KR101469127B1 - Novel benzimidazole derivatives, isomers thereof or pharmaceutically acceptable salt thereof and pharmaceutic composition comprising the same - Google Patents

Abstract

The present invention relates to a novel benzimidazole derivative compound, an isomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutical composition comprising the same. The benzimidazole derivative compound according to the present invention selectively inhibits JNK, particularly JNK3, and can be used as a pharmaceutical composition for the prevention and treatment of neurological diseases.

Description

[0001] The present invention relates to a novel benzimidazole derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the benzimidazole derivative, an isomer thereof or a pharmaceutically acceptable salt thereof,

The present invention relates to a novel benzimidazole derivative, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.

JNK (c-Jun N-terminal kinase), which is classified as a serine / threonine kinase, is one of three subdependencies of mitogen-activated protein kinase, also called SAPK (stress activated protein kinase). Activated JNK promotes the phosphorylation of intracellular proteins such as Bcl2 and p53, which are involved in apoptosis and a number of transcription factors including c-Jun of AP-1. The three JNK genes coding for JNK are known to form a total of 10 different isoforms after splicing. JNK is known to be activated in response to a variety of stimuli such as cytokines, mitogens, osmotic stresses, and ultraviolet irradiation.

Although JNK1 and JNK2 are widely distributed in various tissues, JNK3 is known to be predominantly distributed in the brain and testis, and JNK3 has been proposed to play a unique role in CNS disease . In recent years, JNK3 has been regarded as a degenerative neurotransmitter in pathological aspects since JNK3 has recently been proved to be a target of therapeutic agents for degenerative neurological diseases such as ischemic brain disease, Alzheimer's disease and Parkinson's disease.

In the case of Alzheimer's disease, accumulated beta-amyloid has been proposed to cause neuronal damage and loss. In the case of JNK3-null mice, the beta amyloid-induced cortical (Y. Morishima, et al., J. Neurosci. 21: 7551-7560 (2001)). In the same paper, JNK3 activates c-Jun and increases the expression of Fas ligand, mediating beta amyloid-accumulating cell death. In another paper it is reported that JNK is a major constituent of NFTs (neurofibrillary tangles) and promotes phosphorylation of Tau, another indicator of Alzheimer's disease (CH Reynolds, et al., J. Neurochem. 68: 1736-1744 (1997)). In addition, a modified distribution and activity of JNK was observed in the posterior cranial surface of patients with Alzheimer's disease (X. Zhu, et al., J. Neurochem. 76: 435-414 (2001); JJ Pei, et al. , J. Alzheimer's Dis. 3: 41-48 (2001).

In the case of Parkinson's disease, 1-methyl-4-phenyl-tetrahydropyridine (MPTP), a selective dopaminergic neurotoxin for nigrostriatal, is used in animal models. In one study, MPTP was administered to control mice and knock-out mice with JNK2 or JNK3 genes, indicating that mice treated with the JNK gene had lower dopamine levels and less dopaminergic neurons, JNK3-deficient or JNK substrate, c-Jun (2004), has also demonstrated the involvement of JNK3 The acute MPTP poisoning was reported to be due to the neurotoxicity of hippocampus caused by the administration of kainic acid, an agonist of the glutamate receptor, or to the postmortem specimen of patients with Parkinson's disease the JNK inhibitor is an important target for the treatment of Parkinson's disease because it exhibits the same neuropathological pattern as the specimen.

Based on the results of known prior studies, it is an object of the present invention to provide a novel benzimidazole derivative compound, an isomer thereof or a pharmaceutically acceptable salt thereof, which selectively inhibits JNK, particularly JNK3.

It is still another object of the present invention to provide a pharmaceutical composition for the prevention and treatment of neurological diseases comprising the benzimidazole derivative compound, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

In order to achieve the above objects, the present invention provides a benzimidazole derivative compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

Q1 and Q2 are the same or different and each independently -CH- or -N-;

R1 is aryl having 6 to 20 carbon atoms, alkylaryl having 7 to 20 carbon atoms, or arylalkyl having 7 to 20 carbon atoms, and R1 may be substituted or unsubstituted with halogen, hydroxy or alkoxy;

R2 and R3 are the same or different and each independently hydrogen, hydroxy, alkyl of 1 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms;

R 4 is selected from the group consisting of hydrogen, alkyl having 1 to 10 carbons, hydroxyalkyl having 1 to 6 carbons, cycloalkyl having 3 to 20 carbons, aryl having 6 to 20 carbons, alkylaryl having 7 to 20 carbons, Alkyl, heterocycloalkyl having 3 to 20 carbon atoms, or heteroaryl having 6 to 20 carbon atoms, and R4 may be substituted or unsubstituted with a substituent including a carbonyl group (C = O).

The present invention also provides a pharmaceutical composition for the prevention and treatment of neurological diseases, which comprises the benzimidazole derivative compound represented by Formula 1, an isomer thereof or a pharmaceutically acceptable salt thereof.

The novel benzimidazole derivative compound, an isomer thereof or a pharmaceutically acceptable salt thereof according to the present invention exhibits selective inhibitory activity against JNK, particularly JNK3, and can be used as a pharmaceutical composition for the prevention and treatment of neurological diseases .

FIG. 1 is a view showing the results of immunoblotting of the compounds of Examples 13d, 15c, and 16f of the present invention and the compound of Comparative Example 1. FIG.
Fig. 2 is a photograph of the cell morphology treated with the compounds 13d, 15c, and 16f of the present invention and the compound of Comparative Example 1 by an optical microscope.
Figure 3 is a graph showing the mRNA levels of TNF- [alpha] for cell lines treated with various concentrations of example compound 16f.

In the present invention, the terms first, second, etc. are used to describe various components, and the terms are used only for the purpose of distinguishing one component from another.

Moreover, the terminology used herein is for the purpose of describing exemplary embodiments only and is not intended to be limiting of the present invention. The singular expressions include plural expressions unless the context clearly dictates otherwise. In this specification, the terms "comprising," "comprising," or "having ", and the like are intended to specify the presence of stated features, But do not preclude the presence or addition of one or more other features, integers, steps, components, or combinations thereof.

Also in the present invention, when referring to each layer or element being "on" or "on" each layer or element, it is meant that each layer or element is formed directly on each layer or element, Layer or element may be additionally formed between each layer, the object, and the substrate.

While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that the invention is not intended to be limited to the particular forms disclosed, but includes all modifications, equivalents, and alternatives falling within the spirit and scope of the invention.

Hereinafter, the present invention will be described in detail.

<Compound>

The novel benzimidazole derivative compounds of the present invention are represented by the following formula (1).

[Chemical Formula 1]

In Formula 1,

Q1 and Q2 are the same or different and each independently -CH- or -N-;

R1 is aryl having 6 to 20 carbon atoms, alkylaryl having 7 to 20 carbon atoms, or arylalkyl having 7 to 20 carbon atoms, and R1 may be substituted or unsubstituted with halogen, hydroxy or alkoxy;

R2 and R3 are the same or different and each independently hydrogen, hydroxy, alkyl of 1 to 10 carbon atoms, or alkoxy of 1 to 10 carbon atoms;

R 4 is selected from the group consisting of hydrogen, alkyl having 1 to 10 carbons, hydroxyalkyl having 1 to 6 carbons, cycloalkyl having 3 to 20 carbons, aryl having 6 to 20 carbons, alkylaryl having 7 to 20 carbons, Alkyl, heterocycloalkyl having 3 to 20 carbon atoms, or heteroaryl having 6 to 20 carbon atoms, and R4 may be substituted or unsubstituted with a substituent including a carbonyl group (C = O).

The definition of each substituent in the formula (1) will be described in detail as follows.

"Alkyl" means a straight or branched saturated monovalent hydrocarbon moiety of one to ten, preferably one to six carbon atoms.

"Alkoxy" means that the alkyl group defined above is bonded in a single bond with oxygen.

"Aryl" means a monovalent monocyclic, bicyclic, or tricyclic aromatic hydrocarbon moiety having 6 to 20, preferably 6 to 12, ring atoms.

"Alkylaryl" means that at least one hydrogen atom of the above-defined aryl group is substituted with an alkyl group.

The term "arylalkyl" means that at least one hydrogen atom of the alkyl group defined above is substituted with an aryl group.

"Hydroxyalkyl" means that the hydrogen atom of the alkyl group defined above is substituted with at least one hydroxyl group (-OH).

"Cycloalkyl" means a saturated or unsaturated nonaromatic monovalent monocyclic, bicyclic or tricyclic hydrocarbon moiety of 3 to 20, preferably 3 to 12 ring carbons.

"Heterocycloalkyl" means that the carbon atom of the cycloalkyl as defined above is substituted with one or more heteroatoms.

"Heteroaryl" means that the carbon atom of the above defined aryl is substituted with one or more heteroatoms.

"Substituent containing a carbonyl group" means a hydrocarbon containing a double bond of carbon and oxygen such as an aldehyde, ketone, carboxylic acid, or ester.

According to an embodiment of the present invention, R 1 may be benzyl, phenyl, hydroxybenzyl, chlorobenzyl, dichlorobenzyl, naphthyl, chloronaphthyl or dichloronaphthyl, but the present invention is not limited thereto no.

Each of R 2 and R 3 may independently be hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy. However, the present invention is not limited thereto.

And R4 is selected from the group consisting of cyclohexyl, benzyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Piperazinyl, hydroxymethyl, hydroxymethyl, hydroxyisopropyl, cyclopropylmethanopiperidinyl, and the like, but the present invention is not limited thereto.

Representative examples of the compound of Formula 1 according to the present invention are shown in the following Table 1, but the present invention is not limited thereto.

Compound No. Substituent Q1 Q2 R1 R2 R3 R4 Compound 6a N CH

H H

Compound 6b N CH

H H

Compound 6d N CH

H H

Compound 6j N CH

H OMe

Compound 7a N CH

H H

Compound 8a N CH

H OH

Compound 8b N CH

H OH

Compound 8c N CH

H OH

Compound 8d N CH

H OH

Compound 8e N CH

H H

Compound 8f N CH

H H

Compound 8g N CH

H OH

Compound 13a N N

H H

Compound 13b N N

H H

Compound 13d N N

H OMe

Compound 13g N N

OMe H

Compound 13j N N

H H

Compound 14 N N

H H

Compound 15a N N

H H

Compound 15b N N

H OMe

Compound 15c N N

OMe H

Compound 15d N N

H H

Compound 16a N N

H OH

Compound 16b N N

OH H

Compound 16c N N

H OH

Compound 16d N N

OH H

Compound 16e N N

H OH

Compound 16f N N

OH H

(* Indicates the connection site.)

According to one embodiment of the present invention, preferred examples of the compound of the present invention represented by the above formula (1) are as follows.

(Cyclohexyl- [4- (2-naphthalen-2-yl-benzoimidazol-1-yl) -pyridin- -yl) -pyridin-2-yl] -amine, Compound 6a)

(4- (2-naphthalen-2-yl-benzoimidazol-1 -yl) -2-pyridin- pyridine-2-yl] - (tetrahydro-pyran-4-yl)

(S) -1- (4- (2- naphthalen-2-yl-1-yl) -pyridin-2-ylamino) -propan-2-ol ((S) -1- [4- (2-naphthalen-2-yl-benzoimidazol-1-yl) -pyridin-2- ylamino] -propan-

- cyclohexyl- (4- (2- (3,4-dichloro-phenyl) -5-methoxy-benzoimidazol- 1 -yl) -pyridin- (3,4-dichloro-phenyl) -5-methoxy-benzoimidazol-1-yl] -pyridin-2-yl}

( R ) -cyclopropyl- (3- (4- (2-naphthalen-2-yl-benzoimidazol- 1 -yl) -pyridin- 2- ylamino) -piperidin- (( R ) -cyclopropyl- {3- [4- (2-naphthalen-2-yl-benzoimidazol-1- yl) -pyridin- 2- ylamino] -piperidin-

Synthesis of 1- (2-cyclohexylamino-pyridin-4-yl) -2-naphthalen-2-yl-1 H -benzoimidazol- -naphthalen-2-yl-1 H -benzoimidazol-5-ol, compound 8a)

2-naphthalen-2-yl-l- (2- (tetrahydro-pyran-4-ylamino) pyridin-4-yl) -1 H-benzoimidazol-5-ol (2-naphthalen-2-yl -1- [2- (tetrahydro-pyran- 4-ylamino) -pyridin-4-yl] - 1H- benzoimidazol-5-ol, the compound 8b)

(R) -2-naphthalen-2-yl-1- (2- (piperidin-3-ylamino) pyridin-4-yl) -1 H-benzoimidazol-5-ol ((R) - 2-naphthalen-2-yl- 1- [2- (piperidin-3-ylamino) -pyridin-4-yl] -1 H -benzoimidazol-5-ol, compound 8c)

