GLP-1 Receptor Agonist and Use Thereof

Abstract

The present invention provides novel compounds of chemical formula 1, optical isomers of the compounds, or a pharmaceutically acceptable salts of the compounds, or the optical isomers. The compounds, isomers, and salts exhibits excellent activity as GLP-1 receptor agonists. Particularly, they, as GLP-1 receptor agonists, exhibit excellent glucose tolerance, thus having a great potential to be used therapeutic agents for metabolic diseases. In addition, they exhibits excellent pharmacological safety for cardiovascular systems.

Claims

1. A compound represented by the following Chemical Formula 1, an optical isomer of the compound, or a pharmaceutically acceptable salt of the compound or the optical isomer: ##STR00134## wherein R.sub.1 is —C(═O)R.sub.a; R.sub.a is —OH or —O—(C.sub.1-C.sub.4 alkyl); Y is —CH— or —N—; R.sub.2 is one selected from the group consisting of substituted or unsubstituted C.sub.6 to C.sub.12 aryl, substituted or unsubstituted C.sub.5 to C.sub.12 heteroaryl, substituted or unsubstituted C.sub.3 to C.sub.8 heterocycloalkyl, and substituted or unsubstituted C.sub.3 to C.sub.8 cycloalkyl, where the substituted aryl, heteroaryl, heterocycloalkyl, and cycloalkyl include at least one substitution with —OH, —(C.sub.1-C.sub.4 alkyl), halogen, or —CN; A.sub.1 is ##STR00135## is substituted or unsubstituted C.sub.3 to C.sub.8 heterocycloalkyl containing at least one nitrogen, substituted or unsubstituted C.sub.3 to C.sub.12 spiroheterocycloalkyl containing at least one nitrogen, or substituted or unsubstituted C.sub.3 to C.sub.12 bridged heterobicycloalkyl containing at least one nitrogen, where the substituted heterocycloalkyl, spiroheterocycloalkyl, and heterobicycloalkyl include at least one substitution with —OH, —(C.sub.1-C.sub.4 alkyl), halogen, or —CN; R′ is hydrogen or —(C.sub.1-C.sub.4 alkyl); X is —CR.sub.b— or —N—; R.sub.b is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; W.sub.1 is —CR.sub.c— or —N—, where R.sub.c is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; W.sub.2 is —CR.sub.d— or —N—, where R.sub.d is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; W.sub.3 is —CR.sub.e— or —N—, where R.sub.e is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; J is —O— or —NR″—; R″ is hydrogen or —(C.sub.1-C.sub.4 alkyl); Z.sub.1 is —CR.sub.f— or —N—, where R.sub.f is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; Z.sub.2 is —CR.sub.g— or —N—, where R.sub.g is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; Z.sub.3 is —CR.sub.h— or —N—, where R.sub.h is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; Z.sub.4 is —CR.sub.i— or —N—, where R.sub.i is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl; and R.sub.j is one selected from the group consisting of —H, halogen, —CN, —OH, —O—(C.sub.1-C.sub.4 alkyl), —NH.sub.2, —NO.sub.2, and —C.sub.1-C.sub.4 haloalkyl.

2. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein one of Z.sub.1 to Z.sub.4 is —N—.

3. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein Z.sub.1 is —CR.sub.f—, Z.sub.2 is —CR.sub.g—, Z.sub.3 is —CR.sub.h—, and Z.sub.4 is —CR.sub.i—.

4. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein R.sub.j is halogen or —CN.

5. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 4, wherein R.sub.g is one selected from the group consisting of —H, halogen and —CN.

6. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein J is —O—.

7. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein A.sub.1 is ##STR00136##

8. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 7, wherein ##STR00137## is substituted or unsubstituted C.sub.3 to C.sub.8 heterocycloalkyl containing at least one nitrogen, where the substituted heterocycloalkyl includes at least one substitution with —OH, —(C.sub.1-C.sub.4 alkyl), halogen, or —CN.

9. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 7, wherein ##STR00138## is one selected from the group consisting of substituted or unsubstituted ##STR00139## substituted or unsubstituted ##STR00140## and substituted or unsubstituted ##STR00141## where the substituted ##STR00142## include at least one substitution with —OH, —(C.sub.1-C.sub.4 alkyl), halogen, or —CN.

10. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein R.sub.2 is substituted or unsubstituted C.sub.3 to C.sub.5 heterocycloalkyl or substituted or unsubstituted C.sub.3 to C.sub.5 cycloalkyl, where the substituted heterocycloalkyl and cycloalkyl include at least one substitution with —OH, —(C.sub.1-C.sub.4 alkyl), halogen, or —CN.

11. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 10, wherein R.sub.2 is substituted or unsubstituted ##STR00143## where the substituted ##STR00144## includes at least one substitution with —OH, —(C.sub.1-C.sub.4 alkyl), halogen, or —CN.

12. The compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, wherein the compound represented by the Chemical Formula 1 is one compound selected from the group consisting of the following compounds: (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((4-((4-cyano-2-fluorobenzyl)oxy)-5-fluoropyrimidin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((6-((4-chloro-2-fluorobenzyl)amino)pyridin-2-yl)oxy)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((3-((5-cyanopyridin-2-yl)methoxy)-4-fluorophenyl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((3-((5-chloropyridin-2-yl)methoxy)phenyl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((3-((5-cyanopyridin-2-yl)methoxy)-4-fluorophenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((3-((5-cyanopyridin-2-yl)methoxy)-4-fluorophenyl)amino)pyrrolidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-(((R)-3-((3-((4-cyano-2-fluorobenzyl)oxy)-4-fluorophenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((3-((4-cyano-2-fluorobenzyl)oxy)-4-fluorophenyl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-3-oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; (S)-2-((3-(((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)methyl)azetidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((6-((4-chloro-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; (S)-2-((4-((4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((2-(((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)methyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((S)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((4-((4-cyano-2-fluorobenzyl)oxy-5-fluoropyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((2-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-4-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methyl)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)amino)pyrrolidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; (S)-2-((4-((3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((3-((4-chloro-2-fluorobenzyl)oxy)-4-fluorophenyl)amino)piperidin-1-yl)methyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 2-(((R)-3-((4-((4-chloro-2-fluorobenzyl)oxy-5-fluoropyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((6-((4-chloro-2-fluorobenzyl)oxy)pyrazin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((2-((4-chloro-2-fluorobenzyl)oxy-5-fluoropyrimidin-4-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((3-((5-chloropyridin-2-yl)methoxy)phenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyrazin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)(methyl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-((3-((6-((4-chloro2-fluorobenzyl)amino)pyridin-2-yl)oxy)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((4-((6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)amino)piperidin-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)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2(((R)-3-((6-((5-cyanopyridin-2-yl)methoxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; (S)-2-((3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)azetidin-1-yl)methyl)-1-(oxetan-2 -ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2-(((R)-3-((4-((4-cyano-2-fluorobenzyl)oxy)pyrimidin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; and 2(((R)-3-((6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

13. (canceled)

14. A pharmaceutical composition comprising the compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1, and a pharmaceutically acceptable carrier.

15. (canceled)

16. A method for treating metabolic diseases, comprising administering to a subject in need the compound, the optical isomer, or the pharmaceutically acceptable salt of claim 1.

17. (canceled)

18. (canceled)

19. (canceled)

20. (canceled)

21. The method of claim 16, 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, kidney disease, diabetic retinopathy, adipocyte dysfunction, visceral fat accumulation, sleep apnea, obesity, eating disorders, dyslipidemia, hyperinsulinemia, non-alcoholic fatty liver disease(NAFLD), cardiovascular disease, atherosclerosis, peripheral vascular disease, hypertension, congestive heart failure, myocardial infarction, stroke, hemorrhagic stroke, ischemic stroke, traumatic brain injury, pulmonary hypertension, restenosis after angioplasty, intermittent claudication, postprandial lipidemia, 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, impaired glucose metabolism, symptoms of impaired fasting blood sugar, hyperuricemia, gout, erectile dysfunction, psoriasis, foot ulcers, ulcerative colitis, hyper-spore 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.

22. The method of claim 21, whereint 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.

Description

SYNTHESIS EXAMPLES

Synthesis Example 1: Synthesis of Intermediates 1 to 39

[0203] Exemplary methods of preparing intermediates 1 to 39 are described in detail below. Using the Preparation Methods 1 to 7 described below, those skilled in the art may prepare the compounds listed as intermediates 1 to 39 from appropriate starting materials which are available commercially or may be prepared by methods known in the art.

[0204] 1. Preparation Method 1

##STR00046##

(1) Synthesis of Intermediate 1: 3-fluoro-4-((3-(piperidin-4-ylamino)phenoxy)methyl)benzonitrile trifluoroacetic acid salt

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

[0205] 4-(Bromomethyl)-3-fluorobenzonitrile (10 g), 3-bromophenol (5.46 mL) and potassium carbonate (9.68 g) were dissolved in CH.sub.3CN (100 mL), which was stirred at room temperature for 16 hours. After completion of the reaction as indicated by TLC, 1N NaOH was added and the mixture was extracted twice with ethyl acetate to separate the compound into an organic layer. The resulting organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. Then, the resulting product was separated by silica gel column chromatography eluting with hexane/ethyl acetate, followed by solidification under DCM/hexane conditions to obtain the target compound (11.88 g) as a white solid at a yield of 83%. LC-MS(ES.sup.+): 307 (M+H).sup.+.

2) Synthesis of tert-butyl 4-((3-((4-cyano-2-fluorobenzyl)oxy)phenyl)amino)piperidine-1-carboxylate

[0206] The compound (674 mg) synthesized in the step 1), tert-butyl 4-aminopiperidine-1-carboxylate (529 mg), Pd.sub.2(dba).sub.3 (201 mg), NaOtBu (423 mg), and DavePhos (173 mg) were placed in a round bottom flask and stirred in toluene (4 mL). The air inside the reactor was replaced with nitrogen using a nitrogen balloon. Then, the resulting mixture was heated to 120° C. under N.sub.2 atmosphere and stirred for one day. After completion of the reaction as indicated by TLC, the solution was diluted with ethyl acetate and inorganic substances were filtered under reduced pressure on a Celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure, which was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (177 mg) as a yellow syrup at a yield of 19%. LC-MS(ES.sup.+): 426 (M+H).sup.+.

3) Synthesis of 3-fluoro-4-((3-(piperidin-4-ylamino)phenoxy)methyl)benzonitrile trifluoroacetic acid salt

[0207] The compound (177 mg) synthesized in the step 2) was placed in a round bottom flask, dissolved in DCM (4 mL) and stirred. TFA (4 mL) was added to the mixture, which was stirred at room temperature for 30 minutes. After completion of the reaction as indicated by TLC, the resulting product was filtered under reduced pressure and solidified by adding ether to obtain the target compound. LC-MS(ES.sup.+): 326 (M+H).sup.+.

2. Preparation Method 2

[0208] ##STR00047##

(1) Synthesis of Intermediate 2: 3-fluoro-4-(((6-(piperidin-4-ylamino)pyridin-2-yl)oxy)methyl)benzonitrile trifluoroacetic acid salt

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

[0209] 4-Cyano-2-fluorobenzyl alcohol (3.81 g) was added dropwise at 15° C. to a solution of potassium tert-butoxide (4.24 g) in THF (54 mL) and the mixture was stirred for 45 minutes. 2,4-Dichloropyridine (3.1 g) was added dropwise to the reaction mixture, and the resulting mixture was stirred at 15° C. for 18 hours. The reaction was quenched by adding aqueous NH.sub.4Cl to the reaction mixture. Then, ethyl acetate was added and the mixture was stirred for 15 minutes. The resulting mixture was filtered using a Celite pad to obtain a filtrate. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (4.85 g) as a white solid at a yield of 88%. LC-MS(ES.sup.+): 263 (M+H).sup.+.

2) Synthesis of tert-butyl 3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridine-2-yl)amino)piperidine-1-carboxylate

[0210] The compound (300.0 mg) synthesized in the step 1), 4-amino-N-Boc-piperidine (274.5 mg), Pd.sub.2(dba).sub.3 (52.3 mg), BINAP (71.1 mg), and Cs.sub.2CO.sub.3 (558.2 mg) were dissolved in toluene (3.0 mL). The resulting mixture was stirred at 100° C. for 16 hours under nitrogen atmosphere. The reaction product was cooled to room temperature and filtered through a Celite pad to obtain a filtrate, which was concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (228.2 mg) as a pale yellow solid at a yield of 34.2%. LC-MS(ES.sup.+): 427 (M+H).sup.+.

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

[0211] The compound (220.0 mg) synthesized in the step 2) was dissolved in DCM (3.0 mL). TFA (5.0 mL) was added dropwise and the resulting mixture was stirred at room temperature for 1 hour. The reaction product was concentrated, then isopropyl ether was slowly added dropwise. The resulting product was filtered to obtain the target compound (258 mg) as a bright pale yellow solid at a yield of 95.9%. LC-MS(ES.sup.+): 327 (M+H).sup.+.

