Novel benzimidazole derivative having protein kinase inhibitory activity and use thereof

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 same. The benzimidazole derivative compound according to the present invention exhibits selective inhibitory activity against JNK, particularly JNK3, and thus can be used as a pharmaceutical composition for the prevention and treatment of degenerative brain diseases, such as Alzheimer's disease and Parkinson's disease, or cancer.

Description

Novel benzimidazole derivatives having protein kinase inhibitory activity and their uses

[0001] The present invention relates to a novel benzimidazole derivative having protein kinase JNK3 (c-Jun N-terminal Kinase 3) inhibitory activity and its use.

[0002] In the case of Alzheimer's disease, which manifests as fatal nervous system dysfunction and motor impairment, due to a lack of understanding of its pathological phenomena, existing treatments primarily consist of acetylcholinesterase inhibitors, which alleviate the worsening of symptoms. However, ongoing research into its pathological phenomena has led to a paradigm shift in the development of treatments for degenerative brain diseases, moving from symptom relief to the development of novel target protein inhibitors. At the heart of this paradigm shift are protein kinases, intracellular signaling proteins that govern the life and death (apoptosis and necrosis) of nerve cells.

[0003] Among the MAPK pathway, a representative cell signaling system that regulates cell death, the c-Jun N-terminal kinase 3 (JNK3) isoform is concentrated in brain tissue, unlike the dozen or so isozymes of the same type, and is deeply related to neuronal apoptosis. It is distributed in pyramidal neurons (yellow) located in the CA1 and CA2 regions of the hippocampus of the cerebral cortex, and is known to cause apoptosis due to overexpression of c-Jun, one of the intraneuronal substrates, the degree of phosphorylation by JNK3, and overactivation of JNK3.

[0004] First, JNK3 phosphorylates and activates amyloid precursor protein (APP), a precursor of Aβ, the main cause of Alzheimer's disease, to localize it to the cell membrane and Aβ 42 Endocytosis of phosphorylated APP into cells, particularly during this process, promotes the conversion of Aβ42 It is known to be a crucial step in the production of Aβ. Secondly, it is noteworthy that Tau, the main component of NFT found in the brain cells of Alzheimer's patients, is also phosphorylated by JNK. In addition, it was reported that APP / Aβ-induced neurodegeneration was attenuated (neuroprotective effect) in an animal model in which the JNK3 gene was deleted (Tg2576 / PSM146L transgenic mice), which showed that JNK3 also mediates the production and toxicity of Aβ, and revealed that JNK3 inhibitors may be useful as therapeutic agents for AD.

[0005] The present invention has been conceived to solve the above problems, and the inventors of the present invention have sought to find a novel substance that can be developed as a treatment for degenerative brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, etc., and have made efforts to develop a small molecule inhibitor that can regulate the function of JNK3 (c-Jun N-terminal Kinase) as a molecular target, and as a result of extensive research, a novel benzimidazole derivative exhibiting JNK3 inhibitory activity has been identified, and the present invention has been completed based on this.

[0006] Accordingly, the purpose of the present invention is to provide a novel benzimidazole derivative exhibiting JNK3 inhibitory activity or a pharmaceutically acceptable salt thereof.

[0007] Another object of the present invention is to provide a method for preparing a novel benzimidazole derivative exhibiting JNK3 inhibitory activity.

[0008] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a degenerative brain disease or cancer, comprising the benzimidazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0009] Another object of the present invention is to provide a method for treating a degenerative brain disease or a cancer disease, comprising a step of administering the benzimidazole derivative or a pharmaceutically acceptable salt thereof to a subject or individual in need thereof.

[0010] Another object of the present invention is to provide a benzimidazole derivative or a pharmaceutically acceptable salt thereof for use in the treatment of a degenerative brain disease or a cancer disease.

[0011] Another object of the present invention is to provide a use of the benzimidazole derivative or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for treating a degenerative brain disease or a cancer disease.

[0012] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0013] In order to achieve the above-described purpose of the present invention, a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.

[0014] [Chemical Formula 1]

[0015]

[0016] In the above chemical formula 1,

[0017] R1 is , or and,

[0018] R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms;

[0019] R4 is a hydroxy group or a substituted or unsubstituted carbamate group,

[0020] R5 is a hydrogen atom or a halogen atom,

[0021] X1 is a carbon atom or an oxygen atom,

[0022] X2 is a carbon atom or a nitrogen atom,

[0023] Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms;

[0024] n is an integer between 1 and 2.

[0025] In addition, the present invention provides a pharmaceutical composition for preventing or treating a degenerative brain disease or cancer, comprising a derivative of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0026] As one embodiment of the present invention, the composition can inhibit the activity of JNK3 (c-Jun N-terminal kinase 3).

[0027] The novel benzimidazole derivative or pharmaceutically acceptable salt thereof according to the present invention exhibits inhibitory activity as an excellent target for JNK 3 (c-Jun N-terminal kinase 3), and a pharmaceutical composition containing the derivative can be usefully used for the prevention and treatment of degenerative brain diseases including Alzheimer's disease.

[0028] Figure 1 is a graph confirming the JNK selectivity of compounds 2, 2h, 3, and 3h according to the present invention.

[0029] Figure 2 is a graph showing the JNK3 selectivity percentage of 2h and 3h compounds according to the present invention.

[0030] Figure 3 is Aβ 1-42This is a graph confirming cell viability when treating mouse nerve cells induced with neurotoxicity with the compound of the present invention ((A) Neuroprotective effect after 24-hour incubation of compound 3 (1, 5, 10, 20 μM) and a known JNK inhibitor and (B) after 48-hour incubation, (C) Neuroprotective effect after 24-hour incubation of compounds 1, 2, 2h, 3, and 3h and (D) after 48-hour incubation).

[0031] Figure 4 is a graph confirming the increase in oral activity of a compound according to the present invention.

[0032] FIG. 5 shows the results of confirming the behavioral effects of compound 2h according to the present invention in a homozygous APPswe / PS1dE9 double transgenic mouse model ((A) administration schedule of behavioral tests, (B) spontaneous change (%) in the Y-maze, (C) escape latency (sec) in the passive avoidance test, (D) time spent in the platform quadrant and target zone in the Morris water maze, data are expressed as mean ± SEM (n = 9-13 for each group). *p < 0.05, ***p < 0.001 vs. wild-type (WT) group; #p < 0.05 vs. vehicle-administered group, data were analyzed by one-way ANOVA).

[0033] FIG. 6 shows the results of confirming the behavioral effects of compound 3h according to the present invention in a homozygous APPswe / PS1dE9 double transgenic mouse model ((A) administration schedule of behavioral tests, (B) spontaneous change (%) in the Y-maze, (C) escape latency (sec) in the passive avoidance test, (D) time spent in the platform quadrant and target zone in the Morris water maze, data are expressed as mean ± SEM (n = 9-13 for each group), *p < 0.05, ***p < 0.001 vs. wild-type (WT) group; #p < 0.05 vs. vehicle-administered group, data were analyzed by one-way ANOVA).

[0034] FIG. 7 shows the results of confirming the behavioral effects of compound 3h according to the present invention in a homozygous 3xTg mouse model ((A) 3h administration and behavioral test schedule, (B) spontaneous change (%) in the Y-maze, (C) escape latency (sec) in the passive avoidance test, (D) escape latency in the Morris water maze, (E) path length in the Morris water maze, (F) time spent in the platform quadrant in the Morris water maze, (G) time spent in the target zone in the Morris water maze. Data are expressed as mean ± SEM (n = 9-14 for each group). *p < 0.05, **p < 0.01, ***p < 0.001 vs. wild-type (WT) group; #p < 0.05; ##p < 0.01; ###p < 0.001 vs. vehicle-administered group. Data were analyzed by one-way ANOVA.)

[0035] Figure 8 shows the results of confirming the reduction of phosphorylated tau (pTau) induced by oral administration of compound 3h in hippocampal tissue of 3xTg-AD mice after in vivo behavioral assessment ((A) Western blot showing that 3h induced pTau reduction, (B) pTau reduction at S202 residue in a dose-dependent manner, (C) pTau reduction at T181 residue in a dose-dependent manner).

[0036] Hereinafter, the present invention will be described in detail.

[0037] The present invention provides a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0038] [Chemical Formula 1]

[0039]

[0040] In the above chemical formula 1,

[0041] R1 is , or and,

[0042] R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms;

[0043] R4 is a hydroxy group; or a substituted or unsubstituted carbamate group;

[0044] R5 is a hydrogen atom or a halogen atom,

[0045] X1 is a carbon atom or an oxygen atom,

[0046] X2 is a carbon atom or a nitrogen atom,

[0047] Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms;

[0048] n is an integer between 1 and 2.

[0049] In the present invention, R1 may be the following substituents and isomers thereof:

[0050] .

[0051] Herein, "alkyl" generally means a straight or branched chain saturated hydrocarbon group having a specified number of carbon atoms (e.g., 1 to 12 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and n-heptyl. An alkyl may be attached to a parent group or a substrate at any ring atom, provided that such attachment does not violate valence requirements. Similarly, an alkyl or alkenyl group may include one or more non-hydrogen substituents, provided that such attachment does not violate valence requirements. "Cycloalkyl" may mean a cyclic alkyl among alkyls.

