily have a neuroprotective action. Furthermore, TSA is a pan-HDAC inhibitor and Valproic acid is an agent that inhibits both HDAC class I and HDAC class IIa. MS-275 also acts on HDACs 1, 2 and 3. That is, these compounds are considered to act on cells other than the nervous system, and there is a concern that MS-275 is particularly toxic to hematopoietic stem cells and the like. An object of the present invention is to provide a safe neuroprotective agent that can be used without showing side effects even in nervous system diseases in which a drug needs to be continuously administered over a long period of time, particularly in central nervous system diseases.

  In the above document, thienyl substituted 2-aminobenzamide type HDAC inhibitors having any heterocycle such as piperidine, piperazine, morpholine, etc. are described. However, like dioxopiperazine, a heterocycle having a carbonyl group is described. There is nothing to have.

  As a result of intensive studies, the present inventors have obtained a 2-aminobenzamide structure having a substituent such as an aryl group and a halogen group at the para position of the amino group, with a water-soluble functional group of piperacillin, which is a penum antibiotic. By introducing a certain dioxopiperazine group and other heterocycles containing two carbonyl groups, improvement in physical properties such as water solubility and improvement of antitumor effect can be achieved, and compounds having these groups Found that it stopped the cell cycle of cancer cells and suppressed cell growth, but did not induce cell death. Furthermore, they have found that these compounds have anticancer activity but low toxicity and few side effects.

  Furthermore, a compound having a 2-aminobenzamide structure having a substituent at the para position of the amino group highly specific to HDAC1 and 2 and a dioxopiperazine structure exhibits a protective effect on nervous system cells, Newly found to suppress cell death.

  The present invention has been completed based on such findings, and includes the following aspects.

  Item 1. A neuroprotective agent comprising a compound represented by the following general formula (A) or a pharmaceutically acceptable salt thereof:

{Where
R ′ represents a thienyl group, a furanyl group, a phenyl group, or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (A-2):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² is combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. May be formed];
R ^x is an optionally substituted alkyl group having 1 to 6 carbon atoms, or a hydrogen atom;
n is an integer from 1 to 4;
V is -CO-NH- or a direct bond;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}.
Item 2. Item 2. The neuroprotective agent according to Item 1, wherein R ^a is a carbonyl group, and R ^c is a group represented by the general formula (A-2).
Item 3. Item 3. The neuroprotective agent according to Item 1 or 2, wherein n is 1.
Item 4. Item 4. The neuroprotective agent according to any one of Items 1 to 3, wherein R ′ is a thienyl group, a furanyl group, a phenyl group, or a chlorine atom.
Item 5. The neuroprotective agent according to Item 1, comprising a compound represented by the following general formula (IV), or a pharmacologically acceptable salt thereof:

(In the formula, R ′ is a thienyl group, a furanyl group, a phenyl group, or a chlorine atom.)
Item 6. The neuroprotective agent according to Item 1, comprising a compound represented by any one of the following formulas (1), (18), (2) and (5), or a pharmacologically acceptable salt thereof:

Item 7. Item 7. The neuroprotective agent according to any one of Items 1 to 6, which is used for prevention or treatment of nervous system diseases.
Item 8. Item 8. The neuroprotective agent according to Item 7, wherein the nervous system disease is a neurodegenerative disease.
Item 9. Neurodegenerative diseases are Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's dementia, cerebrovascular dementia, polyglutamine disease, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuritis, Or the neuroprotective agent of claim | item 8 which is multifocal motor neuropathy.
Item 10. Item 8. The neuroprotective agent according to Item 7, wherein the nervous system disease is ischemic brain disease.
Item 11. A compound represented by the following general formula (A), or a pharmaceutically acceptable salt thereof:

{Where
V is -CO-NH- or a direct bond;
When V is —CO—NH—, R ′ represents a furanyl group, a phenyl group, or a halogen atom;
When V is a direct bond, R ′ is a thienyl group, a furanyl group, a phenyl group, or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (A-2):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² is combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. May be formed];
R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}.
Item 12. Item 12. The compound according to Item 11, or a pharmacologically acceptable salt thereof, wherein R ^a is a carbonyl group and R ^c is a group represented by the general formula (A-2).
Item 13. Item 13. The compound according to Item 11 or 12, wherein n is 1, or a pharmaceutically acceptable salt thereof.
Item 14. Item 11. The compound according to Item 11, represented by the following formula (IV), or a pharmaceutically acceptable salt thereof:

(In the formula, R ′ is a furanyl group or a phenyl group.)
Item 15. Item 11. The compound according to Item 11, which is represented by any one of the following formulas (2), (5), (4), (3), (18), (20) and (19), or a pharmacologically acceptable salt thereof Made salt:

Item 16. Item 16. A pharmaceutical composition used for the treatment and / or prevention of cancer, comprising the compound according to any one of Items 11 to 15 or a pharmaceutically acceptable salt thereof.

  According to the present invention, it is possible to provide a nitrogen-containing heterocyclic derivative that suppresses both abnormal cell proliferation and induction of cell death by stopping the cell cycle and making it quiescent without inducing cell death. Moreover, according to this invention, the pharmaceutical composition used for the treatment and / or prevention of the cancer containing the said nitrogen-containing heterocyclic derivative can be provided, and a cell growth inhibitor. Furthermore, according to this invention, the neuroprotective agent containing the said nitrogen-containing heterocyclic derivative can be provided, and the pharmaceutical for the prevention and / or treatment of a nervous system disease can be provided.

The synthesis scheme of K-852, K-854, K-855, K-856 is shown. The synthesis scheme of K-562, K-563, and K-564 is shown. (a) (Boc) ₂ O, triethylamine (Et ₃ N), and THF are reacted overnight at room temperature (b) Pd (PPh ₃ ) ₄ , 2-thiopheneboronic acid, potassium carbonate , Tetrakis (triphenylphosphine) palladium and DME / H ₂ O in the presence of 18 hours at 80 ° C. (c) The reaction was carried out at room temperature in the presence of triethylamine and THF for 4 hours. (d) shows that the reaction was carried out overnight at 50 ° C. in the presence of potassium phthalimide, potassium iodide and DMF. (e) Recirculation in the presence of hydrazine and ethanol for 3 hours. (f) The reaction was carried out overnight at room temperature in the presence of triethylamine and sometimes chloromethane. (g) The reaction was carried out in the presence of THA / dichloromethane at room temperature for 1 hour. The structural formulas of K-560, Merck compound, Ethyl compound and MS-275 are shown. A cell cycle histogram is shown when a colorectal cancer cell line (HCT116 cell) is exposed to K-852, K-853, K-854, K-856 or MS-275, which is a compound of the present invention, for 48 hours. The vertical axis represents the number of cells, and the horizontal axis represents the amount of DNA. A cell cycle histogram is shown when a breast cancer cell line (SKBR3 cell) is exposed to K-852, K-853, K-854, K-856 or MS-275, which is a compound of the present invention, for 24 hours. The vertical axis represents the number of cells, and the horizontal axis represents the amount of DNA. Shows a cell cycle histogram when a neuroblastoma cell line (Neuro2a cell) is exposed to the compounds of the present invention K-852, K-853, K-854, K-856 or MS-275 for 48 hours. . The vertical axis represents the number of cells, and the horizontal axis represents the amount of DNA. N- (2-amino-5- (furan-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide and N- (2-amino- Synthesis examples of 5- (benzene-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide are shown. Synthesis of N-((6- (2-1amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-3-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide An example is shown. The neuronal cell protective effect of K-560 against cerebral ischemia was evaluated by the ratio of dead cells. A shows the percentage of dead cells 24 hours after OGD (hypoxic glucose-free) challenge. B shows the percentage of dead cells 72 hours after OGD loading. DMSO represents a negative control. The vertical axis represents the ratio (%) of dead cells. The result of having evaluated the neuron protective effect with respect to the cerebral ischemia of K-852 or K-853 by the ratio of the dead cell is shown. DMSO represents a negative control. The vertical axis represents the ratio (%) of dead cells. Figure 2 shows the effect of various HDAC inhibitors on excitotoxin (kainic acid). The vertical axis represents the ratio (%) of dead cells. The result of having confirmed that K-560 showed the neuron protective effect in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration Parkinson's disease animal model is shown. A shows an immunostaining image of substantia nigra TH (tyrosine hydroxylase) (NS group: physiological saline administration only, KS group: K-560 administration only, NM group: MPTP and physiological saline administration, KM group: MPTP and K-560 administration). B shows the graph which counted the substantia nigra TH positive cell 2 days after MPTP administration. C shows a graph in which substantia nigra TH positive cells 21 days after MPTP administration were counted. The vertical axis represents the percentage (%) of TH staining positive cells. The result of having confirmed that K-852 showed the neuron protective effect in an in vitro Parkinson experimental model is shown. DMSO represents a negative control. The vertical axis represents the ratio (%) of dead cells. The result of having confirmed the toxicity and neuroprotective action of an Ethyl compound is shown. The vertical axis represents the ratio (%) of dead cells. The result of the cytotoxicity test of MS-275, K-560, and K-852 is shown. A shows the results when each test drug was added at a final concentration of 3 μM. B shows the results when each test drug was added at a final concentration of 10 μM. The vertical axis represents the ratio (%) of dead cells. The result of having evaluated the nerve cell protective effect with respect to the cerebral ischemia of K-852, K-853, and K-854 was evaluated by the ratio of the dead cell. The star in the graph indicates p <0.05. The result of having evaluated the nerve cell protective effect with respect to the cerebral ischemia of the nerve cell protective action of K-562, K-563, K-564, K-560, and K-856 by the ratio of the dead cell is shown. A in the figure is the result when the 24-hour OGD load is performed, and B in the figure is the result when the 48-hour OGD load is performed. The star in the graph indicates p <0.05. Example 22: shows the results of confirming that K-562, K-563, K-564, K-560, and K-856 have neuronal protective effects in an in vtro Parkinson's disease experimental model. The star in the graph indicates p <0.05.

1. Nitrogen-containing heterocyclic derivative The nitrogen-containing heterocyclic derivative of the present invention is a compound represented by the following general formula (A):

{Where
R ′ is a thienyl group, furanyl group, phenyl group, or halogen atom (however, when V is —CO—NH—, R ′ is preferably a furanyl group, a phenyl group, or a halogen atom);
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (A-2):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² forms a saturated ring having 3 to 6 carbon atoms together with R ^x. Good];
R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
V is a direct bond or -CO-NH-;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}.

  R ′ is preferably a thienyl group, a furanyl group, a phenyl group, or a chlorine atom, more preferably a thienyl group or a furanyl group, and still more preferably a thienyl group.

R ^a , R ^b , R ^c , and R ^d are preferably two of R ^a , R ^b , R ^c , and R ^d , and the other two are the same or different and have the above general formula. And R ^a and R ^c are not simultaneously a carbonyl group; more preferably, R ^a is a carbonyl group, and R ^c is the above general formula (A-2). Most preferably, R ^a and R ^b are carbonyl groups.

R ¹ and R ² are preferably a hydrogen atom at the same time; an alkyl group having 1 to 4 carbon atoms at the same time (preferably an alkyl group having 1 to 4 carbon atoms in this case is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group or an isobutyl group, more preferably a methyl group, an ethyl group or a propyl group, and most preferably a methyl group or an ethyl group); or one of which is a hydrogen atom and the other of which has 1 to 4 carbon atoms An alkyl group, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably methyl) Group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group or tert-butyl group, more preferably An aryl group, preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; Group, cyclohexyl group, and tetrahydropyranyl group, preferably a halogen atom of any one of chlorine atom and fluorine atom, methyl group, ethyl group, propyl group, isopropyl group, or hydroxyl group, more preferably A chlorine atom, a fluorine atom, a methyl group or an ethyl group, most preferably a chlorine atom, a fluorine atom or a methyl group).

R ^a, as one embodiment of the time ^R b, are any two of ^{R c,} and ^{R d} is a group represented by the general formula (A-2) is a group represented by the general formula (A-2) Are the same and both R ¹ and R ² are preferably hydrogen atoms.

In another embodiment, when any two of R ^a , R ^b , R ^c , and R ^d are different and are groups represented by the general formula (A-2), one of the general formulas (A- 2) In the group represented by 2), both R ¹ and R ² are hydrogen atoms, and the other is different from the other group represented by the above general formula (A-2) [in this case, R ¹ and R ² are preferably , Both are methyl groups; or ^one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or An optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, or tert -Butyl group etc. and more A methyl group, an ethyl group or a propyl group is preferred, a methyl group or an ethyl group is most preferred; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, and more preferably a phenyl group. A preferable substituent for an aryl group, a cyclohexyl group and a tetrahydropyranyl group is a halogen atom of any one of a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a hydroxyl group, more preferably Is preferably a chlorine atom, a fluorine atom, a methyl group or an ethyl group, most preferably a chlorine atom, a fluorine atom or a methyl group)].

When R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² may be combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. As a saturated 3-membered ring, a saturated 4-membered ring, or a saturated 5-membered ring, and more preferably a saturated 5-membered ring.

R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group, more preferably Linear type. The linear alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, more preferably a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group. Or it is an ethyl group. The branched alkyl group is preferably an isopropyl group, sec-butyl group, isobutyl group, tert-butyl group, isopentyl group, neopentyl group, isohexyl group, or biisopropyl group. An isopropyl group, a sec-butyl group, an isobutyl group, or an isopentyl group is more preferable, and an isopropyl group is more preferable. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

n is any integer of 1 to 4, more preferably 1 or 2, and most preferably 1.
V is a direct bond or —CO—NH—;
W, X, Y, and Z are preferably all of W, X, Y, and Z are CH, or any one or two of W, X, Y, and Z are nitrogen atoms; more preferably Are all W, X, Y, and Z are CH, or any one of W, X, Y, and Z is a nitrogen atom; most preferably all of W, X, Y, and Z are CH.

(1) -1. Compound represented by the above general formula (A) in which V is directly coupled Among the compounds represented by the above general formula (A), a compound in which V is directly coupled is represented by the following general formula (I). A compound.

{Where
R ′ represents a thienyl group, a furanyl group, a phenyl group or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (II):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (II), R ¹ or R ² is combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. Good];
R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}
It is.

  R ′ is preferably a thienyl group, a furanyl group, a phenyl group, or a chlorine atom, more preferably a thienyl group or a furanyl group, and still more preferably a thienyl group.

R ^a , R ^b , R ^c , and R ^d are preferably two of R ^a , R ^b , R ^c , and R ^d , and the other two are the same or different and have the above general formula. And R ^a and R ^c are not simultaneously a carbonyl group; more preferably, R ^a is a carbonyl group and R ^c is represented by the above general formula (II). Most preferably, R ^a and R ^b are carbonyl groups.

R ¹ and R ² are preferably a hydrogen atom at the same time; an alkyl group having 1 to 4 carbon atoms at the same time (preferably an alkyl group having 1 to 4 carbon atoms in this case is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group or an isobutyl group, more preferably a methyl group, an ethyl group or a propyl group, and most preferably a methyl group or an ethyl group); or one of which is a hydrogen atom and the other of which has 1 to 4 carbon atoms An alkyl group, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably methyl) Group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group or tert-butyl group, more preferably An aryl group, preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; Group, cyclohexyl group, and tetrahydropyranyl group, preferably a halogen atom of any one of chlorine atom and fluorine atom, methyl group, ethyl group, propyl group, isopropyl group, or hydroxyl group, more preferably A chlorine atom, a fluorine atom, a methyl group or an ethyl group, most preferably a chlorine atom, a fluorine atom or a methyl group).

As one aspect when any two of R ^a , R ^b , R ^c , and R ^d are groups represented by the general formula (II), two of the groups represented by the general formula (II) are the same It is preferable that both R ¹ and R ² are hydrogen atoms.

As another embodiment, when any two of R ^a , R ^b , R ^c , and R ^d are different and are groups represented by the above general formula (II), one of the above general formulas (II) R ¹ and R ² of the group to be represented are both hydrogen atoms, and the other is different from the other group represented by the above general formula (II) [in this case, R ¹ and R ² are preferably both methyl groups; Alternatively, ^one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. A tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group). More preferred Or a methyl group, an ethyl group or a propyl group, most preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group. A preferable substituent for an aryl group, a cyclohexyl group and a tetrahydropyranyl group is a halogen atom of any one of a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a hydroxyl group, more preferably Is preferably a chlorine atom, a fluorine atom, a methyl group or an ethyl group, most preferably a chlorine atom, a fluorine atom or a methyl group)].