3. Preparation Method 3

[0212] ##STR00048##

(1) Synthesis of Intermediate 3: 3-fluoro-4-(((5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)oxy)methyl)benzonitrile

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

[0213] To a stirred solution of 2,4-dichloropyridine (1.0 g) in toluene (50 mL), was added sodium tert-butoxide (724 mg) at 0° C. and the reaction mixture was stirred for 30 minutes. 4-cyano-2-fluorobenzyl alcohol (760 mg) was added dropwise to the reaction mixture, which was stirred at room temperature for 15 hours. The reaction was quenched by adding aqueous NH.sub.4Cl to the reaction mixture, and the resulting mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (900 mg) as a white solid at a yield of 64%. LC-MS(ES.sup.+): 263 (M+H).sup.+

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

[0214] The compound (200 mg) synthesized in the step 1) was placed in a round bottom flask and dissolved in DMSO (1.4 mL). Then, triethylamine (0.25 mL) and 4-amino-1-Boc-piperidine (285 mg) were added and the resulting mixture was stirred at room temperature. After the air inside the reactor was replaced with nitrogen using a nitrogen balloon, the resulting mixture was stirred at 120° C. for 1 hour. The reaction was quenched by adding distilled water and the resulting mixture was extracted twice with ethyl acetate. The inorganic substances were filtered on a Celite pad under reduced pressure to obtain a filtrate, which was concentrated under reduced pressure, then subjected to silica gel column chromatography eluting with hexane/acetone to obtain the target compound (55 mg) at a yield of 17%. LC-MS(ES.sup.+): 427 (M+H).sup.+

3) Synthesis of 3-fluoro-4-(((5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)oxy)methyl)benzonitrile

[0215] To a stirred solution of the compound (110 mg) synthesized in the step 2) in DCM (1.2 mL), was added TFA (0.6 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by TLC, the mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with saturated aqueous solution of NaHCO.sub.3, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (85 mg) at a yield of 99%. LC-MS(ES.sup.+): 327 (M+H).sup.+

4. Preparation Method 4

[0216] ##STR00049##

(1) Synthesis of Intermediate 4: 3-fluoro-4-(((4-(piperidin-4-ylamino)pyrimidin-2-yl)oxy)methyl)benzonitrile

1) Synthesis of tert-butyl 4-((2-chloropyrimidin-4-yl)amino)piperidine-1-carboxylate

[0217] To a stirred solution of 2,4-dichloropyridine (2.0 g) in DMF (22 mL), triethylamine (2.8 mL) and 4-amino-1-Boc-piperidine (2.9 g) were added at room temperature, which was stirred for 15 hours. The reaction was quenched by adding distilled water to the reaction mixture and the resulting mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (2.6 g) as a white solid at a yield of 62%. LC-MS(ES.sup.+): 313 (M+H).sup.+

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

[0218] The compound (1 g) synthesized in the step 1) was dissolved in THF (16 mL) and sodium hydride (192 mg) was added at room temperature. After stirring at room temperature for 15 minutes, 4-cyano-2-fluorobenzyl alcohol (726 mg) was added and the mixture was stirred at 80° C. for 2 days. After completion of the reaction as indicated by TLC, distilled water was added to terminate the reaction and the resulting mixture was extracted twice with ethyl acetate. The inorganic substances were filtered on a Celite pad under reduced pressure to obtain a filtrate, which was concentrated under reduced pressure, then subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (380 mg) as a white solid at a yield of 28%. LC-MS(ES.sup.+): 428 (M+H).sup.+

3) Synthesis of 3-fluoro-4-(((4-(piperidin-4-ylamino)pyrimidin-2-yl)oxy)methyl)benzonitrile

[0219] The compound (378 mg) synthesized in the step 2) was placed in a round bottom flask, dissolved in DCM (4.4 mL) and stirred. TFA (2.2 mL) was added at room temperature and the resulting mixture was stirred at room temperature for 1.5 hours. After completion of the reaction as indicated by TLC, the mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with saturated aqueous solution of NaHCO.sub.3, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the target compound (140 mg) at a yield of 48%. LC-MS(ES.sup.+): 328 (M+H).sup.+

5. Preparation Method 5

[0220] ##STR00050##

(1) Synthesis of Intermediate 5: 6-((5-chloropyridin-2-yl)methoxy)-N-(piperidin-4-yl)pyridin-2-amine trifluoroacetic acid salt

1) Synthesis of tert-butyl 4-((6-chloropyridin-2-yl)amino)piperidine-1-carboxylate

[0221] 2,6-Dichloropyridine (200 mg), tert-butyl 4-aminopiperidine-1-carboxylate (300 mg), Pd.sub.2(dba).sub.3 (63 mg), Cs.sub.2CO.sub.3 (880 mg), and BINAP (88 mg) were placed in a round bottom flask and stirred in toluene (10 mL). The air inside the reactor was replaced with nitrogen using a nitrogen balloon, then the resulting product was heated to 100° C. under N.sub.2 atmosphere, which was stirred for one day. After completion of the reaction as indicated by TLC, the solution was diluted with ethyl acetate and inorganic substances were filtered under reduced pressure on a Celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure, which was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (295 mg) as a yellow solid at a yield of 70%.

2) Synthesis of tert-butyl 4-((6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)amino)piperidine-1-carboxylate

[0222] The compound (256 mg) synthesized in the step 1), (5-chloropyridin-2-yl)methanol (160 mg), Pd.sub.2(dba).sub.3 (75.1 mg), sodium tert-butoxide (205 mg), and BINAP (76.6 mg) were placed in a round bottom flask and stirred in toluene (10 mL). The air inside the reactor was replaced with nitrogen using a nitrogen balloon, then the resulting product was heated to 100° C. under N.sub.2 atmosphere, which was stirred for one day. After completion of the reaction as indicated by TLC, the solution was diluted with ethyl acetate and inorganic substances were filtered under reduced pressure on a Celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure, which was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (68 mg) as a yellow oil at a yield of 20%.

3) Synthesis of 6-(((5-(chloropyridin-2-yl)methoxy)-N-(piperidin-4-yl)pyridin-2-amine trifluoroacetic acid salt

[0223] To a stirred solution of the compound (68 mg) synthesized in the step 2) in DCM (10 mL), was added TFA (1 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction as indicated by TLC, the mixture was concentrated under reduced pressure to obtain the target compound, which was used in the next reaction without further purification.

6. Preparation Method 6

[0224] ##STR00051##

(1) Synthesis of Intermediate 6: N-(4-chloro-2-fluorobenzyl)-6-(piperidin-4-yloxy)pyridin-2-amine

1) Synthesis of tert-butyl 4-((6-chloropyridin-2-yl)oxy)piperidine-1-carboxylate

[0225] To a stirred solution of 2,4-dichloropyridine (1.0 g) in DMF (33 mL), sodium hydride (810 mg) and tert-butyl-4-hydroxy-1-piperidine carboxylate (2.0 g) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched by adding distilled water to the reaction mixture and the resulting mixture was extracted twice with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (1.3 g) as a transparent oil at a yield of 62%. LC-MS(ES.sup.+): 313 (M+H).sup.+.

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

[0226] The compound (200 mg) synthesized in the step 1), Pd.sub.2(dba).sub.3 (29 mg), BINAP (40 mg), sodium tert-butoxide (105 mg), and (4-chloro-2-fluorophenyl)methanamine (122 mg) were placed in a round bottom flask and stirred in toluene (3.2 mL) at 70° C. for 15 hours. The inorganic substances were filtered on a Celite pad under reduced pressure to obtain a filtrate, which was concentrated under reduced pressure, then subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (245 mg) as a white solid at a yield of 88%. LC-MS(ES.sup.+): 436 (M+H).sup.+.

3) Synthesis of N-(4-chloro-2-fluorobenzyl)-6-(piperidin-4-yloxy)pyridin-2-amine

[0227] The compound (240 mg) synthesized in the step 2) was placed in a round bottom flask, dissolved in DCM (2.7 mL) and stirred. TFA (1.4 mL) was added at room temperature and the resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction as indicated by TLC, the mixture was concentrated under reduced pressure and dissolved in DCM. The organic layer was washed with a saturated aqueous solution of NaHCO.sub.3, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the target compound (179 mg) as a yellow oil at a yield of 97%. LC-MS(ES.sup.+): 336 (M+H).sup.+.

7. Preparation Method 7

[0228] ##STR00052##

(1) Synthesis of Intermediate 7: tert-butyl 3-((6-bromopyridin-2-yl)methyl)pyrrolidine-1-carboxylate

1) Synthesis of tert-butyl 3-((6-bromopyridin-2-yl)methyl)pyrrolidine-1-carboxylate

[0229] Tert-butyl 3-methylenepyrrolidine-1-carboxylate (0.77 g) was dissolved in THF (20 mL) and the solution was degassed at room temperature for 15 minutes with nitrogen. The air inside the reactor was replaced with nitrogen using a nitrogen balloon, then 9-borabicyclo[3.3.1]nonane (8.4 mL, 0.5 M in THF) was added. The reaction mixture was stirred at 60° C. for 3 hours, cooled to room temperature, which was then added to a mixture of 2,6-dibromopyridine (1 g), potassium carbonate (0.75 g), PdCl.sub.2(dppf)CH.sub.2Cl.sub.2 complex (0.1 g, 0.03 eq) in DMF/water (=10 mL: 1 mL), prepared and degassed beforehand. The reaction mixture was stirred at 85° C. for 16 hours. After completion of the reaction, the resulting product was basified to pH 11 with 1NNaOH aqueous solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography to obtain the target compound (0.72 g) as a transparent oil at a yield of 47%. LC-MS(ES.sup.+): 341 (M+H).sup.+

2) Synthesis of tert-butyl 3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)methyl)pyrrolidine-1-carboxylate

[0230] The compound (0.8 g, 2.344 mmol, 1.0 eq.) synthesized in the step 1) was placed in a sealed tube and dissolved in toluene (25 mL). Cesium carbonate (2.28 g), 3-fluoro-4-(hydroxymethyl)benzonitrile (425 mg) and 2-(di-tert-butylphosphino)biphenyl (0.02 g, 0.09 mmol, 0.04 eq.) were added to the solution at room temperature, which was degassed for 15 minutes with nitrogen. After the air inside the reactor was replaced with nitrogen using a nitrogen balloon, tris(dibenzylideneacetone)dipalladium(0) (0.042 g) was added to the reaction mixture at room temperature. The reaction mixture was heated to 110° C. and stirred for 16 hours. After completion of the reaction, the resulting product was cooled to room temperature, diluted with distilled water, and extracted twice with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained concentrated residue was subjected to silica gel column chromatography to obtain the target compound (0.5 g) as a brown oil at a yield of 51%. LC-MS(ES.sup.+): 412 (M+H).sup.+

3) Synthesis of 3-fluoro-4-(((6-(pyrrolidin-3-ylmethyl)pyridin-2-yl)oxy)methyl)benzonitrile

[0231] The compound (1.1 g, 2.67 mmol, 1.0 eq.) synthesized in the step 1) was dissolved in ethyl acetate (35 mL), and para-toluenesulfonic acid (p-TSA, 1.01 g, 5.34 mmol, 2.0 eq.) was added at room temperature. The reaction mixture was stirred at 65° C. for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous NaHCO.sub.3 solution, and extracted twice with DCM. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (0.8 g, crude) as a brown oil. The obtained compound was used in the next reaction without further purification. LC-MS (M+H).sup.+: 312.31