( R ) -cyclopropyl- (3- (4- (5-hydroxy-2- naphthalen-2-yl-benzoimidazol- 1- yl) -pyridin- 2- ylamino) -piperidin- ( R ) -cyclopropyl- {3- [4- (5-hydroxy-2-naphthalen-2- yl-benzoimidazol-1- yl) -pyridin-2- ylamino] -piperidin-1- yl } -methanone, compound 8d)

( R ) -cyclopropyl- (3 - ((4- (2- (3-hydroxyphenyl) -1H-benzo (d) imidazol- 1- yl) -pyridin-2-yl) amino) piperidine 1-yl) -methanone ((R) -cyclopropyl (3 - ((4- (2- (3-hydroxyphenyl) -1 H -benzo [d] imidazol-1-yl) pyridin-2-yl) amino) piperidin-1-yl) methanone, compound 8e)

(S) -3- (1- (2- (2- hydroxy-propylamino) -pyridin-4-yl) -1 H-benzoimidazol-2-yl) -phenol ((S) -3- { 1- [2- (2-hydroxy- propylamino) -pyridin-4-yl] -1 H -benzoimidazol-2-yl} -phenol, compound 8f)

1- (2-cyclohexylamino-pyridin-4-yl) -2- (3, 4-dichloro-phenyl) -1 H-benzoimidazol-5-ol (1- (2-cyclohexylamino-pyridin -4 -yl) -2- (3,4-dichloro- phenyl) -1 H -benzoimidazol-5-ol, compound 8g)

Cyclohexyl- [4- (2-naphthalen-2-yl-benzoimidazol-1-yl) -pyrimidin- 1-yl) -pyrimidin-2-yl] -amine, compound 13a)

(4- (2-naphthalen-2-yl-benzoimidazol-1 -yl) -pyrimidin- 2- yl) - (tetrahydro- Pyrimidin-2-yl] - (tetrahydro-pyran-4-yl)

(Cyclohexyl- [4- (5-methoxy-2-methyl-2-naphthalen- -naphthalen-2-yl-benzoimidazol-1-yl) -pyrimidin-2-yl]

(Cyclohexyl- [4- (6-methoxy-2 &lt; RTI ID = 0.0 &gt; -naphthalen-2-yl-benzoimidazol-1-yl) -pyrimidin-2-yl] -amine, compound 13g)

({4- [2- (3,4-dichloro-phenyl) -benzoimidazol-1 -yl] -pyrimidin- 2- (3,4-dichlorophenyl) -benzoimidazol-1-yl] -pyrimidin-2-yl} - (tetrahydro-pyran- 4- yl)

(R) - (4- (2- naphtha len-2-yl-benzoimidazol-1-yl) -2-pyrimidin-2) -piperidin-3-yl-amine ((R) - 2-yl] -piperidin-3-yl-amine, compound 14) was reacted with &lt; RTI ID =

( R ) -cyclopropyl- (3- (4- (2-naphthalen-2-yl-benzoimidazol- 1 -yl) -pyrimidin-2- ylamino) -piperidin- 1-yl) -pyrimidin-2-ylamino] -piperidin-1-yl} -methanone, compound 15a)

( R ) -cyclopropyl- (3- (4- (5-methoxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- -yl) -methanone ((R) -cyclopropyl- {3- [ 4- (5-methoxy-2-naphthalen-2-yl-benzoimidazol-1-yl) -pyrimidin-2-ylamino] -piperidin-1- yl} -methanone, compound 15b)

( R ) -cyclopropyl- (3- (4- (6-methoxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- -yl) -methanone ((R) -cyclopropyl- {3- [ 4- (6-methoxy-2-naphthalen-2-yl-benzoimidazol-1-yl) -pyrimidin-2-ylamino] -piperidin-1- yl} -methanone, compound 15c)

( R ) -cyclopropyl- (3- (4- (2- (3,4-dichloro-phenyl) -benzoimidazol- 1- yl) -pyrimidin- 2- ylamino) -piperidin- yl) -methanone ((R) -cyclopropyl- (3- { 4- [2- (3,4-dichloro-phenyl) -benzoimidazol-1-yl] -pyrimidin-2-ylamino} -piperidin-1-yl ) -methanone, compound 15d)

Synthesis of 1- (2-cyclohexylamino-pyrimidin-4-yl) -2-naphthalen-2-yl- 1H -benzoimidazol- 2-naphthalen-2-yl-1H-benzoimidazol-5-ol, compound 16a)

1- (2-cyclohexylamino-pyrimidin-4-yl) -2-naphthalen-2-yl -1 H--benzoimidazol-6-ol (1- (2-cyclohexylamino-pyrimidin -4-yl) 2-naphthalen-2-yl-1H-benzoimidazol-6-ol, compound 16b)

2-naphthalen-2-yl-l- (2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl) -1 H-benzoimidazol-5-ol (2-naphthalen-2- yl-1- [2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl] -1H-benzoimidazol-

2-naphthalen-2-yl-l- (2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl) -1 H-benzoimidazol-6-ol (2-naphthalen-2- yl-1- [2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl] -1H-benzoimidazol-

( R ) -cyclopropyl- (3- (4- (5-hydroxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- Yl) -pyrimidin-2-ylamino] -piperidin-1-yl) -methanone (( R ) -cyclopropyl- {3- [4- (5-hydroxy-2-naphthalen- yl} -methanone, compound 16e)

( R ) -cyclopropyl- (3- (4- (6-hydroxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- Yl) -pyrimidin-2-ylamino] -piperidine-l-yl) -methanone (( R ) -cyclopropyl- {3- [4- (6-hydroxy-2-naphthalen- yl} -methanone, compound 16f)

The compound of the present invention represented by Formula 1 may exhibit selective inhibitory activity of c-Jun N-terminal kinase (hereinafter, referred to as JNK), particularly JNK3.

According to one embodiment of the present invention, the benzimidazole derivative compound of Formula 1 according to the present invention can be chemically synthesized by the method shown in Schemes 1 and 2 below, but the present invention is not limited thereto .

[Reaction Scheme 1]

[Reaction Scheme 2]

In the above scheme 1, N - alkyl-amino-4-nitropyridine-1-oxide (N -alkylamino-4-nitropyridine- 1-oxide) derivative (Compound 2a ~ 2d) is reduced in a Raney-Ni conditions: Buchwald reaction conditions Is coupled with 1-bromo-2-nitrobenzene. The coupled reaction product, compounds 4a-4g, undergoes an oxidative cyclization under oxidative and modified conditions to give N -alkyl-4- (2-aryl-1 H -benzoimidazol- ) may be synthesized as 2-amine (N -alkyl-4- (2- aryl-1 H -benzoimidazol-1-yl) pyridin-2-amine) derivative (compound 6a ~ 6j). If compounds 6a to 6j are required as substrates, further dimethylation and acylation reactions can be performed.

In the above Reaction Scheme 2, benzene-1,2-diamine (compound 9a) or 4-methoxybenzene-1, 2-diamine , 2-diamine, compound 9b) as starting materials, an oxidative cyclization reaction can be carried out as the first reaction. Then, in a second reaction, the products of the benzimidazole skeleton (compounds 10a to 10c) were reacted with 4-chloro-2- (methylthio) pyrimidine and the modified Buchwald reaction conditions Lt; / RTI &gt; Then, mCPBA was used to oxidize methyl sulfide (compounds 11a to 11d) to methylsulfoxide (compounds 12a to 12d) and methyl sulfoxide (compounds 12a to 12d) to 1-pyrimidine-benzimidazole (1-pyrimidine-benzimidazole derivatives, compounds 13a to 13l). Further, if necessary for the substrate, an additional dimethylation reaction and an acylation reaction can be further performed.

The thus prepared compounds of formula (I) according to the invention can form salts, in particular pharmaceutically acceptable salts.

The compounds of formula (I) according to the invention include all possible solvates and hydrates thereof, as well as pharmaceutically acceptable salts thereof, as well as all possible isomers. Solvates, hydrates and isomers of the compound of formula (I) may be prepared from compounds of formula (I) using conventional methods.

Suitable pharmaceutically acceptable salts are those conventionally used in the art, such as acid addition salts, and are not particularly limited. Preferred pharmaceutically acceptable acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, orthophosphoric acid or sulfuric acid; Or organic acids such as, for example, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, acetic acid, propionic acid, lactic acid, citric acid, fumaric acid, malic acid, succinic acid, salicylic acid, maleic acid, glycerophosphoric acid or acetylsalicylic acid.

Further, the compound of formula (I) according to the present invention may be prepared in a crystalline form or an amorphous form, and when the compound of formula (1) is prepared in a crystalline form, it may optionally be hydrated or solvated. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound of formula (1) may be included. Solvates of compounds of formula (I) according to the present invention include both stoichiometric and non-stoichiometric solvates.

The benzimidazole derivative compound of formula (I) according to the present invention, its isomer or its pharmaceutically acceptable salt inhibits the activity of JNK by inhibiting phosphorylation of JNK, and thus is useful for prevention or treatment of a neurological disease associated with JNK .

According to another embodiment of the present invention, there is provided a pharmaceutical composition for the prevention and treatment of neurological diseases, which comprises the compound of formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

The neurological disease may be a disease associated with JNK, i.e., a neurological disease requiring treatment to inhibit the activity of JNK. In addition, the nervous system diseases may include cerebral nervous system and central nervous system diseases.

More specifically, the neurological disease is a neurological disease requiring treatment for inhibiting the activity of JNK, more preferably the activity of JNK3. Examples thereof include ischemic brain diseases, degenerative brain diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease And the like, but the present invention is not limited thereto.

JNK, which is classified as serine / threonine kinase, is one of three subdependencies of mitogen activated protein kinase. Activated JNK promotes the phosphorylation of intracellular proteins such as Bcl2 and p53, which are involved in apoptosis and a number of transcription factors including c-Jun of AP-1. Three JNK genes coding for JNK are spliced to form 10 different isoforms, of which JNK1 and JNK2 are widely distributed in cell tissue, whereas JNK3 is predominantly distributed in brain and testis And JNK3 has been suggested to play a unique role in central nervous system (CNS) disease. Recently, JNK3 is regarded as a degenerative signaling agent in pathological aspects because it has been proved that JNK3 can be targeted for the treatment of neurodegenerative diseases such as ischemic brain disease, Alzheimer's disease and Parkinson's disease.

In the case of Alzheimer's disease, accumulated beta-amyloid has been suggested to impair neuronal cell damage and loss. JNK3 gene-deleted mice have been shown to attenuate beta amyloid-induced apoptosis in the cerebral cortex Its relevance has been proven.

In the case of Parkinson's disease, 1-methyl-4-phenyl-tetrahydropyridine (MPTP), a selective dopaminergic neurotoxin for nigrostriatal, is used in animal models. JNK-depleted mice showed higher dopamine levels and less loss of dopaminergic neurons, confirming the link between Parkinson's disease and JNK.

The pharmaceutical compositions according to the present invention may be formulated into oral or parenteral administration forms according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, an additive such as a pharmaceutically acceptable carrier, adjuvant or diluent.

The compound of formula (I) according to the present invention, an isomer thereof or a pharmaceutically acceptable salt, hydrate or solvate thereof has JNK antagonistic activity by itself. However, the compound is absorbed into the body, And the like may not exhibit the pharmacological action as an agonist.

Accordingly, the pharmaceutical dosage form of the benzimidazole derivative of formula (I) according to the present invention, its isomer or pharmaceutically acceptable salt, hydrate or solvate thereof may be in the form of a pharmaceutically acceptable salt or solvate thereof And may also be used alone or in combination with other pharmaceutically active compounds as well as in suitable aggregates.

The benzimidazole derivative compound of Formula 1 according to the present invention, an isomer thereof or a pharmaceutically acceptable salt, hydrate or solvate thereof can be administered orally or parenterally in various formulations upon administration. In the case of formulation, it may be prepared using additives or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants and the like generally used.

Solid formulations for oral administration include tablets, patients, powders, granules, capsules, troches, etc. These solid preparations can be prepared by mixing the compound of formula 1 according to the present invention, its isomer or its pharmaceutically acceptable salt, hydrate , Or may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, or gelatin into the solvate.

Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. In addition to commonly used diluents such as water and liquid paraffin, various excipients such as wetting agents, sweetening agents, fragrances, preservatives and the like are included .

Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like.

The preferred dose of the benzimidazole derivative compound of formula (I) according to the present invention, its isomer or its pharmaceutically acceptable salt, hydrate or solvate is determined depending on the condition and weight of the patient, the severity of the disease, And the period, it can be appropriately selected by a method generally applicable to the technical field to which the present technology belongs.

