WO2014046391A1

WO2014046391A1 - Pharmaceutical composition for treating or preventing ptpς-mediated diseases

Info

Publication number: WO2014046391A1
Application number: PCT/KR2013/007781
Authority: WO
Inventors: 류성언; 박황서; 팜녹첸; 전태진
Original assignee: 한양대학교 산학협력단
Priority date: 2012-09-24
Filing date: 2013-08-29
Publication date: 2014-03-27

Abstract

The present invention relates to a pharmaceutical composition for treating or preventing protein tyrosine phosphatase sigma (PTPσ)-mediated diseases, and provides a pharmaceutical composition for treating or preventing PTPσ-mediate diseases, containing a compound of chemical formulas 1-7 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention can inhibit the dephosphorylation activity of PTPσ even at a low temperature, and thus can be useful for treating or preventing PTPσ-mediated diseases.

Description

【Specification】

[Name of invention]

ΡΤΡ σ Pharmaceutical Compositions for the Treatment or Prevention of Mediated Diseases

The present invention has been made by the project number 2011-0030030 under the support of the Ministry of Science, ICT and Future Planning, the research management specialized organization of the project is the Korea Research Foundation, the research project name is "biomedical technology development project next generation application ohmic", the research project name is " Identification of large-capacity tertiary structure for the activation domain of the bispecific dephosphoryase group ", the lead institution is Hanyang University, and the period of research is 2011. 09. 01 ~ 2014. 08. 31.

This patent application claims priority to Korean Patent Application No. 10-2012-0106128 filed with the Korean Patent Office on September 24, 2012, the disclosure of which is hereby incorporated by reference.

The present invention relates to a pharmaceutical composition for treating or preventing ΤΤΡσ mediated diseases.

Background Art

Since it was found that chondroitin sulfate proteoglycans interfere with the functional regeneration of damaged nerves, many efforts have been made to overcome the problem of inhibiting nerve regeneration by inhibiting the activity of CSPG and to develop therapeutic strategies for neurological diseases. (Yiu, G. et al. CN. Rev. Neurosci. 2006, 7, 617). Research over the last decade has shown that neuronal regeneration inhibitory activity of CSPG is mediated by Protein Tyrosine Phosphatase sigma (Shen, Y. et al. (Science 2009, 326, 592), Sa ieha). , PS et al. (Mol. Cell. Neurosci. 2005, 28, 625), McLean, J. et al. (J. Neurosci. 2002, 22, 5481)). (Ery et al. CGlia 2010, 58, 423). Moreover, the enzyme activity impairment of the ΡΐΡσ is responsible for the activity of phosphorylated kinases related to downstream of the neural regeneration signal pathway. As it has been found to promote (Coles, CH et a 1. (Science 2011, 332, 484)), it is expected that the inhibitor of enzyme activity of ΡΤΡσ will be effective in the treatment of various neurological diseases caused by the inhibition of nerve regeneration. It is increasing. Meanwhile, ΡΤΡσ (Protein Tyrosine Phosphatase sigma) is a dephosphorylation enzyme present as a transmembraine receptor type that penetrates the cell membrane, and an enzyme that removes phosphate groups from phosphorylated tyrosine residues of ligand substrates. to be. The ΡΤΡσ, composed of 1948 amino acids, has two ΡΤΡ intracellular domains, D1 and D2. Among them, the D2 domain was found to play a role in regulating signaling mediated by the ΡΤΡσ without catalytic activity of dephosphorylation, and the D1 domain substantially dephosphorylations the substrate to form a catalytic cysteine residue ( X-ray crystallographic analysis confirmed that Cysl589) was composed of a structure surrounded by the WPD loop.

In line with the structural features of ΡΤΡσ, many researchers have designed and screened the enzyme activity inhibitor of ΡΤΡσ at the small molecule level, but inhibitors that can effectively inhibit the enzyme activity of ΡΤΡσ yet. Is not known.

[Content of invention]

Problem to be solved

It is an object of the present invention to provide a pharmaceutical composition for treating or preventing ΡΤΡσ mediated diseases.

[Task solution]

In order to achieve the above object, one aspect of the present invention is a compound containing the compound of Formula 1 to Formula 7 or a pharmaceutically acceptable salt thereof as an active ingredient, for the treatment or prevention of ΡΤΡσ (Protein Tyrosine Phosphatase sigma) mediated diseases It provides a pharmaceutical composition.

Any one selected from the group consisting of the side is the compound represented by the formula 1 to 7 to the _invention, a composition comprising an acceptable salt thereof with one or more chemical compounds and medicaments thereof as an active ingredient to the target (subject) It provides a method for preventing or treating ΡΤΡσ mediated disease comprising the step of administering.

【Effects of the Invention】

The pharmaceutical composition of the present invention has an effect of inhibiting the dephosphorylation activity of the ΡΤΡσ even at low concentrations, and may be usefully used for the treatment or prevention of ΡΤΡσ mediated diseases.

However, the effects of the present invention are not limited to the above-mentioned effects, and other effects not mentioned will be clearly understood by those skilled in the art from the following description.

[Brief Description of Drawings]

1 is the lowest-energy cxinformat ion that simulates the binding of compounds of Formulas 1-7 to the active site of the ΡΤΡσ D1 domain.

2 is a structure simulating a structure in which a compound of Formula 101 is bound to an active site of a ΡΤΡσ D1 domain.

3 is a structure simulating the structure in which the compound of Formula 201 is bound to the active site of the ΡΤΡσ D1 domain.

Figure 4 shows the results of cell experiments for the verification of the activity of ΡΤΡσ inhibitors.

5A and 5B show dose response curves of compounds.

[Specific contents to carry out invention]

Hereinafter, the present invention will be described in detail.

1. 2-([1,2,4] triazolo [3,4-1)] [1,3,4] thiadiazol-3-yl) quinoline derivative One aspect of the invention is a derivative of 2-([1,2,4] triazolo [3,4-b] [1,3,4] thiadiazol-3-yl) quinoline. l, 2,4] triazok) [3,4-b] [l, 3,4] 1: hiacliazol-3-yl) ciuinolinee '). The '2' ([1,2,4] triazolo [3,4 ')] [1,3,4] thiadiazol-3-yl) quinoline derivative of the present invention is a chemical It is a compound having a structure.

[Formula 1]

1) Rll, R12, R13, R14. R15 and R16

In Formula 1, Rll, R12, R13, R14. R 15 and R 16 may be independently 'hydrogen (H)' or 'a substituent which may form a covalent bond with another molecule'.

The substituents capable of forming covalent bonds with other molecules include ① a group having a large electronegative atom or an atom rich in a non-covalent electron pair, or ② an atom having a high electronegative atom or an abundant non-covalent electron pair Branches can include functional groups.

When the substituent which can form a covalent bond with another molecule is composed of a functional group ¹ having an atom having a large electronegativity or an atom rich in a non-covalent electron pair, the substituent which can form a covalent bond with the other molecule 'May be a functional group 1 to a functional group 10 illustrated in Table 0 below. Therefore, Rll, R12, R13, R14, R15, and R16 may be any one selected from the group consisting of hydrogen and functional groups 1 to 10 of Table 0 independently of each other. In addition, Rll, R12, R13, R14, R15 and R16 are each independently composed of hydrogen and functional groups 1 to 7 of Table 0 below It is more preferably any one selected from the group, and Rll, R12, R14, R15 and R16 is most preferably one selected from the group consisting of hydrogen and functional groups 1 to functional groups independently from each other, but is not limited.

TABLE 0

In addition, when the substituent which can form a covalent bond with another molecule includes a functional group having an atom having a large electronegativity or an atom rich in a non-covalent electron pair, it may form a covalent bond with the other molecule. Substituent 'may be a structure in which the functional groups listed in Table 0 are bonded to a linker. For example, when the functional group included in the substituent which can form a covalent bond with another molecule is functional group 4 of Table 0, Rll, R12, R13, and R14.

R15 or R16 may have a structure of 's Linke' ᅳ CX ^3. The linker may be an atom or non-covalent electron pair having a high electronegativity included in the substituent which may form a covalent bond with another molecule. Without affecting the chemical or physical properties of the functional groups having these rich atoms,

It is a functional group which connects the "functional group which has an atom with a large electronegativity or an atom rich in a lone pair" to the quinoline ring of the said Formula (1). Examples of such linkers include straight chain C1-C10 alkyl or branched α-cioalkyl. Hereinafter, Rll, R12, R13, R14, illustrated in Table 0 above. The functional groups that may be included in R15 or R16 are described in detail.

(1) functional group 1 to functional group 4

In the functional groups 1 to 4, X is independently of one another or optionally a halogen atom. In particular, X is preferably fluorine (F) or chlorine (C1) having a high electronegativity. The functional groups 1 to 4 may form hydrogen bonds with hydrogen in other molecules through the halogen atom having a relatively high electronegativity.

