KR20080006997A - Novel Phenylpropanoic Acid Derivatives, Methods for Making the Same, and Peroxysome Prolifer-Activated Receptor Agonists Containing the Same - Google Patents

Abstract

The present invention relates to a novel phenylpropanoic acid derivative, a method for preparing the same, and a peroxisome proliferator-activated receptor (PPAR) agonist containing the same. The compounds of the present invention can simultaneously activate gamma and alpha peroxysome proliferative-activated receptors, and exhibit such effects as hypoglycemic activity, hypolipidemic activity, and insulin resistance improvement by these activities, which are useful for diabetes and metabolic diseases. Can be used.

Description

NOVEL PHENYLPROPIONIC ACID DERIVATIVES AS PEROXISOME PROLIFERATOR-ACTIVATED ALPHA / GAMMA RECEPTOR AGONISTS, METHOD OF THE SAME, AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME }

The present invention relates to a novel compound represented by the following formula (1), a preparation method thereof and a use thereof.

<Formula 1>

The compound of Formula 1 activates a peroxisome proliferator-activated alpha / gamma receptor (hereinafter referred to as 'PPAR-a / g') to lower blood sugar, lower blood lipids, and It can be usefully used as a PPAR-a / g agonist exhibiting effects such as improving insulin resistance.

Diabetes is a chronic metabolic disease with a prevalence of about 5% of the industrialized population, and type 2 diabetes, which accounts for more than 90%, causes insulin secretion with increased insulin resistance, eventually leading to high blood sugar. Insulin resistance in type 2 diabetes is closely linked to the development of other metabolic disorders, such as obesity, atherosclerotic vascular disease and lipid ligament (Rondinone CM., Exp Opin Ther Targets (2005) 9: 415-419). In patients with type 2 diabetes, the incidence of lipid metabolism abnormalities due to increased triglyceride levels or decreased HDL-cholesterol, both of which act as risk factors for coronary heart disease (Devasthale PV). Et al ., J Med Chem (2005) 48: 2248-2250).

However, recent studies have reported that only low blood glucose therapy is effective in improving cardiovascular risk factors for the treatment of type 2 diabetes (UKPDS, Lancet (1999) 352: 837-853). There is a need for development of methods that can be treated at the same time, in particular drugs that can simultaneously treat insulin resistance and dyslipidemia.

On the other hand, peroxisome proliferator-activated receptors (hereinafter referred to as 'PPARs') are nuclear receptors that are activated by ligand binding and regulate expression of target genes. It is known to play a major role in the maintenance of energy homeostasis and inflammatory responses related to the storage and catabolism of the plant (Lemberger T. et al ., J Med Chem (1996) 12: 335-363; Staels B. et al., Diabetes (2005) 54 2460-2470). Among the PPARs of mammals isolated so far, PPAR-γ is widely distributed in adipose tissue and, when activated, exhibits anti-diabetic action that increases insulin sensitivity. PPAR-α is particularly distributed in the liver and, when activated, reduces triglycerides and increases plasma HDL-cholesterol (Harrity T. et al., Diabetes (2006) 55: 240-248). In addition, the activation of each PPAR is expected to be useful in cardiovascular diseases and metabolic syndrome due to inflammation and vascular reinforcement and vascular remodeling inhibition (Staels B. et al., Diabetes (2005) 54: 2460-2470; Verreth W. et al., Arterioscler Thromb Vasc Biol (2006) e-published ahead), and the simultaneous activation of drugs that selectively activate these two types of PPARs to the experimental animals, a complementary mechanism to inhibit the vascular wall inflammatory response It has been shown to have an effect of reducing atherosclerosis (Buchan K. et al., Med Res Rev (2000) 20: 350-366; Duval C. et al., Trends Mol Med (2002) 8: 422-430).

Recently, there is an active research on the development of a single drug that can simultaneously activate one or more PPARs to treat multiple factors of metabolic syndrome, such as drugs that simultaneously activate PPAR-α and PPAR-γ (Ljung B. et al. , J Lipid Res (2002) 43: 1855-1863; Brooks D. et al ., J Med Chem (2001) 44: 2061-2064; Henke B. et al ., J Med Chem (1998) 41: 5020-5036), PPAR- Drugs that activate δ and PPAR-γ (Edward P., Drug Discov Today (2002) 7 (19): 1022), drugs that activate PPAR-δ and PPAR-α (Kasuga J. et al ., Bioorg Med Chem Lett ( 2006) 16: 554-558) and drugs that activate PPAR-α, PPAR-γ, and PPAR-δ (Tenebaum A. et al., Cardiovasc Diabetol (2005) 4:14). The most active studies have been conducted to simultaneously activate PPAR-α and PPAR-γ, and recent studies have demonstrated the efficacy of blood glucose and lipid metabolism in preclinical and clinical trials (Cox SL, Drugs Today (2005) 41: 579-587; Fagerberg B. et al ., Diabetologia (2005) 48: 1716-1725; Oakes ND. Et al., Am J Physiol Regul Integr Comp Physiol (2005) 289: R938-946).

-33% with fasting hypoglycemic activity in hyperglycemic diabetic mice ( db / db mice) receiving repeated doses of PPAR-α / γ dual agonist muraglitazar at 10 mg / kg for 4 weeks Serum triglyceride-lowering activity has been reported to be significant (p <0.05; Devasthale PV. Et al ., J Med Chem (2005) 48: 2248-2250) and clinically repeated 2.5 months or 5 mg for 6 months in hyperglycemic patients. Even when administered, the effect of improving blood sugar and insulin resistance (p <0.001), blood triglyceride drop (-18%, -27%), HDL-cholesterol increase (+ 10%, + 16%), non-HDL-cholesterol drop (-3%, -5%) action was significantly higher than that of the control group, and the effect of these drugs on blood glucose control and lipid metabolism was demonstrated in clinical trials (p <0.05; Buse JB. Et al ., Clin Ther (2005) 27: 1181-1195).

According to Bechan J. et al., A drug that simultaneously activates PPAR-α and PPAR-γ may be useful for the treatment of type 2 diabetes patients with risk factors for cardiovascular disease (Bechan J. et al., J Am). Med Assoc (2002) 287: 2570-2581; Boden G. et al., Expert Opin Investig Drugs (2006) 15: 243-250). In addition, according to Gershell L., in 2009, 10% of dual agonists will simultaneously activate PPAR-α and PPAR-γ in the global market for type 2 diabetes. It is expected to be replaced (Gershell L., Nature Rev (2005) 4: 367-368). This is the third largest after insulin preparations (22%) and PPAR-γ single agent (23%).

The present inventors have completed the present invention by attempting to synthesize a novel compound having a multifactor of metabolic syndrome, especially insulin resistance and dyslipidemic action by activating both PPAR alpha / gamma.

An object of the present invention is to provide a novel phenylpropanoic acid derivative compound and a preparation method thereof.

In addition, the present invention using the phenylpropanoic acid derivative as an active ingredient, PPAR alpha / gamma dual agonist having a PPAR-mediated disease and blood glucose lowering action, blood lipid lowering action, and insulin resistance improving effect (PPAR alpha / gamma dual Agonist).

The present invention provides a novel phenylpropanoic acid compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof.

In addition, the present invention is a PPAR alpha / gamma dual agonist (PPAR alpha / gamma dual) containing a novel phenylpropanoic acid derivative including the 1,3,5-triazine and a pharmaceutically acceptable salt thereof as an active ingredient Agonist).

Hereinafter, the present invention will be described in more detail.

The present invention provides novel compounds having the structure of Formula 1 and pharmaceutically acceptable salts thereof.

<Formula 1>

In the above formula,

R is -OCH ₂ CH ₃ or -CH ₂ CH ₃ ;

Each X is independently —N—CH ₃ , —NH, —O—, or methylene;

Y and Z are each independently lower alkyl; Lower alkoxy; Lower alkylamines; Lower cycloalkylamines; aniline; Azetidine; Pyrrolidine; Piperidine; Piperazine; Morpholine; Thiomorpholine; Phenyl; Or phenoxy, wherein Y and Z are optionally substituted with C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, nitro, trifluoromethyl, phenyl, benzyl, benzoyl, furan, thiophene May have one or more substituents selected from the group consisting of phenoxy, piperidine; And

n represents the integer of 1-5.

In the formula, phenoxy

중에서 선택되는 것이 좋으며,

It is better to choose from

In the above formula, lower alkyl is preferably selected from methyl, ethyl or isopropyl,

In the above formula, lower alkoxy is preferably -OCH ₃ ,

In the above formula, the lower alkylamine is

중에서 선택되는 것이 바람직하고,

It is preferable to select from

Wherein the lower cycloalkylamine is

중에서 선택되는 것이 바람직하다.

It is preferable to select from.

In the above formula, piperidine is

It is preferably selected from,

In the formula, piperazine is

Is preferably selected from

In the formula, phenyl

It is preferable to select from.

The compound of Formula 1 according to the present invention includes racemates and optical isomers.

Representative examples of the compounds of the present invention include the following compounds.

2- (4- (2- (methyl (4- (piperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4- (pyrrolidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4- (4-methylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4- (4-phenylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-benzylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (diethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (dimethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4-morpholin-4-yl-6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) Ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4- (4-phenylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (cyclopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (isopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxyphenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (3,5-dimethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (2-ethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamino) -6- (4-phenylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamino) -6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl mountain;

2- (4- (2-((4- (diethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2-((4- (cyclohexylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamine) -6- (4-phenylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenylamine) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamine) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl- (4- (phenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2- (methyl- (4- (phenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2- (methyl- (4-methylpiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2- (methyl- (4-morpholin-4-yl-6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid ;

2- (4- (2-((4- (diethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ;

2- (4- (2-((4- (dimethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (isopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ;

2- (4- (2-((4- (cyclopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ;

2- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (3-hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (diethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2-((4- (p-toluidino) -6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyric acid;

2- (4- (2-((4- (p-toluidino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid;

2- (4- (2-((4- (p-toluidino) -6- (cyclopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6-((2-hydroxyethyl) (methyl) amino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (p-toluidino) -6- (4-ethylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenoxy) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Benzyl) butyl acid;

2- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid;

2- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid;

2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (azetidin-1-yl) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxy propanoic acid;

3- (4- (2-((4- (diethylamino) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxy propanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxy propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-((2-hydroxyethyl) (methyl) amino-1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (4-hydroxyphenylamino) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

(S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

(S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-thiomorpholin-4-yl-1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

(S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid;

(S) 3- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid;

(S) 3- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid;

(S) to 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) phenyl) -2-ethoxypropanoic acid;

(S) 2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (isopropylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid;

(S) 3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid;

(S) 3- (4- (2-((4- (cyclobutylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid;

(S) 2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-thiomorpholin-4-yl-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (azetidin-1-yl) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (isopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (cyclopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (furan-2-ylmethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2- (methyl (4-morpholin-4-yl-6-p-tolyl-1,3,5-triazin-2-yl) amino) ethoxy) phenyl Propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-ethylphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-methoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (dimethylamino) -6-p-tolyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-e Oxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-ethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (3-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-isopropylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (4-trifluoromethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid;

3- (4- (2-((4- (p-toluidino) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2 Ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-morpholin-4-yl) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid;

3- (4- (2-((4- (dimethylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid;

3- (4- (2-((4- (isopropylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid;

2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid;

2-ethoxy-3- (4- (2-((4-ethyl-6- (3-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain;

2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain;

2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain;

The compounds of the present invention have asymmetric carbon centers and may exist as racemates and individual optical isomers, all of which are in the form of isomers. Optical isomeric compounds confer optical selectivity through enzymatic reactions from racemic intermediates.

Pharmaceutically acceptable salts of compounds of formula 1 according to the invention are salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid, sulfuric acid, or acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, puma Organic carboxylic acids such as leric acid, mandelic acid, ascorbic acid or malic acid or salts with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, and salts with other acids known and used in addition.

The present invention also provides a method for preparing the compound of Formula 1 and its pharmaceutically acceptable salt.

The present invention

i) reacting the following Chemical Formula 2, 3 or 4 compound with the following Chemical Formula 5 under basic conditions;

Ii) producing a substituted cyanuric compound by reacting the following formula (6) cyanuric chloride with Y as defined in Formula (1) using basic conditions or an alkylmagnesium bromide compound of formula (7);

Iii) reacting the compounds prepared in i) and ii) under basic conditions;

iv) reacting Z defined in Chemical Formula 1 under an amine defined in Chemical Formula 1 or boronic acid of Formula 8; And

v) hydrolysis step

To prepare a compound of Formula 1-1.

<Formula 1-1>

Wherein R is -OCH ₂ CH ₃ or -CH ₂ CH ₃ ; X is each independently a compound of the form -N-CH ₃ , or -NH, n represents an integer of 1 to 5, Y and Z are as defined in formula (1).

The reactions iii) to iii) are nucleophile subtitutions, which increase the electrophilicity of carbon by halogen substituents of highly electronegative reactants, and the starting material or the previous step products are nucleophiles. Acts on the carbon. The iii) reaction can be carried out according to the method described in known literature (Moon, HS; Chang, YT et al. , J. Am. Chem. Soc. 2002, 124, 11608-11609). The reaction of the alkylmagnesium bromide and cyanuric chromide in the reaction ii) is for forming a carbon-carbon bond. Therefore, the reaction under the basic conditions in the step iii) to iii) is to stabilize the unshared electron pair or anion of the nucleophile, and the base used is a base which can achieve the above object, for example potassium carbonate, tree Inorganic and organic bases such as ethylamine, ammonia formate, DIEA (N, N-diisopropylethylamine) and the like. The reaction under boronic acid in addition to the base in this step is to form a carbon-carbon bond (Chang, YT et al . Tetrahedron Lett. (2003), 44, 6141-6144). The compound of formula 5 used in i) is synthesized by using a commercially available amine to protect the amine with triphenylmethyl chloride and then converting the hydroxy group into a reactive substituent. In addition, the step iii) is a reaction to recover from -COOZ to -COOH by a hydrolysis reaction. Z is preferably ethyl.

The invention also

Iii) reacting the compound of Formula 3 or 4 with the compound of Formula 9 under basic conditions and then removing the protected benzyl group through a hydrogenation reaction;

Ii) reacting the cyanuric chloride of Formula 6 with Y as defined in Formula 1 using basic conditions or an alkylmagnesium bromide compound of Formula 7 to produce a substituted cyanuric compound;

Iii) reacting Y defined in Chemical Formula 1 under basic conditions;

Iii) reacting Z defined in Chemical Formula 1 with a base or 0.2 equivalent of boric acid and tetrakis (triphenylphosphine) palladium, and cesium carbonate as a base for 5 hours at 90 ° C. in a dioxane solvent; And

Iii) hydrolysis step

To prepare a compound of formula 1-2, including.

<Formula 1-2>

Wherein R is -OCH ₂ CH ₃ , X is -O- type compound, n represents an integer of 1 to 5, Y and Z are as defined in the formula (1).

In addition, the present invention

i) reacting with cyanuric chloride of formula 6 using magnesium bromide compound as defined in formula 7 below;

Ii) reacting Y defined in Chemical Formula 1 under basic conditions;

Iii) reacting Z defined in Chemical Formula 1 with a base or 0.2 equivalent of boric acid and tetrakis (triphenylphosphine) palladium, and cesium carbonate as a base for 5 hours at 90 ° C. in a dioxane solvent;

iv) removing the alcohol protecting group to produce an alcohol compound and then converting the hydroxy group to a methanesulfonate group;

v) reacting the compound of Formula 2 or 3 under basic conditions; And

iv) hydrolysis

To prepare a compound of formula 1-3, including.

<Formula 1-3>

Wherein R is -OCH ₂ CH ₃ , X is -CH ₂ -form compound, n represents an integer of 1 to 5, Y and Z are as defined in the formula (1).

In the present invention, the reaction is carried out by mixing the starting materials and reactants into the reaction solvent and mixing the agitated reactions in the respective preparation processes, wherein the reaction solvent does not affect the reaction and smoothes the nucleophilic substitution reaction and hydrolysis. Alcohols such as methanol, ethers such as dioxane and tetrahydrofuran (THF), aromatic solvents such as benzene and toluene, chloride hydrocarbons such as dichloromethane and dichloroethane, acetonitrile and dimethylformamide (DMF Organic solvents such as) or mixtures thereof, and the like, and the reaction temperature may be performed in the range of 0 to 150 ° C.

<Formula 2>

The compound of Formula 2 includes an optical isomer, and commercially available 4-benzyloxybenzaldehyde may be used as a starting material, and triethyl 2-phosphonobutrate may be prepared through a hydrogenation reaction after condensation. The condensation step can be carried out as described in Comprehensive Organic Synthesis vol. 1 p. 755-781 Pergamon Press or in Scheme 4 below. Hydrides of alkali metals such as NaH and KH or organic lithium such as CH3Li, BuLi, or alkoxides such as NaOMe, NaOEt, t-BuOK or reacted in the presence of a base such as LiOH or NaOH to synthesize an olefin intermediate, followed by hydrogen gas And the reduction reaction can be carried out using Pd / C, Rh / C, Pt / C catalyst or catalyst mixture. Solvents such as dioxane, acetic acid, ethyl acetate and ethanol can be used. The nature of the solvent is not important. A pressure of 80 psi at atmospheric pressure may be used. The catalyst is preferably 5-10% Pd / C and the amount of catalyst used is 1-100% w / w. The synthesis for compound 2 is described in the following scheme. W is a saturated hydrocarbon of a straight or branched chain, preferably an ethyl group.