The pharmaceutical composition according to the present invention can be administered to mammals including rats, mice, livestock and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerbroventricular injections.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

< Example >

All reagent grade used was purchased from Aldrich, USA. The separation of the compounds by column chromatography was carried out on silica gel 60 (200-300 mesh ASTM, E. Merck, Germany). The amount of silica gel used was 50-100 times the weight of the column. Thin layer chromatography (TLC) was performed on a silica gel coated aluminum sheet (Silica gel 60 GF254, E. Merck, Germany) and visualized in ultraviolet light (254 nm). ¹ H NMR spectra were recorded on a Varian 300 500 MHz and Bruker Advance 400 MHz spectrometer at 25 ° C using tetramethylsilane (TMS) as internal standard. The low resolution MS (LR / MS) experiments for the intermediate compounds proceeded with a Waters AutoPurification ^TM system with a PDA detector and an atmospheric pressure single quadrupole mass spectrometer. High-resolution MS (HR / MS) experiments were performed on a 6500 Series (6500 Series Accurate-Mass Quadrupole Time-of-Flight (Q-TOF) LC / MS, Agilent Technologies) operating in a positive-ion electrospray mode To evaluate the activity of JNK. Experiments to measure K _d values using SPR measurements were performed on ProteOn XPR36 (Bio-Rad). Sybyl X-1.3 (Tripos) was used as a 3D-QSAR tool for molecular modeling, and Glide and Macromodel (Schrodinger) were used to perform receptor-guide alignment.

2- alkylamino -4- nitropyridine  One- oxide  Synthesis of derivatives (compounds 2a to 2d)

2-chloro-4-nitropyridine 1-oxide (Compound 1) (325 mg, 1.86 mmol) and secondary amine (RNH ₂ ) (3.35 mmol) were dissolved in ethanol ) And heated at 80 &lt; 0 &gt; C until compound 1 disappeared from the TLC. After the reaction was completed, the mixture was cooled to ambient temperature and the solvent was removed in vacuo. Concentrated crude product was purified by flash column chromatography on silica gel using a mobile phase of EA: Hex (1: 1) to give compounds 2a to 2d.

Compound 2a as a yellow solid (76%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.23 (1H, br, s), 7.39 (1H, s), 7.36 (1H, br, s), 6.92 (1H, br, s), 3.44 (1H, br, s), 2.04-2.06 (2H, m), 1.72-1.90 (2H, m), 1.56-1.60 (1H, m), 1.42-1.47 (3H, m), 1.26-1.30 (2H, m); _{LRMS (ESI) calcd for C 11} H 16 N 3 O 3 [M + H] +: 238, Found 238.

Compound 2b as a yellow solid (51%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 8.37 (1H, d, J = 7.2 Hz), 7.67 (1H, d, J = 3.2 Hz), 7.45 (1H, d, J = 9.2 Hz), 7.39 (1H, dd, J = 7.2 Hz, J = 3.2 Hz), 3.43- 3.49 (2H, m), 3.28-3.30 (1H, m), 3.16-3.24 (2H, m), 1.49- 1.60 (4H, m); _{LRMS (ESI) calcd for C 10} H 14 N 3 O 4 [M + H] +: 240, Found 240.

Compound 2c as a yellow solid (67%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.23 (1H, d, J = 7.08 Hz), 7.46 (1H, s), 7.41 (1H, dd, J = 4.33 Hz, 2.71 Hz), 7.00 (1H, d, J = 7.65 Hz), 3.96 (1H, d, J = 13.07 Hz), 3.71 (1H, br, s), 3.54 (1H, br, s), 3.13 (2H, m), 2.12 (1H, m ), 1.81 (1H, m), 1.71 (2H, m), 1.47 (9H, s); _{LRMS (ESI) calcd for C 15} H 23 N 4 O 5 [M + H] +: 339, Found 261 (M-78), 239 (M-100), 305 (M-35), 283 (M-55 ), 339 (M + H).

Compound 2d as a yellow solid (99%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.22 (1H, d, J = 6.03 Hz), 7.52 (1H, s), 7.41 (2H, m), 4.20 (1H, s), 3.38 (2H, m ), 3.30 (1H, m), 1.34 (3H, d, J = 6.13 Hz); _{LRMS (ESI) calcd for C 8} H 12 N 3 O 4 [M + H] +: 214, Found 214.

N ² - alkylpyridine -2,4- diamine  Synthesis of derivatives (compounds 3a-3d)

Compounds 2a to 2d (1.24 mmol) and Raney nickel catalyst (Raney Ni) were mixed in methanol (MeOH) (12 ml). The mixture was stirred under hydrogen gas at ambient temperature for 9 hours. After the reaction was completed, the catalyst was removed with a celite pad filtration and the residue was washed with methanol. The solvent was evaporated under reduced pressure. Compounds 3a to 3d were obtained (yield 88-96%) and used in the next step without further purification.

Compound 3a as a crude dark brown solid (88%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 7.46 (1H, d, J = 6.4 Hz), 7.15 (-NH, brs), 5.90 (1H, dd, J = 6.4 Hz, J = 2.0 Hz), 5.59 (1H, d, J = 2.0 Hz), 4.57 (2H, -NH, br, s), 3.22- 3.29 (1H, m), 1.93- 1.97 (2H, m), 1.74- 1.77 (2H, m), 1.57-1.61 (1H, m), 1.25-1.37 (5H, m); _{LRMS (ESI) calcd for C 11} H 18 N 3 [M + H] +: 192, Found 192.

Compound 3b as a crude pale pink solid (83%); ^{1 H-NMR (500 MHz,} CDCl 3) δ 7.47 (1H, d, J = 6.0 Hz), 5.74- 5.77 (2H, m), 5.55 (1H, s), 5.46 (2H, -NH, br, s ), 3.82-3.84 (2H, m), 3.73-3.75 (1H, m), 3.32-3.37 (2H, m), 1.78-1.81 (2H, m), 1.32-1.37 (2H, m); _{LRMS (ESI) calcd for C 10} H 16 N 3 O [M + H] +: 194, Found 194.

Compound 3c as a crude pale yellow solid (96%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 7.96 (1H, s), 5,78 (1H, d, J = 4.5 Hz), 5.69 (1H, d, J = 7.20 Hz), 5.57 (1H, s (1H, br s), 5.47 (1H, br), 5.47 (1H, br) (1 H, m), 1.67 (2 H, m), 1.35 (9 H, s); _{LRMS (ESI) calcd for C 15} H 25 N 4 O 2 [M + H] +: 293, Found 238 (M-55), 293.

Compound 3d as a crude pale yellow solid (9%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 7.45 (1H, d, J = 5.6 Hz), 6.03 (1H, s), 5.81 (1H, dd, d, J = 5.6 Hz, J = 1.6 Hz ), 5.64 (2H, s) , 5.58 (1H, d, J = 1.6 Hz), 3.67- 3.74 (2H, m), 3.02- 3.07 (2H, m), 1.03 (3H, d, J = 6.0 Hz) ; _{LRMS (ESI) calcd for C 11} H 18 N 3 [M + H] +: 192, Found 192.

N ² - alkyl - N ⁴ -(2- nitrophenyl ) 피리딘 -2,4- diamine  Synthesis of Derivatives (Compounds 4a-4g)

The compound 3a-3d (0.83 mmol), 1-bromo-2-nitrobenzene (167 mg, 0.83 mmol) and palladium acetate (Pd (OAC) ₂ ) (18.6 mg, 0.083 mmol ), BINAP (51.5 mg, 0.083 mmol), and the third potassium phosphate _{(K 3 PO 4) (351} mg, 1.6 mmol) with nitrogen (N ₂₎ was purged with (purge), then toluene (3.8 mL) to And mixed. After sonication for 5 min under nitrogen, the mixture was heated to 130 &lt; 0 &gt; C under nitrogen and stirred at 130 &lt; 0 &gt; C for 3 h with no nitrogen. After cooling to ambient temperature, the solvent was removed in vacuo. The crude product was purified by flash column chromatography on silica gel using a mobile phase of EA: Hex (2: 1-1: 1) to give 4a-4g of the compound.

Compound 4a as a yellow solid (66%); ^{1 H-NMR (500 MHz,} CDCl 3) δ 9.20 (1H, s), 8.18 (1H, d, J = 8.5 Hz), 7.89 (1H, d, J = 5.5 Hz), 7.47- 7.56 (2H, m ), 6.94-7.00 (1H, m), 6.41 (1H, dd, J = 5.5 Hz), 6.14 (1H, s), 5.57 (1H, brs) m), 1.75-1.77 (2H, m), 1.61-1.64 (1H, m), 1.32-1.40 (2H, m), 1.22-1.29 (m, 3H); _{LRMS (ESI) calcd for C 17} H 21 N 4 O 2 [M + H] +: 313, Found 313.

Compound 4b as a yellow oil (50%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 9.20 (1H, s), 8.19 (1H, dd, J = 8.8 Hz, J = 1.6 Hz), 7.95 (1H, d, J = 5.6 Hz), 7.48- 7.56 (2H, m), 6.96- 7.00 (1H, m), 6.47 (1H, dd, J = 5.6 Hz, J = 1.6 Hz), 6.18 (1H, d, J = 1.6 Hz), 4.96 (1H, brs ), 3.96-4.02 (2H, m), 3.77-3.84 (1H, m), 3.50-3.56 (2H, m), 2.02 (2H, brd), 1.50-1.60 (2H, m); _{LRMS (ESI) calcd for C 16} H 19 N 4 O 3 [M + H] +: 315, Found 315.

Compound 4c as a pale yellow solid (74%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.00 (1H, s), 8.06 (1H, d, J = 1.58 Hz), 7.81 (1H, d, J = 5.66 Hz), 7.61 (3H, m M), 3.15 (2H, m), 2.13 (2H, m), 7.10 (1H, t, J = 1.01 Hz) (1H, m), 1.96 (1H, m), 1.67 (2H, m), 1.21 (9H, s); _{LRMS (ESI) calcd for C 21} H 28 N 5 O 4 [M + H] +: 414, Found 358.25 (M-55), 414.

Compound 4d as a pale yellow solid (60%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 9.16 (1H, s), 8.17 (1H, dd, J = 1.45 Hz, J = 1.48 Hz), 7.91 (1H, d, J = 5.76 Hz), 7.50 ( (1H, m), 6.94 (1H, td, J = 1.40 Hz), 6.44 (1H, dd, J = 1.86 Hz, J = 1.86 Hz), 6.24 1H, m), 3.54 (1H, br), 3.42 (1H, d, J = 13.7 Hz), 3.24 (1H, m), 1.21 (3H, d, J = 6.28 Hz); _{LRMS (ESI) calcd for C 14} H 17 N 4 O 3 [M + H] +: 289, Found 289.

Compound 4e as a pale yellow solid (58%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 8.46 (1H, s), 7.70 (1H, d, J = 6.00 Hz), 7.54 (1H, d, J = 3.20 Hz), 7.47 (1H, d , J = 9.00 Hz), 7.30 (1H, dd, J = 9.00 Hz, J = 6.00 Hz), 6.12 (1H, dd, J = 6.80 Hz, J = 2.00 Hz), 6.03 (1H, d, J = 6.80 (2H, m), 1.67-1.71 (2H, m), 1.55 (1H, d, J = - 1.58 (1H, m), 1.23-1.33 (2H, m), 1.09-1.81 (3H, m); _{LRMS (ESI) calcd for C 18} H 23 N 4 O 3 [M + H] +: 343, Found 343.

Compound 4f as a pale yellow solid (40%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.67 (1H, s), 7.72 (1H, d, J = 7.2 Hz), 7.67 (1H, d, J = 3.2 Hz), 7.46- 7.55 (2H, m ), 7.24 (1H, dd, J = 9.2 Hz, J = 2.2 Hz), 6.38 (1H, dd, J = 6.4 Hz, J = 2.0 Hz), 6.07 (1H, d, J = 2.0 Hz), 3.99- 4.05 (2H, m), 3.90 (3H, s), 3.87-3.93 (1H, m), 3.52-3.58 (2H, m), 1.98-2.06 (2H, m), 1.68-1.72 (2H, m); _{LRMS (ESI) calcd for C 17} H 21 N 4 O 4 [M + H] +: 345, Found 345.

Compound 4g as a pale yellow solid (43%); ^{1 H-NMR (400 MHz,} CDCl3) δ 8.77 (1H, s), 7.98- 8.00 (1H, m), 7.59- 7.72 (4H, m), 6.26- 6.35 (2H, m), 3.90 (3H, s ), 3.87-3.91 (2H, m), 3.56-3.64 (2H, m), 2.95-3.10 (1H, m), 1.98-2.06 (2H, m), 1.68-1.72 , s); _{LRMS (ESI) calcd for C 22} H 30 N 5 O 5 [M + H] +: 444, Found 444.

N ² - alkyl - N ⁴ -(2- 아민ophenyl ) - 피리딘 -2,4- diamine  Synthesis of Derivatives (Compounds 5a-5g)

Compound 4a to 4g (0.66 mmol) and palladium on activated carbon were over-mixed in methanol (7 ml). The mixture was shaken under hydrogen gas at ambient temperature for 30 minutes. After the yellow of the reaction mixture disappeared, the catalyst was removed using a celite pad filtration and the residue was washed with methanol. The solvent was evaporated under reduced pressure. Compounds 5a to 5g were obtained with a yield of greater than 90% and were used in the next step without further purification.

