GLP-1 RECEPTOR AGONIST AND USE THEREOF

Abstract

Disclosed are novel compounds of Chemical Formula 1, optical isomers of the compounds, and pharmaceutically acceptable salts of the compounds or the optical isomers. The compounds, isomers, and salts exhibit excellent activity as GLP-1 receptor agonists. In particular, they, as GLP-1 receptor agonists, exhibit excellent glucose tolerance, thus having a great potential to be used as therapeutic agents for metabolic diseases. Moreover, they exhibit excellent pharmacological safety for cardiovascular systems.

Claims

1. A method for treating a metabolic disease, the method comprising administering to a subject in need a compound represented by following Chemical Formula 1, an optical isomer of the compound, or a pharmaceutically acceptable salt of the compound or the optical isomer: ##STR00072## wherein: R.sub.1 is —C(═O)R.sub.a, where R.sub.a is —OH; Y is —CH— or —N—; R.sub.2 is unsubstituted ##STR00073## halogen substituted ##STR00074## or unsubstituted ##STR00075## R.sub.b is hydrogen or —(C.sub.1-C.sub.4 alkyl); J is —N—; X is —CR.sub.c— or —N—, where R.sub.c is —H; W.sub.1 is —CR.sub.d—, where R.sub.d is —H; W.sub.2 is —CR.sub.e— or —N—, where R.sub.e is —H; W.sub.3 is —CR.sub.f—, where R.sub.f is —H; and A is ##STR00076## wherein Z.sub.1 is —CR.sub.g—, where R.sub.g is —H, halogen or —CN; Z.sub.2 is —CR.sub.h—, where R.sub.h is —H, halogen or —CN; Z.sub.3 is —N—; Z.sub.4 is —CR.sub.3—, where R.sub.3 is —H, halogen or —CN; and Z.sub.5 is —CR.sub.k—, where R.sub.k is —H, halogen or —CN.

2. The method of claim 1, wherein J is —N—; X is —N—; and W.sub.2 is —CR.sub.e—.

3. The method of claim 1, wherein Y is —CH—.

4. The method of claim 1, wherein J is —N—; X is —N—; W.sub.2 is —CR.sub.e—; Y is —CH—; and R.sub.2 is unsubstituted ##STR00077## halogen substituted ##STR00078## or unsubstituted ##STR00079##

5. The method of claim 1, wherein R.sub.g is —H; R.sub.h is —H or halogen; R.sub.3 is —H; and R.sub.k is —H, halogen or —CN.

6. The method of claim 4, wherein R.sub.2 is unsubstituted ##STR00080##

7. The method of claim 1, wherein X is —N—.

8. The method of claim 1, wherein W.sub.2 is —CR.sub.e—.

9. The method of claim 1, wherein R.sub.h is —H or halogen; and R.sub.k is —H, halogen or —CN.

10. The method of claim 1, wherein R.sub.2 is unsubstituted ##STR00081##

11. The method of claim 1, wherein the compound represented by the Chemical Formula 1 is one selected from a group consisting of: 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-2-ylmethoxy)pyridin-2-yl)piperazin yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl) piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyrazin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-5-carboxylic acid; (S)-2-((4-(3-((5-cyanopyridin-2-yl)methoxy)phenyl)piperazin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; (S)-2-((4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; and 2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-carboxylic acid.

12. The method of claim 1, wherein the compound represented by the Chemical Formula 1 is one selected from a group consisting of: (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-2-ylmethoxy)pyridin-2-yl)piperazin yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazin yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; and (S)-2-((4-(6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl) (oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

13. The method of claim 1, wherein the metabolic diseases are any one selected from the group consisting of diabetes, idiopathic T1D, latent autoimmune diabetes in adults (LADA), early onset T2DM (EOD), younger onset atypical diabetes (YOAD), maturity onset diabetes in young (MODY), malnutrition-related diabetes, gestational diabetes, hyperglycemia, insulin resistance, liver insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease (NAFLD), atherosclerosis, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, metabolic acidosis, ketosis, arthritis, osteoporosis, Parkinson's disease, left ventricular hypertrophy, peripheral arterial disease, loss of vision, cataracts, glomerulosclerosis, chronic renal failure, metabolic syndrome, X syndrome, premenstrual syndrome, angina, thrombosis, transient ischemic attack, vascular restenosis, symptoms of impaired fasting blood sugar, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcers, ulcerative colitis, hyper-apo B lipoproteinemia, Alzheimer's disease, schizophrenia, cognitive impairment, inflammatory bowel disease, short bowel syndrome, Crohn's disease, colitis, irritable bowel syndrome and polycystic ovary syndrome.

14. The method of claim 13, wherein the non-alcoholic fatty liver disease is any one selected from the group consisting of steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma.

15. The method of claim 1, wherein the administering is oral administrating.

16. The method of claim 1, wherein a daily dose of the compound is about 0.001 to 100 mg/kg.

Description

MODE FOR INVENTION

[0185] Hereinafter, preferred examples are set forth to aid in understanding the present disclosure. However, the following examples are provided for easier understanding of the present disclosure, and the present disclosure is not limited thereto.

[0186] Reagents and solvents as mentioned below were purchased from Sigma-Aldrich, TCI, etc., unless otherwise noted. Waters Alliance high-performance liquid chromatography (HPLC) system was used. Biotage Flash purification system was used as a silica gel used for column chromatography. .sup.1H NMR spectra was recorded using Bruker 400 MHz Ascend™ system. Waters Masslynx mass spectrum system was used.

[0187] All of .sup.1H nuclear magnetic resonance (NMR) spectra were consistent with the chemical structures of the compounds of the Examples of the present invention.

[0188] Characteristic chemical shifts (d) are given in parts-per-million (ppm) relative to the residual proton signal in the deuterated solvent (CDCl.sub.3: 7.27 ppm; CD.sub.3OD: 3.31 ppm; DMSO-d.sub.6: 2.50 ppm) and are reported using conventional abbreviations for designation of major peaks: for example, s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; and br: broad.

SYNTHESIS EXAMPLES

Synthesis Example 1: Synthesis of Intermediates 1 to 19

[0189] Exemplary methods of preparing intermediates 1 to 19 are described in detail below. Using the Preparation Methods 1 to 6 described below, those skilled in the art may prepare the compounds listed as intermediates 1 to 19 from appropriate starting materials which are available commercially or may be prepared by methods known in the art.

1. Preparation Method 1

[0190] ##STR00033##

(1) Synthesis of Intermediate 1: (S)-6-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile)

1) Synthesis of 6-(((6-chloropyridin-2-yl)oxy)methyl)nicotinonitrile

[0191] 6-bromomethyl-nicotinonitrile (1.52 g) and 6-chloro-2-hydroxypyridine (1.0 g) were placed in a round bottom flask and stirred in toluene (50 mL). Ag.sub.2CO.sub.3 (4.26 g) was added, and the mixture was heated to 100° C. and stirred for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with ethyl acetate (EA) and filtered through a celite pad, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (1.55 g, 82%) as a white solid. LC-MS(ES.sup.+): 246 (M+H).sup.+

2) Synthesis of tert-butyl (S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl) methylpiperazine-1-carboxylate

[0192] The compound (600 mg) synthesized in the step 1), tert-butyl (S)-2-methylpiperazine carboxylate (539 mg), Pd.sub.2(dba).sub.3 (112 mg), Cs.sub.2CO.sub.3 (1.6 g), and BINAP (152 mg) were placed in a round bottom flask and stirred in toluene (20 mL). The mixture was heated to 120° C. under N.sub.2 and stirred for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with EA, filtered with a celite pad, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with hexane/ethyl acetate eluent system to obtain the target compound (603 mg, 60%) as a syrup LC-MS(ES.sup.+): 410 (M+H).sup.+

3) Synthesis of (S)-6-(((6-(3-methylpiperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile

[0193] The compound (603 mg) synthesized in the step 2) was placed in a round bottom flask, dissolved in DCM (10 mL), and stirred. While the mixture was stirred, TFA (1.5 mL) was dropwise added to the mixture at 0° C. The resulting mixture was then stirred at room temperature for 6 h. After it was confirmed by TLC that the reaction was completed, the mixture was neutralized with sat. aqueous NaHCO.sub.3 solution, extracted with DCM/MeOH 10% solution, dried over anhydrous magnesium sulfate, filtered under reduced pressure, and concentrated under reduced pressure to give the target compound (512 mg) as a brown solid. LC-MS(ES.sup.+): 310 (M+H).sup.+

##STR00034##

(2) Synthesis of Intermediate 2: (S)-3-fluoro-4-(((6-(3-methylpiperazin-1-yl)pyrazin-2-yl)oxy)methyl)benzonitrile trifluoroaceticacid salt

[0194] The intermediate 2 was synthesized according to the Preparation Method 1.