(2) functional group 5 and functional group 6

The functional group 5 may form a hydrogen bond with hydrogen in another molecule through a nitrogen atom. In particular, nitrogen has a high electronegativity and has a non-covalent electron pair, and thus can form a hydrogen bond with hydrogen in another molecule well. In addition, the functional group 6 may form a hydrogen bond with hydrogen in another molecule through an oxygen atom. In particular, oxygen in the functional group 6 has a large electronegativity, has a partial negative charge due to the resonance structure, and has a non-covalent electron pair, which is very advantageous for forming hydrogen bonds.

(3) functional group 7

"ᅳ R ″ i ¹ 1; j In the functional group 7, R 111 may be hydrogen or hydroxy.

In addition, R111 may be straight-chain C1-C10 alkyl, more preferably straight-chain C1-C5 alkyl, most preferably straight-chain C1-C3 alkyl. For example, when R111 is a straight chain C4 alkyl, R111 is n-butyl. In addition, R111 is branched C3-C10 alkyl, more preferably Branched C3-C7 alkyl, most preferably branched C3-C5 alkyl. For example, when R111 is branched C3 alkyl, R111 is isopropyl. In addition, R 111 may be C 1 -C 10 alkoxy, more preferably C 1 -C 5 alkoxy, most preferably C 1 -C 3 alkoxy. For example, when R111 is C2 alkoxy, R111 is ethoxy.

In addition, when two or more of the R11 to R16 is the functional group 7, and R111 is hydrogen, or linear or branched alkyl, it is connected to each other to the R111 selected from R11 to R16 to form a ring structure Can be formed. For example, when Rll, R14, R15, and R16 are hydrogen, and R12 and 13 are configured with a substituent of the functional group 7, quinoline of Formula 1

The ring is

It may have a structure such as H. As described above, when two of R11 to R16 form a ring structure connected to each other with an alkyl group of R111, R111 connecting the two oxygen atoms is linear or branched CI—C5 alkyl, preferably linear or branched. It may be C1-C3 alkyl of the topography.

The functional group 7 has a high electronegativity and can form a hydrogen bond with hydrogen in another molecule through an oxygen atom having a non-covalent electron pair.

(4) functional groups 8 and 9

In the functional groups 8 and 9, R112 may be any substituent selected from the group consisting of hydrogen, hydroxy, halogen, linear C1-C10 alkyl, branched C3-C10 alkyl, and C1-C10 alkoxy. have. In addition, R112 may be C5-C10 aryl, more preferably C5-C7 aryl.

In addition, R112 may be C4-C10 heteroaryl, more preferably C4-C7 heteroaryl containing at least one of nitrogen and oxygen atoms.

The aryl or heteroaryl may be one or more carbons are substituted with linear or branched alkyl, more preferably linear or branched C1-C5 alkyl.

The halogen is as described above in the description of the functional groups 1 to 4, and the alkyl and the alkoxy are the same as described in the description of the functional group 7.

The functional group 8 and the functional group 9 may also form hydrogen bonds with hydrogen in other molecules through an oxygen atom having a high electronegativity and a non-covalent electron pair like the functional group 7.

(5) functional group 10

In the functional group 10, R113 and R114 may be independently any substituent selected from the group consisting of hydrogen, linear C1-C10 alkyl and branched C3-C10 alkyl, and as for the alkyl As described above in the description of functional group 7.

The functional group 10 has a large electronegativity and may form a hydrogen bond with hydrogen in another molecule through a nitrogen atom having a non-covalent electron pair.

2) R17

In Formula 1, R17 may be any substituent selected from the group consisting of hydrogen, linear C1-C10 alkyl, branched C1-C10 alkyl, C1-C10 alkoxy and C5-C10 aryl independently of one another. have.

R17 may be hydrogen.

In addition, R17 is independently of each other straight C1-C10 alkyl, more preferably straight C1-C5 alkyl, most preferably straight C1-C3 It may be alkyl. For example, when R17 is straight C4 alkyl, R111 is n-butyl.

In addition, R17 may be branched C3-C10 alkyl, more preferably branched C3-C7 alkyl, most preferably branched C3-C5 alkyl. For example, when R17 is branched C3 alkyl, R17 is isopropyl.

In addition, R17 may be C1-C10 alkoxy, more preferably C1-C5 alkoxy, most preferably C1-C3 alkoxy. For example, when R17 is C2 alkoxy, R17 is ethoxy.

In addition, R17 may be C5-C10 aryl, more preferably C5-C7 aryl.

In addition, R17 may be C4-C10 heteroaryl, more preferably C4-C7 heteroaryl containing at least one of nitrogen and oxygen atoms. The aryl or heteroaryl may be one or more carbons are substituted with straight or branched alkyl, more preferably straight or branched C1-C5 alkyl. In addition, the aryl or heteroaryl may be one or more carbon is substituted with functional group 1 to functional group 10 of Table 0.

For example, when R17 is C5-C10 aryl, R17 may be the following functional group 11.

[Function 11]

In the functional group 11, n is an integer of any one of 0 to 10, more preferably an integer of any one of 0 to 5, most preferably an integer of any one of 0 to 3. In addition, in the functional group 11, R171 to R175 are independently of each other hydrogen, linear C1-C10 alkyl, branched C1-C10 alkyl and It may be any one functional group selected from the group consisting of functional groups 1 to 10 functional groups in Table 0.

For example, when R17 is heteroaryl, R17 may be the following functional group 12.

[Function 12]

In the functional group 12, m is an integer of any one of 0 to 10, more preferably an integer of any one of 0 to 5, most preferably an integer of any one of 0 to 3. In addition, in the functional group 12, A is oxygen (0) or nitrogen (N) and R176 to R178 are each independently hydrogen, straight-chained C1-C10 alkyl, branched C1-C10 alkyl, and functional groups 1 to 4 in Table 0 above. It may be any one functional group selected from the group consisting of functional groups 10.

3) Example

If the compound represented by the formula (1) is more specifically illustrated as follows.

[Formula 101]

2. (5E) -5-[(1 ᅳ phenyl-L-pyrid-2-yl) methylidene] imidazolidine-2,4-dione derivative

Another aspect of the invention is a derivative of (5Ε) -5 [(1-phenyl-1H-pyr-2-yl) methylidene] imidazolidine-2,4-dione (derivatives of '(5Ε) -5 -[(1-pheny 1 -IH-pyr ro 1-2-y 1) methyl idene] imidazol idine ᅳ 2,4_dione '). The '(5Ε) -5-[(1-phenyl-1H-pyr-2-yl) methylidene] imidazolidine—2 ′ 4-dione derivative of the present invention is represented by the following Chemical Formula 2 It is a compound which has.

[Formula 2]

1) R21, R22 and R23

In Formula 2, R21, R22, and R23 may be independently a hydrogen (H) or a substituent that may form a covalent bond with another molecule, but at least one of R21, R22, and R23 may be It is preferable that it is a substituent which can form a covalent bond with another molecule.

The substituent that can form a covalent bond with another molecule

It may comprise a functional group having atoms having a high electronegativity or an atom rich in a lone pair, or ② a functional group having atoms having a high electronegativity or an atom rich in a lone pair.

The 'substituents that can form covalent bonds with other molecules'

¹ when a group having a large electronegativity or a group having an atom rich in a non-covalent pair of electrons, 'the substituent that can form a covalent bond with another molecule' is the number of functional groups 1 to 10 groups illustrated in Table 0 above have. Accordingly, R21, R22 and R23 may be any one selected from the group consisting of hydrogen and functional groups 1 to 10 of Table 0 independently of each other (except when R21, R22 and R23 are all hydrogen) box). In addition, more preferably, R21, R22 and R23 is independently selected from hydrogen and any one selected from the group consisting of functional groups 5 to 10 of the table 0, wherein R21, R22 and R23 are independently hydrogen, one of the most preferred one is selected from the group consisting of functional groups 6 and 8 _i functional group is not limited to this.

When the substituent capable of forming a covalent bond with another molecule includes a functional group having an atom having a large electronegativity or an atom rich in a non-covalent electron pair, it may form a covalent bond with the other molecule. Substituent 'may be a structure in which the functional groups listed in Table 0 are bonded to a linker. For example, when the functional group included in the substituent capable of forming a covalent bond with another molecule is functional group 4 of Table 0, R21, R22 or R23 may have a structure of L ^mker_CX 3 ". In the present specification, ^ L— X,

^ -L-CH ₂ X ^ -L-CHX ₂

¾_ | — 门 ᅳ 5 I

^ L u Km L c

This description shows that the functional groups in Table 0 are linked by a linker. The linker does not affect the chemical or physical properties of the 'functional group having an atom having a large electronegativity or an atom rich in a non-covalent electron atom included in a substituent capable of forming a covalent bond with another molecule, It is a functional group that connects a 'functional group having an atom having a large electronegativity or an atom rich in a lone pair' to the benzene ring of Formula 2. Examples of such linkers are straight chain C1-C10 alkyl or branched C1-C10 alkyl. Regarding the functional groups which may be included in R21, R22 or R23, illustrated in Table 0, "1. 2-([1,2,4] triazolo [3, 4- b] the description of R11 to R16 in the section [1,3,41thiadiazol-3-yl) quinoline derivatives is used herein, and a detailed description thereof is omitted.