Compound 5a as a crude yellow solid (66%); ^{1 H-NMR (500 MHz,} CD 3 OD) δ 7.41- 7.44 (2H, m), 7.00- 7.50 (m, 2H), 6.64- 6.66 (1H, m), 6.20- 6.22 (1H, m), 5.69 (2H, m), 1.69-1.78 (2H, m), 1.57-1.60 (1H, m), 1.19-1.38 (5H, m); _{LRMS (ESI) calcd for C 17} H 23 N 4 [M + H] +: 283, Found 283.

Compound 5b as a crude yellow solid (70%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 7.97 (1H, s), 7.56 (1H, d, J = 6.00 Hz), 6.91- 6.97 (2H, m), 6.76 (1H, dd, J = 8.0 Hz, J = 1.2 Hz) , 6.53- 6.58 (2H, m), 6.05 (1H, dd, J = 6.4 Hz, J = 1.6 Hz), 5.62 (1H, d, J = 1.6 Hz), 4.87 (2H , s), 3.81-3.83 (3H, m), 3.31-3.37 (2H, m), 1.77-1.80 (2H, m), 1.33-1.39 (2H, m); _{LRMS (ESI) calcd for C 16} H 21 N 4 O [M + H] +: 285, Found 283.3.

Compound 5c as a crude dark brown solid (90%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 7.61 (1H, br, s), 7.10 (2H, d, J = 4.0 Hz), 6.82 (1H, d, J = 7.2 Hz), 6.76 (1H, t (2H, m), 3.38-3.49 (1H, m, J = 7.2 Hz), 6.38 (1H, br.s), 6.02 (1H, d, J = 5.8Hz) m), 2.89-3.13 (1H, m), 2.46-2.62 (4H, with -NH2 m), 1.70-1.73 (1H, m), 1.42-1.44 (3H, m), 1.42 (9H, s); _{LRMS (ESI) calcd for C 21} H 30 N 5 O 2 [M + H] +: 384, Found 384 (M-100), 328 (M-55), 384 (M + H).

Compound 5d as a crude dark red solid (89%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 7.55 (1H, d, J = 6.0 Hz), 7.49 (1H, s), 6.96 (1H, dd, J = 8.0 Hz, J = 1.2 Hz), 6.90 (1H, td, J = 7.6 Hz, J = 1.2 Hz), 6.74 (1H, dd, J = 8.0 Hz, J = 1.26 Hz), 6.55 (1H, td, J = 7.6 Hz, J = 1.2 Hz) , 6.06 (1H, t, J = 5.6 Hz), 5.95 (1H, dd, J = 6.0 Hz, J = 1.6 Hz), 5.63 (1H, d, J = 1.6 Hz), 4.78 (2H, s), 3.67 - 3.71 (1H, m), 3.17 (1H, s), 3.04-3.08 (2H, m), 1.00 (3H, J = 6.4 Hz); _{LRMS (ESI) calcd for C 14} H 19 N 4 O [M + H] +: 259, Found 259.

Compound 5e as a crude dark red solid (99%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 7.71 (1H, d, J = 6.0 Hz), 6.97 (2H, d, J = 8.4 Hz), 6.28- 6.33 (2H, m), 5.88 (1H, dd , J = 6.0 Hz, J = 2.0 Hz), 5.46 (1H, d, J = 2.0 Hz), 5.32 (1H, s), 4.38 (1H, d, J = 6.4 Hz), 3.82 (2H, s), M), 1.66-1.72 (2H, m), 1.55-1.60 (1H, m), 1.31-1.38 (2H, m) ), 1.13-1.20 (3H, m); _{LRMS (ESI) calcd for C 18} H 25 N 4 O [M + H] +: 313, Found 313.

Compound 5f as a crude dark red solid (96%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 7.56 (-NH, brs), 7.31- 7.35 (2H, m), 6.94 (1H, d, J = 8.4 Hz), 6.28- 6.32 (1H, m), 5.96 (1H, d, J = 5.6 Hz), 5.48 (1H, s), 3.90- 3.95 (2H, m), 3.84 (2H, brs), 3.76 (3H, s), 3.58- 3.64 (1H, m) , 3.43-3.49 (2H, m), 1.90-1.93 (2H, m), 1.40-1.52 (2H, m); _{LRMS (ESI) calcd for C 17} H 23 N 4 O 2 [M + H] +: 315, Found 315.

Compound 5g as a crude dark red solid (90%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 7.46- 7.65 (2H, m), 6.98 (2H, d, J = 8.4 Hz), 6.36 (1H, d, J = 6.4 Hz), 6.33 (1H, dd , J = 8.4 Hz, J = 2.8 Hz), 6.00 (1H, dd, J = 6.4 Hz, J = 1.6 Hz), 5.53 (1H, br, s), 3.91- 3.96 (2H, m), 3.78 (3H , s), 3.72-3.80 (2H, m), 3.26-3.39 (1H, m), 1.98-2.00 (2H, m), 1.74-1.75 (2H, m), 1.44 (9H, s); _{LRMS (ESI) calcd for C 22} H 32 N 5 O 3 [M + H] +: 414, Found 358 (M-55), 414.

N ² - alkyl -4- (2- aryl -One H - benzo [d] imidazol-1- yl ) pyridine -2- amine  Synthesis of Derivatives (Compounds 6a-6j)

Compounds 5a to 5g A (0.26 mmol), aldehyde (0.26 mmol), 30% w / hydrogen peroxide (H ₂ O ₂₎ of w (118.24 mg, 1.043 mmol) , NH 4 Ce (NO 3) 6 (14.25 mg, 0.026 mmol) in ethanol ( EtOH) (0.2 ml) at 50 &lt; 0 &gt; C for 8 hours. After the reaction was completed, the reaction mixture was cooled and extracted with methylene chloride (CH ₂ Cl ₂ ). The organic layer was washed with saturated sodium bicarbonate solution (NaHCO ₃ ), water and brine And washed. After drying over anhydrous magnesium sulfate (MgSO ₄ ), the solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using a mobile phase of EA: Hex (1: 1) 6j.

Compound 6a as a white solid (38%); ^{1 H-NMR (500 MHz,} CDCl 3) δ 8.24 (1H, s), 8.15 (1H, d, J = 5.0 Hz), 7.93 (1H, d, J = 6.4 Hz), 7.81- 7.85 (3H, m ), 7.60 (1H, d, J = 8.5 Hz), 7.49- 7.55 (2H, m), 7.45- 7.47 (1H, m), 7.33-7.41 (2H, m), 6.63 (1H, d, J = 5.5 M), 1.57-1.61 (2H, m), 1.03-1.10 (1H, m), 6.18 4H, m), 0.87-0.89 (2H, m); _{HRMS (ESI) calcd for C 28} H 27 N 4 [M + H] +: 419.2230, Found 419.2229.

Compound 6b as a pale pink solid (20%); ^{1 H-NMR (500 MHz,} CDCl 3) δ 8.23 (1H, s), 8.21 (1H, d, J = 5.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.80- 7.84 (3H, m ), 7.50- 7.59 (3H, m ), 7.45 (1H, d, J = 8.0 Hz), 7.39 (1H, t, J = 7.5 Hz), 7.33 (1H, t, J = 7.5 Hz), 6.70 (1H , d, J = 5.0 Hz) , 6.15 (1H, s), 4.73 (1H, br, s), 3.74 (2H, d, J = 11.5 Hz), 3.46- 3.58 (1H, m), 3.24 (2H, t, J = 11.5Hz), 1.67 (1H, d, J = 13.0Hz), 1.29-1.36 (2H, m); HRMS (ESI) calcd for C ₂₇ H ₂₅ N ₄ O [M + H] ⁺ : 421.2023, Found 421.2029.

Compound 6c as a pale yellow solid (38%); ^{1 H-NMR (500 MHz,} CDCl 3) δ 8.24 (1H, s), 8.18 (1H, d, J = 4.5 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.99- 7.85 (3H, m ), 7.61- 7.63 (1H, m ), 7.49- 7.55 (2H, m), 7.44 (1H, d, J = 8.0 Hz), 7.38 (1H, t, J = 8.0 Hz), 7.33 (1H, t, J = 8.0 Hz), 6.58 ( 1H, br, s), 6.33 (1H, br, s), 4.89 (1H, br, s), 3.76- 3.78 (1H, m), 3.60 (1H, br, s) M, shield with impurity), 3.46-3.50 (1H, m), 3.12-3.18 (2H, m), 1.75-1.78 (1H, m), 1.57-1.61 1.28 (9 H, s); _{LRMS (ESI) calcd for C 32} H 34 N 5 O 2 [M + H] +: 520, Found 520.

Compound 6d as a white solid (60%); ¹ H-NMR (400 MHz, CDCl ₃ ) ? 8.20 (1H, s), 7.90-7.92 (2H, m), 7.81-7.85 (3H, m), 7.51-7.56 (3H, m), 7.45-7.47 1H, m), 7.39 (1H , t, J = 7.2 Hz), 7.33 (1H, t, J = 7.2 Hz), 6.95 (1H, br, s), 6.67 (1H, s), 6.49 (1H, d , J = 4.8 Hz), 3.90-3.93 (1H, m), 3.33-3.36 (1H, m), 3.16-3.33 (1H, m), 1.13 (3H, d, J = 6.4 Hz); _{HRMS (ESI) calcd for C 25} H 23 N 4 O [M + H] +: 395.1866, Found 395.1866.

Compound 6e as a pale yellow solid (50%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.18 (1H, s), 8.13 (1H, d, J = 5.2 Hz), 7.76- 7.81 (3H, m), 7.58 (1H, d, J = 8.4 Hz ), 7.45- 7.51 (2H, m ), 7.37 (1H, br, s), 7.31 (1H, d, J = 8.4 Hz), 6.95 (1H, dd, J = 8.8 Hz, J = 1.6 Hz), 6.57 (1H, d, J = 8.4 Hz), 6.12 (1H, s), 4.78 (1H, d, J = 7.2 Hz), 3.89 (3H, s), 3.16-3.19 2H, m), 1.49 (3H, br s), 0.99-1.09 (5H, m); HRMS (ESI) calcd for C ₂₉ H ₂₉ N ₄ O [M + H] ⁺ : 449.2336, Found 449.2332.

Compound 6f as a pale pink solid (15 mg, 33%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.16- 8.18 (2H, m), 7.76- 7.82 (3H, m), 7.46- 7.55 (3H, m), 7.36 (1H, d, J = 2.4 Hz) , 7.31 (1H, d, J = 8.8 Hz), 6.95 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.65 (1H, dd, J = 5.6 Hz, J = 1.6 Hz), 6.10 (1H (d, J = 1.6 Hz), 4.77 (1H, d, J = 7.6 Hz), 3.89 (3H, s), 3.68-3.72 (2H, m), 3.44-3.51 2H, m), 1.62-1.66 (2H, m), 1.239-1.34 (2H, m, mixed with impurity peak); _{LRMS (ESI) calcd for C 28} H 27 N 4 O 2 [M + H] +: 451, Found 451.

Compound 6g as a white solid (44%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.20 (1H, d, J = 0.8 Hz), 8.16 (1H, d, J = 5.2 Hz), 7.78- 7.84 (3H, m), 7.60 (1H, dd , J = 8.4 Hz, J = 2.0 Hz), 7.49- 7.53 (2H, m), 7.39 (1H, d, J = 4.8 Hz), 7.31 (1H, d, J = 4.8 Hz), 6.96 (1H, dd , J = 8.8 Hz, J = 2.4 Hz), 6.55 (1H, d, J = 4.8 Hz), 6.30 (1H, s), 4.83 (1H, br, s), 3.91 (3H, s), 3.75- 3.79 (2H, m), 1.72-1.79 (1H, m), 1.56-1.62 (1H, m), 3.61 , 1.36 (9H, s), 1.25-1.46 (2H, m)); _{LRMS (ESI) calcd for C 33} H 36 N 5 O 3 [M + H] +: 550, Found 494 (M-55), 550.

Compound 6h as a pale pink solid (57%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.18 (1H, d, J = 6.40 Hz), 7.87 (1H, d, J = 7.52 Hz), 7.31 (6H, m), 7.10 (1H, d, J = 7.89 Hz), 6.95 (1H, dd, J = 2.62 Hz, J = 2.80 Hz), 6.54 (1H, d, J = 4.80 Hz), 6.30 2H, m), 3.16 (2H, m), 1.95 (1H, m), 1.60 (4H, m), 1.36 (9H, s); LRMS (ESI) calcd for C ₂₉ H ₃₄ N ₅ O ₃ [M + H] ⁺ : 500, Found 444 (M-55), 500.

