KR101560338B1 - Benzoimidazole derivatives selectively inhibiting the activity of janus kinase 1 - Google Patents

Abstract

The present invention relates to a benzimidazole derivative having activity which selectively inhibits activity of janus kinase 1 and a use as an immunosuppressant of the compound.

Description

FIELD OF THE INVENTION The present invention relates to benzoimidazole derivatives which selectively inhibit the activity of Janus kinase 1,

The present invention relates to a benzimidazole derivative and its selective inhibition of the activity of Janus kinase 1 and its use as an immunosuppressant.

An immunosuppressant is a generic term for an agent that inhibits the immune response of a living body. It is mainly used as a drug for the treatment and prevention of organ transplant rejection and autoimmune diseases.

The ideal immunosuppressive agent should be a specific immunosuppression that selectively inhibits only the clone that specifically reacts with the antigen, but it is not yet a stage that can be used clinically, and the currently used agent has a specificity for the activated immune cells As a non-immunosuppressive agent, it inhibits the host's normal immune response and causes lethal side effects in the kidneys and liver, and causes complications such as infectious diseases and malignant tumors. Until now, a single drug can not achieve sufficient efficacy to prevent rejection, so it is necessary to combine several methods.

Janus kinase (hereinafter referred to as 'JAK') is known to be an enzyme that commands proteins that play a pivotal role in the control of immune and inflammation, and is divided into four types, JAK1, JAK2, JAK3 and TYK2.

JAK is composed of tyrosine kinase, a cytoplasmic receptor related protein. Tyrosine kinase is involved in signal transduction pathway by cytokine and cytokine - like hormone, which are glycoproteins used as signal materials to control and stimulate the defense system of the body.

Among the various functions of JAK, it is most known to provide a rapid signaling pathway to the cytokine with the STAT protein. Briefly, the activated JAK phosphorylates the tyrosine residues of the cytokine receptor and the phosphorylated tyrosine residues binds to STAT, a gene regulatory protein in the cytoplasm. STAT is activated by JAK phosphorylation. The phosphorylated and activated STAT is separated from the receptor to form a dimer and then migrate to the nucleus to promote the expression of a specific gene. In addition to the JAK-STAT signaling pathway, JAK is also known to affect the activation of the major signaling pathways MAPK, PI3-K / Akt, and the like.

The cytokine receptor that binds to IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 is called the 'common cytokine receptor γ-chain' (γc) 'and it is known that only JAK1 and JAK3 are related. Congenital immunodeficiency syndrome (SCID) is known to occur when mutations occur in genes coding for γc or JAK3. Therefore, Jf3-related JAK3 has been developed as a target of various inflammatory diseases, and Pfizer's Tofacitinib (CP-690,550) has been approved by FDA as a therapeutic agent for rheumatoid arthritis ( Science 2003, 302: 875).

However, it has recently been shown that tofacitinib is a general-purpose JAK inhibitor rather than a selective inhibitor of JAK3, and that JAK1 function is more important than JAK3 in signal transduction through γc cytokine receptors (cell 2011, 18: 314) The development of JAK1 selective inhibitors rather than JAK3 is more urgently required in the development of rheumatoid arthritis therapies.

One of the most important considerations in developing a therapeutic agent for rheumatoid arthritis using a selective inhibitor of JAK1 is to ensure selectivity for JAK2 because inhibition of JAK2 can exacerbate inflammatory anemia.

The present invention solves the above problems and aims at developing the novel immunosuppressive agents with minimized side effects by developing novel inhibitors of JAK1 / JAK2 and JAK1 / JAK3 selectivity.

In order to accomplish the above object, the present invention provides a compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

Wherein n is an integer of 2 or 3 and R is Ph, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NH ₂ , cyclohexyl, 4-CN-Ph, 4-Me-Ph , 4-CH (CH ₃ ) ₂ Ph, 4-CF ₃ -Ph, 4-OH-Ph, Pyrimidine, 4-NO ₂ -Ph, 3- (2-NH ₂ ) -pyridine, CH ₂ Ph, 3-isoquinoline, 4- (1,1'- 2- (1,1'-biphenyl), and 3- (1H-indole).

In one embodiment of the present invention, the compound preferably has immunosuppressive activity,

In another embodiment of the present invention, the compound is preferably, but not limited to, selectively inhibits the activity of Janus kinase 1 (Janus kinase 1).

The present invention also provides a composition for immunosuppression comprising a compound of the following formula (1) as an active ingredient:

[Chemical Formula 1]

Wherein n is an integer of 2 or 3 and R is Ph, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NH ₂ , cyclohexyl, 4-CN-Ph, 4-Me-Ph , 4-CH (CH ₃ ) ₂ Ph, 4-CF ₃ -Ph, 4-OH-Ph, Pyrimidine, 4-NO ₂ -Ph, 3- (2-NH ₂ ) -pyridine, CH ₂ Ph, 3-isoquinoline, 4- (1,1'- 2- (1,1'-biphenyl), and 3- (1H-indole).

In one embodiment of the invention, the compound is selected from the group consisting of CH ₂ CH ₂ NH ₂ , 4-OH-Ph, and 4-piperidine, wherein n is 2 and R is selected from the group consisting of More preferably a substituted group, but is not limited thereto.

