KR20140092721A - Novel heteroaryl containing phenoxybenzamide glucokinase activators and processes for the preparation thereof - Google Patents

Abstract

The present invention provides novel heteroaryl-containing phenoxybenzamide, a pharmaceutically acceptable salt of the same, a hydrate or a solvate of the same, a method for producing the same, and a pharmaceutical composition including the same. The novel heteroaryl-containing phenoxybenzamide, the pharmaceutically acceptable salt of the same, or the hydrate or the solvate of the same according to the present invention remarkably activates glucokinase so as to be helpful in treating glucokinase-mediated diseases such as hyperglycemia and diabetes.

Description

TECHNICAL FIELD The present invention relates to a novel heteroaryl-containing phenoxybenzamide glucokinase activator and a method for preparing the same. BACKGROUND ART [0002]

The present invention relates to novel glucokinase activators, and more particularly to a novel compound which activates glucokinase, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; A method for producing the same; And a pharmaceutical composition containing the same.

Glucokinase (GK), as one of the hexokinase families, catalyzes the phosphorylation of glucose, the first step of glucose metabolism, to participate in the production of glucose-6-phosphate (Alexander M. Efanov, David G. Barrett et al. Endocrinology , 146 , 3696-3701, 2007 ), which directly regulates the amount of glucose present in the blood to maintain glucose homeostasis in the body.

Glucokinase is mainly expressed in pancreatic [beta] -cells and hepatocytes. Glucokinase acts as a rate-regulating enzyme in glucose metabolism in the pancreatic β-cells, leading to glucose-dependent insulin secretion, and glucokinase in the liver causes glucose uptake and glycogen synthesis, J. Weiss, C. Weitz, C. Weiss-Collins, C. Li, N. Doliba, J. Grimsby, FM Matschinsky, Biochemical Society Transactions , 33 , 306-310 , 2005 ).

Glucokinase-deficient mice exhibited severe hyperglycemia and reduced baseline glucose levels in mice transfected with a glucokinase (GK) gene and increased expression of glucokinase (GK) in animal models such as high- A close association with the development of diabetes has been demonstrated. These results indicate that glucokinase (GK) acts as an excellent glucose sensor that maintains glucose homeostasis and shows the possibility of developing a drug that increases the activity of glucokinase (GK) as a therapeutic agent for diabetes.

Glucokinase exists in three con- forms - 'open', 'super-open' and 'closed' - with 'slow' or 'fast' . When the glucokinase has a 'closed form', the allosteric pocket is in a state of good binding to a substance that activates the glucokinase (ie, Glucokinase activator (GKA)) (Sarabu, R., Taub, R., Grimsby, J., Drug Discovery Today: Therapeutic Strategies , 4 , 111-115, 2007 ). That is, the glucokinase activator binds to the allosteric pocket of glucokinase to cause minute changes in the glucokinase structure, and as a result, stabilizes the closed form of the glucokinase, thereby activating the glucokinase, the catalyst (Grimsby, J., Sarabu, R. , Corbett, WL, Haynes, NE, Bizzaro, FT, Coffey, JW, Guertin, KR, Hilliard, DW, Kester, RF and Mahaney, PE, Science, 301, 370-373, 2003 ). Thus, the glucokinase activator does not activate other hexokinases but only acts on glucokinases with such an allosteric pocket.

Therefore, the glucokinase activator acts on the? -Cells and hepatocytes of the pancreas, which influence glucose homeostasis, and promotes insulin secretion and glucose metabolism, and therefore research on glucokinase activators as a type 2 diabetes therapeutic agent has been actively conducted . Known glucokinase activators to date include, depending on the chemical skeleton, 'carbon'-centered GKAs, aromatic ring-centered GKAs, amino acids (GKAs) and analogues thereof (Sarabu, R., Berthel, SJ, Kester, RF, Tilley, J., W., Expert Opin. Ther. Patents , 18, 759-768, 2008; Matschinsky , FM, Magnuson, MA, Eds, in Frontiers in Diabetes, 16, 145-154, 2004;. Kamata, K., Mitsuya, M., Nishimura, T., Eiki, J.-i .; Nagata, Y., Structure , 12 , 429, 2004 ; WO03 / 097824; WO08 / 075073). Other examples are described in WO03 / 000267, WO03 / 015774, WO07 / 125103, WO07 / 125105, WO08 / 050117, WO08 / 084043, WO09 / 081782, WO09 / 140624, WO10 / 013161, WO10 / 015849, WO11 / 018445, WO11 / Disclose benzamide derivatives as glucokinase modulators.

In particular, dose titration and bid or bid adjustments have been proposed as strategies for resolving the hypoglycemic problem of glucokinase recently found in clinical trials, and a more fundamental solution is to use low- Strategies to synthesize compounds that exhibit enzyme activity profiles or to synthesize liver selective compounds have been used by global pharmaceutical companies (Pfefferkorn, JA et al., Discovery of ( S ) -6 -... (3-Cyclopentyl -2- (4- (trifluoromethyl) -1 H -imidazol-1-yl) propanamido) nicotinic Acid as a Hepatoselective Glucokinase Activator Clinical Candidate for Treating Type 2 Diabetes Mellitus J. Med Chem 2012, 55 , 1318-1333; Bebernitz, GR Beaulieu, V. Dale, BA Deacon, R. Duttaroy, A. Gao, J. Grondine, MS Gupta, RC Kakmak, M. Kavana, M. Kirman, LC Liang, J. Maniara , WM Munshi, S. Nadkarni, SS Schuster, HF Stams, T. St Denny, I. Taslimi, PM V ash, B. Caplan, SL Investigation of functionally liver selective glucokinase activators for type 2 diabetes. J. Med. Chem. 2009 , 52 , 6142-6152 .; Massa, ML Gagliardino, JJ Francini, F. Liver Glucokinase: An Overcview on the Regulatory Mechanisms of its Activity. Life 2011 , 63 , 1-6.).

WO 2003097824 A1 (Kamata, Kenji) 2003.11.27. WO 2008075073 A1 (Mccabe, James) 2008.06.26. WO 2003000267 A1 (Hayter, Barry, Raymond) 2003.01.03. WO 2003015774 A1 (Boyd, Scott) 2003.02.27. WO 2007125103 A1 (Murray, Anthony) 2007.11.08. WO 2007125105 A1 (Murray, Anthony) 2007.11.08. WO 2008050117 A1 (Martin, Nathaniel, George) 2008.05.02. WO 2008084043 A1 (Murray, Anthony) 2008.07.17. WO 2009081782 A1 (Sagara, Yufu) 2009.07.02. WO 2009140624 A1 (Cheruvallath, Zacharia) 2009.11.19. WO 2010013161 A1 (Benbow, Johnwilliam) 2010.02.04. WO 2010015849 A1 (Bennett, Stuart, Norman, Lile) 2010.02.11. WO 2011018445 A1 (Bachmann, Stephan) 2011.02.17. WO 2011054174 A1 (Zhao, Jinhua) 2011.05.12.

Alexander M. Efanov, David G. Barrett et al. Endocrinology, 2007, Vol. 146, pp. 3696-3701 D. Zelent, H. Najafi, S. Odili, C. Buettger, H. Weik-Collins, C. Li, N. Doliba, J. Grimsby, F.M. Matschinsky. Biochemical Society Transactions, 2005, Vol 33, 306-310 Sarabu, R., Taub, R., Grimsby, J. Drug Discovery Today: Therapeutic Strategies, 2007, Vol 4, pp. 111-115 Wang, R., Corbett, WL, Haynes, NE, Bizzaro, FT, Coffey, JW, Guertin, KR, Hilliard, DW, Kester, RF and Mahaney, 373 pages Sarabu, R., Berthel, S. J., Kester, R. F., Tilley, J., W. Expert Opin. Ther. Patents, 2008, Vol. 18, pp. 759-768 Matschinsky, F. M., Magnuson, M. A., Eds. In Frontiers in Diabetes, 2004, Vol. 16, pp. 145-154 Kamata, K., Mitsuya, M., Nishimura, T., Eiki, J.-i .; Nagata, Y. Structure, 2004, Vol 12, page 429 Pfefferkorn, J. A. et. al. J. Med. Chem., 2012, Vol. 66, pp. 1318-1333 Bebernitz, GR Beaulieu, V. Dale, BA Deacon, R. Duttaroy, A. Gao, J. Grondine, MS Gupta, RC Kakmak, M. Kavana, M. Kirman, LC Liang, J. Maniara, WM Munshi, S. Nadkarni, SS Schuster, HF Stams, T. St Denny, I. Taslimi, PM Vash, B. Caplan, SLJ Med. Chem., 2009, Vol 62, 6142-6152 Massa, M. L. Gagliardino, J. J. Francini, F. Life, 2011, Vol 63, pp. 1-6

The present inventors have found that the benzamide compounds of formula (I) significantly activate glucokinase and thus the derivatives are useful for the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes.

Accordingly, the present invention relates to a novel compound which activates said glucokinase, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; A method for producing the same; And a pharmaceutical composition containing the same. It is also an object of the present invention to provide intermediates useful for the preparation of the compounds or the pharmaceutically acceptable salts thereof, or the hydrates or solvates thereof.

According to one aspect of the present invention, there is provided a novel compound having a hypoglycemic activity, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, by activating a glucokinase.

According to another aspect of the present invention there is provided a process for preparing the compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

According to another aspect of the present invention there is provided a novel intermediate useful for preparing the compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

According to still another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient.

As used herein, the term " heteroaryl " means a 5- to 6-membered monocyclic heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S atoms, Quot; heteroaryl " For example, monocyclic heteroaryl may be substituted with one or more substituents selected from the group consisting of thiazole, pyrazole, oxazole, imidazole, pyrrole, furan, thiophene, isothiazole, isoxazole, triazole, thiazole, tetrazole, , Triazine, pyridine, pyridazine, pyrimidine, pyrazine, and the like. Bicyclic heteroaryls may also be substituted with at least one substituent selected from the group consisting of benzothiazole, benzoxazole, benzimidazole, benzofuran, benzothiophene, benzisoxazole, indole, indoline, quinoline, isoquinoline, quinazoline, imidazopyridine, Pyridine and the like.

The term " aryl " means one or more rings having a covalent pi-electron system, and includes hydrocarbon rings having 6 to 12 carbon atoms such as phenyl, naphthyl, biphenyl and the like.

In addition, the term " alkyl " refers to an aliphatic hydrocarbon radical, including both linear and branched hydrocarbon radicals. For example, C ₁ -C ₆ alkyl is an aliphatic hydrocarbon group having from 1 to 6 carbon atoms, methyl, ethyl, propyl, n - butyl, n - pentyl, n - hexyl, isopropyl, isobutyl, sec - butyl, tert -Butyl, neopentyl, isopentyl, and the like.

In addition, the term " alkoxy " means a radical in which a hydrogen atom of a hydroxy group is substituted with alkyl, unless otherwise defined, for example C ₁ -C ₆ alkoxy is methoxy, ethoxy, propoxy, n- , n-pentyloxy, isopropoxy, sec -butoxy, tert -butoxy, neopentyloxy, isopentyloxy and the like.

The term "halogen" means an element of Group 17 of the periodic table unless otherwise defined. Examples thereof include fluorine (F), chlorine (Cl), bromine (Br), iodine (I) .

The present invention provides a compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Chemical Formula 1]

Wherein,

R ₁ , R ₂ And R < ₃ > are, independently of each other, hydrogen; Linear or branched C ₁ -C ₆ Alkyl; C ₁ -C ₆ alkoxy; halogen; Nitro; Amino; -NH-R < _{4 &} gt ;; Or an -SO ₂ -R _5,

R ₄ is _{-C (O) -R 6, -C} (O) -OR 6, -C (O) -NH-R 6 or _{-C (S) -NH-R 6} ,

R ₅ And R ₆ are independently, C ₁ -C ₆ straight or branched one another Alkyl; C ₁ -C ₆ Alkoxycarbonyl-C ₁ -C ₆ Alkyl; Hydroxycarbonyl-C ₁ -C ₆ Alkyl; Nitro, halogen and C ₁ -C ₆ Aryl substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy; Aryl-C ₁ -C ₆ alkyl; 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N and S; And 5- to 14-membered heteroaryl-C ₁ -C ₆ heteroaryl containing 1 to 3 heteroatoms selected from N and S Alkyl, < / RTI >

A ring is a 5- to 6-membered heteroaryl having at least one N atom and containing from 1 to 3 heteroatoms selected from N and S,

Wherein said A ring heteroaryl is unsubstituted;

halogen;

Linear or branched C ₁ -C ₆ Alkyl (wherein alkyl is halogen, C ₃ -C ₇ Cycloalkyloxy, hydroxycarbonyl, C ₁ -C ₆ Alkoxycarbonyl, NR < ₇ > R < _{8 &} And C (O) -NR < ₇ > R < ₈ >);

Linear or branched C ₁ -C ₆ Alkoxy-C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ Alkoxy is C ₁ -C ₃ Lt; / RTI > may be unsubstituted or substituted with alkoxy;

Pyrrolidinyl-C ₁ -C ₃ Alkyl, wherein pyrrolidine is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, oxo (C = O), linear or branched C ₁ -C ₆ Alkoxycarbonyl, straight or branched C ₁ -C ₆ Alkyl, aminocarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine);

Piperidinyl-C ₁ -C ₃ Alkyl, wherein the piperidine is halogen, hydroxy, oxo (C = O), linear or branched C ₁ -C ₆ Alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkoxycarbonyl, aminocarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine;

Piperazinyl-C ₁ -C ₃ Alkyl, wherein the piperazine is straight-chain or branched C ₁ -C ₆ Alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, alkoxycarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine;

3,6-dihydro- 2H -pyridinyl-C ₁ -C ₃ Alkyl;

Morpholinyl-C ₁ -C ₃ Alkyl;

Azetidinecarbonyl-C ₁ -C ₃ Alkyl wherein the azetidine is selected from the group consisting of straight or branched C ₁ -C ₆ Alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkoxy, halogen, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine;

Pyrrolidinecarbonyl-C ₁ -C ₃ Alkyl wherein pyrrolidine is hydroxy; C ₁ -C ₆ Linear or branched C ₁ -C ₆ substituted or unsubstituted alkoxy Alkyl; Pyridine; Pyrimidine; Pyrrolidine; Piperidine; Piperazine and morpholine); < RTI ID = 0.0 > R < / RTI >

Piperidinecarbonyl-C ₁ -C ₃ Alkyl wherein the piperidine is straight or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, alkoxycarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine;

3,6-dihydro- 2H -pyridinecarbonyl-C ₁ -C ₃ Alkyl;

Piperazinecarbonyl-C ₁ -C ₃ Alkyl, wherein the piperazine is C ₁ -C ₆ Linear or branched C ₁ -C ₆ substituted or unsubstituted alkoxy Alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, alkoxycarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine; or

Morpholinecarbonyl-C ₁ -C ₃ Alkyl wherein the morpholine is one or more straight or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, nitro, cyano,

R ₇ And R < ₈ > are, independently of each other, hydrogen; Linear or branched C ₁ -C ₆ Alkyl (wherein alkyl is hydroxy, C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkoxy, cyano, di-C ₁ -C ₆ alkylamino, tetrahydrofuran, and [1,3] dioxolane; C ₂ -C ₆ Alkynyl; C ₃ -C ₇ Lt; / RTI >

B ring is a 5- to 6-membered heteroaryl having at least one N atom and containing from 1 to 3 heteroatoms selected from N and S, said heteroaryl being selected from straight or branched C ₁ -C ₆ alkyl, Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, hydroxy, C ₁ -C ₆ alkoxy, amino, nitro, and halogen,

R ₁ and R ₂ And R < ₃ > can not be hydrogen at the same time.

In the compound of the above formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, preferably R ₁ , R ₂ And R < ₃ > are, independently of each other, hydrogen; Linear or branched C ₁ -C ₆ Alkyl; Nitro; Or an -SO ₂ -R _5,

Wherein R ₅ is C ₁ -C ₆ straight or branched chain Alkyl; C ₁ -C ₆ Alkoxycarbonyl-C ₁ -C ₆ Alkyl; Hydroxycarbonyl-C ₁ -C ₆ Alkyl, < / RTI >

A ring is heteroaryl selected from the group consisting of thiazole, pyridine, pyrazole, and pyrazine,

Wherein said A ring heteroaryl is unsubstituted;

halogen;

Linear or branched C ₁ -C ₆ Alkyl wherein the alkyl is C ₃ -C ₇ Cycloalkyloxy, C ₁ -C ₆ alkoxycarbonyl, NR ₇ R ₈ And C (O) -NR < ₇ > R < ₈ >);

Linear or branched C ₁ -C ₆ Alkoxy-C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ Alkoxy is C ₁ -C ₃ Lt; / RTI > may be unsubstituted or substituted with alkoxy;

Pyrrolidinyl-C ₁ -C ₃ Alkyl wherein the pyrrolidine may be unsubstituted or substituted with one or more hydroxy;

Piperidinyl-C ₁ -C ₃ Alkyl wherein the piperidine is hydroxy, oxo (C = O), linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkoxycarbonyl, aminocarbonyl, piperidine and pyrrolidine;

Piperazinyl-C ₁ -C ₃ Alkyl, wherein the piperazine is straight-chain or branched C ₁ -C ₆ Alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkoxycarbonyl and pyrimidine;

3,6-dihydro- 2H -pyridinyl-C ₁ -C ₃ Alkyl;

Morpholinyl-C ₁ -C ₃ Alkyl;

Azetidinecarbonyl-C ₁ -C ₃ Alkyl wherein the azetidine is selected from the group consisting of straight or branched C ₁ -C ₆ ≪ / RTI > which may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen and morpholine;

Pyrrolidinecarbonyl-C ₁ -C ₃ Alkyl wherein pyrrolidine is hydroxy and C ₁ -C ₆ Linear or branched C ₁ -C ₆ substituted or unsubstituted alkoxy Alkyl, < / RTI >

Piperidinecarbonyl-C ₁ -C ₃ Alkyl wherein the piperidine is straight or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, hydroxy, alkoxycarbonyl, pyrrolidine and piperidine;

3,6-dihydro- 2H -pyridinecarbonyl-C ₁ -C ₃ Alkyl;

Piperazinecarbonyl-C ₁ -C ₃ Alkyl, wherein the piperazine is C ₁ -C ₆ Linear or branched C ₁ -C ₆ substituted or unsubstituted alkoxy Alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, nitro, cyano, nitro, cyano, or

Morpholinecarbonyl-C ₁ -C ₃ Alkyl wherein the morpholine may be unsubstituted or substituted with one or more straight or branched C ₁ -C ₆ alkyl,

The R ₇ And R < ₈ > are, independently of each other, hydrogen; Linear or branched C ₁ -C ₆ Alkyl (wherein alkyl is hydroxy, C ₁ -C ₆ Alkoxy, cyano, di-C ₁ -C ₆ Alkylamino, tetrahydrofuran, and [1, 3] dioxolane; C ₂ -C ₆ Alkynyl; C ₃ -C ₇ Lt; / RTI >

B ring is heteroaryl selected from the group consisting of pyridine, pyrazole, and pyrazine, and said B ring heteroaryl is straight or branched C ₁ -C ₆ Alkyl, hydroxy carbonyl, C ₁ -C ₆ alkoxy, amino, nitro, and halogen.