<Formula 3>

The compound of Formula 3 may be synthesized by the same method as the compound of Formula 2, by preparing a compound of Formula 10 and performing as described in Comprehensive Organic Synthesis vol. 1 p. 755-781 Pergamon Press or Scheme 2 below. Can be.

<Formula 4>

Compound (4) is a compound having optical selectivity among compound (3).

<Formula 5>

<Formula 6>

<Formula 7>

A is preferably methyl, ethyl or isopropyl.

<Formula 8>

Wherein D is selected from substituted lower alkyl, lower alkoxy, halogen, methylhalogen compounds, and substituents include both momo-substituents and di-substituents.

<Formula 9>

<Formula 10>

Formula 10 may be prepared by reacting diethoxy acetate ethyl ester (Diethoxy Acetic acid Ethyl ester) with acetyl chloride and then triethyl phosphite (Triethyl phosphite).

Formula 6 may be prepared cyanuric derivative substituted from cyanuric chloride as shown in Scheme 1 below.

<Scheme 1>

Reagents used: a) Each amine or phenol, N, N-diisopropylethyl amine (hereinafter referred to as DIEA), tetrahydrofuran (hereinafter referred to as THF), O ^o C, 1 hour. Or YMgBr (magnesium bromide derivative)

Y is as defined in the formula (1).

Scheme 2 below is a synthesis method for preparing Chemical Formula 2.

<Scheme 2>

Reagents used: a) Triethyl 2-phosphonobutyrate, lithium hydroxide (hereinafter referred to as LiOH), molecular sieve, reflux, 5 hours.

                  b) hydrogen, 10% palladiumcarbon, ethanol, 12 h.

Scheme 3 below is a synthesis method for preparing Chemical Formula 3.

<Scheme 3>

Reagents used: a) Formula 9, potassium t-butoxide, toluene, room temperature, 3 hours.

                b) hydrogen, 10% palladiumcarbon, ethanol, 12 hours.

Scheme 4 below is a synthesis method for preparing Chemical Formula 4.

<Scheme 4>

Reagents: a) Viscozyme L, phosphate buffer, room temperature, 48 hours.

                b) thionyl chloride, ethanol, reflux. 3 hours.

The optical isomer compound may be prepared by preparing a preferred (s) -type carboxylic acid by hydrolysis through selective enzymatic reaction from Chemical Formula 3 and then generating an ester (Mats T. Liderberg et al. Organic Process Research & Development) 2004 , 8 , 838-845.). The enzyme used in the synthesis is Viscozyme-L from Novozyme.

The optical activity of the compound can be used to determine the optical purity (ee: enantiomeric excess) of the compound in carboxylic acid form using a column as follows. The ee of the compound is 99.54%.

Column: shiseido capcell pak C18 MG 3.0X250 mm, 5 um

Mobile phase: Methanol / water = 8/2, 0.1% -triethylamine, 0.05% -phosphoric acid.

Flow rate: 0.5 ml / min

Scheme 5 below is a synthesis method for preparing Chemical Formula 5.

Scheme 5

Reagents used: a) Trityl chloride, triethylamine (hereinafter referred to as Et ₃ N), dichloromethane, room temperature, 1 hour.

b) methanesulfonylchloride, Et ₃ N, dichloromethane, room temperature, 30 minutes.

Scheme 6 below is a synthesis method for preparing Chemical Formula 10.

<Scheme 6>

Reagents used: a) Acetyl chloride, iodine, dichloromethane, room temperature → 50 ^o C, 3 hours.

b) triethyl phosphite, 150 ^° C., 40 minutes.

Specifically, the following scheme is shown in the scheme of the preparation of the compound shown in the Examples.

Scheme 7 wherein R is -CH ₂ CH ₃ in the compound of Formula 1-1; Each X independently represents a process for preparing the compound in -N-CH ₃ , or -NH form.

Scheme 7

Reagents used: a) Cesium carbonate, 60 ^o C, 1 hour.

b) DIEA, 0 ^o C, 1 hour.

c) DIEA, 90 ^o C, 1 hour, or boronic acid, 90 ^o C, 2 hours.

                d) 1N NaOH or 2N-LiOH, 2 hours.

As shown in Scheme 7, Compound 7a is formed by reacting with Compound 5 under basic conditions using Compound 2 as a starting material. The trityl protecting group is removed with an acid and then reacted with a single substituted 1,3,5-triazine compound synthesized in Scheme 1 under basic conditions to form compound 7b. Reaction with an amine or boronic acid to replace the remaining chloride of 1,3,5-triazine to form compound 7c and then hydrolysis to obtain the desired compound 7d.

R in the compound of Formula 1-1 is -OCH ₂ CH ₃ ; X independently of each other in the form of -N-CH ₃ , or -NH form the compounds 8d and 9d to proceed in a similar manner to the scheme 7 starting from the formula (3) or 4, as shown in Schemes 8 and 9 You can get it.

Scheme 8

Reagents used: a) Cesium carbonate, 60 ^o C, 1 hr.

b) DIEA, 0 ^o C, 1 hour.

c) DIEA, 90 ^o C, 1 hour, or boronic acid, 90 ^o C, 2 hours.

                d) 1N NaOH or 2N-LiOH.

Scheme 9

Reagents used: a) Cesium carbonate, 60 ^o C, 1 hour.

b) DIEA, 0 ^o C, 1 hour.

c) DIEA, 90 ^o C, 1 hour, or boronic acid, 90 ^o C, 2 hours.

                 d) 1N NaOH or 2N-LiOH.

Scheme 10 shows a method of preparing the compound of formula 1-2 of the present invention by the scheme. The following compounds include racemates and optical isomeric compounds.

Scheme 10

Reagents used: a) Diisopropylazodicarboxylate, triphenylphosphine, room temperature, 2 hours.

                b) hydrogen, 10% palladiumcarbon, ethanol, 12 hours.

                c) DIEA, room temperature, 1 hour.

d) DIEA, 0 ^o C, 1 hour.

e) DIEA, 90 ^o C, 1 hour, or boronic acid, 90 ^o C, 2 hours.

                f) 1N NaOH or 2N-LiOH.

As shown in Scheme 10, compound 10b is prepared by synthesizing compound 10a through a Mitsnov reaction with the phenol group and the benzyloxyethanol of the starting material and then removing the benzyl group through a hydrogenation reaction. Compound 10b was reacted under basic conditions to form compound 9c, and the remaining chloride group was reacted with amine or boronic acid with tetrakis (triphenylphosphine) palladium 0.2 equivalent, and cesium carbonate as a base at 90 ° C. for 5 hours in a dioxane solvent. To form compound 10d, followed by hydrolysis to obtain desired compound 10e.

Scheme 11 below shows a method for preparing the compound of Formula 1-3 of the present invention. The following compounds include racemates and optical isomeric compounds.

Scheme 11

Reagents used: a) Amine, base, room temperature, 30 minutes.

b) 90 ^o C, 2 hours.

               c) acid, room temperature, 30 minutes.

              d) diisopropylazodicarboxylate, triphenylphosphine, room temperature, 2 hours.

               e) 1N NaOH or 2N-LiOH.

Analysis of the compound synthesized according to the present invention was confirmed by ¹ H NMR spectrum with Bruker DPX 400MHz spectrometer and Agelent 1100 series LC / Mass.

The pharmaceutical composition of the present invention may be administered via a route such as oral, skin, subcutaneous tissue, intravenous, intramuscular, rectal, intraoral, nasal, and eye as desired, and lactose according to the purpose of the dosage form. , Excipients such as corn starch, lubricants such as magnesium stearate, emulsifiers, suspending agents, buffers, tonicity agents, and the like which are well known and used, and optionally, pharmaceutical excipients such as sweetening agents and / or flavoring agents may be added. can do.

The dosage of the compound of formula 1 according to the present invention may be administered in one to several doses of 0.1-1000 mg / kg body weight per day. For certain patients, the dosage can be adjusted and varied depending on the drug mix and the severity of the disease.

Hereinafter, preferred preparation examples, examples and experimental examples are presented to help understand the present invention. The preparation example performs preparation of the intermediate produced at the time of preparation of the compound of this invention. However, the following Preparation Examples, Examples and Experimental Examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the Examples.

Preparation Example 1 Preparation of Single Substituted 2,4-Dichloro 1,3,5-triazine

At 0 ^° C. cyanuric chloride (1 eq) is dissolved in THF solvent followed by addition of the desired amine or alcohol (1.1eq) or alkylmagnesium bromide and stirring for 30 minutes while maintaining the temperature. After confirming the TLC the reaction was removed under reduced pressure to extract the solvent using water and ethyl acetate. The organic layer was washed with water and brine, and then separated. The separated organic layer was dried using anhydrous magnesium sulfate, filtered, and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent to obtain the desired compound.

Preparation Example 2 Preparation of 2- (4-hydroxy-benzyl) -butyl acid ethyl ester (2b)

Step 1: Preparation of 3- (4-benzyloxy-phenyl) -2-ethyl-acrylic acid ethyl ester (4a)

4-benzyloxy benzaldehyde (10 g, 47.12 mmole), triethyl 2-phosphonobutyrate (17 ml), lithium hydroxide (2.3 g) and molecular seive were refluxed for 5 hours under THF (150 ml) solvent. The reaction was carried out. After confirming TLC, the reaction product was filtered, the filtrate was removed under reduced pressure, and extracted with water (100 mL) and ethyl acetate (300 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent gave 3- (4-benzyloxy-phenyl) -2-ethyl-acrylic acid ethyl ester (2a) in a yield of 65%.

¹ H NMR (CDCl ₃ , 400 MHz) 7.76-7.74 (d, 2H, J = 8.8 Hz), 7.43-7.38 (m, 5H), 7.03-7.01 (d, 2H, J = 8.8 Hz), 6.88 (s, 1H), 5.12 (s, 2H), 2.49 (m, 2H), 1.25 (t, 2H, J = 7.4 Hz), 1.08 (t, 3H, J = 7.6 Hz)

Step 2: Preparation of 2- (4-hydroxy-benzyl) -ethylbutyrate (2b)

3- (4-Benzyloxy-phenyl) -2-ethyl-ethyl acrylate (2a) (6.0 g, 19.34 mmole) was dissolved in ethanol (150 ml), 10% Pd / C (3 g) was added, and a hydrogenation reaction (50 psi) was performed for 12 hours. TLC was confirmed and the reaction was filtered and the filtrate was removed under reduced pressure. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent yielded 2- (4-hydroxy-benzyl) -ethyl butylate (2b) in 90% yield.

¹ H NMR (CDCl ₃ , 400 MHz) 9.16 (s, 1H), 6.92-6.89 (dd, 2H, J = 6.4 Hz, J = 2.4 Hz), 6.61-6.62 (dd, 2H, J = 6.4 Hz, J = 1.6 Hz), 3.99-3.94 (m, 2H), 2.64-2.58 (m, 2H), 2.45-2.49 (m, 1H), 1.49-1.45 (m, 2H), 1.04-1.08 (t, 3H, J = 7.2 Hz), 0.84 (t, 3H, J = 7.6 Hz).

Preparation Example 3 Preparation of 2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid ethyl ester (3b)

Step 1: Preparation of 3- (4- (benzyloxy) phenyl) -2-ethoxy acrylate ethyl ester (3a)

Toluene (100 ml) was added t-BuOK (12 g) and triethyl 2-ethoxyphosphonoacetate synthesized in Scheme 6 (25 g, 93.19 mmole), followed by 4-benzyloxy benzaldehyde (10 g, 47.12 mmole). Slowly add dropwise to prevent the temperature from rising. The reaction was stirred at room temperature for 30 minutes, adjusted to pH = 2-3 with 2N-HCl, and extracted with ethyl acetate (300 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL) and then separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove the organic solvent. Crystallization at 5 ° C. with ethanol gave the desired compound 3- (4- (benzyloxy) phenyl) -2-ethoxy ethyl acrylate (3a) in 70% yield.

¹ H NMR (CDCl ₃ , 400 MHz) 7.74-7.76 (d, 2H, J = 8.8 Hz), 7.43-7.39 (m, 5H), 7.03-7.01 (d, 2H, J = 8.8 Hz), 6.88 (s, 1H), 5.12 (s, 2H), 4.20 (q, 2H, J = 7.2 Hz), 3.91 (q, 2H, J = 7.0 Hz), 2.49 (m, 2H), 1.26 (t, 2H, J = 7.2 Hz)

Step 2: Preparation of 2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid ethyl ester (3b)

3- (4- (benzyloxy) phenyl) -2-ethoxy acrylate ethyl ester (3a) (8.0 g, 24.53 mmole) obtained in step 1 of Preparation Example 3 was prepared through the hydrogenation reaction of Step 2 of Preparation Example 91. 2-Ethoxy-3- (4-hydroxyphenyl) -butyric acid ethyl ester (3b) in% yield was obtained in the form of a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) 7.09 (d, 2H, J = 8.6 Hz), 6.73 (d, 2H, J = 8.8 Hz), 5.49 (s, 2H), 4.21 (q, 2H, J = 7.2 Hz ), 3.96 (t, 2H, J = 6.9 Hz), 3.58 (m, 1H), 3.34 (m, 1H), 2.92 (d, 2H, J = 6.4 Hz), 1.26 (t, 3H, J = 7.2 Hz ), 1.14 (t, 3H, J = 7.2 Hz)

Preparation Example 4 Preparation of (2S) -2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid ethyl ester (4b)

Step 1: Preparation of (2S) -2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid (4a)

2-Ethoxy-3- (4-hydroxyphenyl) -propanoic acid ethyl ester (3b) (13.7 g, 57.46 mmole) obtained in step 1 of Preparation Example 3 was dissolved in 0.1M Phosphate buffer pH = 7. (100 ml) After dissolving in solvent, Viscozyme L (40 ml) was added and the reaction mixture was stirred for 48 hours while maintaining 25 ^o C. After the reaction solution was removed under reduced pressure, MeOH (70 ml) was added and stirred for 30 minutes, followed by filtration. do. After concentrating MeOH under reduced pressure, unreacted ester was removed using water and t-BME, adjusted to 6N HCl pH = 2 ~ 3, and then extracted twice with t-BME and treated with anhydrous organic solvent to give the desired compound (2S)- 2-Ethoxy-3- (4-hydroxyphenyl) -propanoic acid (4b) was obtained in a yield of 30%. The optical activity of the compound was determined by the following column to determine the compound ee (enantiomeric excess). The ee of the compound is 99.54%.

Column: shiseido capcell pak C18 MG 3.0X250 mm, 5 um

Moblie phase: MeOH / H 2 O = 8/2, 0.1% -TEA, 0.05% -H 3 PO 4.

Flow rate: 0.5 ml / min

[α] ^D =-33.1

¹ H NMR (DMSOd ₆ , 400 MHz) 12.08 (bs, 1H). 7.01 (d, 2H, J = 8.6Hz), 6.65 (d, 2H, J = 8.4Hz), 3.87 (2q, 1H, J = 5.3, 7.7Hz), 3.51-3.46 (m, 1H), 3.29 (m , 1H), 2.95 (m, 1H), 2.80 (m, 1H), 1.11 (t, 3H, J = 7.2 Hz).

Step 2: Preparation of (2S) -2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid ethyl ester (4b)

(2S) -2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid (4b) (3.02 g, 14.36 mmole) prepared in step 1 was dissolved in ethanol (20 ml), followed by SOCl2 (1.2 ml). ) Is added and refluxed for 3 hours. After confirming TLC, the solvent was removed under reduced pressure, and extracted with water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Solidification was performed using ethyl acetate and hexane to give the desired compound (2S) -2-ethoxy-3- (4-hydroxyphenyl) -propanoic acid ethyl ester (4b) as a white solid in a yield of 93%.

[α] ^D =-18.7

¹ H NMR (CDCl ₃ , 400 MHz) 7.09 (d, 2H, J = 8.6 Hz), 6.73 (d, 2H, J = 8.8 Hz), 5.49 (s, 2H), 4.18 (q, 2H, J = 7.2 Hz ), 3.97 (t, 2H, J = 6.9 Hz), 3.61-3.58 (2q, 1H, J = 7.0 Hz), 3.37-3.34 (2q, 1H, J = 7.0 Hz), 2.94 (d, 2H, J = 6.4 Hz), 1.26 (t, 3H, J = 7.2 Hz), 1.14 (t, 3H, J = 7.2 Hz)

Preparation Example 5 Preparation of 2- (methyl- (trityl) amino) ethyl methanesulfonate (5a-2)

Step 1: Preparation of 2- (methyl-tritylamino) -ethanol (5a-1)

2- (methylamino) -ethanol (3.24 ml, 40 mmole), tritylchloride (5.6 g, 10 mmole), and triethylamine (3 ml) were dissolved in methylene chloride (100 ml) and then at room temperature for 1 hour. Stir. After TLC confirmation, the reaction was washed with water (50 mL X 2) and brine (30 mL) and separated, and the separated organic layer was removed with anhydrous magnesium sulfate, filtered and depressurized to remove the solvent. It was. Solidification was performed using ethyl acetate and hexane to give the desired compound 2- (methyl-tritylamino) -ethanol (5a-1) as a white solid in 90% yield.