1) Synthesis of 4-(((6-chloropyrazin-2-yl)oxy)methyl)-3-fluorobenzonitrile

[0195] 6-chloropyrazine-2-ol (1 eq.) and 4-(bromomethyl)-3-fluorobenzonitrile (1 eq.) were placed in a round bottom flask and stirred in CH.sub.3CN (0.1 M). After K.sub.2CO.sub.3 (3 eq.) was added, the resulting mixture was stirred at room temperature for 2 h. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with water and extracted with EA. The resulting organic layer was washed with brine solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a hexane/ethyl acetate to obtain the target compound (82%) as a white solid. LC-MS(ES.sup.+): 264 (M+H).sup.+

2) Synthesis of tert-butyl (S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl) methylpiperazine-1-carboxylate

[0196] The compound (1 eq.) synthesized in the step 1), tert-butyl (S)-2-methylpiperazine carboxylate (1.1 eq.), Cs.sub.2CO.sub.3 (2 eq.), BINAP (0.1 eq.), and Pd.sub.2(dba).sub.3 (0.05 eq.) were placed in a round bottom flask and stirred in toluene (0.2 M). The mixture was heated to 120° C. under nitrogen and stirred for 16 h. After it was confirmed by TLC that the reaction was completed, the reaction mixture was diluted with EA and filtered through a celite pad. Water was added to the filtrate, and the filtrate was extracted with EA. The resulting organic layer was washed with brine solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (73%) as a white solid. LC-MS(ES.sup.+): 428 (M+H).sup.+

3) Synthesis of (S)-3-fluoro-4-(((6-(3-methylpiperazin-1-yl)pyrazin-2-yl)oxy)methyl)benzonitrile

[0197] The compound (710 mg) synthesized in the step 2) was placed in a round bottom flask and stirred in DCM (2 mL). While the mixture was stirred, TFA (1.68 mL) was added dropwise at room temperature. The mixture was then stirred at room temperature for 1 h. After it was confirmed by TLC that the reaction was completed, the mixture was concentrated under reduced pressure to obtain the target compound as a light yellow oil. LC-MS(ES.sup.+): 328 (M+H).sup.+

##STR00035##

(3) Synthesis of Intermediate 3: 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile

[0198] The intermediate 3 was synthesized according to the Preparation Method 1.

1) Synthesis of 4-((3-bromophenoxy)methyl)-3-fluorobenzonitrile

[0199] By using 4-(bromomethyl)-3-fluorobenzonitrile (10 g), 3-bromophenol (5.46 mL) and potassium carbonate (9.68 g), and CH.sub.3CN (100 mL), the target compound (11.88 g, 83%) was obtained. LC-MS(ES.sup.+): 307 (M+H).sup.+

2) Synthesis of tert-butyl 4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazine carboxylate

[0200] The compound (2.45 g) synthesized in the step 1), 1-Boc-piperazine (1.79 g), Pd.sub.2(dba).sub.3 (367 mg), BINAP (498 mg), and Cs.sub.2CO.sub.3 (5.21 g) in toluene (40 mL) were reacted for 14 h to obtain the target compound (668 mg) at a yield of 20%. LC-MS(ES.sup.+): 412 (M+H).sup.+

3) Synthesis of 3-fluoro-4-((3-(piperazin-1-yl)phenoxy)methyl)benzonitrile

[0201] The compound (411 mg) synthesized in the step 2) was dissolved in DCM (5 mL). TFA (5 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. After it was confirmed by TLC that the reaction was completed, the mixture was concentrated under reduced pressure. Diethyl ether was added. The resulting residue was triturated to obtain the target compound (410 mg, 81%). LC-MS(ES.sup.+): 312 (M+H).sup.+

##STR00036##

(4) Synthesis of Intermediate 4: 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile

[0202] The intermediate 4 was synthesized according to the Preparation Method 1.

1) Synthesis of 6-(((6-chloropyridin-2-yl)oxy)methyl)nicotinonitrile

[0203] 6-(bromomethyl)nicotinonitrile (1.52 g) and 6-chloro-2-hydroxy pyridine (1.0 g) were placed in a round bottom flask and stirred in toluene (50 mL). Ag.sub.2CO.sub.3 (4.26 g) was added to the mixture. The resulting mixture was heated to 100° C. and then stirred for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with EA and filtered through a celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (1.55 g, 82%). LC-MS(ES.sup.+): 246 (M+H).sup.+

2) Synthesis of tert-butyl 4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate

[0204] The compound (600 mg) synthesized in the step 1), 1-Boc-piperazine (500 mg), Pd.sub.2(dba).sub.3 (112 mg), Cs.sub.2CO.sub.3 (1.6 g), and BINAP (152 mg) were placed in a round bottom flask and stirred in toluene (20 mL). The mixture was heated to 120° C. under nitrogen and stirred for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with EA and filtered through a celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (751 mg, 78%) as a transparent syrup. LC-MS(ES.sup.+): 396 (M+H).sup.+

3) Synthesis of 6-(((6-(piperazin-1-yl)pyridin-2-yl)oxy)methyl)nicotinonitrile

[0205] The compound (751 mg) synthesized in the step 2) was placed in a round bottom flask, dissolved in DCM (10 mL), and stirred. TFA (1 mL) was dropwise added to the mixture at 0° C. while the mixture was stirred. The resulting mixture was then stirred at room temperature for 6 h. After it was confirmed by TLC that the reaction was completed, the mixture was neutralized with a sat. aqueous NaHCO.sub.3 solution, extracted with a DCM/MeOH 10% solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure. The resulting filtrate was concentrated under reduced pressure to obtain the target compound (600 mg) as a brown solid. LC-MS(ES.sup.+): 296 (M+H).sup.+

2. Preparation Method 2

[0206] ##STR00037##

(1) Synthesis of Intermediate 5: 1-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazine

1) Synthesis of 2-chloro-6-(pyridin-3-ylmethoxy)pyridine

[0207] 3-pyridinemethanol (885 mg) was placed in a round bottom flask and stirred in THF (17 mL). KOtBu (1.37 g) was added portionwise to the mixture. The resulting mixture was stirred for 30 mins. Subsequently, 2,6-chloropyridine (1000 mg) was added to the mixture, and the resulting mixture was stirred at room temperature for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was added to a mixture of sat. aqueous NH.sub.4C.sub.1 solution and EA. The resulting mixture was then stirred for 15 mins. The resulting mixture was filtered through a celite pad and extracted with EA. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (1.20 g, 86%) as a white solid LC-MS(ES.sup.+): 221 (M+H).sup.+

2) Synthesis of tert-butyl 4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazine-1-carboxylate

[0208] The compound (441 mg) synthesized in the step 1), 1-Boc-piperazine (559 mg), Pd.sub.2(dba).sub.3 (92 mg), BINAP (125 mg), and Cs.sub.2CO.sub.3 (1.30 g) were placed in a round bottom flask and stirred in toluene (6 mL). Under nitrogen, the mixture was heated to 90° C. and stirred for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was filtrated with a celite pad. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (225 mg, 31%). LC-MS(ES.sup.+): 371 (M+H).sup.+

3) Synthesis of 1-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazine

[0209] Acetyl chloride (0.3 mL) was slowly added dropwise to a mixed solvent of ethanol (0.4 mL) and EA (3 mL), and the mixture was stirred at 40° C. for 1 h. The compound (225 mg) synthesized in the step 2) was added to the mixture, and the resulting mixture was stirred at 40° C. for 2 h. EA was added to the mixture, the resulting mixture was vehemently stirred at room temperature for 1 h and filtered to obtain a solid. The solid was dissolved in 5% MC/MeOH solution. Sat. aqueous Na.sub.2CO.sub.3 solution was added, and the resulting mixture was stirred for 30 mins. The organic layer obtained from layer separation was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the target compound (135 mg, 86%). LC-MS(ES.sup.+): 271 (M+H).sup.+

3. Preparation Method 3

[0210] ##STR00038##

(1) Synthesis of Intermediate 6: 1-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazine trifluoroaceticacid salt

1) Synthesis of 5-chloro-2-(chloromethyl)-3-fluoropyridine

[0211] (5-chloro-3-fluoropyridin-2-yl)methanol (324 mg) was dissolved in DCM (20 mL), and the mixture was cooled to 0° C. SOCl.sub.2 (0.3 mL) was slowly added to the mixture, and the mixture was stirred at room temperature for 3 h. After it was confirmed by TLC that the reaction was completed, the resulting mixture was concentrated under reduced pressure to obtain the target compound. The target compound was used in the next step below without further purification. LC-MS(ES.sup.+): 181 (M+H).sup.+

2) Synthesis of tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate

[0212] 6-chloropyridin-2(1H)-one (2 g) and N-Boc-piperazine (7.2 g) were dissolved in n-butanol (16 mL). The mixture was stirred at 140° C. for 3 d. Aq. NH.sub.4Cl and brine were added to the mixture. The resulting mixture was extracted with EA twice. The resulting organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The resulting residue was diluted with CH.sub.3CN (40 mL) and H.sub.2O (200 mL) and stirred at room temperature for 2 h. Then, the resulting mixture was filtered to obtain the target compound (1.49 g, 35%) as a solid. LC-MS(ES.sup.+): 280 (M+H).sup.+