When R ^b or R ^d is a group represented by the above formula (II), R ¹ or R ² may be combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. Is a saturated 3-membered ring, a saturated 4-membered ring, or a saturated 5-membered ring, more preferably a saturated 5-membered ring.

R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group, more preferably Linear type. The linear alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, more preferably a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group. Or it is an ethyl group. The branched alkyl group is preferably an isopropyl group, sec-butyl group, isobutyl group, tert-butyl group, isopentyl group, neopentyl group, isohexyl group, or biisopropyl group. An isopropyl group, a sec-butyl group, an isobutyl group, or an isopentyl group is more preferable, and an isopropyl group is more preferable. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is any integer of 1 to 4, more preferably 1 or 2, and most preferably 1.

  W, X, Y, and Z are preferably all of W, X, Y, and Z are CH, or any one or two of W, X, Y, and Z are nitrogen atoms; more preferably Are all W, X, Y, and Z are CH, or any one of W, X, Y, and Z is a nitrogen atom; most preferably all of W, X, Y, and Z are CH.

In a preferred embodiment when R of the compound represented by the general formula (I) 'is a thienyl ^group, R ^a, R b, of ^{R c,} and ^{R d R a} and ^{R b} is carbonyl group, other Are the same or different and are groups represented by the above general formula (II). In this case, R ^c is a group represented by the above general formula (II) (R ¹ and R ² are both hydrogen atoms), and R ^b which is not a carbonyl group or R ^{d which} is not a carbonyl group is the same as R ^c. Or a group represented by the above general formula (II) different from R ^c [in which R ¹ and R ² are both methyl groups; or ^one of R ¹ and R ² is a hydrogen atom and the other is carbon An alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, as an alkyl group having 1 to 4 carbon atoms) Preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, more preferably a methyl group, an ethyl group, or a propyl group, and most preferably Preferably, it is a methyl group or an ethyl group; The aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, and more preferably a phenyl group; substitution of an aryl group, a cyclohexyl group, and a tetrahydropyranyl group The group is preferably a halogen atom such as a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a hydroxyl group, more preferably a chlorine atom, a fluorine atom, a methyl group or an ethyl group, Most preferably, it is a chlorine atom, a fluorine atom or a methyl group)].

When R ^b or R ^d is a group represented by the above formula (II), R ¹ or R ² may be combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. A saturated 5-membered ring is preferred.

R ^x represents a hydrogen atom or an optionally substituted linear alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. More preferably, it is a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group or an ethyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is more preferably 1 or 2, and most preferably 1.

  W, X, Y, and Z are preferably all of W, X, Y, and Z are CH, or any one of W, X, Y, and Z is a nitrogen atom; All of W, X, Y, and Z are CH.

Furthermore, examples of the compound in which R ′ of the compound represented by the general formula (I) is a thienyl group include compounds represented by the following formulas (2) to (10):
N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2- (1H) -yl) Methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((3,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) methyl Benzamide

N- (2-amino-5 (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxo-3-phenylpiperazin-1-yl) methyl) benzamide

N- (2-amino-5 (thiophen-2-yl) phenyl) -4-((3,3,4-trimethyl-2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((3-cyclohexyl-4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxo-3- (tetrahydro-2H-pyran-4-yl) piperazine-1 -Il) methyl) benzamide

In a preferred embodiment when R of the compound represented by the general formula (I) 'is a chlorine ^atom, R ^a, R b, of ^{R c,} and ^{R d R a} and ^{R b} is carbonyl group, other Are the same or different and are groups represented by the above general formula (II). Groups represented by this case ^{R c} is the above-mentioned general formula (II) ^{(R 1} and ^{R 2} are both hydrogen atoms) and, and ^{R d} is either the same as ^{R c,} or ^{R c} is different from the general Group represented by formula (II) [in which R ¹ and R ² are both methyl groups; or ^one of R ¹ and R ² is a hydrogen atom and the other is an alkyl group having 1 to 4 carbon atoms, substituted An optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, an ethyl group, or a propyl group). Group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, etc., more preferably methyl group, ethyl group or propyl group, most preferably methyl group or ethyl group; Aryl The group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; a substituent of an aryl group, a cyclohexyl group, or a tetrahydropyranyl group is preferably a chlorine atom or a fluorine atom Any halogen atom, methyl group, ethyl group, propyl group, isopropyl group or hydroxyl group, more preferably chlorine atom, fluorine atom, methyl group or ethyl group, most preferably chlorine atom, fluorine atom or methyl group It is preferable that

R ^x represents a hydrogen atom or an optionally substituted linear alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. More preferably, it is a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group or an ethyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is more preferably 1 or 2, and most preferably 1.

  As W, X, Y, and Z, preferably all of W, X, Y, and Z are CH or any one of W, X, Y, and Z is a nitrogen atom, most preferably W, All of X, Y, and Z are CH.

Examples of the compound in which R ′ of the compound represented by the general formula (I) is a chlorine atom include compounds represented by the following formula (11).
N- (2-amino-5-chlorophenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

A preferred embodiment of the case where formula R of the compound represented by (I) 'is furanyl group or a phenyl ^group, R ^a, R b, ^{R c,} and ^{R a} and ^{R b} of ^{R d} is a carbonyl group And the rest are the same or different groups represented by the general formula (II). Groups represented by this case ^{R c} is the above-mentioned general formula (II) ^{(R 1} and ^{R 2} are both hydrogen atoms) and, and ^{R d} is either the same as ^{R c,} or ^{R c} is different from the general Group represented by formula (II) [in which R ¹ and R ² are both methyl groups; or ^one of R ¹ and R ² is a hydrogen atom and the other is an alkyl group having 1 to 4 carbon atoms, substituted An optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, an ethyl group, or a propyl group). Group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, etc., more preferably methyl group, ethyl group or propyl group, most preferably methyl group or ethyl group; Aryl The group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; a substituent of an aryl group, a cyclohexyl group, or a tetrahydropyranyl group is preferably a chlorine atom or a fluorine atom Any halogen atom, methyl group, ethyl group, propyl group, isopropyl group or hydroxyl group, more preferably chlorine atom, fluorine atom, methyl group or ethyl group, most preferably chlorine atom, fluorine atom or methyl group It is preferable that

R ^x represents a hydrogen atom or an optionally substituted linear alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. More preferably, it is a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group or an ethyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is more preferably 1 or 2, and most preferably 1.

  W, X, Y and Z are preferably all of W, X, Y and Z are CH or any one of W, X, Y and Z is a nitrogen atom, most preferably W, X , Y, and Z are all CH.

Examples of the compound in which R ′ of the compound represented by the general formula (I) is a furanyl group or a phenyl group include compounds represented by the following formula (12) or (13).
N- (2-amino-5- (furan-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (benzene-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

(1) -2. Method for Synthesizing Compound Represented by General Formula (I) The method for synthesizing the compound represented by General Formula (I) is not particularly limited, and examples thereof include the methods shown in Schemes I-1 and I-2. In Schemes I-1 and I-2, R ′, R ^a , R ^b , R ^c , R ^d , R ¹ , R ² , R ^x , n, W, X, Y, and Z are the above-mentioned 1-1 . Is the same as
(I) Step (a): Synthesis of Compound (Ib) from Compound (Ia) (Scheme I-1)
In order to protect the amino group at the para position of the bromo group of the compound (Ia) with, for example, a tert-butoxycarbonyl (hereinafter referred to as Boc) group, di-tert-dicarbonate in the presence of a base such as triethylamine and tetrahydrofuran (THF). Butyl ((Boc) ₂ O) is reacted according to a conventional method and purified to obtain compound (Ib).
(Ii) Step (b): Synthesis of Compound (Id) from Compound (Ib) (Scheme I-1) To Compound (Ib) obtained in Step (a), water, potassium carbonate, dimethyl ether, triphenylphosphine Fan (Ph ₃ P) is added, compound (Ic) is added, for example tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ) as a catalyst, for example at reflux for 18 hours, or microwave apparatus (Initiator + , biotage, etc.) at 120 ° C. for 30 minutes, bromo group of compound (Ib) and R ′ of compound (Ic) are substituted, and compound (Id) is synthesized and purified.
(Iii) Step (c): Synthesis of Compound (If) from Compound (Id) (Scheme I-1) A base such as triethylamine and THF are added to Compound (Id) obtained in Step (b), and further compound (Ie) was added, and International Publication No. 2008 / 010985A2, Bioorg. Med. Chem Lett., 18 (2008) 726-731, International Publication No. 2009 / 002495A1, and Bioorg. Med. Chem Lett., 19 ( 2009) Compound (If) is obtained according to 1168-1172.
(Iv) Step (d): Synthesis of Compound (Ih) from Compound (If) (Scheme I-2) Compound (Ig) is dissolved in, for example, dimethylformamide (DMF) or the like, and sodium hydride is added under ice-cooling. For example, for 1 to 3 hours. Compound (If) can be further synthesized by adding compound (If), for example, stirring at room temperature for 16 to 24 hours, and reacting the chloro group of compound (If) with NH of compound (Ig). Purification of the compound (Ih) from the reaction solution can be performed by adding ice to the reaction solution, followed by extraction with an organic solvent such as chloroform. The organic layer is washed with, for example, brine, and then dried over sodium sulfate. Concentrate under reduced pressure. For example, chloroform / methanol mixture (eg chloroform: methanol = 9: 1 or chloroform: methanol = 9.5: 0.5) and ethyl acetate / hexane mixture (eg ethyl acetate: hexane = 1: 4) are eluted from the concentrated residue. The resulting compound is subjected to silica gel chromatography as a solvent, and the resulting compound can be recrystallized from chloroform-hexane, ethyl acetate-hexane, or the like to obtain a crystal of compound (Ih).
(V) Step (e): Step of synthesizing compound (I) from compound (Ih) To compound (Ih), a dichloromethane / trifluoroacetic acid mixture (for example, dichloromethane: TFA = 4: 1) is added, and 1 at room temperature. Stir for ~ 3 hours. By this reaction, the Boc group is removed to synthesize compound (I). For purification of the compound (I), for example, saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and then extracted with an organic solvent such as chloroform. The organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography using a chloroform / methanol mixture (eg, chloroform: methanol = 9: 1) as an elution solvent. Compound (I) can be obtained.

(2) -1. The compound represented by the above general formula (A) in which V is —CO—NH— Among the compounds represented by the above general formula (A), the compound in which V is —CO—NH— has the following general formula (III ).

(R ′ is preferably a furanyl group, a phenyl group, or a halogen atom. R ^a , R ^b , R ^c , R ^d , R ¹ , R ² , R ^x , n, W, X, Y, and Z is the same as in general formula (I))
It is.

  R ′ in the general formula (III) is preferably a furanyl group, a phenyl group, or a chlorine atom, more preferably a furanyl group or a phenyl group, and still more preferably a furanyl group.

R ^a , R ^b , R ^c , and R ^{d in} general formula (III) are preferably the same as in general formula (I), but most preferably R ^a and R ^d , or R ^c , and R ^d is simultaneously a carbonyl group.

R ¹ , R ² , R ^x and n in the general formula (III) are preferably the same as those in the general formula (I).

  W, X, Y and Z in general formula (III) are preferably the same as in general formula (I), but most preferably W, X, Y and Z are simultaneously CH; Among X, Y, and Z, either W or Y is a nitrogen atom, and the other is CH.

When R ′ of the compound represented by the general formula (III) is a thienyl group, a chlorine atom, or a furanyl group or a phenyl group, R ^a , R ^b , R ^c , R ^d , R ¹ , Preferred embodiments of R ² , R ^x , n, W, X, Y, and Z are the same as those in general formula (I).

  Among the compounds represented by the above general formula (III), a particularly preferred embodiment is a compound represented by the following general formula (IV):

(In the formula, R ′ represents a furanyl group, a phenyl group, or a chlorine atom.)
Furthermore, examples of the compound represented by the general formula (III) include compounds represented by the following formulas (1) and (14) to (20).
N- (4-((2-amino-5- (thiophen-2-yl) phenyl) carbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) -4-methyl-2,5-dioxopiperazine-1-carboxamide

N-((5- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-2-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N-((6- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-3-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-amino-5-chlorophenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-Amino-5- (furan-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-Amino-5- (benzene-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-amino-5- (furan-3-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

(2) -2. Method for synthesizing compound represented by general formula (III) The method for synthesizing the compound represented by general formula (III) is not particularly limited. From the compound (If) obtained by the steps (a) to (c), the compound can be synthesized by the method exemplified in Scheme III. In Scheme III, R ′, R ^a , R ^b , R ^c , R ^d , R ¹ , R ² , R ^x , n, W, X, Y, and Z are the same as those in 1-1. Is the same as
(I) Step (d): Synthesis of Compound (IIIa) from Compound (If) For example, International Publication No. 2008 / 010985A2, Bioorg. Med. Chem Lett., 18 (2008) 726-731, International Publication No. 2009 / 002495A1 and Bioorg. Med. Chem Lett., 19 (2009) 1168-1172, compound (IIIa) from compound (If) is synthesized and purified.
(Ii) Step (e): Synthesis of Compound (IIIc) from Compound (IIIa) Compound (IIIb) is dissolved in, for example, dichloromethane (CH ₂ Cl ₂ ) and the like, and compound (IIIa) is present in the presence of a base such as triethylamine. And, for example, by stirring at room temperature for 1 to 24 hours, compound (IIIc) can be synthesized. Purification of the compound (IIIc) from the reaction solution can be performed by adding ice to the reaction solution, followed by extraction with an organic solvent such as chloroform. The organic layer is washed with, for example, brine, and then dried over sodium sulfate. Concentrate under reduced pressure. For example, chloroform / methanol mixture (eg chloroform: methanol = 9: 1 or chloroform: methanol = 9.5: 0.5) and ethyl acetate / hexane mixture (eg ethyl acetate: hexane = 1: 4) are eluted from the concentrated residue. The resulting compound is subjected to silica gel chromatography as a solvent, and the obtained compound can be recrystallized from chloroform-hexane, ethyl acetate-hexane or the like to obtain a crystal of compound (IIIc).
(Iii) Step (f): Step of synthesizing Compound (III) from Compound (IIIc) To Compound (IIIc) synthesized in (ii) above, a mixed solution of dichloromethane and trifluoroacetic acid (for example, CH ₂ Cl ₂ : TFA = 4: 1) is added and stirred at room temperature for 1-3 hours. By this reaction, the Boc group is removed to synthesize compound (III). For purification of the compound (III), for example, saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and then extracted with an organic solvent such as chloroform. The organic layer is washed with brine, etc., dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography using a chloroform / methanol mixture (eg, chloroform: methanol = 9: 1) as an elution solvent. Compound (III) can be obtained.

  The pharmaceutically acceptable salt of the compound represented by the general formula (A) is not particularly limited, but inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sulfonic acid, p-toluenesulfone Acid, acid addition salts with organic acids such as trifluoroacetic acid; inorganic salts such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and ornithine; and ammonium Examples include salts. Preferred are organic acid addition salts with sulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid.

2. A compound represented by the following formula (V) or a pharmacologically acceptable salt thereof
2-1. Compounds represented by the following formula (V) Another embodiment of the compounds of the present invention, a compound represented by the following formula (V):

It is.

2-2. Pharmaceutically acceptable salt of the compound represented by the formula (V) The pharmaceutically acceptable salt of the compound represented by the general formula (V) is not particularly limited. The salt as described in the term of a nitrogen-containing heterocyclic derivative can be illustrated.

2-3. Method for synthesizing compound represented by general formula (V) The compound represented by general formula (V) can be synthesized according to the method of Example 2 described later.