8. Synthesis of Intermediates 8 to 41

[0232] The compounds listed as intermediates 8 to 41 in Table 1 below were prepared by using procedures identical or analogous to the synthesis methods of Preparation Methods 1 to 7 from appropriate starting materials that are available commercially or prepared by preparation methods well known to those skilled in the art, or prepared in a similar manner to the route described above for other intermediates. The compounds were purified using methods well known to those skilled in the art, which may include silica gel chromatography, HPLC, or recrystallization from the reaction mixture. The final compounds could be isolated as neutrals or as acid addition or base addition salts and the trifluoroacetic acid (TFA) salt may exist as at least one or more TFA 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+)  8 1 [00053] 6-((2-fluoro-5-(piperidin-4- ylamino)phenoxy)methyl) nicotinonitrile trifluoroacetic acid salt 327 (M + H).sup.+  9 1 [00054] N-(3-((5-chloropyridin-2- yl)methoxy)phenyl)piperidin- 4-amine trifluoroacetic acid salt 318 (M + H).sup.+ 10 1 [00055] 6-(((6-(piperidin-4- ylamino)pyridin-2- yl)oxy)methyl)nicotinonitrile 310 (M + H).sup.+ 11 1 [00056] (R)-6-((2-fluoro-5- (pyrrolidin-3- ylamino)phenoxy)methyl) nicotinonitrile trifluoroacetic acid salt 313 (M + H).sup.+ 12 1 [00057] (R)-3-fluoro-4-((2-fluoro-5- (pyrrolidin-3- ylamino)phenoxy)methyl) benzonitrile trifluoroacetic acid salt 330 (M + H).sup.+ 13 1 [00058] 3-fluoro-4-((2-fluoro-5- (piperidin-4- ylamino)phenoxy)methyl) benzonitrile trifluoroacetic acid salt 344 (M + H).sup.+ 14 1 [00059] (R)-6-(((6-(pyrrolidin-3- ylamino)pyridin-2- yl)oxy)methyl)nicotinonitrile 296 (M + H).sup.+ 15 1 [00060] (R)-N-(3-((4-chloro-2- fluorobenzyl)oxy)-4- fluorophenyl)pyrrolidin-3- amine 339 (M + H).sup.+ 16 1 [00061] N-(3-((4-chloro-2- fluorobenzyl)oxy)-4- fluorophenyl)piperidin-4- amine 353 (M + H).sup.+ 17 2 [00062] 6-((4-chloro-2- fluorobenzyl)oxy)-N- (piperidin-4-yl)pyridin-2- amine 336 (M + H).sup.+ 18 2 [00063] 4-(((6-((azetidin-3- ylmethyl)amino)pyridin-2- yl)oxy)methyl)-3- fluorobenzonitrile trifluoroacetic acid salt 313 (M + H).sup.+ 19 2 [00064] (R)-6-((4-chloro-2- fluorobenzyl)oxy)-N- (pyrrolidin-3-yl)pyridin-2- amine 322 (M + H).sup.+ 20 2 [00065] 3-fluoro-4-(((2-(piperidin-4- ylamino)pyrimidin-4- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 328 (M + H).sup.+ 21 2 [00066] (R)-N-(3-((5-chloropyridin- 2- yl)methoxy)phenyl)pyrrolidin- 3-amine trifluoroacetic acid salt 304 (M + H).sup.+ 22 2 [00067] 3-fluoro-4-(((6-(piperidin-3- ylamino)pyridin-2- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 327 (M + H).sup.+ 23 2 [00068] (R)-3-fluoro-4-(((6- (pyrrolidin-3- ylamino)pyrazin-2- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 314 (M + H).sup.+ 24 2 [00069] 3-fluoro-4-(((6-((pyrrolidin- 2-ylmethyl)amino)pyridin-2- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 327 (M + H).sup.+ 25 2 [00070] (R)-4-((4-chloro-2- fluorobenzyl)oxy)-5-fluoro- N-(pyrrolidin-3- yl)pyrimidin-2-amine 341 (M + H).sup.+ 26 2 [00071] (R)-6-((4-chloro-2- fluorobenzyl)oxy)-N- (pyrrolidin-3-yl)pyrazin-2- amine 323 (M + H).sup.+ 27 2 [00072] 3-fluoro-4-(((6-(piperidin-4- ylamino)pyrazin-2- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 328 (M + H).sup.+ 28 2 [00073] 3-fluoro-4-(((6-(pyrrolidin-3- ylamino)pyridin-2- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 313 (M + H).sup.+ 29 2 [00074] 4-(((6-(azetidin-3- ylamino)pyridin-2- yl)oxy)methyl)-3- fluorobenzonitrile 299 (M + H).sup.+ 30 2 [00075] (R)-3-fluoro-4-(((6- (pyrrolidin-3- ylamino)pyridin-2- yl)oxy)methyl)benzonitrile 313 (M + H).sup.+ 31 2 [00076] 3-fluoro-4-(((6- (methyl(piperidin-4- yl)amino)pyridin-2- yl)oxy)methyl)benzonitrile 341 (M + H).sup.+ 32 2 [00077] (S)-3-fluoro-4-(((6- (pyrrolidin-3- ylamino)pyridin-2- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 313 (M + H).sup.+ 33 2 [00078] (R)-3-fluoro-4-((3- (pyrrolidin-3- ylamino)phenoxy)methyl) benzonitrile 312 (M + H).sup.+ 34 3 [00079] (R)-3-fluoro-4-(((5-fluoro-2- (pyrrolidin-3- ylamino)pyrimidin-4- yl)oxy)methyl)benzonitrile 332 (M + H).sup.+ 35 3 [00080] (R)-3-fluoro-4-(((2- (pyrrolidin-3- ylamino)pyrimidin-4- yl)oxy)methyl)benzonitrile trifluoroacetic acid salt 314 (M + H).sup.+ 36 4 [00081] (R)-3-fluoro-4-(((4- (pyrrolidin-3- ylamino)pyrimidin-2- yl)oxy)methyl)benzonitrile 314 (M + H).sup.+ 37 4 [00082] (R)-2-((4-chloro-2- fluorobenzyl)oxy)-5-fluoro- N-(pyrrolidin-3- yl)pyrimidin-4-amine 341 (M + H).sup.+ 38 5 [00083] (R)-6-((5-chloropyridin-2- yl)methoxy)-A-(pyrrolidin-3- yl)pyridin-2-amine trifluoroacetic acid salt 305 (M + H).sup.+ 39 6 [00084] N-(4-chloro-2-fluorobenzyl)- 6-(pyrrolidin-3- yloxy)pyridin-2-amine trifluoroacetic acid salt 322 (M + H).sup.+ 40 Synthesis method described in WO2018 109607 [00085] methyl (S)-2-(chloromethyl)- 1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6- carboxylate 295 (M + H).sup.+ 41 Synthesis method described in WO2018 109607 [00086] methyl (S)-2-(chloromethyl)- 3-(oxetan-2-ylmethyl)-3H- imidazo[4,5-b]pyridine-5- carboxylate 296 (M + H).sup.+

EXAMPLE

[0233] Synthesis methods of Examples 1 to 44 using the intermediates were described in detail below. The following Preparation Examples A, B, and C show specific examples of the synthesis methods of Examples 1 to 44 using the intermediates above. Those skilled in the art may synthesize the compounds of Examples 1 to 44 according to the present disclosure with reference to the specific examples of Preparation Examples A, B, and C.

1. Preparation Example A

[0234] ##STR00087##

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

1) Synthesis of methyl (S)-2-((4-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0235] Intermediate 2 (250.0 mg), potassium carbonate (198.8 mg), and Intermediate 40 (155.4 mg) were dissolved in CH.sub.3CN (4.0 mL), which was stirred at 80 to 90° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered through a Celite pad to obtain a filtrate. The filtrate was concentrated under reduced pressure, which was then subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (246.8 mg) as a light brown solid at a yield of 88.1%. LC-MS(ES.sup.+): 585 [M+H].sup.+.

2) Synthesis of Final Compound

[0236] The compound (230 mg) obtained in the step 1) was dissolved in 1,4-dioxane/H.sub.2O (4:1, 3 mL), then LiOH (33 mg) was added thereto and the mixture was stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature, neutralized with 1 N HCl, and extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was subjected to silica gel column chromatography eluting with DCM/MeOH to obtain the final compound (92 mg) as a bright yellow solid at a yield of 41.1%. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.81 (brs, 1H), 8.26 (s, 1H), 7.89 (d, J=1.2 Hz, 1H), 7.80 (dd, J=6.8 Hz, J=1.6 Hz, 1H), 7.69 (dd, J=8.0 Hz, J=1.6, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.59 (t, J=7.2 Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 6.47 (d, J=7.2 Hz, 1H), 6.01 (d, J=8.0 Hz, 1H), 5.94 (d, J=7.6 Hz, 1H), 5.40 (s, 2H), 5.11-5.06 (m, 1H), 4.48 (dd, J=15.2 Hz, J=7.6 Hz, 1H), 4.65-4.61 (m, 1H), 4.52-4.47 (m, 2H), 4.40-4.36 (m, 1H), 3.93 (d, J=13.6 Hz, 1H), 3.74 (d, J=13.6 Hz, 1H), 3.48-3.47 (m, 1H), 2.85-2.83 (m, 1H), 2.76-2.67 (m, 2H), 2.46-2.39 (m, 1H), 2.18-2.07 (m, 2H), 1.73 (brs, 2H), 1.36-1.28 (m, 2H); LC-MS(ES.sup.+): 585 [M+H].sup.+.

(2) Synthesis of Examples 2 to 31

[0237] The compounds listed as Examples 2 to 31 in Table 2 below were prepared by using procedures identical or analogous to the synthesis method (Preparation Example A) of Example 1 from appropriate starting materials which are available commercially or prepared by preparation methods well known to those skilled 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 from the reaction mixture. The final compounds could be isolated as neutrals or as acid addition or base addition salts. The compound names, NMR data, and LC-MS data of the Examples prepared above are shown in Table 2 below.