Compound 6i as a pale pink solid (41%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.12 (1H, d, J = 5.60 Hz), 7.91 (2H, m), 7.36 (3H, m), 7.24 (2H, d, J = 8.21 Hz), 7.08 (1H, d, J = 7.76 Hz), 6.96 (1H, dd, J = 2.58 Hz, J = 2.58 Hz), 6.55 (1H, dd, J = 1.69 Hz, J = 1.70 Hz), 6.40 (1H, d, J = 1.22 Hz), 5.43 (1H, s), 3.97 (1H, m), 3.79 (3H, s), 3.44 (1H, m), 3.26 (1H, m), 1.22 (3H, d, J = 6.29 Hz); _{LRMS (ESI) calcd for C 22} H 23 N 4 O 2 [M + H] +: 375, Found 375.

Compound 6j as a white solid (38%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.15 (1H, d, J = 5.2 Hz), 7.84 (1H, d, J = 2.4 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.28- 7.32 (3H, m), 6.95 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.51 (1H, dd, J = 5.2 Hz, J = 2.0 Hz), 6.12 (1H, d, J = 2.0 (2H, m), 1.69-1.74 (2H, m), 1.59-1.62 (1H, m), 5.08 1H, &lt; / RTI &gt; m), 1.12-1.34 (5H, m); _{HRMS (ESI) calcd for C 25} H 25 Cl 2 N 4 O [M + H] +: 467.1400, Found 467.1401.

( R ) -cyclopropyl (3 - ((4- (2- aryl -One H - benzo [d] imidazol-1- yl ) pyridine -2-yl) amino) piperidin-1-yl) 메탄one  Synthesis of derivatives (compounds 7a-7c)

6c, 6g and 6h (0.148 mmol) were dissolved in 1.4 ml of 1,4-dioxane, treated with anhydrous 4 M HCl at ambient temperature and stirred for 30 minutes. The mixture was diluted with ether and stirred until the product separated into a solid. The solid product was filtered and washed with ether to give a crude salt. The salt (0.048 mmol) was cooled to 0 &lt; 0 &gt; C in methylene chloride (0.9 ml) and treated with DIPEA (32 [mu] L, 0.18 mmol). The mixture was maintained at 0 &lt; 0 &gt; C for 30 minutes, then cyclopropanecarbonyl chloride (18 mg, 0.051 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was diluted with methylene chloride and washed with water and saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using EA: Hex (1: 1) mobile phase.

Compound 7a as a white solid (48%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.22 (1H, d, J = 1.2 Hz), 8.02- 8.14 (1H, m), 7.91 (1H, d, J = 8.0 Hz), 7.78-7.83 (3H m), 7.59 (1H, d, J = 8.0Hz), 7.47-7.54 (2H, m), 7.28-7.39 (3H, m), 6.32-6.60 M), 1.78-1.86 (1H, m), 1.54-1.69 (3H, m), 1.37-1.45 (1H, m), 3.99 (1 H, m), 0.81-1.11 (4 H, m); _{HRMS (ESI) calcd for C 31} H 30 N 5 O [M + H] +: 488.2445, Found 488.2447.

Compound 7b as a pale yellow solid (60%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.85 (1H, br, s), 7.94 (1H, s), 7.80- 7.83 (2H, m), 7.46- 7.69 (5H, m), 7.42 (1H, (1H, d, J = 2.0 Hz), 7.27 (1H, d, J = 8.8 Hz), 7.01 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.94 3H, m), 3.91 (3H, s), 2.64-2.99 (2H, m), 1.53-1.75 (4H, m), 0.85-0.97 (5H, m); _{LRMS (ESI) calcd for C 32} H 32 N 5 O 2 [M + H] +: 518, Found 518.

Compound 7c as a pale pink solid (53%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.85 (1H, s), 8.19 (1H, s), 7.92 (1H, d, J = 8.00 Hz), 7.88 (1H, d, J = 7.60 Hz), (1H, m), 7.50 (1H, s), 7.50 (1H, (2H, m), 2.33 (2H, m), 1.68 (4H, m), 0.87 (5H, m); LRMS (ESI) calcd for C ₂₇ H ₂₉ N ₆ O ₂ [M + H] ⁺ : 469, Found 469.

N ² - alkyl -4- (2- aryl -One H - benzo [d] imidazol-1- yl ) pyridine -2- amine  Dimethylation of Derivatives ( 메틸 ) (Compounds 8a-8g)

The compounds 6e, 6f, 6g, 6i, 6j, 7b, and 7c (0.017 mmol) was cooled in methylene chloride (0.34 ml) to -78 [deg.] C and treated slowly with 1 M boron tribromide (16 [mu] M, 0.05 mmol). The reaction mixture was maintained at -78 &lt; 0 &gt; C for 1 h and then allowed to warm to room temperature for 2 h. The mixture was quenched with methanol (0.2 ml) at 0 &lt; 0 &gt; C and stirred at room temperature for an additional hour. The mixture was diluted with methylene chloride (5 ml), washed three times with saturated sodium bicarbonate solution (3 ml), twice with 5 ml of water and twice with 5 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated in vacuo to give the product as a white solid. The crude product was purified by flash column chromatography on silica gel using mobile phase of CH ₂ Cl ₂ : MeOH (40: 1-5: 1).

Compound 8a as a pale yellow solid (55%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.31 (1H, s), 8.21 (1H, s), 8.07 (1H, d, J = 5.2 Hz), 7.89- 7.95 (3H, m), 7.53 - 7.60 (3H, m), 7.22 (1H, d, J = 8.8 Hz), 7.11 (1H, d, J = 2.0 Hz), 6.82 (1H, dd, J = 8.8 Hz, J = 2.0 Hz), 6.61 (1H, d, J = 7.6 Hz), 6.45 (1H, dd, J = 5.2 Hz, J = 2.0 Hz), 6.38 (1H, d, J = 2.0 Hz), 3.62 (1H, br, s), 1.78 - 1.80 (2H, m), 1.51-1.62 (3H, m), 1.04-1.23 (5H, m); _{HRMS (ESI) calcd for C 28} H 27 N 4 O [M + H] +: 435.2179, Found 435.2172.

Compound 8b as a pale yellow solid (47%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.28 (1H, s), 8.21 (1H, s), 8.09 (1H, d, J = 5.2 Hz), 7.90- 7.95 (3H, m), 7.54 - 7.61 (3H, m), 7.23 (1H, d, J = 8.8 Hz), 7.12 (1H, d, J = 2.0 Hz), 6.83 (1H, dd, J = 8.8 Hz, J = 2.0 Hz), 6.74 (1H, d, J = 7.6 Hz), 6.49 (1H, dd, J = 5.2 Hz, J = 1.6 Hz), 6.42 (1H, d, J = 1.6 Hz), 3.74- 3.81 (3H, m), 1.74 - 1.77 (2H, m), 1.31-1.38 (4H, m); HRMS (ESI) calcd for C ₂₇ H ₂₅ N ₄ O ₂ [M + H] &lt; ⁺ &gt;: 437.1972, Found 439.1971.

Compound 8c as a pale yellow solid (67%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 8.21 (1H, s), 8.06 (1H, d, J = 5.2 Hz), 7.89- 7.95 (3H, m), 7.54- 7.61 (3H, m) , 7.21 (1H, d, J = 8.8 Hz), 7.12 (1H, d, J = 2.4 Hz), 6.83 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.70 (1H, d, J = 7.6 Hz), 6.47 (1H, d, J = 1.6 Hz), 6.44 (1H, dd, J = 5.2 Hz, J = 1.6 Hz), 3.76 (1H, br, s), 3.07- 3.09 (1H, m) , 2.80-2.83 (1H, m), 2.33-2.38 (1H, m), 1.94-1.97 (1H, m), 1.81-1.83 (1H, m), 1.54-1.62 2H, m); HRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ O [M + H] ⁺ : 436.2132, Found 436.2130.

Compound 8d as a white yellow solid (37%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.45 (1H, br, s), 8.25 (1H, s), 7.95- 8.08 (4H, m), 7.56- 7.63 (3H, m), 7.28- 7.32 (1H, m), 7.14 (1H, d, J = 2.4 Hz), 6.88 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.70 (1H, br, s), 6.52 (1H, d M, J = 8.8 Hz), 4.78 (1H, br s), 4.23-4.29 (1H, m), 3.96-3.99 (1H, m), 3.72- _{, shielded by H 2 O),} 2.12- 2.22 (1H, m), 1.91- 2.00 (2H, m), 1.16- 1.69 (1H, m), 0.78- 0.85 (5H, m); HRMS (ESI) calcd for C ₃₁ H ₃₀ N ₅ O ₂ [M + H] &lt; ⁺ &gt;: 504.2394, Found 504.2397.

Compound 8e as a pale yellow solid (55%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.92 (1H, s), 8.03 (1H, d, J = 5.65 Hz), 7.88 (1H, d, J = 7.60 Hz), 7.52 (1H, d, J = 4.40 Hz), 7.33 (4H , m), 6.88 (1H, d, J = 7.60 Hz), 6.81 (1H, s), 6.73 (1H, s), 6.32 (1H, d, J = 4.80 Hz), M, mixed with EtOAc), 3.72 (1H, m), 4.72 (1H, m), 4.09-4.15 (1H, m, mixed with EtOAc) ), 1.72-1.85 (3H, m), 0.86-1.05 (5H, m); HRMS (ESI) calcd for C ₂₇ H ₂₈ N ₅ O ₂ [M + H] &lt; ⁺ &gt;: 454.2238, Found 454.2238.

Compound 8f as a pale yellow solid (64%); ^{1 H-NMR (300 MHz,} CD 3 OD) δ 8.07 (1H, d, J = 2.60 Hz), 7.77 (1H, d, J = 8.86 Hz), 7.38 (1H, m), 7.38 (2H, m) , 7.24 (1H, t, J = 7.56 Hz), 7.03 (1H, m), 6.91 (1H, d, J = 6.00 Hz) 6.68 (1H, s), 6.57 (1H, m), 5.57 (1H, s ), 3.54 (1H, m), 3.43 (1H, m), 2.73 (1H, m), 1.01 (3H, d, J = 4.02 Hz); _{HRMS (ESI) calcd for C 21} H 21 N 4 O 2 [M + H] &lt; ⁺ &gt;: 361.1659, Found 361.1660.

Compound 8g as a white solid (54%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.34 (1H, s), 8.10 (1H, d, J = 5.6 Hz), 7.82 (1H, d, J = 2.0 Hz), 7.70 (1H, d , J = 8.4 Hz), 7.44 (1H, dd, J = 8.4 Hz, J = 2.4 Hz), 7.19 (1H, d, J = 8.8 Hz), 7.09 (1H, d, J = 2.4 Hz), 6.83 ( 1H, dd, J = 8.8 Hz , J = 2.4 Hz), 6.71 (1H, d, J = 7.6 Hz), 6.45 (1H, dd, J = 5.6 Hz, J = 1.6 Hz), 6.38 (1H, d, J = 1.6 Hz), 3.61 ( 2H, s), 1.83- 1.85 (2H, m), 1.66- 1.70 (2H, m), 1.55-1.59 (1H, m), 1.23- 1.32 (3H, m), 1.10 -1.19 (3 H, m); HRMS (ESI) calcd for C ₂₄ H ₂₃ Cl ₂ N ₄ O [M + H] ⁺ : 453.1243, Found 453.1239.

2- aryl -One H - benzo Synthesis of [d] imidazole derivatives (Compounds 10a-10c)

Compounds 10a and 10c: Benzene-1,2-diamine (5 mmol) and aldehyde (5 mmol) were stirred in methanol (MeOH) (25 ml) and 30% w / w hydrogen peroxide (H ₂ O ₂ ) (1.2 g, 10 mmol) was added and heated at 50 &lt; 0 &gt; C for 3 h. After the reaction was completed, cooling the reaction mixture was quenched (quench) with sodium bisulfite _{(NaHSO 3) (10 mmol)} . Methanol in the reaction mixture was removed in vacuo when it was 0.1 times the initial volume. The concentrated mixture was filtered and washed with ethyl acetate. The combined organic layers were concentrated in vacuo to give crude compound 10. Without further purification, the crude product was analyzed by LCMS and used in the next step to make compound 11.

Compound 10b: 4-methoxy-benzene-1,2-diamine dihydrochloride (1.0 g, 5 mmol), 2-naphthylaldehyde (781 mg, 5mmol) were stirred at 0 ℃ in methanol (50 ml) added and then triethylamine _{(Et 3 N) (1.4 mL} , 10 mmol). After 30 minutes, hydrogen peroxide (H ₂ O ₂ ) (1.2 g, 10 mmol) was added to the reaction mixture and the mixture was heated at 50 ° C. for 3 hours. After the reaction was completed, cooling the reaction mixture was quenched (quench) with sodium bisulfite _{(NaHSO 3) (10 mmol)} . Methanol in the reaction mixture was removed in vacuo when it was 0.1 times the initial volume. The concentrated mixture was filtered and washed with ethyl acetate. The combined organic layers were concentrated in vacuo to give crude compound 10. The crude product was purified by flash column chromatography on silica gel using acetone: Hex = 2: 1 to EA mobile phase.