3) Synthesis of tert-butyl 4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazine-1-carboxylate

[0213] Tert-butyl 4-(6-hydroxypyridin-2-yl)piperazine-1-carboxylate (559 mg) was dissolved in CH.sub.3CN (5 mL). 5-chloro-2-(chloromethyl)-3-fluoropyridine (2 mmol) and potassium carbonate (553 mg) were added to the mixture, and the mixture was stirred at 40° C. for 14 h. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with distilled H.sub.2O and was extracted with EA twice. The resulting organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane/ethyl acetate to obtain the target compound (249 mg, 29%) as a yellow liquid. LC-MS(ES.sup.+): 423 (M+H).sup.+

4) Synthesis of 1-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperazine trifluoroaceticacid salt

[0214] The compound (220 mg) synthesized in the step 3) was dissolved in DCM (10 mL). TFA (10 mL) was added to the mixture, and the mixture was stirred at room temperature for 1.5 h. After it was confirmed by TLC that the reaction was completed, the mixture was concentrated under reduced pressure to obtain the target compound, which was used without further purification. LC-MS(ES.sup.+): 323 (M+H).sup.+

4. Preparation Method 4

[0215] ##STR00039##

(1) Synthesis of Intermediate 7: 3-fluoro-4-(((6-(piperidin-4-yl)pyridin yl)oxy)methyl)benzonitrile hydrogenchloride salt

1) Synthesis of tert-butyl 4-(3-hydroxyphenyl)piperidine-1-carboxylate

[0216] 3-(piperidin-4-yl)phenol (1 mmol) and (Boc).sub.2O (1 mmol) were placed in a round bottom flask, dissolved in DCM (2 mL), and stirred at room temperature for 1 h. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with water and extracted with DCM. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The target compound was obtained and used without further purification. LC-MS (ES.sup.+): 278 (M+H).sup.+

2) Synthesis of tert-butyl 4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidine-1-carboxylate

[0217] The compound (1 eq.) synthesized in the step 1) and 4-(bromomethyl)-3-fluoro-benzonitrile (1 eq.) were placed in a round bottom flask and stirred in CH.sub.3CN (0.1 M). After potassium carbonate (1.5 eq.) was added, the mixture was stirred at 50° C. for 2 h. After it was confirmed by TLC that the reaction was completed, the mixture was added to an appropriate amount of water and extracted with EA. The resulting organic layer was washed with brine solution, dried over anhydrous magnesium sulfate, filtrated under reduced pressure, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (70%) as a colorless liquid. LC-MS(ES.sup.+): 412 (M+H).sup.+

3) Synthesis of 3-fluoro-4-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)benzonitrile hydrogenchloride salt

[0218] The compound (560 mg) synthesized in the step 2) was dissolved in 1,4-dioxane (4 mL). 4N HCl 1,4-dioxane solution (2.6 mL) was added at room temperature. The mixture was stirred for 4 h. The mixture was then concentrated under reduced pressure, and the resulting residue was treated with MTBE to obtain a solid. The solid was triturated with MTBE for 2 h. The triturated solid was filtrated and dried to obtain the target compound (85%) as a white solid. LC-MS(ES.sup.+): 312 (M+H).sup.+

5. Preparation Method 5

[0219] ##STR00040##

(1) Synthesis of Intermediate 8: 5-chloro-3-fluoro-2-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridine hydrochloride salt

1) Synthesis of tert-butyl 4-(3-hydroxyphenyl)piperidine-1-carboxylate

[0220] Tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxabororain-2-yl)-3,6-dihydroxypyridin-1(2H)-carboxylate, chlorohydroxypyridine, Pd(PPh.sub.3).sub.4, and Na.sub.2CO.sub.3 were placed in a reaction vessel equipped with a reflux condenser. 1,4-dioxane (7 mL), ethanol (3 mL), and water (1 mL) were added. The resulting mixture was heated to 120° C. under nitrogen. After being stirred for overnight, the mixture was cooled to room temperature and filtered through a celite pad using EA (50 mL). The mixture was diluted with water (20 mL), and aqueous layer was extracted with EA (3×50 mL). The resulting organic layer was dried over anhydrous magnesium sulfate, filtered under reduced pressure, and purified by column chromatography (5% MeOH/DCM) to obtain tert-butyl 6-hydroxy-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate as a white solid.

[0221] Tert-butyl 6-hydroxy-3′,6′-dihydro-[2,4′-bipyridine]-1′(2′H)-carboxylate was dissolved in MeOH. 10% Pd/C was added. The mixture was exposed to hydrogen atmosphere (balloon pressure) at room temperature. After 2 h, it was confirmed that the reaction was not completed, and additional 10% Pd/C was added to the mixture. After 3 h, it was confirmed that the reaction was completed, and the mixture was filtered through a celite pad, washed with MeOH, and concentrated under reduced pressure. The residue was purified by column chromatography (33% ethyl acetate/hexane) to obtain the target compound (45%) as a white solid. LC-MS(ES.sup.+): 278 (M+H).sup.+

2) Synthesis of tert-butyl 4-(6-((5-chloro-3-fluoropyridin-2-yl)methoxy)pyridin-2-yl)piperidine-1-carboxylate

[0222] To a solution of (5-chloro-3-fluoro-2-pyridyl)methanol, the compound synthesized in the above step 1), and toluene was added (Bu).sub.3P at room temperature. The mixture was stirred for 15 mins. ADDP was added at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was poured into hexane (30 mL) and filtrated through a filter glass. The resulting organic extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to obtain the target compound (30%) as a colorless oil. LC-MS(ES.sup.+): 422 (M+H).sup.+

3) Synthesis of 5-chloro-3-fluoro-2-(((6-(piperidin-4-yl)pyridin-2-yl)oxy)methyl)pyridine hydrochloride salt

[0223] The compound synthesized in the step 2) was placed in a round bottom flask and stirred in 1,4-dioxane (4 mL). 4N HCl 1,4-dioxane solution (1 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to obtain the target compound as a white solid, which was used in the next step without further purification. LC-MS(ES.sup.+): 322 (M+H).sup.+

6. Preparation Method 6

[0224] ##STR00041##

(1) Synthesis of Intermediate 9: methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

1) Synthesis of methyl (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)picolinate

[0225] Methyl 6-chloro-5-nitropicolinate (1.0 g), TEA (1.93 mL), and (S)-oxetan-2-ylmethanamine (402 mg) were dissolved in DMF (10 mL), and the resulting mixture was stirred at room temperature for overnight. The mixture was concentrated to remove THF, diluted with EA, and washed with brine solution (×2). The resulting organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target compound (1.1 g, 89%) as a yellow solid. LC-MS(ES.sup.+): 268 (M+H).sup.+

2) Synthesis of methyl (S)-5-amino-6-((oxetan-2-ylmethyl)amino)picolinate

[0226] The compound (1.1 g) synthesized in the step 1) and Pd/C (110 mg) were added to MeOH (3.8 mL), and the mixture was stirred at room temperature for 3 h. The mixture was filtered through a celite pad to remove a metal catalyst, and the resulting filtrate was concentrated to obtain the target compound (1.0 g, 100%) as a white solid. LC-MS(ES.sup.+): 238 (M+H).sup.+

3) Synthesis of methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0227] The compound (1.0 g) synthesized in the step 2) and chloroacetic anhydride (754 mg) were added to THF (21 mL), and the mixture was stirred at 60° C. for 1.5 h. The mixture was concentrated to remove THF, and EA and sat. aqueous NaHCO.sub.3 solution were added. The resulting mixture was extracted with EA (×2). The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography to obtain the target compound (760 mg, 61%) as a white solid. LC-MS(ES.sup.+): 296 (M+H).sup.+

##STR00042##

(2) Synthesis of Intermediate 10: methyl 2-(chloromethyl)-1-((1-fluorocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

1) Synthesis of 1-fluorocyclopropane-1-carboxamide

[0228] 1-fluorocyclopropane-1-carboxylic acid (38, 4.0 g) was added to thionyl chloride (1.8 mL), and the mixture was stirred under reflux for 30 mins. The mixture was concentrated under reduced pressure to obtain 1-fluoropropane-1-carbonyl chloride as a liquid state, which was used for the next step without further purification. In a separate reaction flask, 28% aqueous ammonia solution (10 mL) and THF (2 mL) were mixed. Then, 1-fluoropropane-1-carbonyl chloride (38.4 mmol) solution was slowly added dropwise to the mixture at 0° C. The resulting mixture was stirred in an open flask state overnight. The resulting white solid was filtered, washed with ice water, and dried to obtain the target compound (500 mg) as a light yellow solid. LC-MS(ES.sup.+): 104 (M+H).sup.+