TABLE-US-00002 TABLE 2 LC/MS Example No. of No. of Compound data No. Intermediate A Intermediate B name NMR data (ES+) 2 1 40 (S)-2-((4-((3-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 570 fluorobenzyl)oxy)phenyl)amino) d.sub.6): δ 13.78 (brs, 1H), 8.26 (s, (M + H).sup.+ piperidin-1-yl)methyl)-1- 1H), 7.92 (d, J = 8.8 Hz, 1H), (oxetan-2-ylmethyl)-1H- 7.80 (dd, J = 8.4 Hz, J = 1.2 Hz, benzo[d]imidazole-6-carboxylic 1H), 7.72-7.75 (m, 2H), 7.63 acid (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.2 Hz, 1H), 6.16-6.22 (m, 3H), 5.53 (d, J = 8.0 Hz, 1H), 5.15 (s, 2H), 5.08-5.14 (m, 1H), 4.73-4.81 (m, 1H), 4.61- 4.68 (m, 1H), 4.43-4.51 (m, 1H), 4.37-4.41 (m, 1H), 4.12 (brs, 2H), 3.93 (d, J = 13.6 Hz, 1H), 3.75 (d, J = 13.6 Hz, 1H), 3.28-3.39 (m, 1H), 3.15-3.26 (m, 1H), 2.72-2.74 (m, 1H), 2.69-2.79 (m, 2H), 2.40-2.49 (m, 1H), 2.17-2.29 (m, 2H), 1.81-1.90 (m, 2H), 1.28-1.41 (m, 2H). 3 3 40 (S)-2-((4-((4-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 591 fluorobenzyl)oxy)-5- d.sub.6): δ 8.22 (s, 1H), 8.14 (d, (M + H).sup.+ fluoropyrimidin-2- J = 2.8 Hz, 1H), 7.94 (d, J = 10.0 yl)amino)piperidin-1- Hz, 1H), 7.81 (d, J = 8.4 Hz, yl)methyl)-1-(oxetan-2- 1H), 7.76-7.74 (m, 2H), 7.58 ylmethyl)-1H-benzo[d]imidazole- (d, J = 8.4 Hz, 1H), 7.15-7.13 6-carboxylic acid (m, 1H), 5.54 (s, 2H), 5.11- 5.06 (m, 1H), 4.75 (dd, J = 15.2, 7.2 Hz, 1H), 4.63-4.60 (m, 1H), 4.52-4.47 (m, 1H), 4.39 (ddd, J = 12.0, 8.8, 6.0 Hz, 1H), 3.91 (d, J = 13.2 Hz, 1H), 3.74 (d, J = 13.6 Hz, 1H), 2.90-2.87 (m, 1H), 2.77-2.68 (m, 2H), 2.47-2.41 (m, 1H), 2.20-2.08 (m, 2H), 1.76 (m, 2H), 1.43 (m, 2H). 4 4 40 (S)-2-((4-((2-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 572 fluorobenzyl)oxy)pyrimidin-4- d.sub.6): δ 8.24 (s, 1H), 7.91 (d, (M + H).sup.+ yl)amino)piperidin-1- J = 9.2 Hz, 1H), 7.94 (d, J = yl)methyl)-1-(oxetan-2- 10.0 Hz, 1H), 7.80 (d, J = 8.4 Hz, ylmethyl)-1H-benzo[d]imidazole- 2H), 7.72 (d, J = 6.8 Hz, 1H), 6-carboxylic acid 7.65-7.62 (m, 2H), 7.49-7.46 (m, 1H), 6.11 (d, J = 5.2 Hz, 1H), 5.38 (s, 2H), 5.10-5.08 (m, 1H), 4.79-4.74 (m, 1H), 4.64-4.61 (m, 1H), 4.52-4.47 (m, 1H), 4.39 (ddd, J = 9.2, 6.0, 6.0 Hz, 2H), 3.92 (d, J = 13.6 Hz, 1H), 3.77-3.74 (m, 2H), 2.87-2.86 (m, 1H), 2.76- 2.68 (m, 2H), 2.24-2.13 (m, 2H), 1.78 (m, 2H), 1.40-1.37 (m, 2H). 5 6 40 (S)-2-((4-((6-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 580 fluorobenzyl)amino)pyridin-2- d.sub.6): δ 8.26 (d, J = 1.2 Hz, 1H), (M + H).sup.+ yl)oxy)piperidin-1-yl)methyl)- 7.80 (dd, J = 8.4, 1.2 Hz, 1H), 1-(oxetan-2-ylmethyl)-1H- 7.64 (d, J = 8.4 Hz, 1H), 7.37 benzo[d]imidazole-6-carboxylic (dd, J = 10.0, 2.0 Hz, 1H), acid 7.33-7.26 (m, 2H), 7.21 (dd, J = 8.0, 2.0 Hz, 1H), 7.15 (dd, J = 5.6, 5.6 Hz, 1H), 6.08 (d, J = 8.0 Hz, 1H), 5.83 (d, J = 7.6 Hz, 1H), 5.09-5.07 (m, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.71-4.67 (m, 1H), 4.63 (dd, J = 15.2, 2.4 Hz, 1H), 4.52-4.47 (m, 1H), 4.43-4.35 (m, 3H), 3.92 (d, J = 13.2 Hz, 1H), 3.75 (d, J = 13.2 Hz, 1H), 2.74-2.64 (m, 3H), 2.47-2.40 (m, 1H), 2.21-2.14 (m, 2H), 1.77-1.75 (m, 2H), 1.50-1.44 (m, 2H). 6 8 40 (S)-2-((4-((3-((5-cyanopyridin- .sup.1H MR (400 MHz, DMSO- 571 2-yl)methoxy)-4- d.sub.6): δ 12.73 (brs, 1H), 9.06 (s, (M + H).sup.+ fluorophenyl)amino)piperidin-1- 1H), 8.38 (d, J = 8.2, 2.2 Hz, yl)methyl)-1-(oxetan-2-ylmethyl)-1H- 1H), 8.27 (d, J = 0.8 Hz, 1H), benzo[d]imidazole- 7.80 (dd, J = 8.4, 1.6 Hz, 1H), 6-carboxylic acid 7.66 (dd, J = 20.0, 8.4 Hz, 2H), 6.93 (dd, J = 11.6, 8.8 Hz, 1H), 6.34 (dd. J = 7.4, 2.6 Hz, 1H), 6.13-6.10 (m, 1H), 5.41-5.36 (m, 1H), 5.28 (s, 2H), 5.10- 5.07 (m, 1H), 4.81-4.75 (m, 1H), 4.63 (d, J = 12.8 Hz, 1H), 4.51-4.49 (m, 1H), 4.41-4.37 (m, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.75 (d, J = 13.6 Hz, 1H), 3.64-3.57 (m, 1H), 3.19-3.10 (m, 1H), 2.88-2.82 (m, 1H), 2.74-2.69 (m, 2H), 2.46-2.42 (m, 1H), 2.23-2.17 (m, 2H), 1.88-1.76 (m, 2H), 1.33-1.26 (m, 1H). 7 9 40 (S)-2-((4-((3-((5- .sup.1H NMR (400 MHz, DMSO- 562 chloropyridin-2- d.sub.6): δ 12.75 (brs, 1H), 8.63 (d, (M + H).sup.+ yl)methoxy)phenyl)ami- 7 = 2.4 Hz, 1H), 8.26 (s, 1H), no)piperidin-1-yl)methyl)-1- 7.96 (dd, J = 8.6, 2.6 Hz, 1H), (oxetan-2-ylmethyl)-1H- 7.81 (dd, J = 8.6, 1.4 Hz, 1H), benzo[d]imidazole-6-carboxylic 7.63 (d, J = 8.4 Hz, 1H), 7.52 acid (d, J = 8.4 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.20-6.13 (m, 3H), 5.51 (d, J = 8.0 Hz, 1H), 5.15-5.06 (m, 3H), 4.81-4.75 (m, 1H), 4.64 (dd, J = 15.0, 2.6 Hz, 1H), 4.51-4.47 (m, 1H), 4.42-4.38 (m, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.75 (d, J = 13.2 Hz, 1H), 3.26-3.12 (m, 1H), 2.87 (d, J = 11.2 Hz, 1H), 2.76-2.67 (m, 2H), 2.46-2.41 (m, 1H), 2.25-2.19 (m, 2H), 1.86-1.82 (m, 2H), 1.37-1.24 (m, 2H). 8 11 40 2-(((R)-3-((3-((5-cyanopyridin-2- .sup.1H NMR (400 MHz, DMSO- 557 yl)methoxy)-4-fluorophenyl)ami- d.sub.6): δ 12.79 (brs, 1H), 9.05 (t, (M + H).sup.+ no)pyrrolidin-1-yl)methyl)-1- J = 1.2 Hz, 1H), 8.37 (dd, J = (((S)-oxetan-2-yl)methyl)-1H- 8.2, 2.2 Hz, 1H), 8.25 (d, J = benzo[d]imidazole-6-carboxylic 0.8 Hz, 1H), 7.80 (dd, J = 8.6, acid 1.4 Hz, 1H), 7.65 (dd, J = 17.4, 8.2 Hz, 2H), 6.94 (dd, J = 11.6, 8.8 Hz, 1H), 6.31 (dd, J = 7.4, 2.6 Hz, 1H), 6.08-6.05 (m, 1H), 5.68 (d, J = 6.4 Hz, 1H), 5.27 (s, 2H), 5.07-5.04 (m, 1H), 4.78-4.71 (m, 1H), 4.61 (dd, J = 15.2, 2.4 Hz, 1H), 4.48-4.45 (m, 1H), 4.35-4.30 (m, 1H), 4.03 (d, J = 13.6 Hz, 1H), 3.88 (d, J = 13.2 Hz, 1H), 3.84-3.79 (m, 1H), 3.40-3.37 (m, 1H), 2.85-2.80 (m, 1H), 2.68-2.64 (m, 1H), 2.56-2.53 (m, 1H), 2.45-2.33 (m, 2H), 2.20-2.11 (m, 1H), 1.55-1.51 (m, 1H). 9 11 41 2-(((R)-3-((3-((5-cyanopyridin-2- .sup.1H NMR (400 MHz, DMSO- 558 yl)methoxy)-4-fluorophenyl)ami- d.sub.6): δ 9.05 (d, J = (M + H).sup.+ no)pyrrolidin-1-yl)methyl)-3- 1.2 Hz, 1H), 8.38 (dd, (((S)-oxetan-2-yl)methyl)-3H- J = 8.4, 2.0 Hz, 1H), imidazo[4,5-b]pyridine-5- 8.12-8.01 (m, 1H), 7.69 carboxylic acid (d, J = 8.0 Hz, 1H), 7.12- 6.95 (m, 2H), 6.41-6.31 (m, 1H), 6.19-6.08 (m, 1H), 5.30 (s, 2H), 5.12-5.06 (m, 1H), 4.79-4.70 (m, 1H), 4.69-4.60 (m, 1H), 4.49-4.40 (m, 1H), 4.31-4.24 (m, 1H), 3.39-3.23 (m, 4H), 2.69-2.62 (m, 2H), 2.51-2.38 (m, 4H), 2.35-2.30 (m, 2H). 10 12 40 2-(((R)-3-((3-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 574 fluorobenzyl)oxy)-4- d.sub.6): δ 12.74 (brs, 1H), 8.25 (s, (M + H).sup.+ fluorophenyl)amino)pyrrolidin-1- 1H), 7.93 (d, J = 9.6 Hz, 1H), yl)methyl)-1-(((S)-oxetan-2- 7.82-7.69 (m, 3H), 7.64 (d, J = yl)methyl)-1H-benzo[d]imidazole- 8.4 Hz, 1H), 6.92 (dd, J = 6-carboxylic acid 11.2, 8.8 Hz, 1H), 6.37 (dd, J = 7.6, 2.4 Hz, 1H), 6.09-6.06 (m, 1H), 5.70 (d, J = 6.8 Hz, 1H), 5.22 (s, 2H), 5.08-5.04 (m, 1H), 4.79-4.72 (m, 1H), 4.62 (dd, J = 15.0, 2.6 Hz, 1H), 4.48-4.45 (m, 1H), 4.34-4.30 (m, 1H), 4.05 (d, J = 13.6 Hz, 1H), 3.89 (d, J = 13.2 Hz, 1H), 3.87-3.83 (m, 1H), 2.85 (dd, J = 9.4, 6.6 Hz, 1H), 2.70-2.65 (m, 2H), 2.57-2.54 (m, 1H), 2.50-2.34 (m, 2H), 2.24-2.15 (m, 1H), 1.60-1.51 (m, 1H). 11 13 40 (S)-2-((4-((3-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 588 fluorobenzyl)oxy)-4- d.sub.6): δ 12.79 (brs, 1H), 8.27 (s, (M + H).sup.+ fluorophenyl)amino)piperidin- 1H), 7.94 (dd, J = 10.0, 1.2 Hz, 1-yl)methyl)-1-(oxetan-2- 1H), 7.82-7.71 (m, 3H), 7.63 ylmethyl)-1H-benzo[d]imidazole- (d, J = 8.8 Hz, 1H), 6.91 (dd, 6-carboxylic acid J = 11.2, 8.8 Hz, 1H), 6.40 (dd, J = 7.4, 2.6 Hz, 1H), 6.14-6.11 (m, 1H), 5.41 (d, J = 8.0 Hz, 1H), 5.23 (s, 2H), 5.12-5.08 (m, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.64 (d, J = 12.8 Hz, 1H), 4.51-4.47 (m, 1H), 4.42- 4.38 (m, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.19-3.16 (m, 1H), 2.90- 2.83 (m, 1H), 2.76-2.72 (m, 2H), 2.49-2.39 (m, 1H), 2.25- 2.19 (m, 2H), 1.90-1.80 (m, 2H), 1.36-1.24 (m, 2H). 12 17 40 (S)-2-((4-((6-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 580 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.27 (d, J = 1.2 Hz, 1H), (M + H).sup.+ yl)amino)piperidin-1-yl)methyl)- 7.80 (dd, J = 8.4, 1.2 Hz, 1H), 1-(oxetan-2-ylmethyl)-1H- 7.64 (d, J = 8.4 Hz, 1H), 7.49- benzo[d]imidazole-6-carboxylic 7.44 (m, 2H), 7.30-7.26 (m, acid 2H), 6.44 (d, J = 3.6 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 5.90 (d, J = 7.6 Hz, 1H), 5.30 (s, 2H), 5.13-5.07 (m, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.64 (dd, J = 15.2, 2.4 Hz, 1H), 4.53-4.47 (m, 1H), 4.39 (ddd, J = 8.8, 5.6, 5.6 Hz, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.75 (d, J = 13.6 Hz, 1H), 3.57 (m, 1H), 2.88-2.85 (m, 1H), 2.76-2.68 (m, 2H), 2.46-2.41 (m, 1H), 2.23-2.12 (m, 2H), 1.80-1.77 (m, 2H), 1.38-1.32 (m, 2H). 13 17 41 (S)-2-((4-((6-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 581 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.07 (d, J = 8.4 Hz, 1H), (M + H).sup.+ yl)amino)piperidin-1-yl)methyl)- 7.99 (d, J = 8.0 Hz, 1H), 7.48- 3-oxetan-2-ylmethyl)-3H- 7.44 (m, 2H), 7.30-7.26 (m, imidazo[4,5-b]pyridine-5- 2H), 6.45 (d, J = 7.2 Hz, 1H), carboxylic acid 6.01 (d, J = 7.6 Hz, 1H), 5.90 (d, J = 7.6 Hz, 1H), 5.30 (s, 2H), 5.19 (brs, 1H), 4.77-4.71 (m, 2H), 4.50-4.48 (m, 1H), 4.29 (m, 1H), 3.89 (ddd, J = 28.4, 13.6, 13.6 Hz, 1H), 3.57 (m, 2H), 2.86-2.64 (m, 4H), 2.23-2.15 (m, 2H), 1.80 (m, 2H), 1.39-1.34 (m, 2H). 14 18 40 (S)-2-((3-(((6-((4-cyano-2- .sup.1H NMR (400 MHz, CDCl.sub.3): 557 fluorobenzyl)oxy)pyridin-2- δ 7.96 (d, J = 8.4 Hz, 1H), 7.74 (M + H).sup.+ yl)amino)methyl)azetidin-1- (d, J = 8.4, 1H), 7.69 (s, 1H), yl)methyl)-1-(oxetan-2- 7.62 (t, J = 7.40 Hz, 1H), 7.46 ylmethyl)-1H-benzo[d]imidazole- (dd, J = 8.0 Hz, 1.2 Hz, 2H), 6-carboxylic acid 7.39-7.34(m, 2H), 6.12(d, J = 7.6 Hz, 1H), 6.01 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H), 5.07- 5.06 (m, 1H), 4.56-4.44 (m, 4H), 4.32-4.2 (m, 3H), 3.90- 3.86 (m, 2H), 3.69-3.65 (m, 2H), 3.55 (d, J = 6.0 Hz, 2H), 2.69-2.60(m, 1H). 15 19 40 2-(((R)-3-((6-((4-chloro-2- H NMR (400 MHz, DMSO- 566 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.24 (s, 1H), 7.79 (dd, (M + H).sup.+ yl)amino)pyrrolidin-1-yl)methyl)- J = 8.4, 1.2 Hz, 1H), 7.62 (d, 1-(((S)-oxetan-2-yl)methyl)-1H- J = 8.4 Hz, 1H), 7.48-7.41 (m, benzo[d]imidazole-6-carboxylic 2H), 7.31-7.25 (m, 2H), 6.70 acid (d, J = 6.4 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 7.6 Hz, 1H), 5.27 (s, 2H), 5.08- 5.03 (m, 1H), 4.76 (dd, J = 15.6, 7.6 Hz, 1H), 4.62 (dd, J = 15.2, 2.8 Hz, 1H), 4.49-4.43 (m, 1H), 4.32 (ddd, J = 8.8, 6.0, 6.0 Hz, 1H), 4.19(m, 1H), 4.04 (d, J = 13.2 Hz, 1H), 3.86 (d, J = 13.2 Hz, 1H), 2.85 (dd, J = 9.6, 7.2 Hz, 1H), 2.70-2.64 (m, 2H), 2.58-2.54 (m, 1H), 2.42-2.34 (m, 2H), 2.19-2.08 (m, 1H), 1.65-1.60 (m, 1H). 16 19 41 2-(((R)-3-((6-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 567 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.07 (d, J = 8.0 Hz, (M + H).sup.