3. Pharmaceutical composition for treatment and / or prevention of cancer The pharmaceutical composition of the present invention is represented by the compound represented by the above general formula (I), the compound represented by the above general formula (III) or the above formula (V). Or a pharmaceutically acceptable salt thereof, more preferably a compound represented by the above general formula (I) or a compound represented by the above general formula (III), or a pharmaceutically acceptable salt thereof. A salt, more preferably a compound represented by the above general formula (I), or a pharmaceutically acceptable salt thereof.

  The pharmaceutical composition comprises a compound represented by the above general formula (I), a compound represented by the above general formula (III) or a compound represented by the above formula (V), or a pharmaceutically acceptable salt thereof, It can be prepared in combination with a pharmaceutical carrier. As the carrier used in the preparation of the pharmaceutical composition, various ones commonly used for ordinary drugs, such as excipients, binders, disintegrants, lubricants, colorants, flavoring agents, flavoring agents, and surface active agents. An agent etc. can be illustrated.

  The dosage form when the pharmaceutical composition is orally administered is not particularly limited, and examples thereof include tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions and the like. . Moreover, when the said pharmaceutical composition is administered parenterally, an injection, a liquid formulation, an instillation etc. can be illustrated.

  When the pharmaceutical composition is an oral solid pharmaceutical composition such as a tablet, powder, granule, etc., as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystals Excipients such as cellulose, silicic acid, methylcellulose, glycerin, sodium alginate and gum arabic, simple syrup, puddle sugar solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose , Water, ethanol, binders such as potassium phosphate, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl Disintegrants such as sodium acid, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, starch Adsorbents such as lactose, kaolin, bentonite, colloidal silicic acid, etc., lubricants such as purified talc, stearate, boric acid powder, polyethylene glycol and the like can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, multilayer tablets and the like.

  When the pharmaceutical composition is a solid pharmaceutical composition for oral administration of pills, as a carrier, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic Binders such as powder, tragacanth powder and gelatin, and disintegrants such as laminaran and agar can be used.

  When the pharmaceutical composition is a tablet or pill, sucrose, hydroxypropylcellulose (HPC), shellac, gelatin, glycerin, sorbitol, hydroxypropylmethylcellulose (HPMC), ethylcellulose, polyvinylpyrrolidone (PVP), if necessary , Hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), or a methyl methacrylate-methacrylic acid copolymer.

  When the above pharmaceutical composition is an oral solid pharmaceutical composition for capsules, the capsule is mixed with the various carriers exemplified above and filled into hard gelatin capsules, soft capsules, etc. Prepared.

  When the pharmaceutical composition is a liquid pharmaceutical composition, it may be an aqueous or oily suspension, solution, syrup or elixir, and is prepared according to a conventional method using ordinary additives.

  When the pharmaceutical composition is an injection, the carrier is diluted with water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Agent, pH adjuster such as sodium citrate, sodium acetate, sodium phosphate, buffer such as dipotassium phosphate, trisodium phosphate, sodium hydrogen phosphate, sodium citrate, sodium pyrosulfite, EDTA, thioglycolic acid For example, saccharides such as mannitol, inositol, maltose, sucrose, and lactose can be used as stabilizers such as thiolactic acid and molding agents when lyophilized. In this case, a sufficient amount of glucose or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, soothing agent, local anesthetic, etc. may be added. Also good. By adding these carriers, subcutaneous, intramuscular and intravenous injections can be produced by conventional methods.

  When the pharmaceutical composition is an infusion, it can be prepared by dissolving the administered compound in an isotonic electrolyte infusion preparation based on physiological saline, Ringer's solution or the like.

  The dosage of the pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are exhibited, and can be appropriately set depending on the dosage form, patient age, sex, degree of medical condition, etc. In the case of an adult (over 15 years old) (weight approximately 60 kg) in terms of the amount of the compound represented by the above general formula (I), the compound represented by the above general formula (III) or the compound represented by the above formula (V) The amount is about 0.1 to 1,000 mg / kg, preferably about 0.5 to 500 mg / kg per day. In addition, when the pharmaceutical composition is administered by a method other than oral administration, the effective blood concentration is a compound represented by the above general formula (I), a compound represented by the above general formula (III) or the above formula ( The compound represented by IV) can be administered in an amount of 0.2 to 100 μg / ml, more preferably 0.5 to 50 μg / ml.

  The pharmaceutical composition of the present invention can be used for the treatment and / or prevention of cancer. In the present invention, cancer is not particularly limited, but includes both non-epithelial and epithelial malignant tumors. Specifically, respiratory malignant tumors arising from the trachea, bronchi, lungs, etc .; nasopharynx, esophagus, stomach, duodenum, jejunum, ileum, cecum, appendix, ascending colon, transverse colon, sigmoid colon, rectum or anus Gastrointestinal tract benign or malignant tumor arising from the cervix, etc .; liver cancer or bile duct cancer; pancreatic cancer; urinary malignant tumor arising from the bladder, ureter or kidney; Malignant tumor; Breast cancer: Prostate cancer; Skin cancer; Endocrine malignant tumors such as hypothalamus, pituitary gland, thyroid gland, parathyroid gland, adrenal cortex; nervous system malignant tumors such as central nervous system, peripheral nervous system, adrenal medulla; Solid tumors such as malignant tumors arising from tissues, and myelodysplastic syndrome, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelomonocytic leukemia, chronic myelomonocytic Leukemia, acute monocytes Leukemia, chronic monocytic leukemia, acute total myeloid leukemia, acute megakaryocytic leukemia, erythroleukemia, eosinophilic leukemia, chronic neutrophilic leukemia, adult T-cell leukemia, hairy cell leukemia, plasma cell leukemia And hematopoietic malignant tumors such as multiple myeloma and malignant lymphoma; hematopoietic cancers such as lymphoid malignant tumors. More preferably, it is at least one selected from gastrointestinal malignant tumor, female genital malignant tumor, breast cancer, and nervous system malignant tumor. More preferred are neuroblastoma, breast cancer, colon cancer and the like.

4). Cell growth inhibitor The cell growth inhibitor of the present invention is a compound represented by the above general formula (I), a compound represented by the above general formula (III), a compound represented by the above formula (IV), or a pharmaceutical thereof. More preferably, a compound represented by the above general formula (I) or a compound represented by the above general formula (III), or a pharmaceutically acceptable salt thereof, more preferably the above general formula The compound shown by (I), or its pharmaceutically acceptable salt is included.

  Here, “cell growth inhibition” in the present invention refers to stopping the cell cycle at the G0 / G1 phase without inducing cell death. The cell growth-suppressed state is, for example, subG1 indicating apoptotic cells in HCT116 cells that are colon cancer cells in cell cycle analysis using the DNA content of cells according to a conventional method such as flow cytometry as an index. The ratio of the cells fractionated into 10 to 15% or less, more preferably 5 to 10% or less, and / or the ratio of the cells fractionated into the G0 / G1 phase indicating the stationary phase is 60 to 70. % Or more, more preferably 65 to 75% or more, still more preferably 70 to 80% or more.

  The cytostatic agent of the present invention is a compound represented by the above general formula (I), a compound represented by the above general formula (III) or a compound represented by the above formula (IV), or a pharmaceutically acceptable product thereof. In addition to salts, it can be prepared in combination with a pharmaceutical carrier. Examples of the carrier used in the preparation of the pharmaceutical composition include 3. Excipients, binders, disintegrants, lubricants, colorants, flavoring agents, flavoring agents, surfactants and the like described in the section can be exemplified.

  Examples of the dosage form when the above-mentioned cytostatic agent is orally administered include tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions and the like. The preparation of each dosage form is as described in 3. above. Can be carried out according to a method for preparing a pharmaceutical composition for the treatment and / or prevention of cancer.

  The dosage of the cell growth inhibitor of the present invention and the administration control disease are the above-mentioned 3. It is the same as the pharmaceutical composition for the treatment and / or prevention of cancer.

5. Neuroprotective agent The neuroprotective agent of the present invention comprises a compound represented by the following general formula (A), or a pharmaceutically acceptable salt thereof:

{Where
R ′ represents a thienyl group, a furanyl group, a phenyl group, or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (A-2):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² forms a saturated ring having 3 to 6 carbon atoms together with R ^x. Good];
R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
V is a direct bond or -CO-NH-;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}.

  R ′ is preferably a thienyl group, a furanyl group, a phenyl group, or a chlorine atom, more preferably a thienyl group or a furanyl group, and still more preferably a thienyl group.

R ^a , R ^b , R ^c , and R ^d are preferably two of R ^a , R ^b , R ^c , and R ^d , and the other two are the same or different and have the above general formula. And R ^a and R ^c are not simultaneously a carbonyl group; more preferably, R ^a is a carbonyl group, and R ^c is the above general formula (A-2). Most preferably, R ^a and R ^b are carbonyl groups.

R ¹ and R ² are preferably a hydrogen atom at the same time; an alkyl group having 1 to 4 carbon atoms at the same time (preferably an alkyl group having 1 to 4 carbon atoms in this case is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group or an isobutyl group, more preferably a methyl group, an ethyl group or a propyl group, and most preferably a methyl group or an ethyl group); or one of which is a hydrogen atom and the other of which has 1 to 4 carbon atoms An alkyl group, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably methyl) Group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group or tert-butyl group, and more. It is preferably a methyl group, an ethyl group or a propyl group, most preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group. Yes; preferably as a substituent of an aryl group, a cyclohexyl group and a tetrahydropyranyl group, a halogen atom of any one of a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, More preferably, they are a chlorine atom, a fluorine atom, a methyl group, or an ethyl group, and most preferably a chlorine atom, a fluorine atom, or a methyl group.

R ^a, as one embodiment of the time ^R b, are any two of ^{R c,} and ^{R d} is a group represented by the general formula (A-2) is a group represented by the general formula (A-2) Are the same and both R ¹ and R ² are preferably hydrogen atoms.

In another embodiment, when any two of R ^a , R ^b , R ^c , and R ^d are different and are groups represented by the general formula (A-2), one of the general formulas (A- 2) In the group represented by 2), both R ¹ and R ² are hydrogen atoms, and the other is different from the other group represented by the above general formula (A-2) [in this case, R ¹ and R ² are preferably , Both are methyl groups; or ^one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or An optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group, or tert. -Butyl group, etc. More preferably a methyl group, an ethyl group or a propyl group, most preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group or a pyridinyl group, more preferably A phenyl group; preferably as a substituent of an aryl group, a cyclohexyl group and a tetrahydropyranyl group, preferably a halogen atom of any one of a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a hydroxyl group More preferably a chlorine atom, a fluorine atom, a methyl group or an ethyl group, and most preferably a chlorine atom, a fluorine atom or a methyl group)].

When R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² may be combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. As a saturated 3-membered ring, a saturated 4-membered ring, or a saturated 5-membered ring, and more preferably a saturated 5-membered ring.

R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group, more preferably Linear type. The linear alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, more preferably a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group. Or it is an ethyl group. Preferred examples of the branched alkyl group include isopropyl group, sec-butyl group, isobutyl group, tert-butyl group, isopentyl group, neopentyl group, isohexyl group, and biisopropyl group. More preferred is an isopropyl group, sec-butyl group, isobutyl group, or isopentyl group, and even more preferred is an isopropyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

n is any integer of 1 to 4, more preferably 1 or 2, and most preferably 1.
V is a direct bond or —CO—NH—;
W, X, Y, and Z are preferably all of W, X, Y, and Z are CH, or any one or two of W, X, Y, and Z are nitrogen atoms; more preferably Are all W, X, Y, and Z are CH, or any one of W, X, Y, and Z is a nitrogen atom; most preferably all of W, X, Y, and Z are CH.

The salt of the compound represented by the general formula (A) used for the neuroprotective agent is the above-mentioned 1. Examples thereof include the salts described in the section of the nitrogen-containing complex.
(1). Compound represented by the above general formula (A) in which V is directly coupled Among the compounds represented by the above general formula (A), a compound in which V is directly coupled is represented by the following general formula (I). A compound.

{Where
R ′ represents a thienyl group, a furanyl group, a phenyl group or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (II):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (II), R ¹ or R ² is combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. Good];
R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}
It is.

  R ′ is preferably a thienyl group, a furanyl group, a phenyl group, or a chlorine atom, more preferably a thienyl group or a furanyl group, and still more preferably a thienyl group.

R ^a , R ^b , R ^c , and R ^d are preferably two of R ^a , R ^b , R ^c , and R ^d , and the other two are the same or different and have the above general formula. And R ^a and R ^c are not simultaneously a carbonyl group; more preferably, R ^a is a carbonyl group and R ^c is represented by the above general formula (II). Most preferably, R ^a and R ^b are carbonyl groups.

R ¹ and R ² are preferably a hydrogen atom at the same time; an alkyl group having 1 to 4 carbon atoms at the same time (preferably an alkyl group having 1 to 4 carbon atoms in this case is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group or an isobutyl group, more preferably a methyl group, an ethyl group or a propyl group, and most preferably a methyl group or an ethyl group); or one of which is a hydrogen atom and the other of which has 1 to 4 carbon atoms An alkyl group, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably methyl) Group, ethyl group, propyl group, isopropyl group, butyl group, sec-butyl group, isobutyl group or tert-butyl group, more preferably An aryl group, preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; Group, cyclohexyl group, and tetrahydropyranyl group, preferably a halogen atom of any one of chlorine atom and fluorine atom, methyl group, ethyl group, propyl group, isopropyl group, or hydroxyl group, more preferably A chlorine atom, a fluorine atom, a methyl group or an ethyl group, most preferably a chlorine atom, a fluorine atom or a methyl group).

As one aspect when any two of R ^a , R ^b , R ^c , and R ^d are groups represented by the general formula (II), two of the groups represented by the general formula (II) are the same It is preferable that both R ¹ and R ² are hydrogen atoms.

As another embodiment, when any two of R ^a , R ^b , R ^c , and R ^d are different and are groups represented by the above general formula (II), one of the above general formulas (II) R ¹ and R ² of the group to be represented are both hydrogen atoms, and the other is different from the other group represented by the above general formula (II) [in this case, R ¹ and R ² are preferably both methyl groups; Alternatively, ^one of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. A tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group). More preferred Or a methyl group, an ethyl group or a propyl group, most preferably a methyl group or an ethyl group; an aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group. A preferable substituent for an aryl group, a cyclohexyl group and a tetrahydropyranyl group is a halogen atom of any one of a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a hydroxyl group, more preferably Is preferably a chlorine atom, a fluorine atom, a methyl group or an ethyl group, most preferably a chlorine atom, a fluorine atom or a methyl group)].

When R ^b or R ^d is a group represented by the above formula (II), R ¹ or R ² may be combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. Is a saturated 3-membered ring, a saturated 4-membered ring, or a saturated 5-membered ring, more preferably a saturated 5-membered ring.

R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms, and the alkyl group having 1 to 6 carbon atoms is a linear or branched alkyl group, more preferably Linear type. The linear alkyl group is preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, more preferably a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group. Or it is an ethyl group. The branched alkyl group is preferably an isopropyl group, sec-butyl group, isobutyl group, tert-butyl group, isopentyl group, neopentyl group, isohexyl group, or biisopropyl group. An isopropyl group, a sec-butyl group, an isobutyl group, or an isopentyl group is more preferable, and an isopropyl group is more preferable. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is any integer of 1 to 4, more preferably 1 or 2, and most preferably 1.

  W, X, Y, and Z are preferably all of W, X, Y, and Z are CH, or any one or two of W, X, Y, and Z are nitrogen atoms; more preferably Are all W, X, Y, and Z are CH, or any one of W, X, Y, and Z is a nitrogen atom; most preferably all of W, X, Y, and Z are CH.

In a preferred embodiment when R of the compound represented by the general formula (I) 'is a thienyl ^group, R ^a, R b, of ^{R c,} and ^{R d R a} and ^{R b} is carbonyl group, other Are the same or different and are groups represented by the above general formula (II). In this case, R ^c is a group represented by the above general formula (II) (R ¹ and R ² are both hydrogen atoms), and R ^b which is not a carbonyl group or R ^{d which} is not a carbonyl group is the same as R ^c. Or a group represented by the above general formula (II) different from R ^c [in which R ¹ and R ² are both methyl groups; or ^one of R ¹ and R ² is a hydrogen atom and the other is carbon An alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, as an alkyl group having 1 to 4 carbon atoms) Preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group, more preferably a methyl group, an ethyl group, or a propyl group, and most preferably Preferably, it is a methyl group or an ethyl group; The aryl group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, and more preferably a phenyl group; substitution of an aryl group, a cyclohexyl group, and a tetrahydropyranyl group The group is preferably a halogen atom such as a chlorine atom and a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group or a hydroxyl group, more preferably a chlorine atom, a fluorine atom, a methyl group or an ethyl group, Most preferably, it is a chlorine atom, a fluorine atom or a methyl group)].