However, when two or more of the R21 to R23 is the functional group 7, and the R111 is hydrogen, or linear or branched alkyl, the ring structure is connected to each other to any one of the R111 selected from the R21 to R23. Can be formed. For example, when R21 is hydrogen, and R22 and R23 is composed of a substituent of the functional group 7, the benzene ring of Formula 2 is

Like a mall

When two of R21 to R23 form a ring structure connected to each other with an alkyl group of R111, R111 connecting the two oxygen atoms is linear or branched CI— C5 alkyl, preferably linear or branched C1- It may be C3 alkyl.

2) R24 and R25

In Formula 2, R24 and R25 are represented by "1.2z ([1, 2, 4] triazolo [3, 4-b] [l, 3, 4] thiadiazol-3-yl) quinoline derivative" Same as R17. Thus, R24 and R25 are each independently hydrogen, straight-chained C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C4-C10 heteroaryl and C5 containing at least one of the atoms of oxygen and nitrogen It may be any one substituent selected from the group consisting of -C10 aryl.

As for the substituents constituting the R24 or R25 is "1. z

([1,2,4] triazolo [3,4-b] [l, 3,4] thiadiazol-3-yl) quinoline derivatives, including descriptions of R17 in the item, and details thereof Is omitted.

3) Example

When the compound represented by the formula (2) is more specifically illustrated as follows. [Formula 201]

[Formula 205]

3. (Z) -5-((3- (3- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol 4-yl) methylene) -2-thioxothiazolidin-4-one derivative

Another aspect of the invention is (Z) -5-((3- (3- (benzyloxy) phenyl) -1 -phenyl-1H-pyrazol-4-yl) methylene) -2-thioxothiazolidine Derivatives of 4-one (derivatives of '(Z) -5-((3- (3- (benzy 1 oxy) heny 1)-1-pheny 1-ΙΗ-pyr azol -4-y 1) methyl ene) 2-thioxothiazolidin-4-one ') ¾- provides. '(VII) -5-((3- (3- (benzyloxy) phenyl) -1-phenyl-1H-pyrazol-4-yl) methylene) -2-thioxothiazolidine-4 of the present invention The -one derivative is a compound having a chemical structure represented by the following formula (3).

[Formula 3]

1) R31

In Formula 3, R31 is hydrogen (Η), straight-chain C1-C10 alkyl, branched C3-C10 alkyl, at least one carbon is a "functional group having an atom having a high electronegativity or an atom rich in a non-covalent electron pair" Substituted linear alkyl and one or more carbon may be any substituent selected from the group consisting of branched alkyl substituted with 'a group having a high electronegative atom or an atom rich in a non-covalent electron pair'.

R31 may be hydrogen. ·

In addition, R31 may be linear C1-C10 alkyl, more preferably straight-chain C1-C5 alkyl, most preferably straight-chain C1-C3 alkyl. For example, when R211 is a straight chain C4 alkyl, R211 is η-butyl (η_butyl).

In addition, R31 may be branched C3-C10 alkyl, more preferably branched C3-C7 alkyl, most preferably branched C3-C5 alkyl. For example, when R211 is branched C3 alkyl, R211 is isopropyl (i so-propy 1).

As described above, even when R31 is hydrogen or nonpolar alkyl, the compound of Formula 3 is represented by '2 ᅳ thioxothiazolidin-4-one (2-

thioxothiazol idin4-one) ¹ part (

In oxygen and sulfur Unpaired electron pairs can form hydrogen bonds well with hydrogen in other molecules.

In addition, in the linear or branched alkyl as described above, R31 may be substituted with one or more carbon 'functional group having an atom having a large electronegativity or an atom rich in a lone pair'. By such substitution, the '2-thioxothiazolidin-4-one' moiety may form a hydrogen bond with hydrogen in another molecule better.

The linear or branched alkyl may be substituted with any one or more carbon atoms selected from the group consisting of functional groups 1 to 10, and the linear or branched alkyl may be substituted with one or more carbon groups 5 to 10 More preferably, the linear or branched alkyl is substituted with any one or more selected from the group consisting of functional groups 6 to 8, but is not limited thereto. . Regarding the functional groups 5 to 10, the "1.2-([1,2,4] triadro [3,4-b] [l, 3,4] thiadiazol-3-yl) quinoline derivative" Is the same as described in the section ".

2) R32, R33, R34, R35 and R36

In Formula 3, R32 to R36 may be any substituent selected from the group consisting of hydrogen, hydroxy, halogen, and halogenated alkyl independently from each other.

R32 to R36 may be hydrogen.

In addition, R32 to R36 may be hydroxy or halogen. When R32 to R36 are halogen, R32 to R36 are preferably fluorine or chlorine.

In addition, the R32 to R36 may be independently halogenated alkyl. The alkyl is straight chain CI—C10 alkyl, more preferably straight chain C1-C5 alkyl, most preferably straight chain C1-C3 alkyl, or branched C3-C10 alkyl, more preferably branched. Topographic C3-C7 alkyl, most preferably C3-C5 alkyl. The straight or branched alkyl is characterized in that at least one carbon is at least one halogen atom, more preferably fluorine or chlorine. It may be substituted. For example, halogenated alkyl having 1 carbon may be functional group 2 to functional group 4.

3) Example

When the compound represented by the formula (3) is more specifically illustrated as follows.

[Formula 301]

[Formula 304]

Formula 306]

[Formula 308]

[Formula 312]

4. (6E) -6-benzylidene-7-imino-6, gdihydro-5H- [1,2] oxazolo [2,3-a] pyrimidine-5-silver derivative

Another aspect of the invention relates to (6E) -6-benzylidene-7-imino-6,7-dihydro-5H- [1,2] oxazolo [2,3-a] pyrimidin-5-one. Derivative (der ivat ives of ^* (6E) -6- benzy 1 i dene ᅳ 7_ imi no ^~ 6, 7_d i hydr 5H- [1,2] oxazo lo [2,3-a] yr imidi n ᅳ 5 ᅳ Provide one '). The '(6-6-benzylidene-7-imino-6, gdihydro-511— [1,2] oxazolo [2,3-a] pyrimidin-5-one derivative of the present invention' It is a compound which has a chemical structure represented by 4.

[Formula 4]

1) R41, R42 and R43

In Chemical Formula 4, R41, R42, and R43 are "1.2z ([1,2,4] triazolo [3,4Vb] [1,3,4] thiadiazol-3-yl) quinoline derivative" " "Is the same as R1, R12, R13, R14, 15 and R16. Thus, R41, R42 and R43 may be independently of each other 'hydrogen (H)' or 'a substituent that can form a covalent bond with another molecule', at least one of the R41, R42 and R43 It is preferable that it is a "substituent which can form a covalent bond with another molecule."

As for the substituents constituting the above R41, R42 and R43, "J. 2— ([1,2, 4] triazolo [3, 4-b] [l, 3, 4] thiadiazole-3 The descriptions of Rll, R12, R13, R14, R15, and R16 in the "-yl) quinoline derivative" section are omitted herein, and the detailed description thereof is omitted.

2) R44 and R45

In Formula 4, R44 and R45 are the same as the "2z ([1,2,4] triazolo [3,4-bJf 1, 3,4] thiadiazol-3-yl) quinoline derivative" 9 R17 same. Thus, R44 and R45 are each independently selected from hydrogen, linear C1-C10 alkyl, branched CI- C10 alkyl, C1-C10 alkoxy, nitrogen and oxygen atoms. It may be any substituent selected from the group consisting of at least one C4-C10 heteroaryl and C5—C10 aryl.

As for the substituents constituting the R44 or R45, the "1.2z ([1,2,41triazolo [3,4-b] [l, 3,4] thiadiazol-3-yl) quinoline" The description of R17 in the section "Derivatives" is used, and a detailed description thereof is omitted.

However, when R44 and R45 are alkoxy, the alkyl of R44 and R45 may be connected to each other to form a ring structure. When R44 and R45 form a ring structure, of formula (4). R44 and R45 are linked together

rescue

Can be formed, wherein A is straight or branched C1-

C5 alkyl, preferably straight or branched C1-C3 alkyl.

3) Example

When the compound represented by the formula (4) is more specifically illustrated as follows.

[Formula 401] [Formula 402]

[Formula 403]

Formula 405

[Formula 406]

5. (2Z) -2—benzylidene [1,3] thiazolo [3,2-a] benzimidazole—3 (2H) -one derivative Another aspect of the present invention is (2Z) -2-benzylidene Derivatives of [1,3] thiazolo [3,2—a] benzimidazole-3 (2H) _one derivatives of '(2Z) -2- benzy 1 i dene [1, 3] thi azo 1 o [ 3, 2 ′ a] benz imidazol-3 (2H) -one '). Said '(2 ′)-2-benzylidene [1,3] thiazolo [3,2-a] benzimidazole of the present invention

3 (2H) -one derivative 'is a compound having a chemical structure represented by the following formula (5).