+ yl)amino)pyrrolidin-1-yl)methyl)- 1H), 7.97 (d, J = 8.4 Hz, 1H), 3-(((S)-oxetan-2-yl)methyl)-3H- 7.47 (dd, J = 16.4, 16.4 Hz, 1H), imidazo[4,5-b]pyridine-5- 7.42 (dd, J = 10.0, 2.0 Hz, 1H), carboxylic acid 7.29 (dd, J = 7.6, 7.6 Hz, 1H), 7.27 (d, J = 8.0, 1.6 Hz, 1H), 6.72 (d, J = 6.4 Hz, 1H), 6.03 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 7.6 Hz, 1H), 5.31-5.24 (m, 2H), 5.18-5.12 (m, 1H), 4.81- 4.68 (m, 2H), 4.45 (ddd, J = 13.6, 7.6, 7.6 Hz, 1H), 4.28- 4.20 (m, 2H), 4.02 (ddd, J = 30.4, 13.6, 13.6 Hz, 1H), 2.88 (dd, J = 9.2, 7.2 Hz, 1H), 2.74-2.56 (m, 3H), 2.20-2.15 (m, 1H), 1.66-1.62 (m, 1H). 17 20 40 (S)-2-((4-((4-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 572 fluorobenzyl)oxy)pyrimidin-2- d.sub.6): δ 12.75 (brs, 1H), 8.26 (s, (M + H).sup.+ yl)amino)piperidin-1-yl)methyl)- 1H), 8.08-7.98 (m, 1H), 7.90 1-(oxetan-2-ylmethyl)-1H- (dd, J = 21.0, 9.0 Hz, 1H), 7.81 benzo[d]imidazole-6-carboxylic (dd, J = 8.6, 1.4 Hz, 1H), 7.76- acid 7.63 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.15-7.08 (m, 1H), 6.09 (d, J = 5.2 Hz, 1H), 5.46 (s, 2H), 5.14-5.07 (m, 1H), 4.77 (dd, J = 15.2, 7.2 Hz, 1H), 4.63 (d, J = 12.8 Hz, 1H), 4.51- 4.47 (m, 1H), 4.41-4.38 (m, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.74 (d, J = 13.2 Hz, 1H), 3.58-3.41 (m, 2H), 2.93-2.82 (m, 1H), 2.76-2.67 (m, 2H), 2.48-2.40 (m, 1H), 2.22-2.11 (m, 2H), 1.88-1.63 (m, 2H), 1.56-1.33 (m, 2H). 18 24 40 2-((2-(((6-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 571 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.21 (d, J = 2.8 Hz, 1H), (M + H).sup.+ yl)amino)methyl)pyrrolidin-1- 7.89-7.84 (m, 1H), 7.79 (dd, yl)methyl)-1-(((S)-oxetan-2- J = 8.4, 1.6 Hz, 1H), 7.71-7.60 yl)methyl)-1H-benzo[d]imidazole- (m, 2H), 7.31 (td, J = 12.3, 7.9 6-carboxylic acid Hz, 1H), 6.61-6.48 (m, 1H), 6.07 (dd, J = 30.4, 8.0 Hz, 1H), 5.95 (dd, J = 11.6, 7.6 Hz, 1H), 5.42-5.37 (m, 2H), 5.09-5.05 (m, 1H), 4.72-4.67 (m, 1H), 4.50-4.28 (m, 3H), 3.55-3.45 (m, 1H), 3.13-3.05 (m, 1H), 2.99-2.91 (m, 1H), 2.84-2.75 (m, 2H), 2.73-2.66 (m, 1H), 2.65-2.53 (m, 1H), 2.42-2.21 (m, 2H), 1.91-1.80 (m, 1H), 1.68-1.50 (m, 3H), 1.31-1.25 (m, 1H). 19 27 40 (S)-2-((4-((6-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 572 fluorobenzyl)oxy)pyrazin-2- d.sub.6): δ 12.80 (brs, 1H), 8.27 (M + H).sup.+ yl)amino)piperidin-1-yl)methyl)- (d, J = 0.8 Hz, 1H), 7.92 (dd, 1-(oxetan-2-ylmethyl)-1H- J = 9.8, 1.4 Hz, 1H), 7.81 (dd, benzo[d]imidazole-6-carboxylic J = 8.4, 1.6 Hz, 1H), 7.71 (dd, acid J = 7.8, 1.4 Hz, 1H), 7.64 (t, J = 8.0 Hz, 2H), 7.47 (s, 1H), 7.35 (s, 1H), 7.06 (d, J = 7.2 Hz, 1H), 5.43 (s, 2H), 5.11- 5.08 (m, 1H), 4.78 (dd, J = 15.2, 7.2 Hz, 1H), 4.64 (dd, J = 15.2, 2.4 Hz, 1H), 4.53-4.47 (m, 1H), 4.39 (td, J = 9.1, 5.9 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.6 Hz, 1H), 3.53-3.50 (m, 1H), 2.88-2.84 (m, 1H), 2.76-2.71 (m, 2H), 2.47-2.41 (m, 1H), 2.23-2.14 (m, 2H), 1.79-1.73 (m, 2H), 1.39-1.28 (m, 2H). 20 28 40 2-((3-((6-((4-cyano-2- .sup.1H NMR (400 MHz, CDCl.sub.3): 557 fluorobenzyl)oxy)pyridin-2- δ 8.02 (d, J = 8.8 Hz, 1H), 7.97 (M + H).sup.+ yl)amino)pyrrolidin-1- (s, 1H), 7.80 (d, J = 8.8 Hz, yl)methyl)-1-(((S)-oxetan-2- 1H), 7.63 (t, J = 7.6 Hz, 1H), yl)methyl)-1H-benzo[d]imidazole- 7.45 (d, J = 7.6 Hz), 7.37 (d, 6-carboxylic acid J = 9.2 Hz, 2H), 6.11 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H), 5.14 (brs, 1H), 4.62-4.51 (m, 4H), 4.34- 4.4.21 (m, 2H), 4.15(brs, 1H), 2.71(brs, 1H), 2.39-2.35 (m, 4H), 1.92-1.78 (m, 2H) 21 32 40 2-(((5)-3-((6-((4-cyano-2- .sup.1H NMR (400 MHz, CDCl.sub.3): 557 fluorobenzyl)oxy)pyridin-2- δ 8.04 (d, J = 9.6 Hz, 1H), 7.96 (M + H).sup.+ yl)amino)pyrrolidin-1- (s, 1H), 7.81 (d, J = 8.4 Hz, yl)methyl)-1-(((S)-oxetan-2- 1H), 7.63 (t, J = 7.6 Hz, 1H), yl)methyl)-1H-benzo[d]imidazole- 7.46 (d, J = 8.8 Hz, 1H), 7.38- 6-carboxylic acid 7.32 (m, 2H), 6.11 (d, J = 8.0 Hz, 1H), 5.98 (d, J = 8.0 Hz, 1H), 5.42 (s, 2H), 5.14 (brs, 1H), 4.64-4.54 (m, 4H), 4.37- 4.33 (m, 2H), 4.19 (s, 2H), 3.18-3.09 (m, 1H), 2.97-2.92 (m, 3H), 2.76-2.70 (m, 4H), 2.47-2.34 (m, 4H) 22 34 40 2-(((R)-3-((4-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 576 fluorobenzyl)oxy-5- d.sub.6): δ 8.24 (d, J = 0.8 Hz, 1H), (M + H).sup.+ fluoropyrimidin-2- 8.14 (d, J = 3.2 Hz, 1H), 7.92 yl)amino)pyrrolidin-1- (d, J = 9.6 Hz, 1H), 7.79 (dd, yl)methyl)-1-(((S)-oxetan-2- J = 8.4, 1.6 Hz, 1H), 7.74 (m, yl)methyl)-1H-benzo[d]imidazole- 2H), 7.62 (d, J = 8.4 Hz, 1H), 6-carboxylic acid 7.39 (s, 1H), 5.53 (m, 2H), 5.09-5.03 (m, 1H), 4.76 (dd, J = 15.2, 7.2 Hz, 1H), 4.61 (dd, J = 15.2, 2.8 Hz, 1H), 4.49-4.44 (m, 1H), 4.33 (ddd, J = 8.8, 5.6, 5.6 Hz, 1H), 4.18(m, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 2.85-2.81 (m, 1H), 2.73-2.66 (m, 2H), 2.42-2.34 (m, 1H), 2.16-2.08 (m, 1H), 1.72 (m, 1H). 23 36 40 2-(((R)-3-((2-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 558 fluorobenzyl)oxy)pyrimidin-4- d.sub.6): δ 8.24 (s, 1H), 7.89 (d, (M + H).sup.+ yl)amino)pyrrolidin-1-yl)methyl)- J = 10.0 Hz, 1H), 7.81-7.78 (m, 1-(((S)-oxetan-2-yl)methyl)-1H- 2H), 7.72-7.70 (m, 2H), 7.65- benzo[d]imidazole-6-carboxylic 7.61 (m, 2H), 6.16 (d, J = 6.0 acid Hz, 1H), 5.37 (s, 2H), 5.08- 5.03 (m, 1H), 4.75 (dd, J = 15.2, 7.2 Hz, 1H), 4.61 (dd, J = 15.2, 2.4 Hz, 1H), 4.49-4.44 (m, 1H), 4.32 (ddd, J = 8.8, 5.6, 5.6 Hz, 1H), 4.04 (d, J = 13.6 Hz, 1H), 3.88 (d, J = 13.6 Hz, 1H), 2.83-2.79 (m, 1H), 2.74-2.65 (m, 2H), 2.41- 2.33 (m, 1H), 2.20-2.15 (m, 1H), 1.63 (m, 1H). 24 7 40 2-((3-((6-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 556 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.20 (s, 1H), 7.87 (d, (M + H).sup.+ yl)methyl)pyrrolidin-1- J = 6.8 Hz, 1H), 7.75 (dd, yl)methyl)-1-(((S)-oxetan-2- J = 6.8, 1.6 Hz, 1H), 7.69- yl)methyl)-1H-benzo[d]imidazole- 7.57 (m, 4H), 6.85 (d, J = 6-carboxylic acid 4.8 Hz, 1H), 6.69 (dd, J = 6.4, 2.4 Hz, 1H), 5.38-5.35 (m, 2H), 5.07-5.04 (m, 1H), 4.74-4.73 (m, 1H), 4.62-4.56 (m, 1H), 4.48-4.45 (m, 1H), 4.35-4.32 (m, 1H), 3.99 (dd, J = 10.8, 2.8 Hz, 1H), 3.82 (d, J = 10.8 Hz, 1H), 2.65- 2.55 (m, 7H), 2.36 (m, 1H), 2.29 (m, 1H), 1.80 (m, 1H), 1.41 (m, 1H) 25 15 40 2-(((R)-3-((3-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 583 fluorobenzyl)oxy)-4- d.sub.6): δ 12.75 (brs, 1H), 8.26 (s, (M + H).sup.+ fluorophenyl)amino)pyrrolidin-1- 1H), 7.80 (dd, J = 8.4, 1.6 Hz, yl)methyl)-1-(((S)-oxetan-2- 1H), 7.65 (d, J = 8.4 Hz, 1H), yl)methyl)-1H-benzo[d]imidazole- 7.54 (t, J = 8.2 Hz, 1H), 7.48 6-carboxylic acid (dd, J = 10.0, 2.0 Hz, 1H), 7.33 (dd, J = 8.2, 1.8 Hz, 1H), 6.91 (dd, J = 11.4, 9.0 Hz, 1H), 6.38 (dd, J = 7.4, 2.6 Hz, 1H), 6.08- 6.05 (m, 1H), 5.68 (d, J = 4.8 Hz, 1H), 5.11 (s, 2H), 5.06- 5.03 (m, 1H), 4.75 (dd, J = 15.4, 7.4 Hz, 1H), 4.62 (dd, J = 15.0, 2.6 Hz, 1H), 4.47-4.43 (m, 1H), 4.35-4.29 (m, 1H), 4.17-3.98 (m, 1H), 3.92-3.83 (m, 1H), 3.01-2.73 (m, 2H), 2.72-2.58 (m, 4H), 2.40-2.31 (m, 1H), 2.29-2.16 (m, 1H), 1.68-1.55 (m, 1H). 26 15 41 2-(((R)-3-((3-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 584 fluorobenzyl)oxy)-4- d.sub.6): δ 13.01 (brs, 1H), 8.13 (d, (M + H).sup.+ fluorophenyl)amino)pyrrolidin-1- J = 8.0 Hz, 1H), 7.99 (d, J = 8.4 yl)methyl)-3-(((S)-oxetan-2- Hz, 1H), 7.54 (t, J = 8.2 Hz, yl)methyl)-3H-imidazo[4,5- 1H), 7.48 (dd, J = 10.0, 2.0 Hz, b]pyridine-5-carboxylic acid 1H), 7.33 (dd, J = 8.2, 1.8 Hz, 1H), 6.89 (dd, J = 11.6, 8.8 Hz, 1H), 6.38 (dd, J = 7.4, 2.6 Hz, 1H), 6.07 (td, J = 8.8, 3.0 Hz, 1H), 5.66 (d, J = 6.8 Hz, 1H), 5.15-5.10 (m, 3H), 4.79 (dd, J = 14.6, 6.2 Hz, 1H), 4.68 (dd, J = 14.8, 4.0 Hz, 1H), 4.49-4.43 (m, 1H), 4.30 (td, J = 9.1, 6.1 Hz, 1H), 4.06 (q, J = 12.8 Hz, 2H), 3.91-3.78 (m, 1H), 2.92- 2.88 (m, 1H), 2.75-2.58 (m, 3H), 2.51-2.44 (m, 2H), 2.23- 2.18 (m, 1H), 1.60-1.55 (m, 1H). 27 16 40 (S)-2-((4-((3-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 597 fluorobenzyl)oxy)-4- d.sub.6): δ 12.32 (brs, 1H), 8.27 (M + H).sup.+ fluorophenyl)amino)piperidin-1- (brs, 1H), 7.81 (m, 1H), 7.65 yl)methyl)-1-(oxetan-2-ylmethyl)- (m, 1H), 7.56 (dd, J = 8.0, 8.0 1H-benzo[d]imidazole-6-carboxylic Hz, 1H), 7.50 (d, J = 10.0 Hz, acid 1H), 7.34 (d, J = 8.0 Hz, 1H), 6.89 (m, 1H), 6.40 (m, 1H), 6.12 (m, 1H), 5.36 (m, 1H), 5.12 (m, 3H), 4.79 (dd, J = 15.2, 6.8 Hz, 1H) , 4.66-4.62, 4.49 (ddd, J = 13.6, 7.2, 7.2 Hz, 1H), 4.38 (m, 1H), 3.95- 3.77 (m, 2H), 3.18 (m, 1H), 2.86 (m, 1H), 2.74-2.67 (m, 2H), 2.22 (m, 2H), 1.85 (m, 2H), 1.36-1.24 (m, 2H). 28 16 41 (S)-2-((4-((3-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 598 fluorobenzyl)oxy)-4- d.sub.6): δ 12.92 (brs, 1H), 8.15 (d, (M + H).sup.+ fluorophenyl)amino)piperidin-1- J = 6.0 Hz, 1H), 8.00 (d, J = 6.4 yl)methyl)-3-(oxetan-2-ylmethyl)- Hz, 1H), 7.56 (t, J = 6.4 Hz, 3H-imidazo[4, 5-b]pyridine-5- 1H), 7.50 (dd, J = 8.0, 1.2 Hz, carboxylic acid 1H), 7.34 (d, J = 6.4 Hz, 1H), 6.89 (dd, J = 8.8, 7.2 Hz, 1H), 6.40 (d, J = 4.4 Hz, 1H), 6.11 (d, J = 6.8 Hz, 1H), 5.39 (brs, 1H), 5.16-5.11 (m, 3H), 4.84 (dd, J = 11.6, 5.2 Hz, 1H), 4.72 (dd, J = 11.6, 3.6 Hz, 1H), 4.49 (q, J = 5.6 Hz, 1H), 4.40-4.35 (m, 1H), 4.03-3.93 (m, 2H), 3.26-3.12 (m, 1H), 2.89-2.73 (m, 2H), 2.71-2.64 (m, 1H), 2.32-2.21 (m, 2H), 1.94-1.81 (m, 2H), 1.37-1.23 (m, 3H). 29 25 40 2-(((R)-3-((4-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 585 fluorobenzyl)oxy)-5- d.sub.6): δ 8.24 (s, 1H), 8.11 (d, (M + H).sup.+ fluoropyrimidin-2- J = 3.2 Hz, 1H), 7.79 (dd, J = yl)amino)pyrrolidin-1-yl)methyl)- 8.4, 1.2 Hz, 1H), 7.64-7.57 (m, 1-(((S)-oxetan-2-yl)methyl)-1H- 2H), 7.48 (d, J = 9.6 Hz, 1H), benzo[7]imidazole-6-carboxylic 7.33-7.31 (m, 2H), 5.43 (s, acid 2H), 5.08-5.03 (m, 1H), 4.79- 4.73 (m, 1H), 4.64-4.60 (m, 1H), 4.49-4.44 (m, 1H), 4.36- 4.31 (m, 1H), 4.22-4.21 (m, 1H), 4.05 (d, J = 13.6 Hz, 1H), 3.87 (d, J = 13.2 Hz, 1H), 2.88- 2.84 (m, 1H), 2.71-2.65 (m, 2H), 2.60-2.55 (m, 1H), 2.41- 2.36 (m, 1H), 2.19-2.12 (m, 1H), 1.73 (m, 1H). 30 26 40 2-(((R)-3-((6-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO-d.sub.6): 567 fluorobenzyl)oxy)pyrazin-2- δ 8.23 (s, 1H), 7.80-7.77 (M + H).sup.+ yl)amino)pyrrolidin-1-yl)methyl)- (m, 1H), 7.61 (d, J = 8.4 Hz, 1-(((S)-oxetan-2-yl)methyl)-1H- 1H), 7.51-7.47 (m, 2H), 7.43 benzo[d]imidazole-6-carboxylic (dd, J = 10.0, 2.0 Hz, 1H), acid 7.31-7.26 (m, 3H), 5.34-5.30 (m, 2H), 5.07-5.05 (m, 1H), 4.78-4.73 (m, 1H), 4.64-4.60 (m, 1H), 4.46 (ddd, J = 13.6, 7.6, 7.6 Hz, 1H), 4.34-4.29 (m, 1H), 4.22 (m, 1H), 4.05 (d, J = 13.6 Hz, 1H), 3.89 (d, J = 13.6 Hz, 1H), 2.89-2.85 (m, 1H), 2.74-2.63 (m, 2H), 2.59- 2.56 (m, 1H), 2.41-2.33 (m, 2H), 2.23-2.07 (m, 1H), 1.67- 1.63 (m, 1H). 31 37 40 2-(((R)-3-((2-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO- 585 fluorobenzyl)oxy)-5- d.sub.6): δ 8.23 (s, 1H), 7.93 (d, (M + H).sup.+ fluoropyrimidin-4- J = 3.6 Hz, 1H), 7.82 (d, J = 6.4 yl)amino)pyrrolidin-1-yl)methyl)- Hz, 1H), 7.79 (dd, J = 8.4, 1.6 1-(((S)-oxetan-2-yl)methyl)-1H- Hz, 1H), 7.61 (d, J = 8.4 Hz, benzo[d]imidazole-6-carboxylic 1H), 7.49 (dd, J = 8.4, 8.4 Hz, acid 1H), 7.44 (dd, J = 10.0, 2.0 Hz, 1H), 7.29 (dd, J = 8.4, 1.6 Hz, 1H), 5.25 (m, 2H), 5.07-5.04 (m, 1H), 4.73-4.71 (m, 1H), 4.64-4.60 (m, 1H), 4.47-4.31 (m, 3H), 4.05 (d, J = 13.6 Hz, 1H), 3.90 (d, J = 13.6 Hz, 1H), 2.90-2.86 (m, 1H), 2.71-2.65 (m, 2H), 2.59-2.55 (m, 2H), 2.48 (m, 1H), 2.16 (m, 1H), 1.84-1.82 (m, 1H).