2) Synthesis of (1-fluorocyclopropyl)methanamine hydrochloride salt

[0229] The compound (270 mg) synthesized in the step 1) was dissolved in THF (5 mL), and 1 M BH.sub.3 THF solution (10.4 mL) was added at 0° C. The mixture was stirred at 70° C. for overnight. 10% HCl solution (2 mL) was slowly added at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, washed with Et.sub.2O, neutralized to pH 10 with 10% NaOH aqueous solution, and extracted with Et.sub.2O (×3). The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 1.5 mL of 2N HCl in Et.sub.2O solution was dropwise added at 0° C. The resulting mixture was stirred at room temperature for 1 h and filtrated to obtain the target compound (102 mg, 31%) as a green solid without further purification. LC-MS(ES.sup.+): 90 (M+H).sup.+

3) Synthesis of methyl 3-(((1-fluorocyclopropyl)methyl)amino)-4-nitrobenzoate

[0230] The compound (100 mg) synthesized in the step 2) and methyl 3-fluoro-4-nitrobenzoate (158 mg) were dissolved in CH.sub.3CN (2.5 mL), and TEA (0.33 mL) was added dropwise. The mixture was stirred at 85° C. for overnight. The mixture was concentrated under reduced pressure, separated, and purified by column chromatography (12 g SiO.sub.2, 20% EA->50% EA) to obtain the target compound (119 mg, 56%) as a white solid. LC-MS(ES.sup.+): 269 (M+H).sup.+

4) Synthesis of methyl 4-amino-3-(((1-fluorocyclopropyl)methyl)amino)benzoate

[0231] The compound (100 mg) synthesized in the step 3) was dissolved in THF (5 mL), and Pd/C (118 mg) was added. The mixture was stirred at room temperature for 3 h under hydrogen gas. The mixture was filtered and concentrated under reduced pressure to obtain the target compound (71 mg, 80%) as a white solid. LC-MS(ES.sup.+): 239 (M+H).sup.+

5) Synthesis of methyl 2-(chloromethyl)-1-((1-fluorocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0232] The compound (70 mg) synthesized in the step 4) and 2-chloro-1,1,1-trimethoxyethane (0.04 mL) were dissolved in CH.sub.3CN (3 mL), and p-TSA (3 mg) was added. The mixture was stirred at 85° C. for 3 h. The mixture was concentrated under reduced pressure and purified by column chromatography (12 g SiO.sub.2, 20% EA.fwdarw.50% EA) to obtain the target compound (89 mg, 52%) as a white solid. LC-MS(ES.sup.+): 297 (M+H).sup.+

Synthesis of Intermediates 11 to 19

[0233] The compounds listed as intermediates 11 to 19 in Table 1 below were prepared by using procedures identical or analogous to the Preparation Methods 1 to 6 from appropriate starting materials which are available commercially or may be prepared by methods known in the art. The compounds were purified using methods known to those skilled in the art, which may include silica gel chromatography, HPLC, or recrystallization. The final compounds could be isolated as neutrals or as acid addition or base addition salts. The compound names and LC-MS data of the prepared intermediates are shown in Table 1 below.

TABLE-US-00001 TABLE 1 LC-MS Intermediate Preparation data No. Method Structure Compound name (ES+) 11 1 6-(((6-(piperazin-1-yl)pyrazin- 2- yl)oxy)methyl)nicotinonitrile trifluoroaceticacid salt 297 (M + H).sup.+ 12 1 6-((3-(piperazin-1- yl)phenoxy)methyl)nicotino- nitrile trifluoroaceticacid salt 295 (M + H).sup.+ 13 2 [00043] 1-(6-(pyridin-4- ylmethoxy)pyridin-2- yl)piperazine 271 (M + H).sup.+ 14 2 [00044] 1-(6-(pyridin-2- ylmethoxy)pyridin-2- yl)piperazine 271 (M + H).sup.+ 15 3 [00045] 1-(6-((5-chloropyridin-2- yl)methoxy)pyridin-2- yl)piperazine 305 (M + H).sup.+ 16 5 6-(((6-(piperidin-4-yl)pyridin- 2- yl)oxy)methyl)nicotinonitrile hydrochloride salt 295 (M + H).sup.+ 17 5 5-chloro-3-fluoro-2-((3- (piperidin-4- yl)phenoxy)methyl)pyridine hydrochloride salt 321 (M + H).sup.+ 18 6 [00046] methyl (S)-2-(chloromethyl)- 1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6- carboxylate 295 (M + H).sup.+ 19 6 [00047] methyl 2-(chloromethyl)-1- (oxazol-2-ylmethyl)-1H- benzo[d]imidazole-6- carboxylate 292 (M + H).sup.+

EXAMPLES

[0234] Synthesis of the compounds of Examples 1 to 18 using the intermediates above will be described in detail below. The following Preparation Examples A, B, and C show exemplary methods of synthesizing the compounds of Examples 1 to 18 using the intermediates above. Using the Preparation Examples A, B and C, those skilled in the art may prepare the compounds of Examples 1 to 18 of the present disclosure.

1. Preparation Example A

[0235] ##STR00048##

(1) Synthesis of Example 1: 2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

1) Synthesis of methyl 2-(((S)-4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0236] Intermediate 1 (194 mg), intermediate 18 (185 mg), and potassium carbonate (350 mg) were dissolved in CH.sub.3CN (10 mL) in a round bottom flask, and the mixture was stirred at 60° C. for one day. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with EA, and the resulting organic layer was washed using sat. aqueous NaHCO.sub.3, sat. aqueous NH.sub.4C.sub.1, and brine successively in the order. Then, the organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a hexane/ethyl to obtain methyl 2-(((S)-4-(6-((5-cyanopyridin yl)methoxy)pyridin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (241 mg, 67%) as a transparent syrup. LC-MS(ES.sup.+): 568 (M+H).sup.+

2) Synthesis of the Final Compound

[0237] The compound (241 mg) obtained in the step 1) was dissolved in CH.sub.3CN (10 mL) in a round bottom flask, and the mixture was stirred. While the mixture was stirred, 1.0 M TBD aqueous solution (0.85 mL) was added dropwise. Purified water (1 mL) was added to the mixture, and the mixture was stirred at 60° C. for one day. After it was confirmed by TLC that the reaction was completed, the mixture was neutralized to pH 7 with 1 N HCl aqueous solution. The resulting mixture was extracted with DCM/MeOH 10% solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH to obtain the final compound (55 mg, 24%) as a pale green solid. .sup.1H NMR (DMSO-d.sub.6): δ 8.97 (s, 1H), 8.27 (d, J=2.0 Hz, 1H), 8.26 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 6.31 (d, J=8.4 Hz, 1H), 6.16 (d, J=7.6 Hz, 1H), 5.40 (s, 2H), 5.14 (m, 1H), 4.73 (m, 2H), 4.47-4.46 (m, 1H), 4.34-4.25 (m, 2H), 3.70-3.59 (m, 4H), 2.90 (t, J=10.0 Hz, 1H), 2.72-2.61 (m, 3H), 2.38-2.33 (m, 1H), 2.26-2.21 (m, 1H), 1.03 (d, J=6.0 Hz, 3H); LC-MS(ES.sup.+): 554 [M+H].sup.+.

##STR00049##

(2) Synthesis of Example 2: (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

1) Synthesis of methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0238] Intermediate 4 (233 mg), intermediate 18 (232 mg), potassium carbonate (436 mg) were dissolved in CH.sub.3CN (10 mL) in a round bottom flask, and the mixture was stirred at 60° C. for one day. After it was confirmed by TLC that the reaction was completed, the mixture was diluted with EA, and the resulting organic layer was washed using sat. aqueous NaHCO.sub.3, sat. aqueous NH.sub.4Cl, and brine successively. Then, the organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a hexane/ethyl to obtain methyl (S)-2-((4-(6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)piperazin-1-yl)methyl) (oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (390 mg, 89%) as a transparent syrup. LC-MS(ES.sup.+): 554 (M+H).sup.+

2) Synthesis of the Final Compound

[0239] The compound (387 mg) obtained in the step 1) was dissolved in CH.sub.3CN (10 mL) in a round bottom flask, and the mixture was stirred. While the mixture was stirred, 1.0 M TBD aqueous solution (1.4 mL) was added dropwise. Purified water (0.6 mL) was added to the mixture, and the mixture was stirred at 60° C. for 1 d. After it was confirmed by TLC that the reaction was completed, the mixture was neutralized to pH 7 with 1 N HCl aqueous solution, extracted with DCM/MeOH 10% solution, dried over anhydrous magnesium sulfate, and filtered under reduced pressure to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH to obtain the final compound (225 mg, 60%) as a pale green solid. .sup.1H NMR (DMSO-d.sub.6): δ 8.97 (s, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (s, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 6.32 (d, J=8.0 Hz, 1H), 6.18 (d, J=8.0 Hz, 1H), 5.41 (s, 2H), 5.11-5.05 (m, 1H), 4.79 (d, J=7.2 Hz, 1H), 4.75 (d, J=7.2 Hz, 1H), 4.65-4.60 (m, 1H), 4.50-4.45 (m, 1H), 4.39-4.34 (m, 1H), 3.94 (d, J=13.2 Hz, 1H), 3.76 (d, J=13.2 Hz, 1H), 3.34-3.29 (m, 3H, assumed; partially obscured by water peak), 2.66 (m, 1H), 2.50-2.42 (m, 6H, assumed; partially obscured by solvent peak); LC-MS(ES.sup.+): 540 (M+H).sup.+