In the compound of Formula 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, more preferably, R ₁ and R ₂ And R < ₃ > are, independently of each other, hydrogen; methyl; Or it is -SO ₂ -CH _3.

In the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, more preferably, the heteroaryl of the A ring is unsubstituted or substituted;

Fluorine (F);

Linear or branched C ₁ -C ₃ Alkyl wherein alkyl is cyclohexyloxy, ethoxycarbonyl, NR < ₇ > R < _{8 &} And C (O) -NR < ₇ > R < ₈ >);

Ethoxymethyl wherein the ethoxy may be unsubstituted or substituted with methoxy;

Pyrrolidin-1-yl-C ₁ -C ₃ Alkyl wherein the pyrrolidine may be unsubstituted or substituted with one or more hydroxy;

Piperidinyl-1-yl -C ₁ -C ₃ alkyl (where piperidine is hydroxy, oxo (C = O), ethoxycarbonyl, aminocarbonyl, piperidin-1-yl and pyrrolidin 1-yl, < / RTI >

Piperazinyl- ₁ -yl-C ₁ -C ₃ alkyl wherein the piperazine is straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₄ alkoxycarbonyl and pyrimidine-2- Lt; RTI ID = 0.0 > (I) < / RTI >;

3,6-dihydro- 2H -pyridin-1-yl-C ₁ -C ₃ alkyl;

Morpholin-4-yl-C ₁ -C ₃ alkyl;

Azetidin-1-ylcarbonyl-C ₁ -C ₃ Alkyl wherein the azetidine may be unsubstituted or substituted with one or more substituents selected from the group consisting of methoxy, fluorine (F) and morpholin-4-yl;

Pyrrolidin-1-ylcarbonyl-C ₁ -C ₃ alkyl, wherein pyrrolidine may be unsubstituted or substituted with one or more substituents selected from methyl, hydroxy and methyl substituted by methoxy;

Piperidin-1-ylcarbonyl-C ₁ -C ₃ alkyl, wherein the piperidine is optionally substituted with one or more substituents selected from the group consisting of ethoxycarbonyl, pyrrolidin-1-yl and piperidin- Which may be unsubstituted or substituted;

3,6-dihydro- 2H -pyridin-l-ylcarbonyl-C ₁ -C ₃ alkyl;

Piperazin-1-ylcarbonyl-C ₁ -C ₃ alkyl, wherein the piperazine is straight or branched C ₁ -C ₃ alkyl, unsubstituted or substituted with methoxy, straight or branched C ₂ -C ₄ Alkoxycarbonyl, pyridin-2-yl, and pyrimidin-2-yl; or

Morpholin-4-ylcarbonyl-C ₁ -C ₃ alkyl, wherein the morpholine may be substituted with one or more methyl,

R ₇ and R ₈ are, independently of each other, hydrogen; Straight or branched C ₁ -C ₅ alkyl wherein alkyl is hydroxy, methoxy, ethoxy, cyano, dimethylamino, tetrahydrofuran-2-yl, and [1,3] dioxolane- Lt; RTI ID = 0.0 > (I) < / RTI >;Prop-2-ynyl;Cyclopropyl;Cyclobutyl; Or cyclopentyl.

Most preferably, the A ring is selected from the group consisting of thiazol-2-yl, pyrazol-3-yl, and pyrazin-2-yl in the compound of formula 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, - < / RTI >

More preferably, the heteroaryl of the B ring is one or more heteroatoms selected from the group consisting of methyl, methoxy, amino and nitro, in the compound of the formula 1 or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, Lt; / RTI > may be unsubstituted or substituted with a substituent.

In the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, most preferably, the B ring is pyridin-2-yl.

The compound of formula (I) of the present invention may be in the form of a pharmaceutically acceptable salt. The salts may be customary acid addition salts such as salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, Salts derived from organic acids such as malonic acid, methanesulfonic acid, tartaric acid, malic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, 2-acetoxybenzoic acid, fumaric acid, p -toluenesulfonic acid, oxalic acid or trifluoroacetic acid. The salts also include salts derived from metals such as, for example, lithium, sodium, potassium, magnesium, or calcium, in the conventional metal salt form. The acid addition salt or metal salt may be prepared by a conventional method.

The present invention provides a process for preparing a compound of formula 1, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, comprising reacting a compound of formula 2 with a compound of formula 3:

(2)

(3)

Wherein A ring, B ring, R ₁ , R ₂ and R ₃ are the same as defined above, and X is hydroxy or halogen.

In the production process according to an embodiment of the present invention, the compound of the formula (2) is preferably a compound represented by the following formula (2a) when X is a hydroxy group, or a compound represented by the formula :

(2a)

(2b)

In the formula, B ring, R ₁ , R ₂ and R ₃ are the same as defined above, and Hal is halogen.

The present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, comprising reacting a compound of formula (II) with a compound of formula (III)

[Chemical Formula 1]

(2a)

(3)

In the formula, the B ring, R ₁ , R ₂ and R ₃ are the same as defined above.

Specifically, the compound of formula (1) can be prepared through a coupling reaction between formula (2a) and commercially available amine (3).

The coupling or amide coupling can be carried out by a known method such as an acyl halide method, an azide method, a carboxylic acid anhydride reaction method, a carbodiimide method, an active ester method, or a carbonyldiimidazole method (for example, Bodanszky, Principles of Peptide Synthesis , 2nd Ed., 1993 ). Preferably, the carbodiimide method or the acyl halide method can be used.

Coupling reaction according to the carbodiimide method is die-cyclo hexyl-carbodiimide (DCC), diisopropylcarbodiimide, or water-soluble N - ethyl carbodiimide (EDAC) - (3- dimethylaminopropyl) - N ' . ≪ / RTI > If necessary, the reaction can be promoted by the addition of 1-hydroxybenzotriazole (HOBT). The coupling reaction can be carried out in an inert solvent such as dichloromethane, acetonitrile or N, N -dimethylformamide, and also triethylamine, diisopropylethylamine, N -methylmorpholine, N , N -dimethylaminopyridine or N -methylpyrrolidine, at temperatures ranging from room temperature to 50 < 0 > C.

The coupling reaction according to the acyl halide method can be carried out by converting the carboxylic acid to an acyl halide using thionyl chloride or oxalyl chloride in the compound of formula (2), and then reacting the compound with an acyl halide such as pyridine, triethylamine, diisopropylethylamine, N -methyl Can be carried out by reacting the compound of formula (3) in the presence of an organic base such as morpholine, N, N -dimethylaminopyridine or N -methylpyrrolidine. The coupling reaction may be carried out in a reaction solvent such as dichloromethane or pyridine at a temperature from room temperature to 100 캜.

The compound of formula (3) is commercially available, and the compound of formula (2a) can be prepared, for example, according to the following reaction scheme 1:

<Reaction Scheme 1>

In the above formula, B ring, R ₁ , R ₂ and R ₃ are the same as defined above, and Y is a hydroxy-protecting group.

Specifically, the compound of Chemical Formula 4 may be prepared by reacting the compound of Chemical Formula 4 with the compound of Chemical Formula 5 under a base. The compound of Formula 4 and the compound of Formula 5 are commercially available. Reaction of the above formula (4) compound and the formula (5) compounds of cesium carbonate as a base (Cs ₂ CO _3), sodium carbonate (Na ₂ CO _3), potassium carbonate (K ₂ CO _3), potassium fluoride (KF), weapons such as butoxide (tert -BuOK) - cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphonate (K ₃ PO _4), sodium tert - butoxide (tert -BuONa) or potassium tert Base. The reaction may be carried out in a polar organic solvent such as benzene or toluene or a polar organic solvent such as dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane or N, N -dimethylformamide as a reaction solvent at 50 Deg.] C to 150 [deg.] C, preferably 80 [deg.] C to 110 [deg.] C.

The protecting group of the hydroxyl group of the compound of Formula 6 is protected. Here, the hydroxy protecting group (Y) which can be used is preferably a conventional hydroxyl protecting group such as acetoxy, tert -butyldimethylsilyl, benzoyl, trifluoromethanesulfonyloxy or methoxymethyl ether. The hydroxyl protecting group introduction reaction can be carried out according to a known method (Theodora W. Greene and Peter GM Wuts, Protective groups in organic synthesis , 3rd Ed., 1999 ).

For example, the hydroxyl group protecting reaction can be carried out at room temperature in a mixed solvent of dichloromethane and water as a reaction solvent, usually using an organic base such as pyridine. (I.e., C ₁ -C ₆ alkyl) groups such as methyl, ethyl, isobutyl, tert -butyl, and the like.

The compound of formula (7) can be converted into the compound of formula (8) by carrying out a Miyaura borylation reaction. The boron group introduction reaction can be carried out according to a known method (Miyaura N. and Murata M, J. Org. Chem ., 1995, 60, 7508-7510). For example, as a non-polar organic solvent such as benzene or toluene or a polar organic solvent such as dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane or N, N -dimethylformamide as a reaction solvent, Deg.] C to 150 [deg.] C, preferably 80 [deg.] C to 110 [deg.] C. The palladium catalyst may be palladium (II) acetate (Pd (OAc) ₂ ), tris (dibenzylideneacetone) dipalladium, tris (dibenzylideneacetone) dipalladium, Pd ₂ (dba) _3), tetrakis (triphenylphosphine) palladium (Pd (PPh _{3) 4),} or palladium (II), [1,1'- bis (diphenylphosphino) ferrocene] dichloride (PdCl ₂ (dppf) ₂ ) and the like. When the reaction is carried out in the presence of a palladium catalyst, a ligand and a base may be added in addition to the palladium catalyst. The ligand may be selected from the group consisting of (S) -2,2-bis (diphenylphosphino) -1,1-binaphthyl (BINAP), 1,1'-bis (diphenylphosphino) ferrocene (dppf) O- tolyl) phosphine comprises a pin _{(P (O-Tol) 3} ) or the like, the base is cesium carbonate (Cs ₂ CO _3), sodium carbonate (Na ₂ CO _3), potassium carbonate (K ₂ CO _3), potassium fluoride (KF), cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphonate (K ₃ PO _4), sodium tert - butoxide (tert -BuONa) or potassium tert - butoxide ( tert- BuOK).

The compound of formula (9) can be prepared by Suzuki coupling of the compound of formula (8). The reaction may be carried out using a palladium catalyst, which may be palladium (II) acetate (Pd (OAc) ₂ ), tris (dibenzylideneacetone) dipalladium, Pd ₂ dba) _3), tetrakis (triphenylphosphine) palladium (Pd (PPh _{3) 4),} or palladium (II), [1,1'- bis (diphenylphosphino) ferrocene] dichloride (PdCl ₂ (dppf) ₂ ). When the reaction is carried out in the presence of a palladium catalyst, a ligand and a base may be added in addition to the palladium catalyst. The ligand may be selected from the group consisting of (S) -2,2-bis (diphenylphosphino) -1,1-binaphthyl (BINAP), 1,1'-bis (diphenylphosphino) ferrocene (dppf) O- tolyl) phosphine comprises a pin _{(P (O-Tol) 3} ) or the like, the base is cesium carbonate (Cs ₂ CO _3), sodium carbonate (Na ₂ CO _3), potassium carbonate (K ₂ CO _3), potassium fluoride (KF), cesium fluoride (CsF), sodium hydroxide (NaOH), potassium phosphonate (K ₃ PO _4), sodium tert - butoxide (tert -BuONa) or potassium tert - butoxide ( tert- BuOK). The reaction may be carried out in a polar organic solvent such as benzene or toluene or a polar organic solvent such as dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane or N, N -dimethylformamide as a reaction solvent at 50 Deg.] C to 150 [deg.] C, preferably 80 [deg.] C to 110 [deg.] C. Other reaction conditions, including reaction time, can be performed according to known methods for Suzuki reaction (Barbara Czako and Laszlo Kurti, STRATEGIC APPLICATIONS OF NAMED REACTIONS in ORGANIC SYNTHESIS , 2005 ).

The compound of formula (9) can be converted to the compound of formula (2a) through hydrolysis of the ester. The ester hydrolysis reaction can be carried out, for example, using an aqueous solution of sodium hydroxide, lithium hydroxide or potassium hydroxide. As the reaction solvent, water or a mixed solvent of a polar solvent such as tetrahydrofuran or methanol and water may be used as the reaction solvent, and the reaction may be carried out at room temperature to 50 ° C.

The present invention provides a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, comprising reacting a compound of formula (2b) with a compound of formula (3)

[Chemical Formula 1]

(2b)

(3)

Wherein A ring, B ring, R ₁ , R ₂ and R ₃ are the same as defined above, and Hal is halogen.

Specifically, the compound of the formula (1) can be carried out in the same manner as the compound of the formula (2b) and the compound of the formula (3) in the same manner as the amide coupling reaction of the above reaction formula (1).

The coupling reaction according to the acyl halide method may be carried out by converting the carboxylic acid to an acyl halide using thionyl chloride or oxalyl chloride in the compound of formula (2a) in Scheme 1, (9) in the presence of an organic base such as diisopropylethylamine, N -methylmorpholine, N, N -dimethylaminopyridine or N -methylpyrrolidine. The coupling reaction may be carried out in a reaction solvent such as dichloromethane or pyridine at a temperature from room temperature to 100 캜.

The present invention provides a compound of formula 2, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which can be used as an intermediate for the preparation of the compound of formula 1:

(2)

Wherein B ring, R ₁ , R ₂ and R ₃ are the same as defined above, and X is hydroxy or halogen.

The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; And a pharmaceutically acceptable carrier, for the prophylaxis or treatment of glucokinase mediated diseases. The glucokinase mediated diseases include hyperglycemia, diabetes, obesity, type 1 diabetes, insulin resistance in type 2 diabetes, obesity, metabolic syndrome and the like.

The pharmaceutical composition may contain a pharmaceutically acceptable carrier such as an excipient, a disintegrant, a sweetening agent, a lubricant or a flavoring agent, and may be formulated into tablets, capsules, powders, granules and suspensions, Oral preparations such as emulsions or syrups; Or an injectable preparation for parenteral administration. The formulations can be formulated in a variety of forms, such as single dose or multi-dose dosage forms.

In addition, the pharmaceutical composition of the present invention can be administered intravenously and intramuscularly, and preferably, it can be administered orally. The daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof may range from about 10 to about 500 mg / kg, depending on the condition, age, weight, , Symptoms, or route of administration.

The present invention provides a method for preventing or treating a glucokinase mediated disease by administering a compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a mammal including a human.

The present invention relates to the use of a composition comprising the compound represented by the formula (1), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient for the pharmaceutical preparation for the prevention or treatment of a glucokinase mediated disease Lt; / RTI &gt;

The compounds according to the present invention, that is, the benzamide compounds of formula (I), can be usefully used for the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes by prominently activating glucokinase.

Hereinafter, the present invention will be described in more detail through Reference Examples, Examples and Test Examples. However, these reference examples, examples and test examples are for illustrating the present invention, and the present invention is not limited thereto.

Analysis of the compounds prepared in the following examples was carried out as follows: Nuclear magnetic resonance (NMR) spectral analysis was performed on a Bruker 400 MHz spectrometer, chemical shifts were analyzed in ppm, Column chromatography was performed on silica gel (Merck, 70-230 mesh) (WC Still, J. Org. Chem. , 43, 2923, 1978). In addition, abbreviations used in the Examples are as follows: Me is methyl, Et is ethyl, Ph is phenyl, tert - butyloxycarbonyl is BOC, N - (3- dimethylaminopropyl) - N '- Ethyl carbodiimide is abbreviated EDAC, and 1-hydroxybenzotriazole is abbreviated as HOBT. In addition, the starting materials of the respective examples were synthesized according to the literature as known compounds or purchased from Sigma Aldrich.