Compound 10a as a crude brown solid (48%); ^{1 H-NMR (500 MHz,} CD 3 OD) δ 8.57 (1H, s), 8.20 (1H, dd, J = 8.5 Hz, J = 1.5 Hz), 7.70- 7.74 (2H, m), 7.64- 7.66 ( 2H, m), 7.59-7.61 (1H, m), 7.40-7.43 (1H, m), 7.33-7.36 (1H, m), 7.21-7.24 (2H, m), 5.70 (NH, s); _{LRMS (ESI) calcd for C 17} H 13 N 2 [M + H] +: 245, Found 245.

Compound 10b as a brown solid (ratio of two tautomers 10: 1 in DMSO- d , 450 mg, 33%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 12.92 (1H, s), 10.20 (1H, s), 8.68 (1H, s), 8.28 (1H, dd, J = 8.8 Hz, J = 1.6 Hz ), 8.06 (1H, d, J = 8.8 Hz), 8.02- 8.04 (1H, m), 7.97- 7.99 (1H, m), 7.56- 7.62 (2H, m), 6.86 (1H, dd, J = 8.8 Hz, J = 2.0 Hz), 7.52-7.55 (1H, m), 7.10 (1H, br s), 3.83 (3H, s); _{LRMS (ESI) calcd for C 18} H 15 N 2 O [M + H] +: 275, Found 275.

Compound 10c as a crude pale yellow solid (tautomer ratio 1: 0.18 in DMSO- d , 44%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 8.41 (1H, d, J = 2.0 Hz), 8.16 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.61-7.66 (2H, m), 7.24-7.28 (2H, m), 5.75 (1H, s); _{LRMS (ESI) calcd for C 13} H 9 Cl 2 N 2 [M + H] +: 263, Found 263.

1- (2- ( 메틸thio ) pyrimidine -4- yl )-2- aryl -One H - benzo Synthesis of [d] imidazole derivatives (compounds 11a-11d)

Compounds 10a to 10c 4-iodo-2- (methylthio) pyrimidine (320 mg, 1.3 mmol), tris (dibenzylideneacetone) dipalladium (Pd ₂ (dba) ₃ ) (140 mg, 0.13 mmol), BINAP (81 mg, 0.13 mmol) and NaOtBu (242 mg, 2.5 mmol) were purged with nitrogen and then toluene (13 mL) was added and mixed. After sonication for 5 min under nitrogen, the mixture was heated to 130 &lt; 0 &gt; C under nitrogen and stirred at 130 &lt; 0 &gt; C for 3 h with no nitrogen. After cooling to ambient temperature, the reaction mixture was filtered through a celite pad, the solvent was removed in vacuo and purified on silica gel using a mobile phase of EA: Hex (2: 1-1: 1) And purified using flash column chromatography. A mixture of compounds 11 and 10 (2: 1 ratio in ¹ H-NMR) was obtained as a pale yellow solid (yield 70-67%).

A mixture of compound 10a and 11a ; ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.40 (H, d, J = 5.6 Hz), 8.22- 8.23 (1H, m), 7.86- 7.96 (6H, m), 7.50- 7.59 (2H, m) , 7.41-7.44 (2H, m), 6.60 (1H, d, J = 5.6 Hz), 2.49 (3H, s); _{LRMS (ESI) calcd for C 22} H 17 N 4 S [M + H] +: 369, Found 369.

A mixture of compound 11b and compound 11c (ratio 1: 1) as a white solid mixture (80%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.68 (1H, d, J = 5.6 Hz), 8.65 (1H, d, J = 5.6 Hz), 8.22 (1H, d, J = 1.2 Hz), 8.19 ( 1H, d, J = 1.2 Hz ), 7.95- 8.00 (6H, m), 7.80 (1H, d, J = 8.8 Hz), 7.75 (1H, d, J = 8.8 Hz), 7.54- 7.64 (6H, m ), 7.41 (1H, d, J = 2.4 Hz), 7.39 (1H, d, J = 2.4 Hz), 7.11 (1H, d, J = 5.6 Hz), 7.03- 7.06 (3H, m), 3.86 (3H , s), 3.84 (3H, s), 2.28 (3H, s), 2.27 (3H, s); LRMS (ESI) calcd for C ₂₃ H ₁₉ N ₄ OS [M + H] &lt; + &gt;: 399, Found 399.

Compound 11d as a pale yellow solid (4: 1 compound 11d and compound 10c ratio in CDCl _{3 ,} 80%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.54 (1H, d, J = 5.6 Hz), 7.85- 7.87 (1H, m), 7.79- 7.82 (2H, m), 7.46 (1H, d, J = 8.8 Hz), 7.38-7.41 (2H, m), 7.30 (1H, dd, J = 8.8 Hz, J = 2.0 Hz), 6.70 (1H, d, J = 5.6 Hz), 2.46 (3H, s); _{LRMS (ESI) calcd for C 18} H 13 Cl 2 N 4 S [M + H] +: 387, Found 387.

1- (2- ( methylsulfonyl ) pyrimidine -4- yl )-2- aryl -One H - benzo Synthesis of [d] imidazole derivatives (compounds 12a-12d)

Compound 11a-11d (0.51 mmol) and 70% m- CPBA (360 mg, 1.5 mmol) was shaken in methylene chloride (5 ml) at ambient temperature for 8 hours. After compound 11a to 11d has passed from LCMS, the reaction mixture was extracted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate (NaHCO _3). The extracted organic layer was dried over anhydrous magnesium sulfate (MgSO ₄₎ and filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash column chromatography on silica gel using a mobile phase of EA: Hex (1: 1) to give compounds 12a-12d. Compounds 12b and 12c were re-purified using PTLC (scale of 30 mg per time) to give compounds 12b and 12c.

Compound 12a as a white solid (52%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.65 (1H, d, J = 5.6 Hz), 8.19 (1H, s), 8.12- 8.14 (1H, m), 7.84- 7.89 (4H, m), 7.52 - 7.60 (2H, m), 7.41-7.50 (3H, m), 7.03 (1H, d, J = 5.6Hz), 3.25 (3H, s); _{LRMS (ESI) calcd for C 22} H 17 N 4 O 2 S [M + H] +: 401, Found 401.

Compound 12b as a white solid (37%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.60 (1H, d, J = 1.6 Hz), 8.18 (1H, s), 8.08 (1H, d, J = 8.8 Hz), 7.85- 7.90 (3H, m ), 7.50- 7.61 (3H, m ), 7.35 (1H, d, J = 2.4 Hz), 7.05 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.96 (1H, d, J = 5.6 Hz ), 3.90 (3H, s), 3.28 (3H, s); LRMS (ESI) calcd for C ₂₃ H ₁₉ N ₄ O ₃ S [M + H] ⁺ : 431, Found 431.

Compound 12c as a white solid (36%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.01 (1H, d, J = 5.6 Hz), 8.26 (1H, d, J = 1.6 Hz), 8.01 (1H, d, J = 8.4 Hz), 7.77 (1H, d, J = 8.4 Hz), 7.73 (1H, d, J = 2.4 Hz), 7.57- 7.65 (3H, m), 7.47 (1H, d, J = 5.6 Hz), 7.08 (1H, dd , J = 8.4 Hz, J = 2.4 Hz), 3.85 (3H, s), 3.30 (3H, s); LRMS (ESI) calcd for C ₂₃ H ₁₉ N ₄ O ₃ S [M + H] ⁺ : 431, Found 431.

Compound 12d as a white solid (61%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.87 (1H, d, J = 5.6 Hz), 8.07- 8.11 (1H, m), 7.88- 7.91 (1H, m), 7.83 (1H, d, J = 2.0 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.45- 7.49 (2H, m), 7.34 (1H, dd, J = 8.4 Hz, J = 2.0 Hz), 7.13 (1H, d, J = 5.6 Hz), 3.36 (3H, s); _{LRMS (ESI) calcd for C 18} H 13 Cl 2 N 4 O 2 S [M + H] +: 419, Found 419.

N ² - alkyl -4- (2- aryl -One H - benzo [d] imidazol-1- yl ) pyrimidine -2- amine  Synthesis of Derivatives (Compounds 13a-13l)

Compounds 12a-12d (0.025 mmol) and amine (0.05 mmol) were stirred in THF (0.25 ml) at 60 &lt; 0 &gt; C for 5 hours. After compound 12 completely disappeared, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using a mobile phase of EA: Hex (1: 1) to give 13.

Compound 13a as a solid (73%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.20- 8.23 (2H, m), 7.80- 7.90 (5H, m), 7.48- 7.56 (3H, m), 7.32- 7.40 (2H, m), 6.37 ( (1H, br s), 5.31 (1H, br s), 3.23-3.47 (1H, m), 2.02-2.15 (1H, m), 1.46-1.76 (5H, m), 0.91-1.18 ); HRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ [M + H] ⁺ : 420.2183, Found 420.2179.

Compound 13b as a white solid (71%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.29 (1H, br, s), 8.24 (1H, s), 7.89- 7.99 (1H, m), 7.73- 7.87 (4H, m), 7.48- 7.55 ( (1H, m), 3.75-3.30 (2H, m), 7.33-7.41 (2H, m), 6.59 3.16 (2H, m), 1.14- 1.63 (4H, m, mixed with H 2 O); HRMS (ESI) calcd for C ₂₆ H ₂₄ N ₅ O [M + H] ⁺ : 422.1975, Found 422.1973.

Compound 13c as a white solid (41%) and recovered substrate (50%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.32 (1H, br, s), 8.17 (1H, br, s), 7.85- 8.00 (5H, m), 7.46- 7.60 (5H, m), 6.38 ( 1H, br s), 4.61 (1H, br s), 3.73 (1H, m), 3.62 (1H, m), 3.44-4.46 (1H, m), 3.35 (1H, 3.20 (1H, m), 1.79-1.84 (2H, m), 1.60-1.64 (2H, m), 1.45 (9H, s); LRMS (ESI) calcd for C ₃₁ H ₃₃ N ₆ O ₂ [M + H] ⁺ : 521, Found 521, 465 (M-55).

Compound 13d as a white solid (80%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.21 (1H, s), 8.18 (1H, d, J = 5.2 Hz), 7.78- 7.86 (3H, m), 7.71 (1H, d, J = 8.8 Hz ), 7.49- 7.55 (3H, m ), 7.36 (1H, d, J = 2.4 Hz), 6.98 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.31 (1H, br, s), 5.24 (1H, d, J = 7.6 Hz), 3.89 (3H, s), 3.29-3.52 (1H, m), 1.40-1.80 (5H, m), 1.04-1.16 (5H, m); _{HRMS (ESI) calcd for C 28} H 28 N 5 O [M + H] +: 450.2288, Found 450.2285.

Compound 13e as a white solid (86%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.26 (1H, s), 8.20 (1H, d, J = 1.6 Hz), 7.76- 7.85 (3H, m), 7.63 (1H, s), 7.49- 7.54 (3H, m), 7.36 ( 1H, d, J = 2.4 Hz), 6.98 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.34 (1H, br, s), 5.34 (1H, d, M, mixed with (H, m, J = 7.6 Hz), 3.89 (3H, s), 3.49-3.62 (2H, m), 3.24-3.42 EtOAc peak); LRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ O ₂ [M + H] ⁺ : 452, Found 452.

Compound 13f as a white solid (35%) and recovered substrate (65%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.20 (1H, s), 8.16 (1H, d, J = 5.2 Hz), 7.78- 7.84 (3H, m), 7.73- 7.74 (1H, m), 7.49 - 7.55 (3H, m), 7.36 (1H, d, J = 2.4 Hz), 7.05 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.24 (1H, br, s), 5.42 (1H, (2H, m), 1.38-1.66 (4H, m), 1.44 (2H, m), 3.87 (3H, s), 3.87 9H, s); LRMS (ESI) calcd for C ₃₂ H ₃₅ N ₆ O ₃ [M + H] ⁺ : 551, Found 551.

Compound 13g as a white solid (94%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.20 (1H, s), 8.19 (1H, d, J = 5.2 Hz), 7.85 (2H, dd, J = 8.8 H, J = 6.4 H), 7.81 ( 1H, d, J = 8.8 Hz ), 7.57 (1H, d, J = 8.8 Hz), 7.48- 7.57 (3H, m), 7.35 (1H, d, J = 2.4 Hz), 7.02 (1H, dd, J (2H, m), 1.45 (1H, d, J = 8.8 Hz, J = 2.4 Hz), 6.28 (1H, s), 5.34 - 1.64 (3H, m), 1.07 - 1.16 (5H, m); _{HRMS (ESI) calcd for C 28} H 28 N 5 O [M + H] +: 450.2288, Found 450.2282.

Compound 13h as a white solid (71%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.26 (1H, d, J = 4.8 Hz), 8.19 (1H, s), 7.73- 7.86 (4H, m), 7.47- 7.54 (3H, m), 7.24 - 7.26 (1H, mixed with CDCl 3), 7.01 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.48 (1H, s), 5.57 (1H, s), 3.87 (3H, s), 3.68 (2H, m, mixed with EtOAc), 1.42-1.42 (2H, m), 1.22-1.32 (2H, d, J = 10.8 Hz), 3.47-3.66 ; LRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ O ₂ [M + H] ⁺ : 452, Found 452.