##STR00050##

(3) Synthesis of Example 3: (5)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

1) Synthesis of methyl (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0240] Intermediate 7 (1.0 eq.), intermediate 9 (1.0 eq.), and potassium carbonate (3.0 eq.) were dissolved in CH.sub.3CN (0.1 M) in a round bottom flask, and the mixture was stirred at room temperature for 3 d. After it was confirmed by TLC that the reaction was completed, purified water was added to the mixture. The mixture was extracted with EA, and the resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (S)-2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperidin-1-yl)methyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (91%). LC-MS(ES.sup.+): 570 (M+H).sup.+

2) Synthesis of the Final Compound

[0241] The compound obtained in the step 1) was dissolved in CH.sub.3CN (0.1 M) in a round bottom flask, and the mixture was stirred. After 1.0 M TBD aqueous solution was added, the mixture was stirred at 50° C. for 4 hours. After it was confirmed by TLC that the reaction was completed, the mixture was acidified to pH 6 with 2 M citric acid aqueous solution (7.0 mL) and diluted with purified water. The resulting aqueous layer was extracted with DCM/MeOH 5% solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH to obtain the final compound (55%) as a pale yellow solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.08-12.98 (m, 1H), 8.16-8.13 (m, 1H), 8.01-7.90 (m, 2H), 7.77-7.75 (m, 2H), 7.22 (t, J=7.9 Hz, 1H), 6.94-6.84 (m, 3H), 5.23-5.21 (m, 3H), 4.87 (dd, J=14.6, 6.3 Hz, 1H), 4.74 (dd, J=14.6, 4.2 Hz, 1H), 4.53-4.46 (m, 1H), 4.41-4.34 (m, 1H), 4.03-3.91 (m, 2H), 2.95 (dd, J=15.1, 12.8 Hz, 2H), 2.75-2.65 (m, 1H), 2.30-2.18 (m, 2H), 1.80-1.63 (m, 4H); LC-MS(ES.sup.+): 556 (M+H).sup.+

##STR00051##

(4) Synthesis of Example 4: 2-(((S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

1) Synthesis of methyl 2-(((S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0242] Intermediate 2 (1.0 eq), intermediate 18 (1.0 eq), and potassium carbonate (5.0 eq) were dissolved in CH.sub.3CN (0.1 M) in a round bottom flask, and the mixture was stirred at room temperature for 2 days. It was identified that intermediate 2 remained as the reaction was not completed. Thus, 0.5 eq of intermediate 18 was added to the mixture, and the mixture was heated to 60° C. After it was confirmed by TLC that the reaction was completed, the mixture was cooled to room temperature, and purified water was added. The mixture was extracted with EA, and the resulting organic layer was washed with brine. Then, the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a hexane/ethyl to obtain methyl 2-(((S)-4-(6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (70%) as a colorless liquid. LC-MS (ES.sup.+): 586 (M+H).sup.+

2) Synthesis of the Final Compound

[0243] The compound obtained in the step 1) was placed in a round bottom flask and was stirred in CH.sub.3CN (0.1 M). After 1.0 M TBD aqueous solution was added, the mixture was stirred at 60° C. for 3 hours. After it was confirmed by TLC that the reaction was completed, the mixture was acidified to pH 6 with 2 M citric acid aqueous solution (7.0 mL) and diluted with purified water. The mixture was extracted with DCM/MeOH 5% solution. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH to obtain the final compound. The purity was not enough with MPLC. Thus, further separation was performed using PTLC (7% DCM/MeOH) to obtain the final compound (26%) as a yellow foam. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.83 (brs, 1H), 8.28 (d, J=0.8 Hz, 1H), 7.89 (dd, J=9.2, 1.2 Hz, 1H), 7.84 (s, 1H), 7.82 (dd, J=8.4, 1.6 Hz, 1H), 7.73-7.65 (m, 3H), 7.53 (s, 1H), 5.43 (s, 2H), 5.18-5.15 (m, 1H), 4.76 (d, J=4.4 Hz, 2H), 4.49-4.45 (m, 1H), 4.36 (d, J=14.0 Hz, 1H), 4.31-4.26 (m, 1H), 3.88 (d, J=10.8 Hz, 1H), 3.80 (d, J=13.2 Hz, 1H), 3.68 (d, J=14.0 Hz, 1H), 3.15-3.09 (m, 1H), 2.94 (dd, J=12.8, 8.6 Hz, 1H), 2.73-2.62 (m, 3H), 2.42-2.31 (m, 2H), 1.11 (d, J=6.2 Hz, 3H); LC-MS(ES.sup.+): 572 (M+H).sup.+

(5) Synthesis of Examples 5 to 10

[0244] By using procedures identical or analogous to the procedures to prepare the compounds of Examples 1, 2, 3 and to 4, the compounds of Examples 5 to 10 in Table 2 below were prepared from appropriate starting materials which are available or may be prepared by methods known in the art. The compounds were purified using methods well known to those skilled in the art, which may include silica gel chromatography, HPLC, or recrystallization. The final compounds could be isolated as neutrals or as acid addition or base addition salts. The names, NMR data, and LC-MS data of the compounds of the Examples 5-10 are shown in Table 2 below.