[Formula 5]

1) R51, R52 and R53

In Formula 5, R51, R52 and R53 are the "1.2z ([1,2, 4] triazolo [3, 4-b] [l, 3, 4] thiadiazol-3-yl) quinoline derivatives" Is the same as "^ R11, R12, R13, R14, R15 and R16. Accordingly, R51, R52 and R53 may be independently a hydrogen (H) or a substituent capable of forming a covalent bond with another molecule, independently of each other, at least one of R51, R52 and R53 It is preferable that it is a substituent which can form a covalent bond with another molecule.

As for the substituents constituting the R51, R52 and R53, "1.

2-([1,2,4] triazolo [3, 4-b] [l, 3,4] thiadiazol-3-yl) quinoline derivatives "Rll, R12, R13 ₍ R14, R15 and The description about R16 is used, and the detailed description is abbreviate | omitted.

2) R54, R55, R56 and R57

In Formula 5, R54, R55, R56 and R57 are "1.2z ([1, 2, 4] triazolo [3, 4-b] [1,3,4] thiadiazol-3-yl)" Quinoline derivatives "^ R17. Thus, R54, R55, R56 and R57 are independently of each other hydrogen, linear C1-C10 alkyl, branched C1-C10 alkyl, CI— C10 It may be any substituent selected from the group consisting of C4-C10 heteroaryl and C5-C10 aryl containing one or more of alkoxy, nitrogen and oxygen atoms.

As for the substituents constituting the R54, R55, R56 and R57, "1. 2-([1, 2, 4] triazolo [3, 4-bJfl, 3, 4] thiadiazole-3- The description of R17 in the "I) quinoline derivative" item is incorporated herein, and the detailed description thereof is omitted.

However, when two or more of R54 to R57 are alkoxy, any two alkyl selected from R54 to R57 may be connected to each other to form a ring structure. For example, wherein R54 and R55 are hydrogen, R54 to the case of two ^'or more of R57 is alkoxy, it is selected from the above R54 to R57

Which two substituents are linked to each other ring structure

And D is straight or branched C1-C5 alkyl, preferably straight or branched C1-C3 alkyl.

3) Example

When the compound represented by the formula (5) is more specifically illustrated as follows.

Formula 501

[Formula 503]

Formula 508

[Formula 510]

[Formula 511]

[Formula 512]

[513]

Formula 514

6. 6-benzylidene-5-imino-2-phenyl-5, 6-dihydro-7H- [1,3,4] thiadiazolo [3,2—a] pyrimidine-ion derivatives

Another aspect of the present invention is 6-benzylidene-5-imino-2 ᅳ phenyl-5, 6-dihydro-7H- [1,3,4] thiadiazolo [3,2-a] pyrimidine- 7-on

Derivatives (der ivat ives of '6-benzy 1 i dene-5-imi no ^to 2-pheny 1 -5, 6-di hydr o-7H- [l, 3,4] thiadiazok) [3,2—a] pyrimidin-7-one ').

The 6-benzylidene ᅳ 5-imino-2-phenyl-5, 6-dihydro-7H- [1,3, 4] thiadiazolo [3, 2-a] pyrimidine-7- of the present invention 'One derivative' is a compound having a chemical structure represented by the following formula (6). [Formula 6]

1) Type E and Z

6-benzylidene ᅳ 5-imino-2-phenyl-5,6-dihydro- 7H- [1,3,4] thiadiazolo [3,2-a] pyrimidine represented by Formula 6 7-one derivative 'benzene

) May be bonded in the form of E or Z form with respect to the double bond.

When the benzene ring is bonded in the form of E with respect to the double bond, the compound of Formula 6 has a structure of the following Formula 61: '(6Ε) -6-benzylidene-5-imino-2-phenyl-5,6 -Dihydro-7Η- [1, 3, 4] thiadiazol to give [3, 2-a] pyrimidine-ion 'derivatives.

[Formula 61]

In addition, when the benzene ring is bonded in a Z form with respect to a double bond, the compound of Formula 6 has a structure of the following formula (62) -6-benzylidene-5-imino— 2-phenyl— 5 , 6-dihydro-77— [1, 3, 4] thiadiazole to form a [3,2-a] pyrimidine-gion 'derivative.

[Formula 62]

2) R61, R62 and R63

In Chemical Formula 6 (or Chemical Formula 61 and Chemical Formula 62), R61, R62, and R63 may be represented by the "1.2 ᅳ ([1,2,4] triazolo [3, 4 ^to b] [l, 3, 4] thia Diazol-3-yl) quinoline derivatives " ^ Rll, R12, R13, R14, R15 and R16. Accordingly, R61, R62, and R63 may be independently a hydrogen (H) or a substituent capable of forming a covalent bond with another molecule, but at least one of R61, R62, and R63 may be another molecule. It is preferable that it is a substituent which can form a covalent bond with.

As for the substituents constituting the R61, 62 and R63, the "1.

2-([1, 2, 4] triazolo [3, 4-b] [l, 3, 4] thiadiazol-3-yl) quinoline derivatives "Rll, R12, R13, R14, R15 and The description of R16 is used, and the detailed description thereof is omitted.

3) R64, R65, R66, R67 and R68

In Chemical Formula 6 (or Chemical Formula 61 and Chemical Formula 62), R64, R65, R66,

R57 and R68 are the same as "1.2-([1, 2, 4] triazolo [3, 4 ^- b] [l, 3, 4] thiadiazol-3-yl) quinoline derivative" ^ R17 . Therefore, the groups R64, R65, R66, R57 and R68 are each independently composed of a group consisting of hydrogen, linear C1-C10 alkyl, branched C1-C10 alkyl, C1-C10 alkoxy and C5-C10 aryl. It may be any one substituent selected from. As for the substituents constituting the above R64, 65, R66, R57 and R68, "1. 2-([1,2, 4] triazolo [3, 4-b] [l, 3, 4] thia The description of R17 in the "Diazol-3-yl) quinoline derivative" item is incorporated herein and the detailed description thereof is omitted.

However, when at least two of R64 to R68 are alkoxy, any two substituents selected from R64 to R68 may be linked to each other to form a ring structure.

And E is linear or branched C1-C5 alkyl, preferably straight or branched C1-C3 alkyl. For example, when R64, R65 and R68 are hydrogen, and R66 and R67 are alkoxy,

Benzene ring of Formula 6 is

It may have the same structure.

4) Example

When the compound represented by the formula (6) is more specifically illustrated as follows.

[Formula 601]

Formula 603

7. 2- (5, 6-di (furan-2-yl) —1, 2,4-triazine-3 ylthio) -N- (2-nitrophenyl) acetamide derivative

Another aspect of the invention is a derivative of 2- (5,6-di (furan-2-yl) -1,2,4-triazine-3 ylthio) -N- (2-nitrophenyl) acetamide ( derivatives of '2- (5,6-di (furan-2-yl) -l, 2,4-triazin-3-ylthio) -N- (2-nitrophenyl)

acetamide ').

The 2- (5,6-di (furan-2-yl) -1,2,4-triazine-3 ylthio) -N- (2-nitrophenyl) acetamide derivative of the present invention is It is a compound which has a chemical structure represented by 7. [Formula 7]

1) R71

In Formula 7, R71 represents "1. 2— ([1,2, 4] triazolo [3, 4-b] [1,3,4] thiadiazol-3-yl) quinoline derivative" ^ Rll , R12, R13, 14 ₍ same as R15 and R16. Thus, R71 may be a hydrogen (H) or a substituent that can form a covalent bond with another molecule, but R71 is a 'other molecule' It is preferable that it is a substituent 'which can form a covalent bond.

As for the substituents constituting the R71, the "1.2z ([1,2,4] triazolo [3, 4-b] [l, 3, 4] thiadiazol-3-yl) quinoline derivative" The descriptions of Rll, R12, R13, R14, R15, and R16 in the item "are used, and the detailed description thereof is omitted.

2) R72, R73, R74, R75, R76 and R77

In Formula 7, R72, R73, R74, R75, R76 and R77 are the three ([1,2, 4] triazolo [3, 4-bJ [l, 3, 4] thiadiazol-3-yl) And R72, R73, R74, R75, 76 and R77 are each independently hydrogen, straight-chained C1-C10 alkyl, branched C1-C10 alkyl, C1-C10 alkoxy and It may be any one substituent selected from the group consisting of C5-C10 aryl.

As for the substituents constituting R72, R73, R74, R75, R76 and R77, "1. 2-([1, 2, 4] triazol [3, 4-b] [l, 3, 4] ] Thiadiazole-3-yl) quinoline derivative "is a description of the above R17, the detailed description thereof is omitted. However, when any two or more of R72 to R74 or two or more of R75 to R77 are alkoxy, any two substituents selected from R72 to R74 or R75 to are linked to each other to form a ring structure

Z may be linear or branched Q-C5 alkyl, preferably straight or branched C1-C3 alkyl. For example, when R74 is hydrogen and R72 and R73 are alkoxy (or the R75 hydrogen and R76 and R77 are alkoxy),

The furan ring of formula 7 is

It may have a structure.

3) Example

When the compound represented by the formula (7) is more specifically illustrated as follows.