[0052] Here, "halogen" refers to elements belonging to group 17 of the periodic table, including fluorine, chlorine, bromine, and iodine.

[0053] Here, “halogenated alkyl” refers to alkyl substituted with a halogen atom.

[0054] Here, “aryl” means an unsaturated aromatic ring compound having 5 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).

[0055] Here, "heterocycloalkyl" refers to a saturated or unsaturated (but not aromatic) cyclohydrocarbon, which may be optionally unsubstituted, monosubstituted or polysubstituted, in the structure of which at least one C atom is substituted by a heteroatom of N, O or S.

[0056] Here, "heterocycle" means an aromatic ring compound, which may be optionally unsubstituted, monosubstituted or polysubstituted, and in the structure of which at least one C atom is substituted with a heteroatom of N, O or S.

[0057] Here, “carbamate group” means a substituent having the general structure of R2NC(O)OR.

[0058] In one specific example of the present invention, the compound of Chemical Formula 1 may be a compound having a structure of Chemical Formula 2 below.

[0059] [Chemical Formula 2]

[0060]

[0061] In the above chemical formula 2,

[0062] R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms;

[0063] R4 is a hydroxyl group; or ; and,

[0064] R5 is a hydrogen atom or a halogen atom,

[0065] X1 is a carbon atom or an oxygen atom,

[0066] X2 is a carbon atom or a nitrogen atom.

[0067] As another embodiment of the present invention, in the chemical formula 2,

[0068] R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3 include the carbon atom to which they are attached. , or ; and form,

[0069] R4 is and,

[0070] R5 is a hydrogen atom or a halogen atom,

[0071] X1 is a carbon atom or an oxygen atom,

[0072] X2 is a carbon atom or a nitrogen atom.

[0073] As another embodiment of the present invention, the compound of the above chemical formula 1 may be a compound having a structure of the following chemical formula 3.

[0074] [Chemical Formula 3]

[0075]

[0076] In the above chemical formula 3,

[0077] R2 and R3 are each independently a halogen atom, or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms;

[0078] R4 is a hydroxyl group, , , , or and,

[0079] R5 is a hydrogen atom or a halogen atom,

[0080] X2 is a carbon atom,

[0081] Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

[0082] As another embodiment of the present invention, in the chemical formula 3,

[0083] R2 and R3 are each independently a halogen atom or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3 include the carbon atom to which they are attached. ; and form,

[0084] R4 is a hydroxyl group, , , , or and,

[0085] R5 is a hydrogen atom or a halogen atom,

[0086] X2 is a carbon atom,

[0087] Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

[0088] As another embodiment of the present invention, the chemical formula 3 may be the following chemical formula 3a.

[0089] [Chemical Formula 3a]

[0090]

[0091] In chemical formula 3a,

[0092] R2, R3, R4, R5, and X2 are as defined in the above chemical formula 3.

[0093] As another embodiment of the present invention, the compound of the above chemical formula 1 may be a compound having a structure of the following chemical formula 4.

[0094] [Chemical Formula 4]

[0095]

[0096] In the above chemical formula 4,

[0097] R2 and R3 are each independently a halogen atom, or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms;

[0098] R4 is a hydroxyl group or and,

[0099] R5 is a hydrogen atom or a halogen atom,

[0100] X2 is a carbon atom,

[0101] Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

[0102] As another embodiment of the present invention, in the chemical formula 4,

[0103] R2 and R3 are each independently a halogen atom or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3 include the carbon atom to which they are attached. ; and form,

[0104] R4 is and,

[0105] R5 is a hydrogen atom or a halogen atom,

[0106] X2 is a carbon atom,

[0107] Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

[0108] As another embodiment of the present invention, the chemical formula 4 may be the following chemical formula 4a.

[0109] [Chemical Formula 4a]

[0110]

[0111] In chemical formula 4a,

[0112] R2, R3, R4, R5, and X2 are as defined in the above chemical formula 4.

[0113] As another embodiment of the present invention, the compound of formula 1,

[0114] (S)-Cyclopropyl(3-((4-(6-hydroxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone (2);

[0115] (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2h);

[0116] (S)-Cyclopropyl(3-((4-(4-fluoro-6-hydroxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone (3);

[0117] (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-ylmethylcarbamate (3h):

[0118] (R)-1-(2-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2ah);

[0119] (R)-1-(2-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2aah);

[0120] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2bh);

[0121] 2-(Quinolin-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2ch);

[0122] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(quinolin-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2dh);

[0123] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2eh);

[0124] 2-(Benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2fh);

[0125] 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino) pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2gh);

[0126] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2hh);

[0127] 2-(Benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2ih);

[0128] (R)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2jh);

[0129] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2kh);

[0130] 2-(naphthalen-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2lh);

[0131] (R)-2-(Benzofuran-5-yl)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino) pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2mh);

[0132] (R)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2nh);

[0133] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2oh);

[0134] 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2ph);

[0135] (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl dimethylcarbamate (2qh);

[0136] (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl ethylcarbamate (2rh); or

[0137] (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl carbamate (2sh);

[0138] The present invention provides a pharmaceutical composition for the prevention or treatment of a degenerative brain disease or cancer, comprising a compound of the above chemical formulas 1 to 4, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0139] As another embodiment of the present invention, the degenerative brain disease may be Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, or stroke.

[0140] In another embodiment of the present invention, the cancer disease may be squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, cutaneous or intraocular melanoma, rectal cancer, anal cancer, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, Barrett's esophagus, colonic adenomas and polyps, breast fibroadenomas and cysts, monoclonal gammopathy of musculoskeletal syndrome (MGUS), or monoclonal lymphocytosis.

[0141] As another embodiment of the present invention, the composition may inhibit the activity of JNK3 (c-Jun N-terminal kinase 3).

[0142] Meanwhile, the compound of the present invention can be used in the form of a pharmaceutically acceptable salt, and as a salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.

[0143] The term "salt" as used in the present invention may be an acid addition salt formed by a pharmaceutically acceptable free acid. The acid addition salts are obtained from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, or phosphorous acid, and non-toxic organic acids such as aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, and alkanedioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyn-1,4-dioate, hexane-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, Contains phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

[0144] The acid addition salt according to the present invention can be prepared by conventional methods, for example, by dissolving the compound in an excess aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, the salt can be prepared by evaporating the solvent or excess acid from the mixture and then drying it, or by suction filtration of the precipitated salt.

[0145] Additionally, pharmaceutically acceptable metal salts can be prepared using bases. Alkali metal or alkaline earth metal salts can be prepared, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the undissolved compound salt, and evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are pharmaceutically suitable as metal salts. The corresponding silver salts are prepared by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0146] In addition, the compound of the present invention includes not only pharmaceutically acceptable salts but also all salts, isomers, hydrates and solvates that can be prepared by conventional methods.

[0147] As can be seen from the examples below, the compound of formula 1 can be used as a JNK3 inhibitor, and as described in the background of the invention, it is a well-known fact to those skilled in the art that JNK3 inhibitors can be used for the treatment of degenerative brain diseases or cancer diseases.

[0148] The present invention provides a pharmaceutical composition for preventing or treating a degenerative brain disease or a cancer disease, comprising a compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, more specifically, a pharmaceutical composition for preventing or treating a degenerative brain disease or a cancer disease, a use of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof for treating the disease, and a method for treating the disease, comprising administering to a subject a therapeutically effective amount of the compound of the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0149] The term “prevention” used in the present invention means any act of inhibiting or delaying the onset of a degenerative brain disease by administering a pharmaceutical composition according to the present invention.

[0150] The term "treatment" used in the present invention means any action in which the symptoms of a degenerative brain disease are improved or beneficially changed by administration of a pharmaceutical composition according to the present invention.

[0151] The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient. At this time, the pharmaceutically acceptable carrier is one commonly used in formulations, and includes, but is not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. In addition to the above ingredients, the composition may further include a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

[0152] The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the dosage varies depending on the patient's condition and weight, the degree of disease, the drug form, the route of administration, and the time, but can be appropriately selected by a person skilled in the art.

[0153] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level may be determined based on the type and severity of the patient's disease, the activity and sensitivity of the drug to the drug, the time of administration, the route of administration and excretion rate, the duration of treatment, concomitant drugs, and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take all of the above factors into consideration and administer an amount that achieves the maximum effect with the minimum amount without causing side effects, and this can be easily determined by those skilled in the art.

[0154] Specifically, the effective dose of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption rate, inactivation rate and excretion rate of the active ingredient in the body, type of disease, and concomitantly administered drugs, and is generally 0.0001 to 1000 mg per 1 kg of body weight, preferably 0.001 to 500 mg, administered daily or every other day, or divided into 1 to 3 times a day. However, since the dosage may increase or decrease depending on the route of administration, severity of obesity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

[0155] In the present invention, the term "subject" means a subject requiring treatment for a disease, and more specifically, means a mammal such as a human or non-human primate, mouse, dog, cat, horse, or cow.

[0156] Hereinafter, preferred manufacturing examples and examples are presented to aid in understanding the present invention. However, the following examples are provided solely to facilitate a better understanding of the present invention, and the scope of the present invention is not limited to the following manufacturing examples and examples.