When R ^b or R ^d is a group represented by the above formula (II), R ¹ or R ² may be combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. A saturated 5-membered ring is preferred.

R ^x represents a hydrogen atom or an optionally substituted linear alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. More preferably, it is a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group or an ethyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is more preferably 1 or 2, and most preferably 1.

  W, X, Y, and Z are preferably all of W, X, Y, and Z are CH, or any one of W, X, Y, and Z is a nitrogen atom; All of W, X, Y, and Z are CH.

Furthermore, examples of the compound in which R ′ of the compound represented by the general formula (I) is a thienyl group include compounds represented by the following formulas (2) to (10):
N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2- (1H) -yl) Methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((3,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) methyl Benzamide

N- (2-amino-5 (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxo-3-phenylpiperazin-1-yl) methyl) benzamide

N- (2-amino-5 (thiophen-2-yl) phenyl) -4-((3,3,4-trimethyl-2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((3-cyclohexyl-4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxo-3- (tetrahydro-2H-pyran-4-yl) piperazine-1 -Il) methyl) benzamide

In a preferred embodiment when R of the compound represented by the general formula (I) 'is a chlorine ^atom, R ^a, R b, of ^{R c,} and ^{R d R a} and ^{R b} is carbonyl group, other Are the same or different and are groups represented by the above general formula (II). Groups represented by this case ^{R c} is the above-mentioned general formula (II) ^{(R 1} and ^{R 2} are both hydrogen atoms) and, and ^{R d} is either the same as ^{R c,} or ^{R c} is different from the general Group represented by formula (II) [in which R ¹ and R ² are both methyl groups; or ^one of R ¹ and R ² is a hydrogen atom and the other is an alkyl group having 1 to 4 carbon atoms, substituted An optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, an ethyl group, or a propyl group). Group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, etc., more preferably methyl group, ethyl group or propyl group, most preferably methyl group or ethyl group; Aryl The group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; a substituent of an aryl group, a cyclohexyl group, or a tetrahydropyranyl group is preferably a chlorine atom or a fluorine atom Any halogen atom, methyl group, ethyl group, propyl group, isopropyl group or hydroxyl group, more preferably chlorine atom, fluorine atom, methyl group or ethyl group, most preferably chlorine atom, fluorine atom or methyl group It is preferable that

R ^x represents a hydrogen atom or an optionally substituted linear alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. More preferably, it is a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group or an ethyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is more preferably 1 or 2, and most preferably 1.

  As W, X, Y, and Z, preferably all of W, X, Y, and Z are CH or any one of W, X, Y, and Z is a nitrogen atom, most preferably W, All of X, Y, and Z are CH.

Examples of the compound in which R ′ of the compound represented by the general formula (I) is a chlorine atom include compounds represented by the following formula (11).
N- (2-amino-5-chlorophenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

A preferred embodiment of the case where formula R of the compound represented by (I) 'is furanyl group or a phenyl ^group, R ^a, R b, ^{R c,} and ^{R a} and ^{R b} of ^{R d} is a carbonyl group And the rest are the same or different groups represented by the general formula (II). Groups represented by this case ^{R c} is the above-mentioned general formula (II) ^{(R 1} and ^{R 2} are both hydrogen atoms) and, and ^{R d} is either the same as ^{R c,} or ^{R c} is different from the general Group represented by formula (II) [in which R ¹ and R ² are both methyl groups; or ^one of R ¹ and R ² is a hydrogen atom and the other is an alkyl group having 1 to 4 carbon atoms, substituted An optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted tetrahydropyranyl group (in this case, the alkyl group having 1 to 4 carbon atoms is preferably a methyl group, an ethyl group, or a propyl group). Group, isopropyl group, butyl group, sec-butyl group, isobutyl group, tert-butyl group, etc., more preferably methyl group, ethyl group or propyl group, most preferably methyl group or ethyl group; Aryl The group is preferably a phenyl group, a morpholyl group, or a pyridinyl group, more preferably a phenyl group; a substituent of an aryl group, a cyclohexyl group, or a tetrahydropyranyl group is preferably a chlorine atom or a fluorine atom Any halogen atom, methyl group, ethyl group, propyl group, isopropyl group or hydroxyl group, more preferably chlorine atom, fluorine atom, methyl group or ethyl group, most preferably chlorine atom, fluorine atom or methyl group It is preferable that

R ^x represents a hydrogen atom or an optionally substituted linear alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group. More preferably, it is a methyl group, an ethyl group, or a propyl group, and most preferably a methyl group or an ethyl group. The substituent for the alkyl group having 1 to 6 carbon atoms is preferably a chlorine atom or any halogen atom of a fluorine atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a hydroxyl group, more preferably chlorine. An atom, a fluorine atom, a methyl group, or an ethyl group, most preferably a chlorine atom, a fluorine atom, or a methyl group.

  n is more preferably 1 or 2, and most preferably 1.

  W, X, Y and Z are preferably all of W, X, Y and Z are CH or any one of W, X, Y and Z is a nitrogen atom, most preferably W, X , Y, and Z are all CH.

Examples of the compound in which R ′ of the compound represented by the general formula (I) is a furanyl group or a phenyl group include compounds represented by the following formula (12) or (13).
N- (2-amino-5- (furan-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

N- (2-amino-5- (benzene-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide

(2). The compound represented by the above general formula (A) in which V is —CO—NH— Among the compounds represented by the above general formula (A), the compound in which V is —CO—NH— has the following general formula (III ).

(R ′, R ^a , R ^b , R ^c , R ^d , R ¹ , R ² , R ^x , n, W, X, Y, and Z are the same as in general formula (I))
It is.

  R ′ in the general formula (III) is preferably a thienyl group, a furanyl group, a phenyl group, or a chlorine atom, more preferably a thienyl group, a furanyl group, or a phenyl group, and further preferably a thienyl group. It is.

R ^a , R ^b , R ^c , and R ^{d in} general formula (III) are preferably the same as in general formula (I), but most preferably R ^a and R ^d , or R ^c , and R ^d is simultaneously a carbonyl group.

R ¹ , R ² , R ^x and n in the general formula (III) are preferably the same as those in the general formula (I).

W, X, Y and Z in general formula (III) are preferably the same as in general formula (I), but most preferably W, X, Y and Z are simultaneously CH; Among X, Y, and Z, either W or Y is a nitrogen atom, and the other is CH.
When R ′ of the compound represented by the general formula (III) is a thienyl group, a chlorine atom, or a furanyl group or a phenyl group, R ^a , R ^b , R ^c , R ^d , R ¹ , Preferred embodiments of R ² , R ^x , n, W, X, Y, and Z are the same as those in general formula (I).

  Among the compounds represented by the above general formula (III), a particularly preferred embodiment is a compound represented by the following general formula (IV):

(In the formula, R ′ is a thienyl group, a furanyl group, a phenyl group, or a chlorine atom.)
Furthermore, examples of the compound represented by the general formula (III) include compounds represented by the following formulas (1) and (14) to (20).
N- (4-((2-amino-5- (thiophen-2-yl) phenyl) carbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) -4-methyl-2,5-dioxopiperazine-1-carboxamide

N-((5- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-2-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N-((6- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-3-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-amino-5-chlorophenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-Amino-5- (furan-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-Amino-5- (benzene-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

N- (4- (2-amino-5- (furan-3-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide

  The neuroprotective agent of this invention contains the compound shown by the said general formula (A), or its pharmaceutically acceptable salt.

  The neuroprotective agent can be prepared in combination with a pharmaceutical carrier in addition to the compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof. As the carrier used in the preparation of the neuroprotective agent, various carriers widely used for ordinary drugs, for example, the above-mentioned 3. The same excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, surfactants and the like as the pharmaceutical composition for the treatment and / or prevention of cancer can be exemplified.

  The dosage form when the above-mentioned neuroprotective agent is orally administered is not particularly limited, and examples thereof include tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions and the like. . Moreover, when the said neuroprotective agent is administered parenterally, an injection, a liquid formulation, an infusion, etc. can be illustrated.

  Preparation of each dosage form of the neuroprotective agent is performed in the above 3. It can carry out according to the preparation method of said pharmaceutical composition.

  The dose of the neuroprotective agent of the present invention is not particularly limited as long as the effect of the present invention is exhibited, and can be appropriately set depending on the dosage form, patient age, sex, degree of disease, etc. Formula (A) In terms of the amount of the compound represented by the above formula (IV), adult (over 15 years old) (calculated as a body weight of about 60 kg) daily dose of about 0.1 to 1,000 mg / kg, preferably It is about 0.5 to 500 mg / kg. When the neuroprotective agent is administered by a method other than oral administration, the effective blood concentration is the amount of the compound represented by the amount of the compound represented by the general formula (A) and the formula (IV). It can be administered at 2 to 100 μg / ml, more preferably 0.5 to 50 μg / ml.

  In the present invention, the “neuroprotective agent” refers to a drug exhibiting an action of suppressing cell death of nervous system cells. In addition, “cell death” means that a cell is killed, and the mechanism includes all mechanisms such as apoptosis, necrosis, autophagy pathway, and is not particularly limited. Furthermore, “suppression of cell death” refers to decreasing the number or ratio of cells that die.

  In the present invention, neural cells include nerve cells, glial cells, astrocytes, microglia, oligodendrocytes, Schwann cells and the like.

  In addition, the neuroprotective agent of the present invention selectively inhibits HDAC1 and HDAC2, but rather not induces cell death such as apoptosis, but rather suppresses cell death such as autophagy and induces cell death of nervous system cells. It is thought to suppress. The neuroprotective agent of the present invention suppresses cell death of nerve cells such as nerve cells, glial cells, astrocytes, microglia, oligodendrocytes, and Schwann cells, and preferably, nerve cells, glial cells And oligodendrocyte cell death are suppressed, and more preferably, neuronal cell death is suppressed.

  The neuroprotective agent of the present invention can be used for prevention and / or treatment of nervous system diseases. In the present invention, “neurological diseases” include neurodegenerative diseases, ischemic brain diseases, traumatic brain disorders and the like.

  In the present invention, “neurodegenerative disease” means a disease in which nervous system cells are killed due to causes other than ischemia, and the neuroprotective agent of the present invention can prevent and / or treat neurodegenerative diseases. Examples of neurodegenerative diseases include Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, polyglutamine disease, prion disease, multiple sclerosis, myasthenia gravis, Guillain-Barre syndrome, Fisher syndrome, chronic inflammatory Demyelinating polyneuritis, multifocal motor neuropathy, Crow-Fukase syndrome, HTLV-1-related myelopathy (HAM), central and peripheral demyelination. The neuroprotective agent of the present invention is notably Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's dementia, cerebrovascular dementia, polyglutamine disease multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating Polyneuritis or multifocal motor neuropathy can be prevented and / or treated. Among these diseases, the neuroprotective agent of the present invention is preferably used for prevention / treatment of Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's dementia, or cerebrovascular dementia, and more preferably It is suitably used for the prevention / treatment of Parkinson's disease and amyotrophic lateral sclerosis.

  In the present invention, “ischemic brain disease” means a disease that develops due to cerebral ischemia, such as cerebral infarction such as atherothrombotic cerebral infarction, cardiogenic cerebral embolism, lacunar infarction, etc. . In the acute phase of cerebral infarction, nerve cells are killed by ischemia, but at present, the death of nerve cells cannot be suppressed after several hours from the onset.

  The neuroprotective agent of the present invention is particularly useful in the acute phase of cerebral infarction, and can be administered preferably within 72 hours, more preferably 48 hours, and even more preferably within 24 hours from onset.

6). Agent for Preventing and / or Treating Nervous System Disease One aspect of the present invention includes an agent for preventing and / or treating a nervous system disease containing the compound represented by the above general formula (A) or a salt thereof.

  The preventive and / or therapeutic agent of the present invention can be prepared in combination with a pharmaceutical carrier in addition to the compound represented by the above general formula (A) or a salt thereof. The carrier, dosage form, and preparation method thereof used in the preparation of the prophylactic and / or therapeutic agent are the same as those of the “neuroprotectant”. The dosage of the preventive and / or therapeutic agent of the present invention and the disease to be administered are the same as those of the above-mentioned “neuroprotective agent”.

7). Pharmaceutical composition for prevention and / or treatment of nervous system disease As one aspect of the present invention, for prevention and / or treatment of nervous system disease comprising a compound represented by the above general formula (A) or a salt thereof A pharmaceutical composition is included.

  The pharmaceutical composition of the present invention can be prepared in combination with a pharmaceutical carrier in addition to the compound represented by the above general formula (A) or a salt thereof. Carriers used in the preparation of the pharmaceutical composition include excipients, binders, disintegrants, lubricants, coloring agents, flavoring agents, flavoring agents, surfactants and the like described in the above “neuroprotective agent”. It can be illustrated.

  Examples of the dosage form when the pharmaceutical composition is orally administered include tablets, coated tablets, powders, granules, capsules, solutions, pills, suspensions, emulsions and the like. Moreover, when the said pharmaceutical composition is administered parenterally, an injection, a liquid formulation, an instillation etc. can be illustrated. The preparation method of each dosage form can be performed according to the preparation method of the above-mentioned “neuroprotective agent”.

  The dosage of the pharmaceutical composition of the present invention and the disease to be administered are the same as those of the above-mentioned “neuroprotective agent”.

8). Method for preventing and / or treating nervous system disease One embodiment of the present invention includes a method for preventing and / or treating nervous system disease using the above-mentioned “compound represented by the above general formula (A) or a salt thereof”. It is. Specific examples of nervous system diseases and the method of administering neuroprotective agents are as described above.

  EXAMPLES Hereinafter, although an Example is shown and this invention is demonstrated further in detail, this invention is not limited to the aspect of an Example.

  The animal experiments shown below were performed at the Animal Experiment Facility attached to the Osaka University School of Medicine with the approval of the Animal Experiment Committee of the Osaka University Graduate School of Medicine based on the Osaka University Animal Experiment Regulations. Also, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium (MPP +) were used and discarded according to the safety data sheet (MSDS).

In the following examples, MP-500P (Yanaco) was used for the melting point measurement. LCMS-IT-TOF (SIMADZU) was used for HR-ESI-MS. JEOL-EX-400 (400 MHz) was used as the nuclear magnetic resonance apparatus (NMR). Thin layer chromatography (TLC) was Silica gel 60 F ₂₅₄ (Merck). W-Prep 2XY-10VW (Yamazen) was used for the medium pressure preparative chromatograph, and Biotage ZIP ^™ (Biotage) was used for the flash column chromatography cartridge.

Reference Synthesis Example 1: N- (4-((2-amino-5- (thiophen-2-yl) phenyl) carbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide [N- Synthesis of (4-((2-amino-5- (thiophen-2-yl) phenyl) carbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide: K-560 (Formula 1)]
K-560 is compound 8b described in Hirata Y et al (Bioorg Med Chem Lett. 2012 Mar 1; 22 (5): 1926-30).

Example 1: N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide [ N- ( Synthesis of 2-amino-5- (thiophen-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide: K-852 (Formula 2)]

(1) tert-butyl 2- (4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate [tert-butyl 2- Synthesis of (4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate] (K-852a) Ethyl 2,3-dioxopiperazine (0.30 g, 2.1 mmol) was dissolved in anhydrous DMF (5 ml), sodium hydride (0.10 g, 4.2 mmol) was added under ice cooling, and the mixture was stirred for 2 hours. Subsequently, tert-butyl 2- (4- (chloromethyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate (0.33 g, 0.74 mmol) was added to the reaction solution, and the mixture was returned to room temperature and stirred overnight. did. Ice was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using chloroform / methanol mixture (CHCl ₃ : MeOH = 9: 1) as an elution solvent, and compound K-852a (0.17 g, yield 41.9%) as white powdery crystals Got.