TABLE-US-00002 TABLE 2 Intermediate Intermediate LC-MS Example A B data No. No. No. Compound name NMR data (ES+) 5 4 9 (S)-2-((4-(6-((5- .sup.1H NMR (DMSO-d.sub.6): δ 8.97 (s, 1H), 8.28 (dd, J = 541 cyanopyridin-2- 8.0, 2.4 Hz, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.00 (M + H).sup.+ yl)methoxy)pyridin- (d, J = 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.48 2-yl)piperazin-1- (t, J =8.0 Hz, 1H), 6.32 (d, J =8.0 Hz, 1H), 6.18 yl)methyl)-3- (d, J =8.0 Hz, 1H), 5.41 (s, 2H), 5.16 (m, 1H), (oxetan-2- 4.86-4.81 (m, 2H), 4.72-4.68 (m, 1H), 4.49-4.47 ylmethyl)-3H- (m, 1H), 4.38-4.35 (m, 1H), 4.00-3.89 (m, 2H), imidazo[4,5- 3.35-3.33 (brs, 4H, assumed; partially obscured b]pyridine-5- by water peak), 2.68-2.66 (m, 2H), 2.50-2.47 (m, carboxylic acid 3H, assumed; partially obscured by solvent peak). 6 1 9 2-(((S)-4-(6-((5- .sup.1H NMR (DMSO-d.sub.6): δ 8.97 (s, 1H), 8.27 (dd, J = 555 cyanopyridin-2- 8.2, 2.0 Hz, 1H), 8.26 (d, J = 2.4 Hz, 1H), 8.14 (M + H).sup.+ yl)methoxy)pyridin- (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.54 2-yl)-2- (d, J = 8.4 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 6.32 methylpiperazin-1- (d, J = 8.0 Hz, 1H), 6.17 (d, J = 8.0 Hz, 1H), 5.40 yl)methyl)-3-(((S)- (s, 2H), 5.23-5.21 (m, 1H), 4.77-4.76 (m, 2H), oxetan-2- 4.50-4.44 (m, 2H), 4.21-4.18 (m, 1H), 3.76-3.63 yl)methyl)-3H- (m, 3H), 2.88 (m, 1H), 2.68-2.60 (m, 4H), 2.5 (m, imidazo[4,5- 1H), 2.25 (m, 1H), 1.06 (d, J = 6.0 Hz, 3H). b]pyridine-5- carboxylic acid 7 13 19 1-(oxazol-2- .sup.1H NMR (DMSO-d.sub.6): δ 12.89 (brs, 1H), 8.51 (d, 526 ylmethyl)-2-((4-(6- J = 6.0 Hz. 2H), 8.21 (s, 1H), 8.03 (s, 1H), 7.85-7.83 (M + H).sup.+ (pyridin-4- (m, 1H), 7.70-7.68 (m, 1H), 7.44 (t, J = 8.0 ylmethoxy)pyridin- Hz, 1H), 7.35 (d, 7 = 6.0 Hz, 2H), 7.11 (s, 1H), 2-yl)piperazin-1- 6.26 (d, J = 8.0 Hz, 1H), 6.13 (d, J = 8.0 Hz, 1H), yl)methyl)-1H- 5.89 (s, 2H), 5.29 (s, 2H), 3.87 (s, 2H), 3.19-3.13 benzo[d]imidazole- (m, 4H), 2.39-2.35 (m, 4H). 6-carboxylic acid 8 8 18 (S)-2-(4-(6-(5- .sup.1H NMR (400 MHz, MeOD): δ 8.39 (s, 1H), 8.35 567 chloro-3- (s, 1H), 8.00 (s, 1H), 7.83-7.81 (m, 1H), 7.70-7.68 (M + H).sup.+ fluoropyridin-2- (m, 1H), 7.60-7.57 (m, 1H), 6.84-6.82 (m, 1H), yl)methoxy)pyridin- 6.67-6.65 (m, 1H), 5.55-5.47 (m, 2H), 5.33-5.27 2-yl)piperidin-1- (m, 1H), 4.78 (m, 1H), 4.75-4.74 (m, 1H), yl)methyl)-1- 4.52-4.47 (m, 1H), 4.13-3.99 (m, 2H), 3.15-3.11 (oxetan-2- (m, 1H), 3.04-3.01 (m, 1H), 2.88-2.80 (m, 1H), ylmethyl)-1H- 2,70-2.51 (m, 2H), 2.46-2.35 (m, 2H), 1.89-1.82 benzo[d]imidazole- (m, 4H). 6-carboxylic acid 9 16 18 (S)-2-((4-(6-((5- 1H NMR (400 MHz, CDCl.sub.3): δ 8.89 (s, 1H) 8.33 539 cyanopyridin-2- (s, 1H), 8.16-8.13 (m, 1H), 7.99-7.97 (m, 2H), (M + H).sup.+ yl)methoxy)pyridin- 7.68-7.61 (m, 3H), 6.87-6.85 (m, 1H), 6.78-6.76 2-yl)piperidin-1- (m, 1H), 5.57 (s, 2H), 5.30-5.28 (m, 1H), yl)methyl)-1- 4.72-4.65 (m, 1H), 4.52-4.46 (m, 1H), 4.07-4.04 (oxetan-2- (m, 1H), 3.96-3.91 (m, 1H), 3.08-3.05 (m, 1H), ylmethyl)-1H- 2.97-2.94 (m, 1H), 2.86-2.82 (m, 1H), 2.58-2.51 benzo[d]imidazole- (m, 2H), 2.38-2.28 (m, 2H), 1.82-1.72 (m, 3H). 6-carboxylic acid 10 17 18 (S)-2-((4-(3-((5- .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 8.56 (d, J = 566 chloro-3- 1.3 Hz, 1H), 8.28-8.26 (m, 1H), 8.18 (dd, J = 9.7, (M + H).sup.+ fluoropyridin-2- 1.9 Hz, 1H), 7.83-7.79 (m, 1H), 7.65-7.61 (m, 1H), yl)methoxy)phenyl) 7.24-7.18 (m, 1H), 6.90-6.84 (m, 3H), 5.21-5.19 piperidin-1- (m, 2H), 5.16-5.06 (m, 1H), 4.81 (dd, J = yl)methyl)-1- 15.3, 7.3 Hz, 1H), 4.67 (dd, J = 15.2, 2.6 Hz, (oxetan-2- 1H), 4.54-4.47 (m, 1H), 4.42-4.34 (m, 1H), 3.95 ylmethyl)-1H- (d, J = 13.5 Hz, 1H), 3.82-3.76 (m, 1H), 3.00 (d, benzo[d]imidazole- J = 11.0 Hz, 1H), 2.87 (t, J = 7.6 Hz, 1H), 6-carboxylic acid 2.78-2.67 (m, 1H), 2.47-2.39 (m, 1H), 2.28-2.12 (m, 2H), 1.76-1.74 (m, 4H).

2. Preparation Example B

[0245] ##STR00052##

(1) Synthesis of Example 11: 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-fluorocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

1) Synthesis of methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-fluorocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0246] Intermediate 3 (0.3 mmol), intermediate 10 (89 mg), and potassium carbonate (124 mg, 0.9 mmol) were dissolved in CH.sub.3CN (3.0 mL) in a round bottom flask, and the mixture was stirred at 80° C. or 4 hours. The mixture was cooled to room temperature and filtered through a celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a hexane/ethyl to obtain methyl 2-((4-(3-((4-cyano-2-fluorobenzyl)oxy)phenyl)piperazin-1-yl)methyl)-1-((1-fluorocyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (93 mg, 57%) as a white solid. LC-MS(ES.sup.+): 572 (M+H).sup.+

2) Synthesis of the Final Compound

[0247] The compound (60 mg) obtained in the step 1) was dissolved in 1,4-dioxane/water (4:1, 2.5 mL). After 1 N NaOH aqueous solution (0.2 mL) was added dropwise, the mixture was stirred at room temperature for 24 hours. The mixture was neutralized with 1 N HCl aqueous solution. Then, the mixture was extracted with DCM/MeOH 5% solution. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH (12 g SiO.sub.2, 5% methanol in DCM.fwdarw.10% methanol in DCM) to obtain the final compound (25 mg, 46%) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.82 (m, 1H), 8.29 (s, 1H), 7.91 (d, J=10.4 Hz, 1H), 7.83-7.80 (m, 1H), 7.77-7.73 (m, 2H), 7.70-7.64 (m, 1H), 7.14-7.09 (m, 1H), 6.57-6.55 (m, 2H), 6.47-6.45 (m, 1H), 5.20 (s, 2H), 4.99 (d, J=22.0 Hz, 2H), 3.87 (s, 2H), 3.13 (m, 4H), 2.60 (s, 4H), 1.07-1.02 (m, 4H); LC-MS(ES.sup.+): 556 (M+H).sup.+