[0157] <Preparation Example 1> N-(5-methoxy-2-nitrophenyl)-2-(methylthio)pyrimidin-4-amine (4) and N-(3-fluoro-5-methoxy-2-nitrophenyl)-2-(methylthio)pyrimidin-4-amine (5)

[0158]

[0159] 5-Methoxy-2-nitroaniline (1.0 g, 5.95 mmol) was dissolved in DMF (30 ml), and 55% NaH (1.2 equiv., 7.2 mmol) was slowly added while stirring at 0°C for 1 min. Then, 4-chloro-2-(methylthio)pyrimidine (1 equiv., 5.95 mmol) was added, and the mixture was stirred at room temperature for 2 h, and water was added. The resulting solid was filtered and washed with water to obtain the desired compound 4 (1.56 g, 90% yield); 1 H NMR (400 MHz, CDCl3) δ10.65 (s,1H), 8.63 (d,J= 2.7 Hz, 1H), 8.26 (d,J= 5.7 Hz, 1H), 8.22 (d,J= 9.5 Hz, 1H), 6.59 (dd,J= 9.5, 2.7 Hz, 1H), 6.50 (d,J= 5.7 Hz, 1H), 3.93 (s, 3H), 2.57 (s, 3H); ; 13C NMR (100 MHz, DMSO-d6) δ 170.8 (s), 164.2 (s), 159.5 (s), 156.8 (s), 136.1 (s), 134.3 (s), 128.2 (s), 110.5 (s), 108.8 (s), 104.5 (s), 56.5 (s), 13.6 (s); HRMS (ESI + ) calculated C 12 H 12 N4O3S [M+H] + : 293.0703, found 293.0705; MP 114℃

[0160] Compound 5 was prepared using the same procedure as that used for the synthesis of compound 4, but using 3-fluoro-5-methoxy-2-nitroaniline (55%); 1 H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 8.28 (dd,J= 5.7, 2.6 Hz, 1H), 8.19 (d,J= 1.6 Hz, 1H), 6.47 - 6.42 (m, 2H), 3.92 (d,J= 2.6 Hz, 3H), 2.56 (d,J= 2.6 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 171.3, 161.2, 159.6, 158.3, 134.7, 132.1, 132.4, 118.4, 119.1 (d,J= 30.1 Hz), 110.9 (d,J= 18.2 Hz), 59.0, 15.8; HRMS (ESI + ) calculated C 12 H1FN4O3S [M+H] + : 310.3034, found 310.3036; IR(ATR) υ 　 max / cm -1 : 3328, 1579, 1330, 1239, 1212, 504.

[0161] <Preparation Example 2> 5-Methoxy-3-methyl-N1-(2-(methylthio)pyrimidin-4-yl)benzene-1,2-diamine (6) and 3-fluoro-5-methoxy-N1-(2-(methylthio)pyrimidin-4-yl)benzene-1,2-diamine (7)

[0162]

[0163] Compound 4 (1.3 g, 4.19 mmol) was dissolved in MeOH (20 ml), 10% Pd / C (10 wt%, 0.13 g) was added, stirred for 4 h under H2 gas conditions, filtered through Celite, and concentrated to obtain the desired compound 6, which was used in the next reaction without further purification (99%).; 1 H NMR (400 MHz, CDCl3) δ7.99 (d,J= 5.9 Hz, 1H), 7.02 (s, 1H), 6.78 (d,J= 2.8Hz, 1H), 6.74 (d,J= 8.7 Hz, 1H), 6.68 (dd,J= 8.7, 2.8 Hz, 1H), 6.07 (d,J= 5.9 Hz, 1H), 3.78 (s, 2H), 3.69 (s, 3H), 2.46 (d,J= 5.1 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 170.6, 161.1, 155.7, 151.1, 138.2, 136.8, 124.5, 117.1, 112.6, 111.7, 55.8, 13.7; HRMS (ESI + ) calculated C 12 H 14 N4OS [M+H] + : 263..0961, found 263.0964; MP 82℃

[0164] 3-Fluoro-5-methoxy-N1-(2-(methylthio)pyrimidin-4-yl)benzene-1,2-diamine (7) Compound 7 was synthesized using 5 according to the procedure used for 6; 1H NMR (400 MHz, CDCl3) δ 8.07 (d,J= 5.9 Hz, 1H), 6.96 (s, 1H), 6.77 - 6.75 (m, 1H), 6.58 (dd,J= 11.8, 2.7 Hz, 1H), 6.22 (d,J= 5.9 Hz, 1H), 3.73 (s, 3H), 3.70 - 3.63 (m, 2H), 2.52 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 171.5 , 161.4 , 157.4 , 153.9 , 136.8 , 134.6 , 128.7 , 125.0 , 122.9 (d,J= 30.1 Hz), 118.1 (d,J= 18.2 Hz), 58.3, 15.9 ; HRMS (ESI + ) calculated C 12 H 13 FN4OS [M+H] + : 281.3289, found 281.3290; IR(ATR) υ max / cm -1 : 3330, 2924, 1568, 1508, 1352, 1195, 750.

[0165] <Preparation Example 3> 6-Methoxy-1-(2-(methylthio)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole (8) and 4-fluoro-6-methoxy-1-(2-(methylthio)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole (9)

[0166]

[0167] To a solution of compound 6 (1.0 g, 3.81 mmol) in DMF (38 ml), Na2S2O5 (1.5 equiv., 1.1 g, 5.72 mmol) and 2-naphthalaldehyde (1.1 equiv., 0.65 g, 4.2 mmol) were added, and the resulting mixture was heated to reflux at about 155 °C. After the reaction was completed, the product was extracted using ethyl acetate and washed several times with distilled water and brine. After completely removing moisture from the organic layer using anhydrous magnesium sulfate, the organic layer was filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography to obtain compound 8 (EtOAc: hexane = 1:4 -> 1:2, yield 60%, 0.91 g); 1 H NMR (400 MHz, CD3OD) δ 8.51 (d,J= 5.4 Hz, 1H), 8.10 (s, 1H), 7.94 - 7.86 (m, 3H), 7.68 (d,J= 8.8 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.50 (dd,J= 8.5, 1.7 Hz, 1H), 7.42 (d,J= 2.4 Hz, 1H), 7.06 (dd,J= 8.8, 2.4 Hz, 1H), 6.91 (d,J= 5.4 Hz, 1H), 3.87 (s, 3H), 2.29 (s, 3H); ; 13 C NMR (100 MHz, DMSO-d6) δ 172.9, 160.3, 157.7, 157.0, 151.4, 141.0, 137.7, 135.7, 133.5, 129.3, 128.9, 128.6, 128.4 , 128.1 , 127.8 , 127.3 , 126.4 , 120.8 , 113.5 , 112.4 , 96.3 , 56.1 , 13.7 ; HRMS (ESI + ) calculated C 23 H 18 N4OS [M+H] + : 399.1274, found 399.1277; IR(ATR) υ 　max / cm -1 : 2153, 1550, 1211, 1025, 821, 588

[0168] Compound 9 was synthesized as 7 (76%) following the same procedure as 8; 1 H NMR (400 MHz, CDCl3) δ 8.38 (d,J= 5.4 Hz, 1H), 8.21 (s, 1H), 7.86 (t,J= 9.1 Hz, 3H), 7.61 - 7.48 (m, 3H), 7.29 (s, 1H), 6.78 (d,J= 11.5 Hz, 1H), 6.54 (d,J= 5.4 Hz, 1H), 3.88 (s, 3H), 2.54 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 173.8, 160.6, 159.4, 159.8, 154.8, 139.6, 135.5, 134.9, 130.7, 129.8, 129.8, 128.7, 125.7 , 120.6 , 116.5 (d,J= 30.1 Hz), 117.9 (d,J= 18.2 Hz), 106.4 (d), 101.1 , 99.9 , 96.8 (d), 61.2 , 62.9 , 20.9 ; HRMS (ESI + ) calculated C 23 H 17 FN4OS [M+H] + : 417.4819, found 417.4820.