¹ H NMR (CDCl ₃ , 400 MHz) 7.75 (d, 6H, J = 7.6 Hz), 7.25 (m, 6H), 7.14 (t, 3H, J = 0.8 Hz), 3.76 (t, 2H, J = 6.4 Hz ), 2.44-2.42 (m, 3 H), 2.05 (s, 3 H).

Step 2: Preparation of 2- (methyl- (trityl) amino) ethyl methanesulfonate (5a-2)

2- (methyl-tritylamino) -ethanol (5 g, 15.75 mmole), methanesulfonyl chloride (1.5 ml), and triethylamine (1 ml) synthesized in step 1 were dissolved in methylene chloride (50 ml). After stirring at room temperature for 30 minutes. After TLC confirmation, the reaction was washed with an aqueous sodium hydrogen carbonate solution (10 mL X 2) and brine (10 mL), separated, and the separated organic layer was removed using anhydrous magnesium sulfate, filtered and depressurized. Solvent was removed. Solidification was performed using ethyl acetate and hexane to give the desired compound 2- (methyl- (trityl) amino) ethyl methanesulfonate (5a-2) in 95% yield.

¹ H NMR (CDCl ₃ , 400 MHz) 7.48 (m, 6H, J = 7.6 Hz), 7.27 (m, 6H), 7.14 (t, 3H, J = 0.8 Hz), 4.42 (t, 2H, J = 6.4 Hz ), 3.03 (s, 3H), 2.54 (m, 2H), 2.12 (s, 3H).

Preparation of 2-((trityl) amino) ethyl methanesulfonate (5b-2) described in Scheme 5 was prepared in the same manner as in Preparation Example 5 described above.

Preparation Example 6 Preparation of 2- (4- [2- (methyl-trityl-ethyl) -amino] -ethoxy) -benzyl) -butyric acid ethyl ester (7a)

2- (4-hydroxy-benzyl) -butyl acid ethyl ester (2b) (1.33 g, 6.0 mmole) and cesium carbonate (2eq), and 2- (methyl- (trityl) amino) ethyl methanesulfonate (5a -2) (2.6 g, 5.1 mmole) is stirred for 1 hour at 60 ^° C. under acetonitrile (100 ml) solvent. After TLC confirmation, the reaction mixture was filtered, the filtrate was removed under reduced pressure to remove the solvent, and extracted with water (100 mL) and ethyl acetate (300 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as the developing solvent gave the desired compound 2- (4- [2- (methyl-trityl-ethyl) -amino] -ethoxy) -benzyl)-in 80% yield. Butyl ethyl ester was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 7.50 (d, 6H, J = 7.2 Hz), 7.24 (m, 6H), 7.11 (m, 3H), 7.06-7.04 (d, 2H, J = 8.8 Hz), 6.81 -6.79 (dd, 2H, J = 6.4Hz, J = 1.6Hz), 4.16 (m, 2H), 4.06 (m, 2H), 2.83 (m, 1H), 2.68 (m, 1H), 2.58-2.55 ( 3H, m), 2.15 (s, 3H), 1.54 (m, 1H), 1.18 (t, 3H, J = 7.2 Hz), 0.89 (t, 3H, J = 7.6 Hz).

Preparation Example 7 Preparation of Ethyl-2-ethoxy-3- (4- (2- (methyl (trityl) amino) ethoxy) phenyl) propanoate (8a-1)

Ethyl-2-ethoxy-3 (4-hydroxyphenyl) propanoate (3b) (4.0 g, 16.8 mmole) and cesium carbonate (2eq), and 2- (methyl- (trityl) amino) ethyl methanesulfo Nate (5a-2) (6.5 g, 16.4 mmole) is stirred under acetonitrile (100 ml) solvent at 60 ^° C. for 1 hour. After TLC confirmation, the reaction mixture was filtered, the filtrate was removed under reduced pressure to remove the solvent, and extracted with water (100 mL) and ethyl acetate (300 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent, desired compound ethyl-2-ethoxy-3- (4- (2- (methyl (trityl) amino) ethoxy) phenyl in 82% yield ) Propanate was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 7.51 (d, 6H, J = 7.2 Hz), 7.27 (m, 6H), 7.11 (m, 3H), 7.06-7.04 (d, 2H, J = 8.8 Hz), 6.82 (d, 2H, J = 6.6 Hz), 4.18 (m, 2H), 3.97 (t, 1H, = 6.8 Hz), 3.58 (m, 1H), 3.33 (m, 1H), 2.93 (m, 2H), 2.57 (m, 2H), 2.15 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz), 1.15 (t, 3H, J = 7.6 Hz).

Preparation Example 8 Preparation of (S) -ethyl-2-ethoxy-3- (4- (2- (methyl (trityl) amino) ethoxy) phenyl) propanoate (9a-1)

(S) -ethyl-2-ethoxy-3- (4-hydroxyphenyl) propanoate (3b) (5.0 g, 20.9 mmole) and cesium carbonate (2eq), and 2- (methyl- (trityl) Amino) ethyl methanesulfonate (5a-2) (11.7 g, 22.9 mmole) is stirred under acetonitrile (100 ml) solvent at 60 ^° C. for 1 hour. After TLC confirmation, the reaction mixture was filtered, the filtrate was removed under reduced pressure to remove the solvent, and extracted with water (100 mL) and ethyl acetate (300 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as the developing solvent, desired compound (S) -ethyl-2-ethoxy-3- (4- (2- (methyl (trityl) amino)) in 84% yield Ethoxy) phenyl) propanonate was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 7.54 (d, 6H, J = 7.6 Hz), 7.26 (m, 6H), 7.15 (m, 5H), 6.84 (d, 2H, J = 8.8 Hz), 4.21 (m , 4H), 3.98 (t, 2H, J = 6.9 Hz), 3.62 (m, 1H), 3.37 (m, 1H), 2.97 (m, 2H), 2.60 (m, 2H), 2.18 (s, 3H) , 1.26 (t, 3H, J = 7.2 Hz), 1.19 (t, 3H, J = 7.2 Hz)

Example 1 2- (4- (2- (methyl (4- (piperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-tri Azin-2-yl) amino) ethoxy) benzyl) butyl acid

Step 1: 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino}- Synthesis of Ethoxy) -benzyl] -Butyl Ethyl Ester

Compound 7a (1.6 g, 3.07 mmol) is dissolved in dichloromethane (20 ml) solvent and 1N trifluoro acetic acid (1 ml) is added dropwise. After TLC check, after confirming that the starting material disappeared, the solvent of the reactant was removed under reduced pressure. Removed solvent, (4,6-dichloro- [1,3,5] triazin-2-yl)-(4-trifluoromethyl-phenyl) amine synthesized in Preparation Example 1 (850 mg, 2.75 mmol), and DIEA as a base and stirred for 30 minutes at 0 ^° C. in THF (20 ml) solvent. After confirming the TLC, the reaction was removed under reduced pressure to remove the solvent and extracted with water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent, desired compound 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino) in 90% yield -[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -benzyl] -butyl acid ethyl ester was obtained in the form of a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) 7.68-7.62 (m, 2H), 7.57-7.53 (m, 2H), 7.10 (br, 1H), 7.06-7.02 (t, 2H, J = 6.0 Hz), 6.80- 6.74 (t, 2H, J = 8.8 Hz), 4.18-4.15 (m, 2H), 4.02-3.98 (m, 4H), 3.33-3.31 (d, 3H, J = 5.2 Hz), 2.82 (m, 1H) , 2.62 (m, 1H), 2.45 (m, 1H), 1.56 (m, 1H), 1.56 (t, 3H, J = 7.2 Hz), 0.87 (t, 3H, J = 6.8 Hz).

Step 2: 2- [4- (2- {methyl- [4-piperidin-1-yl-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazine-2 -Yl] -amino} -ethoxy) -benzyl] -butyric acid ethyl ester

2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) Benzyl] -butyric acid ethyl ester (400 mg, 0.76 mmol), piperidine (2 eq), and DIEA (0.2 ml) are stirred at 90 ^° C. under dioxane (5 ml) solvent for 2 hours. After confirming the TLC, the reaction was removed under reduced pressure to remove the solvent and extracted with water (50 mL) and ethyl acetate (100 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as the developing solvent yielded the desired compound 2- [4- (2- {methyl- [4-piperidin-1-yl-6- (4-) in 90% yield. Trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -amino} -ethoxy) -benzyl] -butyric acid ethyl ester was obtained in the form of a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) 7.68 (m, 2H, ph), 7.49 (m, 2H, -ph), 7.03 (d, 2H, J = 8.4 Hz, -ph), 6.78-7.76 (d, 2H , J = 8.8 Hz, -ph), 4.17 (m, 2H), 4.04-3.98 (m, 2H), 3.92 (m, 2H), 3.72 (bs, 4H, piperidine), 3.24 (s, 3H, -NCH ₃ ), 2.87 (m, 1H), 2.65 (m, 1H), 2.50 (m, 1H), 1.68-1.54 (m, 6H, piperidine), 1.17 (t, 3H, J = 7.2 Hz), 0.89 (t , 3H, J = 6.8 Hz).

Step 3: 2- (4- (2- (methyl (4- (piperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- Synthesis of 2-yl) amino) ethoxy) benzyl) butyl acid

Synthesized 2- [4- (2- {methyl- [4-piperidin-1-yl-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazine-2 -Yl] -amino} -ethoxy) -benzyl] -butyric acid ethyl ester (360 mg, 0.6 mmole) was diluted to 60 ^o with THF (3 ml), EtOH (1 ml), and 1N NaOH (2 ml). React at C for 2 hours. After confirming the TLC, the reaction was removed under reduced pressure to remove the organic solvent, neutralized with 1N-HCl, and extracted with water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with water (10 mL X 2) and brine (10 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using methanol and dichloromethane as a developing solvent and the desired compound 2- (4- (2- (methyl (4- (piperidin-1-yl) -6- (4) in 90% yield -(Trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid (Example 1) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.04 (s, 1H, -COOH), 9.02 (d, 1H, J = 9.6 Hz, -NH), 7.93-7.87 (m, 2H, ph), 7.57-7.49 (m, 2H, -ph), 7.05 (m, 2H, -ph), 6.83 (m, 2H, -ph), 4.17 (d, 2H, J = 6.6 Hz), 4.15 (m, 2H), 3.88 ( m, 2H), 3.70 (bs, 4H, piperidine), 3.33 (m, 1H), 3.16 (d, 3H, -NCH ₃ ), 2.68 (m, 1H), 2.48 (m, 1H), 2.39 (m, 1H), 1.59-1.47 (m, 6H, piperidine), 0.89 (t, 3H, J = 6.8 Hz).

Example 2 2- (4- (2- (methyl (4- (pyrrolidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-tri Azin-2-yl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and pyrrolidine to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2- ( Methyl (4- (pyrrolidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl An acid (Example 2) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 9.43 (m, 1H, -NH), 7.97 (m, 2H, -ph), 7.56-7.54 (m, 2H, ph), 7.04 (d, 2H, J = 8.4 Hz, -ph), 6.84 (m, 2H, -ph), 4.14 (q, 2H, J = 6.6 Hz), 3.88 (m, 2H), 3.49-3.44 (m, 4H), 3.17 (d, 3H , -NCH ₃ ), 2.72 (m, 1H), 2.49 (m, 1H), 2.39 (m, 1H), 1.88-1.92 (m, 4H), 0.86 (t, 3H, J = 6.8 Hz).

Example 3 2- (4- (2- (methyl (4- (4-methylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3, 5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-methylpiperidine to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to give the compound 2- (4- ( 2- 2- (4- (2- (methyl (4- (4-methylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid (Example 3) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.01 (s, 1H, -COOH), 9.45 (d, 1H, -NH), 7.92-7.86 (m, 2H, ph), 7.59-7.50 (m, 2H, -ph), 7.05 (m, 2H, -ph), 6.83 (m, 2H, -ph), 4.57 (m, 2H), 4.14 (m, 2H), 3.88 (m, 2H), 3.18 (d, 3H , -NCH ₃ ), 2.84-2.72 (m, 3H), 2.58 (m, 1H), 2.39 (m, 1H), 1.71-1.60 (m, 5H), 1.28 (m, 1H), 0.99 (d, 3H ), 0.84 (t, 3H, J = 6.8 Hz).

Example 4 2- (4- (2- (methyl (4- (4-phenylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3, 5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-phenylpiperidine to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to obtain a compound 2- (4- ( 2- (methyl (4- (4-phenylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) Ethoxy) benzyl) butyl acid (Example 4) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.03 (s, 1H, -COOH), 9.47 (d, 1H, -NH), 7.93-7.91 (m, 2H, ph), 7.56-7.48 (m, 2H, -ph), 7.27-7.24 (m, 4H, -ph), 7.17 (m, 1H, -ph), 7.03 (d, 2H, J = 8.4 Hz, -ph), 6.82 (d, 2H, J = 8.4 Hz, -ph), 4.81 (m, 2H), 4.17 (m, 2H), 3.96 (m, 2H), 3.18 (d, 3H, -NCH ₃ ), 2.86-2.81 (m, 2H), 2.80-2.65 (m, 2H), 2.49 (m, 1H), 2.39 (m, 1H), 1.76-1.66 (m, 5H), 1.28 (m, 1H), 0.82 (t, 3H, J = 6.8 Hz).

Example 5 2- (4- (2-((4- (4-benzylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5 -Trizin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-benzylpiperidine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 compound 2- (4- ( 2-((4- (4-benzylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-trizin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid (Example 5) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.03 (s, 1H, -COOH), 9.59 (d, 1H, -NH), 7.86 (m, 2H, ph), 7.60-7.53 (dd, 2H, -ph ), 7.27 (m, 4H, -ph), 7.17 (m, 3H, -ph), 7.03 (d, 2H, J = 8.4 Hz, -ph), 6.81 (d, 2H, J = 8.4 Hz, -ph ), 4.59 (m, 2H), 4.14 (s, 2H), 3.91-3.84 (m, 2H), 3.19 (d, 3H, -NCH ₃ ), 2.64-2.61 (m, 3H), 2.45 (m, 1H ), 2.39 (m, 1H), 1.84-1.78 (m, 3H), 1.68-2.59 (m, 2H), 1.24-1.22 (m, 2H), 0.83 (t, 3H, J = 6.7 Hz).

Example 6 2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3 , 5-trizin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-hydroxypiperidine to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-trizin-2-yl) amino ) Ethoxy) benzyl) butyl acid (Example 6) was obtained.

MS (ESI ⁺ ) m / z 588.7 (M ⁺¹ )

Example 7 2- (4- (2-((4- (diethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-trizin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and diethylamine were used to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 1 to give the compound 2- (4- (2- ( (4- (diethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-trizin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ( Example 7) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 9.59 (bs, 1H), 7.92 (m, 2H, ph), 7.59-7.55 (dd, 2H, -ph), 7.05 (d, 2H, J = 7.8 Hz, -ph), 6.81 (d, 2H, J = 8.4 Hz, -ph), 4.16 (m, 2H), 3.56-3.42 (m, 4H), 3.18 (d, 3H, -NCH ₃ ), 2.74-2.69 ( m, 1H), 2.56 (m, 1H), 2.39 (m, 1H), 1.68-1.59 (m, 2H), 1.08 (m, 6H), 0.84 (t, 3H, J = 6.7 Hz).

Example 8 2- (4- (2-((4- (dimethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-trizin-2-yl) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and diethylamine were used to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 1 to give the compound 2- (4- (2- ( (4- (dimethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (implemented Example 8) was obtained.

MS (ESI ⁺ ) m / z 532.8 (M ⁺¹ )

Example 9 2- (4- (2- (methyl (4-morpholin-4-yl-6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and morpholine were used to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 1 to give the compound 2- (4- (2- (meth). Methyl (4-morpholin-4-yl-6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid Example 9) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 9.51 (d, 1H), 7.93-7.86 (m, 2H, ph), 7.59-7.51 (dd, 2H, -ph), 7.06 (m, 2H, -ph) , 6.82 (d, 2H, J = 8.4 Hz, -ph), 4.12 (m, 2H), 3.91-3.88 (m, 2H), 3.70-3.61 (m, 8H), 3.17 (d, 3H, -NCH ₃ ), 2.72-2.66 (m, 1H), 2.58 (m, 1H), 2.39 (m, 1H), 1.56-1.48 (m, 2H), 0.84 (t, 3H, J = 6.7 Hz).

Example 10 2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5 -Trizin-2-yl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-methyl piperazine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 compound 2- (4- (2) -(Methyl (4- (4-methylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy Benzyl) butyl acid (Example 10) was obtained.