The present invention also provides a composition for selective inhibition of Janus kinase 1 comprising the compound of formula (1) as an active ingredient:

[Chemical Formula 1]

Wherein n is an integer of 2 or 3 and R is Ph, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NH ₂ , cyclohexyl, 4-CN-Ph, 4-Me-Ph , 4-CH (CH ₃ ) ₂ Ph, 4-CF ₃ -Ph, 4-OH-Ph, Pyrimidine, 4-NO ₂ -Ph, 3- (2-NH ₂ ) -pyridine, CH ₂ Ph, 3-isoquinoline, 4- (1,1'- Is preferably a substituent selected from the group consisting of 2- (1,1'-biphenyl) and 3- (1H-indole), wherein n is 2 and R is CH ₂ CH ₂ NH ₂ , 4-OH-Ph, and 4-piperidine, but is not limited thereto.

The present invention also provides a composition for the prophylaxis and treatment of inflammatory diseases, which comprises a compound of the following formula (1) as an active ingredient:

[Chemical Formula 1]

Wherein n is an integer of 2 or 3 and R is Ph, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NH ₂ , cyclohexyl, 4-CN-Ph, 4-Me-Ph , 4-CH (CH ₃ ) ₂ Ph, 4-CF ₃ -Ph, 4-OH-Ph, Pyrimidine, 4-NO ₂ -Ph, 3- (2-NH ₂ ) -pyridine, CH ₂ Ph, 3-isoquinoline, 4- (1,1'- Is preferably a substituent selected from the group consisting of 2- (1,1'-biphenyl), 3- (1H-indole), and the compound is the substituent selected from the group consisting of CH ₂ CH ₂ NH ₂ , 4-OH-Ph, and 4-piperidine, but is not limited thereto.

The present invention also relates to a process for the production of 4-fluoro-3-nitrobenzoamide by condensation reaction of 4-fluoro-3-nitrobenzoic acid with NH3-HOBT to give 4-fluoro-3- Amide can be obtained by a substitution reaction with 1,3-diaminopropane or ethylenediamine to give 4 - ((3-aminopropyl) amino) -3-nitrobenzamide or 4- ( ) Amino) -3-nitrobenzoamide in which the 3-nitro substituent is reduced with hydrogen to give 3-amino-4 - ((3-aminopropyl) amino) (2-aminoethyl) amino) benzoamide and condensing these materials in the presence of an aldehyde in the presence of NaHSO ₃ .

The present invention also relates to a process for the production of 4-fluoro-3-nitrobenzoamide by condensation reaction of 4-fluoro-3-nitrobenzoic acid with NH3-HOBT to give 4-fluoro-3- Amide can be obtained by a substitution reaction with 1,3-diaminopropane or ethylenediamine to give 4 - ((3-aminopropyl) amino) -3-nitrobenzamide or 4- ( ) Amino) -3-nitrobenzoamide and converting the 4 - ((3-aminopropyl) amino) -3-nitrobenzoamide or 4 - the primary amine by performing a masking reaction to the functional groups Boc tert-butyl (3 - ((4-carbamoyl-2-nitrophenyl) amino) propyl) carbamate, or tert-butyl (2 - ((4-carbamoyl -2 -nitrophenyl) amino) ethyl) obtain a carbamate, obtained tert-butyl (3 - ((4-carbamoyl-2-nitrophenyl) amino) propyl) carbamate, or tert-butyl (2 - ((4-carbazole Amino-ethyl) carbamate is subjected to reduction of the nitro group, condensation with an aldehyde, and removal of the Boc bridging group to give a compound of the following formula 5j to 5v: .

The present invention also relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound of the invention together with a pharmaceutical carrier or diluent. Optionally, the pharmaceutical composition may comprise at least one compound of the present invention in combination with compounds exhibiting different activities, such as antibiotics or other pharmacologically active substances.

The dosage form of the present invention will vary depending upon the compound of the invention used, the mode of administration and the desired treatment. However, a generally satisfactory result is obtained when about 0.5 mg to about 1000 mg, preferably about 1 mg to about 500 mg of a compound of the invention is conveniently provided in a sustained release form, once to five times a day, Loses. Typically, dosage unit forms suitable for oral administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg, of a compound of the present invention mixed with a pharmaceutical carrier or diluent.

The compounds of the present invention may be administered in the form of a pharmaceutically acceptable acid addition salt or, where possible, as a metal or a C1-6-alkylammonium salt. Such salt forms exhibit activity to the extent that they are in the free acid form.

The present invention also relates to pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, such compositions typically also comprising a pharmaceutical carrier or diluent. Compositions comprising the compounds of the present invention can be prepared by conventional procedures and are provided in the form of convenient forms such as capsules, tablets, solutions or suspensions.

The pharmaceutical carrier used may be a conventional solid or liquid carrier. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.

Similarly, the carrier or diluent may be any delayable material known in the art, such as glyceryl monostearate or distearic acid glyceryl, either alone or mixed with wax. If a solid carrier is used for oral administration , The preparation may be tabletted in hard gelatine capsules in the form of powders or pellets, or it may be in the form of troches or medicinal drops. The amount of solid carrier varies widely, but is usually from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, an emulsion, a soft gelatin capsule or a sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.

In general, the compounds of the present invention are dispersed in a unit dose form which contains 10 to 200 mg of active ingredient in or with a pharmaceutically acceptable carrier per unit dose.

The unit dose of the compounds according to the invention is from 1 to 500 mg per day as a drug when administered to a patient, such as a human, for example, about 100 mg per dose.

The acylated monoglyceride administration route used as a plasticizer for film coating can be any route as long as it effectively transports the active compound to the appropriate or desired site of action. For example, oral or parenteral routes such as rectal, transdermal, subcutaneous, intramuscular, intramuscular, topical, intravenous, intraurethral, intraocular or ointment are possible and oral routes are preferred.

Hereinafter, the present invention will be described.