2. Preparation Example B

[0238] ##STR00088##

(1) Synthesis of Example 32: 2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

1) Synthesis of methyl 2-(((R)-3-((6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)amino)pyrrolidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0239] Intermediate 30 (0.35 mmol), potassium carbonate (152 mg), and Intermediate 40 (118 mg) were dissolved in CH.sub.3CN (5.0 mL), which was stirred at 80 to 90° C. for 4 hours. The reaction product was cooled to room temperature. Then, the obtained mixture was filtered through a Celite pad and the filtrate was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (12 g SiO.sub.2, 50% EA.fwdarw.100% EA) to obtain the target compound (130 mg) as a white solid at a yield of 66%. LC-MS(ES.sup.+): 571 [M+H].sup.+.

2) Synthesis of Final Compound

[0240] The compound (120 mg) obtained in the step 1) was dissolved in 1,4-dioxane/H.sub.2O (4/1, 2.0 mL). Then, 1N aqueous NaOH solution (0.3 mL) was added dropwise and the mixture was stirred at room temperature for 24 hours. The reaction product was cooled to room temperature, neutralized with 1N HCl and extracted with 5% DCM/MeOH solution. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, separated, and purified by silica gel column chromatography (DCM: MeOH: AcOH=10: 1: 0.01) to obtain the final compound (72 mg) as a white solid at a yield of 62%. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 8.01 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 7.80 (d, J=7.4 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.38 (m, 2H), 6.11 (d, J=8.0 Hz, 1H), 6.00 (d, J=8.0 Hz, 1H), 5.42 (s, 2H), 5.13 (brs, 1H), 4.69-4.59 (m, 4H), 4.42-4.33 (m, 5H), 4.05 (brs, 1H), 3.13-2.35 (m, 4H), 1.92-1.78 (m, 2H); LC-MS(ES.sup.+): 557 [M+H].sup.+.

(2) Synthesis of Examples 33 to 38

[0241] The compounds listed as Examples 33 to 38 in Table 3 below were prepared by using procedures identical or analogous to the synthesis method (Preparation Example B) of Example 32 from appropriate starting materials which are available commercially or prepared by preparation methods well known to those skilled in the art. The compounds were purified using methods well known to those skilled in the art, which may include silica gel column chromatography, HPLC, or recrystallization from the reaction mixture. The final compounds could be isolated as neutrals or as acid addition or base addition salts. The compound names, NMR data, and LC-MS data of the Examples prepared above are shown in Table 3 below.