MS (ESI ⁺ ) m / z 587.8 (M ⁺¹ )

Example 11 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5 -Triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-ethyl piperazine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 compound 2- (4- (2) -((4- (4-ethylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid (Example 11) was obtained.

MS (ESI ⁺ ) m / z 601.8 (M ⁺¹ )

Example 12 2- (4- (2- (methyl (4- (4-phenylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5 -Triazin-2-yl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and 4-ethyl piperazine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 compound 2- (4- (2) -(Methyl (4- (4-phenylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy ) Benzyl) butyl acid (Example 12) was obtained.

MS (ESI ⁺ ) m / z 649.9 (M ⁺¹ )

Example 13 2- (4- (2-((4- (cyclopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and cyclopropylamine were used to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 1 to give the compound 2- (4- (2- ( (4- (cyclopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ( Example 13) was obtained.

MS (ESI ⁺ ) m / z 544.8 (M ⁺¹ )

Example 14 2- (4- (2-((4- (isopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 1, 2- [4- (2-{[4-chloro-6- (4-trifluoromethyl-phenylamino)-[1,3,5] triazin-2-yl] -methylamino} -ethoxy) -Benzyl] -butyl acid ethyl ester and isopropylamine were used to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2- ( (4- (isopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ( Example 14) was obtained.

MS (ESI ⁺ ) m / z 546.8 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.90-7.86 (m, 2H, ph), 7.63-7.67 (m, 2H, -ph), 7.04 (m, 2H, -ph), 6.82 (d, 2H, J = 8.4 Hz, -ph), 4.16 (m, 2H), 3.83 (m, 2H), 3.21 (s, 3H, -NCH ₃ ), 2.71-2.69 (m, 2H), 2.59 (m, 1H), 2.40 (m, 1H), 1.48-1.45 (m, 2H), 1.18 (m, 6H), 0.84 (t, 3H, J = 6.7 Hz).

Example 15 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

Step 1: ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) Butanoate Synthesis

In the same manner as in Step 1 of Example 1, Compound ethyl 2- (4- (2-((4-chloro) via a coupling reaction with 4- (4,6-dichloro-1,3,5-triazin-2-ylamino) phenol -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate was obtained.

MS (ESI ⁺ ) m / z 499.8 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.38 (m, 1H), 7.25 (m, 1H), 7.05 (m, 2H), 6.91 (m, 1H), 6.85 (m, 3H), 4.19-4.16 (m, 2H), 4.03-3.99 (m, 2H), 3.92 (m, 1H), 3.82 (m, 1H), 3.26 (s, 3H), 2.78 (m, 1H), 2.65 (m, 1H), 1.68-1.60 (m, 2H), 1.52 (t, 3H, J = 7.2 Hz), 0.88 (t, 3H, J = 6.8 Hz).

Step 2: 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 15 (methyl) ) Amino) ethoxy) benzyl) butanoate and piperidine to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- ( 2-((4- (4-hydroxyphenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyl acid (Example 15) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.03 (s, 1H, -COOH), 9.05 (bs, 1H), 7.38 (m, 2H, ph), 7.06 (d, 2H, J = 8.4 Hz, -ph ), 6.81 (d, 2H, J = 8.4 Hz, -ph), 6.56 (m, 2H, -ph), 4.12 (s, 2H), 3.87 (m, 2H), 3.69 (bs, 4H), 3.16 ( s, 3H, -NCH ₃ ), 2.74 (m, 1H), 2.58 (m, 1H), 2.37 (m, 1H), 1.63-1.61 (bs, 2H), 1.48-1.41 (bs, 6H), 0.83 ( t, 3H, J = 6.4 Hz).

Example 16 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 15, Ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butanoate and pyrrolidine were used to obtain the ester compound of the desired form, and then hydrolyzed to give the desired compound 2- (4- (2-((4- (4-hydroxyphenylamino) -6- ( Pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 16) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.01 (s, 1H, -COOH), 9.05 (bs, 1H), 7.41 (m, 2H, ph), 7.05 (d, 2H, J = 8.4 Hz, -ph ), 6.84 (m, 2H, -ph), 6.63 (m, 2H, -ph), 4.14 (bs, 2H), 3.89 (m, 2H), 3.41 (m, 4H), 3.17 (s, 3H,- NCH ₃ ), 2.76 (m, 1H), 2.58 (m, 1H), 2.37 (m, 1H), 1.96-1.87 (bs, 4H), 1.46-1.41 (m, 2H), 0.83 (t, 3H, J = 6.4 Hz).

Example 17 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 15, ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and 4-methylpiperidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4) -(4-hydroxyphenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 17) was obtained.

MS (ESI ⁺ ) m / z 535.1 (M ⁺¹ )

Example 18 2- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 15, Ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) buta The ester compound of the desired form was obtained using noate and dimethylamine, and then hydrolyzed to give the compound 2- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) of the desired form. ) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 18) was obtained.

MS (ESI ⁺ ) m / z 481.1 (M ⁺¹ )

Example 19 2- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 15, ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and morpholine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (4- Hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 19) was obtained.

MS (ESI ⁺ ) m / z 523.1 (M ⁺¹ )

Example 20 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) 1,3,5-triazine-2- (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 15, Ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) buta The ester compound of the desired form was obtained using noate and 4-methylpiperazine, and then hydrolyzed to give the compound 2- (4- (2-((4- (4-hydroxyphenylamino) -6-). Morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 20) was obtained.

MS (ESI ⁺ ) m / z 536.1 (M ⁺¹ )

Example 21 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) 1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 15, Ethyl 2- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) buta Noate and isopropylamine are used to obtain an ester compound of the desired form, and then hydrolyzed to give the desired compound 2- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholino -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 21) was obtained.

MS (ESI ⁺ ) m / z 536.1 (M ⁺¹ )

Example 22 2- (4- (2-((4- (4-fluorophenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

Step 1: ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) Butanoate Synthesis

In the same manner as in Step 1 of Example 1, Compound ethyl 2- (of desired form via coupling reaction using 4,6-dichloro-N- (4-fluorophenyl) -1,3,5-triazin-2-amine synthesized in Preparation Example 1 4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate was obtained .

MS (ESI ⁺ ) m / z 502.1 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.50-7.43 (m, 2H), 7.06-6.94 (m, 4H), 6.80-6.73 (m, 2H), 4.19-4.16 (m, 2H), 4.07-4.04 (m , 2H), 3.98-3.94 (m, 2H), 3.28 (s, 3H), 2.82 (m, 1H), 2.68 (m, 1H), 2.51 (m, 1H), 1.68-1.60 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 0.87 (t, 3H, J = 6.8 Hz).

Step 2: 2- (4- (2-((4- (4-fluorophenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) ( Synthesis of methyl) amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 22 (methyl) ) Amino) ethoxy) benzyl) butanoate and piperidine to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- ( 2-((4- (4-fluorophenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyl acid (Example 22) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.62 (m, 2H, ph), 7.15 (m, 2H, ph), 7.05 (d, 2H, J = 8.4 Hz, -ph), 6.81 (d, 2H, J = 8.4 Hz, -ph), 4.14 (s, 2H), 3.91 (m, 2H), 3.69 (bs, 4H), 3.21-3.17 (d, 3H, -NCH ₃ ), 2.72 (m, 1H), 2.49 (m, 1H), 2.39 (m, 1H), 1.61-1.60 (bs, 2H), 1.48-1.41 (m, 6H), 0.83 (t, 3H, J = 6.4 Hz).

Example 23 2- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and pyrrolidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (4 -Fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 23) Got it.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.65 (m, 2H, ph), 7.21-7.11 (m, 2H, -ph), 7.05 (d, 2H, J = 8.4 Hz, -ph), 6.84 (d , 2H, J = 8.4 Hz, -ph), 4.16 (m, 2H), 3.93 (m, 2H), 3.52-3.43 (m, 4H), 3.22 (s, 3H, -NCH ₃ ), 2.76 (m, 1H), 2.58 (m, 1H), 2.38 (m, 1H), 1.98-1.88 (bs, 4H), 1.45-1.41 (m, 2H), 0.84 (t, 3H, J = 6.4 Hz).

Example 24 2- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and 4-methylpiperidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4) -(4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 24) was obtained.

MS (ESI ⁺ ) m / z 537.1 (M ⁺¹ )

Example 25 2- (4- (2-((4- (3,5-dimethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and 3,5-dimethylpiperidine to give the desired ester compound, followed by hydrolysis to give the desired compound 2- (4- (2-((4 -(3,5-dimethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyl acid (Example 25) was obtained.

MS (ESI ⁺ ) m / z 551.1 (M ⁺¹ )

Example 26 2- (4- (2-((4- (2-ethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) buta Noate and 2-ethylpiperidine were used to obtain an ester compound of the desired form, and then hydrolyzed to give the desired compound 2- (4- (2-((4- (2-ethylpiperidine-1- Il) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 26) was obtained.

MS (ESI ⁺ ) m / z 551.1 (M ⁺¹ )

Example 27 2- (4- (2-((4- (4-fluorophenylamino) -6- (4-phenylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and 4-phenylpiperidine to obtain the desired ester compound, followed by hydrolysis to yield 2- (4- (2-((4- (4-fluoro) Phenylamino) -6- (4-phenylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 27) Got it.

MS (ESI ⁺ ) m / z 599.2 (M ⁺¹ )

Example 28 to 2- (4- (2-((4- (4-fluorophenylamino) -6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) Methoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and morpholine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (4- Fluorophenylamino) -6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 28) was obtained.

MS (ESI ⁺ ) m / z 599.2 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.61 (m, 2H, ph), 7.15-7.09 (m, 2H, -ph), 7.05 (d, 2H, J = 8.0 Hz, -ph), 6.82 (d , 2H, J = 8.4 Hz, -ph), 4.14 (m, 2H), 3.93 (bs, 2H), 3.71-3.62 (m, 8H), 3.21 (d, 3H, -NCH ₃ ), 2.74 (m, 1H), 2.58 (m, 1H), 2.39 (m, 1H), 1.45-1.42 (m, 2H), 0.84 (t, 3H, J = 6.4 Hz).

Example 29 2- (4- (2-((4- (diethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and diethylamine to obtain the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (di Ethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 29) was obtained.

MS (ESI ⁺ ) m / z 511.1 (M ⁺¹ )

Example 30 2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and dimethylamine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (diethyl Amino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 30) was obtained.

MS (ESI ⁺ ) m / z 511.1 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.61 (m, 2H, ph), 7.19-7.14 (m, 2H, -ph), 7.05 (d, 2H, J = 8.0 Hz, -ph), 6.82 (d , 2H, J = 8.4 Hz, -ph), 4.16 (m, 2H), 3.94 (m, 2H), 3.23-3.21 (d, 3H, -NCH ₃ ), 3.13 (s, 6H), 2.73 (m, 1H), 2.60 (m, 1H), 2.39 (m, 1H), 1.44-1.42 (m, 2H), 0.84 (t, 3H, J = 6.4 Hz).

Example 31 2- (4- (2-((4- (cyclohexylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) buta Noate and cyclohexylamine were used to obtain the ester compound of the desired form, and then hydrolyzed to give the compound of the desired form 2- (4- (2-((4- (cyclohexylamino) -6- (4-fluoro). Phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 31) was obtained.

MS (ESI ⁺ ) m / z 537.1 (M ⁺¹ )

Example 32 2- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and cyclohexylamine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (cyclo (cyclo)) Propylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 32) was obtained.

MS (ESI ⁺ ) m / z 495.1 (M ⁺¹ )

Example 33 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-phenylpiperazin-1-yl) -1,3,5-triazine-1 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and 4-phenylpiperazine to obtain the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-phenylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl) amino) ethoxy) benzyl) butyl acid (implemented Example 33) was obtained.

MS (ESI ⁺ ) m / z 600.1 (M ⁺¹ )

Example 34 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-1 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) buta The ester compound of the desired form was obtained using noate and 4-methylpiperazine, and then hydrolyzed to give the compound 2- (4- (2-((4- (4-fluorophenylamine) -6-6). (4-Methylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 34) was obtained.

MS (ESI ⁺ ) m / z 538.1 (M ⁺¹ )

Example 35 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamine) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 22, ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butanoate and 4-ethylpiperazine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamine) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (implemented Example 35) was obtained.

MS (ESI ⁺ ) m / z 552.1 (M ⁺¹ )

Example 36 2- (4- (2- (methyl- (4- (phenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) amino ) Ethoxy) benzyl) butyl acid

Step 1: ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butano Synthesis of Eight

In the same manner as in Step 2 of Example 1, Compound 4,6-dichloro-N-phenyl-1,3,5-triazin-2-amine synthesized in Preparation Example 1 was subjected to a coupling reaction to give the desired compound ethyl 2- (4- (2- ( (4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate was obtained.

¹ H NMR (CDCl ₃ , 400 MHz) 7.46-7.39 (m, 2H), 7.25-7.19 (m, 4H), 7.05-6.98 (m, 2H), 6.79 (m, 1H), 4.18-4.16 (m, 2H ), 4.07-4.04 (m, 2H), 3.98-3.94 (m, 2H), 3.26 (s, 3H), 2.82 (m, 1H), 2.68 (m, 1H), 2.51 (m, 1H), 1.68- 1.60 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 0.88 (t, 3H, J = 6.8 Hz).

Step 2: in 2- (4- (2- (methyl- (4- (phenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) amino) Synthesis of oxy) benzyl) butyl acid

To ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 35) To obtain the ester compound of the desired form using oxy) benzyl) butanoate and piperidine, and then hydrolyzed in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2- (methyl) -(4- (phenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid (Example 36) was obtained. .

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.02 (bs, 1H), 9.58 (bs, 1H), 7.53-7.25 (m, 3H, ph), 7.21 (d, 2H, J = 8.4 Hz, -ph) , 7.05 (d, 1H, J = 8.4 Hz, -ph), 6.97 (d, 1H, J = 8.0 Hz, -ph), 6.82 (d, 1H, J = 8.0 Hz, -ph), 6.66 (d, 1H, J = 8.2 Hz, -ph), 4.16 (s, 2H), 3.91-3.85 (m, 2H), 3.74-3.54 (bs, 4H), 3.16 (s, 3H, -NCH ₃ ), 2.72 (m , 1H), 2.49 (m, 1H), 2.39 (m, 1H), 1.61-1.60 (bs, 2H), 1.45-1.30 (m, 6H), 0.82 (t, 3H, J = 6.4 Hz).

Example 37 2- (4- (2- (methyl- (4- (phenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and pyrrolidine to give the ester compound of the desired form and then hydrolyzed to give the compound 2- (4- (2- (methyl- (4- (phenylamino)) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid (Example 37) was obtained.

MS (ESI ⁺ ) m / z 491.1 (M ⁺¹ )

Example 38 2- (4- (2- (methyl- (4-methylpiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and 4-methylpiperidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2- (methyl- (4-methyl) Piperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid (Example 38) was obtained.

MS (ESI ⁺ ) m / z 519.1 (M ⁺¹ )

Example 39 2- (4- (2- (methyl- (4-morpholin-4-yl-6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy Benzyl) butyric acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and morpholine to obtain the ester compound of the desired form, and then hydrolyzed to give the compound 2- (4- (2- (methyl- (4-morpholin-4-) Il-6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid (Example 39) was obtained.

MS (ESI ⁺ ) m / z 507.2 (M ⁺¹ )

Example 40 2- (4- (2-((4- (diethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy Benzyl) butyric acid

In the same manner as in Step 2 of Example 36, Ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate and di Ethylamine was used to obtain the ester compound in the desired form, and then hydrolyzed to give the desired compound 2- (4- (2-((4- (diethylamino) -6- (phenylamino) -1,3, 5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 40) was obtained.

MS (ESI ⁺ ) m / z 493.1 (M ⁺¹ )

Example 41 2- (4- (2-((4- (dimethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyric acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butanoate and dimethylamine are used to obtain the ester compound of the desired form and then hydrolyzed to give the compound 2- (4- (2-((4- (dimethylamino) -6). -(Phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 41) was obtained.

MS (ESI ⁺ ) m / z 465.1 (M ⁺¹ )

Example 42 2- (4- (2-((4- (isopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy Benzyl) butyric acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and isopropylamine to obtain the ester compound of the desired form, and then hydrolyzed to give the compound 2- (4- (2-((4- (isopropylamino)-) 6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 42) was obtained.

MS (ESI ⁺ ) m / z 479.1 (M ⁺¹ )

Example 43 2- (4- (2-((4- (cyclopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy Benzyl) butyric acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and cyclopropamine to obtain the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (cyclopropylamino)) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 43) was obtained.

MS (ESI ⁺ ) m / z 477.1 (M ⁺¹ )

Example 44 2- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (phenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and 2-hydroxyethylamine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4-((2 -Hydroxyethyl) (methyl) amino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 44) was obtained. .

MS (ESI ⁺ ) m / z 495.1 (M ⁺¹ )

Example 45 2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and 4-hydroxypipepidine to obtain the ester compound of the desired form and then hydrolyzed to give the desired compound 2- (4- (2-((4- (4 Hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 45) Got it.