Formula 701]

8. Pharmaceutical Composition

The present invention provides a pharmaceutical composition for treating or preventing ΤΤΡσ (Protein Tyrosine Phosphatase sigraa) mediated disease, which contains the compounds of Formulas 1 to 7 or pharmaceutically acceptable salts thereof as an active ingredient.

Formula 1 to Formula 7 are represented by the "2. 2- [6- (pyrazin-2-yl) [1, 2 '4] triazolo [3, 4 ^~ b] [l, 3, 4] thiadiazole-3 Ylyl] quinoline derivatives ”to 、 7. 2- (5, 6-di (furan-2 ᅳ yl) -1,2,4-triazine-3 ylthio) -N- (2-nitrophenyl) acetamide derivative "Are the same as described above. Therefore, in this regard," 1. 2- [6- (pyrazin-2-yl) [1,2,4] triazolo [3, 4-b] [1,3,4] thiadiazol-3-yl] quinoline derivatives "to V. 2- (5,6-di (furan-2-yl) -1,2,4-triazine-3 ylthio) -N- (2-nitrophenyl) acetamide derivative ", the details of which are hereby omitted. Hereinafter, only the configuration specific to the 'pharmaceutical composition' will be described.

The compounds of Formula 1 to Formula 7 inhibit the enzyme activity of ΡΤΡσ. In a specific embodiment of the present invention, the compounds of Formula 101, Formula 201, Formula 301, Formula 401, Formula 501, Formula 601, and Formula 701 corresponding to the compounds of Formula 1 to Formula 7 are reacted with ΡΤΡσ and the enzyme activity of the ΡΤΡσ As a result of confirming the IC ₅₀ value for inhibition, the compounds of Formula 101, Formula 201, Formula 301, Formula 401, Formula 501, Formula 601 and Formula 701 have dephosphorylation activity of FTP ο at very low concentrations of 0.1 μΜ to 1.3 μΜ. By confirming that the effect of inhibiting 50% (see Table 2), it was confirmed that the compounds of Formula 1 to Formula 7 can be used as an activity inhibitor of ΡΤΡσ.

Hereinafter, the principles of the compounds of Formula 1 to Formula 7 inhibit the enzyme activity of ΡΤΡσ in the structural aspect of the formula (structural approach).

1 is the lowest-energy conformation that mimics the compounds of Formulas 1-7 bound to the active site of the ΡΤΡσ D1 domain. Referring to FIG. 1, the compounds of Formulas 1 to 7 bind to an active site of the ΡΤΡσ Dl domain to inhibit the enzyme activity of the FTP σ. That is, the compounds of Formula 1 to Formula 7 are activity inhibitors of ΡΤΡσ. As shown in FIG. 1, the compounds of Formula 1 to Formula 7 are characterized by the hydrophilic moiety acting as a surrogate of a phosphotyrosine functional group in the substrate and the ΡΤΡ loop of ΡΤΡσ. It interacts and binds to the active site of the ΡΤΡ σ Dl domain in a pattern that forms a hydrophobic interacting ion with the WPD loop, a hydrophobic moiety.

In particular, the compounds of Formulas 1 to 7 have a hydrophilic part to play an important role in inhibiting the enzyme activity of the ΡΤΡσ, wherein the hydrophilic portion forms a hydrogen bond with the ΡΤΡ loop of the ΡΤΡσ to activate the ΡΤΡσ The site is structurally stabilized and the hydrophilic moiety is placed adjacent to the Cysl589 residue of the FTP loop to inhibit dephosphorylation activity by the Cysl589.

Table 1 below shows hydrophilic moieties that serve as surrogate of phosphotyrosine functional groups in the substrate of ΡΤΡσ in the compounds of Formulas 1 to 7.

[1,2,4] thiadiazole ([1,2,4] 32010 [3,4-1] is represented by [1,2,4] triazole as shown in Table 1 above. )] [: 1,3,4] ^ 13 ^ 320½) moiety, the 2-thioxothiazolidin-4-one moiety shown in Table 1 in Formula 3 above, 2 and 4 to 6, the banshen ring shown in Table 1 and the acetamide moiety shown in Table 1 in Formula 7 are each disposed adjacent to the Cysl589 residue of the PTP loop to inhibit dephosphorylation activity by the Cysl589. The substituents capable of forming covalent bonds with other molecules in the hydrophilic moiety shown in Table 1 form hydrogen bonds with the residues constituting the active site of ΡΤΡσ to structurally stabilize the active site of ΡΤΡσ. The compounds of Formula 1 to Formula 7 serve as a surrogate of phosphotyrosine functional groups in the substrate in the manner described above to inhibit the dephosphorylation enzyme activity of the ΡΤΡσ.

In a specific embodiment of the present invention, among the compounds of Formula 1 to Formula 7, the compound of Formula 101, which is one of the compounds having the structure of Formula 1, and the compound having the structure of Formula 2 Compounds of 201 were selected to simulate the structure bound to the active site of the ΡΤΡσ D1 domain.

As a result, in the compound of Formula 101, the [1,2,4] triazole is [3,4-b] [l, 3,4] thiadiazole moiety of 3 A to 5 A in Cysl589 in the PTP loop. Adjacently spaced apart to inhibit dephosphorylation activity by Cysl589, wherein two nitrogen atoms of the [3,4-b] [1,3,4] thiadiazole moiety are Hydrogen bonds were formed with Alal591 residues and Glyl594 residues in the FTP loop to structurally stabilize the active site of FTP σ. Furthermore, it was confirmed that the nitrogen of quinoline in the compound of Formula 101 further stabilized the active site of the ΡΤΡσ by forming additional hydrogen bonds with Glnl633 residues in the PTP loop (see FIG. 2).

In addition, in the compound of Formula 201, the benzene ring moiety (carbon atom substituted with carboxyl group in the benzene ring) is disposed adjacent to Cysl589 in the ΡΤΡ loop by a distance of 3.56 A, thereby causing It was confirmed that the dephosphorylation activity was inhibited and two oxygen atoms in the carboxy group of the benzene ring formed hydrogen bonds with Alal591 residues and Glyl594 residues in the PTP loop, respectively, to structurally stabilize the active site of the ΡΤΡσ. Furthermore, in imidazolidine-2,4-dione in the compound of Formula 201, oxygen forming a double bond with carbon disposed between two nitrogen atoms in the PTP loop It was confirmed that the active site of ΡΤΡσ was further stabilized by forming additional hydrogen bond with Thrl634 residue (see FIG. 3).

As described above, the compounds of Formula 1 to Formula 7 that inhibit the enzyme activity of ΡΤΡσ can be used for the treatment or prevention of diseases mediated by ΡΤΡσ. The disease mediated by ΡΤΡσ may be a neurological disease, and more specifically, a neurological disease associated with neuronal cell death or degeneration due to trauma, ischemia, hypoxia or hypoglycemia. Diseases mediated by ΡΤΡσ are Alzheimer's disease, Parkinson's disease, Huntington's disease, Down's syndrome, Amyotrophic Lateral Sclerosis, Korsakoff's disease, Brain ischemia, Traumatic injury, Shock, Glutamate neurotoxicity Or neurodegenerative disease caused by hypoxia.

The compounds of Formula 1 to Formula 7 may be included in the pharmaceutical composition as well as in the form of pharmaceutically acceptable salts of the compounds of Formula 1 to Formula 7. As the salts, acid addition salts formed with pharmaceutically acceptable free acids are useful. The acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates and hydroxy alkanoates. And non-toxic organic acids such as alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, Iodide, Fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propyrate, oxalate, malonate, succinate, suverate, sebacate ， Fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, mesoxybenzoate , Phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β_hydroxybutyrate, glycolate Maleate, tartrate, methanesulfonate, propanesulfonate, Naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

The pharmaceutical composition may contain one or more active ingredients exhibiting the same or similar functions in addition to the compounds of Formulas 1 to 7 or pharmaceutically acceptable salts of the compounds, and for the preparation of pharmaceutical compositions It may further include suitable carriers, excipients and diluents commonly used. The carriers, excipients and diluents are lactose, dextrose, sucrose, sucrose, sorbitol, mannitol, xyl itol, erythritol. ), Maltitol, starch, gum Arabic, alginate, gelatin, gel phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinyl pyrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate , Talc, magnesium stearate and mineral oil, but are not limited thereto. When the pharmaceutical composition is formulated, diluents or excipients such as layering agents, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. which are generally used may be used, but are not limited thereto.

The pharmaceutical composition may be administered by various routes such as oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular, preferably It may be administered orally. The pharmaceutical composition may be formulated for oral administration such as powders, granules, tablets, capsules, suspensions, or parenteral dosage forms such as ointments, external preparations, suppositories, and sterile injectable solutions, depending on the route of administration during actual clinical administration. Can be formulated and used. Solid preparations for oral administration may be prepared by mixing the fraction with at least one excipient, for example calcium carbonate, sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration may be prepared by mixing at least one diluent or excipient, for example wetting agents, sweeteners, fragrances, preservatives, etc., in the fraction. Preparations for parenteral administration can be prepared by mixing sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilizers, and the like. As non-aqueous solvents or suspensions, propylene glycol, polyethylene glycol, and olive oil can be prepared. injectable esters such as vegetable oil ethyloleate, such as olive oil, and the like. In particular, when formulated as a suppository, witepsol, polyethylene glycol, tween 61, cacao butter, laurin butter, glycerogelatin, etc. may be used as the substrate. .