Reference Example 1. Preparation of 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-

Step 1: 3-Hydroxy-5- (4-methanesulfonyl-phenoxy) -benzoic acid methyl ester

75.0 g of 3,5-dihydroxybenzoate, 70.6 g of 4-fluorophenylmethylsulfone and 198.2 g of cesium carbonate were added to 500.0 mL of N , N -dimethylformamide, and the mixture was stirred at 180 ° C for 3 hours, The reaction mixture was cooled to room temperature and 300.0 mL of distilled water was added to the residue. The mixture was filtered through a pad of celite and extracted three times with ethyl acetate. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue . The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 45.0 g (yield 39.1%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ )? 7.91-7.89 (m, 2H), 7.41-7.40 (m, 1H), 7.26-7.25 , &Lt; / RTI &gt; 1H), 3.89-3.88 (d, 3H), 3.06 (s,

Step 2: 3- (4-Methanesulfonyl-phenoxy) -5-trifluoromethanesulfonyloxybenzoic acid methyl ester

45.0 g of 3-hydroxy-5- (4-methanesulfonyl-phenoxy) -benzoic acid methyl ester prepared in Step 1, 44.0 mL of trifluoromethanesulfonic anhydride, and 60.3 mL of triethylamine were dissolved in dichloromethane Methane, and the mixture was stirred at -78 ° C for 2 hours and then stirred at room temperature for 12 hours while raising the temperature. The reaction mixture was washed with aqueous ammonium chloride solution and brine, and then concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give the title compound (30.8 g, Yield: 38.9%) as a yellow solid.

_{^{1 H-NMR (CDCl 3)}} δ 7.99-7.97 (m, 2H), 7.77-7.73 (m, 2H), 7.22-7.21 (m, 1H), 7.18-7.16 (d, 2H), 3.95 (s, 3H ), 3.09 (s, 3H)

Step 3: 3- (4-Methanesulfonyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane-2- yl) benzoic acid methyl ester

19.9 g of potassium acetate, 1.7 g of palladium (II) [1,1'-bis (diphenylphosphino) ferrocene] dichloride and 1.1 g of 1,1'-bis (diphenylphosphine) And the mixture was stirred for 30 minutes. To the 300.0 mL of 1,4-dioxane was added a solution of 3- (4-methanesulfonyl-phenoxy) -5-trifluoromethanesulfonyloxybenzoic acid methyl ester 30.8 and 19.30 g of bis (pinacolato) diboron were slowly added thereto, and the mixture was stirred at 85 ° C for 48 hours. The reaction mixture was washed with an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic solvent layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to obtain 22.2 g of the title compound (yield: 76.2%) as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 8.33 (brs, 1H), 7.90-7.88 (s, 1H), 7.82 (s, 1H), 7.69-7.68 (d, 1H), 7.08-7.05 (d, 2H), 3.70 (s, 3H), 3.06 (s, 3H), 1.35 (s, 12H)

Step 4: 3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid methyl ester

(4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane-2-yl) benzoic acid the methyl ester 17.0 g N, N - dimethylformamide was dissolved was added to 250.0 mL, where the tetrakis (triphenyl phosphino) palladium _{(Pd (PPh 3) 4)} 2.2 g, 2- bromo-3-methylpyridine After adding 8.7 g, a solution prepared by dissolving 12.5 g of sodium carbonate in 250.0 mL of distilled water was added thereto, followed by stirring at 80 ° C for 18 hours. The reaction mixture was cooled to room temperature, and ethyl acetate was added to the residue to dilute. The residue was washed once with aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to obtain 12.0 g (yield: 76.1%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 8.55 (m, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.95-7.90 (m, 2H), 7.76 (s, 1H), 7.48-7.44 ( (s, 3H), 3.06 (s, 3H), 2.38 (s, 3H)

Step 5: 3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-

12.0 g of methyl 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid methyl ester prepared in Step 4 was dissolved in 50.0 mL of tetrahydrofuran and 50.0 mL of methanol And 3.6 g of sodium hydroxide in 10.0 mL of distilled water was slowly added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, acidified with 3 N hydrochloric acid solution, extracted with ethyl acetate, washed once with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 9.2 g of the title compound as a white solid (yield: 77.4% .

_{^{1 H-NMR (CDCl 3)}} δ 8.65 (d, 1H), 8.25 (s, 1H), 7.95-7.90 (m, 2H), 7.65 (d, 1H), 7.57-7.52 (m, 2H), 7.49- 3H), 2.40 (s, 3H), 7.44 (m, 1H), 7.22-7.16

Reference Example 2. N - (4-Chloro-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide

Step 1: 3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid chloride

Referential Example 1 3.3 g of 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid prepared in Step 5 was dissolved in 10.0 mL of thionyl chloride, And then cooled to room temperature. The reaction mixture was concentrated under reduced pressure to give the title compound (3.46 g) as a yellow liquid.

Step 2: N - (4-Chloromethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

3.46 g of 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid chloride prepared in Step 1 was dissolved in 50.0 mL of dichloromethane, 2-ylamine (1.8 g) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was washed with 1 N hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4.80 g (Yield: 100.0%) of the title compound as yellowish solid.

¹ H-NMR (DMSO)? 8.53-8.51 (d, 1H), 8.20 (s, 1H), 7.98-7.95 (m, 3H), 7.79-7.77 2H), 1.35 (s, 1H), 1.29-1.23 (m, 2H), 7.38-7.31 (m, 4H) , 2H)

Reference Example 3. Synthesis of {2- [3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- pyridin- 2-yl) -benzoylamino] -thiazol-

Step 1: Preparation of {2- [3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- pyridin- 2-yl) -benzoylamino] -thiazol-4- yl} -acetic acid ethyl ester

Reference Example 1 3.7 g of 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid prepared in Step 5 was dissolved in 60.0 mL of dichloromethane, 1.49 g , 2.11 g of EDAC, 2.47 g of N, N-diisopropylethylamine and 1.97 g of ethyl 2-aminothiazole-4-acetate were added and stirred overnight at room temperature. The reaction mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: petroleum ether / ethyl acetate = 1/1) to give 5.1 g (yield: 95.0%) of the title compound as a white solid.

Step 2: {2- [3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl- pyridin- 2- yl) -benzoylamino] -thiazol-

Yl} -benzoylamino] -thiazol-4-yl} -acetic acid ethyl ester prepared in step 1 (0.25 g, 5.1 g of the ester was dissolved in 50.0 mL of tetrahydrofuran and 50.0 mL of methanol, and a solution of 1.11 g of sodium hydroxide dissolved in 10.0 mL of distilled water was slowly added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, acidified with 1 N hydrochloric acid solution, extracted with dichloromethane, washed with brine, and concentrated under reduced pressure to give 4.0 g (yield: 82.0%) of yellowish solid title compound.

^{1 H-NMR (DMSO) δ} 12.63 (brs, 2H), 8.53-8.52 (d, 1H), 8.20 (s, 1H), 7.99-7.92 (m, 3H), 7.79-7.77 (d, 1H), 7.65 (S, 3H), 3.65 (s, 3H), 2.51 (s, 3H)

Reference Example 4. Preparation of 3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-

Step 1: 3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2- yl) -benzoic acid methyl ester

Reference Example 1 To a solution of 3- (4-methanesulfonyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane- (Triphenylphosphine) palladium (40.0 mg) and 2-chloro-3-nitropyridine (122.0 mg) were added to a solution of sodium carbonate (300.0 mg) in N , N -dimethylformamide 222.0 mg of distilled water was added to the solution, and the mixture was stirred at 85 ° C for one day. The reaction mixture was cooled to room temperature, and distilled water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 63.0 mg (yield: 21.0%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ )? 8.89 (d, IH), 8.26-8.24 (m, IH), 8.08 (s, IH), 7.95-7.93 3H), 3.07 (s, 3H), 3.40 (s, 3H)

Step 2: 3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-

63.0 mg of 3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) -benzoic acid methyl ester prepared in Step 1 was dissolved in 7.0 mL of tetrahydrofuran and 7.0 mL of methanol , 5.0 mL of a 3N sodium hydroxide solution was added slowly, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, acidified with 1 N hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 61.0 mg (Yield: 97.4%) of the title compound as a yellow liquid.

¹ H-NMR (CDCl ₃ )? 8.92-8.90 (d, IH), 8.29-8.27 (m, IH), 8.11 (s, IH), 7.95-7.93 2H), 3.08 (s, 3H), 7.58-7.56 (m,

Reference Example 5. Synthesis of 3- (4-methyl-phenoxy) -5- (4,4,5,5-terphenyl- [1,3,2] dioxaborolane-

Step 1: 3-Hydroxy-5- (4-methyl-phenoxy) -benzoic acid methyl ester

4.8 g of 3,5-dihydroxybenzoate, 3.9 g of 3-methylphenylboronic acid and 7.7 g of copper acetate were added to 100.0 mL of N , N -dimethylformamide and the mixture was stirred at 110 DEG C overnight, The mixture was cooled to room temperature, and 150.0 mL of distilled water was added to the residue. The mixture was filtered through a pad of celite and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 2/1) to give 720.0 mg (Yield: 9.8%) of the title compound as a brown liquid.

_{^{1 H-NMR (CDCl 3)}} δ 7.23-7.22 (m, 1H), 7.20-7.09 (m, 1H), 6.97 (m, 1H), 6.84-6.81 (m, 2H), 6.68-6.67 (m, 2H ), 3.89 (s, 3H), 2.34 (s, 3H)

Step 2: 3- (4-Methyl-phenoxy) -5-trifluoromethanesulfonyloxybenzoic acid methyl ester

720.0 mg of 3-hydroxy-5- (4-methyl-phenoxy) -benzoic acid methyl ester prepared in Step 1, 0.7 mL of trifluoromethanesulfonic anhydride and 0.8 mL of triethylamine were dissolved in dichloromethane 10.0 mL, stirred at -78 ° C for 2 hours, and stirred at room temperature for 12 hours while raising the temperature. The reaction mixture was washed with aqueous ammonium chloride solution and brine, and then concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30/1) to give 720.0 mg (Yield: 24.7%) of the title compound as a yellow solid.

_{^{1 H-NMR (CDCl 3)}} δ 7.64-7.62 (m, 2H), 7.30-7.25 (m, 2H), 7.07-7.03 (m, 1H), 6.86-6.83 (m, 2H), 3.92 (s, 3H ), 2.40-2.36 (d, 3H)

Step 3: 3- (4-Methyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane-2- yl) benzoic acid methyl ester

190.0 mg of [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium and 120.0 mg of palladium (II) [1,1'-bis (diphenylphosphino) ferrocene] Was added to 20.0 mL of 1,4-dioxane and stirred for 30 minutes. To 300.0 mL of 1,4-dioxane was added a solution of 3- (4-methyl-phenoxy) -5-trifluoromethanesulfonyloxybenzoic acid Methyl ester and 2.16 g of bis (pinacolato) diboron were slowly added thereto, followed by stirring overnight at 85 ° C. The reaction mixture was washed with an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic solvent layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to give 446.0 mg (Yield: 63.7%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 8.31 (brs, 1H), 7.30-7.26 (m, 2H), 7.20-7.10 (m, 1H), 6.97 (m, 1H), 6.86-6.82 (m, 1H), 2H), 3.86 (s, 3H), 2.33 (s, 3H), 1.35 (s, 12H)

Example 1. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (thiazol-2-yl) benzamide

1.0 g of 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid prepared in Reference Example 1 was dissolved in 20.0 mL of dichloromethane, 705.0 mg of HOBT, , 0.73 mL of triethylamine and 313.0 mg of 2-aminothiazole were added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was washed three times with 1 N hydrochloric acid, saturated sodium hydrogencarbonate, distilled water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to obtain 387.0 mg (Yield: 31.9%) of the title compound as white liquid.

¹ H-NMR (CDCl ₃ )? 11.46 (s, IH), 8.55-8.54 (d, IH), 7.95-7.91 (m, 2H), 7.71-7.61 (m, 3H), 7.56-7.44 ), 7.29-7.27 (m, 1H), 7.26-7.16 (m, 2H), 6.93-6.90 (m, 1H), 3.08 (s, 3H), 2.38 (s, 3H); MS m / z 466.5 (m + H) &lt; ⁺ & gt ^;

Example 2. 3- (4-Methanesulfonyl-phenoxy) - N - (1 -methyl-1 H -pyrazol-3-

Prepared in Reference Example 1 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzoic acid used, and 2-amino-thiazole instead of 1-methyl -1 H It was prepared pyrazol-3-amine (1-methyl-1 H -pyrazol -3-amine) compound of example 2 in the same manner as in example 1, except for using 303.6 mg.

Yield: 41.6%

_{^{1 H-NMR (CDCl 3)}} δ 8.70 (s, 1H), 8.53 (d, 1H), 7.98-7.88 (m, 3H), 7.66-7.61 (m, 2H), 7.45 (s, 1H), 7.28- 2H), 7.28 (s, 3H), 7.23 (m, 1H), 7.19-7.16 (m, 2H), 6.80 (s, MS m / z 463.5 (m + H) &lt; ⁺ & gt ^;

Example 3. Preparation of N- (5-fluoro-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

(4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid prepared in Reference Example 1 was used instead of 2- The compound of Example 3 was prepared in the same manner as in Example 1, except that 369.3 mg of 5-fluoro-2-thiazolamine was used.

Yield: 22.6%

_{^{1 H-NMR (CDCl 3)}} δ 11.07-11.03 (d, 1H), 8.54-8.53 (d, 1H), 7.97-7.43 (m, 3H), 7.19-7.14 (m, 2H), 6.93-6.92 (s , &Lt; / RTI &gt; 1H), 3.06 (s, 3H), 2.37 (s, 3H); MS m / z 484.5 (m + H) &lt; ⁺ & gt ^;

Example 4. N - (1- cyclo hexyloxy-methyl -1 H-pyrazol-3-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide

(3-methyl-pyridin-2-yl) -benzoic acid prepared in Reference Example 1 was used instead of 2-aminothiazole and 1-cyclohexyloxymethyl 3-amino -1 H - a compound of pyrazole example 4 in the same manner as in example 1, except for using 259.7 mg (1-cyclohexyloxymethyl-3 -amino-1 H -pyrazole) was prepared.

Yield: 77.0%

_{^{1 H-NMR (CDCl 3)}} δ 10.50 (s, 1H), 8.52-8.51 (d, 1H), 8.02 (s, 1H), 7.97-7.95 (d, 2H), 7.78-7.73 (m, 2H), 2H), 5.47 (s, 2H), 3.33 (s, 2H), 7.59 (s, 1H), 7.49-7.48 (d, 1H), 7.38-7.35 1H), 1.22 (s, 3H), 2.37 (s, 3H), 1.64-1.53 (brs, 4H) ; MS m / z 561.7 (M + H) &lt; ⁺ & gt ^;

Example 5. -Benzoylamino] -pyrazol-1-yl} -acetic acid ethyl ester (prepared as described in Example 1)

(3-Amino-pyridin-2-yl) -benzoic acid was used instead of 2-aminothiazole by using 3- (4-methanesulfonyl-phenoxy) 1 H - pyrazol-1-yl) acetate the compound of (ethyl (3-amino-1H -pyrazol-1-yl) acetate) example 5 in the same manner as in example 1, except for using 528.8 mg .

Yield: 13.3%

MS m / z 535.2 (M + H) &lt; ⁺ & gt ^;

Example 6. 2-yl) -benzoylamino] -pyrazol-1-yl} -propionic acid ethyl ester

(3-methyl-pyridin-2-yl) -benzoic acid prepared in Reference Example 1 was used instead of 2-aminothiazole, and ethyl 2- (3- amino -1 H - pyrazol-1-yl) propionate conducted (ethyl 2- (3-amino- 1H-pyrazol-1-yl) same procedure as in example 1, except for using 572.6 mg propanoate The compound of Example 6 was prepared.

Yield: 27.5%

MS m / z 549.2 (m + H) &lt; ⁺ & gt ^;

Example 7. N - (ethoxymethyl-1- -1 H-pyrazol-3-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) Benzamide

(4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid prepared in Reference Example 1 and replacing 2-aminothiazole with 1-ethoxymethyl- The compound of Example 7 was prepared in the same manner as in Example 1 except that 441.2 mg of 1- H -pyrazol-3-amine (1- (ethoxymethyl) -1 H -pyrazol-3-amine)

Yield: 11.2%

MS m / z 507.2 (m + H) &lt; ⁺ & gt ^;

Example 8. N - [1- (2- diethyl-amino-ethyl) -1 H-pyrazol-3-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-2- Yl) benzamide

Benzoic acid was used in place of 2-aminothiazole, which had been prepared in Reference Example 1, and that 1- [2- ((4-methanesulfonyl-phenoxy) diethylamino) ethyl] -1 H - pyrazol-3-amine (1- [2- (diethylamino) ethyl ] -1 as in example 1, except that -pyrazol-3-amine) using 569.7 mg H The compound of Example 8 was prepared in the same manner.

Yield: 7.9%

MS m / z 548.2 (M + H) &lt; ⁺ & gt ^;

Example 9. 3- (4-methanesulfonyl-phenoxy) - N - [1- (2- methoxy-ethoxymethyl) -1 H-pyrazol-3-yl] -5- (3-methyl - pyridin-2-yl) benzamide

(4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoic acid prepared in Reference Example 1 was used instead of 2- ethoxy-to-pyrazol (1- (2-methoxyethoxymethyl) -3 -amino-1 the same way as in example 1, except for using 535.1 mg H -pyrazole) - ethoxymethyl) -1 H-3-amino-a The compound of Example 9 was prepared.