MS (ESI ⁺ ) m / z 521.1 (M ⁺¹ )

Example 46 2- (4- (2-((4- (3-hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and 3-hydroxypiperidine to obtain the ester compound of the desired form, and then hydrolyzed to give the compound 2- (4- (2-((4- (3) Hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 46) Got it.

MS (ESI ⁺ ) m / z 521.1 (M ⁺¹ )

Example 47 2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) Amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, Ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate and 4 -Obtain the ester compound of the desired form using methyl piperazine, and then hydrolyze to give the compound of the desired form 2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6-) (Phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid (Example 47) was obtained.

MS (ESI ⁺ ) m / z 520.1 (M ⁺¹ )

Example 48 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 36, ethyl 2- (4- (2-((4-chloro-6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butanoate and 4-ethylpiperazine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (4-ethyl) Piperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 48) was obtained.

MS (ESI ⁺ ) m / z 534.1 (M ⁺¹ )

Example 49 2- (4- (2-((4- (p-toluidino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butyl acid

Step 1: ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl Synthesis of Butanoate

In the same manner as in Step 1 of Example 1, Compound ethyl 2- (4- (2- in desired form via coupling reaction using 4,6-dichloro-Np-tolyl-1,3,5-triazin-2-amine synthesized in Preparation Example 1 ((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate was obtained.

MS (ESI ⁺ ) m / z 498.1 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.38-7.32 (m, 2H), 7.12-7.09 (m, 2H), 7.01 (d, 2H, J = 8.4 Hz, -ph), 6.84 (d, 2H, J = 8.2 Hz, -ph), 4.19-4.16 (m, 2H), 4.07-4.04 (m, 2H), 3.98-3.94 (m, 2H), 3.28 (s, 3H), 2.82 (m, 1H), 2.68 ( m, 1H), 2.51 (m, 1H), 2.41 (s, 3H), 1.68-1.60 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 0.87 (t, 3H, J = 6.8 Hz ).

Step 2: 2- (4- (2-((4- (p-toluidino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl Synthesis of Amino) ethoxy) benzyl) butyl Acid

Ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 49 Amino) ethoxy) benzyl) butanoate and piperidine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2) -((4- (p-Toludino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 49) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.01 (bs, 1H), 9.48 (bs, 1H), 7.39-7.35 (m, 2H), 7.08-7.06 (m, 2H), 7.01 (d, 2H, J = 8.4 Hz, -ph), 6.71 (d, 2H, J = 8.2 Hz, -ph), 4.16 (s, 2H), 3.91-3.85 (m, 2H), 3.74-3.54 (bs, 4H), 3.16 ( s, 3H, -NCH ₃ ), 2.72 (m, 1H), 2.49 (m, 1H), 2.43 (s, 3H), 2.39 (m, 1H), 1.61-1.60 (bs, 2H), 1.45-1.30 ( m, 6H), 0.82 (t, 3H, J = 6.4 Hz).

Example 50 2- (4- (2-((4- (p-toluidino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, Ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butano Eate and pyrrolidine to give the ester compound of the desired form, and then hydrolyzed to give the compound of the desired form 2- (4- (2-((4- (p-toluidino) -6- (pyrrolidine) -1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 50) was obtained.

MS (ESI ⁺ ) m / z 505.1 (M ⁺¹ )

Example 51 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and 4-methylpiperidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (implemented Example 51) was obtained.

MS (ESI ⁺ ) m / z 533.1 (M ⁺¹ )

Example 52 2- (4- (2-((4- (p-toluidino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and morpholine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (p-tol) Ludino--6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 52) was obtained.

MS (ESI ⁺ ) m / z 521.1 (M ⁺¹ )

Example 53 2- (4- (2-((4- (p-toluidino) -6- (diethylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and diethylamino are used to obtain the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (p-tol) Ludino--6- (diethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 53) was obtained.

MS (ESI ⁺ ) m / z 507.1 (M ⁺¹ )

Example 54 2- (4- (2-((4- (p-toluidino) -6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, Ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butano Using ester and dimethylamino to obtain ester compound of desired form, and then hydrolyzed to give compound 2- (4- (2-((4- (p-toluidino) -6- (dimethylamino) -1 , 3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 54) was obtained.

MS (ESI ⁺ ) m / z 479.1 (M ⁺¹ )

Example 55 2- (4- (2-((4- (p-toluidino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, Ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butano Ethyl and isopropyl are used to obtain the ester compound of the desired form, and then hydrolyzed to give the desired compound 2- (4- (2-((4- (p-toluidino) -6- (isopropyl)-). 1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 55) was obtained.

MS (ESI ⁺ ) m / z 493.1 (M ⁺¹ )

Example 56 2- (4- (2-((4- (p-toluidino) -6- (cyclopropylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and cyclopropyl to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (p-tol) Ludino--6- (cyclopropyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 56) was obtained.

MS (ESI ⁺ ) m / z 491.1 (M ⁺¹ )

Example 57 2- (4- (2-((4- (p-toluidino) -6-6 ((2-hydroxyethyl) (methyl) amino) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, Ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butano Using ester and 2- (methylamino) ethanol to obtain an ester compound of the desired form, and then hydrolyzing to give the compound of the desired form 2- (4- (2-((4- (p-toluidino) -6- ((2-hydroxyethyl) (methyl) amino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 57) was obtained.

MS (ESI ⁺ ) m / z 509.1 (M ⁺¹ )

Example 58 2- (4- (2-((4- (p-toluidino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and 4-hydroxypiperidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4) -(p-toluidino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 58) was obtained.

MS (ESI ⁺ ) m / z 535.1 (M ⁺¹ )

Example 59 2- (4- (2-((4- (p-toluidino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and 3-hydroxypiperidine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4) -(p-toluidino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 59) was obtained.

MS (ESI ⁺ ) m / z 535.1 (M ⁺¹ )

Example 60 2- (4- (2-((4- (p-toluidino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and 2-hydroxyethylamine to give the ester compound of the desired form, followed by hydrolysis to give the compound 2- (4- (2-((4- (p-toluidino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 60) was obtained.

MS (ESI ⁺ ) m / z 495.1 (M ⁺¹ )

Example 61 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2- (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butanoate and 4-methylpiperazine to obtain the ester compound of the desired form, followed by hydrolysis to obtain the compound of the desired form 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid (Example 61) was obtained.

MS (ESI ⁺ ) m / z 534.1 (M ⁺¹ )

Example 62 2- (4- (2-((4- (p-toluidino) -6- (4-ethylpiperazin-1-yl) -1,3,5-triazine-2- (Methyl) amino) ethoxy) benzyl) butyl acid

In the same manner as in Step 2 of Example 49, Ethyl 2- (4- (2-((4- (p-toluidino) -6-chloro-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butano Using ester and 4-ethylpiperazine to obtain ester compound of desired form, and then hydrolyzed to give compound 2- (4- (2-((4- (p-toluidino) -6- (4). Ethylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 62) was obtained.

MS (ESI ⁺ ) m / z 548.1 (M ⁺¹ )

Example 63 2- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid

Step 1: ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) Butanoate Synthesis

In the same manner as in Step 1 of Example 1, Compound ethyl 2- (4- in desired form via coupling reaction using 2,4-dichloro-6- (4-fluorophenoxy) -1,3,5-triazine synthesized in Preparation Example 1 (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butanoate was obtained.

MS (ESI ⁺ ) m / z 503.1 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.10-7.04 (m, 6H), 6.78 (d, 1H, J = 8.4 Hz, -ph), 6.69 (d, 1H, J = 8.2 Hz, -ph), 4.15 ( m, 1H), 4.06-3.97 (m, 2H), 3.77 (m, 1H), 3.30, 3.15 (each s, 3H), 2.84 (m, 1H), 2.66 (m, 1H), 2.45 (m, 1H ), 1.62-1.50 (m, 2H), 1.18 (t, 3H, J = 7.2 Hz), 0.87 (t, 3H, J = 6.8 Hz).

Step 2: 2- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) ( Synthesis of methyl) amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 63 ) Amino) ethoxy) benzyl) butanoate and pyrrolidine to give the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- ( 2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyl acid (Example 63) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.18-7.35 (m, 3H), 7.06 (m, 2H), 6.82 (d, 1H, J = 8.4 Hz, -ph), 6.86 (d, 1H, J = 8.2 Hz, -ph), 4.12 (m, 1H), 3.95 (m, 1H), 3.84 (m, 1H), 3.65 (m, 1H), 3.44-3.28 (m, 6H), 3.15, 2.98 (each s , 3H), 2.75 (m, 1H), 2.49 (m, 1H), 1.82 (bs, 6H), 1.61-1.60 (m, 2H), 1.45-1.30 (m, 6H), 0.84 (t, 3H, J = 6.4 Hz).

Example 64 2- (4- (2-((4- (4-fluorophenoxy) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 63 ) Amino) ethoxy) benzyl) butanoate and 4-methylpiperidine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- ( 4- (2-((4- (4-fluorophenoxy) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid (Example 64) was obtained.

MS (ESI ⁺ ) m / z 538.1 (M ⁺¹ )

Example 65 2- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 63 ) Amino) ethoxy) benzyl) butanoate and morpholine to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2) -((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (implemented Example 65) was obtained.

MS (ESI ⁺ ) m / z 526.1 (M ⁺¹ )

Example 66 2- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 63 ) Amino) ethoxy) benzyl) butanoate and azetidine to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2) -((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 66) was obtained.

MS (ESI ⁺ ) m / z 496.1 (M ⁺¹ )

Example 67 2- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 63 ) Amino) ethoxy) benzyl) butanoate and diethylamine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to give the compound 2- (4- ( 2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (implemented Example 67) was obtained.

MS (ESI ⁺ ) m / z 512.1 (M ⁺¹ )

Example 68 2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid

Ethyl 2- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 63 ) Amino) ethoxy) benzyl) butanoate and dimethylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- (4- (2) -((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid (Example 68).

MS (ESI ⁺ ) m / z 498.1 (M ⁺¹ )

Example 69 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Step 1: ethyl 3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Synthesis of Phenyl) -2-ethoxypropanoate

Ethyl 2-ethoxy-3- (4- (2- (methyl (trityl) amino) ethoxy) phenyl) propanoate (8a-1) (3.0 g, 5.58 mmol) synthesized in Preparation Example 7 was prepared. Dissolve in dichloromethane (20 ml) solvent and add 1N trifluoro acetic acid (1 ml) dropwise. After TLC check, after confirming that the starting material disappeared, the solvent of the reactant was removed under reduced pressure. Removed solvent, (4,6-dichloro- [1,3,5] triazin-2-yl)-(4-trifluoromethyl-phenyl) amine synthesized in Preparation Example 1 (1.2 g, 4.63 mmol), and DIEA as base to stir for 30 minutes at 0 ^° C. in THF (20 ml) solvent. After confirming the TLC, the reaction was removed under reduced pressure to remove the solvent and extracted with water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent, desired compound ethyl 3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1) in 90% yield , 3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained in the form of a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) 7.50-7.42 (m, 2H), 7.14 (m, 2H), 7.01 (m, 2H), 6.77 (m, 2H), 4.18 (m, 4H), 3.96 (m, 2H), 3.58 (m, 1H), 3.35 (m, 1H), 3.28 (s, 3H), 2.92 (m, 2H), 1.23 (t, 3H, J = 7.2 Hz), 1.15 (t, 3H, J = 7.6 Hz).

Step 2: 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazine- Synthesis of 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-Ethoxypropanoate (500 mg, 0.97 mmol), piperidine (2 eq), and DIEA (0.2 ml) are stirred at 90 ^° C. under dioxane (5 ml) solvent for 2 hours. After confirming the TLC, the reaction was removed under reduced pressure to remove the solvent and extracted with water (50 mL) and ethyl acetate (100 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent to synthesize the ester compound of the desired form in 90% yield, and then synthesized ester compound THF (3 ml), EtOH (1 ml), and 1N React at 60 ^° C. for 2 hours with NaOH (2 ml). After confirming the TLC, the reaction was removed under reduced pressure to remove the organic solvent, neutralized with 1N-HCl, and extracted with water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with water (10 mL X 2) and brine (10 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using methanol and dichloromethane as a developing solvent, the desired compound 2-Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6) in 90% yield -(Pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 69) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.64 (m, 2H), 7.19 (m, 2H), 7.09 (m, 2H), 6.82 (m, 2H), 4.17 (m, 2H), 3.94 (m, 3H), 3.58-3.42 (m, 5H), 3.23 (m, 4H), 2.84-2.78 (m, 2H), 1.99-1.87 (m, 4H), 1.08 (t, 3H, J = 7.6 Hz).

Example 70 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3, 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 4-methylpiperidine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 Compound 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 70) was obtained.

MS (ESI ⁺ ) m / z 553.2 (M ⁺¹ )

Example 71 2-Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-morpholin-4-yl-1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and morpholine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- of the desired form. Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 71) was obtained.

MS (ESI ⁺ ) m / z 541.3 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.61 (m, 2H), 7.11 (m, 4H), 6.82 (d, 2H, J = 7.6 Hz), 4.15 (m, 2H), 3.93 (m, 3H) , 3.72-3.62 (m, 8H), 3.48 (m, 1H), 3.28 (m, 1H), 3.22, 3.18 (ss, 3H), 2.85-2.79 (m, 2H), 1.08 (t, 3H, J = 7.6 Hz).

Example 72 3- (4- (2-((4- (azetidin-1-yl) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) -2-ethoxy propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and azetidine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 3- ( 4- (2-((4- (azetidin-1-yl) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxy propanoic acid (Example 72) was obtained.

MS (ESI ⁺ ) m / z 511.2 (M ⁺¹ )

Example 73 3- (4- (2-((4- (diethylamino) -6- (4-fluorofluoroamino) -1,3,5-triazin-2-yl) (methyl) ) Amino) ethoxy) phenyl) -2-ethoxy propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and diethylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 1 to obtain the compound of the desired form 3- (4- (2-((4- (diethylamino) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxy propanoic acid (Example 73) was obtained.

MS (ESI ⁺ ) m / z 527.2 (M ⁺¹ )

Example 74 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxy propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and dimethylamine were used to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 1 to obtain compound 3- ( 4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2 -Ethoxy propanoic acid (Example 74) was obtained.

MS (ESI ⁺ ) m / z 513.2 (M ⁺¹ )

Example 75 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (isopropylamino) -1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and isopropylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2- of the desired form. Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) propanoic acid (Example 75) was obtained.

MS (ESI ⁺ ) m / z 512.2 (M ⁺¹ )

Example 76 3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) -2-ethoxypropanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and cyclopropylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to obtain the compound 3- of the desired form. (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-Ethoxypropanoic acid (Example 76) was obtained.

MS (ESI ⁺ ) m / z 511.2 (M ⁺¹ )

Example 77 2-Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-((2-hydroxyethyl) (methyl) amino-1,3, 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 2- (methylamino) ethanol were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 1 Compound of 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-((2-hydroxyethyl) (methyl) amino-1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 77) was obtained.

MS (ESI ⁺ ) m / z 529.3 (M ⁺¹ )

Example 78 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-hydroxypiperidin-1-yl) -1,3 , 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 4-hydroxypiperidine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 1 to form the desired form. Compound of 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-hydroxypiperidin-1-yl) -1,3,5- Triazine-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 78) was obtained.

MS (ESI ⁺ ) m / z 555.3 (M ⁺¹ )

Example 79 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (3-hydroxypiperidin-1-yl) -1,3 , 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 3-hydroxypiperidine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to form the desired form. Compound of 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (3-hydroxypiperidin-1-yl) -1,3,5- Triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 79) was obtained.

MS (ESI ⁺ ) m / z 555.3 (M ⁺¹ )

Example 80 2-Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (2-hydroxyethylamino) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 2-aminoethanol were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 1 to give the compound 2 of the desired form. -Ethoxy-3- (4- (2- ((4- (4-fluorophenylamino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid (Example 80) was obtained.

MS (ESI ⁺ ) m / z 515.2 (M ⁺¹ )

Example 81 2-Ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5 -Triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 4-methylpiperazine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give a compound of the desired form 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 81) was obtained.

MS (ESI ⁺ ) m / z 554.2 (M ⁺¹ )

Example 82 2-ethoxy-3- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamino) -1,3,5 -Triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

3- (4- (2-((4-chloro-6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 69) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 3-methylpiperazine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 Compound 2-Ethoxy-3- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 82) was obtained.

MS (ESI ⁺ ) m / z 568.3 (M ⁺¹ )

Example 83 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Step 1: ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Synthesis of Phenyl) -2-ethoxypropanoate

In the same manner as in Step 1 of Example 69, Compound ethyl 3- (4- in desired form via coupling reaction using 4- (4,6-dichloro-1,3,5-triazin-2-yl-amino) phenol synthesized in Preparation Example 1 (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropano Obtained eight.

¹ H NMR (CDCl ₃ , 400 MHz) 7.46 (m, 1H), 7.24-7.19 (m, 1H), 7.12-7.04 (m, 4H), 6.77 (m, 4H), 4.20 (m, 4H), 3.96 ( m, 2H), 3.57 (m, 1H), 3.35 (m, 1H), 3.25 (s, 3H), 2.92 (m, 2H), 1.23 (t, 3H, J = 7.2 Hz), 1.15 (t, 3H , J = 7.6 Hz).