The preferred dosage of the pharmaceutical composition varies depending on the age, condition, weight, degree of disease, type of drug, route of administration and time of the patient, but generally, the dosage of the active ingredient for the desired effect is 0.001 to 1 The amount of rag / kg, preferably 0.001 to 0.1 rag / kg is to be administered, it can be divided into several times a day, preferably 1 to 6 times at regular intervals according to the judgment of the doctor or pharmacist. Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are only for the understanding of the present invention, and the present invention is not limited to the following examples. Example 1

Confirmation of ΡΤΡσ Inhibition of Enzyme Activity

BamHI of the expression vector pET28a (Novagen, USA), which expresses the gene (ΡΤΡσ-cat) (SEQ ID NO: 2), which encodes the intracellular enzymatic domian (SEQ ID NO: 1 amino acid sequence) of ΡΤΡσ. Cloned to EcoRI restriction enzyme site. The cloned pET28a vector was transformed into E. and treated with 0.2 mM IPTG to induce the expression of the ΡΤΡσ-cat and then incubated at 18 ^° C. for 16 hours. To obtain the cells cultured as above, 50 mM Tris-HCKpH 7.5), 0.5 M NaCl, 1% PMSF and 5% glycerol in (lysisol) containing (glycerol) and suspended. Let's do it. After dissolving the cell suspension on the ice by sonication method, ΡΤΡσ-cat expressed with six histidine tags at the N ᅳ terminus was purified by Ni-NTA agarose column and 20 mM of Tris-HCKpH 8.0 ), 5 mM EDTA, 50 mM NaCl and 5% glycerol were filtered out. Purified and obtained 10 ΡΤΡσ-cat (0.39 nM) as described above to 10 μΜ of 6,8_difluoro-4-methylumbelelliperylphosphate (6,8-difluoro-4-methyl-umbel 1 if eryl phosphate, DiFMUP) and added to 180 i semi-fibroblast solution (20 mM Tris-HCKpH 8.0), 0.01% Triton X-100 and 5 mM DTT) and dissolved in 10 DMS0. , And reacted separately with the compounds of the formula 301, 401, 501, 601 and 701 (INTERBIOSCREEN Limited, Moscow, Russia) to induce hydrolysis of DiFMUP. The reaction was carried out at room temperature for 20 minutes and the reaction was terminated by addition of sodium orthovanadate at a final concentration of 1 mM. Thereafter, fluorescence of 460 nm wavelength was measured with Perkin Elmer 2030. IC ₅₀ values for the dephosphorylation inhibitory activity of ΡΤΡσ were measured two or more times as described above, and the average values are shown in Table 2.

[Table 2]

As a result, the compounds of Formula 101, Formula 201, Formula 301, Formula 401, Formula 501, Formula 601 and Formula 701 exhibited an effect of inhibiting dephosphorylation activity of ΡΤΡσ by 50% at very low concentrations of 0.1 μΜ to 1.3 μΜ. It was confirmed.

From the above results, it can be seen that the compounds of Formula 1 to Formula 7 as an inhibitor of the activity of ΡΤΡσ, can be used for the treatment or prevention of ΡΤΡσ mediated diseases. Example 2

Structural analysis of the inhibitory effect of ΡΤΡ σ enzyme activity

<2-1> Binding Structure Analysis of ΡΤΡσ of Compound 1

The chemical formula which is one of the compounds having the structure of Chemical Formula 1

The structure of the compound of 101 bound to the active site of the ΡΤΡσ D1 domain was simulated, and the binding structure was analyzed.

As a result, in the compound of Formula 101,

[1,2,4] triazolo [3,4-1)] [1,3,4] thiadiazole moiety is placed adjacent to Cysl589 in the PTP loop by a distance of 3 A to 5 A apart from the Cysl589. Inhibits dephosphorylation activity, and the two nitrogen atoms of the [3,4-b] [1,3,4] thiadiazole moiety to the [1, 2,4] triazole are combined with the Alal591 residue and the Glyl594 residue in the PTP loop. It was confirmed that by forming a hydrogen bond to structurally stabilize the active site of the ΡΤΡσ. Furthermore, it was confirmed that the nitrogen of quinoline in the compound of Formula 101 further stabilized the active site of ΡΤΡσ by forming additional hydrogen bonds with Glnl633 residues in the PTP loop (see FIG. 2). <2-2> Analysis of the binding structure of the compound of Formula 2 to ΡΤΡσ Simulates a structure in which the compound of Formula 201, which is one of the compounds having the structure of Formula 2, is bound to the active site of the ΡΤΡσ D1 domain The binding structure was analyzed.

As a result, in the compound of Formula 201, the benzene ring moiety (carbon atom substituted by carboxyl group in the benzene ring) is disposed adjacent to Cysl589 in the ΡΓΡ loop by a distance of 3.56 A, thereby inhibiting dephosphorylation activity by Cysl589. It was confirmed that two oxygen atoms in the carboxy group of the benzene ring form hydrogen bonds with the Alal591 residue and the Glyl594 residue in the PTP loop, respectively, to structurally stabilize the active site of the ΡΤΡσ. Furthermore, in imidazolidine-2,4-dione in the compound of Formula 201, oxygen forming a double bond with carbon disposed between two nitrogen atoms in the PTP loop It was confirmed that the active site of ΡΤΡσ was further stabilized by forming additional hydrogen bond with Thrl634 residue (see FIG. 3).

Example 3

Validation of ΡΤΡσ Inhibitors

In order to measure the effect of neuronal regeneration, neutrophil extension was observed by treatment with ΡΤΡσ inhibitor in an environment in which neuronal regeneration was inhibited with CSPG (chondro in sulfate). PC12 neurons (Korea Cell Line Bank) were cultured 60% confluent in 96 well plates. The medium was a mixture of RPMI 1640 (Invitrogen), 10% BSA (Gibco), 1% Antibiotic— Antiinycotic (penicillin 10,000 units / ml, Straptomycin 10,000 mg / ml, and Fungi zone 25 mg / ml , Life technologies).

After aspirating and removing the medium from each well of the plate where the PC12 neurons were grown, a new medium containing a neural growth factor (NGF), CSPG (Mi 11 ipore), and an inhibitor was added thereto. . In PC12 neurons, neurite extension was observed when NGF was treated, and this phenomenon did not occur when NGF and CSPG were treated simultaneously. CSPG Inhibits regeneration of nerve cells. It was observed that the ΡΤΡσ inhibitor restored the regeneration of neurons by CSPG again (see FIG. 4).

The final volume of each well was 100 ml, NGF (nerve growth factor) was 100 ng / ml and CSPG (chondroit in sulfate proteoglycan) was added at a concentration of 20 mg / ml. FTP σ inhibitors used a concentration similar to the IC50 concentration. After changing to the medium treated with inhibitors and NGF, CSPG, etc., incubation for 40-50 hours in a C0 ₂ 5%, 37 ^° C incubator and observed neurite extension. Example 4

Activity measurement by inhibitor concentration

The inhibitory activity of ΡΤΡσ with inhibitor concentration was measured for inhibitor compound 1-7. Compared to the enzyme activity when no inhibitor was added, the activity with the inhibitor added was expressed as relative activity. Curve fitting using the measured values was performed using a Sigmaplot program (Systat software inc.) (See FIGS. 5A and 5B). In the above described exemplary embodiments of the present invention by way of example, the scope of the present invention is not limited to the specific embodiments as described above, those skilled in the art that the scope described in the claims of the present invention It will be possible to change accordingly.