[0169] <Preparation Example 4> 6-Methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole (10) and 4-fluoro-6-methoxy-1-(2-(methylsulfonyl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazole (11)

[0170]

[0171] Compound 8 (1.5 g, 3.76 mmol) was dissolved in dichloromethane (7.5 ml), and 70% mCPBA (3 equiv., 2.78 g, 11.3 mmol) was added at 0 ° C and stirred at room temperature for 3 h. Saturated aqueous NaHCO3 solution was added, and the organic layer was extracted after adding dichloromethane. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and purified using column chromatography to obtain compound 10. (EtOAc: hexane = 1:2 ~ 1:1, yield 85%, 1.38 g); 1 H NMR (400 MHz, DMSO-d6) δ 9.01 (d,J= 5.5 Hz, 1H), 8.27 (d,J= 1.2 Hz, 1H), 8.01 (d,J= 8.2 Hz, 3H), 7.77 (d,J= 8.8 Hz, 1H), 7.73 (d,J= 2.5 Hz, 1H), 7.66 - 7.59 (m, 3H), 7.47 (d,J= 5.5 Hz, 1H), 7.08 (dd,J= 8.8, 2.5 Hz, 1H), 3.85 (s, 3H), 3.31 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 169.2, 161.1, 158.1, 154.3, 151.0, 137.7, 136.0, 133.5, 132.9, 129.4, 128.8, 128.4, 127.9 , 127.7 , 127.5 , 127.1 , 126.3 , 120.6 , 113.0 , 106.0 , 101.0 , 49.0 , 28.7 ; IR(ATR) υ 　 max / cm -1 : 3442, 1681, 1407, 1024, 821, 597,

[0172] Compound 11 was synthesized using 9 following the same procedure as compound 10; 1H NMR (400 MHz, CDCl3) δ 8.64 (d,J= 5.6 Hz, 1H), 8.23 ​​(s, 1H), 7.90 (t,J= 8.5 Hz, 3H), 7.74 (d,J= 1.8 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.54 (dd,J= 8.5, 1.6 Hz, 1H), 6.97 (d,J= 5.6 Hz, 1H), 6.81 (dd,J= 11.4, 2.0 Hz, 1H), 3.92 (s, 3H), 3.37 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 170.1, 161.4, 159.8, 157.1, 154.4, 136.3, 133,8, 132.7, 130.1, 129.9, 129.7, 128.5, 125.2 , 120.2 , 116.2 (d,J= 30.1 Hz), 117.7 (d,J= 18.2 Hz), 106.3 (d), 99.7 , 96.3 (d), 94.7 , 72.8 , 65.9 , 55.8 , 35.9

[0173] <Preparation Example 5> (S)-Cyclopropyl(3-((4-(6-methoxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone (12) and (S)-Cyclopropyl(3-((4-(4-fluoro-6-methoxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone (13)

[0174]

[0175] Compound 10 (11.5 g, 2.67 mmol) was dissolved in THF (50 mL), and (S)-(3-aminopiperidin-1-yl)(cyclopropyl)methanone hydrochloride (2 equiv., 8.99 g, 5.54 mmol) and TEA (10 equiv., 37.2 mL, 26.7 mmol) were added, and the mixture was stirred at 80 °C for 15 h. The reaction mixture was filtered, concentrated, and purified using column chromatography to give compound 12. (EtOAc: dcm (1:5 -> 1:1) ; 1 H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 8.18 (s, 1H), 7.89 - 7.74 (m, 5H), 7.57 - 7.48 (m, 3H), 7.32 (s, 1H), 7.02 (dd,J= 8.6, 1.7 Hz, 1H), 6.30 (s, 1H), 4.06 (s, 1H), 3.88 (s, 3H), 3.77 (s, 2H), 3.54 (s, 2H), 3.24 (s, 1H), 1.73 (s, 2H), 1.50 (s, 2H), 0.97 (s, 2H), 0.76 (s, 2H) ; 13 C NMR (100 MHz, CDCl3) δ 172.3, 162.1, 160.1, 158.2, 157.5, 151.6, 137.9, 135.7, 133.7, 132.8, 129.1, 128.5, 128.0 , 127.7 , 127.2 , 126.7 , 126.0 , 120.6 , 112.4 , 106.0 , 95.9 , 55.9 , 49.9 , 47.9 , 47.0 , 42.6 , 30.4 , 22.7 , 11.0 , 7.7 ; HRMS (ESI + ) calculated C 31 H 30 N6O2[M+H] + : 519.2503, found 519.2506; MP 109℃

[0176] Compound 13 was synthesized according to the same procedure as 12; 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.21 (s, 1H), 7.96 (d,J= 6.3 Hz, 3H), 7.75 (s, 1H), 7.59 (t,J= 6.4 Hz, 3H), 7.13 (s, 1H), 6.91 (d,J= 11.7 Hz, 1H), 6.72 (s, 1H), 4.05 (d,J= 7.0 Hz, 1H), 3.91 (s, 1H), 3.83 (s, 3H), 3.19 (s, 1H), 3.03 (s, 1H), 2.86 (s, 1H), 2.67 (s, 1H), 1.44 (d,J= 46.0 Hz, 4H), 0.78 - 0.41 (m, 4H); 13 C NMR (100 MHz, DMSO-d6) δ 173.2, 162.4 , 161.8 , 161.0 , 160.9 , 158.6 (d,J= 46.4 Hz), 156.1 , 153.4 , 150.5 , 138.5 , 133.5 , 132.9 , 130.0 , 129.6 , 129.4, 128.1 , 125.0 , 119.7 , 115.9 (d,J= 30.1 Hz), 117.3 (d,J= 18.2 Hz), 106.0 (d), 99.7 , 95.7 (d), 94.7 , 67.7 , 66.8 , 62.1 , 56.7 , 37.2 , 34.9 , 13.7 , 7.96 ; HRMS (ESI + ) calculated C 31 H 29 FN6O2[M+H] + : 537.6189, found 537.6189; IR(ATR) υ 　 max / cm -1 : 3300, 2926, 1617, 1585, 1458, 1369, 1226, 820, 738

[0177] <Example 1> (S)-Cyclopropyl(3-((4-(6-hydroxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone (2) and (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2h)

[0178]

[0179]

[0180] 2

[0181] A 50 mL solution of compound 12 (5.3 g, 0.01 mol) in methylene chloride was prepared. Then, 40 mL (4 equiv., 0.04 mol) of 1 M BBr3 (DCM) was added dropwise to the mixture at 0°C, and the resulting mixture was stirred at 0°C for 2 h. To stop the reaction, methanol was added, and the mixture was neutralized with saturated aqueous NaHCO3 solution, and the organic layer was extracted by adding methylene chloride. The organic layer was dried over MgSO4, filtered, concentrated, and purified by column chromatography to give compound 2 (EtOAc 100%) (4.24 g, 84%); >95% HPLC purity; 1H NMR (400 MHz, cdcl3) δ 9.38 (s, 1H), 8.18 (s, 1H), 7.95 (d,J= 5.4 Hz, 1H), 7.85 (d,J= 6.3 Hz, 2H), 7.81 (d,J= 8.6 Hz, 1H), 7.76 (d,J= 2.0 Hz, 1H), 7.69 (d,J= 8.7 Hz, 1H), 7.57 - 7.47 (m, 3H), 6.98 (dd,J= 8.7, 2.2 Hz, 1H), 5.93 (d,J= 5.3 Hz, 1H), 5.20 (d,J= 12.4 Hz, 1H), 4.26 (dd,J= 21.6, 11.6 Hz, 2H), 3.12 (t,J= 11.9 Hz, 1H), 2.51 - 2.39 (m, 1H), 2.31 (d,J= 11.9 Hz, 1H), 1.96 (d,J= 12.9 Hz, 1H), 1.82 (td,J= 7.9, 4.1 Hz, 2H), 1.77 - 1.66 (m, 1H), 1.54 (ddd,J= 25.1, 12.7, 3.9 Hz, 1H), 1.21 - 1.14 (m, 1H), 1.13 - 1.07 (m, 1H), 0.88 (dd,J= 8.0, 2.2 Hz, 2H); 13 C NMR (100 MHz, DMSO-d6) δ 171.3 , 162.7 , 160.9 , 158.6 , 155.5 , 150.9 , 136.8 , 134.5 , 134.2 , 132.8 , 129.7 , 128.5 , 127.6 , 127.2 , 126.8, 126.2, 124.3, 120.6, 115.2 , 113.5 , 106.2 , 97.9 , 49.6 , 48.5 , 45.6 , 30.0 , 23.4 , 10.9 , 8.03 , 7.04 ; HRMS (ESI + )-calculated C 30 H 28 N6O2[M+H] + :505.2347, found 505.2352.; MP 104 ℃

[0182]

[0183] 2h

[0184] Compound 2 (0.1 g, 0.198 mmol) was dissolved in methylene chloride (1 mL), followed by the addition of triethylamine (1 equiv., 0.03 mL, 0.198 mmol) and methylaminoformyl chloride (1.5 equiv., 0.03 g, 0.198 mmol). After completion of the reaction, the solvent was removed in vacuo, and the reaction mixture was purified using column chromatography to obtain compound 2h (100 mg, 90.1%); > 95% purity by HPLC.; 1 H NMR (400 MHz, cdcl3) δ 8.20 (s, 2H), 7.84 (dd,J= 14.2, 5.6 Hz, 4H), 7.65 (s, 1H), 7.54 (s, 3H), 7.15 (d,J= 8.0 Hz, 1H), 6.47 (s, 1H), 5.42 (s, 1H), 5.12 (s, 1H), 4.26 (s, 1H), 3.90 (s, 1H), 3.75 (s, 2H), 3.47 (s, 2H), 3.20 (s, 1H), 3.03 (s, 1H), 2.91 (d,J= 4.9 Hz, 3H), 1.75 (s, 2H), 1.47 (s, 2H), 0.98 (s, 2H), 0.81 (s, 2H) ; 13 C NMR (100 MHz, DMSO-d6) δ 171.4, 162.5, 161.7, 160.9, 157.1, 155.6, 153.4, 148.4, 140.6, 135.4, 133.5, 132.9, 129.7 , 128.9 , 128.5 , 128.1 , 127.8 , 127.2 , 126.3 , 120.2 , 119.2 , 118.6 , 106.3 , 105.6 , 60.2 , 55.3 , 49.5 , 30.1, 27.6 , 14.5 , 10.9 , 7.3 ; HRMS (ESI + ) calculated C 32 H 31 N7O3[M+H] +: 562.2561, found 562.2562.; MP 135℃