Substances exhibiting selective Janus kinase 1 (JAK1) inhibitory activity are highly likely to be developed as effective and safe immunosuppressants. However, JAK1 inhibitors currently under development, including CP-690,550, have the problem that they can induce inflammatory anemia due to lack of selectivity for JAK2, particularly JAK2, belonging to the same JAK family. As a result of efforts to find inhibitors having selectivity, a substance having JAK1 inhibition ability which is much higher than that of JAK2 among benzoimidazole derivatives was discovered and the invention was completed.

In the present invention, an inhibitor having a selective inhibitory effect on JAK1 was developed more than JAK2.

First, CP-690,550, which is well-known as a JAK3 inhibitor, was analyzed by JAK1, JAK2, and JAK3 combined with JAK1, JAK2, and JAK3. As a result, JAK kinase inhibition activity of CP- ) And the two substituents located on both sides of the piperidine ring, namely the CH ₂ CN and Me functional groups, and the anaerobic interactions (B and C, Figure 1) of the enzymatic period of action were very important ). However, a substance binding to the binding site D located on the lower side to which CP-690,550 binds has not yet been developed. Therefore, in the present invention, binding sites of A, B, and C of JAK kinase, To develop new materials.

Therefore, in the present invention, a novel derivative in which a long chain substituent is introduced into the benzimidazole mononuclear structure to induce binding to a new binding site D (FIG. 2), and these compounds are chemically synthesized (FIG. 3) , JAK2 and JAK3 inhibitors (Table 1), found new uses as selective JAK1 inhibitors and completed the invention.

Synthesis of benzimidazole derivatives is as shown in Fig. To begin with, a commercially available 4-fluoro-3-nitrobenzoic acid (1) is first subjected to EDC condensation reaction with NH3-HOBT to obtain compound 2. Compound 2 is converted to 3a or 3b through a substitution reaction with 1,3-diaminopropane or ethylenediamine. Here, the 3-nitro substituent group is reduced with hydrogen to obtain 3-amino derivatives 4a and 4b. The benzoimidazole skeleton is completed by condensing these substances in the presence of an appropriate aldehyde and NaHSO3 to synthesize derivatives 5a to 5i . On the other hand, for the synthesis of the benzimidazole derivatives 5j to 5v, it was necessary to shield the primary amine of the derivative 3a or 3b with a Boc functional group. Thus, the resulting derivative 6a or 6b was subjected to a series of reactions such as reduction of a nitro group, condensation with an aldehyde, and elimination of a Boc cleavage group to obtain a benzimidazole derivative 5j to 5v.

The JAK kinase inhibitory activity of the synthesized benzimidazole derivatives was verified using the Z'-LYTE ^™ Kinase Assay Kit Tyr 6 Peptide (JAK1 to JAK3) and Tyr 3 Peptide (Tyk2) from Invitrogen, The protocol of The IC50 values of the resulting benzoimidazole derivatives 5a to 5v for inhibitory activity against JAK kinase are shown in Table 1.

Compound IC ₅₀ ([mu] M) Selectivity JAK1 JAK2 JAK3 TYK2 JAK1 / JAK2 5a 15.72 + - 2.76 > 200 25.09 + - 2.78 36.80 +/- 1.41 5b 0.15 ± 0.00 53.20 ± 0.00 26.48 ± 0.28 57.10 ± 2.26 354.7 5c 3.68 ± 0.78 27.43 + - 1.13 21.18 ± 0.78 41.49 + - 0.28 7.5 5d 14.16 + - 0.85 37.58 ± 1.63 17.28 ± 0.57 55.54 ± 1.06 2.7 5e 5.57 ± 1.13 49.29 + 1.63 25.87 ± 0.28 40.70 +/- 1.15 8.8 5f 3.86 ± 0.21 36.02 ± 1.34 21.96 ± 1.34 34.46 ± 1.06 9.3 5g 4.79 ± 0.23 32.90 ± 0.00 32.12 ± 0.78 42.27 ± 2.26 6.9 5h 4.00 ± 1.27 74.28 + - 4.95 23.53 + - 0.28 32.90 ± 2.19 18.6 5i 11.81 ± 1.06 46.95 ± 2.19 26.65 ± 0.21 39.92 + 1.34 4.0 5j 10.64 ± 1.91 36.80 ± 0.57 22.74 + - 0.85 104.74 ± 0.85 3.5 5k 0.14 + 0.02 16.50 ± 1.70 29.77 ± 1.13 38.36 + 0.78 117.9 5l 4.00 ± 0.28 32.12 ± 2.12 30.94 + 0.28 43.05 + 0.14 8.0 5m 0.08 ± 0.01 54.76 ± 1.70 21.18 ± 0.21 61.79 ± 0.57 684.5 5n 43.83 + - 1.06 181.26 ± 3.89 32.12 ± 0.78 57.88 +/- 1.70 4.1 5o 4.28 ± 0.14 20.40 ± 1.27 28.50 + 0.07 32.90 ± 0.28 4.8 5p > 0.1 > 0.1 > 0.1 > 0.1 - 5q 13.37 ± 0.00 64.91 + - 3.25 23.53 + 0.07 54.76 ± 1.06 4.9 5r 27.43 + - 2.95 28.21 + - 0.57 22.74 ± 0.78 85.21 + - 6.65 1.0 5s 4.00 0.40 43.83 + - 0.57 20.79 ± 0.99 36.40 ± 1.91 11.0 5t 4.79 ± 0.21 33.68 ± 1.27 31.33 + - 0.78 39.14 + - 0.23 7.0 5u 1.04 + 0.07 52.42 ± 1.56 33.68 + - 0.14 29.77 ± 1.20 50.4 5v 4.28 ± 0.28 46.17 + 1.84 36.80 ± 0.85 55.54 ± 2.26 10.8

Table 1 shows JAK1, JAK2, JAK3 and Tyk2 inhibitory activities by benzoimidazole derivatives represented by Chemical Formula 1

As a result of JAK kinase inhibition assay, selective JAK1 inhibitory activity was observed at 5b , 5k and 5m . Specifically, the compound 5b are showed IC ₅₀ is 0.15μM the yeoteuna JAK2 is approximately 355 times the JAK1 selective inhibitory activity to 53.2μM in JAK1, compound 5k is about 118-fold with each of 0.14μM and 16.5μM, and compound 5m , It was confirmed that JAK1 selective inhibitory activity was about 685 times as 0.08 μM and 54.76 μM.