Claims

[Patent Claims]

[Claim 1]

A composition for inhibiting ΡΤΡσ enzyme activity comprising at least one compound selected from the group consisting of compounds represented by the following Chemical Formulas 1 to 7 and pharmaceutically acceptable salts thereof as an active ingredient:

Formula 1

In Formula 1, Rll, 12, R13, R14. R15 and R16 are each

L is C 1 -C 10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; At least two selected from R11 to R16

And when R 111 is hydrogen or linear or branched alkyl, any two selected from R 11 to R 16 may be connected to each other to R 111 to form a ring structure, and in the ring structure, two oxygen atoms may be R 111 to connect is straight or branched C 1 -C 5 alkyl; R112 is each Independently hydrogen, hydroxy, halogen, straight and C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C4-C10 heteroaryl and C5-C10 aryl containing one or more of Any one selected from the group consisting of: wherein the heteroaryl or aryl may be one or more carbons substituted with linear or branched C1-C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, straight-chain C1-C10 alkyl and branched C3-C10 alkyl; R17 is a group consisting of C4-C10 heteroaryl and C5-C10 aryl containing at least one of hydrogen, straight-chain C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, nitrogen and oxygen atoms Is any one selected from, wherein the heteroaryl or aryl is one or more carbon of straight or branched

May be substituted;

In Formula 2, R21, R22, and R23 are each independently hydrogen, ᅳ CH ₂ X | — CHX ₂ CX ₃ l—C≡N 1— Ν.0 ₂ : ^ Θπ111

Is branched alkyl; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R21 to R23 is I ᅳ ⁰ ᅳ and R111 is hydrogen, or linear or branched alkyl, any two selected from R21 to R23 are connected to each other to R111 to form a ring structure. R 111 connecting two oxygen atoms in the above ring structure may be linear or branched C 1 -C 5 alkyl; Each R 112 is independently C 4 -C 10 heteroaryl including one or more of hydrogen, hydroxy, halogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy, nitrogen and oxygen atoms; Any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with straight or branched C1-C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, straight-chain C1-C10 alkyl and branched C3-C10 alkyl; 24 and R25 are each independently selected from hydrogen, linear C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C5-C10 aryl;

Formula 3

In Formula 3, R31 is hydrogen, straight C1-C10 alkyl or branched C3-C10 alkyl; The straight or branched alkyl is one or more carbon

May be substituted with any one or more selected from the group consisting of ¾; R32 to R36 may be any one selected from the group consisting of hydrogen, hydroxy, halogen, and halogenated alkyl of C1'C10 independently from each other;

Formula 4

Each independently hydrogen _:

— —,。 — — ^R " ₂ lLK ¹¹³

L ^{to UK} 111 _; — L— C— R ₁₁₂ , or R ″ ⁴ ;

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R41 to R43 is ᅳ ^Rl ", and R111 is hydrogen, or linear or branched alkyl, any two selected from R41 to R43 may be connected to each other to R111 to form a ring structure. In the above ring structure, R 111 connecting two oxygen atoms is linear or branched C1-C5 alkyl, and R112 is hydroxy, halogen, linear CI-C10 alkyl, branched C3, respectively. -C10 alkyl, C1-C10 alkoxy, any one selected from the group consisting of C4-C10 heteroaryl and C5-C10 aryl containing one or more of the nitrogen and oxygen atoms, wherein the heteroaryl or aryl is one or more carbons May be substituted with straight or branched C1-C5 alkyl; R113 and R114 are each independently composed of hydrogen, straight-chain C1-C10 alkyl and branched C3-C10 alkyl. R 44 and R 45 independently of one another are hydrogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy, C 4 -C 10 heteroaryl including at least one of oxygen and oxygen atoms; And C5-C10 aryl, wherein the heteroaryl or aryl is one or more carbon- straight or branched C1-C5 alkyl, N, i Sil :,】 — CHX ₂ ^ CX ₃ ^ ®m

—0— R "t ，

May be, and when R44 and R45 are alkoxy, the R44 and R45 are mutually

Connected ring structure

And A is straight or branched C1-C5 alkyl;

Formula 5

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, straight chain C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; Out of R51 to R53 When at least two selected from ᅳ 0— R ¹¹¹ , and _Rm is hydrogen, or linear or branched alkyl, any two selected from R51 to R53 may be linked to each other to R111 to form a ring structure; In the above ring structure, R 111 connecting two oxygen atoms is straight or branched C 1 -C 5 alkyl; Each R 112 is independently C 4 -C 10 heteroaryl including one or more of hydrogen, hydroxy, halogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy, nitrogen and oxygen atoms; Any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with straight or branched C1 C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, straight-chain C1-C10 alkyl and branched C3-C10 alkyl; R54, R55, R56 and R57 are independently of each other hydrogen, straight-chain C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C4-C10 heteroaryl containing at least one of the oxygen and oxygen atoms And C5-C10 aryl, wherein the heteroaryl or aryl is one or more carbon atoms of straight or branched form.

-CH ₂ X ^ -L-CHX ₂ -L-CX ₃ ^ -LC≡N \-L -N0 ₂

r ^L -0-Rin 卜 L— cR ₁₁₂ , or may be substituted with ₁₄ , when two or more of R54 to R57 is alkoxy, any two substituents selected from R54 to R57 are connected to each other ring rescue

May form D, wherein D is straight or branched alkyl;

Formula 6

remind

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, Branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R61 to R63 is ^ ^υ , and the hydrogen, or linear or branched alkyl, any two selected from R61 to R63 may be connected to each other to R111 to form a ring structure. In the ring structure, R 111 connecting two oxygen atoms is linear or branched and C 1 -C 5 alkyl; R112 is each independently hydrogen, hydroxy, halogen, linear C1-C10 alkyl, branched C3-C10 C1-C10 alkoxy, C4-C10 heteroaryl and C5- containing one or more of the atoms of nitrogen and oxygen Any one selected from the group consisting of C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with linear or branched C1-C5 alkyl; 113 and R114 are each independently selected from the group consisting of hydrogen, linear C1-C10 alkyl and branched C3-C10 alkyl; R64, R65, R66, R67 and R68 are independently of each other hydrogen, straight chain C1-C10 alkyl, branched C3-C10 alkyl C1-C10 alkoxy, C4-C10 hetero containing one or more of the atoms of nitrogen and oxygen Aryl and C5-C10 aryl, wherein the heteroaryl or aryl is one or more carbon atoms of the straight or branched

It may be substituted with ¾ or, if any two or more of the R64 to R68 is alkoxy, selected from the R64 to R68

Which two substituents are linked to each other ring structure

Can be formed, wherein E is straight or branched C1-C5 alkyl;

In Formula 7, R71 is hydrogen, ᅳ X, I ^-CH 2>

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; Each R 112 is independently C 4 -C 10 heteroaryl including one or more of hydrogen, hydroxy, halogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy, nitrogen and oxygen atoms; Any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with straight or branched C1-C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, linear C1-C10 alkyl and branched C3-C10 alkyl; R72, R73, R74, R75, R76 and R77 are hydrogen, straight chain C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C4-C10 hetero containing at least one of the atoms of oxygen and nitrogen Aryl and any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl is One or more carbons are straight or branched C1-C5 alkyl, f ^to ¾

-L-O-Rm ，

Substituted; When at least two of R72 to R74 or at least one of R75 to R77 is alkoxy, one of R72 to R74 or R75 to

Any two substituents selected from one another are linked to each other to form a ring structure

^May form ⁰ /, where τ is straight-chain or branched ci-C5 alkyl

[Claim 2]

The composition of claim 1, wherein R17 is C4-C10 heteroaryl containing one or more of nitrogen and oxygen atoms.

[Claim 3]

The method of claim 1, wherein at least one of R21, R22, and R23 is .. _¾ , ο

CCH ₂ X '— CHX ₂ , — CX ₃ , —C≡N, —N0 ₂ ; ^ -0-R _111; _{-CR 112J} → 漏 ᅳ R _M

o and

A composition, characterized in that any one selected from the group consisting of.

[Claim 4]

The composition of claim 3, wherein at least one of R21, R22, and R23 is H ^ or NH ₂ .

[Claim 5]

The method of claim 1, wherein at least one of R32 to R36 is fluorine. Goat; Or linear or branched C1-C10 alkyl of fluorine or chlorine substitution.

[Claim 6]

The composition of claim 5, wherein at least one of R32 to R36 is fluorine or chlorine.

[Claim 7] The method according to claim 1, wherein at least one of R41 to R43 is ^^, ^ ᅳ CH ₂ X CHX ₂ ᅳ CX ₃ ᅳ C≡N ᅳ N0 ₂ firmware "CR ₁₁₂ _卜 | — _Rl12

I and H 嗎^RI13 , wherein the composition is any one selected from the group consisting of.

[Claim 8]

8. The composition of claim 7, wherein at least one of R41 to R43 is ^^ ^Rl ". [Claim 9]

The method of claim 1, wherein at least one of R51 to R53 is f *

[Claim 12]

71 is ¾, —CH ₂ X, ᅳ CHX ₂ , 卜 CX ₃ '

¾-N ^{/ RI13}

-C—R ₁₁₂ .. A composition characterized by aryl substituted with I.::: Or ^' .

[Claim 13]

According to claim 1, Formulas 101, 201 to 207, 301 to 314,

ΡΤΡσ enzyme activity inhibiting composition comprising at least one compound selected from the group consisting of compounds represented by 401 to 406, 501, 514, 601 to 603, and 701 and pharmaceutically acceptable salts thereof as an active ingredient :

Formula 101

Chemical Cutting 205

Formula 206

Chemistry 302

Formula 304

Formula 307

Formula 308

Formula 310

Formula 311

Formula 314

Formula 403

Formula 406

Formula 504

Formula 508

Formula 512

Formula 602

[Claim 14]

The method according to claim 13, wherein the composition is any one or more compounds selected from the group consisting of compounds represented by the following formulas 101, 201, 301, 401, 501, 601 and 701 and pharmaceutically acceptable salts thereof as an active ingredient ΡΤΡσ composition for inhibiting enzyme activity, comprising: Formula 101

Formula 201

Formula 301

Formula 401

Formula 701

[Claim 15]

The composition of claim 1, wherein the compound represented by any one of Formulas 1 to 7 has an IC ₅₀ value of 0.1 μΜ to 1.3 μΜ.