Yield: 58.6%

_{^{1 H-NMR (CDCl 3)}} δ 8.85-8.54 (t, 2H), 7.94-7.92 (m, 2H), 7.89-7.88 (m, 1H), 7.65-7.64 (m, 2H), 7.62 (s, 1H ), 7.52-7.52 (d, 1H), 7.46-7.45 (m, IH), 7.19-7.17 (m, 2H), 6.93-6.92 , 2H), 3.51-3.49 (m, 2H), 3.36 (s, 3H), 3.07 (s, 3H), 2.39 (s, 3H); MS m / z 537.2 (M + H) &lt; ⁺ & gt ^;

Example 10. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [1- (2- morpholine-4-yl-ethyl) -1 H -pyrazol-3-yl] benzamide

Benzoic acid was used in place of 2-aminothiazole, which had been prepared in Reference Example 1, and that 1- [2- ((4-methanesulfonyl-phenoxy) morpholine-4-yl) -ethyl] -1 H-3-amino-pyrazole (1- [2- (morpholin-4 -yl) -ethyl] -3-amino-1 H -pyrazole) using 613.3 mg The compound of Example 10 was prepared in the same manner as in Example 1,

Yield: 13.3%

MS m / z 562.2 (M + H) &lt; ⁺ & gt ^;

Example 11 N- (4-Diethylaminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) Trifluoroacetic acid salt

See the N prepared in Example 2- (4-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide 150.0 mg was dissolved in 5.0 mL of N , N -dimethylformamide, 18.0 mg of 33% diethylamine aqueous solution, 54.0 mg of potassium carbonate and 4.8 mg of iodotassium were added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with distilled water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white liquid residue. The residue was purified by Prep-HPLC (developing solvent: dichloromethane / methanol = 5/1; 5% trifluoroacetic acid) to give 10.0 mg (Yield: 26.5%) of the title compound as white liquid.

MS m / z 551.9 (M + H) &lt; ⁺ & gt ^;

Example 12. Synthesis of N - (4- [1,4 '] bipiperidinyl-l'-yl-methyl-thiazol-2-yl) -3- (4- methanesulfonyl- phenoxy) 3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 22.2 mg of 4-piperidinopiperidine was used instead of 33% aqueous solution of diethylamine, to thereby prepare the compound of Example 12.

Yield: 25.1%

_{^{1 H-NMR (CDCl 3)}} δ 8.75-8.73 (t, 1H), 8.29-8.27 (d, 1H), 8.22 (s, 1H), 7.99-7.95 (m, 3H), 7.82-7.82 (d, 1H 2H), 3.50-3.47 (m, 3H), 2.56 (m, 2H), 7.43 (s, s, 3H), 2.24-2.21 (d, 2H), 1.93 (m, 4H); MS m / z 523.7 (M + H) &lt; ⁺ & gt ^;

Example 13. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (4- (pyrimidin-2-yl) -piperazine Yl-methyl) -thiazol-2-yl] benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 21.7 mg of 2- (1-piperazinyl) pyrimidine instead of 33% diethylamine aqueous solution was used in place of 33% diethylamine aqueous solution. 13 &lt; / RTI &gt;

Yield: 18.3%

¹ H-NMR (CDCl ₃ )? 8.78-8.77 (d, 1H), 8.41-8.40 (d, 2H), 8.32-8.30 ), 7.85-7.82 (m, 1 H), 7.46 (s, 1 H), 7.26 (s, 6H), 6.72-6.69 (t, 2H), 4.31 s, 4H), 3.08-3.07 (d, 3H), 2.58 (s, 3H); MS m / z 643.1 (M + H) &lt; ⁺ & gt ^;

Example 14. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (4- (pyrrolidin-1-yl-methyl) -thiazole Yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 9.4 mg of pyrrolidine was used in place of the 33% aqueous solution of diethylamine, the compound of Example 14 was prepared.

Yield: 11.2%

_{^{1 H-NMR (CDCl 3)}} δ 8.77-8.76 (d, 1H), 8.27 (s, 1H), 8.04-8.02 (t, 2H), 7.96-7.94 (d, 2H), 7.60-7.55 (m, 3H 2H), 3.07 (s, 3H), 3.07 (s, 3H), 2.27 (s, 2.53 (s, 3H), 2.04-2.00 (t, 2H), 1.92-1.89 (t, 2H); MS m / z 549.1 (m + H) &lt; ⁺ & gt ^;

Example 15. 3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-ethylamino) methyl] thiazol-2-yl} -5- (3-methyl-pyridine Yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 9.9 mg of 2-methoxyethylamine instead of the 33% aqueous solution of diethylamine was used in place of the 33% diethylamine aqueous solution.

Yield: 4.4%

MS m / z 553.3 (M + H) &lt; ⁺ & gt ^;

Example 16. Preparation of 4- {2- [3- (4-methanesulfonyl-phenoxy) -5- - piperazine-1-carboxylic acid ethyl ester trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 18.8 mg of ethyl N-piperazinecarboxylate in place of the 33% aqueous solution of diethylamine, the compound of Example 16 was prepared.

Yield: 5.2%

MS m / z 636.2 (m + H) &lt; ⁺ & gt ^;

Example 17. N - [4- (4-Hydroxy-piperidin-l-yl-methyl) -thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) -5- 3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 13.4 mg of 4-hydroxypiperidine was used instead of 33% aqueous solution of diethylamine. The procedure of Example 11 was repeated except for using 13 mg of 4-hydroxypiperidine.

Yield: 15.5%

MS m / z 579.8 (m + H) &lt; ⁺ & gt ^;

Methyl-pyridin-2-yl) -benzoylamino] -thiazol-4-yl-methyl} -piperidine- -Piperidine-4-carboxamide &lt; / RTI &gt; trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 16.9 mg of isonipecotamide was used in place of the 33% aqueous solution of diethylamine, the compound of Example 18 was prepared.

Yield: 12.0%

MS m / z 606.9 (m + H) &lt; ⁺ & gt ^;

Example 19. 3- (4-methanesulfonyl-phenoxy) - N - [4- (4-methyl-piperazin-1-yl-methyl) thiazol-2-yl] -5- (3 Methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 1-methylpiperazine (13.2 mg) was used instead of 33% diethylamine aqueous solution, the compound of Example 19 was prepared.

Yield: 23.6%

MS m / z 578.9 (m + H) &lt; ⁺ & gt ^;

Example 20 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (morpholine-4-yl-methyl) -thiazole- 2-yl] benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.5 mg of morpholine was used instead of 33% diethylamine aqueous solution, the compound of Example 20 was prepared.

Yield: 25.3%

MS m / z 565.8 (m + H) &lt; ⁺ & gt ^;

Example 21. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (piperazin-1-yl-methyl) -thiazole- 2-yl] benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.4 mg of piperazine was used in place of the 33% aqueous solution of diethylamine, the compound of Example 21 was prepared in the same manner as in Example 11.

Yield: 8.4%

MS m / z 564.8 (m + H) &lt; ⁺ & gt ^;

Example 22. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (4- (pyrrolidin-1-yl) - P 1-yl-methyl) -thiazol-2-yl] benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 Was used in place of diethylamine and 20.4 mg of 4- (1-pyrrolidinyl) piperidine was used in place of 33% aqueous solution of diethylamine. The compound of Example 22 was prepared.

Yield: 33.3%

MS m / z 633.0 (m + H) &lt; ⁺ & gt ^;

Example 23. Preparation of N - [4- (4-ethyl-piperazin-1-yl-methyl) -thiazol- Methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 15.1 mg of 1-ethylpiperazine instead of 33% aqueous solution of diethylamine was used in place of 33% diethylamine aqueous solution.

Yield: 16.3%

MS m / z 592.9 (m + H) &lt; ⁺ & gt ^;

Example 24. N - [4- (4-Isopropyl-piperazin-1-yl-methyl) -thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) Methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 16.9 mg of 1-isopropylpiperazine was used in place of 33% aqueous solution of diethylamine. The procedure of Example 11 was repeated except for using 16.9 mg of 1-isopropylpiperazine.

Yield: 3.4%

MS m / z 606.2 (m + H) &lt; ⁺ & gt ^;

Example 25. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (4-piperidin-1-yl-methyl-thiazol -2 - yl) benzamide

See the N prepared in Example 2- (4-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide 150.0 mg of the title compound was dissolved in 5.0 mL of N , N -dimethylformamide, 26.6 mg of piperidine, 54.0 mg of potassium carbonate and 4.8 mg of iodopotassium was added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was washed with distilled water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a white liquid residue. The residue was purified by Prep-HPLC (developing solvent: dichloromethane / methanol = 5/1) to give the title compound as white liquid.

Yield: 30.3%

_{^{1 H-NMR (CDCl 3)}} δ 8.55-8.55 (d, 1H), 7.95-7.92 (m, 3H), 7.68-7.62 (m, 2H), 7.52-7.51 (t, 1H), 7.27-7.24 (t 2H), 7.20-7.17 (m, 2H), 6.81 (s, IH), 3.51 (s, 2H), 3.08 (s, 3H), 2.40 (brs, 1.43 (s, 2 H); MS m / z 563.9 (M + H) &lt; ⁺ & gt ^;

Example 26. N- (4-dimethylaminomethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 6.0 mg of dimethylamine instead of piperidine was used in place of piperidine, the compound of Example 26 was prepared.

Yield: 6.6%

MS m / z 523.7 (M + H) &lt; ⁺ & gt ^;

Example 27. 4- {2- [3- (4-Methanesulfonyl-phenoxy) -5- -Piperazine-1-carboxylic acid tert-butyl ester

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 Was used in place of piperidine and 24.6 mg of 1-boc-piperazine was used in place of piperidine, the compound of Example 27 was prepared.

Yield: 3.3%

MS m / z 664.2 (M + H) &lt; ⁺ & gt ^;

Example 28. N - (4 - {[bis (2-methoxy-ethyl) -amino] -methyl} thiazol-2-yl) -3- (4- methanesulfonyl- phenoxy) 3-methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 Was used in place of piperidine and 17.6 mg of bis (2-methoxyethyl) amine was used in place of piperidine, to thereby prepare the compound of Example 28 .

Yield: 8.9%

MS m / z 611.2 (m + H) &lt; ⁺ & gt ^;

Example 29. l- {2- [3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl- -Piperidine-4-carboxylic acid ethyl ester

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And ethyl isonipecotate (20.8 mg) was used instead of piperidine, the compound of Example 29 was prepared.

Yield: 2.6%

MS m / z 635.2 (m + H) &lt; ⁺ & gt ^;

Example 30. 3- (4-methanesulfonyl-phenoxy) - N - (4 - { [(2- methoxy-ethyl) -methyl-amino] -methyl} - thiazol-2-yl) -5- (3-methyl - pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 use, piperidine instead of the N - (2-methoxyethyl) methylamine (N - (2-methoxyethyl) methylamine) compounds of those conducted in example 25 was carried out as in example 30 except that 11.8mg .

Yield: 5.1%

¹ H-NMR (CDCl ₃ )? 8.48-8.47 (q, 1 H), 7.97-7.97 (t, 1H), 7.88-7.85 (q, 2H), 7.68-7.67 2H), 3.48-3.45 (t, 2H), 3.28 (s, 3H), 3.54 (s, ), 3.01 (s, 3H), 2.68-2.59 (t, 2H), 2.35 (s, 3H), 2.22 (s, 3H); MS m / z 567.1 (m + H) &lt; ⁺ & gt ^;

Example 31. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (4-oxo-piperidin-1-yl-methyl ) -Thiazol-2-yl] benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 13.1 mg of 4-piperidone was used instead of piperidine, the compound of Example 31 was prepared.

Yield: 4.8%

_{^{1 H-NMR (CDCl 3)}} δ 8.51 (s, 1H), 7.99 (s, 1H), 7.87-7.84 (d, 2H), 7.72 (s, 1H), 7.68-7.66 (d, 1H), 7.41 ( (s, 3H), 3.67 (s, 3H), 2.27 (s, 3H) (s, 4 H), 2.36 (s, 3 H); MS m / z 577.1 (m + H) &lt; ⁺ & gt ^;

Example 32. N- (4-Diethylaminomethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 18.0 mg of 33% diethylamine aqueous solution instead of piperidine was used in place of piperidine, and the compound of Example 32 was prepared.

Yield: 20.8%

_{^{1 H-NMR (CDCl 3)}} δ 8.48-8.47 (m, 1H), 7.91-7.90 (m, 1H), 7.88-7.85 (m, 2H), 7.62-7.62 (t, 1H), 7.58-7.56 (t (S, 2H), 3.51 (s, 2H), 3.01 (s, 3H) ), 2.53-2.47 (q, 4H), 2.34 (s, 3H), 1.00-0.96 (t, 6H); MS m / z 551.0 (M + H) &lt; ⁺ & gt ^;

Example 33. N - [4- (3,6-dihydro- 2H -pyridin-l-yl-methyl) -thiazol- 5- (3-Methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.0 mg of 1,2,3,6-tetrahydropyridine instead of piperidine was used in place of piperidine, the procedure of Example 33 was repeated except for using 11.0 mg of 1,2,3,6-tetrahydropyridine instead of piperidine Lt; / RTI &gt;

Yield: 63.4%

MS m / z 561.0 (M + H) &lt; ⁺ & gt ^;

Example 34. 3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-ethylamino) methyl] thiazol-2-yl} -5- (3-methyl-pyridine Yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 Was used in place of piperidine and 9.9 mg of 2-methoxyethylamine was used instead of piperidine, the compound of Example 34 was prepared.

Yield: 4.4%

_{^{1 H-NMR (CDCl 3)}} δ 8.51-8.49 (t, 1H), 8.10 (s, 1H), 7.93-7.89 (m, 2H), 7.81-7.81 (d, 1H), 7.62-7.60 (d, 1H ), 7.44-7.43 (t, IH), 7.24-7.16 (m, 3H), 6.91 (s, IH), 4.01 (s, 2H), 3.64-3.62 3.07 (s, 3H), 2.99 - 2.96 (t, 2H), 2.39 (s, 3H); MS m / z 553.0 (M + H) &lt; ⁺ & gt ^;

Example 35. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (morpholine-4-yl-methyl) -thiazole- 2-yl] benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.5 mg of morpholine was used in place of piperidine, the compound of Example 35 was prepared in the same manner as in Example 25.

Yield: 69.6%

¹ H-NMR (CDCl ₃ )? 8.51-8.49 (t, 1H), 7.90-7.86 (m, 3H), 7.61-7.60 (q, 1H), 7.58-7.56 (q, 1H), 7.44-7.43 , 7.20-7.18 (m, 1H), 7.13-7.13 (d, 1H), 7.11-7.11 (d, 1H), 6.74 (s, 1H), 3.66-3.64 , 2H), 3.01 (s, 3H), 2.41-2.39 (t, 4H), 2.34 (s, 3H); MS m / z 565.0 (M + H) &lt; ⁺ & gt ^;

Example 36. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (piperazin-1-yl-methyl) -thiazole- 2-yl] benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.4 mg of piperazine was used in place of piperidine, the compound of Example 36 was prepared.

Yield: 8.4%

¹ H-NMR (CDCl ₃ )? 8.47-8.46 (q, 1 H), 7.91-7.85 (m, 3H), 7.63-7.63 4H), 2.87-2.84 (t, 4H), 3.45 (s, 2H) ), 2.41 (s, 4 H), 2.33 (s, 3 H); MS m / z 564.0 (M + H) &lt; ⁺ & gt ^;

Example 37. N - (4-cyclopentyl-aminomethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy) Amide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.2 mg of cyclopentylamine was used in place of piperidine, the compound of Example 37 was prepared.

Yield: 39.2%

^{1 H-NMR (MeOD) δ} 8.69-8.69 (d, 1H), 8.44-8.43 (d, 1H), 8.11-8.11 (t, 1H), 8.00-7.97 (m, 3H), 7.92-7.88 (q, 2H), 3.30-3.28 (m, IH), 3.12 (s, 3H), 2.49 (s, 3H) , 2.14-2.10 (m, 2H), 1.82-1.64 (m, 6H); MS m / z 563.0 (M + H) &lt; ⁺ & gt ^;

Example 38. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (4 - { [( Tetrahydro-furan-2-yl-methyl) Amino] methyl} thiazol-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 13.4 mg of tetrahydrofurfurylamine was used instead of piperidine, the compound of Example 38 was prepared. &Lt; tb &gt; __________________________________ &lt; tb &gt; __________________________________ &lt; tb &gt;

Yield: 49.7%

MS m / z 579.0 (m + H) &lt; ⁺ & gt ^;

Example 39. N - {4 - [(1,2-Dimethyl-propylamino) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) - pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.5 mg of 1,2-dimethylpropylamine instead of piperidine was used in place of piperidine, and the compound of Example 39 was prepared.

Yield: 2.3%

MS m / z 565.0 (M + H) &lt; ⁺ & gt ^;

Example 40. 3- (4-methanesulfonyl-phenoxy) - N - {4 - [ {(2- methoxy-1-methyl) ethylamino} methyl] thiazole-2-yl} -5- ( 3-methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 2-methoxyisopropylamine (11.8 mg) was used instead of piperidine in place of piperidine, the compound of Example 40 was prepared.

Yield: 22.2%

MS m / z 567.0 (m + H) &lt; ⁺ & gt ^;

Example 41. N - [4- (sec-butylaminomethyl) -thiazol-2-yl] -3- (4- methanesulfonyl-phenoxy) ) Benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 9.7 mg of sec-butylamine was used in place of piperidine, the compound of Example 41 was prepared.

Yield: 42.7%

MS m / z 551.0 (M + H) &lt; ⁺ & gt ^;

Example 42. N - {4 - [(2,2-dimethyl- propylamino) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) - pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.5 mg of neopentylamine was used in place of piperidine, the compound of Example 42 was prepared.

Yield: 12.7%

MS m / z 565.0 (M + H) &lt; ⁺ & gt ^;

Example 43. N - {4 - [(2,2-dimethoxy-ethylamino) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) Methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 13.9 mg of aminoacetaldehyde dimethyl acetal instead of piperidine was used in place of piperidine, to thereby prepare the compound of Example 43.

Yield: 59.3%

^{1 H-NMR (MeOD) δ} 8.70-8.69 (d, 1H), 8.43-8.41 (d, 1H), 8.12-8.11 (t, 1H), 8.01-7.98 (m, 3H), 7.66-7.66 (t, 2H), 3.12 (s, 3H), 3.45 (s, 3H) , 2.49 (s, 3H); MS m / z 583.0 (M + H) &lt; ⁺ & gt ^;

Example 44. N - [4- (isobutylaminomethyl) -thiazol-2-yl] -3- (4- methanesulfonyl-phenoxy) Benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 9.7 mg of isobutylamine was used in place of piperidine, the compound of Example 44 was prepared.