[0185] <Example 2> (S)-Cyclopropyl(3-((4-(4-fluoro-6-hydroxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone (3) and (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-ylmethylcarbamate (3h):

[0186]

[0187] 3

[0188] Compound 3 was obtained by HPLC with the same procedure used for the synthesis of compound 2 (82%); > 95% purity; 1 H NMR (400 MHz, cdcl3) δ 9.63 (s, 1H), 8.22 (s, 1H), 7.97 (dd,J= 5.3, 1.1 Hz, 1H), 7.90 - 7.83 (m, 2H), 7.81 (d,J= 8.5 Hz, 1H), 7.58 - 7.51 (m, 3H), 6.72 (d,J= 11.7 Hz, 1H), 5.94 (dd,J= 5.4, 1.1 Hz, 1H), 5.41 (d,J= 9.6 Hz, 1H), 5.18 (d,J= 11.0 Hz, 1H), 4.27 (dd,J= 23.1, 11.7 Hz, 2H), 3.14 (t,J= 12.1 Hz, 1H), 2.51 - 2.39 (m, 1H), 2.32 (d,J= 12.0 Hz, 1H), 1.98 (d,J= 13.5 Hz, 1H), 1.88 - 1.79 (m, 1H), 1.75 (d,J= 13.0 Hz, 1H), 1.68 (d,J= 13.3 Hz, 1H), 1.61 - 1.48 (m, 1H), 1.14 (t,J= 4.8 Hz, 1H), 1.10 (t,J= 4.7 Hz, 1H), 0.93 - 0.85 (m, 2H) ; 13C NMR (100 MHz, DMSO-d6) δ 172.2 , 162.4 , 161.8 , 161.4 , 160.4 , 157.9 (d,J= 46.4 Hz), 155.0 , 152.2 , 151.0 , 138.5 , 134.1 , 132.9 , 129.2 , 128.9 , 128.3 , 128.1 , 127.8 , 127.2 , 126.2 (d,J= 30.1 Hz), 125.1 (d,J= 18.2 Hz), 106.0 (d), 99.7, 94.4, 67.4, 55.3 , 49.5 , 30.2 , 23.3 , 11.0 , 7.3 ; HRMS (ESI + ) calculated C 30 H 27 FN6O2[M+H] + : 523.2252, found 523.2253; MP 117℃

[0189]

[0190] 3h

[0191] Compound 3 (1 g, 1.91 mmol) was dissolved in methylene chloride (10 mL) and stirred with methylamino formyl chloride (1.5 equiv., 0.27 g, 2.87 mmol) and trityramine (4 equiv., 1.1 mL). The reaction mixture was concentrated and purified using column chromatography to obtain compound 3h. (EtOAc: DCM =1:1) (0.91 g, 70%); 1H NMR (400 MHz, cdcl3) δ 8.19 (s, 2H), 7.82 (d,J= 7.7 Hz, 2H), 7.78 (d,J= 8.6 Hz, 1H), 7.55 - 7.45 (m, 3H), 7.42 (s, 1H), 6.90 (d,J= 9.5 Hz, 1H), 6.45 (s, 1H), 5.57 (s, 1H), 5.32 (s, 1H), 3.85 (s, 1H), 3.69 (s, 1H), 3.45 (s, 2H), 3.19 (s, 1H), 2.96 (s, 1H), 2.88 (d,J= 4.7 Hz, 3H), 1.73 (s, 2H), 1.49 (s, 2H), 0.96 (s, 2H), 0.74 (s, 2H) ; 13 C NMR (100 MHz, DMSO-d6) δ 171.2 , 162.5 , 162.0 , 157.8 , 157.2 , 155.2 , 154.0 , 153.3 (d,J= 19.4 Hz), 151.5 , 148.4 (d,J=9.9Hz), 137.4 (d), 134.2 , 132.8 , 129.7 , 129.0 , 128.5 , 128.3 , 128.1 , 127.6 , 127.3 , 126.2 , 105.8 (d,J=9.9Hz), 102.3 , 50.2 , 48.5 , 45.4 , 30.5 , 30.1 , 27.6 , 23.3 , 10.9 , 7.1 ; HRMS (ESI + ) calculated C 32 H 30 FN7O3[M+H] + :580.2467, found: 580.2471; MP 126℃

[0192] In a similar manner, the following examples were synthesized.

[0193] <Example 3> (R)-1-(2-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2ah)

[0194]

[0195] 2ah

[0196] 1 H NMR (400 MHz, CDCl3) δ 8.22 (d, J= 5.2 Hz, 2H), 7.90 - 7.81 (m, 4H), 7.62 (d, J= 2.2 Hz, 1H), 7.58 - 7.49 (m, 3H), 7.17 (dd, J= 8.9, 2.3 Hz, 1H), 6.18 (d,J= 5.2 Hz, 1H), 5.63 (d,J= 7.8 Hz, 1H), 5.03 (d,J= 5.1 Hz, 1H), 4.17 (d,J= 13.1 Hz, 1H), 4.00 (p,J= 3.8 Hz, 1H), 3.85 (s, 1H), 3.40 (dd, J = 12.9, 7.6 Hz, 2H), 2.94 (d,J= 4.9 Hz, 3H), 1.91 (m, 1H), 1.66-1.6(m, 2H), 1.30 - 1.26 (m, 1H), 1.00 - 0.94 (m, 2H), 0.74 - 0.69 (m, 2H); LRMS (ESI) calculated C 32 H 31 N7O3[M+H] + : 562.2561, Found 562.56

[0197] <Example 4> (R)-1-(2-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2aah)

[0198]

[0199] 2aah

[0200] 1H NMR (400 MHz, CDCl3) δ 8.21 (d,J= 4.3 Hz, 2H), 7.89 - 7.85 (m, 2H), 7.82 (d,J= 8.6 Hz, 1H), 7.72 (d,J= 2.2 Hz, 1H), 7.57 (t, J= 1.6 Hz, 1H), 7.55 (d,J= 1.7 Hz, 1H), 7.54 (t,J= 2.0 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.19 (d,J= 8.7 Hz, 1H), 6.17 (d,J= 5.3 Hz, 1H), 5.75 (d,J= 7.8 Hz, 1H), 4.17 (dd,J= 13.1, 3.8 Hz, 1H), 4.00 (s, 1H), 3.90 - 3.80 (m, 1H), 3.43 (d,J= 11.9 Hz, 2H), 2.91 (d,J= 4.9 Hz, 3H), 1.98 - 1.89 (m, 1H), 1.55 - 1.45 (m, 2H), 1.32 - 1.26 (m, 2H), 1.00 - 0.92 (m, 2H), 0.74 - 0.67 (m, 2H); LRMS (ESI) calculated C 32 H 31 N7O3[M+H] + : 562.2561, Found 562.52

[0201] <Example 5> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2bh)

[0202]

[0203] 2bh

[0204] 1H NMR (400 MHz, CDCl3) δ 8.33 (d,J= 5.2 Hz, 1H), 7.80 (d,J= 8.7 Hz, 2H), 7.55 (d,J= 2.3 Hz, 1H), 7.45 (d,J= 8.3 Hz, 1H), 7.32 (dd,J= 8.3, 2.1 Hz, 1H), 7.12 (dd, J= 8.7, 2.3 Hz, 1H), 6.46 (s, 1H), 5.25 (d, J= 8.2 Hz, 1H), 5.03 (d, J= 5.0 Hz, 1H), 3.38 (m, 1H), 2.91 (d,J= 4.9 Hz, 3H), 1.80 - 1.64 (m, 4H), 1.27 - 1.04 (m, 6H); LRMS (ESI) calculated C 25 H 24 Cl2N6O2[M+H] + : 562.2561, Found 562.52

[0205] <Example 6> 2-(Quinolin-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2ch)

[0206]

[0207] 2ch

[0208] 1H NMR (400 MHz, CDCl3) δ 8.39 (d,J= 5.2 Hz, 1H), 8.29 - 8.26 (m, 2H), 7.88 (d,J= 8.7 Hz, 1H), 7.85 - 7.82 (m, 1H), 7.74 - 7.70 (m, 1H), 7.68 - 7.64 (m, 2H), 7.59 - 7.54 (m, 2H), 7.48 (d,J= 2.2 Hz, 1H), 7.15 (dd,J= 8.8, 2.3 Hz, 1H), 6.63 (s, 1H), 5.00 (s, 1H), 3.27 - 3.22 (m, 2H), 2.93 (dd,J= 8.2, 4.9 Hz, 4H), 2.85 (d,J= 4.6 Hz, 1H), 2.81 (d,J= 4.7 Hz, 1H). 1.54-1.52 (m, 4H); LRMS (ESI) calculated C 28 H 27 N7O3[M+H] + : 496.2092, Found 496.28

[0209] <Example 7> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(quinolin-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2dh)

[0210]