(2) Synthesis of Examples 12 to 17

[0248] By using procedures identical or analogous to the procedure to prepare the compound of Example 11, the compounds of Examples 12 to 17 in Table 3 below were prepared from appropriate starting materials which are available commercially or may be prepared by methods known in the art. The compounds were purified using methods well known to those skilled in the art, which may include silica gel chromatography, HPLC, or recrystallization. The final compounds could be isolated as neutrals or as acid addition or base addition salts. The names, NMR data, and LC-MS data of the compounds of Examples 12-17 are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Intermediate Intermediate LC-MS Example A B data No. No. No. Compound name NMR data (ES+) 12 11 18 (S)-2-((4-(6- .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.84 (s, 1H), 8.21 (s, 541 (5-cyanopyridin- 1H), 8.05 (dd, J = 8.4, 1.2 Hz, 1H), 7.96 (dd, J = 8.0, (M + H).sup.+ 2-yl)methoxy) 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.68 (d, 7 = 3.6 pyrazin-2- Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 5.48 (s, 2H), 5.30 (s, yl)piperazin-1- 2H), 5.24-5.22 (m, 1H), 4.71-4.62 (m, 3H), 4.39-4.36 yl)methyl)-1- (m, 1H), 4.10-3.95 (m, 3H), 3.48 (s, 4H), 2.79-2.68 (m, (oxetan-2- 1H), 2.63 (s, 4H), 2.47-2.44 (m, 1H), 2.04 (s, 3H), 1.31- ylmethyl)-1H- 1.23 (m, 3H), 0.89-0.85 (m, 1H). benzo[d]imida zole-6- carboxylic acid 13 12 9 (S)-2-((4-(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 9.04 (brs, 1H), 8.35 540 (5-cyanopyridin- (dd, J = 8.2, 2.2 Hz, 1H), 8.03 (d, J = 8.0Hz, 1H), 7.96 (M + H).sup.+ 2-yl)methoxy) (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.11 (t, J = phenyl)piperazin- 8.2 Hz, 1H), 6.58-6.54 (m, 2H), 6.44 (dd, J = 8.0, 2.0 1-yl)methyl)- Hz, 1H), 5.25 (s, 2H), 5.19-5.17 (m, 1H), 4.78 (brs, 3-(oxetane-2 - 2H), 4.48-4.45 (m, 1H), 4.28-4.25 (m, 1H), 3.94 (q, J = yl-methyl)-3H- 14.0 Hz, 2H), 3.13 (s, 4H), 2.65-2.60 (m, 5H), 2.51- imidazo[4,5- 2.45 (m, 1H). b]pyridine-5- carboxylic acid 14 12 18 (S)-2-((4-(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.83 (bs, 1H), 9.04 539 (5-cyanopyridin- (dd, J = 2.0, 0.8 Hz, 1H), 8.36 (dd, J = 6.0, 1.6 Hz, 1H), (M + H).sup.+ 2-yl)methoxy) 8.28 (d, J = 1.2 Hz, 1H), 7.81 (dd, J = 8.4, 1.6 Hz, 1H), phenyl)piperazin- 7.67 (dd, J = 18.0, 8.0 Hz, 2H), 7.11 (t, J =8.0 Hz, 1H), 1-yl)methyl)- 6.58-6.54 (m, 2H), 6.43 (dd, J = 8.0, 2.0 Hz, 1H), 5.25 1-(oxetane-2 - (s, 1H), 5.12-5.07 (m, 1H), 4.79 (dd, J = 15.2, 7.4 Hz, ylmethyl)-1H- 1H), 4.65 (dd, J = 15.2, 2.6 Hz, 1H), 4.51-4.46 (m, 1H), benzo[d] 4.41-4.35 (m, 1H), 4.00 (d, J = 13.5 Hz, 1H), 3.81 (d, J = imidazole-6- 13.5 Hz, 1H), 3.13-3.12 (m, 1H), 2.74-2.67 (m, 1H), carboxylic acid 2,65-2.56 (m, 4H), 2.46-2.35 (m, 2H), 2.47-2.41 (m, 1H), 1.89-1.82 (m, 4H). 15 14 19 1-(oxazol-2- .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.60 (d, J = 4.0 Hz, 526 ylmethyl)-2- 1H), 8.29 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.80 (d, J = (M + H).sup.+ ((4-(6-(pyridin-2- 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.47 ylmethoxy) (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H), 7.22-7.19 pyridin-2- (m, 1H), 7.08 (s, 1H), 6.21 (d, J = 8.0 Hz, 1H), 6.13 (d, yl)piperazin-1- J = 8.0 Hz, 1H), 5.81 (s, 2H), 5.48 (s, 2H), 3.99 (s, 2H), yl)methyl)-1H- 3.49 (s, 1H), 3.37 (s, 4H), 2.59 (s, 4H). benzo[d] imidazole-6- carboxylic acid 16 6 18 (S)-2-((4-(6- .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.50 (d, J = 1.2 Hz, 567 ((5-chloro-3- 1H), 8.28 (s, 1H), 8.10 (dd, J = 9.8, 1.8 Hz, 1H), 7.82 (M + H).sup.+ fluoropyridin- (dd, 7 = 8.4, 1.2 Hz, 1H), 7.65 (d, 7 = 8.4 Hz, 1H), 7.45 2-yl)methoxy) (t, 7 = 8.0 Hz, 1H), 6.32 (d, 7= 8.0 Hz, 1H), 6.09 (d, 7 = pyridin-2- 7.6 Hz, 1H), 5.38 (d,7 = 1.6 Hz, 2H), 5.11 (dd, 7 = yl)piperazin-1- 7.2, 2.4 Hz, 1H), 4.80 (dd, 7 = 15.4, 7.4 Hz, 1H), 4.65 yl)methyl)-1- (dd, 7 = 15.0, 2.6 Hz, 1H), 4.51-4.46 (m, 1H), 4.41-4.37 (oxetan-2- (m, 1H), 3.97 (d, 7 = 13.2 Hz, 1H), 3.80 (d, 7 = ylmethyl)-1H- 13.6 Hz, 1H), 3.41 (t, 7 = 4.6 Hz, 4H), 2.74-2.68 (m, benzo[d] 1H), 2.56-2.48 (m, 4H), 2.46-2.43 (m, 1H). imidazole-6- carboxylic acid 17 15 18 (S)-2-((4-(6- .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.78 (brs, 1H), 549 (5-chloropyridin- 8.58 (dd, J = 2.5 Hz, 1H), 8.27 (d, J = 1.0 Hz, 1H), 7.91 (M + H).sup.+ 2-yl)methoxy) (dd, 7 = 8.4, 2.5 Hz, 1H), 7.81 (dd, 7 = 8.4, 1.5 Hz, 1H), pyridin-2- 7.65 (d, 7 = 8.4 Hz , 1H), 7.50-7.43 (m, 2H), 6.32 (d, 7 = yl)piperazin-1- 8.1 Hz, 1H), 6.15 (d, 7 = 7.8 Hz, 1H), 5.34 (s, 2H), yl)methyl)-1- 5.11-5.08 (m, 1H), 4.79 (dd, 7 = 15.3, 7.4 Hz, 1H), 4.65 (oxetan-2- (dd, 7 = 15.2, 2.5 Hz, 1H), 4.51-4.46 (m, 1H), 4.0-4.35 ylmethyl)-1H- (m, 1H), 3.96 (d, 7 = 13.6 Hz, 1H), 3.78 (d, 7 = 13.6 Hz, benzo[d] 1H), 3.41-3.36 (m, 4H), 2.74-2.66 (m, 1H), 2.48-2.38 imidazole-6- (m, 4H). carboxylic acid

3. Preparation Example C

[0249] ##STR00053##

(1) Synthesis of Example 18: 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

1) Synthesis of methyl 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0250] Intermediate 5 (130 mg), intermediate 19 (147 mg), and potassium carbonate (332 mg) were dissolved in CH.sub.3CN (1.5 mL) in a round bottom flask, and the mixture was stirred at 50° C. for 4 hours. After purified water was added, the mixture was cooled to room temperature and stirred at the same temperature for 2 hours. The resulting solid was filtered, washed with purified water: CH.sub.3CN (2:1), and was dried to obtain methyl 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3-ylmethoxy)pyridin-2-yl)piperazin-1-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (52 mg, 20%). LC-MS(ES.sup.+): 540 (M+H).sup.+

2) Synthesis of the Final Compound

[0251] The compound (45 mg) obtained in the step 1) was dissolved in 1,2-dichloroethane (3.0 mL). After Me.sub.3SnOH (49 mg) was added, the mixture was stirred at 80° C. for 6 days. The mixture was concentrated and extracted with EA. The resulting organic layer was washed with aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with DCM/MeOH/AcOH to obtain the final compound (8 mg, 18%) as a brown solid. .sup.1H NMR (400 MHz, MeOD): δ 8.60 (d, J=1.8 Hz, 1H), 8.46 (dd, J=4.8, 0.8 Hz, 1H), 8.27 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.91-7.89 (m, 2H), 7.72 (d, J=8.4 Hz, 1H), 7.46-7.42 (m, 2H), 7.14 (s, 1H), 6.25 (d, J=8.0 Hz, 1H), 6.14 (d, J=7.6 Hz, 1H), 5.38 (s, 2H), 3.98 (s, 2H), 3.37-3.34 (m, 4H), 2.55 (t, J=4.8 Hz, 4H); LC-MS(ES.sup.+): 526 (M+H).sup.+

[0252] The chemical structures and names of the compounds of Examples 1 to 18 prepared using the Preparation Examples A, B and C are shown in Table 4 below.

TABLE-US-00004 TABLE 4 Examples Structure Compound names  1 [00054] 2-(((S)-4-(6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)-2-methylpiperazin- 1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)- 1H-benzo[d]imidazole-6-carboxylic acid  2 [00055] (S)-2-((4-(6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid  3 [00056] (S)-2-((4-(3-((4-cyano-2- fluorobenzyl)oxy)phenyl)piperidin-1- yl)methyl)-3-(oxetan-2-yl-methyl)-3H- imidazo[4,5-b]pyridine-5-carboxylic acid  4 [00057] 2-(((S)-4-(6-((4-cyano-2- fluorobenzyl)oxy)pyrazin-2-yl)-2- methylpiperazin-1-yl)methyl)-1-(((S)-oxetan- 2-yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid  5 [00058] (S)-2-((4-(6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)piperazin-1- yl)methyl)-3-(oxetane-2-ylmethyl)-3H- imidazo[4,5-b]pyridine-5-carboxylic acid  6 [00059] 2-(((S)-4-(6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)-2-methylpiperazin- 1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H- imidazo[4,5-b]pyridine-5-carboxylic acid  7 [00060] 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-4- ylmethoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid  8 [00061] (S)-2-((4-(6-((5-chloro-3-fluoropyridin-2- yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid  9 [00062] (S)-2-((4-(6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)piperidin-1- yl)methyl)-1-(oxetane-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid 10 [00063] (S)-2-((4-(3-((5-chloro-3-fluoropyridin-2- yl)methoxy)phenyl)piperidin-1-yl)methyl)-1- (oxetane-2-ylmethyl)-1H-benzo[d]imidazole- 6-carboxylic acid 11 [00064] 2-((4-(3-((4-cyano-2- fluorobenzyl)oxy)phenyl)piperazin-1- yl)methyl)-1-((1-fluorocyclopropyl)methyl)- 1H-benzo[d]imidazole-6-carboxylic acid 12 [00065] (S)-2-((4-(6-((5-cyanopyridin-2- yl)methoxy)pyrazin-2-yl)piperazin-1- yl)methyl)-1-(oxetane-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid 13 [00066] (S)-2-((4-(3-((5-cyanopyridin-2- yl)methoxy)phenyl)piperazin-1-yl)methyl)-3- (oxetan-2-ylmethyl)- 3H-imidazo[4,5- b]pyridine-5-carboxylic acid 14 [00067] (S)-2-((4-(3-((5-cyanopyridin-2- yl)methoxy)phenyl)piperazin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6- carboxylic acid 15 [00068] 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-2- ylmethoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid 16 [00069] (S)-2-((4-(6-((5-chloro-3-fluoropyridin-2- yl)methoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid 17 [00070] (S)-2-((4-(6-((5-chloropyridin-2- yl)methoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1-(oxetane-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid 18 [00071] 1-(oxazol-2-ylmethyl)-2-((4-(6-(pyridin-3- ylmethoxy)pyridin-2-yl)piperazin-1- yl)methyl)-1H-benzo[d]imidazole-6- carboxylic acid