TABLE-US-00003 TABLE 3 Example No. of No. of LC/MS data No. Intermediate A Intermediate B Compound name NMR data (ES+) 33 21 40 2-(((R)-3-((3- .sup.1H NMR (400 MHz, CDCl.sub.3):   548.4 ((5-chloropyridin-2- δ 8.57 (d, J = 2.4 Hz, 1H), (M + H).sup.+ yl)methoxy)phenyl)ami- 8.05-8.03 (m, 2H), 7.81 (d, no)pyrrolidin-1-yl)methyl)- J = 8.4 Hz, 1H), 7.70 (dd, 1-(((S)-oxetan-2-yl)methyl)- J = 8.4, 2.4 Hz, 1H), 7.50 1H-benzo[d]imidazole- (d, J = 8.4 Hz, 1H), 7.07(t, 6-carboxylic acid J = 8.0 Hz, 2H), 6.33-6.30 (m, 1H), 6.23-6.21 (m, 1H), 5.18-5.17 (m, 1H), 5.15 (s, 2H), 4.65- 4.59 (m, 3H), 4.38-4.33 (m, 1H), 4.18 (s, 2H), 4.07 (brs, 1H), 3.10-3.08 (m, 1H), 3.06- 2.96(m, 4H), 2.75-2.68 (m, 4H), 2.45-2.26 (m, 3H), 1.80- 1.76 (m, 1H). 34 22 40 2-((3-((6-((4-cyano-2- .sup.1H NMR (400 MHz, CDCl.sub.3):   571.5 fluorobenzyl)oxy)pyridin- δ 8.13 (d, J = 11.6 Hz, 1H), (M + H).sup.+ 2-yl)amino)piperidin-1- 8.02 (dd, J = 8.6, 4.2 Hz, 1H), yl)methyl)-1-(((S)-oxetan- 7.79 (dd, J = 8.4, 4.0 Hz, 1H), 2-yl)methyl)-1H- 7.62-7.41(m, 1H), 7.45 (d, J = benzo[d]imidazole-6- 7.6 Hz, 1H), 7.38 (d, J = 9.2 carboxylic acid Hz, 1H), 7.35-7.31 (m, 2H), 6.06 (dd, J = 7.8, 3.4 Hz, 1H), 5.96 (d, J = 8.0 Hz, 1H), 5.41- 5.38(m, 1H), 5.24-5.20 (m, 2H), 4.82-4.78 (m, 1H), 4.68- 4.60 (m, 3H), 4.40-4.37 (m, 1H), 4.03-3.85 (m, 3H), 2.92- 2.73 (m, 2H), 2.63-2.38 (m, 4H). 35 23 40 2-(((R)-3-((6-((4-cyano-2- .sup.1H NMR (400 MHz, CDCl.sub.3): 558 fluorobenzyl)oxy)pyrazin- δ 7.99 (s, 2H), 7.79 (brs, 1H), (M + H).sup.+ 2-yl)amino)pyrrolidin-1- 7.56 (t, J = 6.60 Hz, 1H), yl)methyl)-1-(((S)-oxetan- 7.51-7.49 (m, 2H), 7.46-7.42 2-yl)methyl)-1H- (m, 1H), 7.36 (dd, J = 8.6, 5.0 benzo[d]imidazole-6- Hz, 1H), 6.11 (brs, 1H), 5.41 carboxylic acid (s, 2H), 5.17 (brs, 1H), 4.61- 4.57 (m, 3H), 4.32 (s, 2H), 4.17-4.09 (m, 1H), 3.9 (brs, 1H), 3.09 (brs, 2H), 2.90- 2.82 (m, 2H), 2.38 (brs, 2H), 1.83 (brs, 1H). 36 31 40 (S)-2-((4-((6-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 585 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.26 (s, 1H), 7.91 (M + H).sup.+ yl)(methyl)amino)piperidin- (dd, J = 10.0, 1.2 Hz, 1H), 7.80 1-yl)methyl)-1-(oxetan- (dd, J = 8.8, 1.2 Hz, 1H), 7.69 2-ylmethyl)-1H- (dd, J = 8.0, 1.2, 1H), 7.63 (d, benzo[d]imidazole-6- J = 8.4 Hz, 1H), 7.58 (t, J = 7.6 carboxylic acid Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 6.14 (d, J = 8.0 Hz, 1H), 6.07 (d, J = 7.6 Hz, 1H), 5.44 (s, 2H), 5.12-5.06 (m, 1H), 4.79 (dd, J = 15.4, 7.0 Hz, 1H), 4.67-4.63 (m, 1H), 4.53- 4.47 (m, 1H), 4.40-4.35 (m, 1H), 4.22-4.16 (m, 1H), 3.93 (d, J = 13.6 Hz, 1H), 3.78 (d, J = 13.2 Hz, 1H), 2.87-2.75 (m, 2H), 2.74-2.73 (m, 1H), 2.46-2.39 (m, 1H), 2.18-2.06 (m, 2H), 1.70-1.59 (m, 2H), 1.43-1.42 (m, 2H) 37 33 40 2-(((R)-3-((3-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 556 fluorobenzyl)oxy)phenyl)ami- d.sub.6): δ 8.25 (s, 1H), 7.91 (d, (M + H).sup.+ no)pyrrolidin-1-yl)methyl)- J = 10.0 Hz, 1H), 7.81 (d, 1-(((S)-oxetan-2-yl)methyl)- J = 8.4 Hz, 1H), 7.75-7.69 (m, 1H-benzo[d]imidazole-6- 2H), 7.65-7.63 (m, 1H), 6.96 carboxylic acid (dd, J = 8.0, 8.0 Hz, 1H), 6.20-6.15 (m, 3H), 5.82 (d, J = 6.0 Hz, 1H), 5.14 (s, 2H), 5.09-5.03 (m, 1H), 4.78-4.72 (m, 1H), 4.63-4.60 (m, 1H), 4.46 (d, J = 8.8, 5.6 Hz, 1H), 4.34-4.29 (m, 1H), 4.08-4.04 (m, 1H), 3.91-3.88 (m, 2H), 2.87 (m, 1H), 2.71-2.63 (m, 2H), 2.57-2.55 (m, 1H), 2.39- 2.34 (m, 1H), 2.22-2.19 (m, 1H), 1.61-1.59 (m, 1H). 38 39 40 2-((3-((6-((4-chloro-2- .sup.1H NMR (400 MHz, DMSO-   566.1 fluorobenzyl)amino)pyridin- d.sub.6): δ 12.79 (brs, 1H), 8.25 (s, (M + H).sup.+ 2-yl)oxy)pyrrolidin-1- 1H), 7.80 (dd, J = 8.4, 1.2 Hz, yl)methyl)-1-(((S)-oxetan-2- 1H), 7.64 (d, J = 8.4 Hz, 1H), yl)methyl)-1H- 7.35 (dd, J = 10.2, 2.2 Hz, benzo[d]imidazole-6- 1H), 7.31-7.27 (m, 1H), 7.20 carboxylic acid (dd, J = 8.4, 1.6 Hz, 1H), 7.13 (t, J = 5.8 Hz, 1H), 6.08 (d, J = 8.0 Hz, 1H), 5.86 (d, J = 8.0 Hz, 1H), 5.14 (brs, 1H), 5.08- 5.02 (m, 1H), 4.74 (dd, J = 15.2, 7.2 Hz, 1H), 4.60 (dd, J = 15.2, 2.4 Hz, 1H), 4.49- 4.41 (m, 3H), 4.39-4.37 (m, 1H), 3.85-3.84 (brs, 1H), 2.78-2.64 (m, 4H), 2.41-2.34 (m, 1H), 2.12-1.99 (m, 1H), 1.72 (brs, 1H).

3. Preparation Example C

[0242] ##STR00089##

(1) Synthesis of Example 39: (S)-2-((4-((6-((5-chloropyridin-2-yl)methoxy)pyridin-2-yl)amino)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

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

[0243] Intermediate 5 (crude), Intermediate 40 (47 mg), and potassium carbonate (90 mg) were placed in a round bottom flask and dissolved in CH.sub.3CN (5 mL). The resulting mixture was stirred at 60° C. for one day. After completion of the reaction as indicated by TLC, the solution was diluted with ethyl acetate and the organic layer was washed with saturated brine. 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, which was subjected to silica gel column chromatography eluting with hexane/ethyl acetate to obtain the target compound (86 mg) as a transparent syrup at a yield of 93%.

2) Synthesis of Final Compound

[0244] The compound (86 mg) synthesized in the step 1) was placed in a round bottom flask, dissolved in CH.sub.3CN (10 mL), and stirred. TBD 1.0M aqueous solution (0.3 mL) was added dropwise and stirred. Then, purified water (1 mL) was added and the reaction mixture was stirred at room temperature for one day. After completion of the reaction as indicated by TLC, the solution was neutralized to pH 7 with 1 N HCl aqueous solution. The compound was extracted using 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, which was subjected to silica gel column chromatography eluting with DCM/MeOH to obtain the final compound (7 mg) as a white solid at a yield of 8%. .sup.1H NMR (DMSO-d.sub.6): δ 8.57 (d, J=2.4 Hz, 1H), 8.23 (s, 1H), 7.89 (dd, J=8.4 Hz, J=2.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 6.41 (d, J=7.2 Hz, 1H), 5.97 (dd, J=16.4 Hz, J=8.0 Hz, 2H), 5.31 (s, 2H), 5.09-5.04 (m, 1H), 4.76 (dd, J=14.8 Hz, J=7.2 Hz, 1H), 4.63-4.59 (m, 1H), 4.49-4.46 (m, 1H), 4.40-4.35 (m, 1H), 3.90 (d, J=13.6, 1H), 3.72 (d, J=13.2, 1H), 2.79 (d, J=11.2 Hz, 1H), 2.72-2.66 (m, 2H), 2.46-2.39 (m, 2H), 2.13-2.02 (m, 2H), 1.66 (brs, 2H), 1.29-1.23 (m, 2H); LC-MS(ES.sup.+): 563 [M+H].sup.+.

(2) Synthesis of Examples 40 to 44

[0245] The compounds listed as Examples 40 to 44 in Table 4 below were prepared by using procedures identical or analogous to the synthesis of Example 39 from appropriate starting materials which are available commercially or prepared by preparation methods well known to those skilled 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 from the reaction mixture. The final compounds could be isolated as neutrals or as acid addition or base addition salts. The compound names, NMR data, and LC-MS data of the Examples prepared above are shown in Table 4 below.