The physical properties of Compound K-852a were as follows: mp 119-121 ° C; ¹ HNMR (399.65 MHz, CDCl ₃ ): 1.15 (3H, t, J = 6.4 Hz, -CH ₃ ), 1.48 (9H, s, -Boc), 3.41-3.50 (6H, m), 4.66 (2H, d, J = 6.4 Hz), 7.00-8.01 (10H, m), 9.71 (1H, brs, -CONH-); HR-ESI -MS m / z: (M + H) ⁺ calcd for C ₂₉ H ₃₃ N ₄ O ₅ S, 549.2171; found, 549.2173.

(2) From compound K-852a to N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide Synthesis of [N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) -Benzamide] (K-852) 3 ml of dichloromethane / trifluoroacetic acid mixed solution (CH ₂ Cl ₂ : TFA = 4: 1) was added to compound K-852a (0.05 g, 0.091 mmol), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to obtain white powdery crystals of K-852 (0.02 g, yield 35.3%).

The physical properties of K-852 were as follows: mp 130-131 ° C; ¹ HNMR (399.65 MHz, CDCl ₃ ): 1.14 (3H, t, J = 6.4 Hz, -CH ₃ ), 3.41-3.50 ( 6H, m), 4.66 (2H, d, J = 6.4 Hz), 7.00-7.61 (10H, m), 7.94 (1H, brs, -CONH-); HR-ESI-MS m / z: (M + H ) ⁺ calcd for C ₂₄ H ₂₅ N ₄ O ₅ S, 449.1647; found, 449.1660.

Example 2: Ethyl 2- (1- (4- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) pyrrolidone-2-carboxamide) acetate [ ethyl 2- (1- (4- Synthesis of (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) pyrrolidine-2-carboxamido) acetate: K-853]

(1) 2- (1- (4- (2- (tert-butoxycarbonylamino) -5 (thiophen-2-yl) phenylcarbamoyl) benzyl) pyrrolidine-2-carboxamide) acetate [ethyl 2- (1- ( 4- (2- (tert-butoxycarbonylamino) -5- (thiophen-2-yl) phenylcarbamoyl) benzyl) pyrrolidine-2-carboxamido) acetate] (K-853a)
2- (Pyrrolidine-2-carboxamide) acetate (0.30 g, 1.00 mmol) was dissolved in anhydrous DMF (5 ml), sodium hydride (0.10 g, 4.2 mmol) was added under ice cooling, and the mixture was stirred for 2 hours. Subsequently, tert-butyl 2- (4- (chloromethyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate (0.33 g, 0.70 mmol) was added to the reaction mixture, and the mixture was allowed to warm to room temperature and stirred overnight. did. Ice was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using chloroform / methanol mixture (CHCl ₃ : MeOH = 9: 1) as an elution solvent, and compound K-853a (0.15 g, yield 35.3%) as white powder crystals Got.

The physical properties of Compound K-853a were as follows: mp 75-79 ° C .; HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₃₂ H ₃₉ N ₄ O ₆ S, 607.2590; found, 607.2581.

(2) Ethyl 2- (1- (4- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) pyrrolidone-2-carboxamide) acetate from compound K-853a [ethyl 2- ( Synthesis of 1- (4- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) pyrrolidine-2-carboxamido) acetate] (K-853) Compound K-853a (0.1 g, 0.09 mmol) 3 ml of a dichloromethane / trifluoroacetic acid mixed solution (CH ₂ Cl ₂ : TFA = 4: 1) was added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-hexane to obtain white powdery crystals of K-853 (0.017 g, yield 37.3%).

The physical properties of K-853 were as follows: mp 69-72 ° C; HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₂₇ H ₃₁ N ₄ O ₄ S, 507.2066; found , 507.2053.
Example 3: N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazine-2- (1H) -Yl) methyl) benzamide [N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2- (1H ) -yl) methyl) benzamide: K-854 (Formula 3)]

(1) tert-butyl 2- (4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) methyl) -benzamide) -4- (thiophene-2 -Yl) phenylcarbamate [tert-butyl 2- (4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin-2 (1H) -yl) methyl) -benzamido) -4- (thiophen- Synthesis of 2-yl) phenylcarbamate] (K-854a) Hexahydropyrrolo [1,2-a] pyrazine-1,4-dione (0.30 g, 2.11 mmol; optically active form S) in anhydrous DMF (5 ml) Then, sodium hydride (0.10 g, 4.2 mmol) was added under ice-cooling and stirred for 2 hours. Subsequently, tert-butyl 2- (4- (chloromethyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate (0.31 g, 0.70 mmol) was added to the reaction solution, and the mixture was returned to room temperature and stirred overnight. . Ice was added to the resulting reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography using an ethyl acetate / hexane mixed solution and a chloroform / methanol mixed solution (EtOAc: hexane = 1: 4, then CHCl ₃ : MeOH = 95: 5) as an elution solvent to obtain white Compound K-854a (0.12 g, yield 32.9%) as powdery crystals was obtained.

The physical properties of Compound K-854a were as follows: mp 113-116 ° C; ¹ HNMR (399.65 MHz, CDCl ₃ ): 1.49, 1.50, 1.52 (9H, each s, -Boc), 1.87-2.48 ( 4H, m, -CH _2- × 2), 3.52-3.78 (3H, m, -CH- × 3), 4.00 (1H, d, J = 16.4 Hz, -CH-), 4.15 (1H, t, J = 7.2 Hz, -CH-), 4.49 (1H, d, J = 14.8 Hz, -CH-) 4.80 (1H, d, J = 14.8 Hz, -CH-), 7.14-7.41 (6H, m, Ar- H ₆ ), 7.89-7.97 (3H, m, Ar-H ₃ ), 9.40 (1H, brs, NH); HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₃₀ H ₃₃ N ₄ O ₅ S, 561.2171; found, 561.2178.

(2) N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazine- from compound K-854a 2- (1H) -yl) methyl) benzamide [N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((1,4-dioxo-hexahydropyrrolo [1,2-a] pyrazin -2 (1H) -yl) methyl) benzamide] (K-854) Compound K-854a (0.10 g, 0.17 mmol) and dichloromethane / trifluoroacetic acid mixture (CH ₂ Cl ₂ : TFA = 4: 1) Was added and stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with CHCl ₃ . The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography using a chloroform / methanol mixture (CHCl ₃ : MeOH = 9: 1) as an elution solvent, and the resulting compound was recrystallized from chloroform-hexane to obtain white powdery crystals. K-852 (0.03 g, yield 38.2%) was obtained.

The physical properties of K-854 were as follows: mp 187-190 ° C; ¹ HNMR (399.65 MHz, CDCl ₃ ): 1.90, 2.23 (4H, each m, -CH _2- × 2), 3.69 (1H , d, J = 16.4 Hz, -CH-), 4.17 (1H, d, J = 16.8 Hz, -CH-), 4.31 (1H, t, J = 7.2 Hz, -CH-), 4.63 (2H, s , -NH ₂ ), 5.17 (2H, s, -CH _2- ) 6.74-7.50 (7H, m, Ar-H ₇ ), 7.96 (2H, m, Ar-H ₂ ), 9.68 (1H, m, NH ); HR-ESI-MS m / z: (M + H) + calcd for C 25 H 25 N 4 O 3 S, 461.1647; found, 461.01630.
Example 4: N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((2,5-dioxopiperazin-1-yl) methyl) benzamide [N- (2-amino- Synthesis of 5- (thiophen-2-yl) phenyl) -4-((2,5-dioxopiperazin-1-yl) methyl) benzamide: K-855 (Formula 4)]

(1) tert-butyl 2- (4-((2,5-dioxopiperazin-1-yl) methyl) benzamido) -4- (thiophen-2-yl) -phenylcarbamate [tert-butyl 2- (4 -((2,5-dioxopiperazin-1-yl) methyl) benzamido) -4- (thiophen-2-yl) -phenylcarbamate] (K-855a) Glycine anhydride (1.00 g, 8.76 mmol) in anhydrous DMF This was suspended in (20 ml), sodium hydride (0.42 g, 17.52 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction vessel was heated and stirred for 6 hours while gradually raising the external temperature of the reaction vessel from room temperature to 100 degrees. The reaction solution was returned to room temperature, tert-butyl 2- (4- (chloromethyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate (0.49 g, 1.10 mmol) was added, and the mixture was stirred at room temperature overnight. . Ice was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using chloroform / methanol mixture (CHCl ₃ : MeOH = 9: 1) as an elution solvent to obtain white solid compound K-855a (0.07 g, yield 12.2%). Obtained.

The physical properties of Compound K-855a were as follows: mp 139-142 ° C; ¹ HNMR (399.65 MHz, CDCl ₃ ): 1.14 (3H, t, J = 6.4 Hz, -CH ₃ ), 3.41-3.50 (6H, m), 4.66 (2H, d, J = 6.4 Hz), 7.00-7.61 (10H, m), 7.94 (1H, bs, -CONH-); HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₂₇ H ₂₉ N ₄ O ₅ S, 521.1858; found, 521.1849.

(2) N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((2,5-dioxopiperazin-1-yl) methyl) benzamide [N- (2) from compound K-855a Synthesis of (2-amino-5- (thiophen-2-yl) phenyl) -4-((2,5-dioxopiperazin-1-yl) methyl) benzamide] (K-855) Compound K-855a (0.05 g, 0.09 mmol) was added 3 ml of a mixed solution of dichloromethane and trifluoroacetic acid (CH ₂ Cl ₂ : TFA = 4: 1) and stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography using chloroform / methanol mixture (CHCl ₃ : MeOH = 9: 1) as an elution solvent, and white powdery crystal K-855 (0.03 g, yield 64%) was obtained. Obtained.

The physical properties of Compound K-855 were as follows: mp 147-149 ° C .; HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₂₂ H ₂₁ N ₄ O ₃ S, 421.1334; found, 421.1340.
Example 5: N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamide [N- ( Synthesis of 2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamide: K-856 (Formula 5)]

(1) Synthesis of 1-methylpiperazine-2,5-dione [1-methylpiperazine-2,5-dione] (K-856a) Glycylsarcosine (1.00 g, 6.80 mmol) to ethylene glycol (10 ml) and dehydration Magnesium sulfate as an agent (2 g) was added, and the mixture was heated to reflux at 200 ° C. for 4 hours. The reaction solution was subjected to suction filtration, and the obtained filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography using a chloroform / methanol mixture (CHCl ₃ : MeOH: H ₂ O = 12: 5: 1) as an elution solvent, and the resulting compound was recrystallized from isopropanol to give a white Compound K-856a (0.32 g, yield 36.8%) as powdery crystals was obtained.

The physical properties of Compound K-856a were as follows: mp 138-139 ° C; ¹ H NMR ((CD ₃ ) ₂ SO) δ: 2.80 (3H, s, -CH ₃ ), 3.76 (2H, s , -COCH _2- ), 3.86 (2H, s, -COCH _2- ), 8.09 (1H, s, -NH-);
HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₅ H ₉ N ₂ O ₂ , 129.0665; found, 129.0658.

(2) tert-butyl 2- (4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate from compound K-856a Synthesis of [tert-butyl 2- (4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) benzamido) -4- (thiophen-2-yl) phenylcarbamate] (K-856b) Compound K -856a (0.10 g, 0.78 mmol) was dissolved in anhydrous DMF (5 ml), sodium hydride (0.075 g, 1.87 mmol) was added under ice cooling, and the mixture was stirred for 2 hr. To the reaction solution was added tert-butyl 2- (4- (chloromethyl) -benzamide) -4- (thiophen-2-yl) phenylcarbamate (0.35 g, 0.78 mmol), and the mixture was returned to room temperature and stirred for 3 hours. After adding ice to the reaction solution, chloroform was added and shaken. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography using chloroform / methanol mixture (CHCl3: MeOH = 9: 1) as an elution solvent, and pale yellow amorphous crystal compound K-856b (178.0 mg, yield 42.7%) Got.

The physical properties of Compound K-856b were as follows: mp 110-112 ° C; ¹ HNMR (399.65 MHz, CDCl ₃ ): 1.51 (9H, brs, -Boc), 2.99 (3H, s, -CH ₃ ), 3.88 (2H, s, -COCH _2- ), 4.07 (2H, s, -COCH _2- ), 4.64 (2H, brs, -CH _2- ), 7.00-7.98 (10H, m, Ar-H) , 9.38 (1H, s, -NH-);
HR-ESI-MS m / z: (M + H) ⁺ calcd for C ₂₈ H ₃₁ N ₄ O ₅ S, 535.2016; found, 535.2013.

(3) N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) from compound K-856b Benzamide [N- (2-amino-5- (thiophen-2-yl) phenyl) -4-((4-methyl-2,5-dioxopiperazin-1-yl) methyl) -benzamide trifluoroacetate] (K-856) Synthesis of Compound K-856b (30 mg, 0.056 mmol) 0.3 ml of dichloromethane / trifluoroacetic acid mixed solution (CH ₂ Cl ₂ : TFA = 4: 1) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was washed three times with chloroform and ethanol, and further concentrated under reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain K-856 (13.5 mg, 55%) as pale green crystals.

The physical properties of K-856 were as follows: mp 214-216 ° C; ¹ H NMR ((CD ₃ ) ₂ SO) δ: 2.84 (3H, brs, -CH ₃ ), 3.87 (2H, s, -COCH _2- ), 4.06 (2H, s, -COCH _2- ), 4.61 (2H, s, -CH _2- ), 5.17 (3H, s, NH ₃ ⁺ ), 6.72-8.00 (10H, m, ArH ), 9.74 (1H, brs, -NH -); HR-ESI-MS m / z: (M + H) + calcd for C 23 H 23 N 4 O 3 S, 435.1492; found, 435.1479.

  The synthesis scheme of Examples 1 and 3-5 is shown in FIG.

Example 6: N- (4- (2-Amino-5- (benzene-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide [N- (4- Synthesis of (4-aminobiphenyl-3-ylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide (K-562)]

(1) Synthesis of tert-butyl 2-amino-4-bromophenylcarbamate (compound 9 in FIG. 2)
4-Bromo-o-phenylenediamine (Compound 8: 25 g, 133.7 mmol) was dissolved in THF (150 ml) and triethylamine (Et ₃ N) (150 ml), and (Boc) ₂ O (35 g, 160.4 mmol). ) And stirred at room temperature overnight. After the reaction, the solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with brine, and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure, and the obtained product was recrystallized from ethyl acetate to obtain colorless crystalline compound 9 (22.2 g, 58%).
mp 141.6-142.7 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.50 (9H, s, CH ₃ × 3), 3.81 (2H, brs, NH ₂ ), 6.17 (1H, brs, NH), 6.89-6.91 (2H, m, Ar-H ₂ ), 7.14 (1H, d, J = 8.0 Hz, Ar-H).
HR-ESI-MS m / z : 285.0224 (MH) - calcd for C 11 H 14 BrN 2 O 2 285.0239.

(2) Synthesis of tert-butyl 3-aminobiphenyl-4-ylcarbamate (compound 10a in FIG. 2) Compound 9 (3.0 g, 10.5 mmol), phenylboronic acid (2.15 g, 17.6 mmol) and tri-o-tolyl Phosphine (1.35 g, 4.4 mmol) dissolved in DME (30 ml), potassium carbonate (5.55 g, 40.16 mmol) and tetrakis (triphenylphosphine) palladium (0.9 g, 0.78 mmol) dissolved in water (18 ml) ), And the solution suspended by sonication was heated to reflux at 90 ° C. for 18 hours. After the reaction, chloroform was added to the suspension, washed with water, and dried over sodium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain pale yellow crystalline compound 10a (2.1 g, 70%).
mp 153.0-154.2 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.48 (9H, s, CH ₃ × 3), 3.81 (2H, brs, NH ₂ ), 6.28 (1H, brs, NH), 6.98-7.23 (2H, m, Ar-H _{2), 7.29-7.42 (4H, m} , Ar-H 4), 7.52-7.54 (2H, m, Ar-H 2).
HR-ESI-MS m / z: 285.1582 (M + H) ⁺ calcd for C ₁₇ H ₂₁ BN ₂ O ₂ 285.1603.