As described above, it has been confirmed that benzoimidazole derivatives having a chained amino substituent can be selectively inhibited against JAK1 as compared with kinase activity of JAK2. As a result, it was confirmed that JAK kinase inhibitor It can be used as a safe immunosuppressant which does not cause problems such as malignant anemia which has been pointed out as a side effect of the immunosuppressant used.

Figure 1 illustrates the general mode of coupling between the known JAK kinase inhibitors CP-690,550 and JAK kinase.
2 illustrates the structure of a benzimidazole derivative represented by the general formula (1).
FIG. 3 illustrates a process for synthesizing a benzimidazole derivative represented by the formula (1).

Hereinafter, the present invention will be described in more detail with reference to Examples. It will be apparent to those skilled in the art that these examples are for illustrative purposes only and that the scope of the invention is not construed as being limited by these examples.

Example 1 : Preparation of 4- fluoro- 3- nitrobenzoamide ( 2 )

Compound 1 (1.0 g, 5.4 mmol) was dissolved in acetonitrile (20 ml) and dimethylformamide (5 ml), and then 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide g, 10.8 mmol) and HOBT-NH ₃ (1.6 g, 10.8 mmol), and the mixture is stirred at room temperature for 4 hours. Water (20 ml) was added to the mixture, and the mixture was extracted three times with ethyl acetate (20 ml). The resulting organic layer was washed once more with an aqueous solution of sodium hydrogencarbonate and then magnesium sulfate was added to remove residual water. Filter by using. The mixture was concentrated under reduced pressure, and the obtained concentrate was purified by column chromatography on a silica gel column (hexane: ethyl acetate = 1: 3) to obtain a compound ( 2 ) in the form of a yellow solid. (960 mg, 5.2 mmol, 96% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.64 (dd, J = 7.1, 2.3 Hz, 1H), 8.23-8.27 (m, 1H), 7.53 (dd, J = 10.7, 8.7 Hz, 1H ); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 170.9, 162.1, 159.4, 138.4, 134.5, 129.2, 122.1.

Example  2. Preparation of 4 - ((3-aminopropyl) amino) -3- Nitrobenzoamide  (3a): < EMI ID =

Compound 2 (230 mg, 1.3 mmol) was dissolved in isopropyl alcohol (5 ml), and then N, N-diisopropylethylamine (DIPEA) (0.7 ml, 3.8 mmol) and 1,3-diaminopropane mmol), and the mixture is refluxed at 90 DEG C for 5 hours. The mixture was concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to obtain a compound ( 3a ) . (240 mg, 1.1 mmol, 85% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.76 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 9.1, 2.2 Hz, 1H), 7.10 (d, J = 9.1 Hz, J = 7.0 Hz, 2H), 3.49 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H), 1.89 (q, J = 7.0 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 170.9, 148.8, 136.2, 132.8, 128.5, 121.6, 115.4, 41.3, 39.6, 32.1.

Example 3. Preparation of 4 - ((2 -aminoethyl ) amino) -3- nitrobenzoamide ( 3b )

Compound 2 (380 mg, 2.1 mmol) was dissolved in isopropyl alcohol (8 ml) and N, N-diisopropylethylamine (DIPEA) (1.1 ml, 6.3 mmol) and ethylenediamine (0.4 ml, 6.3 mmol) Followed by heating at 90 ° C under reflux for 9 hours. The mixture was concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to obtain compound ( 3b ) in the form of a yellow solid . (350 mg, 1.6 mmol, 76% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.73 (d, J = 2.2 Hz, 1H), 7.98 (dd, J = 9.1, 2.2 Hz, 1H), 7.10 (d, J = 9.1 Hz, 1H), 3.55 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.4 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 168.9, 147.0, 134.6, 131.6, 126.9, 120.3, 113.7, 43.6, 39.4.

Example  4. 3-Amino-4 - ((3-aminopropyl) amino) Benzoamide  (4a): < EMI ID =

Compound 3a (320 mg, 1.4 mmol) is dissolved in methanol (15 ml) and palladium / charcoal (10% w / w, 32 mg) is added. The resulting concentrate was purified by column chromatography on a silica gel column (dichloromethane: methanol: ammonia solution: water = 60: 35: 5: 5) and the mixture was stirred at room temperature for 8 hours in the presence of hydrogen. To give compound ( 4a ) in the form of a purple solid. (270 mg, 1.3 mmol, 94% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 7.29 (dd, J = 8.3, 2.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 8.4 Hz, 1H), 3.24 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H), 1.88 (q, J = 7.0 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 172.5, 141.5, 133.8, 121.7, 120.9, 115.4, 109.3, 41.2, 39.2, 30.6.