Step 2: 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazine- Synthesis of 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 83 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and pyrrolidine to give the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to give the compound 2 of the desired form. -Ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid (Example 83) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 9.24 (bs, 1H), 7.38 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 6.84 (d, 1H, J = 8.4H), 6.67 (m, 2H), 4.16 (m, 2H), 3.94 (m, 3H), 3.58-3.42 (m, 5H), 3.23 (m, 4H), 2.84-2.78 (m, 2H), 1.94-1.82 (m, 4H), 1.09 (t, 3H, J = 7.6 Hz).

Example 84 2-Ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 83 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and morpholine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to obtain the compound 2- of the desired form. Ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 84) was obtained.

MS (ESI ⁺ ) m / z 539.3 (M ⁺¹ )

Example 85 3- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 83 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and dimethylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 to obtain the compound 3- of the desired form. (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-Ethoxypropanoic acid (Example 85) was obtained.

MS (ESI ⁺ ) m / z 497.2 (M ⁺¹ )

Example 86 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 83 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and isopropylamine to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 1 to compound 2 of the desired form. -Ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 86) was obtained.

MS (ESI ⁺ ) m / z 511.2 (M ⁺¹ )

Example 87 2-ethoxy-3- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (4-hydroxyphenylamino) -1,3 , 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 83 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 2-methylaminoethanol to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 Compound 2-ethoxy-3- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (4-hydroxyphenylamino) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 87) was obtained.

MS (ESI ⁺ ) m / z 527.2 (M ⁺¹ )

Example 88 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5 -Triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 83 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and 2-methylpiperazine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 1 Compound 2-Ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 88) was obtained.

MS (ESI ⁺ ) m / z 552.2 (M ⁺¹ )

Example 89 (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3 , 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Step 1: (S) -ethyl-3- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) Synthesis of amino) ethoxy) phenyl) -2-ethoxypropanoate

Compound 9a-1 (5.0 g, 9.30 mmol) is dissolved in dichloromethane (40 ml) solvent and 1N trifluoro acetic acid (2 ml) is added dropwise. After TLC check, after confirming that the starting material disappeared, the solvent of the reactant was removed under reduced pressure. The solvent was removed from the reaction, 2,4-dichloro-6- (4-fluorophenoxy) -1,3,5-triazine (2.90 g, 11.12 mmol) synthesized in Preparation Example 1, and DIEA was base. Stir for 30 minutes at 0 ^o C under THF (50 ml) solvent. After confirming the TLC, the reaction was removed under reduced pressure to remove the solvent and extracted with water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent, yielded the desired compound (S) -ethyl-3- (4- (2-((4-chloro-6- (4-) in 90% yield. Fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained in the form of a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) 7.12 (m, 4H), 6.99 (m, 2H), 6.79-6.65 (m, 2H), 4.17 (m, 4H), 3.95 (m, 2H), 3.66 (m, 1H), 3.37 (m, 1H), 3.31, 3.09 (ss, 3H), 2.91 (m, 2H), 1.21 (t, 3H, J = 7.2 Hz), 1.13 (t, 3H, J = 7.2 Hz)

Step 2: (S) -ethyl-2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3 Synthesis of, 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoate

To (S) -ethyl-3- (4- (2-((4-chloro-6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Methoxy) phenyl) -2-ethoxypropanoate (520 mg, 1.00 mmol), piperidine (2 eq), and DIEA (0.2 ml) in dioxane (5 ml) solvent at 90 ^° C. for 2 hours. Stir. After confirming the TLC, the reaction was removed under reduced pressure to remove the solvent and extracted with water (50 mL) and ethyl acetate (100 mL). The organic layer was washed with water (50 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent, yielded the desired compound (S) -ethyl-2-ethoxy-3- (4- (2-((4- (4-fluorine) in 90% yield. Lofenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoate was obtained as a colorless oil. .

¹ H NMR (CDCl ₃ , 400 MHz) 7.13 (m, 4H), 6.99 (m, 2H), 6.80-6.70 (m, 2H), 4.17 (m, 4H), 3.95 (m, 2H), 3.66 (m, 1H), 3.57-3.46 (m, 4H), 3.36 (m, 1H), 3.31, 3.09 (ss, 3H), 2.91 (m, 2H), 1.89 (m, 6H), 1.21 (t, 3H, J = 7.2 Hz), 1.13 (t, 3H, J = 7.2 Hz)

Step 3: (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5 Synthesis of -triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Synthesized (S) -ethyl-2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3, 5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoate (380 mg, 0.61 mmole) in THF (3 ml), EtOH (1 ml), and 1N NaOH (2 ml) Reaction is carried out at 60 ^o C for 2 hours. After confirming the TLC, the reaction was removed under reduced pressure to remove the organic solvent, neutralized with 1N-HCl, and extracted with water (10 mL) and ethyl acetate (20 mL). The organic layer was washed with water (10 mL X 2) and brine (10 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using methanol and dichloromethane as a developing solvent and the desired compound (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) in 90% yield C) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 89) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.19 (m, 4H), 7.11 (m, 2H), 6.87-6.75 (m, 2H), 4.11 (m, 2H), 3.95 (m, 2H), 3.66 ( m, 1H), 3.57-3.43 (m, 4H), 3.36 (m, 1H), 3.31, 3.09 (ss, 3H), 2.91 (m, 2H), 1.89 (m, 6H), 1.02 (t, 3H, J = 7.2 Hz)

Example 90 (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-thiomorpholin-4-yl-1,3,5 -Triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and thiomorpholine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 89 to obtain the compound of the desired form ( S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-thiomorpholin-4-yl-1,3,5-triazine-2- Il) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 90) was obtained.

MS (ESI ⁺ ) m / z 558.3 (M ⁺¹ )

Example 91 (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5- Triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and morpholine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 89 to obtain the compound of the desired form ( S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid (Example 91) was obtained.

MS (ESI ⁺ ) m / z 541.9 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.20 (m, 4H), 7.14 (m, 2H), 6.81 (m, 2H), 4.02 (m, 2H), 3.98 (m, 2H), 3.72 (m, 1H), 3.58-3.41 (m, 4H), 3.32 (m, 1H), 3.13, 3.00 (ss, 3H), 2.81-2.74 (m, 2H), 1.01 (t, 3H, J = 7.2 Hz)

Example 92 (S) -3- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazine-) 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and azetidine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 89 to give the compound of the desired form (S ) -3- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid (Example 92) was obtained.

MS (ESI ⁺ ) m / z 512.2 (M ⁺¹ )

Example 93 (S) -3- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) ) (Methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and diethylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound of the desired form ( S) -3- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid (Example 93) was obtained.

MS (ESI ⁺ ) m / z 528.1 (M ⁺¹ )

Example 94 (S) -3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and dimethylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound of the desired form (S ) -3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid (Example 94) was obtained.

MS (ESI ⁺ ) m / z 500.1 (M ⁺¹ )

Example 95 (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (isopropylamino) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and isopropylamine to obtain an ester compound of the desired form, and then hydrolyzed in the same manner as in Step 3 of Example 89 to obtain a compound of the desired form ( S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (isopropylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid (Example 95) was obtained.

MS (ESI ⁺ ) m / z 514.2 (M ⁺¹ )

Example 96 (S) -3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) ) (Methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and cyclopropylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound of the desired form ( S) -3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid (Example 96) was obtained.

MS (ESI ⁺ ) m / z 512.2 (M ⁺¹ )

Example 97 (S) -3- (4- (2-((4- (cyclobutylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) ) (Methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and cyclobutylamine to obtain the ester compound of the desired form, and then hydrolyzed in the same manner as in step 3 of Example 89 to obtain the compound of the desired form ( S) -3- (4- (2-((4- (cyclobutylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid (Example 97) was obtained.

MS (ESI ⁺ ) m / z 526.2 (M ⁺¹ )

Example 98 (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (propylamino) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) -1 methyl synthesized in step 1 of Example 89 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and propylamine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 89 to give the compound of the desired form ( S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid (Example 97) was obtained.

MS (ESI ⁺ ) m / z 514.2 (M ⁺¹ )

Example 99 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (pyrrolidin-1-yl) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Step 1: ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Synthesis of Phenyl) -2-ethoxypropanoate

In the same manner as in Step 1 of Example 69, Compound ethyl 3- (4- in desired form via coupling reaction using 2,4-dichloro-6- (4-methoxyphenoxy) -1,3,5-triazine synthesized in Preparation Example 1 (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropano Obtained eight.

MS (ESI ⁺ ) m / z 531.2 (M ⁺¹ )

Step 2: 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazine- Synthesis of 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and pyrrolidine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in Step 2 of Example 89 to give compound 2 of the desired form. -Ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid (Example 99) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.11 (d, 2H, J = 8.4 Hz), 7.06 (m, 2H), 6.88 (m, 2H), 6.77 (m, 2H), 4.12 (m, 1H) , 3.96 (m, 1H), 3.94 (m, 3H), 3.72 (m, 2H), 3.68, 3.65 (ss, 3H), 3.51-3.38 (m, 2H), 3.25 (m, 2H), 3.12, 2.99 (ss, 3H), 2.84-2.78 (m, 2H), 1.83 (m, 4H), 1.02 (t, 3H, J = 7.6 Hz).

Example 100 2-Ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-thiomorpholin-4-yl-1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and thiomorpholine to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound 2 of the desired form. -Ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-thiomorpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid (Example 100) was obtained.

MS (ESI ⁺ ) m / z 570.3 (M ⁺¹ )

Example 101 2-Ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-morpholin-4-yl-1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and morpholine to obtain an ester compound, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound 2-ethoxy- 3- (4- (2-((4- (4-methoxyphenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid (Example 101) was obtained.

MS (ESI ⁺ ) m / z 534.3 (M ⁺¹ )

Example 102 3- (4- (2-((4- (azetidin-1-yl) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and azetidine to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 89 to give the compound 3- of the desired form. (4- (2-((4- (azetidin-1-yl) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid (Example 102) was obtained.

MS (ESI ⁺ ) m / z 524.2 (M ⁺¹ )

Example 103 2-Ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (propylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and propylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound 2- of the desired form. To ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) (methyl) amino) Methoxy) phenyl) propanoic acid (Example 103) was obtained.

MS (ESI ⁺ ) m / z 534.3 (M ⁺¹ )

Example 104 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and dimethylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 89 to give the compound 3- of the desired form. (4- (2-((4- (dimethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxy propanoic acid (Example 104) was obtained.

MS (ESI ⁺ ) m / z 512.2 (M ⁺¹ )

Example 105 2-ethoxy-3- (4- (2-((4- (isopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and isopropylamine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound 2 of the desired form. -Ethoxy-3- (4- (2-((4- (isopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 105) was obtained.

MS (ESI ⁺ ) m / z 526.3 (M ⁺¹ )

Example 106 3- (4- (2-((4- (cyclopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and cyclopropylamine were used to obtain the ester compound of the desired form, followed by hydrolysis in the same manner as in Step 3 of Example 89 to give the compound 3 of the desired form. -(4- (2-((4- (cyclopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid (Example 106) was obtained.

MS (ESI ⁺ ) m / z 524.2 (M ⁺¹ )

Example 107 2-ethoxy-3- (4- (2-((4- (furan-2-ylmethylamino) -6- (4-methoxyphenoxy) -1,3,5-tri Azin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl 3- (4- (2-((4-chloro-6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) synthesized in step 1 of Example 99 ) Amino) ethoxy) phenyl) -2-ethoxypropanoate and furan-2-ylmethanamine to obtain an ester compound of the desired form, followed by hydrolysis in the same manner as in step 3 of Example 89 Compound 2-Ethoxy-3- (4- (2-((4- (furan-2-ylmethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazine-) 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 107) was obtained.

Example 108 2-ethoxy-3- (4- (2- (methyl (4-morpholin-4-yl-6-p-tolyl-1,3,5-triazin-2-yl) amino ) Ethoxy) phenyl) propanoic acid

Step 1: ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2- Synthesis of Ethoxypropanoate

In the same manner as in Step 1 of Example 69, Compound ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained.

MS (ESI ⁺ ) m / z 494.2 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.12 (d, 2H, J = 8.4 Hz), 6.82 (m, 2H), 4.14 (m, 4H), 3.94 (m, 2H), 3.79-3.68 (m, 8H) , 3.59 (m, 1H), 3.34 (m, 1H), 3.24, 3.21 (ss, 3H), 2.92 (m, 2H), 1.23 (t, 3H, J = 7.2 Hz), 1.14 (t, 3H, J = 7.2 Hz)

Step 2: 2-ethoxy-3- (4- (2- (methyl (4-morpholin-4-yl-6-p-tolyl-1,3,5-triazin-2-yl) amino) Synthesis of oxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 108 ) Phenyl) -2-ethoxypropanoate (200 mg, 0.41 mmole), 4-methylphenylboronic acid (72 mg, 0.53 mmole), cesium carbonate (2 eq), and tetrakis (triphenylphosphine) palladium ( 71 mg, 0.62 mmole) was reacted for 5 hours at 90 ° C. under dioxane solvent using dioxane (10 mL) as a solvent, and then the reaction was cooled to room temperature. Water was added to the reaction and extracted with ethyl acetate (50 mL). The organic layer was washed with water (30 mL X 2) and brine (30 mL), separated, and water was removed from the separated organic layer using anhydrous magnesium sulfate, filtered, and reduced pressure to remove ethyl acetate. Purification by silica gel column chromatography using ethyl acetate and hexane as a developing solvent to synthesize the ester of the desired form in a yield of 60%, followed by hydrolysis to hydrolyze in the same manner as in step 3 of Example 89 Compound of the desired form 2-ethoxy-3- (4- (2- (methyl (4-morpholin-4-yl-6-p-tolyl-1,3,5-triazin-2-yl) amino) Ethoxy) phenyl) propanoic acid (Example 108) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.53 (bs, 1H), 8.22 (dd, 2H, J = 8.0, 8.4 Hz), 7.25 (d, 2H, J = 8.0), 7.10 (m, 2H), 6.84 (m, 2H), 4.18 (m, 2H), 4.03 (m, 1H), 3.92 (m, 2H), 3.78 (m, 4H), 3.63 (m, 4H), 3.43 (m, 1H), 3.32 , 3.18 (ss, 3H), 2.83-2.78 (m, 2H), 2.36 (s, 3H), 1.02 (t, 3H, J = 7.6 Hz).

Example 109 2-ethoxy-3- (4- (2-((4- (4-ethylphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 108 ) Phenyl) -2-ethoxypropanoate and 4-ethylphenyl boronic acid were used to obtain the desired ester compound through the same reaction as in Step 2 of Example 108, followed by hydrolysis to give the compound 2-ethoxy of the desired form. -3- (4- (2-((4- (4-ethylphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid (Example 109) was obtained.

MS (ESI ⁺ ) m / z 536.2 (M ⁺¹ )

Example 110 2-ethoxy-3- (4- (2-((4- (4-methoxyphenyl) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 108 ) Phenyl) -2-ethoxypropanoate and 4-methoxyphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to give the desired compound 2 -Ethoxy-3- (4- (2-((4- (4-methoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 110) was obtained.

MS (ESI ⁺ ) m / z 538.2 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.47 (bs, 1H), 8.24 (dd, 2H, J = 8.0, 8.4 Hz), 7.10 (d, 2H, J = 7.6), 6.98 (d, 2H, J = 8.0), 6.85 (m, 2H), 4.18 (m, 2H), 4.03 (m, 1H), 3.92 (s, 3H), 3.90 (m, 4H), 3.65 (m, 4H), 3.48 (m, 1H), 3.29, 3.18 (ss, 3H), 2.88-2.78 (m, 2H), 2.36 (s, 3H), 1.02 (t, 3H, J = 7.6 Hz).

Example 111 2-Ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 108 ) Phenyl) -2-ethoxypropanoate and 4-ethoxyphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to give the desired compound 2 -Ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 111) was obtained.

MS (ESI ⁺ ) m / z 552.3 (M ⁺¹ )

Example 112 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 108 ) Phenyl) -2-ethoxypropanoate and 3-ethoxyphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to give the desired compound 2 -Ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 112) was obtained.

MS (ESI ⁺ ) m / z 552.3 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 12.42 (bs, 1H), 7.81 (m, 2H), 7.35 (t, 1H, J = 7.6), 7.08 (m, 3H), 6.84 (m, 2H), 4.18 (m, 2H), 4.02 (m, 3H), 3.98 (m, 2H), 3.82-3.72 (m, 4H), 3.62 (m, 4H), 3.45 (m, 1H), 3.34 (m, 2H) , 3.29, 3.18 (ss, 3H), 2.88-2.78 (m, 2H), 2.36 (s, 3H), 1.34 (t, 3H, J = 7.6 Hz), 1.02 (t, 3H, J = 7.6 Hz).

Example 113 2-Ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 108 ) Phenyl) -2-ethoxypropanoate and 4-fluorophenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to obtain the desired compound 2 -Ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid (Example 113) was obtained.