Compound 13i as a white solid (35%) and recovered substrate (50%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.19 (1H, d, J = 5.2 Hz), 8.18 (1H, s), 7.81- 7.85 (2H, m), 7.79 (1H, d, J = 8.8 Hz ), 7.75 (1H, d, J = 8.8 Hz), 7.49- 7.54 (3H, m), 7.34 (1H, d, J = 2.4 Hz), 6.99 (1H, dd, J = 8.8 Hz, J = 2.4 Hz ), 6.26 (1H, s), 5.44 (1H, br s), 3.91 (3H, s), 3.62-3.75 (2H, m), 3.25-3.50 (3H, 1.22-1.61 (4H, m); LRMS (ESI) calcd for C ₃₂ H ₃₅ N ₆ O ₃ [M + H] +: 551, Found 551.

Compound 13j as a white solid (80%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 8.53 (1H, s), 7.82- 7.84 (2H, m), 7.74 (1H, d, J = 8.0 Hz), 7.67- 7.76 (1H, m) , 7.60 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 8.0 Hz), 7.37-7.42 (2H, m), 6.92 3.09-3.24 (2H, m), 1.23-1.39 (4H, m); _{HRMS (ESI) calcd for C 22} H 20 Cl 2 N 5 O [M + H] +: 440.1039, Found 440.1036.

Compound 13k as a white solid (40%) and recovered substrate (50%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.36 (1H, d, J = 4.8 Hz), 7.84- 7.87 (2H, m), 7.74- 7.76 (1H, m), 7.46 (1H, d, J = (2H, m), 3.42-3.47 (1H, m), 3.26 (1H, br s) - 3.36 (2H, m), 1.88 (2H, br s), 1.62 (2H, br s), 1.41 (9H, s); LRMS (ESI) calcd for C ₂₇ H ₂₉ Cl ₂ N ₆ O ₂ [M + H] ⁺ : 539, Found 539.

3- [4- (2- naphthalen -2- yl - benzoimidazole -One- yl ) - pyrimidine -2- ylamino ] - piperidinium  Synthesis of Compound (Compound 14)

Compound 13c (20 mg, 0.038 mmol) was dissolved in 0.38 ml of 1,4-dioxane and treated with 0.19 ml of 4 M-HCl in 1,4-dioxane at ambient temperature. The reaction mixture was stirred at ambient temperature for 20 minutes. The mixture was diluted with ether and stirred until the product separated into solids. The solid product was filtered, washed with ether and then with hexane And washed. The crude product was then crystallized.

Compound 14 as a pale yellow solid (63%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.03- 9.38 (1H, m), 8.48- 8.68 (1H, m), 8.27 (1H, s), 7.98- 8.01 (3H, m), 7.85- 7.87 (1H, m), 7.79 (1H, d,, J = 7.2 Hz), 7.58- 7.65 (3H, m), 7.40- 7.45 (2H, m), 6.41- 6.77 (1H, m), 4.24 (1H , br s), 2.87-3.19 (2H, m), 2.67-2.78 (3H, m), 1.60-1.98 (4H, m); HRMS (ESI) calcd for C ₂₆ H ₂₅ N ₆ [M + H] &lt; ⁺ &gt;: 421.2135, Found 421.2141.

( R ) -cyclopropyl (3 - ((4- (2- aryl -One H - benzo [d] imidazol-1- yl ) pyrimidine -2- yl ) amino ) piperidin-1-yl) methanone derivatives (compounds 15a-15c)

The compounds 15a to 15d were synthesized in the same manner as the compounds 7a to 7c except that the compounds 13c, 13f, 13i and 13k (0.013 mmol) were used as substrates, respectively.

Compound 15a as a white solid (72%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.25 (2H, br, s), 7.82- 7.94 (5H, m), 7.50- 7.57 (3H, m), 7.39- 7.43 (2H, m), 6.35- M), 1.64-1.73 (2H, m), 1.56-1.62 (1 H, m) ), 0.81-1.04 (1H, m), 0.78-0.96 (4H, m); _{HRMS (ESI) calcd for C 30} H 29 N 6 O [M + H] +: 489.2397, Found 489.2396.

Compound 15b as a white solid (74%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.18- 8.21 (2H, m), 7.84- 7.86 (2H, m), 7.69- 7.79 (1H, m), 7.49- 7.56 (3H, m), 7.37 ( (1H, d, J = 2.4 Hz), 6.98-7.02 (1H, m), 6.18-6.42 (1H, m), 5.44 m), 3.19-3.46 (3H, m), 1.39-1.72 (5H, m), 0.69-0.94 (4H, m); HRMS (ESI) calcd for C ₃₁ H ₃₁ N ₆ O ₂ [M + H] &lt; + &gt;: 519.2503, Found 519.2500.

Compound 15c as a white solid (59%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.20 (1H, s), 8.19 (1H, s), 7.80- 7.85 (3H, m), 7.78 (1H, d, J = 8.8 Hz), 7.51- 7.54 (1H, br s), 3.87 (1H, br s), 7.30 (1H, s), 7.02 (1H, dd, J = 8.8 Hz, J = 2.4 Hz) (2H, m), 3.12-3.31 (1H, m), 1.54-1.78 (5H, m), 0.93-0.97 0.72-0.75 (2H, m); _{HRMS (ESI) calcd for C 31} H 31 N 6 O 2 [M + H] +: 519.2503, Found 519.2500.

Compound 15d as a white solid (60%); ^{1 H-NMR (400 MHz,} CDCl 3) δ 8.36 (1H, br, s), 7.87 (1H, d, J = 8.0 Hz), 7.70- 7.76 (2H, m), 7.48 (1H, d, J = 8.0 Hz), 7.39-7.43 (3H, m), 6.48 (1H, br s), 5.35-5.81 (1H, m), 4.04-4.14 - 2.14 (1H, m), 1.76 (2H, br s), 1.57 (2H, br s), 0.80-0.99 (4H, m); HRMS (ESI) calcd for C ₂₆ H ₂₅ Cl ₂ N ₆ O [M + H] ⁺ : 507.1461, Found 507.1473.

N ² - alkyl -4- (2- aryl -One H - benzo [d] imidazol-1- yl ) pyrimidine -2- amine  Derivative Dimeration  (Compounds 16a-16f)

The compounds 16a to 16f were synthesized in the same manner as the compounds 8a to 8g except that the compounds 13d, 13g, 13e, 13h, 15b and 15c (0.013 mmol) were used as substrates, respectively.

Compound 16a as a white solid (52%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.35 (1H, s), 8.40 (1H, s), 8.21 (1H, s), 7.95- 8.00 (2H, m), 7.52- 7.80 (4H, m), 7.29 (1H, s ), 7.14 (1H, s), 6.87 (1H, dd, J = 8.8 Hz, J = 2.4 Hz), 6.71 (1H, s), 5.22 (1H, br, s), 2.90 (1H, br s), 1.15-1.25 (6H, m), 0.67-0.91 (4H, m); HRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ O [M + H] ⁺ : 436.2132, Found 436.2127.

Compound 16b as a white solid (13%) and recovered substrate 76 (20%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 8.42 (1H, s), 8.15 (1H, s), 7.93- 7.95 (4H, m), 7.28- 7.62 (5H, m), 7.07 (1H, s), 6.85 (1H, dd , J = 8.8 Hz, J = 2.4 Hz), 6.72 (1H, -NH, s), 2.89 (1H, br, s), 1.23 (6H, m), 0.66- 0.85 ( 4H, m); HRMS (ESI) calcd for C ₂₇ H ₂₆ N ₅ O [M + H] ⁺ : 436.2132, Found 436.2128.

Compound 16c as a white solid (23%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.34 (1H, s), 8.45 (1H, s), 8.21 (1H, s), 7.92- 8.00 (3H, m), 7.37- 7.61 (5H, m), 7.13 (1H, d, J = 2.0 Hz), 6.86 (1H, dd, J = 8.8 Hz, J = 2.0 Hz), 4.78 (2H, m), 1.14 (2H, m), 1.45 (1H, d, J = m); HRMS (ESI) calcd for C ₂₆ H ₂₄ N ₅ O ₂ [M + H] ⁺ : 438.1925, Found 438.1918.

Compound 16d as a white solid (33%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.54 (1H, s), 8.47 (1H, s), 8.16 (1H, s), 7.91- 7.97 (3H, m), 7.39- 7.62 (5H, m), 7.06 (1H, s ), 6.84-6.87 (1H and -NH, m), 3.03- 3.07 (1H, m), 2.63- 2.67 (1H, m), 1.98 (1H, d, J = 14.0 Hz ), 1.72-1.75 (1H, m), 1.46 (1H, s), 1.14-1.24 (2H, m), 1.02-1.10 (2H, m); HRMS (ESI) calcd for C ₂₆ H ₂₄ N ₅ O ₂ [M + H] ⁺ : 438.1925, Found 438.1919.

Compound 16e as a white solid (55%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.36 (1H, s), 8.18- 8.42 (2H, m), 7.94- 7.96 (3H, m), 7.54- 7.61 (5H, m), 7.11 ( (1H, d, J = 2.4 Hz), 6.84 (1H, d, J = 7.6 Hz), 6.25-6.67 - 3.17 (2H, m), 1.91-1.97 (2H, m), 1.75 (1H, br s), 1.14-1.45 (4H, m), 0.69-0.85 (2H, m); _{HRMS (ESI) calcd for C 30} H 29 N 6 O 2 [M + H] +: 505.2347, Found 505.2343.

Compound 16f as a white solid (62%); ^{1 H-NMR (400 MHz,} DMSO- d 6) δ 9.52 (1H, s), 8.15- 8.45 (2H, m), 7.92- 7.95 (3H, m), 7.55- 7.61 (5H, m), 6.84 ( 1H, dd, J = 8.8 Hz , J = 2.0 Hz), 6.34- 6.67 (1H, m), 3.87- 4.39 (3H, m), 3.30 (1H, shielded by H 2 O), 2.80- 3.05 (1H, m), 1.98 (1H, m), 1.34-1.51 (4H, m), 0.70-0.85 (4H, m); _{HRMS (ESI) calcd for C 30} H 29 N 6 O 2 [M + H] +: 505.2347, Found 505.2340.

< Experimental Example >

One. JNK3  Active measurement

JNK3 Preparation of Kd How to measure the value

JNK3 is described by Lisnock et al. Expressed and purified as described in &lt; RTI ID = 0.0 &gt; Briefly, the catalytic domain of human JNK3 from S40 to E402 was amplified by PCR and then ligated to pET15b (Merch, USA) with NcoI (NEB, MA, USA) and BamHI (NEB, Germany) vector. A recombinant protein containing an N-terminal 6 histidine tag and a tobacco etch viral protease (TEV) cleavage site was expressed in E. coli BL21 (DE3). Ni-NTA affinity chromatography and ion exchange chromatography were performed using Mono-Q resin to purify the histidine-tagged fusion protein. After cleavage of TEV, the catalytic domain of JNK3 was purified by size-exclusion chromatography. The final yield of protein was 10 mg or more per liter of culture.

As a direct binding assay for JNK3, surface plasmon resonance (SPR) measurements were performed on ProteOn ^™ XPR36 (Bio-Rad Laboratories Inc.). All reagents and buffers used were purchased from Bio-Rad. Kinase was synthesized according to the method described in the literature (CH Reynolds, MA Utton, GM Gibb, A. Yates, BH Anderton, J. Neurochem 68 (1997) 1736-1744). JNK3 (mean 25,000 RU) was immobilized by a standardized amine coupling chemistry on the GLH chip. Binding experiments were performed using PBST buffer (phosphate buffered saline pH 7.4, 0.005% Tween 20) as running buffer. The compound was dissolved in 10 mM DMSO and then diluted with PBST buffer to make 1% DMSO solution. To calculate the Kd value, each 100 μM experimental compound in 1% DMSO PBST solution was sequentially diluted 3-fold from 100 μM to 0.01 μM using 1% DMSO in PBST solution to determine the final DMSO content and the concentration of each compound The concentration was adjusted. Five consecutive samples from nine serial dilutions of triplicate and an empty PBST containing 1% DMSO were injected into the six analytes from the SPR instrument. The optimum concentration range was calculated by at least three measurements. In order to obtain a reliable deviation value between the reaction units of apo-protein and protein-bound protein, standard values were normalized using an interspot reference and an in vivo solution containing 1% DMSO. The curves were adjusted to the log data using the Protein Manager ^TM Langmuir equation.

JNK3  Active measurement results

The physiological activity values of 28 compounds according to the present invention for JNK3 were measured and are shown in Table 2 below.