Yield: 46.8%

^{1 H-NMR (MeOD) δ} 8.72-8.70 (d, 1H), 8.47-8.45 (d, 1H), 8.12-8.12 (t, 1H), 8.00-7.96 (m, 3H), 7.93-7.90 (q, 2H), 2.49 (s, 3H), 2.27 (s, 3H) , 2.04-2.01 (t, 1H), 1.02-1.00 (d, 6H); MS m / z 551.0 (M + H) &lt; ⁺ & gt ^;

Example 45. N- (4-ethylaminomethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 6.0 mg of ethylamine instead of piperidine was used in place of piperidine, the compound of Example 45 was prepared.

Yield: 34.5%

MS m / z 523.0 (M + H) &lt; ⁺ & gt ^;

Example 46. N - (4-cyclobutylaminomethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 9.4 mg of cyclobutylamine was used in place of piperidine, the compound of Example 46 was prepared.

Yield: 41.2%

MS m / z 549.0 (m + H) &lt; ⁺ & gt ^;

Example 47. N - [4- (isopropylaminomethyl) -thiazol-2-yl] -3- (4- methanesulfonyl-phenoxy) Benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 7.8 mg of isopropylamine was used in place of piperidine, the compound of Example 47 was prepared.

Yield: 35.1%

MS m / z 537.0 (m + H) &lt; ⁺ & gt ^;

Example 48. N - {4 - [(ethyl-methyl-amino) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) - yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 the use, piperidine instead of N - to prepare a compound of ethyl methyl amine (N -ethylmethylamine) example 48 in the same manner as in example 25 except for using 7.8 mg.

Yield: 47.7%

MS m / z 537.0 (m + H) &lt; ⁺ & gt ^;

Example 49. 3- (4-Methanesulfonyl-phenoxy) - N - {4 - [(methyl- propyl- amino) methyl] thiazol- - yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.5 mg of N-propylmethylamine was used in place of piperidine, the compound of Example 49 was prepared.

Yield: 47.4%

MS m / z 551.0 (M + H) &lt; ⁺ & gt ^;

Example 50. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [(4-prop-2-ynyl-amino) methyl-thiazol- 2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 7.3 mg of propargylamine was used in place of piperidine, the compound of Example 50 was prepared.

Yield: 24.1%

MS m / z 533.0 (M + H) &lt; ⁺ & gt ^;

Example 51. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (methyl-propylamino) - thiazol-2-yl] benzamide Amide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 7.8 mg of propylamine was used in place of piperidine, the compound of Example 51 was prepared.

Yield: 45.1%

MS m / z 537.0 (m + H) &lt; ⁺ & gt ^;

Example 52. N - [4- (3-hydroxy-pyrrolidin- 1 -yl-methyl) -thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) -5- 3-methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 11.5 mg of 3-pyrrolidinol instead of piperidine was used in place of piperidine, to thereby prepare the compound of Example 52.

Yield: 23.0%

MS m / z 565.0 (M + H) &lt; ⁺ & gt ^;

Example 53. N - (4-cyclopropylaminomethyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy)

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 7.5 mg of cyclopropylamine was used instead of piperidine, the compound of Example 53 was prepared. &Lt; tb &gt; &lt; TABLE &gt;

Yield: 20.7%

MS m / z 535.0 (m + H) &lt; ⁺ & gt ^;

Example 54. N - {4 - [( [1,3] dioxin-2-turbulence-ylmethyl-methyl-amino) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy ) -5- (3-methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 Was used in place of piperidine and 13.6 mg of 2-methylaminomethyl-1,3-dioxolane was used in place of piperidine instead of 2-methylaminomethyl-1,3-dioxolane. Lt; / RTI &gt;

Yield: 7.2%

MS m / z 595.0 (m + H) &lt; ⁺ & gt ^;

Example 55. N - [4- (3-hydroxy-piperidin- 1 -yl-methyl) -thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) -5- 3-methyl-pyridin-2-yl) benzamide

3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide prepared in Reference Example 2 And 13.4 mg of 3-hydroxypiperidine was used instead of piperidine, the compound of Example 55 was prepared. The procedure of Example 25 was repeated except that 13.4 mg of 3-hydroxypiperidine was used instead of piperidine.

Yield: 19.1%

MS m / z 579.0 (m + H) &lt; ⁺ & gt ^;

Example 56. N - (4-Diethylcarbamoyl-methyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy) Benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) 100.0 mg was dissolved in 10.0 mL of dichloromethane, 29.6 mg of HOBT, 42.2 mg of EDAC, 49.3 mg of N, N -diisopropylethylamine and 27.9 mg of diethylamine were added and stirred at room temperature overnight. The reaction mixture was added with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by Prep-HPLC (developing solvent: methanol / dichloromethane = 5/95; 5% trifluoroacetic acid) to give 65.2 mg (yield 59.3%) of the title compound as a white solid.

MS m / z 579.9 (m + H) &lt; ⁺ & gt ^;

Example 57. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (2- oxo-2-pyrrolidin-1-yl -Ethyl) -thiazol-2-yl] benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And pyrrolidine (9.4 mg) was used instead of diethylamine, the compound of Example 57 was prepared.

Yield: 5.6%

MS m / z 642.1 (m + H) &lt; ⁺ & gt ^;

Example 58. N - {4 - [(2,2-Dimethoxy-ethylcarbamoyl) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) Methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 70.9 mg of aminoacetaldehyde dimethyl acetal instead of diethylamine was used in place of diethylamine, to thereby prepare the compound of Example 58.

Yield: 88.2%

_{^{1 H-NMR (CDCl 3)}} δ 8.77-8.76 (d, 1H), 8.71-8.16 (d, 1H), 7.97-7.87 (m, 4H), 7.54-7.52 (q, 1H), 7.48-7.45 (m (T, 1H), 7.26-7.21 (m, 2H), 6.95 (s, 1H), 6.63-6.61 , 8H), 3.08-3.07 (d, 3H), 2.49-2. 48 (d, 3H); MS m / z 612.2 (m + H) &lt; ⁺ & gt ^;

Example 59. 3- (4-methanesulfonyl-phenoxy) - N - (4- {2- [4- (2- methoxy-ethyl) -piperazin-1-yl] -2-oxo-ethyl } Thiazol-2-yl) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of diethylamine and 97.2 mg of 1- (2-methoxyethyl) piperazine was used in place of diethylamine, the compound of Example 59 .

Yield: 62.7%

_{^{1 H-NMR (CDCl 3)}} δ 8.63-8.62 (d, 1H), 8.11 (s, 1H), 7.96-7.86 (m, 4H), 7.51-7.49 (t, 2H), 7.23-7.20 (d, 2H ), 6.88 (s, 1H), 5.30 (s, 2H), 4.04-4.02 (t, 2H), 3.80 (s, 3H), 3.77-3.70 3.20 (t, 3 H), 3.07 (s, 3 H), 2.47 (s, 3 H); MS m / z 651.2 (m + H) &lt; ⁺ & gt ^;

Example 60. N - (4 - {[Bis (2-methoxy-ethyl) -carbamoyl] -methyl} thiazol- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of diethylamine and 89.8 mg of bis (2-methoxyethyl) amine was used instead of diethylamine to give the compound of Example 60 .

Yield: 28.3%

MS m / z 640.2 (m + H) &lt; ⁺ & gt ^;

Example 61. 4- (2- {2- [3- (4- Methanesulfonyl-phenoxy) -5- (3-methyl- pyridin- 2- yl) -benzoylamino] -thiazol- } -Acetyl) -piperazine-1-carboxylic acid ethyl ester trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) the use, and diethylamine instead of ethyl N - to prepare a compound of-piperazinecarboxylate example 61 the same procedure as in example 56 except for using 106.6 mg (ethyl N -piperazinecarboxylate).

Yield: 8.7%

MS m / z 665.1 (M + H) &lt; ⁺ & gt ^;

Example 62. 4- (2- {2- [3- (4-Methanesulfonyl-phenoxy) -5- (3- methyl- pyridin- 2- yl) -benzoylamino] -thiazol- } -Acetyl) -piperazine-1-carboxylate tert-butyl ester trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And using 125.5 mg of 1-boc-piperazine instead of diethylamine, the compound of Example 62 was prepared.

Yield: 58.1%

MS m / z 693.2 (M + H) &lt; ⁺ & gt ^;

Example 63. N - {4- [2- (4-Ethyl-piperazin-1-yl) -2-oxo-ethyl] thiazol- ) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 1-ethylpiperazine (76.9 mg) was used instead of diethylamine, the compound of Example 63 was prepared.

Yield: 69.8%

MS m / z 621.2 (M + H) &lt; ⁺ & gt ^;

Example 64. N - {4- [2- (4-Isopropyl-piperazin-1-yl) -2-oxo-ethyl] thiazol- Yl) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 86.4 mg of 1-isopropylpiperazine was used in place of diethylamine, the compound of Example 64 was prepared.

Yield: 29.3%

MS m / z 635.2 (m + H) &lt; ⁺ & gt ^;

Example 65. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- {2- ( piperidin-1-yl) -2 -Oxo-ethyl} thiazol-2-yl] benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 57.4 mg of piperidine was used in place of diethylamine, the compound of Example 65 was prepared.

Yield: 1.5%

MS m / z 591.1 (m + H) &lt; ⁺ & gt ^;

Example 66. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-pyrrolidin- Yl-piperidin-l-yl) -ethyl] thiazol-2-yl} -benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And the reaction was carried out in the same manner as in Example 56, except that 103.9 mg of 4- (1-pyrrolidinyl) piperidine was used instead of diethylamine, to obtain the compound of Example 66 .

Yield: 65.1%

MS m / z 661.3 (M + H) &lt; ⁺ & gt ^;

Example 67. N - [4- {2 - ([1,4 '] - Bipiperidinyl-1'-yl) -2-oxo-ethyl} thiazol- Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 113.4 mg of 4-piperidinopiperidine instead of diethylamine was used in place of diethylamine. Example 67 was repeated except that 4-piperidinopiperidine was replaced by 113.4 mg of diethylamine.

Yield: 45.5%

MS m / z 675.3 (M + H) &lt; ⁺ & gt ^;

Example 68. 3- (4-methanesulfonyl-phenoxy) - N - (4 - { [(2- methoxyethyl) -methyl-carbamoyl] methyl} thiazol-2-yl) -5- ( 3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) the use, and diethylamine instead of N -, the compound of example 68 with (2-methoxyethyl) same procedure as in example 56 except for using methylamine 60.1 mg - (2- methoxyethyl) methylamine (N .

Yield: 25.1%

MS m / z 595.2 (m + H) &lt; ⁺ & gt ^;

Example 69. N - {4 - [(2-ethoxy-ethylcarbamoyl) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) Pyridin-2-yl) benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of diethylamine and 60.1 mg of 2-ethoxyethylamine was used in place of diethylamine, the compound of Example 69 was prepared.

Yield: 36.3%

MS m / z 595.2 (m + H) &lt; ⁺ & gt ^;

Example 70. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-pyrimidin -2 Yl-piperazin-l-yl) -ethyl] thiazol-2-yl} -benzamide trifluoroacetic acid salt

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of diethylamine and 110.7 mg of 2- (1-piperazinyl) pyrimidine instead of diethylamine was used in place of diethylamine, the compound of Example 70 .

Yield: 23.5%

MS m / z 670.2 (M + H) &lt; ⁺ & gt ^;

Example 71. 3- (4-methanesulfonyl-phenoxy) - N - {4 - [(3-methoxy-propyl carbamoyl) methyl] thiazol-2-yl} -5- (3-methyl- Pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) 100.0 mg was dissolved in 10.0 mL of dichloromethane, and 29.6 mg of HOBT, 42.2 mg of EDAC, 49.3 mg of N, N -diisopropylethylamine and 60.1 mg of 3-methoxypropylamine were added thereto, . The reaction mixture was added with ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by Prep-HPLC (developing solvent: methanol / dichloromethane = 5/95) to give the title compound as a white solid.

Yield: 33.7%

¹ H-NMR (CDCl ₃ )? 8.55-8.54 (d, 1H), 8.08-8.04 (d, 1H), 7.94-7.91 ), 7.47 (s, 1 H), 7.29-7.26 (m, 1 H), 7.20-7.17 (m, 2 H), 6.81 3.38 (t, 2H), 3.33-3.29 (q, 2H), 3.22 (s, 3H), 3.07-3.07 (d, 3H), 2.40 (s, 3H), 1.73-1.67 (m, 2H); MS m / z 595.1 (m + H) &lt; ⁺ & gt ^;

Example 72. l- (2- {2- [3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl- pyridin- 2- yl) -benzoylamino] -thiazol- } -Acetyl) -piperidine-4-carboxylic acid ethyl ester

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 105.9 mg of ethyl isonipecotate was used in place of 3-methoxypropylamine, the compound of Example 72 was prepared.

Yield: 25.4%

MS m / z 663.1 (M + H) &lt; ⁺ & gt ^;

Example 73. N - {4- [2- (3,6-dihydro- 2H -pyridin- l-yl) -2-oxo-ethyl] thiazol- Sulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 56.0 mg of 1,2,3,6-tetrahydropyridine instead of 3-methoxypropylamine was used instead of 3-methoxypropylamine. The compound of Example 73 was prepared.

Yield: 23.4%

MS m / z 589.1 (m + H) &lt; ⁺ & gt ^;

Example 74. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-pyridin-2- Yl-piperazin-l-yl) -ethyl] thiazol-2-yl} -benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 110.0 mg of 1- (2-pyridyl) piperazine was used in place of 3-methoxypropylamine, Lt; / RTI &gt;

Yield: 62.2%

MS m / z 669.2 (m + H) &lt; ⁺ & gt ^;

Example 75. 3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-ethylcarbamoyl) methyl] thiazol-2-yl} -5- (3-methyl- Pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 50.6 mg of 2-methoxyethylamine was used in place of 3-methoxypropylamine, the compound of Example 75 was prepared.

Yield: 29.9%

MS m / z 581.1 (m + H) &lt; ⁺ & gt ^;

Example 76. N - {4- [2- (2,6-dimethyl-morpholin-4-yl) -2-oxo-ethyl] thiazol- -Phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 77.6 mg of 2,6-dimethylmorpholine was used instead of 3-methoxypropylamine, the compound of Example 76 was prepared in the same manner as in Example 71 .

Yield: 20.5%

MS m / z 621.1 (M + H) &lt; ⁺ & gt ^;

Example 77. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (2- oxo-2-piperazin-1-yl- Ethyl) -thiazol-2-yl] benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 38.1 mg of piperazine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine, the compound of Example 77 was prepared.

Yield: 28.9%

MS m / z 592.2 (m + H) &lt; ⁺ & gt ^;

Example 78. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-pyrimidin -2 Yl-piperazin-l-yl) -ethyl] thiazol-2-yl} -benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 110.7 mg of 2- (1-piperazinyl) pyrimidine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine in the same manner as in Example 71, 78 was prepared.

Yield: 33.5%

MS m / z 670.2 (M + H) &lt; ⁺ & gt ^;

Example 79. N- (4-Cyclopropylcarbamoyl-methyl-thiazol-2-yl) -3- (4- methanesulfonyl- phenoxy) Benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 38.5 mg of cyclopropylamine was used in place of 3-methoxypropylamine, the compound of Example 79 was prepared.

Yield: 71.1%

^{1 H-NMR (DMSO) δ} 8.52-8.51 (d, 1H), 8.18 (s, 1H), 8.04-8.03 (d, 1H), 7.98-7.93 (m, 3H), 7.78-7.76 (d, 1H) , 7.59 (s, IH), 7.37-7.30 (m, 3H), 6.95 (s, IH), 3.43 (s, 2H), 3.22 , 3H), 0.61-0.57 (m, 2H), 0.40-0.36 (m, 2H); MS m / z 563.0 (M + H) &lt; ⁺ & gt ^;

Example 80. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (4 - { [( Tetrahydro-furan-2-yl-methyl) Carbamoyl] methyl} thiazol-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 68.2 mg of tetrahydrofurfurylamine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine, the compound of Example 80 was prepared.

Yield: 91.1%

MS m / z 607.0 (M + H) &lt; ⁺ & gt ^;

Example 81. N - [4- (isopropylcarbamoyl-methyl) -thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) Yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 39.8 mg of isopropylamine was used in place of 3-methoxypropylamine, the compound of Example 81 was prepared.

Yield: 50.3%

¹ H-NMR (CDCl ₃ )? 8.56-8.55 (d, 1H), 7.97-7.92 (m, 3H), 7.74-7.73 (t, 1H), 7.66-7.64 , 7.29-7.26 (m, 1H), 7.20-7.17 (m, 2H), 6.80 (s, 1H), 5.99-5.97 , 2H), 3.07 (s, 3H), 2.40 (s, 3H), 1.11-1.09 (d, 6H); MS m / z 565.0 (M + H) &lt; ⁺ & gt ^;

Example 82. N - (4-cyclopentylcarbamoyl-methyl-thiazol-2-yl) -3- (4- methanesulfonyl- phenoxy) Benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And cyclopentylamine (57.4 mg) was used instead of 3-methoxypropylamine, the compound of Example 82 was prepared.

Yield: 66.8%

MS m / z 591.0 (M + H) &lt; ⁺ & gt ^;

Example 83. N - {4 - [(2-hydroxy-ethylcarbamoyl) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) Pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 41.2 mg of ethanolamine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine, the compound of Example 83 was prepared.

Yield: 60.7%

MS m / z 567.0 (m + H) &lt; ⁺ & gt ^;

Example 84. N - {4 - [(Cyanomethyl-carbamoyl) methyl] thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) 2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 37.8 mg of aminoacetonitrile was used instead of 3-methoxypropylamine, the compound of Example 84 was prepared.