MS (ESI ⁺ ) m / z 526.2 (M ⁺¹ )

Example 114 3- (4- (2-((4- (dimethylamino) -6-p-tolyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid

Step 1: ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- Synthesis of 2-ethoxypropanoate

In the same manner as in Step 1 of Example 69, Compound ethyl-3- (4- in desired form through coupling reaction using 4,6-dichloro-N, N-dimethyl-1,3,5-triazin-2-amine synthesized in Preparation Example 1 (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained.

MS (ESI ⁺ ) m / z 452.2 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.12 (d, 2H, J = 8.0 Hz), 6.80 (m, 2H), 4.15 (m, 4H), 3.94 (m, 2H), 3.57 (m, 3H), 3.34 (m, 1H), 3.23, 3.22 (ss, 3H), 3.17-3.07 (m, 6H), 2.92 (m, 2H), 1.23 (t, 3H, J = 7.2 Hz), 1.14 (t, 3H, J = 7.2 Hz)

Step 2: 3- (4- (2-((4- (dimethylamino) -6-p-tolyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-methylphenyl boronic acid were used to obtain an ester compound of the desired form through a coupling reaction in the same manner as in Example 108. In the same manner, the compound is hydrolyzed to give the desired form of 3- (4- (2-((4- (dimethylamino) -6-p-tolyl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid (Example 114) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.22 (m, 2H), 7.26 (d, 2H, J = 8.0 Hz), 7.11 (d, 2H, J = 7.6 Hz), 6.85 (d, 1H, J = 8.0 Hz), 6.65 (m, 2H, J = 8.0 Hz), 4.19 (m, 2H), 3.99 (m, 1H), 3.91 (m, 2H), 3.46 (m, 1H), 3.32-3.08 (m, 10H), 2.88-2.78 (m, 2H), 2.34 (s, 3H), 1.02 (t, 3H, J = 7.6 Hz).

Example 115 to 3- (4- (2-((4- (dimethylamino) -6- (4-ethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) Methoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-ethylphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to obtain the compound of the desired form. 3- (4- (2-((4- (dimethylamino) -6- (4-ethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-Ethoxypropanoic acid (Example 115) was obtained.

MS (ESI ⁺ ) m / z 494.2 (M ⁺¹ )

Example 116 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-methoxyphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to obtain the desired form. Compound 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid (Example 116) was obtained.

MS (ESI ⁺ ) m / z 496.2 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.26 (m, 2H), 7.11 (d, 1H, J = 8.4 Hz), 7.00 (d, 1H, J = 8.4 Hz), 6.85 (d, 2H, J = 8.0 Hz), 6.65 (m, 2H, J = 8.0 Hz), 4.18 (m, 2H), 4.01 (m, 1H), 3.91 (m, 2H), 3.81 (s, 3H), 3.45 (m, 1H) , 3.36-3.03 (m, 10H), 2.88-2.78 (m, 2H), 1.02 (t, 3H, J = 7.6 Hz).

Example 117 3- (4- (2-((4- (dimethylamino) -6- (4-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-ethoxyphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, followed by hydrolysis to obtain the desired form. Compound 3- (4- (2-((4- (dimethylamino) -6- (4-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid (Example 117) was obtained.

MS (ESI ⁺ ) m / z 510.2 (M ⁺¹ )

Example 118 3- (4- (2-((4- (dimethylamino) -6- (3-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 3-ethoxyphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to obtain the desired form. Compound 3- (4- (2-((4- (dimethylamino) -6- (3-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid (Example 118) was obtained.

MS (ESI ⁺ ) m / z 510.2 (M ⁺¹ )

Example 119 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-fluorophenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, followed by hydrolysis to obtain the desired form. Compound 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid (Example 119) was obtained.

MS (ESI ⁺ ) m / z 484.2 (M ⁺¹ )

Example 120 3- (4- (2-((4- (dimethylamino) -6- (4-isopropylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-isopropylphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to obtain the desired form. Compound 3- (4- (2-((4- (dimethylamino) -6- (4-isopropylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid (Example 119) was obtained.

MS (ESI ⁺ ) m / z 508.1 (M ⁺¹ )

Example 121 3- (4- (2-((4- (dimethylamino) -6- (4-trifluoromethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) synthesized in step 1 of Example 114 Ethoxy) phenyl) -2-ethoxypropanoate and 4-trifluoromethylphenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, followed by hydrolysis to obtain the desired form. Compound of 3- (4- (2-((4- (dimethylamino) -6- (4-trifluoromethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid (Example 119) was obtained.

MS (ESI ⁺ ) m / z 534.2 (M ⁺¹ )

Example 122 3- (4- (2-((4- (p-toluidino) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid

Step 1: ethyl 3- (4- (2-((4-chloro-6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2- Synthesis of oxypropanoate

In the same manner as in Step 1 of Example 69, Compound of the desired form, ethyl-3- (4- (2-((4-,), via coupling reaction using commercially available 2,4-dichloro-6-methoxy-1,3,5-triazine. Chloro-6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained.

MS (ESI ⁺ ) m / z 439.2 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.14 (m, 2H), 6.79 (m, 2H), 4.17 (m, 4H), 3.96 (m, 6H), 3.57 (m, 1H), 3.24 (m, 1H) , 3.31, 3.29 (ss, 3H), 2.92 (m, 2H), 1.21 (t, 3H, J = 7.0 Hz), 1.14 (t, 3H, J = 7.2 Hz)

Step 2: 3- (4- (2-((4- (p-toluidino) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl Synthesis of 2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 122 Using a) phenyl) -2-ethoxypropanoate and p-toluidine in the same manner as in Step 2 of Example 89 to obtain an ester compound of the desired form, the same as in Step 3 of Example 89 Hydrolysis by the compound of the desired form 3- (4- (2-((4- (p-toluidino) -6-methoxy-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) -2-ethoxypropanoic acid (Example 122) was obtained.

MS (ESI ⁺ ) m / z 482.2 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 9.42 (bs, 1H), 7.58 (m, 2H), 7.12 (d, 2H, J = 8.0 Hz), 7.06 (m, 2H), 6.84 (m, 2H) , 4.15 (m, 2H), 3.92 (m, 3H), 3.82, 3.78 (ss, 3H), 3.45 (m, 1H), 3.25 (m, 1H), 3.19, 3.16 (ss, 3H), 2.86-2.78 (m, 2H), 2.21 (s, 3H), 1.01 (t, 3H, J = 7.6 Hz).

Example 123 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-methoxy-1, 3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 122 ) Phenyl) -2-ethoxypropanoate and 4-fluorophenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, and then hydrolyzed to give the desired compound 2 -Ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid (Example 119) was obtained.

MS (ESI ⁺ ) m / z 471.2 (M ⁺¹ )

Example 124 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid

Step 1: ethyl 3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxy Synthesis of Propanoate

In the same manner as in Step 1 of Example 69, Compound 2,4-dichloro-6-ethyl-1,3,5-triazine synthesized in Preparation Example 1 was subjected to a coupling reaction to give compound ethyl-3- (4- (2-((4 -Chloro-6-ethyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained.

MS (ESI ⁺ ) m / z 436.2 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.15 (m, 2H), 6.79 (m, 2H), 4.16 (q, 2H, J = 7.2 Hz), 4.11 (m, 2H), 3.91 (m, 1H), 3.84 (m, 2H), 3.58 (m, 1H), 3.34 (m, 1H), 2.92 (m, 2H), 2.72 (m, 2H), 1.26 (m, 3H), 1.14 (t, 3H, J = 7.2 Hz)

Step 2: 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) Synthesis of ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) synthesized in step 1 of Example 124) Example 89 step of obtaining an ester compound of the desired form through a coupling reaction in the same manner as in step 2 of Example 108 using phenyl) -2-ethoxypropanoate and 4-methoxyphenyl boronic acid Hydrolyzed in the same manner as 3 to give the desired form of compound 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 124) was obtained.

MS (ESI ⁺ ) m / z 481.2 (M ⁺¹ )

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.34 (d, 1H, J = 8.8 Hz), 8.27 (d, 1H, J = 8.8 Hz), 7.12 (m, 2H), 7.03 (m, 2H), 6.85 (m, 2H), 6.75 (m, 2H), 4.22 (m, 2H), 4.08 (m, 1H), 4.00 (m, 1H), 3.91 (m, 1H), 3.82 (s, 3H), 3.51 ( m, 1H), 3.32, 3.26 (ss, 3H), 3.25 (m, 1H), 2.83-2.78 (m, 2H), 2.65 (m, 2H), 1.25 (m, 3H), 1.04 (m, 3H) .

Example 125 2-Ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1, 3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) synthesized in step 1 of Example 124) Phenyl) -2-ethoxypropanoate and 4-fluorophenyl boronic acid were used to obtain an ester compound of the desired form through the same reaction as in Step 2 of Example 108, followed by hydrolysis to obtain a compound 2- of the desired form. Ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) Propanoic acid (Example 119) was obtained.

MS (ESI ⁺ ) m / z 469.2 (M ⁺¹ )

Example 126 2-ethoxy-3- (4- (2-((4- (4-morpholin-4-yl) -6- (p-tolyloxy) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Step 1: ethyl-3- (4- (2-((4-chloro-6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl Synthesis of 2-2-ethoxypropanoate

In the same manner as in Step 1 of Example 69, Compound 2,4-dichloro-6- (p-tolyloxy) -1,3,5-triazine synthesized in Preparation Example 1 was subjected to a coupling reaction to give compound ethyl-3- (4- ( 2-((4-chloro-6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained .

¹ H NMR (CDCl ₃ , 400 MHz) 7.14 (m, 4H), 7.00 (m, 2H), 6.78 (d, 1H, J = 8.4 Hz), 6.71 (d, 1H, J = 8.4 Hz), 4.15 (m , 2H), 3.97 (m, 2H), 3.78 (m, 1H), 3.38 (m, 1H), 3.32 (m, 1H), 3.29, 3.15 (ss, 3H), 2.93 (m, 2H), 1.23 ( t, 3H, J = 7.2 Hz), 1.14 (t, 3H, J = 7.6 Hz).

Step 2: 2-ethoxy-3- (4- (2-((4- (4-morpholin-4-yl) -6- (p-toryloxy) -1,3,5-triazine-2 Synthesis of -yl) (methyl) amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 126) Amino) ethoxy) phenyl) -2-ethoxypropanoate and morpholine to obtain the ester compound of the desired form, followed by hydrolysis to give the compound 2-ethoxy-3- (4- (2- ((4- (4-morpholin-4-yl) -6- (p-toryloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid ( Example 126) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.17-7.10 (m, 4H), 7.02 (m, 2H), 6.81 (m, 2H), 6.67 (m, 2H), 4.12 (m, 1H), 3.97 ( m, 1H), 3.89 (m, 1H), 3.82 (m, 1H), 3.82 (m, 2H), 3.52-3.46 (m, 8H), 3.26 (m, 1H), 3.13, 3.00 (ss, 3H) , 2.94-2.78 (m, 2H), 2.28, 2.25 (ss, 3H), 1.02 (t, 3H, J = 7.6 Hz).

Example 127 to 3- (4- (2-((4- (dimethylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) Methoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 126) Amino) ethoxy) phenyl) -2-ethoxypropanoate and dimethylamine were used to obtain the ester compound of the desired form, and then hydrolyzed to obtain 3- (4- (2-((4- (dimethylamino)-). 6- (p-Toryloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid (Example 127) was obtained.

MS (ESI ⁺ ) m / z 496.2 (M ⁺¹ )

Example 128 3- (4- (2-((4- (isopropylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid

Ethyl-3- (4- (2-((4-chloro-6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) synthesized in step 1 of Example 126) Amino) ethoxy) phenyl) -2-ethoxypropanoate and isopropylamine were used to obtain the ester compound of the desired form, and then hydrolyzed to obtain 3- (4- (2-((4- (isopropylamino). ) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoic acid (Example 128) was obtained.

MS (ESI ⁺ ) m / z 510.2 (M ⁺¹ )

Example 129 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid

Step 1: ethyl-3- (4- (2-((4-chloro-6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2- Synthesis of Ethoxypropanoate

In the same manner as in Step 1 of Example 69, Compound 4-3--4- (2-(() was prepared by coupling reaction using 4,6-dichloro-6-isopropyl-1,3,5-triazine synthesized in Preparation Example 1. 4-chloro-6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained.

MS (ESI ⁺ ) m / z 451.2 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.15 (m, 2H), 6.80 (m, 2H), 4.15 (m, 2H), 4.09 (m, 2H), 3.95 (m, 1H), 3.86 (m, 2H) , 3.56 (m, 1H), 3.37 (m, 1H), 3.21, 3.18 (ss, 3H), 2.92 (m, 2H), 1.28 (m, 9H), 1.14 (t, 3H, J = 7.2 Hz)

Step 2: 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino Synthesis of) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 129 ) Phenyl) -2-ethoxypropanoate and 3-ethoxyphenyl boronic acid to obtain the ester compound of the desired form through a coupling reaction in the same manner as in Example 108, and then hydrolyzed to obtain the compound of the desired form 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid (Example 129) was obtained.

¹ H NMR (DMSO-d ₆ , 400 MHz) 7.86 (m, 1H), 7.39 (m, 1H), 7.12 (m, 2H), 7.06 (m, 1H), 6.82 (m, 2H), 6.29 (m, 2H), 4.21 (m, 1H), 4.08 (m, 3H), 3.91 (m, 2H), 3.46 (m, 1H), 3.32-3.08 (m, 10H), 2.88-2.78 (m, 2H), 2.92 (m, 2H), 1.28 (m, 6H), 1.04 (t, 3H, J = 7.2 Hz).

Example 130 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 129 ) Phenyl) -2-ethoxypropanoate and 4-fluorophenyl boronic acid to obtain the ester compound of the desired form, and then hydrolyzed to 2-ethoxy-3- (4- (2-((4 -(4-fluorophenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 130) was obtained.

MS (ESI ⁺ ) m / z 483.2 (M ⁺¹ )

Example 131 2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy synthesized in step 1 of Example 129 ) Phenyl) -2-ethoxypropanoate and 4-ethoxyphenyl boronic acid to obtain the ester compound of the desired form, and then hydrolyzed to 2-ethoxy-3- (4- (2-((4 -(3-fluorophenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid (Example 130) was obtained.

MS (ESI ⁺ ) m / z 509.2 (M ⁺¹ )

Example 132 to 2-ethoxy-3- (4- (2-((4-ethyl-6- (3-methoxyphenyl) -1,3,5-triazin-2-yl-amino) Methoxy) phenyl) propanoic acid

Step 1: ethyl 3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl-amino) ethoxy) phenyl) -2-ethoxypropanoate Synthesis of

In the same manner as in Step 1 of Example 1 using 9a-2 synthesized in Preparation Example 8 as a starting material, Compound 4-3- (4- (2-((4) in the desired form via coupling reaction using 4,6-dichloro-6-ethyl-1,3,5-triazine synthesized in Preparation Example 1 -Chloro-6-ethyl-1,3,5-triazin-2-yl-amino) ethoxy) phenyl) -2-ethoxypropanoate was obtained.

MS (ESI ⁺ ) m / z 423.2 (M ⁺¹ )

¹ H NMR (CDCl ₃ , 400 MHz) 7.15 (m, 2H), 6.80 (m, 2H), 6.04 (bs, 1H), 4.16 (q, 2H, J = 7.2 Hz), 4.09 (m, 2H), 3.93 (m, 1H), 3.85 (m, 2H), 3.56 (m, 1H), 3.37 (m, 1H), 2.93 (m, 2H), 2.64 (m, 2H), 1.27 (m, 6H), 1.14 ( t, 3H, J = 7.2 Hz)

Step 2: 2-Ethoxy-3- (4- (2-((4-Etic-6- (3-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) Synthesis of Phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl-amino) ethoxy) phenyl) synthesized in step 1 of Example 132)- Using 2-ethoxypropanoate and 3-methoxyphenyl boronic acid in the same manner as in Example 108 to obtain an ester compound of the desired form through a coupling reaction, and then hydrolyzed to obtain the compound 2-ethoxy of the desired form. 3- (4- (2-((4-Etic-6- (3-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propanoic acid (Example 132).

¹ H NMR (DMSO-d ₆ , 400 MHz) 8.13 (m, 1H), 7.94 (m, 1H), 7.88 (m, 1H), 7.41 (m, 1H), 7.12 (m, 2H), 6.85 (m, 2H), 4.21 (m, 2H), 3.85 (m, 1H), 3.80-3.70 (m, 6H), 3.46 (m, 1H), 3.21 (m, 1H), 2.90-2.72 (m, 2H), 2.62 (m, 2H), 1.26 (m, 3H), 1.01 (t, 3H, J = 7.2 Hz).

Example 133 to 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl-amino) Methoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl-amino) ethoxy) phenyl) synthesized in step 1 of Example 132)- 2-ethoxypropanoate and 4-methoxyphenyl boronic acid were used to obtain an ester compound of the desired form, followed by hydrolysis to yield 2-ethoxy-3- (4- (2-((4-ethyl-6 -(4-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propanoic acid (Example 130) was obtained.