Example 5. Preparation of 3-amino-4 - ((2 -aminoethyl ) amino) benzoamide ( 4b )

Compound 3b (350 mg, 1.6 mmol) is dissolved in methanol (8 ml) and palladium / charcoal (10% w / w, 32 mg) is added. The resulting concentrate was purified by column chromatography on a silica gel column (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1), and the mixture was concentrated under reduced pressure for 8 hours at room temperature. To give compound ( 4b ) in the form of a purple solid. (200 mg, 1.1 mmol, 70% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 7.30 (dd, J = 8.3, 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 3.23 (d, J = 6.0 Hz, 1H), 2.86 (d, J = 6.0 Hz, 1H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 173.8, 142.8, 135.4, 123.3, 122.3, 116.9, 110.7, 47.1, 42.0.

Example 6: Preparation of 1- (3-aminopropyl) -2- phenyl- 1H- benzo [d] imidazole -5 -carboxamide ( 5a )

Compound 4a (70 mg, 0.3 mmol) was dissolved in methanol (5 ml), benzaldehyde (0.04 ml, 0.4 mmol) and sodium bisulfate (61 mg, 0.5 mmol) do. The mixture was filtered through a filter paper using methanol (10 ml). The filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by column chromatography on a silica gel column (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to give a compound ( 5a ) in the form of a dark yellow solid . (23 mg, 23% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.27 (s, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.71-7.77 (m, 3H), 7.61-7.63 (m, 3H ), 4.43 (t, J = 7.5 Hz, 2H), 2.56 (t, J = 7.2 Hz, 2H), 1.89-1.97 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 170.2, 154.5, 140.7, 136.7, 129.4, 128.5, 128.2, 127.9, 127.6, 125.7, 121.8, 117.6, 109.5, 42.9, 41.4, 38.1.

Example 7 : Preparation of benzimidazole derivatives ( 5b to 5i )

The compound 4b (180 mg, 0.9 mmol) was dissolved in methanol (6 ml), tert -butyl (3-oxopropyl) carbamate (190 mg, 1.1 mmol) and sodium bisulfate (166 mg, 1.4 mmol) RTI ID = 0.0 > 60 C. < / RTI > The mixture was filtered through a filter paper using methanol (5 ml). The filtrate was concentrated under reduced pressure and the obtained concentrate was purified by column chromatography on silica gel column (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to give 5b to 5i as a dark yellow solid .

(2-aminoethyl) -1H-benzo [d] imidazole-5-carboxamide 5b (21 mg, 59%

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.18 (d, J = 1.3 Hz, 1H), 7.84 (dd, J = 8.5, 1.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 4.32 (t, J = 6.7 Hz, 2H), 3.29-3.31 (m, 2H), 3.19 (t, J = 6.6 Hz, 2H), 3.06 (t, J = 6.7 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 172.8, 156.3, 142.9, 138.8, 129.3, 123.5, 119.5, 111.0, 46.9, 41.9, 39.6, 29.3.

Benzo [d] imidazole-5-carboxamide 5c (14 mg, 75% yield):

^{1 H NMR (400 MHz, D} 2 O) δ (ppm) 8.13 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 4.70-4.74 ( (m, 2H), 3.52 (t, J = 6.5 Hz, 2H), 3.26 (t, J = 7.5 Hz, 2H), 3.20 (t, J = 7.6 Hz, 2H), 2.25-2.35 ¹³ C NMR (100 MHz, D ₂ O)? (Ppm) 169.6, 152.9, 141.1, 132.7, 127.4, 121.9, 113.2, 108.8, 38.8, 36.0, 35.1, 21.1, 20.6.

Benzod [d] imidazole-5-carboxamide 5d (78 mg, 56% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.27 (d, J = 1.0 Hz, 1H), 7.92 (dd, J = 8.5, 1.4 Hz, 1H), 7.74-7.77 (m, 2H), 7.72 (d, J = 8.6 Hz, 1H), 7.59-7.61 (m, 3H), 4.45 (t, J = 7.2 Hz, 2H), 3.03 (t, J = 7.2 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 170.2, 154.7, 140.8, 136.9, 129.5, 128.4, 128.3, 128.0, 127.7, 122.0, 117.7, 109.5, 44.5, 39.0.

Benzo [d] imidazole-5-carboxamide 5e (67 mg, 37% yield): 1 - (2-aminoethyl) -2-cyclohexyl-

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.16 (d, J = 1.2 Hz, 1H), 7.83 (dd, J = 8.5, 1.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 4.33 (t, J = 7.1 Hz, 2H), 3.04-3.06 (m, 1H), 3.02 (t, J = 7.0 Hz, 2H), 1.73-2.00 (m, 10H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 172.9, 162.8, 142.9, 138.6, 129.3, 123.4, 119.3, 111.0, 46.6, 42.3, 37.3, 33.2, 27.2, 27.0.

Benzo [d] imidazole-5-carboxamide 5f (48 mg, 28% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.25 (d, J = 1.2 Hz, 1H), 7.91 (dd, J = 8.6, 1.6 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 4.40 (t, J = 7.2 Hz, 2H), 2.97 (t, J = 7.2 Hz, 2H) , ≪ / RTI > 2.43 (s, 3H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 171.3, 155.8, 141.7, 140.9, 137.9, 129.4, 129.1, 128.5, 126.5, 122.7, 118.5, 110.3, 46.1, 40.3, 20.2.

5 g (71 mg, 37% yield) of 1- (2-aminoethyl) -2- (p-tolyl) -lH- benzo [d] imidazole-

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.26 (d, J = 1.2 Hz, 1H), 7.91 (dd, J = 8.6, 1.6Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.40 (t, J = 7.2 Hz, 2H), 3.30-3.31 (m, 1H), 2.97- 3.03 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 174.3, 158.8, 154.7, 144.7, 141.0, 132.3, 131.5, 130.0, 129.9, 125.8, 121.6, 113.4, 49.2, 43.3, 37.1, 26.0.