[0211] 2dh

[0212] 1H NMR (400 MHz, CDCl3) δ 8.35 (d,J= 5.3 Hz, 1H), 8.30 - 8.23 ​​(m, 2H), 7.87 (d,J= 8.7 Hz, 1H), 7.83 (d,J= 8.1 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.68 - 7.65 (m, 1H), 7.58 - 7.54 (m, 1H), 7.51 - 7.47 (m, 1H), 7.17 - 7.12 (m, 1H), 6.55 (s, 1H), 5.02 - 4.97 (m, 1H), 3.70 - 3.62 (m, 1H), 2.92 (d,J= 5.0 Hz, 3H), 1.54 - 1.51 (m, 6H), 1.48 - 1.43 (m, 4H); LRMS (ESI) calculated C 28 H 27 N7O2[M+H] + :494.2299, Found 494.29

[0213] <Example 8> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2eh)

[0214]

[0215] 2eh

[0216] 1 H NMR (400 MHz, CDCl3) δ 8.37 (d,J= 5.1 Hz, 1H), 7.97 (d,J= 6.4 Hz, 1H), 7.71 (s, 1H), 7.65 (d,J= 8.8 Hz, 1H), 7.60 (d,J= 2.2 Hz, 1H), 7.23 (t,J= 9.3 Hz, 2H), 7.17 (dd,J= 8.8, 2.3 Hz, 1H), 6.47 (s, 1H), 5.03 (d,J= 5.3 Hz, 1H), 3.42 - 3.24 (m, 1H), 2.93 (d,J= 4.9 Hz, 3H), 1.77 - 1.60 (m, 4H), 1.31 - 1.02 (m, 6H); LRMS (ESI) calculated C26 H 24 F4N6O2[M+H] + :529.1970, Found 529.45

[0217] <Example 9> 2-(Benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2fh)

[0218]

[0219] 2fh

[0220] 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.91 (d,J= 1.6 Hz, 1H), 7.68 (d,J= 2.2 Hz, 2H), 7.59 (d,J= 2.2 Hz, 1H), 7.51 (d,J= 8.7 Hz, 1H), 7.44 (d,J= 8.7 Hz, 1H), 7.14 (dd,J= 8.8, 2.3 Hz, 1H), 7.03 (s, 1H), 6.81 (dd,J= 2.2, 0.9 Hz, 1H), 5.18 (d,J= 7.8 Hz, 1H), 5.01 (d,J= 5.6 Hz, 1H), 4.31 - 4.18 (m, 1H), 3.25 (d,J= 7.1 Hz, 1H), 2.94 (d,J= 4.9 Hz, 2H), 2.85 (d,J= 4.6 Hz, 3H), 2.81 (d,J= 4.7 Hz, 2H) 1.48 - 1.46(m, 4H); LRMS (ESI) calculated C 26 H 24 N6O4[M+H] + :485.1932, Found 485.28

[0221] <Example 10> 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino) pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2gh)

[0222]

[0223] 2gh

[0224] 1 H NMR (400 MHz, CDCl3) δ 8.27 (d,J= 5.3 Hz, 1H), 7.77 (d,J= 8.7 Hz, 1H), 7.61 (d,J= 2.3 Hz, 1H), 7.14 (s, 1H), 7.10 (d,J= 2.3 Hz, 1H), 7.03 (d,J= 2.1 Hz, 1H), 6.86 (d,J= 8.4 Hz, 1H), 6.34 (s, 1H), 5.25 (d,J= 7.8 Hz, 1H), 4.32 - 4.23 (m, 4H), 3.96 (s, 2H), 3.48 (s, 2H), 3.25 (d,J= 7.1 Hz, 2H), 2.91 (d,J= 4.9 Hz, 3H), 2.85 (d,J= 4.6 Hz, 2H), 2.81 (d,J= 4.7 Hz, 1H); LRMS (ESI) calculated C 26 H 26 N6O5[M+H] + :503.2038, Found 503.48

[0225] <Example 11> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2hh)

[0226]

[0227] 2hh

[0228] 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(d,J= 5.2 Hz, 1H), 7.76 (d,J= 8.7 Hz, 1H), 7.62 (d,J= 2.3 Hz, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 7.09 (dd,J= 8.7, 2.3 Hz, 1H), 7.05 (dd,J= 8.4, 2.1 Hz, 1H), 6.86 (d,J= 8.4 Hz, 1H), 6.27 (s, 1H), 5.24 (d,J= 8.2 Hz, 1H), 4.32 - 4.23 (m, 4H), 3.68 (s, 1H), 2.90 (d,J= 4.9 Hz, 3H), 1.93 (s, 2H), 1.73 (s, 2H), 1.34 (s, 4H); LRMS (ESI) calculated C 26 H 26 N6O4[M+H] + :501.2245, Found 501.59

[0229] <Example 12> 2-(Benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2ih)

[0230]

[0231] 2ih

[0232] 1H NMR (400 MHz, CDCl3) δ 8.28 - 8.28 (m, 1H), 8.23 ​​(s, 1H), 7.95 (s, 1H), 7.90 - 7.89 (m, 1H), 7.81 (d,J= 8.7 Hz, 1H), 7.71 - 7.68 (m, 1H), 7.65 (s, 1H), 7.51 (d,J= 7.7 Hz, 1H), 7.44 (s, 1H), 7.13 - 7.10 (m, 1H), 7.02 (s, 1H), 5.21 - 5.19 (m, 1H), 5.00 (s, 1H), 3.67 (s, 2H), 2.93 (d,J= 5.1 Hz, 1H), 2.86 (s, 3H), 2.04 (s, 1H), 1.43 - 1.40 (m, 2H), 1.38 - 1.36 (m, 2H); LRMS (ESI) calculated for C 26 H 24 N6O4[M+H] + : 485.1937 found 485.38

[0233] <Example 13> (R)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2jh)

[0234]

[0235] 2jh

[0236] 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.99 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 7.60 (d,J= 1.8 Hz, 1H), 7.23 (d,J= 9.0 Hz, 1H), 7.17 (dd,J= 8.8, 2.0 Hz, 1H), 6.40 (s, 1H), 5.41 (d,J= 49.8 Hz, 1H), 5.06 (d,J= 4.7 Hz, 1H), 4.02 (d,J= 31.2 Hz, 1H), 3.69 (dd,J= 27.4, 22.2 Hz, 3H), 2.93 (d,J= 4.9 Hz, 3H), 2.85 (d,J= 4.7 Hz, 1H), 2.03 (d,J= 6.8 Hz, 1H), 1.70 (d,J= 39.8 Hz, 4H), 0.98 (d,J= 4.1 Hz, 2H), 0.84 - 0.72 (m, 2H); LRMS (ESI) calculated for C 29 H 27 F4N7O3[M+H] + : 598.2184 found 598.53

[0237] <Example 14> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2kh)

[0238]

[0239] 2kh

[0240] 1H NMR (400 MHz, CDCl3) δ 8.36 (d,J= 5.1 Hz, 1H), 7.97 (d,J= 5.0 Hz, 1H), 7.81 (d,J= 8.7 Hz, 1H), 7.69 (s, 1H), 7.54 (d,J= 1.8 Hz, 1H), 7.22 (t,J= 9.2 Hz, 1H), 7.13 (dd,J= 8.7, 2.1 Hz, 1H), 6.48 (s, 1H), 5.24 (s, 1H), 5.03 (d,J= 4.6 Hz, 1H), 3.34 (s, 1H), 2.92 (d,J=4.9 Hz, 3H), 1.68 (s, 4H), 1.61 - 1.55 (m, 1H), 1.18 (s, 5H); LRMS (ESI) calculated for C 26 H 24 F4N6O2[M+H] + : 529.1970 found 529.54

[0241] <Example 15> 2-(naphthalen-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2lh)

[0242]

[0243] 2lh

[0244] 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 8.23 ​​(s, 1H), 7.85 (dd,J= 19.9, 10.6 Hz, 4H), 7.64 (s, 1H), 7.57 - 7.49 (m, 3H), 7.14 (dd,J= 8.7, 2.1 Hz, 1H), 7.03 (s,J= 12.5 Hz, 1H), 6.53 (s, 1H), 5.18 (s, 1H), 5.01 (d,J= 5.0 Hz, 1H), 3.64 (s, 2H), 2.93 (d,J= 4.9 Hz, 3H), 2.85 (d,J= 4.7 Hz, 1H), 2.06 - 1.99 (m, 1H), 1.53 - 1.44 (m, 2H), 1.36 - 1.28 (m, 2H); LRMS (ESI) calculated for C 28 H 26 N6O3[M+H] + : 495.2139 found 495.52

[0245] <Example 16> (R)-2-(Benzofuran-5-yl)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino) pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate (2mh)

[0246]

[0247] 2mh

[0248] 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.88 (s, 1H), 7.80 (d,J= 8.7 Hz, 1H), 7.68 (d,J= 2.1 Hz, 1H), 7.65 (s, 1H), 7.51 (d,J= 7.9 Hz, 1H), 7.46 (s, 1H), 7.14 (d,J= 7.6 Hz, 1H), 7.02 (d,J= 17.6 Hz, 2H), 6.80 (d,J= 1.7 Hz, 1H), 5.36 (s, 1H), 5.09 (s, 1H), 3.80 (s, 1H), 3.23 (s, 3H), 2.91 (d,J= 4.9 Hz, j2H), 2.85 (d,J= 4.7 Hz, 5H), 2.03 (d,J= 7.0 Hz, 1H), 1.62 (s, 4H); LRMS (ESI) calculated for C 30 H 29 N7O4[M+H] + : 552.2354 found 552.57