Yield: 63.8%

MS m / z 560.9 (m + H) &lt; ⁺ & gt ^;

Example 85. N - {4- [2- (3-Hydroxy-pyrrolidin-l-yl) -2-oxo-ethyl] thiazol- Phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 58.7 mg of 3-pyrrolidinol was used instead of 3-methoxypropylamine, the compound of Example 85 was prepared.

Yield: 79.0%

MS m / z 593.0 (m + H) &lt; ⁺ & gt ^;

Example 86. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- (2- methyl-pyrrolidin-1 Yl) -2-oxo-ethyl] thiazol-2-yl} -benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 2-methylpyrrolidine (57.4 mg) was used instead of 3-methoxypropylamine, the compound of Example 86 was prepared.

Yield: 88.8%

MS m / z 591.0 (M + H) &lt; ⁺ & gt ^;

Example 87. N - [4- {2- (Azetidin-1-yl) -2-oxo-ethyl} thiazol-2-yl] -3- (4- methanesulfonyl- phenoxy) (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 38.5 mg of azetidine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine, the compound of Example 87 was prepared.

Yield: 79.5%

_{^{1 H-NMR (CDCl 3)}} δ 8.56-8.55 (d, 1H), 7.97-7.92 (m, 3H), 7.70-7.64 (t, 2H), 7.47 (s, 1H), 7.29-7.26 (m, 1H 2H), 3.50-3.49 (d, 2H), 3.08 (s, 3H) ), 2.40 (s, 3H), 2.27 - 2.23 (t, 2H); MS m / z 563.0 (M + H) &lt; ⁺ & gt ^;

Example 88. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- (3-morpholine-4-azepin Yl) -2-oxo-ethyl] thiazol-2-yl} -benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) , And 96.8 mg of 4- (azetidin-3-yl) morpholine instead of 3-methoxypropylamine was used instead of 4- (azetidin-3-yl) morpholine , The compound of Example 88 was prepared.

Yield: 49.3%

MS m / z 648.0 (M + H) &lt; ⁺ & gt ^;

Example 89. N - (4-ethylcarbamoyl-methyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy) Amide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 30.4 mg of ethylamine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine, the compound of Example 89 was prepared.

Yield: 22.8%

MS m / z 550.8 (m + H) &lt; ⁺ & gt ^;

Example 90. N - {4- [2- (2,5-Dimethyl-pyrrolidin-l-yl) -2-oxo-ethyl] thiazol- Fluoro-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 66.8 mg of 2,5-dimethylpyrrolidine was used instead of 3-methoxypropylamine to prepare the compound of Example 90 Respectively.

Yield: 42.6%

MS m / z 604.8 (m + H) &lt; ⁺ & gt ^;

Example 91. 3- (4-methanesulfonyl-phenoxy) - N - {4- [2- (3-methoxy-azetidin-1-yl) -2-oxo-ethyl] thiazol-2 Yl} -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 58.7 mg of 3-methoxyazetidine was used instead of 3-methoxypropylamine, to thereby prepare the compound of Example 91.

Yield: 42.7%

MS m / z 592.8 (m + H) &lt; ⁺ & gt ^;

Example 92. N - (4-cyclobutylcarbamoyl-methyl-thiazol-2-yl) -3- (4- methanesulfonyl-phenoxy) Benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 47.9 mg of cyclobutylamine instead of 3-methoxypropylamine was used in place of 3-methoxypropylamine, the compound of Example 92 was prepared.

Yield: 40.8%

MS m / z 577.0 (m + H) &lt; ⁺ & gt ^;

Example 93. N - {4 - [(2,2-Dimethylamino-ethylcarbamoyl) methyl] thiazol-2-yl} -3- (4- methanesulfonyl- phenoxy) -Methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used instead of N, N-dimethylethylenediamine, and 59.4 mg of N, N-dimethylethylenediamine was used instead of 3-methoxypropylamine to prepare the compound of Example 93 Respectively.

Yield: 68.8%

MS m / z 594.0 (m + H) &lt; ⁺ & gt ^;

Example 94. 3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [(4-prop-2-ynyl-carbamoyl) -methyl- Thiazol-2-yl] benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 37.8 mg of propargylamine was used instead of 3-methoxypropylamine, the compound of Example 94 was prepared.

Yield: 65.6%

^{1 H-NMR (DMSO) δ} 8.61 (s, 1H), 8.52-8.51 (d, 1H), 8.18 (s, 1H), 7.98-7.43 (q, 3H), 7.78-7.76 (d, 1H), 7.59 (s, 3H), 2.39 (s, 3H), 3.39 (s, 2H) ); MS m / z 561.9 (M + H) &lt; ⁺ & gt ^;

Example 95. 3- (4-methanesulfonyl-phenoxy) - N - {4- [2- (2- methoxymethyl-pyrrolidin-1-yl) -2-oxo-ethyl] thiazole - 2- yl} -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 77.6 mg of 2- (methoxymethyl) pyrrolidine was used in place of 3-methoxypropylamine, the compound of Example 95 .

Yield: 69.3%

MS m / z 621.0 (M + H) &lt; ⁺ & gt ^;

Example 96. 3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-1-methyl-ethylcarbamoyl) methyl] thiazol-2-yl} -5- ( 3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) Was used in place of 3-methoxypropylamine and 60.1 mg of 2-methoxyisopropylamine was used instead of 3-methoxypropylamine, the compound of Example 96 was prepared.

Yield: 41.3%

MS m / z 595.0 (m + H) &lt; ⁺ & gt ^;

Example 97. N - {4- [2- (3-Fluoro-azetidin-l-yl) -2-oxo-ethyl] thiazol- Yl) -5- (3-methyl-pyridin-2-yl) benzamide

Yl} -benzoylamino] -thiazol-4-yl} - acetic acid (prepared as described in Reference Example 3) And 50.6 mg of 3-fluoroazetidine instead of 3-methoxypropylamine was used in place of 3-fluoroazetidine.

Yield: 54.1%

MS m / z 581.0 (M + H) &lt; ⁺ & gt ^;

Example 98. Preparation of 3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -thiazol-

61.0 mg of 3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) -benzoic acid prepared in Reference Example 4 was dissolved in 6.0 mL of dichloromethane, 40.0 mg of HOBT, 57.0 mg, triethylamine (0.04 mL) and 2-aminothiazole (18.0 mg) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1N hydrochloric acid and aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain 20.6 mg (yield: 27.7%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 12.1 (brs, 1H), 8.87-8.86 (m, 1H), 8.26-8.24 (m, 1H), 8.01-7.94 (m, 3H), 7.81 (s, 1H), 7.55-7.52 (m, 1H), 7.43 (s, 1H), 7.20-7.17 (m, 3H), 6.88 (m, 1H), 3.08 (s, 3H); MS m / z 497.5 (m + H) &lt; ⁺ & gt ^;

Example 99. N- (5-Fluoro-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy)

(3-nitro-pyridin-2-yl) -benzoic acid prepared in Reference Example 4 was used instead of 2-aminothiazole and 5-fluoro- -Thiazolamine (21.2 mg) in the same manner as in Example 98, the title compound was obtained as a pale-yellow amorphous solid.

Yield: 16.5%

¹ H-NMR (CDCl ₃ )? 11.4 (s, IH), 8.88-8.87 (d, IH), 8.27-8.25 (m, IH), 7.97-7.93 7.57-7.54 (m, 1H), 7.42 (s, 1H), 7.19-7.17 (m, 2H), 6.84-6.83 (d, 1H), 3.08 (s, 3H); MS m / z 515.5 (m + H) &lt; ⁺ & gt ^;

Example 100. 3- (4-methanesulfonyl-phenoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5- (3-nitro-pyridin-2-yl) benzamide

(3-Nitro-pyridin-2-yl) -benzoic acid prepared in Reference Example 4 and replacing 2-aminothiazole with 1-methyl- 1H was prepared pyrazol-3-amine compound of (1-methyl-1 H -pyrazol -3-amine) and example 100 as is, the same method as in example 98 except for using 17.5 mg.

Yield: 35.5%

¹ H-NMR (CDCl ₃ )? 9.10 (s, IH), 8.88-8.87 (d, IH), 8.25-8.23 (m, IH), 7.95-7.90 2H), 6.79-6.78 (d, IH), 3.73 (s, 3H), 7.27-7.26 (m, ), 3.07 (s, 3H); MS m / z 494.5 (m + H) &lt; ⁺ & gt ^;

Example 101. 3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -pyrazin-

Step 1: 3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin- 2-yl) -benzoic acid chloride

In the same manner as in Reference Example 2, Step 1, except for using 3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin- Example 101 The compound of step 1 was prepared.

Step 2: 3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -pyrazin-

(3-nitro-pyridin-2-yl) -benzoic acid chloride prepared in Step 1 and using 2-aminopyrazine instead of 2-aminothiazole ), 25.0 mg of the title compound was obtained in the form of a white solid.

Yield: 12.6%

_{^{1 H-NMR (CDCl 3)}} δ 9.70 (s, 1H), 8.87-8.86 (d, 2H), 8.50 (d, 1H), 8.30-8.19 (m, 2H), 7.98-7.92 (m, 3H), 7.58-7.55 (m, 2H), 7.52-7.49 (m, 3H), 3.08-3.06 (d, 3H); MS m / z 492.5 (m + H) &lt; ⁺ & gt ^;

Example 102. 3- (3-amino-pyridin-2-yl) -5- (4-Methanesulfonyl-phenoxy) - N-thiazol-2-yl-benzamide

12.0 mg of 3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) -N -thiazol-2- yl) benzamide prepared in Example 98 was dissolved in 3.0 mL And 1.0 mL of dichloromethane, 10.0 mg of 10% palladium was added, and the mixture was stirred overnight at room temperature under hydrogen gas balloon pressure. The reaction mixture was filtered using a celite pad, and then concentrated under reduced pressure to obtain 2.6 mg (yield: 21.6%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ )? 8.20 (m, 1H), 7.91 (m, 2H), 7.72-7.64 (m, 4H), 7.56-7.53 7.19-7.09 (m, 4 H), 3.07 (s, 3 H); MS m / z 467.5 (m + H) &lt; ⁺ & gt ^;

Example 103. 3- (3-Amino-pyridin-2-yl) - N- (5-fluoro-thiazol-

(4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -thiazol-2-yl) benzamide prepared in Example 98 instead of 3- The title compound was prepared in analogy to the procedure described for the preparation of Example 1, except using N- (5-fluoro-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) , The compound of Example 103 was prepared in the same manner as in Example 102.

Yield: 4.7%

_{^{1 H-NMR (CDCl 3)}} δ 8.05 (m, 1H), 7.91-7.89 (m, 2H), 7.69-7.64 (m, 2H), 7.60-7.53 (m, 2H), 7.48-7.44 (m, 2H ), 7.17-7. 15 (m, 3H), 3.06 (s, 3H); MS m / z 485.5 (m + H) &lt; ⁺ & gt ^;

Example 104. 3- (3-amino-pyridin-2-yl) -5- (4-Methanesulfonyl-phenoxy) - N - (1- methyl -1H- pyrazol-3-yl) benzamide

(4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -thiazol-2-yl) benzamide prepared in Example 98 instead of 3- to a solution of 3- (4-methanesulfonyl-phenoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5- (3-nitro-pyridin-2-yl) benzamide was used for The compound of Example 104 was prepared in the same manner as in Example 102.

Yield: 29.4%

¹ H-NMR (MeOD)? 7.96 (s, IH), 7.89-7.84 (m, 3H), 7.64 (s, IH), 7.47 1H), 7.23-7.19 (m, 3H), 6.51 (s, IH), 3.72 (s, 3H), 3.02 (s, 3H); MS m / z 464.5 (m + H) &lt; ⁺ & gt ^;

Example 105. 3- (4-methanesulfonyl-phenoxy) -5-pyridin-2-yl- N -thiazol-

Step 1: 3- (4-Methanesulfonyl-phenoxy) -5-pyridin-2-yl-benzoic acid methyl ester

Reference Example 1 To a solution of 3- (4-methanesulfonyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane- yl) benzoic acid methyl ester with 300.0 mg N, N - dimethylformamide was dissolved was added to 5.0 mL, here, tetrakis (triphenylphosphine) palladium, 40.0 mg, and then 2-chloro-pyridin placed 122.0 mg, 222.0 mg of sodium carbonate in distilled water 1.0 mL was added to the solution, and the mixture was stirred at 85 ° C for one day. The reaction mixture was cooled to room temperature, and distilled water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain 49.0 mg (yield: 16.3%) of the title compound as a white solid.

Step 2: 3- (4-Methanesulfonyl-phenoxy) -5-pyridin-2-yl-benzoic acid

49.0 mg of 3- (4-methanesulfonyl-phenoxy) -5-pyridin-2-yl-benzoic acid methyl ester prepared in Step 1 was dissolved in 1.0 mL of tetrahydrofuran and 1.0 mL of methanol, and 3N sodium hydroxide solution 4.0 mL was slowly added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, acidified with 1 N hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 34.0 mg (Yield: 69.4%) of yellow liquid.

Step 3: 3- (4-Methanesulfonyl-phenoxy) -5-pyridin-2-yl- N -thiazol-

34.0 mg of 3- (4-methanesulfonyl-phenoxy) -5-pyridin-2-yl-benzoic acid prepared in Step 2 was dissolved in 6.0 mL of dichloromethane, 40.0 mg of HOBT, 57.0 mg of EDAC, and 18.0 mg of 2-aminothiazole were added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 N hydrochloric acid and aqueous ammonium chloride solution, respectively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 2.4 mg (yield: 7.1%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 7.95-7.92 (m, 3H), 7.80-7.78 (m, 3H), 7.69-7.64 (m, 2H), 7.07-7.06 (m, 3H), 6.54-6.53 (d , &Lt; / RTI &gt; 2H), 3.08 (s, 3H); MS m / z 452.5 (m + H) &lt; ⁺ & gt ^;

Example 106. 3- (4-methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-2-yl) - N-thiazol-2-yl-benzamide

Step 1: 3- (4-Methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-2- yl) -benzoic acid methyl ester

Reference Example 1 To a solution of 3- (4-methanesulfonyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxoboronale- Benzoic acid methyl ester was dissolved in 10.0 mL of N , N -dimethylformamide, to which 54.0 mg of tetra-triphenylphosphine palladium and 155.0 mg of 2-chloro-4-nitropyridine were added. 296.0 mg of sodium carbonate Dissolved in distilled water (2.0 mL), and the mixture was stirred at 85 ° C for one day. The reaction mixture was cooled to room temperature, and distilled water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 104.0 mg (Yield: 26.0%) of the title compound as a white solid.

Step 2: 3- (4-Methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-

104.0 mg of 3- (4-methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-2-yl) -benzoic acid methyl ester prepared in Step 1 was dissolved in 2.0 mL of tetrahydrofuran and 2.0 mL of methanol , 3.0 mL of 3N sodium hydroxide solution was added slowly, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, acidified with 1 N hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 39.0 mg of the title compound (yield: 37.5%) as a yellow liquid.

Step 3: 3- (4-Methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-2-yl) - N -thiazol-

39.0 mg of 3- (4-methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-2-yl) -benzoic acid prepared in Step 2 was dissolved in 6.0 mL of dichloromethane, 26.0 mg of HOBT, mg, 0.03 mL of triethylamine and 19.0 mg of 2-aminothiazole were added, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 N hydrochloric acid and aqueous ammonium chloride solution, respectively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to obtain 12.1 mg (Yield: 31.0%) of the title compound as a white solid.

¹ H-NMR (CDCl ₃ )? 11.6 (s, 3H), 8.60-8.40 (m, 1H), 8.05-7.89 (m, 3H), 7.74-7.73 7.32-7.29 (m, 1 H), 7.26-7.16 (m, 3 H), 6.98-6.84 (m, 1 H), 3.07 (s, 3 H); MS m / z 497.5 (m + H) &lt; ⁺ & gt ^;

Example 107. 3- (6-methoxy-3-nitro-pyridin-2-yl) -5- (4-Methanesulfonyl-phenoxy) - N - (1- methyl -1 H-pyrazol -3 - yl) benzamide

Step 1: 3- (6-Methoxy-3-nitro-pyridin-2-yl) -5- (4- methanesulfonyl-phenoxy) -benzoic acid methyl ester

Reference Example 1 To a solution of 3- (4-methanesulfonyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane- Benzoic acid methyl ester (400.0 mg) was dissolved in 10.0 mL of N , N -dimethylformamide, to which 54.0 mg of tetrakis (triphenylphosphine) palladium and 2-chloro-6-methoxy-3-nitropyridine 184.0 mg, and a solution prepared by dissolving 296.0 mg of sodium carbonate in 2.0 mL of distilled water was added thereto, followed by stirring at 85 ° C for one day. The reaction mixture was cooled to room temperature, and distilled water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 114.0 mg (Yield: 28.5%) of the title compound as a white solid.

Step 2: 3- (6-Methoxy-3-nitro-pyridin-2-yl) -5- (4-methanesulfonyl-phenoxy)

2.0 mL of the tetrahydrofuran solution of 114.0 mg of 3- (6-methoxy-3-nitro-pyridin-2-yl) -5- (4- methanesulfonyl- phenoxy) -benzoic acid methyl ester prepared in Step 1 and To 2.0 mL of methanol, 3.0 mL of 3N sodium hydroxide solution was added slowly, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, acidified with 1 N hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 35.0 mg (Yield: 30.7%) of yellow liquid.