Benzo [d] imidazole-5-carboxamide 5h (62 mg, 30% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.29 (d, J = 1.3 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.90-7.95 (m, 3H), 7.74 ( d, J = 8.6 Hz, 1H), 4.41 (t, J = 7.1 Hz, 2H), 2.99 (t, J = 7.1 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 174.5, 157.4, 145.1, 141.3, 136.8, 135.4, 133.5, 132.2, 129.1, 126.5, 126.1, 122.2, 114.0, 50.0, 43.9.

Benzo [d] imidazole-5-carboxamide 5i (46 mg, 26% yield): 1 - (2-aminoethyl) -2- (4- (trifluoromethyl)

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.29 (s, 1H), 7.94-8.05 (m, 5H), 7.76 (d, J = 8.5 Hz, 1H), 4.42 (t, J = 7.0 Hz, < / RTI > 2H), 2.99 (t, J = 7.0 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 171.4, 154.0, 142.1, 138.3, 134.3, 133.0, 130.6, 129.2, 123.6, 119.3, 118.1, 114.2, 111.0, 47.0, 40.8.

Example 8. Preparation of tert -butyl (3 - ((4- carbamoyl -2 -nitrophenyl ) amino) propyl) carbamate ( 6a )

Compound 3a (100 mg, 0.4 mmol) potassium carbonate (120mg, 0.8mmol) and di- tert -butoxy dicarbonyl ((Boc) 2 O) was dissolved in acetone (6 ml) and water (6 ml) (110 mg, 0.5 mmol), and the mixture is stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the remaining aqueous solution was extracted three times with ethyl acetate (20 ml). The organic layer obtained by extraction was added with magnesium sulfate to remove the remaining water, and filtered using a filter paper to obtain Compound ( 6a ) in the form of a yellow solid. (110 mg, 0.3 mmol, 75% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.77 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H) , 3.45-3.48 (m, 2H), 3.22-3.26 (m, 2H), 1.88-1.93 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 169.9, 158.2, 148.1, 135.9, 132.0, 128.1, 120.9, 114.7, 80.2, 41.4, 38.8, 30.1, 29.0.

Example 9: Preparation of tert -butyl (2 - ((4- carbamoyl -2 -nitrophenyl ) amino) ethyl) carbamate ( 6b )

Compound 3b (2.0 g, 8.8 mmol) was dissolved in acetone (25 ml) and water (25 ml), and then potassium carbonate (1.83 g, 13.3 mmol) and di- tert -butoxy dicarbonyl ((Boc) ₂ O) , 13.3 mmol), and the mixture is stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the remaining aqueous solution was extracted three times with ethyl acetate (20 ml). The organic layer obtained by extraction was added with magnesium sulfate to remove the remaining water, and filtered using a filter paper to obtain a compound ( 6b ) in the form of a yellow solid. (2.3 g, 7.0 mmol, 79% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.74 (s, 1H), 7.98 (dd, J = 9.1, 1.8 Hz, 1H), 7.13 (d, J = 9.1 Hz, 1H), 3.46- 3.53 (m, 2H), 3.34 - 3.37 (m, 2H), 1.41 (s, 9H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 168.5, 156.8, 146.8, 134.0, 130.8, 126.4, 119.6, 113.3, 78.3, 42.2, 39.5, 26.9.

Example 10. Preparation of 3-amino-4 - ((3-aminopropyl) amino) benzoamide ( 7a )

Compound 6a (112 mg, 0.3 mmol) is dissolved in methanol (8 ml) and palladium / charcoal (10% w / w, 32 mg) is added. After stirring the mixture at room temperature for 8 hours in the presence of hydrogen, after concentration under reduced pressure the mixture, and the resulting concentrate was subjected to silica gel tube chromatography (dichloromethane: methanol = 10: 1) to give a purple the compound (7a) In solid form. (76 mg, 0.2 mmol, 67% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 7.28 (d, J = 7.7 Hz, 1H), 7.22 (s, 1H), 6.55 (d, J = 8.3 Hz, 1H), 3.15-3.23 ( m, 4H), 1.78-1.83 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 172.8, 158.3, 142.0, 134.0, 121.9, 121.3, 115.8, 109.5, 79.6, 41.4, 38.6, 30.0, 28.3.

Example 11. Preparation of tert -butyl (2 - ((2-amino-4- carbamoylphenyl ) amino) ethyl) carbamate ( 7b )

Compound 6b (2.3 g, 7.0 mmol) is dissolved in methanol (40 ml) and palladium / charcoal (10% w / w, 32 mg) is added. After the mixture was stirred at room temperature for 8 hours in the presence of hydrogen, the mixture was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (dichloromethane: methanol = 8: 1) to give compound ( 7b ) In solid form. (1.9 g, 6.4 mmol, 91% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 7.29 (dd, J = 8.3, 2.1 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 6.60 (d, J = 8.3 Hz, 1H), 3.29-3.31 (m, 4H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 173.9, 159.5, 143.0, 135.2, 123.3, 122.5, 117.1, 110.6, 80.9, 45.3, 41.4, 29.5.