(3) Synthesis of tert-butyl 3- (4- (chloromethyl) benzamido) biphenyl-4-ylcarbamate (compound 11a in FIG. 2) Compound 10a (1.0 g) was dissolved in THF (14 ml) and triethylamine (0.566 ml) P- (Chloromethyl) benzoyl chloride (798.4 mg, 4.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The solution obtained after filtration and concentration under reduced pressure was purified by flash column chromatography to obtain colorless crystalline compound 11a (1.1 g, 70%).
mp 140.2-141.3 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.45 (9H, s, CH ₃ × 3), 4.61 (2H, s, CH ₂ ), 6.95 (1H, brs, NH), 7.26-7.61 (9H, m, Ar-H _{9), 7.96-7.98 (3H, m} , Ar-H 3), 9.37 (1H, brs, NH).
HR-ESI-MS m / z : 435.1448 (MH) - calcd for C 25 H 24 ClN 2 O 3 435.1476.

(4) Synthesis of tert-butyl 3- (4-((1,3-dioxoisoindoline-2-yl) methyl) benzamido) biphenyl-4-ylcarbamate (compound 12a in FIG. 2) Compound 11a (500 mg , 1.1 mmol) was dissolved in DMF (5 ml), potassium phthalimide (233.6 mg, 1.3 mmol) and potassium iodide (38.0 mg, 0.23 mmol) were added, and the mixture was stirred at 50 ° C overnight. After the reaction, toluene was added to the reaction solution, followed by concentration under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain pale yellow crystalline compound 12a (595 mg, 95%).
mp 104.4-106.0 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.46 (9H, s, CH ₃ × 3), 5.40 (2H, s, CH ₂ ), 6.85 (1H, brs, NH), 7.26-7.39 (5H, m, Ar-H ₅ ), 7.49-7.56 (4H, m, Ar-H ₄ ), 7.72-7.75 (2H, m, Ar-H ₂ ), 7.86-7.88 (2H, m, Ar-H ₂ ), 7.92-7.97 (3H , m, Ar-H ₃ ), 9.18 (1H, brs, NH).
HR-ESI-MS m / z : 546.2037 (MH) - calcd for C 33 H 28 N 3 O 5 546.2029.

(5) Synthesis of tert-butyl 3- (4- (aminomethyl) benzamido) biphenyl-4-ylcarbamate (compound 13a in FIG. 2) Compound 12a (500 mg, 0.91 mmol) was suspended in EtOH (6 ml). Hydrazine monohydrate (0.1 ml, 2.699 mmol) was added, and the mixture was heated to reflux for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain pale yellow crystalline compound 13a (431 mg, 45%).
mp 105.8-107.7 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.46 (9H, s, CH ₃ × 3), 3.94 (2H, s, CH ₂ ), 6.91-8.06 (13H, m, Ar-H ₁₂ , NH), 9.31 (1H, brs, NH).
HR-ESI-MS m / z: 418.2120 (M + H) ⁺ calcd for C ₂₅ H ₂₈ N ₃ O ₃ 418.2130.

(6) Synthetic compound 13a of tert-butyl 3- (4-((4-ethyl-2,3-dioxopiperazine-1-carboxamido) methyl) benzamido) biphenyl-4-ylcarbamate (compound 14a in FIG. 2) (150 mg, 0.36 mmol) was dissolved in dichloromethane (2 ml) and triethylamine (0.6 ml), 1,4-dioxopiperazinyl chloride (88.3 mg, 0.43 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain pale yellow crystals 14a (112.5 mg, 54%).
mp 217.3-218.3 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.0 Hz, CH ₃ ), 1.51 (9H, s, CH ₃ × 3), 3.53-3.67 (4H, m, CH ₂ × 2), 4.08 -4.10 (2H, m, CH ₂ ), 4.56-4.58 (2H, m, CH ₂ ), 7.07-7.97 (13H, m, Ar-H ₁₂ , NH), 9.31 (1H, brs, NH), 9.39 ( 1H, brs, NH).
HR-ESI-MS m / z : 584.2477 (MH) - calcd for C 32 H 34 N 5 O 6 584.2509.

(7) Synthesis of N- (4- (4-aminodiphenyl-3-ylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide (K-562) Compound 14a (100 mg, 0.21 mmol) was dissolved in dichloromethane (1 ml) and TFA (1 ml) and stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate was added to the reaction solution to adjust to pH 9 and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, recrystallized with ethanol, and subjected to suction filtration to obtain pale yellow crystals of K-562 (95.8 mg, 100%).
mp 125-128 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.13-1.16 (3H, m, CH ₃ ), 3.43-3.50 (4H, m, CH ₂ × 2), 3.97-4.00 (2H, m, CH ₂ ), 4.03 (2H, brs, NH ₂ ), 6.82-7.87 (12H, m, Ar-H ₁₂ ), 8.45 (1H, brs, NH), 9.35 (1H, brs, NH).
HR-ESI-MS m / z: 486.2137 (M + H) ⁺ calcd for C ₂₇ H ₂₈ N ₅ O ₄ 486.2141.

Example 7: N- (4- (2-Amino-5- (furan-3-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide N- (4- ( Synthesis of 2-a-5- (furan-3-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide (K-563)

(1) tert-butyl 2-amino-4- (furan-3-yl) phenylcarbamate (compound 10b in FIG. 2)
Compound 9 (3 g, 10.4 mmol), 3-furanboronic acid (1.51 g, 13.5 mmol) and tri-o-tolylphosphine (1.35 g, 4.4 mmol) were dissolved in DME (30 ml) and dissolved in water (18 ml). Dissolved potassium carbonate (5.55 g, 40.16 mmol) and tetrakis (triphenylphosphine) palladium (0.9 g, 0.78 mmol) were added, and the solution suspended by sonication and suspension was heated to reflux at 90 ° C. for 18 hours. After the reaction, chloroform was added to the suspension, washed with water, and dried over sodium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethyl acetate-hexane: 7: 7) to obtain pale yellow crystalline compound 10b (2.4 g, 82%).
mp 140.4-143.1 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.52 (9H, s), 3.78 (2H, s), 6.25 (1H, s), 6.62 (1H, s), 6.88-6.90 (2H, m), 7.26-7.28 (1H , d, J = 8.0 Hz), 7.44 (1H, s), 7.66 (1H, s).
HR-ESI-MS m / z: 275.1355 (M + H) ⁺ calcd for C ₁₅ H ₁₉ N ₂ O ₃ 275.1395.

(2) tert-butyl 2- (4- (chloromethyl) benzamido) -4- (furan-3-yl) phenylcarbamate (Compound 11b in FIG. 2)
Compound 10b (500 mg, 1.8 mmol) is dissolved in THF (10 ml) and pyridine (0.3 ml), and p- (chloromethyl) benzoyl chloride (411 mg, 2.2 mmol) is added under ice-cooling at room temperature. Stir for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure, and the resulting product was purified by flash column chromatography (ethyl acetate-hexane = 1: 2) to obtain compound 11b (715 mg, 92%) as pale yellow crystals.
mp 67.5-70.0 ° C. ¹ HNMR (CDCl ₃ ) δ: 1.50 (9H, s), 4.63 (2H, s), 6.64-6.65 (1H, m), 6.86 (1H, s), 7.20-7.28 (2H , m), 7.42-7.49 (3H, m), 7.68 (1H, s), 7.92 (1H, s), 7.96 -7.98 (2H, d, J = 8.0 Hz), 9.35 (1H, s). ESI- MS m / z: 425.1273 (MH) ⁺ calcd for C ₂₃ H ₂₂ ClN ₂ O ₄ 425.1268.

(3) tert-butyl 2- (4-((1,3-dioxoisoindoline-2-yl) methyl) benzamido) -4- (furan-3-yl) phenylcarbamate (compound 12b in FIG. 2) Synthesis Compound 11b (500 mg, 1.173 mmol) was dissolved in DMF (5 ml), potassium phthalimide (239.12 mg, 1.291 mmol) and potassium iodide (39.01 mg, 0.235 mmol) were added, and the mixture was stirred at 50 ° C overnight. did. After the reaction, toluene was added to the reaction solution, followed by concentration under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na ₂ SO ₄ . The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography (ethyl acetate-hexane = 1: 2) to obtain compound 12b (271 mg, 43%) as pale yellow crystals.
mp 97.4-100.1 ° C. ¹ HNMR (CDCl ₃ ) δ: 1.49 (1H, s), 4.91 (2H, s), 6.64 (1H, s), 6.83 (1H, s), 7.24-7.26 (3H, d , J = 8.0 Hz), 7.41-7.45 (1H, m), 7.49 -7.51 (2H, d, J = 8.0 Hz), 7.66-7.68 (1H, d, J = 8.0 Hz), 7.73-7.75 (2H, d, J = 8.0 Hz), 7.87 (2H, s), 7.91 -7.93 (2H, d, J = 8.0 Hz), 9.19 (1H, s).
HR-ESI-MS m / z: 536.1819 (MH) ⁺ calcd for C ₃₁ H ₂₆ N ₃ O ₆ 536.1822.

(4) Synthesis of tert-butyl 2- (4- (aminomethyl) benzamido) -4- (furan-3-yl) phenylcarbamate (Compound 13b in FIG. 2) Compound 12b (500 mg, 0.931 mmol) was dissolved in ethanol ( 6 ml), gin monohydrate (0.09 ml, 2.699 mmol) was added, and the mixture was heated to reflux at 95 ° C. for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography (chloroform-methanol = 9: 1) to obtain compound 13b (341 mg, 90%) as pale yellow crystals.
mp 118.7-120.0 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.50 (9H, s), 3.96 (2H, s), 6.64 (1H, s), 7.01 (1H, s), 7.22 (1H, s), 7.26 (1H, s), 7.38 -7.42 (3H, m), 7.64 (1H, s), 7.88 (2H, s), 7.91 -7.9 3 (2H, d, J = 8.0 Hz), 9.28 (1H, s).
HR-ESI-MSm / z: 408.19081 (M + H) ⁺ calcd for C ₂₃ H ₂₆ N ₃ O ₄ 408.1923.

(5) Synthesis of tert-butyl 2- (4-((4-ethyl-2,3-dioxopiperazine-1-carboxamido) methyl) benzamido) -4- (furan-3-yl) phenylcarbamate (14b) Compound 13b (337.8 mg, 0.832 mmol) was dissolved in dichloromethane (5 ml) and triethylamine (1.5 ml), 1,4-dioxopiperazinyl chloride (204.2 mg, 0.998 mmol) was added, and the mixture was stirred overnight at room temperature. did. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography (chloroform-methanol (98: 2) + triethylamine 0.35%) to obtain pale yellow crystalline compound 14b (259 mg, 54%).
mp 103.6-105.4 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.23-1.28 (4H, m), 1.50 (9H, s), 3.53-3.58 (4H, m), 4.09-4.12 (2H, m), 4.57-4.59 (2H, d, J = 8.0 Hz), 6.65 (1H, s), 6.95 (1H, s), 7.23-7.25 (1H, d, J = 8.0 Hz), 7.37-7.39 (2H, d, J = 8.0 Hz), 7.44 ( 1H, s), 7.67 (1H, s), 7.89 (1H, s), 7.93-7.95 (2H, d, J = 8.0 Hz), 9.39 (1H, s), 9.40 (1H, s).
HR-ESI-MS m / z: 574.2299 (MH) ⁺ calcd for C ₃₀ H ₃₂ N ₅ O ₇ 574.2302.

(6) Synthesis of N- (4- (2-amino-5- (furan-3-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide (K-563) Compound 14b (200 mg, 0.348 mmol) was dissolved in dichloromethane (2 ml) and TFA (2 ml) and stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate was added to the reaction solution to adjust to pH 9 and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, recrystallized with ethanol, and pale yellow crystal compound K-563 (94.2 mg, 57%) was obtained by suction filtration.
mp 176-178 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.19-124 (3H, m), 3.48-3.56 (4H, m), 3.74 (2H, s), 4.06-4.08 (2H, m), 4.57-4.58 (2H, d, J = 5.6 Hz), 6.62 (1H, s), 6.83-6.85 (1H, d, J = 8.0 Hz), 7.26 (1H, s), 7.39 -7.43 (3H, m), 7.49 (1H, s), 7.63 (1H, s), 7.87-7.89 (2H, d, J = 8.0 Hz), 8.08 (1H, s), 9.40 (1H, s).
HR-ESI-MS m / z: 476.1916 (M + H) ⁺ calcd for C ₂₅ H ₂₆ N ₅ O ₅ 476.1934.

Example 8: N- (4- (2-amino-5- (furan-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide [N- (4- Synthesis of (2-amino-5- (furan-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide (K-564)]

(1) Synthesis of tert-butyl 2-amino-4- (furan-2-yl) phenylcarbamate (Compound 10c in FIG. 2) Compound 9 (3 g, 10.4 mmol) and 2-furanboronic acid (1.51 g, 13.5 mmol) ) And tri-o-tolylphosphine (1.35 g, 4.4 mmol) in DME (30 ml) and potassium carbonate (5.55 g, 40.16 mmol) and tetrakis (triphenylphosphine) in water (18 ml) Palladium (0.9 g, 0.78 mmol) was added, and the solution suspended by sonication and suspension was heated to reflux at 90 ° C. for 18 hours. After the reaction, chloroform was added to the suspension, washed with water, and dried over sodium sulfate. The solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (ethanol: hexane = 3: 7) to obtain pale yellow crystalline compound 10c (2.3 g, 80%).
mp: 142.4-143.2 ° C;
¹ H NMR (CDCl ₃ ) δ: 1.48 (9H, s), 6.43-6.44 (1H, m), 6.51 (1H, s), 6.55 (1H, d, J = 3.2 Hz), 7.10-7.11 (3H, m), 7.28-7.31 (2H, m), 7.42 (1H, s); HR-ESI-MS m / z: 273.1251 (MH) ⁺ calcd.for C ₁₅ H ₁₇ N ₂ O ₃ 273.1239

(2) Synthesis of tert-butyl 2- (4- (chloromethyl) benzamido) -4- (furan-2-yl) phenylcarbamate (compound 11c in FIG. 2) Compound 10c (500 mg, 1.8 mol) was converted to THF ( 10 ml) and triethylamine (1.5 ml), p- (chloromethyl) benzoyl chloride (413.8 mg, 2.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The solution was filtered and concentrated under reduced pressure, and the resulting product was purified by flash column chromatography to obtain Compound 11c (1.0 g, 65%) as colorless crystals.
mp 171.0-172.0 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.44 (9H, s, CH ₃ × 3), 4.62 (2H, s, CH ₂ ), 6.41-7.98 (11H, m, Ar-H ₁₀ , NH), 9.51 (1H, brs, NH).
HR-ESI-MS m / z : 425.1278 (MH) - calcd for C 23 H 22 N 2 O 4 425.1268.

(3) tert-butyl 2- (4-((1,3-dioxoisoindoline-2-yl) methyl) benzamido) -4- (furan-2-yl) phenylcarbamate (compound 12c in FIG. 2) Synthesis Dissolve compound 11c (500 mg, 1.2 mol) in DMF (5 ml), add potassium phthalimide (239.1 mg, 1.30 mol) and potassium iodide (39.0 mg, 0.23 mol), and stir at 50 ° C overnight. did. After the reaction, toluene was added to the reaction solution, followed by concentration under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain uncrystallized compound 12c (433 mg, 69%).
mp 101.6-102.6 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.45 (9H, s, CH ₃ × 3), 4.89 (2H, s, CH ₂ ), 6.36-7.92 (15H, m, Ar-H ₁₄ , NH), 9.48 (1H, brs, NH).
HR-ESI-MS m / z : 536.1817 (MH) - calcd for C 31 H 26 N 3 O 6 536.1822 ..