Step 3: 3- (6-methoxy-3-nitro-pyridin-2-yl) -5- (4-Methanesulfonyl-phenoxy) - N - (1- methyl -1 H-pyrazole-3 Yl) benzamide

32.6 mg of 3- (6-methoxy-3-nitro-pyridin-2-yl) -5- (4-methanesulfonyl- phenoxy) -benzoic acid prepared in Step 2 was dissolved in 4.0 mL of dichloromethane, 20.0 mg of EDAC, 28.0 mg of EDAC, 0.02 mL of triethylamine and 14.0 mg of 1-methyl- 1H -pyrazole-3-amine were added and stirred overnight at room temperature. The reaction mixture was washed with 1 N hydrochloric acid and aqueous ammonium chloride solution, respectively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/2) to obtain 7.4 mg (yield: 22.7%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 8.41 (s, 1H), 8.25-8.23 (d, 1H), 7.96-7.93 (d, 2H), 7.86 (s, 1H), 7.67 (s, 1H), 7.35 ( (s, 1H), 7.30-7.29 (m, 1H), 7.20-7.18 (m, 2H), 6.87-6.85 3H), 3.08 (s, 3H); MS m / z 524.5 (m + H) &lt; ⁺ & gt ^;

Example 108. 3- (3-nitro-pyridin-2-yl) - N-thiazol-2-yl -5- m-tolyl-yloxy-benzamide

Step 1: 3- ( m -Tolyloxy) -5- (3-nitro-pyridin-2-yl) -benzoic acid methyl ester

Reference Example 5 To a solution of 3- (4-methyl-phenoxy) -5- (4,4,5,5, -tetramethyl- [l, 3,2] dioxaborolane- Benzoic acid methyl ester was dissolved in 5.0 mL of N , N -dimethylformamide. 74.0 mg of tetrakis (triphenylphosphine) palladium (Pd (PPh ₃ ) ₄ ), 2-chloro-3- nitropyridine 222.0 mg, and then a solution prepared by dissolving 405.0 mg of sodium carbonate in 1.0 mL of distilled water was added thereto, followed by stirring at 85 ° C for one day. The reaction mixture was cooled to room temperature, and distilled water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a black liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 307.0 mg (Yield: 65.9%) of the title compound as yellow solid.

_{^{1 H-NMR (CDCl 3)}} δ 8.88 (d, 1H), 8.21-8.19 (m, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 7.50-7.47 (m, 1H), 7.35- 3H), 2.35 (s, 3H), 3.90 (d, IH)

Step 2: 3- ( m -Tolyloxy) -5- (3-nitro-pyridin-2-yl)

307.0 mg of 3- (m-toluyloxy) -5- (3-nitro-pyridin-2-yl) -benzoic acid methyl ester prepared in Step 1 was dissolved in 6.0 mL of tetrahydrofuran and 6.0 mL of methanol, Sodium solution (4.0 mL) was slowly added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, acidified with 1 N hydrochloric acid solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 247.0 mg (Yield: 80.5%) of yellowish solid.

Step 3: 3- (3-Nitro- pyridin-2-yl) -N-thiazol-2-yl-5-m-tolyloxy-benzamide

123.0 mg of 3- (3-nitro-pyridin-2-yl) -5- m -tolyloxy-benzoic acid prepared in Step 2 was dissolved in 5.0 mL of dichloromethane, 135.0 mg of HOBT, 135.0 mg of EDAC, And 42.0 mg of 2-aminothiazole were added thereto, and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1 N hydrochloric acid and aqueous ammonium chloride solution, respectively. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a yellow liquid residue. The residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1/1) to give 24.7 mg (Yield: 20.1%) of the title compound as a white solid.

_{^{1 H-NMR (CDCl 3)}} δ 12.2 (brs, 3H), 8.84-8.83 (m, 1H), 8.21-8.19 (m, 1H), 7.87 (s, 1H), 7.68 (d, 1H), 7.51- 7.49 (m, 1H), 7.34-7.20 (m, 3H), 7.00 (m, 1H), 6.87 (m, 3H), 2.35 (s, 3H); MS m / z 433.5 (m + H) &lt; ⁺ & gt ^;

Test Example 1. Glucokinase Activation Assay

NADPH (Nicotinamide adenine dinucleotide phosphate), which is the final product of glucose phosphorylation by glucose phosphoenolytic enzymes, was measured and the activity of glucose phosphoenolase was measured in terms of the activity of glucose phosphorylase.

Glucokinase (GK) enzyme reaction was carried out in a reaction solution [25 mM HEPES {4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid} pH 7, 25 mM KCl, 1 mM MgCl 2, 10 mM D , 1 mM ATP, 1 mM NADP, 1 mM DTT (Dithiothreitol) and 2.5 μg / mL G6PDH (Glucose-6-phosphate dehydrogenase)] was added to Glucokinase isoform 1 (ProteinOne) at a concentration of 100 ng / , And the compounds of Examples 1 to 108 were treated at concentrations ranging from 10 μM to 100 pM, and the initial absorbance was measured at a wavelength of 340 nm. After the initial absorbance measurement, the cells were cultured at 24 ° C for 15 minutes. Then, the absorbance was measured at a wavelength of 340 nm and the activity of glucokinase by the compound was measured by the change of optical density (OD). Results time processing, the maximum value of the activity compared to the control group not treated with Compound E _max compound la, and the active compound concentration change with statistical analysis software Prism (Prism), (GraphPad Prism version 5.0, GraphPad Software, Inc.) Was used to calculate the EC ₅₀ . The results are shown in Table 1 below.

As shown in Table 1, the compounds according to the present invention can be usefully used for the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes by activating glucokinase.

Test Example 2. Analysis of glucose uptake assay using rat hepatocyte glucose uptake assay (Rat hepatocyte glucose uptake assay)

Male Sprague-Dawley rats weighing 150 to 250 g at 6 weeks were purchased from Orient Bio Inc. (Seongnam city, Korea) and maintained under constant conditions (temperature: 20 ± 2 ℃, humidity: 40-60%, name / cancer cycle: 12 hours). Ten hours before the experiment, the liver of the experimental rats fed only with water was perfused with collagenase for 10 minutes to sufficiently dissolve the liver tissues. The liver was then separated and washed with cold nutrient medium (DMEM) (Gibco BRL Was used. The liver tissue was transferred to a culture dish, cut with surgical scissors to allow hepatocytes isolated from the tissue to flow out, and then passed through sterile gauze to remove the hepatocyte lumps. The hepatocytes that passed through the gauze were treated with culture medium (MF806, Korea) for 5 minutes at 1000 rpm, centrifuged, and the supernatant was discarded. The remaining cells were left in the nutrient medium. The cell solution was placed on a percoll 55% nutrient medium solution and centrifuged at a speed of 270 times of the gravity for 5 minutes. The supernatant was discarded and the precipitated cells were centrifuged 2-3 times with a nutrient medium (MF806, Korea) And centrifuged at 1000 rpm for 5 minutes. The final isolated hepatocytes were dissolved in DMEM high glucose 10% FBS, and the viability and viability of the cells were checked. Twelve well plates (12 wells) for cell culture in which collagen 1 Millions of live hepatocytes were dispensed per well in the wells, and the cells were stabilized by incubating them in a 5% CO 2 incubator for two days. After the culture was completed, the culture medium was removed, and the medium was replaced with 5.6 mM glucose (DMEM low glucose) for 12 hours to eliminate the influence of serum. After 12 hours, the medium was replaced with a medium containing 10 μM of the drug (2-deoxy-D- ( ¹ H3) glucose) in a nutrient medium (DMEM low glucose) containing 2 μCi / ml And cultured for 4 hours. After 4 hours, rinse twice with cold phosphate buffer (phophate base saline), dissolve in 0.1 N sodium hydroxide (NaOH) solution, add radioactivity solution (ACS2 from Amersham), add liquid scintillation counter The amount of radiolabeled glucose was measured using a scintillation counter (Tri-Carb2910TR manufactured by Perkin Elmer), and 1 nM PSN control compound was treated in the same manner, Respectively. The results are shown in Table 2 below.

As shown in Table 2, the compounds according to the present invention can be usefully used for the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes by activating glucokinase.

Test Example 3. Oral Glucosr Tolerance Test (OGTT)

The oral glucose tolerance test (OGTT, oral glucose tolerance test), which is a method for evaluating the oral glucose tolerance test for reducing the blood glucose level and improving the glucose tolerance due to the activation of glucokinase, was measured.

Experimental methods were as follows: Andrikopoulos S, Blair AR, Deluca N, Fam BC, Proietto J, Am J Physiol Endocrinol Metab . 2008, Vol 295, E1323-1332. A concrete description will be given below.

First, 20-25 g of C57BL / 6 male mice at 8 weeks of age were injected into Orient Bio Inc. (Seongnam city, Korea) and maintained under constant conditions (temperature: 20 ± 2 ℃, humidity: 40-60%, name / cancer cycle: 12 hours). Ten hours before the experiment, only water was provided and fasted. Fully fasted animals were measured for fasting body weight and blood glucose, and group separation was performed so that the average blood glucose level of each group was similar. Group separation was performed based on blood glucose. When the grouping was completed, the vehicle (MC1500 powder sold by Sigma) was used as a 0.5% aqueous solution and the test materials (Examples 1 to 108) were orally administered to the test animals. After 30 minutes, 20% glucose The solution was further orally administered in an amount of 0.1 ml per 10 g of body weight. Blood glucose was measured at the tail end of the test animal 1 ~ 2 mm immediately before the administration of the glucose solution and at 30, 60, 120, 180 and 240 minutes after the administration of the glucose solution, And measured with a glucose meter (GLM doctor, AGM-3000, Olmetecus). Using the measured blood glucose values, a time-blood glucose concentration graph was created and the area under the curve (AUC _glucose ) was determined. The results were compared using the results of the excipient-treated group (negative control group) (%) By evaluating the anti-diabetic efficacy of the test substance.

The results are shown in Table 3 below.

As shown in Table 3, the compounds according to the present invention can be usefully used for the treatment of glucokinase mediated diseases such as hyperglycemia and diabetes by activating glucokinase.

Claims (12)

A compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
&Lt; Formula 1 >

Wherein,
R ₁ , R ₂ and R ₃ are, independently of each other, hydrogen; Linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxy; halogen; Nitro; Amino; -NH-R &lt; _{4 &} gt ;; Or an -SO ₂ -R _5,
R ₄ is _{-C (O) -R 6, -C} (O) -OR 6, -C (O) -NH-R 6 or _{-C (S) -NH-R 6} ,
R ₅ and R ₆ are, independently of each other, linear or branched C ₁ -C ₆ alkyl; C ₁ -C ₆ alkoxycarbonyl-C ₁ -C ₆ alkyl; Hydroxycarbonyl-C ₁ -C ₆ alkyl; Nitro, halogen and C ₁ -C ₆ alkoxy; Aryl-C ₁ -C ₆ alkyl; 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N and S; And 5- to 14-membered heteroaryl-C ₁ -C ₆ alkyl comprising 1 to 3 heteroatoms selected from N and S,
A ring is a 5- to 6-membered heteroaryl having at least one N atom and containing from 1 to 3 heteroatoms selected from N and S,
Wherein said A ring heteroaryl is unsubstituted;
halogen;
C ₁ -C ₆ alkyl, wherein the alkyl is halogen, C ₃ -C ₇ cycloalkyloxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, NR ₇ R ₈ and C (O) - NR &lt; ₇ &gt; R &lt; ₈ &gt;);
Straight or branched C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ alkoxy may be substituted or unsubstituted with C ₁ -C ₃ alkoxy;
Pyrrolidinyl -C ₁ -C ₃ alkyl (where the pyrrolidine is halogen, hydroxy, oxo (C = O), a linear or branched C ₁ -C ₆ alkoxycarbonyl of carbonyl, linear or branched C ₁ - C ₁ -C ₆ alkyl, aminocarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine);
Piperidinyl -C ₁ -C ₃ alkyl (where piperidine is C ₁ -C ₆ a halogen, hydroxy, oxo (C = O), a linear or branched C ₁ -C ₆ alkyl, linear or branched C Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of alkoxycarbonyl, aminocarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine;
Piperazinyl-C ₁ -C ₃ alkyl wherein piperazine is straight or branched C ₁ -C ₆ alkyl, straight or branched C ₁ -C ₆ alkoxycarbonyl, pyridine, pyrimidine, pyrrolidine, Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of piperidines, piperazines, and morpholines;
3,6-dihydro- 2H -pyridinyl-C ₁ -C ₃ alkyl;
Morpholinyl -C ₁ -C ₃ alkyl;
Azetidin-carbonyl -C ₁ -C ₃ alkyl (where the azetidine is a linear or branched C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ alkoxy, halogen, pyridine, pyrimidine, pyrrolidine , Piperidine, piperazine, and morpholine); &lt; RTI ID = 0.0 &gt; R &lt; / RTI &gt;
Pyrrolidinecarbonyl-C ₁ -C ₃ alkyl, wherein pyrrolidine is hydroxy, straight-chain or branched C ₁ -C ₆ alkyl optionally substituted by C ₁ -C ₆ alkoxy, pyridine, pyrimidine; Pyrrolidine, piperidine, piperazine and morpholine); &lt; RTI ID = 0.0 &gt;
Piperidinecarbonyl-C ₁ -C ₃ alkyl wherein piperidines are selected from straight or branched C ₁ -C ₆ alkoxycarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt;
3,6-dihydro- 2H -pyridinecarbonyl-C ₁ -C ₃ alkyl;
Piperazine carbonyl -C ₁ -C ₃ alkyl (where the piperazine is a substituted or unsubstituted straight or branched chain with C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, alkoxycarbonyl, pyridine, pyrimidine, pyrrolidine, piperidine, piperazine and morpholine; or
Morpholinecarbonyl-C ₁ -C ₃ alkyl, wherein the morpholine is one or more straight or branched C ₁ -C ₆ alkyl, straight or branched C ₁ -C ₆ alkoxycarbonyl, pyridine, pyrimidine, Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxy,
R ₇ and R ₈ are, independently of each other, hydrogen; Is selected from the group consisting of straight or branched C ₁ -C ₆ alkyl wherein alkyl is hydroxy, C ₁ -C ₆ alkoxy, cyano, di-C ₁ -C ₆ alkylamino, tetrahydrofuran, and [1,3] dioxolane &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt; C ₂ -C ₆ alkynyl; C ₃ -C ₇ cycloalkyl,
B ring is a 5- to 6-membered heteroaryl having at least one N atom and containing from 1 to 3 heteroatoms selected from N and S, said heteroaryl being selected from straight or branched C ₁ -C ₆ alkyl, Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy, carboxy, hydroxy, C ₁ -C ₆ alkoxy, amino, nitro, and halogen,
Provided that R ₁ , R ₂ and R ₃ can not be simultaneously hydrogen. The compound according to claim 1, wherein R ₁ , R ₂ And R &lt; ₃ &gt; are, independently of each other, hydrogen; Linear or branched C ₁ -C ₆ Alkyl; Nitro; Or an -SO ₂ -R _5,
Wherein R ₅ is C ₁ -C ₆ straight or branched chain Alkyl; C ₁ -C ₆ Alkoxycarbonyl-C ₁ -C ₆ Alkyl; Hydroxycarbonyl-C ₁ -C ₆ Alkyl, &lt; / RTI &gt;
A ring is heteroaryl selected from the group consisting of thiazole, pyridine, pyrazole, and pyrazine,
Wherein said A ring heteroaryl is unsubstituted;
halogen;
A straight or branched C ₁ -C ₆ alkyl wherein alkyl is C ₃ -C ₇ cycloalkyloxy, C ₁ -C ₆ alkoxycarbonyl, NR ₇ R ₈ and C (O) -NR ₇ R ₈ Lt; / RTI &gt; may be unsubstituted or substituted with one or more substituents selected from halogen;
Straight or branched C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, wherein C ₁ -C ₆ alkoxy may be substituted or unsubstituted with C ₁ -C ₃ alkoxy;
Pyrrolidinyl-C ₁ -C ₃ alkyl wherein the pyrrolidine may be unsubstituted or substituted with one or more hydroxy;
Piperidinyl-C ₁ -C ₃ alkyl wherein piperidine is hydroxy, oxo (C = O), straight or branched C ₁ -C ₆ alkoxycarbonyl, aminocarbonyl, piperidine and pyrrole &Lt; / RTI &gt; and / or &lt; / RTI &gt;
Piperazinyl-C ₁ -C ₃ alkyl wherein the piperazine is selected from the group consisting of straight or branched C ₁ -C ₆ alkyl, straight or branched C ₁ -C ₆ alkoxycarbonyl and pyrimidines, Lt; / RTI &gt; may be unsubstituted or substituted with a substituent;
3,6-dihydro- 2H -pyridinyl-C ₁ -C ₃ Alkyl;
Morpholinyl -C ₁ -C ₃ alkyl;
Azetidinecarbonyl-C ₁ -C ₃ alkyl, wherein the azetidine may be unsubstituted or substituted with one or more substituents selected from the group consisting of straight or branched C ₁ -C ₆ alkoxy, halogen and morpholine;
Pyrrolidinecarbonyl-C ₁ -C ₃ alkyl wherein pyrrolidine is optionally substituted with one or more substituents selected from hydroxy and C ₁ -C ₆ alkyl, straight or branched, substituted or unsubstituted with C ₁ -C ₆ alkoxy Lt; / RTI &gt;
Piperidinecarbonyl-C ₁ -C ₃ alkyl, wherein piperidines are substituted with one or more substituents selected from the group consisting of straight or branched C ₁ -C ₆ alkoxycarbonyl, pyrrolidines and piperidines, Can be unsubstituted);
3,6-dihydro- 2H -pyridinecarbonyl-C ₁ -C ₃ Alkyl;
Piperazine carbonyl -C ₁ -C ₃ alkyl (where the piperazine is a substituted or unsubstituted straight or branched chain with C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl, linear or branched C ₁ -C ₆ Which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, cyano, nitro, cyano, nitro, cyano, nitro, cyano, or
Morpholinecarbonyl-C ₁ -C ₃ alkyl, wherein the morpholine may be substituted or unsubstituted with one or more straight or branched C ₁ -C ₆ alkyl,
R ₇ and R ₈ are, independently of each other, hydrogen; Is selected from the group consisting of straight or branched C ₁ -C ₆ alkyl wherein alkyl is hydroxy, C ₁ -C ₆ alkoxy, cyano, di-C ₁ -C ₆ alkylamino, tetrahydrofuran, and [1,3] dioxolane &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt; C ₂ -C ₆ alkynyl; C ₃ -C ₇ cycloalkyl,
B ring is heteroaryl selected from the group consisting of pyridine, pyrazole and pyrazine, wherein said heteroaryl of B ring is selected from straight or branched C ₁ -C ₆ alkyl, hydroxycarbonyl, C ₁ -C ₆ alkoxy, amino, nitro , And a halogen, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The compound according to claim 2, wherein R ₁ , R ₂ And R &lt; ₃ &gt; are, independently of each other, hydrogen; methyl; Or -SO ₂ -CH ₃ in the compounds of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 3. The compound of claim 2, wherein the heteroaryl of the A ring is unsubstituted;
Fluorine (F);
C ₁ -C ₃ alkyl, a straight or branched chain (where alkyl is cyclo-hexyloxy, ethoxycarbonyl, NR ₇ R ₈ and C (O) -NR or substituted with one or more substituents selected from the group consisting of ₇ R ₈ Can be unsubstituted);
Ethoxymethyl wherein the ethoxy may be unsubstituted or substituted with methoxy;
Pyrrolidin-1-yl-C ₁ -C ₃ alkyl wherein the pyrrolidine may be unsubstituted or substituted with one or more hydroxy;
Piperidinyl-1-yl -C ₁ -C ₃ alkyl (where piperidine is hydroxy, oxo (C = O), ethoxycarbonyl, aminocarbonyl, piperidin-1-yl and pyrrolidin 1-yl, &lt; / RTI &gt;
Piperazinyl- ₁ -yl-C ₁ -C ₃ alkyl wherein the piperazine is straight or branched C ₁ -C ₃ alkyl, straight or branched C ₁ -C ₄ alkoxycarbonyl and pyrimidine-2- Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;;
3,6-dihydro- 2H -pyridin-1-yl-C ₁ -C ₃ alkyl;
Morpholin-4-yl-C ₁ -C ₃ alkyl;
Azetidin-1-ylcarbonyl-C ₁ -C ₃ Alkyl wherein the azetidine may be unsubstituted or substituted with one or more substituents selected from the group consisting of methoxy, fluorine (F) and morpholin-4-yl;
Pyrrolidin-1-ylcarbonyl-C ₁ -C ₃ alkyl, wherein pyrrolidine may be unsubstituted or substituted with one or more substituents selected from methyl, hydroxy and methyl substituted by methoxy;
Piperidin-1-ylcarbonyl-C ₁ -C ₃ alkyl, wherein the piperidine is optionally substituted with one or more substituents selected from the group consisting of ethoxycarbonyl, pyrrolidin-1-yl and piperidin- Which may be unsubstituted or substituted;
3,6-dihydro- 2H -pyridin-l-ylcarbonyl-C ₁ -C ₃ alkyl;
Piperazin-1-ylcarbonyl-C ₁ -C ₃ alkyl, wherein the piperazine is straight or branched C ₁ -C ₃ alkyl, unsubstituted or substituted with methoxy, straight or branched C ₂ -C ₄ Alkoxycarbonyl, pyridin-2-yl, and pyrimidin-2-yl; or
Morpholin-4-ylcarbonyl-C ₁ -C ₃ alkyl, wherein the morpholine may be substituted with one or more methyl,
R ₇ and R ₈ are, independently of each other, hydrogen; Straight or branched C ₁ -C ₅ alkyl wherein alkyl is hydroxy, methoxy, ethoxy, cyano, dimethylamino, tetrahydrofuran-2-yl, and [1,3] dioxolane- Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;;Prop-2-ynyl;Cyclopropyl;Cyclobutyl; Or cyclopentyl, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. 5. The compound of formula (I) according to claim 4, wherein said heteroaryl of ring A is heteroaryl selected from the group consisting of thiazol-2-yl, pyrazol-3-yl and pyrazin- Or a hydrate or solvate thereof. 3. The compound of claim 2, wherein the heteroaryl of the B ring is optionally substituted with one or more substituents selected from the group consisting of methyl, methoxy, amino and nitro, a pharmaceutically acceptable salt thereof, Or a hydrate or solvate thereof. 7. The compound of claim 6, wherein the heteroaryl of the B ring is pyridin-2-yl, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. The compound according to claim 1, wherein the compound is
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (thiazol-2-yl) -benzamide;
3- (4-methanesulfonyl-phenoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5- (3-methyl-pyridin-2-yl) -benzamide;
N - (5-Fluoro-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - (1 -cyclohexyloxymethyl-1 H -pyrazol-3-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
{3- [3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoylamino] -pyrazol-1-yl} -acetic acid ethyl ester;
2- {3- [3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzoylamino] -pyrazol-1-yl} -propionic acid ethyl ester;
N - (1-Ethoxymethyl-1 H -pyrazol-3-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - [1- (2- diethylamino-ethyl) -1 H-pyrazol-3-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-2- Yl) benzamide;
3- (4-methanesulfonyl-phenoxy) - N - [1- (2- methoxy-ethoxymethyl) -1 H-pyrazol-3-yl] -5- (3-methyl-pyridin -2 -Yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [1- (2- morpholine-4-yl-ethyl) -1 H-pyrazol Yl] benzamide;
N - (4-diethylamino-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -benzamide trifluoroacetic acid salt;
N - (4- [1,4 '] bipiperidinyl-1'-yl-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- Pyridin-2-yl) benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (4- (pyrimidin-2-yl) -piperazin-1-yl -Methyl) -thiazol-2-yl] benzamide trifluoroacetic acid salt;
2-yl) - N- (4- (pyrrolidin-1 -yl-methyl) -thiazol-2- ) Benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-ethylamino) methyl] thiazol-2-yl} -5- (3-methyl-pyridin-2-yl ) Benzamide trifluoroacetic acid salt;
4-yl-methyl} -piperazine-1-carboxylic acid methyl ester was prepared from 4- {2- [3- (4-methanesulfonyl-phenoxy) 1-carboxylic acid ethyl ester trifluoroacetic acid salt;
N - [4- (4-hydroxy-piperidin-1-yl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- Pyridin-2-yl) benzamide trifluoroacetic acid salt;
Yl} -methyl} -piperidine &lt; / RTI &gt;&lt; RTI ID = 0.0 &gt; -4-carboxamide trifluoroacetic acid salt;
Yl) -5- (3-methyl-pyridin-l-yl) -methanone [ 2-yl) benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (morpholine-4-yl-methyl) thiazol-2-yl; Benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (piperazin-1-yl-methyl) thiazol-2-yl; Benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (4- (pyrrolidin-1-yl) -piperidin -1 -Yl-methyl) -thiazol-2-yl] benzamide trifluoroacetic acid salt;
N - [4- (4-ethyl-piperazin-1-yl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin- 2-yl) benzamide trifluoroacetic acid salt;
N - [4- (4-isopropyl-piperazin-1-yl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridine -2-yl) benzamide trifluoroacetic acid salt;
Methyl-pyridin-2-yl) - N - (4-piperidin-l-yl-methyl- Amide;
N - (4-dimethylaminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
4-yl-methyl} -piperazine-1-carboxylic acid methyl ester was prepared from 4- {2- [3- (4-methanesulfonyl-phenoxy) 1-carboxylic acid tert-butyl ester;
N - (4 - {[bis (2-methoxy-ethyl) -amino] -methyl} - thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- Pyridin-2-yl) benzamide;
Yl} -methyl} -piperidine &lt; / RTI &gt;&lt; RTI ID = 0.0 &gt; Carboxylic acid ethyl ester;
3- (4-methanesulfonyl-phenoxy) - N - (4 - { [(2- methoxy-ethyl) -methyl-amino] -methyl} - thiazol-2-yl) -5- (3-methyl -Pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (4-oxo-piperidin-1-yl-methyl) -thiazole -2-yl] benzamide;
N - (4-Diethylaminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - [4- (3,6- dimethyl dihydro -2 H - pyridin-1-yl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3 -Methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-ethylamino) methyl] thiazol-2-yl} -5- (3-methyl-pyridin-2-yl ) Benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (morpholine-4-yl-methyl) thiazol-2-yl; Benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (piperazin-1-yl-methyl) thiazol-2-yl; Benzamide;
N - (4-cyclopentyl-aminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (4 - { [( Tetrahydro-furan-2-yl-methyl) amino] methyl} Thiazol-2-yl) benzamide;
N - {4 - [(1,2- dimethyl-propylamino) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin -2 -Yl) benzamide;
3- (4-methanesulfonyl-phenoxy) - N - {4 - [ {(2- methoxy-1-methyl) ethylamino} methyl] thiazole-2-yl} -5- (3-methyl- Pyridin-2-yl) benzamide;
N - [4- (sec-butylaminomethyl) -thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - {4 - [(2,2- dimethyl-propylamino) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin -2 -Yl) benzamide;
N - {4 - [(2,2- dimethoxy-ethylamino) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin- 2-yl) benzamide;
N - [4- (isobutylaminomethyl) -thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - (4-ethylaminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - (4-cyclobutylaminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - [4- (isopropylaminomethyl) -thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - {4 - [(ethyl-methyl-amino) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide Amide;
3- (4-methanesulfonyl-phenoxy) - N - {4 - [ ( methyl-propyl-amino) methyl] thiazol-2-yl} -5- (3-methyl-pyridin-2-yl) benzamide Amide;
Methyl-pyridin-2-yl) - N - [(4-prop-2-ynylamino) methyl-thiazol- Benzamide;
3- (4-Methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) -N- [4- (propylaminomethyl) -thiazol-2-yl] benzamide;
N - [4- (3-hydroxy-pyrrolidin-1-yl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- Pyridin-2-yl) benzamide;
N - (4 -cyclopropylaminomethyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - {4 - [([ 1,3] dioxin-2-turbulence-ylmethyl-methyl-amino) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5 (3-methyl-pyridin-2-yl) benzamide;
N - [4- (3-hydroxy-piperidin-1-yl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl- Pyridin-2-yl) benzamide;
N - (4-diethyl-carbamoyl-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetate Rosacetate;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (2- oxo-2-pyrrolidin-1-yl-ethyl) Thiazol-2-yl] benzamide trifluoroacetic acid salt;
N - {4 - [(2,2- dimethoxy-ethylcarbamoyl) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridine -2-yl) benzamide trifluoroacetic acid salt;
L -yl] -2-oxo-ethyl} -thiazol-2-one &lt; / RTI & 2-yl) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt;
N - (4 - {[bis (2-methoxy-ethyl) -carbamoyl] -methyl} - thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl -Pyridin-2-yl) benzamide trifluoroacetic acid salt;
-Benzoylamino] -thiazol-4-yl} -acetyl) - &lt; / RTI &gt; -Piperazine-1-carboxylic acid ethyl ester trifluoroacetic acid salt;
-Benzoylamino] -thiazol-4-yl} -acetyl) - &lt; / RTI &gt; -Piperazine-1-carboxylate tert-butyl ester trifluoroacetic acid salt;
N - {4- [2- (4-ethyl-piperazin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5 (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt;
N - {4- [2- (4-isopropyl-piperazin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5 - (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- {2- ( piperidin-1-yl) -2-oxo-ethyl } Thiazol-2-yl] benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-pyrrolidin-1-yl- Piperidin-l-yl) -ethyl] thiazol-2-yl} -benzamide trifluoroacetic acid salt;
N - [4- {2 - ( [1,4 '] - piperidinyl-1'-bi-yl) -2-oxo-ethyl} thiazol-2-yl] -3- (4-methanesulfonyl- Phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) - N - (4 - { [(2- methoxyethyl) -methyl-carbamoyl] methyl} thiazol-2-yl) -5- (3-methyl- Pyridin-2-yl) benzamide trifluoroacetic acid salt;
N - {4 - [(2- ethoxy-ethyl carbamoyl) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-2- Yl) benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-piperazine L-yl) -ethyl] thiazol-2-yl} -benzamide trifluoroacetic acid salt;
3- (4-methanesulfonyl-phenoxy) - N - {4 - [(3-methoxy-propyl carbamoyl) methyl] thiazol-2-yl} -5- (3-methyl-2- Yl) benzamide;
-Benzoylamino] -thiazol-4-yl} -acetyl) -benzoic acid methyl ester was prepared from 1- (2- {2- [3- (4- methanesulfonyl- phenoxy) -Piperidine-4-carboxylic acid ethyl ester;
N - {4- [2- (3,6- dimethyl dihydro -2 H - pyridin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy Yl) -5- (3-methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-pyridin-2-yl-piperazine -1-yl) -ethyl] thiazol-2-yl} -benzamide;
Yl) -5- (3-methyl-pyridin-2-yl) - N- (4- methanesulfonyl-phenoxy) Yl) benzamide;
N - {4- [2- (2,6- Dimethyl-morpholine-4-yl) ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - [4- (2- oxo-2-piperazin-1-yl-ethyl) Im Azol-2-yl] benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- oxo-2- (4-piperazine L-yl) -ethyl] thiazol-2-yl} -benzamide;
N - (4-Cyclopropylcarbamoyl-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - (4 - { [( Tetrahydro-furan-2-yl-methyl) carbamoyl] methyl Gt; thiazol-2-yl) &lt; / RTI &gt;benzamide;
N - [4- (isopropyl-carbamoyl-methyl) thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide ;
N - (4-cyclopentylcarbamoyl-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - {4 - [(2- hydroxy-ethyl carbamoyl) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-2- Yl) benzamide;
N - {4 - [(cyanomethyl-carbamoyl) methyl] thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) Benzamide;
N - {4- [2- (3- hydroxy-pyrrolidin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) 5- (3-Methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- (2- methyl-pyrrolidin-1-yl) -2 -Oxo-ethyl] thiazol-2-yl} -benzamide;
N - [4- {2- (azetidin-1-yl) -2-oxo-ethyl} thiazol-2-yl] -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl -Pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) - N - {4- [2- (3-morpholine-4-yl-azetidin-1 Yl) -2-oxo-ethyl] thiazol-2-yl} -benzamide;
N - (4-Ethylcarbamoyl-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - {4- [2- (2,5- Dimethyl-pyrrolidin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy ) -5- (3-methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) - N - {4- [2- (3-methoxy-azetidin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -5 - (3-methyl-pyridin-2-yl) benzamide;
N - (4-Cyclobutylcarbamoyl-methyl-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridin-2-yl) benzamide;
N - {4 - [(2,2- dimethyl-amino-ethylcarbamoyl) methyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5- (3-methyl-pyridine -2-yl) benzamide;
Methyl-pyridin-2-yl) - N - [(4-prop-2-ynyl-carbamoyl) -methyl-thiazol- - &lt; / RTI &gt;benzamide;
3- (4-methanesulfonyl-phenoxy) - N - {4- [2- (2- methoxymethyl-pyrrolidin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -5- (3-methyl-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) - N - {4 - [ (2- methoxy-1-methyl-ethylcarbamoyl) methyl] thiazol-2-yl} -5- (3-methyl- Pyridin-2-yl) benzamide;
N - {4- [2- (3-fluoro-azetidin-1-yl) -2-oxo-ethyl] thiazol-2-yl} -3- (4-methanesulfonyl-phenoxy) -5 - (3-methyl-pyridin-2-yl) benzamide;
3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -thiazol-2-yl) benzamide;
N - (5-Fluoro-thiazol-2-yl) -3- (4-methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) benzamide;
3- (4-methanesulfonyl-phenoxy) - N - (1- methyl -1 H-pyrazol-3-yl) -5- (3-nitro-pyridin-2-yl) -benzamide;
3- (4-Methanesulfonyl-phenoxy) -5- (3-nitro-pyridin-2-yl) - N -pyrazin-2-yl-benzamide;
3- (3-Amino-pyridin-2-yl) -5- (4-methanesulfonyl-phenoxy) - N -thiazol-2-yl-benzamide;
3- (3-amino-2-yl) - N - (5-fluoro-thiazol-2-yl) -5- (4-Methanesulfonyl-phenoxy) -benzamide;
3- (3-amino-pyridin-2-yl) -5- (4-Methanesulfonyl-phenoxy) - N - (1- methyl -1H- pyrazol-3-yl) -benzamide;
3- (4-Methanesulfonyl-phenoxy) -5-pyridin-2-yl- N -thiazol-2-yl-benzamide;
3- (4-Methanesulfonyl-phenoxy) -5- (4-nitro-pyridin-2-yl) - N -thiazol-2-yl-benzamide;
N - (l-methyl-lH-pyrazol-3-yl) benzene &lt; / RTI &gt;Amide;
3- (3-nitro-pyridin-2-yl) - N-thiazol-2-yl -5- m-tolyl-yloxy-benzamide
Or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. A process for preparing a compound of formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, comprising reacting a compound of formula (2) with a compound of formula
&Lt; Formula 1 >

(2)

(3)

Wherein A ring, B ring, R ₁ , R ₂ and R ₃ are the same as defined in the above 1, and X is a hydroxyl group or a halogen. A compound of formula (2), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof:
(2)

Wherein R ₁ , R ₂ and R ₃ are the same as defined in claim 1, and X is hydroxy or halogen. For the prophylaxis or treatment of glucokinase mediated diseases comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof A pharmaceutical composition. 12. The pharmaceutical composition according to claim 11, wherein the glucokinase mediated disease is at least one disease selected from the group consisting of obesity hyperglycemia, obesity, type 1 diabetes and type 2 diabetes.