[0249] <Example 17> (R)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2nh)

[0250]

[0251] 2nh

[0252] 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.81 (s, 1H), 7.67 (s, 1H), 7.59 (d,J= 1.7 Hz, 1H), 7.46 (d,J= 8.3 Hz, 1H), 7.33 (s, 1H), 7.16 (dd,J= 8.9, 2.2 Hz, 1H), 6.45 - 6.34 (m, 1H), 5.44 - 5.34 (m, 1H), 5.01 (d,J= 4.5 Hz, 1H), 3.61 (s, 1H), 3.49 (s, 3H), 3.04 (s, 1H), 2.94 (d,J= 4.9 Hz, 3H), 2.02 (s, 1H), 1.80 - 1.70 (m, 4H), 1.47 - 1.41 (m, 2H), 1.39 - 1.34 (m, 2H); LRMS (ESI) calculated for C 28 H 27 Cl2N7O3[M+H] + : 580.162 found 580.43

[0253] <Example 18> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2oh)

[0254]

[0255] 2oh

[0256] 1H NMR (400 MHz, CDCl3) δ 8.25 (d,J= 5.2 Hz, 1H), 7.73 (d,J= 7.8 Hz, 1H), 7.55 (d,J= 2.1 Hz, 1H), 7.15 (s, 1H), 7.11 (dd,J= 8.8, 2.2 Hz, 1H), 7.05 (dd,J= 8.4, 2.1 Hz, 1H), 6.87 (d,J= 8.4 Hz, 1H), 6.27 (s, 1H), 5.22 (d,J= 8.2 Hz, 1H), 4.99 (d,J= 5.0 Hz, 1H), 4.28 (ddd,J=11.5, 3.7, 1.8 Hz, 4H), 3.66 (s, 1H), 2.93 (d,J= 4.9 Hz, 3H), 2.06 - 1.95 (m, 2H), 1.92 (s, 2H), 1.74 (d,J= 12.9 Hz, 2H), 1.63 (d,J= 11.3 Hz, 1H), 1.48 - 1.31 (m, 3H); LRMS (ESI) calculated for C 27 H 28 N6O4[M+H] + : 501.2245 found 501.59

[0257] <Example 19> 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate (2ph)

[0258]

[0259] 2ph

[0260] 1H NMR (400 MHz, CDCl3) δ 8.35 (d,J= 5.2 Hz, 1H), 7.81 (s, 1H), 7.66 (d,J= 8.8 Hz, 1H), 7.59 (d,J= 2.1 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.33 (dd,J= 8.3, 2.0 Hz, 1H), 7.16 (dd,J= 8.8, 2.2 Hz, 1H), 6.46 (s, 1H), 5.24 (d,J= 6.4 Hz, 1H), 5.04 (d,J= 4.7 Hz, 1H), 3.48 - 3.29 (m, 1H), 2.93 (d,J= 4.9 Hz, 3H), 2.06 - 1.65 (m, 5H), 1.28 (s, 2H), 1.19 (s, 3H); LRMS (ESI) calculated for C 25 H 24 Cl2N6O2[M+H] + : 511.1411 found 511.54

[0261] <Example 20> (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl dimethylcarbamate (2qh)

[0262]

[0263] 2qh

[0264] 1H NMR (400 MHz, cd3od) δ 8.46 - 8.26 (m, 1H), 8.18 (s, 1H), 7.97 - 7.85 (m,J= 7.1 Hz, 3H), 7.78 (d,J= 8.7 Hz, 1H), 7.66 - 7.46 (m, 4H), 7.18 (d,J= 8.5 Hz, 1H), 6.80 (s, 1H), 6.24 (s, 1H), 4.08 - 3.83 (m,J= 41.1 Hz, 2H), 3.16 (s, 3H), 3.01 (s, 3H), 2.95 - 2.69 (m,J= 42.5 Hz, 2H), 1.90 (s, 1H), 1.48 (s, 3H), 0.96 - 0.30 (m,J= 154.8, 69.7 Hz, 6H); LRMS (ESI) calculated C 33 H 33 N7O3[M+H] + : 576.2718

[0265] <Example 21> (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl ethyl carbamate (2rh)

[0266]

[0267] 2rh

[0268] 1H NMR (400 MHz, cdcl3) δ 8.20 (s, 2H), 7.88 - 7.79 (m, 3H), 7.64 (s, 1H), 7.58 - 7.43 (m,J= 5.2 Hz, 3H), 7.15 (d,J= 7.9 Hz, 1H), 6.58 - 6.03 (m, 2H), 5.44 (s, 1H), 5.17 (s, 1H), 3.97 - 3.59 (m, 2H), 3.41 (s, 1H), 3.38 - 3.26 (m, 2H), 3.26 - 3.09 (m, 1H), 1.86 - 1.35 (m,J=110.3 Hz, 5H), 1.22 (t,J= 7.2 Hz, 3H), 0.97 (s, 2H), 0.89 - 0.69 (m,J= 49.5 Hz, 2H), 0.47 (s, 1H); LRMS (ESI) calculated C 33 H 33 N7O3[M+H] + : 576.2718

[0269] <Example 22> (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl carbamate (2sh)

[0270]

[0271] 2sh

[0272] 1H NMR (400 MHz, cdcl3) δ 8.28 - 8.12 (m, 2H), 7.93 - 7.80 (m, 4H), 7.70 (s, 1H), 7.60 - 7.48 (m, 3H), 7.18 (d,J= 8.6 Hz, 1H), 6.53 - 6.15 (m, 2H), 5.40 (s, 1H), 5.20 - 4.89 (m, 2H), 3.83 - 3.70 (m, 1H), 3.57 - 3.12 (m, 4H), 1.77-1.62 (m, 4H), 1.08 - 0.94 (m, 2H), 0.81 - 0.70 (m, 1H), 0.60 - 0.43 (m, 1H); LRMS (ESI) calculated C 31 H 29 N7O3[M+H] + : 548.2405

[0273] The synthesis method of the above manufacturing examples and examples can be represented as shown in the following reaction scheme 1.

[0274] [Reaction Formula 1]

[0275]

[0276] Representative examples: Synthesis of JNK3 inhibitors 2, 3 and their carbamates 2H, 3H. Reagents and reaction conditions: i) 4-chloro-2-(methylthio)pyrimidine, 60%; NaH, DMF, 0 ℃ to rt, 2 h, 55-90%; (ii) Pd / C, H2, MeOH, rt, 6 h, 99%; (iii) 2-naphthalaldehyde, Na2S2O5, DMF, reflux, 60-76%; (iv) mCPBA, methylene chloride, 0 ℃ to rt, 1 h, 85%; (v) (S)-(3-aminopiperidin-1-yl)(cyclopropyl)methanone, THF, reflux, 5 h, 60%; (vi) BBr3, methylene chloride, 0 ℃ ~ rt, 1 hour, 82~84% (vii) Methylcarbamic chloride, trimethylamine, methylene chloride, 0 ℃ ~ rt, 70~90.1%.

[0277] Experimental Example 1. Measurement of JNK3 enzyme activity

[0278] The change in JNK3 enzyme activity by treatment with benzimidazole derivatives according to the present invention is shown in Table 1 below. 50 It was confirmed through .

[0279]

[0280] IC of JNK3 of synthesized compounds 50 The values ​​were measured and organized as in Table 1. The JNK selectivity of compounds 2, 2h, 3, and 3h among the compounds of the present invention was confirmed and is shown in Figures 1 and 2. Looking at Table 1, Figures 1 and 2, it can be confirmed that the compounds of the present invention have selectivity for JNK3 and also have excellent inhibitory activity.

[0281] Experimental Example 2. Cell Viability Test

[0282] Aβ 1-42 To confirm the neuroprotective effect of the compound of the present invention from Aβ-induced neurotoxicity 1-42 Experiments were performed to investigate the effects of JNK3 inhibitors 2, 2h, 3, and 3h after treatment on the survival of primary mouse neurons, and the results are shown in Table 2 and Fig. 3.

[0283] Cell viability tests for amyloid-β were evaluated as follows: on day 5 of mouse primary cortical neuron differentiation, each compound was pretreated for 90 minutes, followed by 10 μM amyloid-β. 1-42 (HIFP treatment) was treated for 24 or 48 hours, and cell viability was measured using the MTT assay.

[0284]

[0285] Looking at (A) and (B) of Figure 3, the three compounds of the present invention are Aβ 1-42It can be confirmed that the cell viability is significantly higher than that of other known JNK inhibitors at both 24 and 48 hours after treatment, and the neuronal cell viability of compounds 2, 2h, 3, and 3h of the present invention can be confirmed in Table 2 and (C) and (D) of Figure 3. It can be seen that the compound of the present invention has an excellent neuronal cell protective effect.

[0286] Experimental Example 3. Pharmacokinetic Profile

[0287] After confirming the effects of compounds 2, 3, 2h, and 3h as JNK3 inhibitors in the test tube system in Experimental Example 2 above, the oral pharmacokinetic profiles of 2, 2h, 3, and 3h were also confirmed in mice and are shown in Fig. 4. Compounds 2 and 3 were not detected upon oral administration, but 2h and 3h were detected upon oral administration.