(4) Synthesis of tert-butyl 2- (4- (aminomethyl) benzamido) -4- (furan-2-yl) phenylcarbamate (compound 13c in Fig. 2) Compound 12c (430 mg, 0.80 mol) was dissolved in ethanol ( 5 ml), hydrazine monohydrate (0.1 ml, 2.7 mmol) was added, and the mixture was heated to reflux for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain pale yellow crystalline compound 13c (241 mg, 74%).
mp 171.1-172.4 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.50 (9H, s, CH ₃ × 3), 3.94 (2H, s, CH ₂ ), 6.43-8.15 (11H, m, Ar-H ₁₀ , NH), 9.38 (1H, brs, NH).
HR-ESI-MS m / z: 408.1923 (M + H) ⁺ calcd for C ₂₃ H ₂₆ N ₃ O ₄ 408.1923.

(5) tert-butyl 2- (4-((4-ethyl-2,3-dioxopiperazine-1-carboxamido) methyl) benzamido) -4- (furan-2-yl) phenylcarbamate (compound of FIG. 2) 14c)
Compound 13c (400 mg, 0.98 mmol) in dichloromethane (5 ml) and triethylamine (1.5 ml) were dissolved, 1,4-dioxopiperazinyl chloride (241.2 mg, 1.2 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, and purified by silica gel chromatography to obtain pale yellow crystalline compound 14c (588 mg, 100%).
mp 196.3-198.0 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.22 (3H, t, J = 7.0 Hz, CH ₃ ), 1.49 (9H, s, CH ₃ × 3), 3.46-3.57 (4H, m, CH ₂ × 2), 4.09 -4.12 (2H, m, CH ₂ ), 4.58-4.59 (2H, m, CH ₂ ), 6.43-8.14 (11H, m, Ar-H ₁₀ , NH), 9.27 (1H, brs, NH), 9.42 ( 1H, brs, NH).
HR-ESI-MS m / z : 574.2301 (MH) - calcd for C 30 H 32 N 5 O 7 574.2302.

(6) N- (4- (2-Amino-5- (furan-2-yl) phenylcarbamoyl) benzyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide (K-564)
Compound 14c (100 mg) was dissolved in dichloromethane (1 ml) and TFA (1 ml) and stirred at room temperature for 1 hour. Saturated sodium hydrogen carbonate was added to the reaction solution to adjust to pH 9 and stirred for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with saturated sodium bicarbonate and brine, and dried over sodium sulfate. The organic layer was filtered, concentrated under reduced pressure, recrystallized with ethanol, and subjected to suction filtration to obtain pale yellow crystals of K-564 (73 mg, 88%).
mp 122-125 ° C.
¹ HNMR (CDCl ₃ ) δ: 1.19 (3H, t, J = 7.2 Hz), 3.51 (2H, q, J = 7.2 Hz), 3.63-3.66 (2H, m), 4.05-4.08 (2H, m), 4.59 (2H, d, J = 6.0 Hz), 6.45-6.46 (1H, m), 6.59 (1H, d, J = 3.2 Hz), 7.00 (1H, d, J = 8.0 Hz), 7.45-7.51 (4H , m), 7.58 (1H, s), 7.98 (2H, d, J = 8.4 Hz), 9.49 (1H, s).
HR-ESI-MS m / z: 476.1937 (M + H) ⁺ calcd for C ₂₅ H ₂₆ N ₅ O ₅ 476.1934.

Example 9: Cancer cell line growth inhibitory activity test using WST-8 In order to determine the IC ₅₀ of the compound of the present invention, the following experiment was conducted.
(1) Experimental method Human colon cancer cell line HCT116 cells were present in 5% CO _{2 in} McCoy's 5A medium (GIBCO) containing 10% fetal bovine serum (FBS), 50 μg / ml penicillin G and 50 μg / ml streptomycin sulfate. Then, the cells were cultured at 37 ° C. When the cells grew to 70-80% confluence, they were treated with a 0.25% trypsin solution (1 ml), and the detached cells were collected and then centrifuged at 1,000 rpm for 5 minutes. After completion of the centrifugation, the supernatant was removed, and the cells were resuspended to 10,000 cells / ml with the above medium, and then seeded in a 96-well plate. Test compounds adjusted to each concentration after 24 hours (K-852, K-853, K-854, K-855, K-856, K-560, Merck compound and Ethyl compound (K-560, Merck compound and Ethyl compound) 3) was added, and the mixture was cultured at 37 ° C. for 72 hours in the presence of 5% CO ₂ . After the culture, WST-8 (Dojindo) was added and cultured at 37 ° C. for 2 hours. After culturing, the absorbance (main wave 450 nm, subwave 630 nm) was measured using an autoplate reader, and the cell growth inhibitory activity (IC ₅₀ ) of each compound was calculated. The details of the experiment followed the protocol provided by the manufacturer. K-560 is compound 8b described in Hirata Y et al (Bioorg Med Chem Lett. 2012 Mar 1; 22 (5): 1926-30). The compound of the present invention (for example, K-852) is different in that dioxopiperazine group and N- (4- (2-amino-5- (thiophen-2-yl) phenylcarbamoyl) benzyl) are bonded. Is different from K-560, which is linked via CONH (carboxamide). The Ethyl compound is the compound of Example 37 of JP-T-2010-531359.

(2) Results Table 1 shows the results. The test compounds, except for K-855, showed similar or lower IC ₅₀ values than the typical thienyl group-introduced 2-benzamide-type Merck compound (IC ₅₀ : 0.84 μM).

Example 10: Solubility test In order to investigate the water solubility of the compound according to the present invention, the following experiment was conducted.

The test compound was dissolved in 100% DMSO and adjusted with 100% DMSO to a concentration of 1 to 10 mg / ml.
These 100% DMSO sample solutions were diluted 10-fold with distilled water to prepare 0.1-1 mg / ml 10% DMSO / H ₂ O sample solutions, respectively. The sample solution was sonicated at 25 ° C. for 15 minutes, followed by treatment with Vortex shaking for 30 seconds and then allowed to stand for 5 minutes. The solution after the treatment was observed with a magnifying glass (magnification 10 times), and the concentration at which fine particles were slightly suspended but no precipitate was formed was defined as the solubility of the test compound. As a result, as shown in Table 1, the water solubility of the compounds K-852, K-853, K-854, K-855, and K-856 according to the present invention is similar to Merck compounds and Ethyl compounds that are of the same family. (Respectively 0.5 mg / ml).

  From this, it has been clarified that the compound represented by the general formula (I) according to the present invention is superior in water solubility to the known thienyl group-introduced 2-benzamide type compound.

Example 11: Cell cycle analysis To demonstrate that the compounds of the present invention place cells in a quiescent state without inducing apoptosis of the cells, each stage of the cell cycle in cancer cells exposed to each test compound. The proportion was observed.
(1) Method Human colorectal cancer cell line HCT116 cell, breast cancer cell line SKBR3 cell, neuroblastoma cell line Neuro2a cell, 10% fetal bovine serum (FBS), 50 μg / ml penicillin G and 50 μg / ml, respectively. The cells were cultured at 37 ° C. in the presence of 5% CO _{2 in} McCoy's 5A medium (HCT116 cells), RPMI1640 medium (SKBR cells), and EMEM medium (Neuro2a cells) containing streptomycin sulfate. Cells were grown to 70-80% confluence, treated with 0.25% trypsin solution (1 ml) (Invitrogen Life Technologies, USA), detached cells were collected, and centrifuged at 1000 rpm for 5 minutes. After completion of the centrifugation, the supernatant was removed, and the cells were resuspended with the above medium to 1.0 × 10 ⁶ cells / ml, and then seeded on a 60 mm dish. After culturing for 24 hours, the medium was replaced with the above serum-free medium and cultured for 24 hours. After removing the medium, the cells were washed 3 times with 1 ml of the above serum-free medium, a test compound-containing serum-free medium (each test drug was added to a final concentration of 10 μM), and cultured for 24 or 48 hours. MS-275 (S. Baltan, et al., The Journal of Neuroscience, 2011 31 (11): 3990-3999; FIG. 3) was used as a control compound. The control was 0.1% DMSO. After culturing, the floating cells were collected, and the cells adhering to the dish were peeled off with a 0.25% trypsin solution and used in the experiment together with the floating cells. Treat all these cells with the Cycle Test Plus DNA reagent Kit according to the manufacturer's protocol, analyze the proportion of each stage of the cell cycle by flow cytometry, and the proportion of SubG1 cells containing apoptotic cells to the total cells Asked.

(2) Results FIG. 4 shows a DNA histogram obtained by exposing HCT116 cells to a test compound for 48 hours. The K-852, K-853, K-854, and K-856 treated cells of the present invention clearly have fewer SubG1 cells compared to MS-275 exposed cells (SubG1 15.8%, G0 / G1 77.9%). In particular, the percentages of SubG1 cells in cells exposed to K-852 and K-853 were 4.4% and 2.5%, respectively, which were almost the same level as control cells (3.6%). These values were also low compared to 6.7% of K-560 exposed cells. Furthermore, Sub-G1 cells of K-856-exposed cells also showed 6.3%, lower values than those of MS-275 or K-560-exposed cells. The proportion of SubG1 cells in K-854-exposed cells was 10.8%, which was less prominent than that of K-852 and K-853-exposed cells, but the proportion of SubG1 cells was reduced compared to MS-275-exposed cells. Furthermore, when the ratio of G0 / G1 was compared, MS-275-exposed cells showed 77.9%, which was lower than the control cells, compared to 78.3% of control cells. In contrast, in the cells exposed to K-852, K-853, K-854, and K-856, the ratios of G0 / G1 were 84.9%, 89.1%, 79.6%, and 79.2%, respectively. It was higher than 275 exposed cells. This revealed that the number of cells in the stationary phase (G0 / G1) increased in the cells exposed to the compound of the present invention.

  FIG. 5 shows a DNA histogram obtained by exposing SKBR3 cells to a test compound for 24 hours. The cells exposed to MS-275 showed a high SubG1 cell rate (31.4%), but the percentages of SubG1 cells exposed to K-852, K-853, K-854, and K-856 were 4.9% and 6.8%, respectively. Although it was 15.5% and 5.4%, both exceeded the ratio of the control cells (3.2%), but showed a significantly lower ratio than the cells exposed to MS-275. The ratio of SubG1 cells in K-560 exposed cells was 8.7%, and those exposed to K-852, K-853, and K-856 showed lower values. Furthermore, when comparing the ratio of G0 / G1, MS-275-exposed cells showed 57.4%, which was lower than the control cells, compared with 61.0% of control cells. In contrast, in the cells exposed to K-852, K-853, K-854, and K-856, the G0 / G1 ratios were 68.9%, 65.3%, 53.3%, and 67.7%, respectively. The value was higher than 58.6%.

  FIG. 6 shows a DNA histogram obtained by exposing Neuro2a cells to a test compound for 48 hours. The cells of the present invention, K-853, K-854, and K-856 exposed cells clearly have fewer SubG1 cells compared to MS-275 exposed cells (SubG1 16.7%), and the ratio of SubG1 cells is 6.9%, respectively. 11.4% and 5.5%. The percentage of SubG1 cells in cells exposed to K-560 is 16.7%, which is significantly higher than those exposed to K-852, K-853, K-854, and K-856, suggesting a strong apoptosis-inducing effect. It was done. In addition, when the ratio of G0 / G1 was compared, 65.9% of cells exposed to MS-275 and 60.8% of cells exposed to K-560 were 65.9% and 79.3% higher for cells exposed to K-852 and K-856. showed that.

  From these data, it was shown that the compound of the present invention does not induce apoptosis in cancer cells. Further, by treating the cells with the compounds of the present invention, K-852, K-853, K-854, K-856, cells in the quiescent G0 / G1 phase are increased, while apoptotic cells ( SubG1 cells) were shown to increase. And it was clarified that MS-275, which is a known compound, has no such action. Furthermore, it was shown that the compound of the present invention has a low apoptosis-inducing action as compared with the known compound K-560.

  From the above results, it can be seen that the compounds of the present invention are more effective than the known compounds having no thienyl group and 2-benzamide type compounds having an amide group adjacent to the dioxopiperazine group and having a substituent at the para position of the amino group. It was considered that the compound was stronger in inhibiting apoptosis.

Example 12: Cell growth inhibitory activity test and solubility test of K-562, K-563, and K-564 (1) Method In order to examine the cell growth inhibitory activity of a test compound, human colon cancer cell line HCT116 and Niyu The cell line SKBR3 (1 x 10 ⁴ cells / ml) is seeded in a 96-well plate, pre-incubated for 24 hours, and then each drug dissolved in DMSO has a final concentration of 100, 50, 10, 1, or 0.1 μM. Was added as follows. At this time, the final concentration of DMSO was adjusted to 0.25%. After culturing for 3 days, add WST-1 reagent (Cell counting Kit, DOJINDO) or WST-8 reagent (Cell counting Kit-8, DOJINDO) to each well. After 4 hours (WST-1) or 1 hour ( The absorbance (measurement wavelength: 450 nm, reference wavelength: 630 nm) was measured on WST-8) using a micro plate reader (AUTOREADER III, Sanko Junyaku Co., Ltd.), and the IC ₅₀ value was determined.

To examine the solubility of test compounds in water, each test compound was dissolved in DMSO and adjusted to 10 mg / ml, water was added, and 10% DMSO / H ₂ O suspension (1 mg / ml) was added. ml). Sonication was performed for 15 minutes, vortexed for 30 seconds, allowed to stand for 5 minutes, and the solubility was visually confirmed. A sample DMSO solution (100 mg / ml) was serially diluted with DMSO and treated in the same manner as above to evaluate the solubility.

Moreover, in order to examine the selection of test compounds HDAC1 and HDAC3, the inhibitory activity of HDAC1 and HDAC3 was measured. HDAC1,3 inhibitory activity was measured using Enzo Life Sciences Fluorimetric Drug Discover Kit (Catalog No. are # AK-511 and # AK-531, respectively) according to the method described in the catalog to determine IC50 value.
(2) Results
IC ₅₀ values and solubility are shown in Table 2.

  K-563 showed high water solubility. K-562, K-563 and K-564 showed high selectivity for HDAC1.

Reference synthesis example 2: N- (2-amino-5- (furan-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide and N- Synthesis example of (2-amino-5- (benzene-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide
N- (2-amino-5- (furan-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide or N- (2-amino- 5- (Benzene-2-yl) phenyl) -4-((4-ethyl-2,3-dioxopiperazin-1-yl) methyl) benzamide is synthesized according to the synthesis example shown in FIG.

Reference Synthesis Example 3: N-((6- (2-Amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-3-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1 -Carboxamide synthesis example
N-((6- (2-1amino-5- (thiophen-2-yl) phenylcarbamoyl) pyridin-3-yl) methyl) -4-ethyl-2,3-dioxopiperazine-1-carboxamide is Synthesis is performed according to the synthesis example shown in FIG.

Example 13: Compound structure, physical properties, and HDAC isoform inhibitory activity Table 3 shows the structure and physical properties of the compounds used in the following Examples.

The method for determining the IC _{50 of} each compound is as follows.

Human colorectal cancer cell line HCT116 cells were cultured in McCoy's 5A medium (GIBCO) containing 10% fetal bovine serum (FBS), 50 μg / ml penicillin G and 50 μg / ml streptomycin sulfate at 37 ° C. in the presence of 5% CO _2. Cultured. When the cells grew to 70-80% confluence, they were treated with a 0.25% trypsin solution (1 ml), and the detached cells were collected and then centrifuged at 1,000 rpm for 5 minutes. After completion of the centrifugation, the supernatant was removed, and the cells were resuspended to 10,000 cells / ml with the above medium, and then seeded in a 96-well plate. After 24 hours, test compounds adjusted to the respective concentrations were added, and cultured in the presence of 5% CO ₂ at 37 ° C. for 72 hours. After the culture, WST-8 (Dojindo) was added and cultured at 37 ° C. for 2 hours. After culturing, the absorbance (main wave 450 nm, subwave 630 nm) was measured using an autoplate reader, and the cell growth inhibitory activity (IC ₅₀ ) of each compound was calculated. The details of the experiment followed the protocol provided by the manufacturer. K-560 and Ethyl compounds are compound 8b and compound 2 described in Hirata Y et al (Bioorg Med Chem Lett. 2012 Mar 1; 22 (5): 1926-30). The Ethyl compound is also the compound of Example 37 of JP 2010-531359.