EXPERIMENTAL EXAMPLES

1. Experimental Example 1: cAMP Assay

[0253] A cAMP assay test was performed according to a method optimized based on a protocol provided by a cAMP assay kit manufacturer (CISBIO). GLP-1 receptor CHO-K1 cells were dispensed into 96-well plates for cAMP measurement (low volume, white) at 6×10.sup.3 cells/well/5 mL. As a control substance, 5 mL of Exendin-4 at the concentration of 0, 1, 10, 100, 1000, and 10000 pM was treated to each of the wells of one of the plates. 5 mL of the compounds according to the Examples 1, 2, 3, 4, 5, 10, 11, 13, 14, 16 and 17 at the concentration of 0, 1, 10, 100, 1000, 10000 nM was treated to each of the wells of the other plates, respectively. The cells were incubated at room temperature for 7 minutes. A cAMP-d.sub.2 conjugate reagent was prepared by mixing a cAMP conjugate with an elution buffer at a ratio of 1:4. An anti-cAMP cryptate conjugate reagent was prepared by mixing a cGMP conjugate with an elution buffer at a ratio of 1:4. Then, 5 mL of the cAMP-d.sub.2 conjugate reagent was added to each of the wells. Subsequently, 5 mL of the anti-cAMP cryptate conjugate reagent was added to each of the wells. After incubation of the cells at room temperature for 1 hour, HTRF signals at wavelengths of 665 nm and 620 nm of the culture were measured using a FlexStaton 3 (Molecular Devices) instrument. The ratio of 665/620 was calculated from the measured values at 665 nm and 620 nm with regard to Exendin-4 and the compounds of the Examples, respectively. By converting the ratio with regard to Exendin-4 to 100%, Emax values of the compounds of the Examples were calculated as the cAMP stimulation ratio of the compounds. The results are shown in Table 5 below. In the table, ++means that EC.sub.50 is smaller than 50 nM, and +means that EC.sub.50 is 50˜100 nM.

TABLE-US-00005 TABLE 5 Example No. EC.sub.50 (nM) E.sub.max (%) 1 ++ 103.79 2 ++ 107.81 3 ++ 108.19 4 ++ 108.76 5 + 110.68 10 + 96.41 11 ++ 96.45 13 ++ 128.05 14 ++ 91.37 16 ++ 101.90 17 ++ 100.52

2. Experimental Example 2: Analysis of Intravenous Glucose Tolerance Via Intravenous Administration

[0254] (1) Sample Preparation

[0255] Before the intravenous glucose tolerance test (ivGTT) was performed, monkeys to be used in the test were fasted for 16 hours. After the fasting, fasting blood sugar was measured on the day of the test, and the monkeys were grouped to minimize blood sugar deviation. Each of the monkeys was fixed on a correction chair and anesthetized. A tube catheter was inserted into a saphenous vein of the monkey immediately before glucose administration (0 minute), and the test substance (1 mg/mL/kg) was administered intravenously. After the drug administration, glucose (0.25 g/kg, 50% dextrose solution 0.5 mL/kg) was intravenously administered through the tube catheter inserted into the vein. Blood was collected from the femoral vein immediately before the glucose administration (0 minute) and on 15, 30, 40, 50, 60, and 120 minutes after the glucose administration, and then plasma was separated via centrifugation within 30 minutes after the blood collection. The separated plasma samples were stored in a frozen state until insulin analysis.

[0256] (2) Insulin Analysis Method

[0257] The frozen plasma samples were slowly thawed on ice. An ELISA test was performed according to a protocol provided with a Monkey insulin ELISA kit (LSBio, Cat No. LS-F10306). An insulin concentration was calculated by drawing a standard curve using the absorbance of the insulin standard and applying the absorbance of each measured sample thereto. The analysis results with regard to the compounds of some of the Examples are shown in Table 6 below. In the table, ++means that a maximum insulin concentration is greater than 250 IU/mL, and +means that a maximum insulin concentration is 200-250 IU/mL.

TABLE-US-00006 TABLE 6 Monkey ivGTT (iv) insulin.sub.max Example No. (IU/mL) 1 ++ 3 ++ 4 ++ 6 ++ 13 + 14 + 17 +

[0258] The result of the intravenous glucose tolerance analysis shows that the compounds according to the present disclosure exhibited insulin secretion efficacy.

3. Experimental Example 3: Analysis of Intravenous Glucose Tolerance Via Oral Administration

[0259] (1) Preparation for Experiment

[0260] Before performing the ivGTT, the monkeys to be used in the test were fasted for 16 hours. After the fasting, fasting blood sugar was measured on the day of the test, and then the monkeys were grouped to minimize blood sugar deviation. On 60 minutes before glucose administration (−60 minutes), each of the monkeys was fixed on a correction chair, and the test substance (50 mg/5 mL/kg) was administered orally using a catheter for oral administration. The monkey fixed on the correction chair was anesthetized, and glucose (0.25 g/kg, 50% dextrose solution 0.5 mL/kg) was intravenously administered through a tube catheter inserted into the vein. Blood was collected from the femoral vein immediately before the glucose administration (0 minute) and on 15, 30, 40, 50, 60, and 120 minutes after the glucose administration, and plasma was separated via centrifugation within 30 minutes after the blood collection. The separated plasma samples were stored in a frozen state until insulin analysis.

[0261] (2) Insulin Analysis Method

[0262] The frozen plasma samples were slowly thawed on ice. An ELISA test was performed according to a protocol provided with a Monkey insulin ELISA kit (LSBio, Cat No. LS-F10306). An insulin concentration was calculated by drawing a standard curve using the absorbance of the insulin standard and applying the absorbance of each measured sample thereto. The analysis results with regard to the compounds of some of the Examples are shown in Table 7 below. In the table, ++means that a maximum insulin concentration is greater than 100 IU/mL, and +means that a maximum insulin concentration is 50-100 IU/mL.

TABLE-US-00007 TABLE 7 Monkey ivGTT (po) insulin.sub.max Example No. (IU/mL) 1 + 2 ++ 3 ++ 4 ++ 6 + 11 ++

[0263] The compounds according to the present disclosure exhibited excellent insulin secretion efficacy also in the oral administration mode.

4. Experimental Example 4: hERG Analysis

[0264] The inhibition of activity of hERG (human ether-a-go-go related gene) potassium channel by the compounds was evaluated by using an automatic whole-cell patch clamp system (QPatch 48 HT, Sophion Bioscience) that can directly measure the flow of ions through the potassium channel in cells. A CHO-K1 cell line stably expressing human hERG cDNA (Kv11.1, KCNH2) was used. The composition of the intracellular solution (mM) used for the analysis is 70 KF, 60 KCl, 15 NaCl, 5 HEPES, 5 EGTA, 5 MgATP, pH 7.3 by KOH. The composition of the extracellular solution (mM) used for the analysis is 137 NaCl, 4 KCl, 1 MgCl.sub.2, 1.8 CaCl.sub.2), 10 HEPES, 10 glucose, pH 7.35 by NaOH.

[0265] The hERG-expressing CHO-K1 cell line was treated with each compound at five concentrations (1, 3, 10, 30 and 100 μM), and incubated with each test concentration for 5 minutes in duplicate. All experiments were conducted at room temperature. Change in current amplitude through the hERG channel was recorded every 8 seconds.

[0266] Stock solution for each compound is prepared in DMSO at 300× the final assay concentrations, and stored at −20° C. until the day of assay. On the day of the experiment, the stock was diluted into an extracellular solution to make final treatment concentration. To ensure the validity of the test system, a positive control substance E-4031 (0.003 to 0.3 μM) was used for each test. A final concentration of 0.33% DMSO is maintained for each concentration of the assay compounds and controls.

[0267] The change in hERG current before and after treatment with the test substance was recorded using the automatic whole cell patch clamp, and the hERG inhibition percentage (%) was calculated based on the control group.

[0268] IC.sub.50 (the concentration of the compound at which 50% of channel inhibition was observed) was calculated using GraphPad Prism based on an average value of the hERG inhibition percentages (%) based on concentrations of each substance. In this calculation, an inhibitor dose-response curve analyzed by using a curve fitting program that uses a 4-parameter logistic dose response equation was used. Thus, a potential risk of QT prolongation depending on the dose of each substance was predicted. The analysis results with regard to the compounds of some of the Examples are shown in following Table 8. Example 4A-01 described in WO2018109607 of Pfizer was used as a control substance.

TABLE-US-00008 TABLE 8 Example No. IC.sub.50 (μM) Control substance 4.3 1 >100 2 >100 3 34.6 4 55.8 6 >100 11 18.5 13 >100 14 >100 16 >100 17 >100

[0269] The result of the experiment that the hERG inhibition percentage of the compounds according to the present disclosure is lower than that of the control substance shows that the safety of the compounds according to the present disclosure is improved.