Example 12. Preparation of 2- (2 -aminoethyl ) -1- (3-aminopropyl) -1H- benzo [d] imidazole -5 - carboxamide ( 5j )

Compound 7a (22 mg, 0.07 mmol) was dissolved in methanol (3 ml), tert- butyl (3-oxopropyl) carbamate (14 mg, 0.08 mmol) and sodium bisulfate (13 mg, 0.1 mmol) Lt; RTI ID = 0.0 > 60 C. < / RTI > The mixture was filtered through a filter paper using methanol (5 ml). The filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to obtain a benzimidazole derivative as a dark yellow solid . This benzimidazole derivative is dissolved in methanol, and thereto is added 6N hydrochloric acid (0.1 ml), followed by stirring at room temperature for 8 hours. This mixture was concentrated under reduced pressure, and the resulting concentrate was purified by column chromatography on a silica gel column (dichloromethane: methanol: ammonia solution: water = 60: 35: 5: 5) to obtain a compound ( 5j ) . (11 mg, 95% yield);

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.33 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.00 (d, J = 8.7 Hz, 1H), 4.67 (t, J = 7.1 Hz, 2H), 3.73 (t, J = 7.4 Hz, 2H), 3.59 (t, J = 7.4 Hz, 2H), 3.19 (t, J = 7.6 Hz, 2H), 2.28-2.36 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 167.6, 153.5, 144.9, 134.9, 132.1, 125.4, 115.9, 112.2, 42.6, 37.1, 36.9, 27.6, 24.4.

Example 13 : Preparation of benzimidazole derivative ( 5k to 5w )

Compound 7b (70 mg, 0.2 mmol) was dissolved in methanol (4 ml), followed by addition of 1-boc-piperidine-4-carboxaldehyde (60 mg, 0.3 mmol) and sodium bisulfate (30 mg, 0.3 mmol) Lt; RTI ID = 0.0 > 60 C. < / RTI > The mixture was filtered through a filter paper using methanol (5 ml). The filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to obtain a benzimidazole derivative as a dark yellow solid . This benzimidazole derivative was dissolved in methanol (5 ml), and 6N hydrochloric acid (2 ml) was added. The mixture was stirred at room temperature for 8 hours. The mixture was concentrated under reduced pressure, and the resulting concentrate was purified by silica gel column chromatography (dichloromethane: methanol: ammonia solution: water = 80: 20: 1: 1) to obtain 5k to 5w as a yellow solid .

Benzo [d] imidazole-5-carboxamide 5k (24 mg, 81% yield): 1 - (2-aminoethyl) -2-

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.24 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 4.56 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 170.9, 159.7, 155.7, 141.5, 137.4, 130.6, 128.5, 122.6, 119.3, 118.2, 115.5, 109.8, 42.3, 38.1.

1- (2-aminoethyl) -2- (2,4-dihydroxyphenyl) -1H- benzo [d] imidazole-5-carboxamide 5l (28 mg, 89% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.24 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.50-6.54 (m, 2H), 4.59-4.63 (m, 2H), 3.30-3.35 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 174.4, 164.6, 160.4, 157.8, 144.8, 140.4, 135.4, 131.6, 126.0, 121.5, 113.0, 110.9, 110.1, 105.8, 45.0, 41.0.

5m (14 mg, 71% yield): 1 - (2-aminoethyl) -2- (piperidin-

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.83 (dd, J = 4.6, 1.6 Hz, 2H), 8.33 (d, J = 1.2 Hz, 1H), 8.01 (dd, J = 8.6, 1.6 Hz, 1H), 7.87 (dd , J = 4.5, 1.6 Hz, 2H), 7.82 (d, J = 8.6 Hz, 1H), 4.70 (t, J = 7.4 Hz, 2H), 3.29-3.31 (m, 2H ); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 172.1, 153.5, 151.2, 143.3, 139.0, 139.0, 130.7, 125.3, 125.1, 120.6, 111.7, 43.6, 39.4.

Benzo [d] imidazole-5-carboxamide 5n (33 mg, 89% yield) was obtained as a colorless oil from 1- (2-aminoethyl) -2- (pyridin-

¹ H NMR (400 MHz, CD ₃ OD)? (Ppm) 9.39 (s, 1H), 9.25 (s, 2H), 8.32 (d, J = 1.3 Hz, 1H), 7.98-8.00 7.82 (d, J = 8.7 Hz, 1H), 4.71 (t, J = 7.3 Hz, 2H), 3.37 (t, J = 7.4 Hz, 2H); ¹³ C NMR (100 MHz, D ₂ O)? (Ppm) 174.3, 160.9, 159.3, 151.2, 143.5, 139.7, 130.3, 126.1, 125.9, 121.3, 113.1, 44.2, 40.2.

Benzo [d] imidazole-5-carboxamide 5o (19 mg, 83% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.48 (d, J = 8.8 Hz, 2H), 8.33 (d, J = 1.2 Hz, 1H), 8.06 (d, J = 8.7 Hz, 2H) , 8.00 (dd, J = 8.6 , 1.5 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 4.62 (t, J = 7.2 Hz, 2H), 3.22 (t, J = 7.2 Hz, 2H) ; ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 174.3, 156.7, 152.7, 145.4, 141.2, 138.6, 134.2, 132.7, 127.3, 127. 122.6, 113.8, 46.7, 42.1.

Benzo [d] imidazole-5-carboxamide 5p (19 mg, 82% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.08 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 4.65 (t, J = 6.8 Hz, 2H), 3.60 (d, J = 13.0 Hz, 2H), 3.44-3.49 (m, 3H), 3.23 (td, J = 13.0, 2.9 Hz, 2H), 2.25 (d, J = 13.0 Hz, < / RTI > 2H), 2.13-2.20 (m, 2H); ¹³ C NMR (100 MHz, D ₂ O)? (Ppm) 174.6, 160.1, 142.4, 138.6, 129.2, 124.4, 119.6, 111.8, 50.3, 45.0, 39.9, 32.7, 28.8.