[0288] Experimental Example 4. Confirmation of improved cognitive function

[0289] 4-1. Behavioral evaluation of AD disease animals (APP / PS1 mice)

[0290] The effects of JNK3 inhibitors 2h and 3h were confirmed in a homozygous APP / PS1 double transgenic mouse model and are shown in Figures 5 and 6.

[0291] Compounds 2h and 3h were orally administered daily at doses of 30 or 60 mg / kg to 7-month-old APP / PS1 AD mice46, and behavioral evaluations were performed 2 months after administration (Figs. 5 and 6 (A)).

[0292] The Y-maze test is a behavioral test that demonstrates a typical mouse characteristic of attempting to move to a new location rather than immediately returning to the same location (Figs. 5 and 6 (B)). In the Y-maze test, mice administered APP / PS1 showed a decrease in spontaneous changes compared to wild-type (WT) mice, confirming cognitive impairment in the former. Increasing the dose of compound 2h and 3h resulted in behavioral improvements.

[0293] The results of the passive avoidance test (PAT) are shown in Figures 5 and 6 (C). Similarly, the response latency times of the compound 2h and 3h administration groups were significantly lower than those of the WT (wild type) group, and were confirmed to be improved compared to the vehicle control group.

[0294] Morris water maze test results (Figures 5 and 6 (D)) showed that the escape latency and path length of WT mice increased over time during the 5-day hidden platform training. In contrast, APP / PS1 mice did not show this trend, and the escape time and distance traveled decreased when compounds 2h and 3h were administered. On the 6th day of the experiment, the platform was removed, and a probe test was conducted. The time spent in the target zone and the average distance (proximity distance) from the platform decreased, confirming cognitive impairment in APP / PS1 mice. Compared to APP / PS1 mice, mice administered compounds 2h and 3h showed dose-dependent increases in the time spent in the quadrant where the escape zone was located and within a 20-cm radius of the escape zone, with the most significant improvement observed at a dose of 60 mg / kg. The average distance from the escape zone also decreased, indicating improved cognitive function. These results provide strong evidence for the dose-dependent cognitive-enhancing effects of compounds 2h and 3h in mice and support their potential therapeutic application for Alzheimer's disease.

[0295] 4-2. Behavioral evaluation of AD disease animals (3xTg mice)

[0296] Next, the effect of the JNK3 inhibitor 3h was further confirmed in the 3xTg AD model, which is shown in Fig. 7. The 3xTg mice used in this evaluation are a suitable model for Alzheimer's disease because they have three specific mutant genes (APP, Tau, PS1) that induce amyloid β accumulation and neurofibrillary tangles (NFT).

[0297] Compound 3h was orally administered daily to 10-month-old 3xTg AD mice at doses of 30 or 60 mg / kg (Fig. 7(A)). Behavioral evaluations (Y-maze test, PAT, and Morris water maze test) were performed 4 months after administration. The Y-maze test performed 119 days after the start of administration showed that the change levels in the 3xTg, 3h 60 mg / kg administration groups were significantly higher than those in the 3xTg-vehicle control group, and a dose-dependent effect was confirmed in the 3h administration group (at 30 and 60 mg / kg, Fig. 7(B)). In the PAT test, the response latency time in the 3h 60 mg / kg administration group was also relatively higher than that in the 3xTg-vehicle control group (Fig. 7(C)). Morris water maze test also showed improvement in the compound 3h administration group compared to the 3xTg-vehicle control group, similar to Experimental Example 4-2 above, which is strong evidence for the cognitive improvement effect.

[0298] To determine whether compound 3h affects Tau pathology after behavioral assessment and what mechanism affects cell death, the level of phosphorylated Tau (pTau) in the hippocampal tissue of 3xTg AD mice after 3h in vivo behavioral assessment was measured using Western blotting, and is shown in Fig. 8. Fig. 8 (A) shows that administration of 3h induced a decrease in pTau, and a dose-dependent decrease in pTau was confirmed at the S202 residue and T181 residue (Fig. 8 (B) and Fig. 8 (C)).

[0299] The foregoing description of the present invention is provided for illustrative purposes only. Those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive.

Claims

1. A compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, R1 is , or and, R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms; R4 is a hydroxy group; or a substituted or unsubstituted carbamate group; R5 is a hydrogen atom or a halogen atom, X1 is a carbon atom or an oxygen atom, X2 is a carbon atom or a nitrogen atom, Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms; n is an integer between 1 and 2.

2. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 2: [Chemical Formula 2] In the above chemical formula 2, R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms; R4 is a hydroxyl group or and, R5 is a hydrogen atom or a halogen atom, X1 is a carbon atom or an oxygen atom, X2 is a carbon atom or a nitrogen atom.

3. In paragraph 2, In the above chemical formula 2, R2 and R3 are each independently a halogen atom or a halogenated alkyl group having 1 to 3 carbon atoms; or R2 and R3 include the carbon atom to which they are attached. , or ; and form, R4 is and, R5 is a hydrogen atom or a halogen atom, X1 is a carbon atom or an oxygen atom, X2 is a compound in which a carbon atom or a nitrogen atom is present.

4. In paragraph 1, The compound of the above chemical formula 1 is a compound having a structure of the following chemical formula 3: [Chemical Formula 3] In the above chemical formula 3, R2 and R3 are each independently a halogen atom, or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms; R4 is a hydroxyl group, , , , or and, R5 is a hydrogen atom or a halogen atom, X2 is a carbon atom, Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

5. In paragraph 4, In the above chemical formula 3, R2 and R3 are each independently a halogen atom or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3 include the carbon atom to which they are attached. ; and form, R4 is a hydroxyl group, , , , or and, R5 is a hydrogen atom or a halogen atom, X2 is a carbon atom, A compound wherein Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

6. In paragraph 1, The compound of the above chemical formula 1 is a compound having the structure of the following chemical formula 4: [Chemical Formula 4] In the above chemical formula 4, R2 and R3 are each independently a halogen atom, or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3, including the carbon atom to which they are attached, form a heterocycloalkyl, heterocycle, or aryl having 4 to 6 carbon atoms; R4 is a hydroxyl group or and, R5 is a hydrogen atom or a halogen atom, X2 is a carbon atom, Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

7. In paragraph 6, In the above chemical formula 4, R2 and R3 are each independently a halogen atom or a halogenated alkyl having 1 to 3 carbon atoms; or R2 and R3 include the carbon atom to which they are attached. ; and form, R4 is and, R5 is a hydrogen atom or a halogen atom, X2 is a carbon atom, A compound wherein Y is an amino group substituted with one or more methyl groups; or a cycloalkyl group having 3 to 5 carbon atoms.

8. In paragraph 1, The compound of the above chemical formula 1 is (S)-Cyclopropyl(3-((4-(6-hydroxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone; (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; (S)-Cyclopropyl(3-((4-(4-fluoro-6-hydroxy-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-yl)amino)piperidin-1-yl)methanone; (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-4-fluoro-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-ylmethylcarbamate: (R)-1-(2-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate; (R)-1-(2-(3-(cyclopropanecarboxamido)piperidin-1-yl)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 2-(quinolin-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(quinolin-2-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate; 2-(Benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate; 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino) pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 2-(Benzofuran-5-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; (R)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-6-yl methylcarbamate; 2-(naphthalen-2-yl)-1-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; (R)-2-(Benzofuran-5-yl)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino) pyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl methylcarbamate; (R)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1H-benzo[d]imidazol-5-yl methylcarbamate; 1-(2-(cyclohexylamino)pyrimidin-4-yl)-2-(3,4-dichlorophenyl)-1H-benzo[d]imidazol-5-yl methylcarbamate; (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl dimethylcarbamate; (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl ethylcarbamate; or (S)-1-(2-((1-(cyclopropanecarbonyl)piperidin-3-yl)amino)pyrimidin-4-yl)-2-(naphthalen-2-yl)-1H-benzo[d]imidazol-6-yl carbamate; compound.

9. A pharmaceutical composition for the prevention or treatment of a degenerative brain disease or cancer, comprising a compound of any one of claims 1 to 8, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

10. In paragraph 9 A pharmaceutical composition characterized in that the above degenerative brain disease is Alzheimer's disease, Parkinson's disease, multiple sclerosis, Huntington's disease, senile dementia, epilepsy, Lou Gehrig's disease, or stroke.

11. In paragraph 9 A pharmaceutical composition characterized in that the cancer disease is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung, peritoneal cancer, skin cancer, cutaneous or intraocular melanoma, rectal cancer, anal cancer, esophageal cancer, small intestine cancer, endocrine adenocarcinoma, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, chronic or acute leukemia, lymphocytic lymphoma, hepatocellular carcinoma, gastric cancer, stomach cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, large intestine cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, head and neck cancer, brain cancer, osteosarcoma, Barrett's esophagus, colonic adenomas and polyps, breast fibroadenomas and cysts, monoclonal gammopathy of musculoskeletal syndrome (MGUS), or monoclonal lymphocytosis.

12. In paragraph 9 A pharmaceutical composition characterized in that the composition inhibits the activity of JNK3 (c-Jun N-terminal kinase 3).

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