[Claim 16]

A pharmaceutical composition for the prevention or treatment of ΡΤΡσ mediated disease, comprising the composition of claim 1.

[Claim 17]

17. The method of claim 16, wherein the ΡΤΡσ mediated disease comprises: neurological diseases associated with neuronal cell death or degeneration due to trauma, ischemia, hypoxia or hypoglycemia; Alzheimer's disease; Parkinson's disease; Huntington's disease; Down syndrome; Amyotrophic Lateral Sclerosis; Korsakoff's disease; And neurodegenerative diseases caused by cerebral ischemia, traumatic injury, shock, glutamate neurotoxicity, or hypoxia.

[Claim 18]

Any one or more compounds selected from the group consisting of compounds represented by the following Chemical Formulas 1 to 7 and pharmaceutically acceptable salts thereof Administering to the subject a composition comprising as an active ingredient

Methods of prevention or treatment of ΡΤΡσ mediated diseases, including:

Formula 1

In Formula 1, Rli, R12, R13, R14. R15 and R16 are each independently hydrogen,

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R11 to R16 is ᅳ ⁰ — ^Rl “, and when R111 is hydrogen, or linear or branched alkyl, any two selected from R11 to R16 are connected to each other at R111 to form a ring structure. Wherein R 111 connecting two oxygen atoms in the ring structure is a straight or branched C 1 -C 5 alkyl group, and R 112 is independently hydrogen, hydroxy, halogen, or straight C 1 -C. C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, nitrogen and Any one selected from the group consisting of C4-C10 heteroaryl and C5-C10 aryl containing at least one of the oxygen atoms, wherein the heteroaryl or aryl is one or more carbon is straight or branched C1-C5 alkyl May be substituted; R113 and R114 are each independently selected from the group consisting of hydrogen, linear C1-C10 alkyl and branched C3-C10 alkyl; R17 is a group consisting of C4-C10 heteroaryl and C5-C10 aryl containing one or more of hydrogen, straight-chain C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, nitrogen and oxygen atoms Any one selected from, wherein the heteroaryl or aryl is one or more carbon- straight or branched C1-C5 alkyl,

In Formula 2, R21, R22 and R23 are independently of each other hydrogen

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R21 to R23 is ¹ ″ and Rill is hydrogen, or linear or branched alkyl, any two selected from R21 to R23 are connected to each other to R111 to form a ring structure. In the above ring structure, R 111 connecting two oxygen atoms is linear or branched C 1 -C 5 alkyl; and R 112 is independently hydrogen, hydroxy, halogen or linear C 1 -C 10 alkyl. , Branched C3-C10 alkyl, C1-C10 alkoxy, any one selected from the group consisting of C4-C10 heteroaryl and C5-C10 aryl containing at least one of nitrogen and oxygen atoms, the heteroaryl or aryl Is one or more carbons may be substituted with straight or branched CI—C5 alkyl; R113 and R114 are independently of each other hydrogen, straight C1 C C10 alkyl and branched C3-C10 R 24 and R 25 are each independently selected from the group consisting of hydrogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy and C 5 -C 10 aryl. Which is either; Formula 3

In Formula 3, R31 is hydrogen, straight-chain C1-C10 alkyl or branched C3-C10 alkyl; The straight or branched alkyl may be one or more

May be substituted with any one or more selected from the group; R32 to R36 may be any one selected from the group consisting of hydrogen, hydroxy, halogen, and halogenated alkyl of C1-C10 independently from each other;

Formula 4

In Formula 4, R41, R42 and R43 are each independently hydrogen

--Rm

L is Lingze

Halogen element;

Branched C3-C10

Two or more selected are hydrogen or straight-chained

Or branched alkyl, selected from R41 to R43, ᅵ may be connected to each other by R111 to form a ring structure, and in the ring structure, R111 connecting two oxygen atoms is straight or branched. Topographic C1-C5 alkyl; Each R 112 is independently C 4 -C 10 heteroaryl including at least one of hydrogen, hydroxy, halogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy, nitrogen and oxygen atoms; Any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with straight or branched C1-C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, linear C1-C10 alkyl and branched C3-C10 alkyl; R44 and R45 are each independently hydrogen, straight-chain C1-C10 alkyl, branched C3-C10 alkyl, C1 C10 alkoxy, C4-C10 heteroaryl and C5-C10 aryl containing at least one of nitrogen and oxygen atoms Any one selected from the group consisting of, wherein the heteroaryl or aryl is one or more carbon of straight or branched

5- L-N0 ₂

-Q 一 R '_; r L ^L -—C-—R ^K ₁ ¹ ₁ ¹ ₂ ² ,

High; remind

L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R51 to R53 is ᅳ 0˜ ^{~ Rl} “, and R _ln is hydrogen, or linear or branched alkyl, any two selected from R51 to R are connected to each other as R111. A ring structure, wherein R 111 connecting two oxygen atoms in the ring structure is a straight-chain or branched Cl-C5 alkyl; and R 112 is independently hydrogen, hydroxy, halogen, or straight-chain. Any one selected from the group consisting of C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C4-C10 heteroaryl and C5-C10 aryl containing one or more of nitrogen and oxygen atoms, Heteroaryl or aryl may be one or more carbons are substituted with straight or branched C1-C5 alkyl; R113 and R114 are independently of each other hydrogen, straight-chain C1-C10 alkyl and branched C3- C10 alkyl It is selected from the group consisting of; wherein R54, R55, R56 and R57 are independently C1-C10 alkyl, C3-C10 for branched minutes of hydrogen, straight-chain one another

In the case where two or more of R54 to R57 are alkoxy, any two substituents selected from R54 to R57 may be linked to each other to form a ring structure.

Branched alkyl; X is a halogen element; R111 is hydrogen, hydroxy, straight C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; When at least two selected from R61 to R63 is ⁱ H «, and when R111 is hydrogen, or linear or branched alkyl, R61 to

Any two selected from R 63 may be linked to each other with R 111 to form a ring structure, and in the ring structure, R 111 connecting two oxygen atoms is straight-chain or branched CI-C5 alkyl; Each R 112 is independently C 4 -C 10 heteroaryl including at least one of hydrogen, hydroxy, halogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 ᅳ C 10 alkoxy, nitrogen and oxygen atoms; Any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with straight or branched C1-C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, linear C1-C10 alkyl and branched C3-C10 alkyl; R64, R65, R66, R67 and R68 are independently of each other hydrogen, straight-chain C1-C10 alkyl, branched C3-C10 alkyl, C1-C10 alkoxy, C4-C10 containing one or more of the atoms of oxygen Heteroaryl or aryl is any one selected from the group consisting of heteroaryl and C5-C10 aryl, wherein at least one carbon is linear or branched — CHX ₂ , 卜 CX ₃ , C≡N 卜 N0 ₂

If any two or more of the R64 to R68 is alkoxy, any two substituents selected from the R64 to R68 are connected to each other

Ring structure

E is straight or branched C1-C5 alkyl;

In Formula 7, R71 is hydrogen, ᅳ ^x , "CHX ₂

¾ ~ ^"CH 2 ^X

;-I -N

Rii4; L is C1-C10 straight or branched alkyl as a linker; X is a halogen element; R111 is hydrogen, hydroxy, linear C1-C10 alkyl, branched C3-C10 alkyl or C1-C10 alkoxy; Each R 112 is independently C 4 -C 10 heteroaryl including one or more of hydrogen, hydroxy, halogen, linear C 1 -C 10 alkyl, branched C 3 -C 10 alkyl, C 1 -C 10 alkoxy, nitrogen and oxygen atoms; Any one selected from the group consisting of C5-C10 aryl, wherein the heteroaryl or aryl may be one or more carbons substituted with straight or branched C1-C5 alkyl; R113 and R114 are each independently selected from the group consisting of hydrogen, straight-chain C1-C10 alkyl and branched C3-C10 alkyl; R72, R73, R74 R75, R76 and R77 are hydrogen, linear C1-C10 alkyl, branched C3-C10 alkyl, C 1 -C 10 alkoxy, any one selected from the group consisting of C 4 -C 10 heteroaryl and C 5 -C 10 aryl containing one or more of nitrogen and oxygen atoms, wherein the heteroaryl or aryl is linear or branched with one or more carbon atoms. Topographic

May be; When any two or more of R72 to R74 or any two or more of R75 to R77 are alkoxy, any two substituents selected from R72 to R74 or R75 to R77 are connected to each other to form a ring structure

And Z is straight or branched C1-C5 alkyl.

[Claim 19]

19. The method of claim 18, wherein the ΡΤΡσ mediated disease is a neurological disease associated with neuronal cell death or degeneration due to trauma, ischemia, hypoxia or hypoglycemia; Alzheimer's disease; Parkinson's disease; Huntington's disease; Down syndrome; Amyotrophic Lateral Sclerosis; Korsakoff's disease; And neurodegenerative diseases caused by cerebral ischemia, traumatic injury, shock, glutamate neurotoxicity or hypoxia.