  Moreover, the water solubility of each compound was measured by the following method.

The test compound was dissolved in 100% DMSO and adjusted with 100% DMSO to a concentration of 1 to 10 mg / ml.
These 100% DMSO sample solutions were diluted 10-fold with distilled water to prepare 0.1-1 mg / ml 10% DMSO / H ₂ O sample solutions, respectively. The sample solution was sonicated at 25 ° C. for 15 minutes, followed by treatment with Vortex shaking for 30 seconds and then allowed to stand for 5 minutes. The solution after the treatment was observed with a magnifying glass (magnification 10 times), and the concentration at which fine particles were slightly suspended but no precipitate was formed was defined as the solubility of the test compound. As a result, as shown in Table 3, the water solubility of the compounds K-852 and K-853 according to the present invention was improved compared to the Ethyl compound (each 0.5 mg / ml) which is a compound of the same family.

  K-560 and K-852 are HDAC inhibitor compounds having a 2-aminobenzamide structure having a thienyl group and a dioxopiperazine structure. MS-275 does not have a thienyl group and does not have a dioxopiperazine structure. Ethyl compounds have a 2-aminobenzamide structure having a thienyl group but no dioxopiperazine structure.

Table 4 shows the inhibitory activity IC ₅₀ of the HDAC isoform of each compound. K-560 specifically inhibited HDAC1 and HDAC2, but not HDAC3 at all. Other compounds inhibited HDAC3 as well as HDAC1 and HDAC2.

Example 14: N- cell protective effect of K-560 against cerebral ischemia As described above, K-560 selectively inhibits HDAC1 and HDAC2, but does not inhibit HDAC3. In order to examine whether K-560 has an effect of protecting nerve cells from cell death due to ischemia, the following experiment was conducted.

(1) Method According to a conventional method, a primary neuronal cell culture system was established from the rat cerebral cortex on embryonic day 16 (E16), and the cells on the 10th to 12th day after the culture were subjected to the experiment. As a medium, Neurobasal (registered trademark) medium (Life Technologies) supplemented with B-27 (registered trademark) Supplement (Life Technologies) and antibiotics (penicillin-streptomycin-ampicillin) (hereinafter, Neurobasal + B27 + P / S) / Amp medium) was used. As an in vitro ischemia, 3.5 hours of Oxygen Glucose Deprivation (OGD) was performed. Specifically, K-560, K-350, or DMSO was added to the medium at a final concentration of 10 μM 30 minutes before OGD was performed, and the primary neuronal cell culture medium was defined as a glucose-free medium (OGD medium). The cells were incubated in a 95% N ₂ , 5% CO _2, 1% O ₂ environment for 3.5 hours. After incubation, replace the OGD medium with Neurobasal + B27 + P / S / Amp medium (containing 10 μM K-560, K-350 or DMSO at the final concentration) and culture under normal conditions. After 24 hours from OGD loading, After 48 hours and 72 hours, the culture medium was collected and subjected to LDH assay (Roche Cytotoxicity Detection Kit) according to the conventional method, and the ratio of dead cells was measured. As a control showing 100% cell death, a sample containing N-methyl-D-aspartic acid (NMDA) with a final concentration of 2 mM was used. The ratio of dead cells was determined from the relative value of absorbance (LDH activity).

  Here, K-350 is a compound having no thienyl group and diketopiperazine group.

(2) Results FIG. 9A shows a graph comparing the proportion of dead cells in cells to which each test substance was added 24 hours after loading with OGD. Addition of K-350 reduced the proportion of dead cells compared to cells to which DMSO, a negative control, was added. Furthermore, the addition of K-560 markedly decreased the proportion of dead cells compared to the addition of DMSO.

  FIG. 9B shows the result 72 hours after the OGD load. Addition of K-560 significantly reduced the percentage of dead cells compared to the negative control.

  From this, it was suggested that K-560 and the like having a 2-aminobenzamide structure having a thienyl group and a diketopiperazine structure have a protective action against cerebral ischemia and may be less toxic to nerve cells.

Example 15: Neuronal cell protective action of a novel HDAC inhibitor compound having a 2-aminobenzamide structure having a thienyl group and a dioxopiperazine structure Using a primary neuronal cell culture system established from rat cerebral cortex as in Example 14, We also examined the neuronal protective effects of K-852 and K-853 other than 10 μM K-560 at a final concentration 24 hours after OGD loading and OGD loading. Here, K-852 is a compound having a 2-aminobenzamide structure having a thienyl group and a dioxopiperazine structure, and K-853 has a 2-aminobenzamide structure having a thienyl group, but a dioxopiperazine structure. Is a compound that does not have.

  As shown in FIG. 10, K-852 suppressed cell death caused by ischemia, similar to K-560.

  From this, it was revealed that a novel HDAC inhibitor compound having a 2-aminobenzamide structure having a thienyl group and a diketopiperazine structure has a protective action against cerebral ischemia and has little toxicity to nerve cells.

Example 16: Neuronal protective effect against excitotoxicity of K-560
In order to examine whether K-560 has an effect of protecting neurons from cell death caused by excitotoxicity, the following experiment was conducted.

(1) Method As described above, a primary neuron culture system was established from the E16 rat cerebral cortex, and cells 10 to 12 days after the culture were subjected to the experiment. 72 hours before kainic acid addition TSA (Trichostatin A: final concentration 50 nM), SAHA (Vorinostat: final concentration 150 nM), VPA (valproic acid: final concentration 0.5 mM), K-560 (final concentration 10 μM), or MS-275 (final concentration 1 μM) was added in advance, and after culturing in the presence of each test substance, kainic acid was added to the medium so that the final concentration was 1 mM, and excitotoxic loading with kainic acid was performed. 24 hours after the addition of kainic acid, LDH assay was performed in the same manner as in Example 14 to measure the ratio of dead cells.

  Where TSA and SAHA are pan-HDAC inhibitors, VPA is an inhibitor of HDAC 1, 2, 3, 8, 4, 5, 7, and 9 and MS-275 is HDAC 1, 2, and 3 inhibitors.

(2) Results As shown in FIG. 11, cell death by addition of kainic acid was significantly suppressed in cells pretreated with K-560, compared to cells pretreated with a test substance other than K-560. .

  This revealed that the novel HDAC inhibitor compound having a 2-aminobenzamide structure having a thienyl group and a diketopiperazine structure has a protective action against excitotoxicity.

Example 17: Neuronal cell protective effect of K-560 in Parkinson's disease animal model
To examine whether K-560 has a protective effect on nigrodopamine cells in a pathologic model of Parkinson's disease treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) The experiment was conducted.

(1) Method
To C57BL6 / J mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Fluka Biochem) was intraperitoneally administered at a dose of 30 mg / kg every 24 hours for a total of 5 times. K-560 (45 mg / kg) was administered by oral administration every other day (every other day) from 2 days before MPTP administration, a total of 7 times. The administration groups are as follows:
NS group (only physiological saline administration)
KS group (K-560 administration only)
NM group (MPTP and physiological saline administration)
KM group (MPTP and K-560 administration).

  The physiological saline was administered according to the administration of each test substance.

  Two days and 21 days after MPTP administration, the mice were perfused and fixed with 4% paraformaldehyde / PB under anesthesia, and the tissue was removed and postfixed with 4% paraformaldehyde / PB to prepare frozen sections. Substantia nigra TH (tyrosine hydroxylase) was immunostained by the floating method, and the number of positive cells was counted under a microscope. Immunostaining was visualized with peroxidase and DAB according to a conventional method using an anti-TH antibody (CALBIOCHEM) as a primary antibody.

  To count TH positive cells, create a coronal section (thickness 20 μm) of the entire substantia nigra, perform TH staining on a total of 15 sections every 4 sheets, count the number of TH positive cells in each section, and total 15 The total of TH positive cells was graphed.

(2) Results FIG. 12A shows TH immunostained images of each group. As is clear from the photograph, a decrease in TH positive cells was observed in the NM group.

  FIG. 12B is a graph showing the number of TH positive cells two days after MPTP administration, and FIG. 12C is a graph showing the number of TH positive cells 21 days after MPTP administration. As shown in FIG. 12B, two days after MPTP administration, the number of TH positive cells was reduced to about half in the NM group compared to the NS group or the KS group, but in the KM group, it was significant compared to the NM group. The number of TH positive cells recovered. Similarly, even 21 days after MPTP administration, the number of TH positive cells was significantly recovered in the KM group as compared to the NM group (FIG. 12C).

  From these results, it became clear that K-560 exhibits a neuronal protective effect in an animal model of Parkinson's disease.

Example 18: Neuroprotective action in an experimental model of Parkinson's disease in vitro Next, the neuronal protective action of a novel HDAC inhibitor compound having a 2-aminobenzamide structure having a thienyl group other than K-560 and a diketopiperazine structure is confirmed. Therefore, the following experiment was conducted.
(1) Method SH-SY5Y cells, which are cultured human neuroblastoma cells, were cultured in DMEM medium supplemented with 10% FBS and penicillin / streptomycin. Prior to treatment with 1-methyl-4-phenylpyridinium (MPP +), the medium was replaced with 10 μM retinoic acid and 3% FBS-added DMEM, and cultured for 8 days to differentiate SH-SY5Y cells.

  MPP + was added to the differentiated SH-SY5Y cells to a final concentration of 1 mM or 2 mM. K-852 or K-853 had a final concentration of 1 μM. Simultaneously with the addition of MPP +, K-852 or K-853 was added. Cells were collected 48 hours after the addition of MPP + and the percentage of dead cells was determined by LDH assay. DMSO represents a negative control.

(2) Results As shown in FIG. 13, when MPP + was present at a final concentration of 1 mM or 2 mM, K-852 had a reduced proportion of dead cells compared to the negative control.

  From this, it was confirmed that the novel HDAC inhibitor compound having a 2-aminobenzamide structure having a thienyl group and a diketopiperazine structure exhibits a protective effect on nerve cells in an experimental model of Parkinson's disease.

Reference Example: Effect of Ethyl Compound in vitro in Parkinson's Disease Experimental Model For the Ethyl compound shown in Table 1 and FIG. 3 which are known compounds having a thienyl-2-aminobenzamide structure, the same experiment as in Example 18 was performed in vitro. It was confirmed whether or not it exhibited a neuroprotective action in an experimental model of Parkinson's disease.
(1) Method The experimental method was changed to K-852 and K-853 of Example 5 using a final concentration of 100 nM, 1 μM, 5 μM, and 10 μM Ethyl compound, and MPP + had a final concentration of 0 mM or 3 mM. Except that, it is the same as the fifth embodiment.
(2) Results As shown in the right of FIG. 14, in the absence of MPP + (MPP−), cells to which the Ethyl compound was added increased dead cells depending on the concentration of the Ethyl compound. From this, it was clarified that a high concentration of Ethyl compound shows cytotoxicity.

  Moreover, even when the Ethyl compound was added in the presence of 3 mM MPP + (MPP + (3 mM)), the ratio of the number of dead cells did not change, and it was confirmed that the Ethyl compound has no neuroprotective action.

Example 19: Comparison of Toxicity of Test Compounds To demonstrate that the compounds of the present invention are less toxic than the known compound MS-275, DMSO (DMSO ( Negative control), MS-275, K-560, or K-852 was administered, and LDH activity was measured over time. MS-275, K-560, and K-852 were added to the medium so that the final concentrations were 3 μM and 10 μM, respectively.

  As a result, as shown in FIG. 15, the LDH activity of the cells treated with 3 μM or 10 μM K-560 and K-852 at 24, 48 and 96 hours after the addition of the test drug was determined by adding MS-275. Lower value. This indicates that the compound of the present invention is less toxic than MS-275.

Example 20: Neuronal cell protective effect of K-852, K-853, and K-854 in OGD loading Using the same experimental system as in Example 15 , neuronal cell protection of K-852, K-853, and K-854 The effect was confirmed.

  As a result, as shown in FIG. 15, neuronal cell death was suppressed with K-852 and K-854, and particularly with K-852, a significant difference (stars: p <0.05) in the Student's t-test compared to the control. ) Was recognized.

Example 21: N-cell protective action of K-562, K-563, K-564, K-560, and K-856 under OGD loading Using the same experimental system as in Example 15, K-562, K-563 , K-564, K-560, and K-856 were confirmed for their neuroprotective effects.

  As a result, as shown in FIG. 16, no significant difference was observed compared with the control at 24 hours after OGD loading, but K-564 and K-856 suppressed neuronal cell death at 48 hours after OGD loading. In the Student's t test, a significant difference (asterisk: p <0.05) was observed.

Example 22: Neuroprotective action of K-562, K-563, K-564, K-560, and K-856 in an in vtro Parkinson's disease experimental model K-562 using the same experimental system as in Example 18 , K-563, K-564, K-560, and K-856 were confirmed for their neuronal protective effects.

  As a result, as shown in FIG. 17, K-856 suppressed neuronal cell death, and a significant difference (asterisk: p <0.05) was recognized in Student's t test.

Claims (15)

A neuroprotective agent comprising a compound represented by the following general formula (A) or a pharmaceutically acceptable salt thereof:

{Where
R ′ represents a thienyl group, a furanyl group, a phenyl group, or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (A-2):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² is combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. May be formed];
R ^x is an optionally substituted alkyl group having 1 to 6 carbon atoms, or a hydrogen atom;
n is an integer from 1 to 4;
V is -CO-NH- or a direct bond;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}. The neuroprotective agent according to claim 1, wherein R ^a is a carbonyl group, and R ^c is a group represented by the general formula (A-2). The neuroprotective agent according to claim 1 or 2, wherein n is 1. The neuroprotective agent according to any one of claims 1 to 3, wherein R 'is a thienyl group, a furanyl group, a phenyl group, or a chlorine atom. The neuroprotective agent according to claim 1, comprising a compound represented by the following general formula (IV), or a pharmaceutically acceptable salt thereof:

(In the formula, R ′ is a thienyl group, a furanyl group, a phenyl group, or a chlorine atom.) The neuroprotective agent according to claim 1, comprising a compound represented by any one of the following formulas (1), (18), (2) and (5), or a pharmaceutically acceptable salt thereof:

  The neuroprotective agent according to any one of claims 1 to 6, which is used for prevention or treatment of nervous system diseases.   The neuroprotective agent according to claim 7, wherein the nervous system disease is a neurodegenerative disease.   Neurodegenerative diseases are Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's dementia, cerebrovascular dementia, polyglutamine disease, multiple sclerosis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuritis, Or the neuroprotective agent of Claim 8 which is multifocal motor neuropathy.   The neuroprotective agent according to claim 7, wherein the nervous system disease is an ischemic brain disease. A compound represented by the following general formula (A), or a pharmaceutically acceptable salt thereof:

{Where
V is -CO-NH- or a direct bond;
When V is —CO—NH—, R ′ represents a furanyl group, a phenyl group, or a halogen atom;
When V is a direct bond, R ′ is a thienyl group, a furanyl group, a phenyl group, or a halogen atom;
Two of R ^a , R ^b , R ^c , and R ^d are carbonyl groups, and the other two are the same or different and are represented by the following general formula (A-2):

[R ¹ and R ² are the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted aryl group, an optionally substituted cyclohexyl group, or an optionally substituted group. When it is a tetrahydropyranyl group and R ^b or R ^d is a group represented by the above formula (A-2), R ¹ or R ² is combined with R ^x to form a saturated ring having 3 to 6 carbon atoms. May be formed];
R ^x is a hydrogen atom or an optionally substituted alkyl group having 1 to 6 carbon atoms;
n is an integer from 1 to 4;
W, X, Y, and Z are the same or different and are CH or a nitrogen atom}. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R ^a is a carbonyl group and R ^c is a group represented by the general formula (A-2). The compound according to claim 11 or 12, wherein n is 1, or a pharmacologically acceptable salt thereof.
The compound according to claim 11 or a pharmaceutically acceptable salt thereof represented by any one of the following formulas (2), (5), (3), (4) and the following formula (IV):

(In the formula, R ′ is a furanyl group or a phenyl group.) The pharmaceutical composition used for the treatment and / or prevention of the cancer containing the compound as described in any one of Claims 11-14, or its pharmaceutically acceptable salt.

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