1- (2-aminoethyl) -2- (2-Amino-3-yl) -1H- benzo [d] imidazole-5-carboxamide 5q (13 mg, 44% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.31 (s, 1H), 8.17 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 6.9 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.00 (t, J = 6.6 Hz, 1H), 4.63 (t, J = 7.2 Hz, 2H), 3.35-3.37 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 170.8, 161.9, 155.5, 149.8, 143.0, 141.9, 137.2, 128.9, 123.5, 119.1, 112.6, 110.7, 110.2, 41.6, 37.7.

Benzo [d] imidazole-5-carboxamide 5r (10 mg, 67% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.29 (s, 1H), 8.10-8.17 (m, 2H), 7.48-7.48 (m, 4H), 4.74-4.81 (m, 2H), 3.41 -3.53 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 158.6, 137.4, 134.7, 134.2, 132.6, 132.5, 131.5, 128.8, 117.6, 115.4, 45.5, 40.7, 35.0.

Benzo [d] imidazole-5-carboxamide 5s (34 mg, 77% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.38 (d, J = 8.6 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 8.28 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.90-7.93 (m, 2H), 7.78-7.82 (m, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 5.02 (t, J = 6.5 Hz, 2H), 3.44 (t, J = 6.5 Hz, 2H); ^{13 C NMR (100 MHz, CD} 3 OD) δ (ppm) 173.2, 153.5, 150.9, 149.2, 143.7, 141.1, 139.5, 132.4, 131.4, 130.9, 130.2, 129.9, 125.8, 123.4, 121.5, 112.5, 48.4, 42.8 .

5t (29 mg, 79% yield) was obtained as colorless crystals from 2 - ([1,1'- biphenyl] -4-yl) :

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.29 (s, 1H), 7.94 (dd, J = 8.5, 1.5 Hz, 1H), 7.83-7.88 (m, 4H), 7.74 (d, J J = 7.2 Hz, 2H), 3.03 (t, 2H), 7.47-7.51 (m, 2H), 7.38-7.42 J = 7.2 Hz, 2H); ^{13 C NMR (100 MHz, CD} 3 OD) δ (ppm) 173.0, 157.3, 145.2, 143.7, 141.7, 139.9, 131.7, 130.7, 130.5, 130.1, 129.7, 129.2, 128.7, 124.8, 120.5, 112.3, 48.1, 42.2 .

2 - ([1,1'-biphenyl] -2-yl) -1- (2-aminoethyl) -1H- benzo [d] imidazole-5-carboxamide 5u (19 mg, 64% yield) :

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.29 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.59-7.76 (m, 4H), 7.51 (d, J = 8.6 Hz, 1H), 7.22-7.27 (m, 5H), 3.78 (t, J = 7.1 Hz, 2H), 3.30-3.34 (m, 2H); ¹³ C NMR (100 MHz, CD ₃ OD)? (Ppm) 171.7, 155.9, 142.3, 140.2, 137.2, 132.0, 131.7, 130.7, 129.3, 129.0, 128.3, 123.5, 119.2, 110.6, 44.2, 39.1.

Benzv [d] imidazole-5-carboxamide 5v (38 mg, 82% yield):

^{1 H NMR (400 MHz, CD} 3 OD) δ (ppm) 8.28 (d, J = 1.2 Hz, 1H), 7.90-7.96 (m, 3H), 7.81 (d, J = 8.5 Hz, 1H), 7.54 ( d, J = 8.2 Hz, 1H), 7.19-7.29 (m, 2H), 4.81 (m, 2H), 3.28-3.32 (m, 2H); ^{13 C NMR (100 MHz, CD} 3 OD) δ (ppm) 175.0, 155.5, 141.1, 140.9, 140.4, 132.3, 130.7, 130.1, 126.5, 124.6, 123.4, 121.8, 121.6, 115.6, 113.5, 106.5, 45.3, 41.6 .

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereby. something to do. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (8)

Claims 1. A compound of the formula 1: < EMI ID =
[Chemical Formula 1]

Wherein n is an integer of 2 or 3 and R is Ph, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NH ₂ , cyclohexyl, 4-CN-Ph, 4-Me-Ph , 4-CH (CH ₃ ) ₂ Ph, 4-CF ₃ -Ph, 4-OH-Ph, Pyrimidine, 4-NO ₂ -Ph, 3- (2-NH ₂ ) -pyridine, CH ₂ Ph, 3-isoquinoline, 4- (1,1'- 2- (1,1'-biphenyl), and 3- (1H-indole). The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound has immunosuppressive activity. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein said compound selectively inhibits the activity of Janus kinase 1. A composition for immunosuppression comprising a compound of the following formula (1) as an active ingredient:
[Chemical Formula 1]

Wherein n is an integer of 2 or 3 and R is Ph, CH ₂ CH ₂ NH ₂ , CH ₂ CH ₂ CH ₂ NH ₂ , cyclohexyl, 4-CN-Ph, 4-Me-Ph , 4-CH (CH ₃ ) ₂ Ph, 4-CF ₃ -Ph, 4-OH-Ph, Pyrimidine, 4-NO ₂ -Ph, 3- (2-NH ₂ ) -pyridine, CH ₂ Ph, 3-isoquinoline, 4- (1,1'- 2- (1,1'-biphenyl), and 3- (1H-indole). 5. The composition of claim 4, wherein the composition selectively inhibits the activity of Janus kinase 1. 5. The composition according to claim 4, wherein the composition has an effect of preventing or treating an inflammatory disease. 7. The composition of claim 6, wherein the composition is an inflammatory disease arthritis. The compound according to any one of claims 4 to 7, wherein n is 2 in the formula (1) and R is CH ₂ CH ₂ NH ₂ , 4-OH-Ph, and piperidine Lt; / RTI > is a substituent selected from the group consisting of < RTI ID = 0.0 >

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