TABLE-US-00004 TABLE 4 LC/MS Example No. of No. of data No. Intermediate A Intermediate B Compound name NMR data (ES+) 39 5 40 (S)-2-((4-((6- .sup.1H NMR (400 MHz, DMSO- 563 ((5-chloropyridin- d.sub.6): δ 8.57 (d, J = 2.4 Hz, 1H), (M + H).sup.+ 2-yl)methoxy)pyridin-2- 8.23 (s, 1H), 7.89 (dd, J = 8.4 yl)amino)piperidin-1- Hz, J = 2.8 Hz, 1H), 7.79 (d, yl)methyl)-1-(oxetan-2- J = 8.8 Hz, 1H), 7.61 (d, J = ylmethyl)-1H- 8.4 Hz, 1H), 7.35 (d, J = 8.4 benzo[d]imidazole-6- Hz, 1H), 7.28 (t, J = 8.0 Hz, carboxylic acid 1H), 6.41 (d, J = 7.2 Hz, 1H), 5.97 (dd, J = 16.4 Hz, J = 8.0 Hz, 2H), 5.31 (s, 2H), 5.09- 5.04 (m, 1H), 4.76 (dd, J = 14.8 Hz, J = 7.2 Hz, 1H), 4.63-4.59 (m, 1H), 4.49-4.46 (m, 1H), 4.40-4.35 (m, 1H), 3.90 (d, J = 13.6, 1H), 3.72 (d, J = 13.2, 1H), 2.79 (d, J = 11.2 Hz, 1H), 2.72-2.66 (m, 2H), 2.46-2.39 (m, 2H), 2.13- 2.02 (m, 2H), 1.66 (brs, 2H), 1.29-1.23 (m, 2H) 40 10 40 (S)-2-((4-((6-((5- .sup.1H NMR (400 MHz, DMSO- 554 cyanopyridin-2- d.sub.6): δ 9.0 (s, 1H), 8.27 (dd, (M + H).sup.+ yl)methoxy)pyridin-2- J = 8.4 Hz, J = 2.4 Hz, 1H), yl)amino)piperidin-1- 8.24 (s, 1H), 7.79 (dd, J = 8.4 yl)methyl)-1-(oxetan-2- Hz, J = 1.2 Hz, 1H), 7.62 (d, ylmethyl)-1H- J = 8.4 Hz, 1H), 7.49 (d, J = benzo[d]imidazole-6- 8.4 Hz, 1H), 7.30 (t, J = 8.0, carboxylic acid 1H), 6.42 (d, J = 7.6 Hz, 1H), 6.01-5.98 (m, 2H), 5.40 (s, 1H), 5.09-5.06 (m, 1H), 4.75 (dd, J = 15.6 Hz, J = 7.2 Hz, 1H), 4.63-4.59 (m, 1H), 4.51- 4.46 (m, 1H), 4.41-4.35 (m, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.73 (d, J = 13.6 Hz, 1H), 2.80-2.65 (m, 3H), 2.44- 2.39 (m, 1H), 2.10-1.99 (m, 2H), 1.61-1.59 (m, 2H), 1.30- 1.19 (m, 3H) 41 14 40 2-(((R)-3-((6- .sup.1H NMR (400 MHz, DMSO- 540 ((5-cyanopyridin- d.sub.6): δ 8.98 (d, J = 1.6 Hz, 1H), (M + H).sup.+ 2-yl)methoxy)pyridin-2- 8.25 (dd, J = 8.4 Hz, J = 2.0 yl)amino)pyrrolidin-1- Hz, 1H), 8.23 (s, 1H), 7.79 yl)methyl)-1-(((S)-oxetan-2- (dd, J = 8.4 Hz, J = 1.2 Hz, yl)methyl)-1H- 1H), 7.62 (d, J = 8.4 Hz, 1H), benzo[d]imidazole-6- 7.49 (d, J = 8.0 Hz, 1H), 7.32 carboxylic acid (t, J = 7.6 Hz, 1H), 6.68 (d, J = 6.4 Hz, 1H), 6.02 (dd, J = 10.8 Hz, J = 8.0 Hz, 2H), 5.41 (s, 2H), 5.06-5.02 (m, 1H), 4.73 (dd, J = 15.2 Hz, J = 7.2 Hz, 1H), 4.59 (dd, J = 15.2 Hz, J = 2.8 Hz, 1H), 4.49-4.43 (m, 1H), 4.33-4.28 (m, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.29-3.25 (m, 1H), 2.68- 2.59 (m, 3H), 2.49-2.40 (m, 1H), 2.38-2.33 (m, 2H), 2.03- 1.98 (m, 1H), 1.53-1.49 (m, 1H). 42 29 40 (S)-2-((3-((6-((4-cyano-2- .sup.1H NMR (400 MHz, DMSO- 543 fluorobenzyl)oxy)pyridin-2- d.sub.6): δ 8.24 (s, 1H), 7.85 (d, (M + H).sup.+ yl)amino)azetidin-1-yl)methyl)- J = 8 Hz, 1H), 7.79 (d, J = 8 Hz, 1-(oxetan-2-ylmethyl)-1H- 1H), 7.71 (d, J = 1.2 Hz, 1H), benzo[d]imidazole-6- 7.69-7.62 (m, 2H), 7.33 (t, carboxylic acid J = 8 Hz, 1H), 7.03 (d, J = 6.4 Hz, 1H), 6.02 (d, J = 8 Hz, 1H), 5.98 (d, J = 7.6 Hz, 1H), 5.38 (s, 2H), 5.07-5.05 (m, 1H), 4.75-4.70 (m, 1H), 4.62- 4.58 (m, 1H), 4.48-4.46 (m, 1H), 4.32-4.26 (m, 2H), 3.99 (d, J = 13.6 Hz, 1H), 3.89 (d, J = 13.6 Hz, 1H), 3.59 (dt, J = 6.4 Hz, J = 20.8 Hz, 2H), 3.01-2.98 (m, 2H), 2.71-2.67 (m, 1H), 2.41-2.36 (m, 1H). 43 35 40 2-(((R)-3-((4-((4-cyano-2- .sup.1H NMR (400 MHz, CDCl.sub.3): 558 fluorobenzyl)oxy)pyrimidin- δ 8.02-7.98 (m, 3H), 7.77 (d, (M + H).sup.+ 2-yl)amino)pyrrolidin-1- J = 8.4 Hz, 1H), 7.59 (t, J = yl)methyl)-1-(((S)-oxetan-2- 7.6 Hz, 1H), 7.49 (d, J = 7.2 yl)methyl)-1H- Hz, 1H), 7.41 (d, J = 8.8 Hz, benzo[d]imidazole-6- 1H), 6.11 (d, J = 6.0 Hz, 1H), carboxylic acid 5.52 (s, 2H), 5.05-5.03 (m, 2H), 4.67-4.58 (m, 2H), 4.47 (q, J = 6.8 Hz, 1H), 4.27-4.10 (m, 3H), 3.10-3.04 (m, 2H), 2.66-2.54 (m, 2H), 2.35-2.21 (m, 3H), 1.84 (brs, 1H) 44 38 40 2-(((R)-3-((6-((5- .sup.1H NMR (400 MHz, DMSO- 549 chloropyridin-2- d.sub.6): δ 8.57 (d, J = 2.4 Hz, 1H), (M + H).sup.+ yl)methoxy)pyridin-2- 8.21 (s, 1H), 7.88 (dd, J = yl)amino)pyrrolidin-1- 8.4 Hz, J = 2.8 Hz, 1H), 7.78 yl)methyl)-1-(((S)- (dd, J = 8.8 Hz, J = 1.6 Hz, oxetan-2-yl)methyl)-1H- 1H), 7.59 (d, J = 8.4 Hz, 1H), benzo[d]imidazole-6- 7.37 (d, J = 8.8 Hz, 1H), 7.30 carboxylic acid (t, J = 8.0 Hz, 1H), 6.67 (d, J = 6.0 Hz, 1H), 6.02 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 8.0 Hz, 1H), 5.76 (s, 1H), 5.31 (s, 2H), 5.06-5.03 (m, 1H), 4.73 (dd, J = 15.2 Hz, J = 7.2 Hz, 1H), 4.59 (dd, J = 14.8 Hz, J = 2.4 Hz, 1H), 4.46- 4.43 (m, 1H), 4.32-4.30 (m, 1H), 4.08 (m, 1H), 3.99 (d, J = 13.2 Hz, 1H), 3.82 (d, J = 13.2 Hz, 1H), 2.73-2.62 (m, 3H), 2.41-2.37 (m, 2H), 2.07 (m, 1H), 1.56-1.54 (m, 1H)

[0246] Structures and compound names of the compounds of Examples 1 to 44 prepared in Preparation Examples A, B, and C are shown in Table 5 below.

TABLE-US-00005 TABLE 5 Ex- am- ple No. Structure Compound Name  1 [00090] (S)-2-((4-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid  2 [00091] (S)-2-((4-((3-((4-cyano-2- fluorobenzyl)oxy)phenyl)amino) piperidin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid  3 [00092] (S)-2-((4-((4-((4-cyano-2- fluorobenzyl)oxy)-5- fluoropyrimidin-2-yl)amino) piperidin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid  4 [00093] (S)-2-((4-((2-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-4- yl)amino)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo [d]imidazole-6-carboxylic acid  5 [00094] (S)-2-((4-((6-((4-chloro-2- fluorobenzyl)amino)pyridin-2- yl)oxy)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo [d]imidazole-6-carboxylic acid  6 [00095] (S)-2-((4-((3-((5-cyanopyridin- 2-yl)methoxy)-4-fluorophenyl) amino)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6- carboxylic acid  7 [00096] (S)-2-((4-((3-((5-chloropyridin- 2-yl)methoxy)phenyl)amino) piperidin-1-yl)methyl)-1- (oxetan-2-ylmethyl)-1H- benzo[d]imidazole-6-carboxylic acid  8 [00097] 2-(((R)-3-((3-((5-cyanopyridin- 2-yl)methoxy)-4-fluorophenyl) amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid  9 [00098] 2-(((R)-3-((3-((5-cyanopyridin- 2-yl)methoxy)-4-fluorophenyl) amino)pyrrolidin-1-yl)methyl)- 3-(((S)-oxetan-2-yl)methyl)- 3H-imidazo[4,5-b]pyridine- 5-carboxylic acid 10 [00099] 2-(((R)-3-((3-((4-cyano-2- fluorobenzyl)oxy)-4- fluorophenyl)amino)pyrrolidin- 1-yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid 11 [00100] (S)-2-((4-((3-((4-cyano-2- fluorobenzyl)oxy)-4- fluorophenyl)amino)piperidin- 1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d]imidazole- 6-carboxylic acid 12 [00101] (S)-2-((4-((6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2- yl)amino)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo [d]imidazole-6-carboxylic acid 13 [00102] (S)-2-((4-((6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2- yl)amino)piperidin-1-yl)methyl)- 3-oxetan-2-ylmethyl)-3H-imidazo [4,5-b]pyridine-5-carboxylic acid 14 [00103] (S)-2-((3-(((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)methyl)azetidin-1- yl)methyl)-1-(oxetan-2-ylmethyl)- 1H-benzo[d]imidazole-6- carboxylic acid 15 [00104] 2-(((R)-3-((6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6- carboxylic acid 16 [00105] 2-(((R)-3-((6-((4-chloro-2- fluorobenzyl)oxy)pyridin-2- yl)amino)pyrrolidin-1-yl)methyl)- 3-(((S)-oxetan-2-yl)methyl)-3H- imidazo[4,5-b]pyridine-5- carboxylic acid 17 [00106] (S)-2-((4-((4-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-2- yl)amino)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo [d]imidazole-6-carboxylic acid 18 [00107] 2-((2-(((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)methyl)pyrrolidin-1- yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid 19 [00108] (S)-2-((4-((6-((4-cyano-2- fluorobenzyl)oxy)pyrazin-2- yl)amino)piperidin-1-yl)methyl)- 1-(oxetan-2-ylmethyl)-1H-benzo [d]imidazole-6-carboxylic acid 20 [00109] 2-((3-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 21 [00110] 2-(((S)-3-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 22 [00111] 2-(((R)-3-((4-((4-cyano-2- fluorobenzyl)oxy-5- fluoropyrimidin-2-yl)amino) pyrrolidin-1-yl)methyl)-1-(((S)- oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 23 [00112] 2-(((R)-3-((2-((4-cyano-2- fluorobenzyl)oxy)pyrimidin-4- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 24 [00113] 2-((3-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)methyl)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 25 [00114] 2-(((R)-3-((3-((4-chloro-2- fluorobenzyl)oxy)-4- fluorophenyl)amino)pyrrolidin- 1-yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid 26 [00115] 2-(((R)-3-((3-((4-chloro-2- fluorobenzyl)oxy)-4- fluorophenyl)amino)pyrrolidin- 1-yl)methyl)-3-(((S)-oxetan-2- yl)methyl)-3H-imidazo[4,5- b]pyridine-5-carboxylic acid 27 [00116] (S)-2-((4-((3-((4-chloro-2- fluorobenzyl)oxy)-4- fluorophenyl)amino)piperidin- 1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid 28 [00117] (S)-2-((4-((3-((4-chloro-2- fluorobenzyl)oxy)-4- fluorophenyl)amino)piperidin- 1-yl)methyl)-3-(oxetan-2- ylmethyl)-3H-imidazo[4,5- b]pyridine-5-carboxylic acid 29 [00118] 2-(((R)-3-((4-((4-chloro-2- fluorobenzyl)oxy)-5- fluoropyrimidin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 30 [00119] 2-(((R)-3-((6-((4-chloro-2- fluorobenzyl)oxy)pyrazin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 31 [00120] 2-(((R)-3-((2-((4-chloro-2- fluorobenzyl)oxy)-5- fluoropyrimidin-4-yl)amino) pyrrolidin-1-yl)methyl)-1- (((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 32 [00121] 2-(((R)-3-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 33 [00122] 2-(((R)-3-((3-((5-chloropyridin- 2-yl)methoxy)phenyl)amino) pyrrolidin-1-yl)methyl)-1-(((S)- oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 34 [00123] 2-((3-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)amino)piperidin-1- yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid 35 [00124] 2-(((R)-3-((6-((4-cyano-2- fluorobenzyl)oxy)pyrazin-2- yl)amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 36 [00125] (S)-2-((4-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin-2- yl)(methyl)amino)piperidin- 1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid 37 [00126] 2-(((R)-3-((3-((4-cyano-2- fluorobenzyl)oxy)phenyl) amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 38 [00127] 2-((3-((6-((4-chloro-2- fluorobenzyl)amino)pyridin- 2-yl)oxy)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)-1H- benzo[d]imidazole-6-carboxylic acid 39 [00128] (S)-2-((4-((6-((5-chloropyridin-2- yl)methoxy)pyridin-2-yl)amino) piperidin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid 40 [00129] (S)-2-((4-((6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)amino) piperidin-1-yl)methyl)-1-(oxetan- 2-ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid 41 [00130] 2-(((R)-3-((6-((5-cyanopyridin-2- yl)methoxy)pyridin-2-yl)amino) pyrrolidin-1-yl)methyl)-1-(((S)- oxetan-2-yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid 42 [00131] (S)-2-((3-((6-((4-cyano-2- fluorobenzyl)oxy)pyridin- 2-yl)amino)azetidin- 1-yl)methyl)-1-(oxetan-2- ylmethyl)-1H-benzo[d] imidazole-6-carboxylic acid 43 [00132] 2-(((R)-3-((4-((4-cyano-2- fluorobenzyl)oxy)pyrimidin- 2-yl)amino)pyrrolidin-1- yl)methyl)-1-(((S)-oxetan-2- yl)methyl)-1H-benzo[d] imidazole-6-carboxylic acid 44 [00133] 2-(((R)-3-((6-((5-chloropyridin- 2-yl)methoxy)pyridin-2-yl) amino)pyrrolidin-1-yl)methyl)- 1-(((S)-oxetan-2-yl)methyl)- 1H-benzo[d]imidazole-6- carboxylic acid

EXPERIMENTAL EXAMPLES

1. Experimental Example 1: cAMP Assay

[0247] The cAMP assay test was performed according to a method optimized based on a protocol provided by 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 μL. As a control substance, 5 μL 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. 54, of the compounds according to the Examples 1, 2, 5, 8, 12, 13, 15, 16, 19, 20, 23, 29, 32, 37, 39 and 43 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 μL, of the cAMP-d.sub.2 conjugate reagent was added to each of the wells. Subsequently, 5 μL, 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 100 nM, and + means that EC.sub.50 is 100˜200 nM.

TABLE-US-00006 Example No. EC.sub.50 (nM) E.sub.max (%) 1 ++ 96.26 2 + 101.6 5 + 106.73 8 ++ 99.59 12 ++ 102.62 13 ++ 94.48 15 ++ 99.63 16 ++ 94.96 19 + 97.05 20 ++ 96.3 23 + 99.8 29 ++ 99.22 32 ++ 96.94 37 ++ 126.93 39 + 96.61 43 ++ 110.44