Example No. Compound No. K _d (μM) pK _d Example 1 Compound 6a 5.26 5.28 Example 2 Compound 6b 4.65 5.33 Example 3 Compound 6d 12.7 4.9 Example 4 Compound 6j 18.1 4.74 Example 5 Compound 7a 10.7 4.97 Example 6 Compound 8a 24.5 4.61 Example 7 Compound 8b 10 5 Example 8 Compound 8c 6.05 5.22 Example 9 Compound 8d 27.7 4.56 Example 10 Compound 8e 2.64 5.58 Example 11 Compound 8f 19.1 4.72 Example 12 Compound 8g 13.8 4.86 Example 13 Compound 13a 1.75 5.76 Example 14 Compound 13b 2.33 5.63 Example 15 Compound 13d 0.743 6.13 Example 16 Compound 13g 1.77 5.76 Example 17 Compound 13j 21.8 4.66 Example 18 Compound 14 2.98 5.53 Example 19 Compound 15a 1.93 5.71 Example 20 Compound 15b 2.91 5.54 Example 21 Compound 15c 1.17 5.93 Example 22 Compound 15d 7.69 5.11 Example 23 Compound 16a 1.89 5.72 Example 24 Compound 16b 31.7 4.5 Example 25 Compound 16c 1.66 5.78 Example 26 Compound 16d 6.00 5.22 Example 27 Compound 16e 2.65 5.58 Example 28 Compound 16f 0.0461 7.34

Referring to Table 2, in the benzimidazole derivative of the formula (1), when a pyrimidine group is substituted for the pyridine group in the structure, when a cycloalkyl group or a heterocycloalkyl group is introduced to R 4, a hydroxy group or a methoxy group is introduced into R 2 or R 3 , The inhibitory activity against JNK3 was generally increased.

Among the synthesized compounds of the Examples, the compound 16f PK _d of 46 nM and exhibited the highest activity.

2. Cell based JNK  Measurement of activity

Methods for measuring cell-based activity

Cell culture

Human neuroblastoma SH-SY5Y cells (Korean Cell Line Bank, Korea) were supplemented with 10% heat-inactivated fetal bovine serum (WelGene) in a humidified 95%, 5% CO ₂ incubator Dulbecco ' s modified Eagle ' s medium (DMEM; WelGene, Korea). Cells were confluence at 70% -80% of area and then treated with 10 μM of various JNK inhibitors for 1 h before treatment with 10 μg anismaicin (Sigma, USA) for 30 min under serum-free conditions . JNK inhibitor SP600125 (Sigma) was used as a positive control. All treatment chemicals were dissolved in dimethyl sulfoxide (DMSO) and the final concentration of DMSO was 0.2%.

In immunoblotting  Cell base by JNK  Active measurement

After treatment, the cells were collected from the plate and lysed in an ice-cold lysis buffer. Protein content of the lysate was determined using a Bio-Rad Protein Assay Reagent, and the same amount of protein was loaded on an SDS-PAGE gel, separated and blotted on a PVDF membrane (Millipore, USA) Respectively. The membranes were blocked with 5% nonfat milk or bovine serum albumin and then incubated with primary anti-phospho-c-Jun (p-Ser73; Cell Signaling, USA) Biotechnology Inc., USA), or anti-beta-actin (Sigma). Membranes were then incubated with horseradish-peroxidase-linked secondary antibody to detect chemiluminescence. Band strength was quantified by Quantity One software (Bio-Rad).

Cell-based JNK  Active measurement results

Cell-based immunoblotting was performed to test whether the compounds according to the present invention have a protective effect on nerve injury diseases in the cell line for JNK. In cell experiments, SH-SY5Y cells, a neuroblastoma, were selected to confirm the efficacy of JNK3 inhibitors in apoptotic environments. As a reference material for comparing the degree of phosphorylation of c-Jun, a substrate of JNK at the cell level, SP600125, a known JNK inhibitor, was used as Comparative Example 1.

First, SH-SY5Y cells were treated with Compound 13d, 15c and 16f of the present invention and Comparative Example 1 at 10 μM for 1 hour, respectively.

Next, the cells treated with the example and comparative compound were treated with 10 μg / ml of anisomycin, a cytotoxic substance against pc-Jun (p-Ser73), for 30 minutes, The degree of blocking the phosphorylation of pc-Jun was compared.

Fig. 1 is a view showing the results of immunoblotting of the compound of Example of the present invention and the compound of Comparative Example 1. Fig.

Referring to FIG. 1, it can be seen that the phosphorylation of c-Jun of cells was inhibited by the compound of the example of the present invention. Compounds 13d, 15c, and 16f of the present invention were found to be more effective in inhibiting phosphorylation of c-Jun than SP600125 of Comparative Example 1. In particular, compound 16f almost completely blocked phosphorylation of c-Jun.

FIG. 2 is a photograph of the cell morphology treated with the compound of Example of the present invention and the compound of Comparative Example 1 by an optical microscope. FIG.

Changes in cellular morphology are an indicator of the cytotoxic effect of JNK activity by somaicin. That is, when the cells are reacted with somaicin, nerve damage and neurite growth are decreased. When the cells of the present invention are treated with the compound of the present invention, an isomicin- The inhibitory effect of c-Jun on phosphorylation can be confirmed.

Referring to FIG. 2, it can be seen that the compound of Example of the present invention has a protective effect on cytotoxicity. Thus, the inhibitory effect of JNK3 of the compound of the present invention of the present invention can be expected to have clinical effects in degenerative neurological diseases including Alzheimer's disease.

3. IC ₅₀  Measure value

Quantitative real-time PCR ( real - time PCR )On by IC ₅₀  How to measure the value

IC ₅₀ values were determined by measuring tumor necrosis factor-alpha (TNF-a mRNA) using SYBR Green real-time PCR analysis. SH-SY5Y cells were anosomycin (10 μg / ml ) Was pretreated with compound 16f (0, 0.1, 0.5, 1, 5, 10 [mu] M) for 1 hour before treatment with total RNA. RNA was isolated using RNAiso (Takara, Japan) For amplification of the cDNA, all reactions were performed using the StepOne ^™ real-time PCR system (Applied Biosystems, USA) for 2 h at RT using a SuperScript Fist-strand Synthesis System for RT-PCR (Invitrogen, USA) was performed using amplification reaction to determine the gene expression was performed using the SYBR ^® Green PCR Master Mix (Applied Biosystems) according to the manufacturer's protocol. PCR product was identified by analysis of melting curves. human GAPDH (glycealdehyde 3-phosphate d TNF-α upstream primer 5'-TTTGATC CCTGACATCTGGA-3 ', downstream primer 5 (SEQ ID NO: 2), and the downstream primer 5 '-GGCCTAAGGTCCACTTGTGT-3'), GAPDH ( upstream primer 5'-GAGTCCACTGGCGTCTTCAC-3 ', downstream primer 5'-GTTCACACCCATGACGAACA-3'). the relative level of expression of the gene was analyzed by using 2- ^△△ Ct method.

IC ₅₀  Value measurement result

First, Example Compound 16f of the present invention was treated with SH-SY5Y cells at various concentrations for 1 hour. Next, the cells treated with the compound 16f were treated with 10 μg / ml of anisomycin for 30 minutes. Total RNA was extracted and TNF-α mRNA levels were measured by quantitative real-time PCR. The results were expressed as relative percent (%) for the control group treated with only an isomicin (n = 4).

Figure 3 is a graph of TNF-alpha mRNA levels measured for cell lines treated with various concentrations of the compound of Example 16f.

Referring to Figure 3, a dose-dependent reduction of TNF-mRNA levels by the compound 16f of the present invention was observed and IC ₅₀ values were 1.09 mM and IC ₅₀ The JNK inhibitory effect is much lower than that of SP600125.

From the above experimental examples, the compounds according to the present invention showed physiological activity against JNK3 in vitro and drastically decreased c-Jun phosphorylation on the cells and confirmed that they were effective and selective inhibitors of JNK3. This suggests that the compound according to the present invention can be used as a therapeutic agent for nerve cell death.

Claims (8)

A benzimidazole derivative compound represented by the following formula (1): or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,
Q1 and Q2 are the same or different and each independently -CH- or -N-;
R1 is benzyl, phenyl, hydroxybenzyl, chlorobenzyl, dichlorobenzyl, naphthyl, chloronaphthyl, or dichloronaphthyl;
R2 and R3 are each independently hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy;
R4 is selected from the group consisting of cyclohexyl, benzyl, furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, Piperazinyl, hydroxymethyl, hydroxymethyl, hydroxyisopropyl, or cyclopropylmethanopiperidinyl.
delete The method according to claim 1,
The benzimidazole derivative compound represented by Formula 1 is a benzimidazole derivative compound selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof:
(4- (2-naphthalen-2-yl-benzoimidazol-1-yl) -pyridin-2-yl) -amine
Yl) - (tetrahydro-pyran-4-yl) -amine (prepared as described for the preparation of 4- (2-naphthalen-
( S ) -1- (4- (2-naphthalen-2-yl-benzoimidazol- 1 -yl) -pyridin- 2- ylamino)
- (4- (2- (3,4-Dichloro-phenyl) -5-methoxy-benzoimidazol- 1 -yl) -pyridin-
( R ) -cyclopropyl- (3- (4- (2-naphthalen-2-yl-benzoimidazol- 1 -yl) -pyridin- 2- ylamino) -piperidin-
Synthesis of 1- (2-cyclohexylamino-pyridin-4-yl) -2-naphthalen-2-yl-1 H -benzoimidazol-
2-naphthalen-2-yl-l- (2- (tetrahydro-pyran-4-ylamino) pyridin-4-yl) -1 H-benzoimidazol-5-ol
(R) -2-naphthalen-2-yl-1- (2- (piperidin-3-ylamino) pyridin-4-yl) -1 H-benzoimidazol-5-ol
( R ) -cyclopropyl- (3- (4- (5-hydroxy-2- naphthalen-2-yl-benzoimidazol- 1- yl) -pyridin- 2- ylamino) -piperidin- Yl) -methanone
( R ) -cyclopropyl- (3 - ((4- (2- (3-hydroxyphenyl) -1H-benzo (d) imidazol- 1- yl) -pyridin-2-yl) amino) piperidine -1-yl) methanone
(S) -3- (1- (2- (2- hydroxy-propylamino) -pyridin-4-yl) -1 H-benzoimidazol-2-yl) -phenol
1- (2-cyclohexylamino-pyridin-4-yl) -2- (3, 4-dichloro-phenyl) -1 H-benzoimidazol-5-ol
(4- (2-naphthalen-2-yl-benzoimidazol-1 -yl) -pyrimidin-
(4- (2-naphthalen-2-yl-benzoimidazol-l-yl) -pyrimidin- 2- yl) - (tetrahydro-
(4-methoxy-2-naphthalen-2-yl-benzoimidazol-1 -yl) -pyrimidin-
Yl) -pyrimidin-2-yl) -amine &lt; / RTI &gt;
(4- (2- (3,4-Dichloro-phenyl) -benzoimidazol-1 -yl) -pyrimidin-2- yl) - (tetrahydro-
( R ) - (4- (2-naphthalen-2-yl-benzoimidazol- 1 -yl) -2- pyrimidin- 2-yl) -piperidin-
( R ) -cyclopropyl- (3- (4- (2-naphthalen-2-yl-benzoimidazol- 1 -yl) -pyrimidin-2- ylamino) -piperidin- Rice field
( R ) -cyclopropyl- (3- (4- (5-methoxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- - yl) -methanone
( R ) -cyclopropyl- (3- (4- (6-methoxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- - yl) -methanone
( R ) -cyclopropyl- (3- (4- (2- (3,4-dichloro-phenyl) -benzoimidazol- 1- yl) -pyrimidin- 2- ylamino) -piperidin- Yl) -methanone
Synthesis of 1- (2-cyclohexylamino-pyrimidin-4-yl) -2-naphthalen-2-yl-1 H -benzoimidazol-
Synthesis of 1- (2-cyclohexylamino-pyrimidin-4-yl) -2-naphthalen-2-yl-1 H -benzoimidazol-
2-naphthalen-2-yl-l- (2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl) -1 H-benzoimidazol-5-ol
2-naphthalen-2-yl-l- (2- (tetrahydro-pyran-4-ylamino) -pyrimidin-4-yl) -1 H-benzoimidazol-6-ol
( R ) -cyclopropyl- (3- (4- (5-hydroxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- - yl) -methanone
( R ) -cyclopropyl- (3- (4- (6-hydroxy-2-naphthalen-2-yl-benzoimidazol- 1- yl) -pyrimidin-2- ylamino) -piperidin- - day) - methanone.
A pharmaceutical composition comprising the benzimidazole derivative compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and capable of preventing neurological diseases selected from the group consisting of ischemic brain diseases, degenerative brain diseases, Alzheimer's disease, Parkinson's disease and Huntington's disease And a pharmaceutical composition for therapeutic use.
delete delete delete 5. The method of claim 4,
Wherein the activity of JNK3 is inhibited to prevent or treat the aforementioned neurological diseases.

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