MS (ESI ⁺ ) m / z 467.2 (M ⁺¹ )

Example 134 to 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl-amino) Methoxy) phenyl) propanoic acid

Ethyl-3- (4- (2-((4-chloro-6-ethyl-1,3,5-triazin-2-yl-amino) ethoxy) phenyl) synthesized in step 1 of Example 132) 2-ethoxypropanoate and 4-fluorophenylboronic acid were used to obtain the ester compound of the desired form, followed by hydrolysis to yield 2-ethoxy-3- (4- (2-((4-ethyl- 6- (4-fluorophenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propanoic acid (Example 130) was obtained.

MS (ESI ⁺ ) m / z 455.2 (M ⁺¹ )

Experimental Example 1 Activation Ability Test of PPAR-α and PPAR-γ

1. Experimental Materials and Methods

PPAR-α and PPAR-γ were transiently expressed in cells to evaluate the ability of the compounds of the present invention to activate respective PPARs to induce transcriptional activation as a meaning of efficacy (transactivation assay).

Cells were used as the kidney cells of monkey CV-1 cells, PPAR-α and γ were used in the mouse (murine) and human, and the samples are the Examples 4, 16, 19, 48, 64, 68, 76 The compounds prepared in, 77, 78, 79 and 95 were used. Positive controls for PPAR-α and γ include compounds 3-4- [2- (2-phenyl-4-methyl-1,3-oxa, which have been suspended in phase III clinically as PPAR-α and γ agonists, Sol) ethyloxy] phenyl- (2S)-[(1-methyl-3-oxo-3-phenyl) propenyl] aminopropanoic acid was used. Chimeric receptors were used to rule out interference due to endogenous receptor activation (Jian-Shen Q. et al., Mol Cell Biol (1995) 15 (3): 1817-1825), and chimeric receptors are ligand-binding of PPAR-α and γ. Each domain was generated in the form of fusion to the DNA binding site of the yeast transcription factor GAL4.

Each DNA construct expressing the chimeric receptor and five copies of the DNA binding region of GAL4 and a DNA construct capable of inducing the expression of firefly luciferase (Firefly luciferase) and Renilla Luciferase (Renilla Luciferase) DNA constructs expressing were transiently transfected into the cells using Lipofectamine Plus reagent (Invitrogen, USA). After 3 hours transfection the sample and DMEM medium containing 10% fetal calf serum were exchanged. After 24 hours, the same amount of Dual luciferase assay reagent (Promega, USA) was added to the immersed medium, and the firefly luciferase activity and the renilla luciferase activity were continuously assayed. Renilla luciferase activity was calibrated for transfection efficiency. (Motomura W. et al., Int J Cancer (2004) 108 (1): 41-6).

The activity efficacy of PPAR-α and γ was determined by measuring the percentage (Relative Response%) of the maximum effect of the positive control, and then subjected to multiple concentration evaluations of the compounds of the present invention. The concentration causing activation (EC ₅₀ ) was calculated using nonlinear regression analysis.

2. Experimental Results

Representative compounds of the present invention showed a value of 4 ~ 1000 nM EC ₅₀ for human PPAR-α, and a value of 6 ~ 300 nM for human PPAR-γ (Table 1). In addition, EC ₅₀ showed 20 to 200 nM of mouse PPAR-α, and 20 to 2000 nM of mouse PPAR-γ. Therefore, the compound of formula 1 of the present invention was able to confirm that PPAR-α and γ is activated even at a small concentration, the pharmaceutical composition containing the compound of the present invention is hypoglycemic action, blood lipid lowering action, and insulin resistance It can be usefully used as a PPAR agonist that exhibits effects such as amelioration.

Experimental Example 2 Test of Hypoglycemic Activity in Hyperglycemic Diabetic Mice

1. Experimental Materials and Methods

We evaluated the efficacy of PAR compounds on blood glucose in 7-week-old male diabetic mice ( db / db mice). Blood of diabetic mice to which the drug was administered once a day for 5 days was measured by a blood glucose meter (ACCU CHEK Active ^(R) ) after sampling through the microvein. Rosiglitazone 3 mg / kg was used as a positive control.

2. Experimental Results

In vitro reporter assay, nine PAR compounds with excellent activity against PPAR α and γ were selected and orally administered at 1 or 3mg / kg dose. An average of 45-50% hypoglycemic activity was observed by rosiglitazone, a control drug, and an excellent hypoglycemic effect of rosiglitazone equivalent or higher was observed.

As described above, the present invention provides a novel compound of Formula 1 and a preparation method thereof. EC ₅₀ of the compound Through measurement As a result of confirming the PPAR activating action, it can be seen that the compound exhibits efficacy such as hypoglycemic action, hypolipidemic action, and insulin resistance improving action. Therefore, the pharmaceutical composition containing the compound according to the present invention can be usefully used as a PPAR agonist capable of preventing and treating diseases related to PPAR, ie, obesity, diabetes, hypertension, hypertriglyceridemia and the like.

Claims (14)

A racemic compound of formula 1, an optical isomer and a pharmaceutically acceptable salt thereof. <Formula 1>

In the above formula, R is -OCH ₂ CH ₃ or -CH ₂ CH ₃ , Each X is independently —N—CH 3, —NH, —O—, or methylene, Y and Z are each independently lower alkyl; Lower alkoxy; Lower alkylamines; Lower cycloalkylamines; aniline; Azetin; Pyrrolidine; Pipepidine; Piperazine; Morpholine; Thiomorpholine; Phenyl; Or phenoxy, wherein Y and Z are optionally substituted with C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, nitro, trifluoromethyl, phenyl, benzyl, benzoyl, furan, tee May have one or more substituents selected from the group consisting of offen, phenoxy, piperidine, n represents the integer of 1-5. The method of claim 1 wherein phenoxy

; Lower alkoxy is -OCH ₃ ; Lower alkyl is methyl, ethyl, isopropyl; Lower alkylamines

; Lower cycloalkylamines

; Piperidine

; Piperazine is

; Phenyl

; Racemic compound, optical isomer and pharmaceutically acceptable salt of formula (I) characterized in that it is selected from The compound of claim 1, wherein the compound is selected from the group consisting of: 2- (4- (2- (methyl (4- (piperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (pyrrolidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-methylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-phenylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-benzylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (diethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4-morpholin-4-yl-6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-phenylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (cyclopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (isopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (3,5-dimethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (2-ethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (4-phenylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl mountain; 2- (4- (2-((4- (diethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (cyclohexylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-phenylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamine) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl- (4- (phenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2- (methyl- (4- (phenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2- (methyl- (4-methyl (piperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2- (methyl- (4-morpholin-4-yl-6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4- (diethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4- (dimethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (isopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4- (cyclopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxy (piperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (3-hydroxy (piperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (diethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6- (cyclopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6-((2-hydroxyethyl) (methyl) amino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-ethylpiperazin-1-yl) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenoxy) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Benzyl) butyl acid; 2- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (azetidin-1-yl) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxy propanoic acid; 3- (4- (2-((4- (diethylamino) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxy propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxy propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-((2-hydroxyethyl) (methyl) amino-1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (4-hydroxyphenylamino) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-thiomorpholin-4-yl-1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) 3- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; (S) 3- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) 2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (isopropylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid; (S) 3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) 3- (4- (2-((4- (cyclobutylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) 2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-thiomorpholin-4-yl-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (azetidin-1-yl) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (isopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (cyclopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (furan-2-ylmethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2- (methyl (4-morpholin-4-yl-6-p-tolyl-1,3,5-triazin-2-yl) amino) ethoxy) phenyl Propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethylphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6-p-tolyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2- Oxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-ethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (3-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-isopropylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-trifluoromethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid; 3- (4- (2-((4- (p-toluidino) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2 Ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-morpholin-4-yl) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid; 3- (4- (2-((4- (isopropylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-ethyl-6- (3-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain; Iii) reacting a compound represented by Formula 2, Formula 3, or Formula 4 with Formula 5; Ii) reacting cyanuric chloride of formula 6; Iii) Y as defined in Formula 1 Reacting; Iii) reacting Z as defined in Formula 1 below; And Iii) hydrolysis; Method for producing a compound represented by the following formula (1). <Formula 1>

In the above formula, R is -OCH ₂ CH ₃ or -CH ₂ CH ₃ , Each X is independently —N—CH 3, —NH, —O—, or methylene, Y and Z are each independently lower alkyl; Lower alkoxy; Lower alkylamines; Lower cycloalkylamines; aniline; Azetin; Pyrrolidine; Pipepidine; Piperazine; Morpholine; Thiomorpholine; Phenyl; Or phenoxy, wherein Y and Z are optionally substituted with C _1-6 alkyl, C _1-6 alkoxy, hydroxy, amino, nitro, trifluoromethyl, phenyl, benzyl, benzoyl, furan, tee May have one or more substituents selected from the group consisting of offen, phenoxy, piperidine, n represents the integer of 1-5. <Formula 2>

W represents a methyl or ethyl group. <Formula 3>

W represents a methyl or ethyl group. <Formula 4>

W represents a methyl or ethyl group. <Formula 6>

The method of claim 4, wherein i) reacting a compound of formula 2, 3 or 4 described below with a compound of formula 5 below under basic conditions; Ii) generating a substituted cyanuric compound by reacting the cyanuric chloride of Formula 6 with Y as defined in Formula 1-1 using basic conditions or an alkylmagnesium bromide of Formula 7; Iii) reacting the compound prepared in i) and ii); iv) reacting Z defined in Chemical Formula 1-1 under an amine defined in Chemical Formula 1-1 or boronic acid of Chemical Formula 8; And v) hydrolysis step Method for preparing a compound of formula 1-1 <Formula 1-1>

R is -OCH ₂ CH ₃ or -CH ₂ CH ₃ ; Each X is independently a compound of the form -N-CH ₃ , or -NH, n represents an integer of 1 to 5, and Y and Z are as defined in formula (1) as defined in claim 4. <Formula 2>

W represents a methyl or ethyl group. <Formula 3>

W represents a methyl or ethyl group. <Formula 4>

W represents a methyl or ethyl group. <Formula 5>

<Formula 6>

<Formula 7>

A is methyl, ethyl, or isopropyl. The method of claim 4, wherein Iii) reacting the compound of Formula 3 or 4 with the compound of Formula 9 under basic conditions and then removing the protected benzyl group through a hydrogenation reaction; Ii) reacting the cyanuric chloride of Formula 6 with Y as defined in Formula 1-2 below using basic conditions or an alkylmagnesium bromide compound of Formula 7 to produce a substituted cyanuric compound; Iii) reacting Y defined in Chemical Formula 1-2 under basic conditions; Iii) reacting Z defined in Chemical Formula 1 with a base or 0.2 equivalent of boric acid and tetrakis (triphenylphosphine) palladium, and cesium carbonate as a base for 5 hours at 90 ° C. in a dioxane solvent; And Iii) hydrolysis step Method for preparing a compound of formula 1-2 below. <Formula 1-2>

Wherein R is —OCH ₂ CH ₃ , X is a compound of the form —O—, n represents an integer of 1 to 5, and Y and Z are as defined in formula 1 as defined in claim 4. <Formula 3>

W represents a methyl or ethyl group. <Formula 4>

W represents a methyl or ethyl group. <Formula 6>

<Formula 7>

A is methyl, ethyl, or isopropyl. <Formula 8>

D is a substituted lower alkyl, lower alkoxy, halogen, methylhalogen compound and the substituents include both momo-substituents and di-substituents. <Formula 9>

The method of claim 4, wherein i) reacting the compound of Formula 6 with the compound of Formula 7; Ii) reacting Y as defined in Formula 1-3; Iii) reacting Z defined in Chemical Formula 1-3 with base or 0.2 equivalents of boric acid and tetrakis (triphenylphosphine) palladium, and cesium carbonate as a base at 90 ° C. for 5 hours in a dioxane solvent. ; iv) removing the alcohol protecting group to produce an alcohol compound and then converting the hydroxy group to a methanesulfonate group; v) reacting the compound of Formula 2 or 3 under basic conditions; And iv) hydrolysis Method for preparing a compound of Formula 1-3 consisting of. <Formula 1-3>

R is -OCH ₂ CH ₃ , X is a compound of the form -CH _2- , n represents an integer of 1 to 5, Y and Z are as defined in formula (1) according to claim 4. <Formula 2>

W represents a methyl or ethyl group. <Formula 3>

W represents a methyl or ethyl group. <Formula 6>

<Formula 7>

A is methyl, ethyl, or isopropyl. <Formula 8>

D is a substituted lower alkyl, lower alkoxy, halogen, methylhalogen compound and the substituents include both momo-substituents and di-substituents. The process according to claim 4, wherein the reaction is carried out using a base selected from potassium carbonate, triethylamine, ammonia formate and N, N-diisopropylethylamine (DIEA) in steps (iii) to (iii). Way. The method of claim 4, wherein in step (iii), Z defined in Chemical Formula 1 according to claim 4 is reacted under boronic acid of Chemical Formula 8. <Formula 8>

D is substituted lower alkyl, lower alkoxy, halogen compound, and the substituent includes both momo-substituents and di-substituents. Method for producing an optical isomer compound represented by the following formula (4) using Viscozyme L from the formula (3). <Formula 3>

W represents a methyl or ethyl group. <Formula 4>

W represents a methyl or ethyl group. A peroxisome proliferator-activated receptor (PPAR) agonist containing the compound of formula 1 according to claim 1. A therapeutic agent for diabetes comprising the compound of formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. An X-syndrome prophylactic or therapeutic agent comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. A dual agonist of peroxisome proliferator-activated receptor (PPAR) containing a compound selected from the group consisting of the following compounds. 2- (4- (2- (methyl (4- (piperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (pyrrolidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-methylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-phenylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-benzylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (diethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4-morpholin-4-yl-6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-methylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine- 2-yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-ethylpiperidin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-phenylpiperazin-1-yl) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazine-2 -Yl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (cyclopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (isopropylamino) -6- (4- (trifluoromethyl) phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (3,5-dimethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (2-ethylpiperidin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6- (4-phenylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamino) -6-morpholino-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl mountain; 2- (4- (2-((4- (diethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (cyclohexylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-phenylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenylamine) -6- (4-methylpiperazin-1-yl) -1,3,5-triazin-1-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamine) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl- (4- (phenylamino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2- (methyl- (4- (phenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2- (methyl- (4-methylpiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2- (methyl- (4-morpholin-4-yl-6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4- (diethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4- (dimethylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (isopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4- (cyclopropylamino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) butyl acid ; 2- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (3-hydroxypiperidin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2- (methyl (4- (4-methylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (phenylamino) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (piperidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (diethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6- (dimethylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6- (cyclopropylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2- (4- (2-((4- (p-toluidino) -6-((2-hydroxyethyl) (methyl) amino) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (methyl) amino) Oxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (p-toluidino) -6- (4-ethylpiperidin-1-yl) -1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenoxy) -6- (4-methylpiperidin-1-yl) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Benzyl) butyl acid; 2- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) benzyl) butyl acid; 2- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Benzyl) butyl acid; 2- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) benzyl ) Butyric acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperidin-1-yl) -1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (azetidin-1-yl) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid; 3- (4- (2-((4- (diethylamino) -6- (4-luorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) -2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6-((2-hydroxyethyl) (methyl) amino-1,3,5-triazine- 2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-hydroxypiperidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (3-hydroxypiperidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (2-hydroxyethylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethylpiperazin-1-yl) -6- (4-fluorophenylamino) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-hydroxyphenylamino) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (isopropylamino) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-((2-hydroxyethyl) (methyl) amino) -6- (4-hydroxyphenylamino) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-hydroxyphenylamino) -6- (4-methylpiperazin-1-yl) -1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazine -2-yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-thiomorpholin-4-yl-1,3,5-triazine-2 -Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6-morpholin-4-yl-1,3,5-triazine-2- Yl) (methyl) amino) ethoxy) phenyl) propanoic acid; (S) -3- (4- (2-((4- (azetidin-1-yl) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid; (S) -3- (4- (2-((4- (diethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) -3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (isopropylamino) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; (S) -3- (4- (2-((4- (cyclopropylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) -3- (4- (2-((4- (cyclobutylamino) -6- (4-fluorophenoxy) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) -2-ethoxypropanoic acid; (S) -2-ethoxy-3- (4- (2-((4- (4-fluorophenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (pyrrolidin-1-yl) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-thiomorpholin-4-yl-1,3,5-triazin-2-yl) ( Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl ) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (azetidin-1-yl) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) Ethoxy) phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenoxy) -6- (propylamino) -1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (isopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (cyclopropylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) -2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (furan-2-ylmethylamino) -6- (4-methoxyphenoxy) -1,3,5-triazin-2-yl ) (Methyl) amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2- (methyl (4-morpholin-4-yl-6-p-tolyl-1,3,5-triazin-2-yl) amino) ethoxy) phenyl Propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethylphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) amino ) Ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-methoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-morpholin-4-yl-1,3,5-triazin-2-yl) (methyl) Amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6-p-tolyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2-e Oxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-ethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (3-ethoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-isopropylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (4-trifluoromethylphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl ) -2-ethoxypropanoic acid; 3- (4- (2-((4- (p-toluidino) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) -2 Ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-methoxy-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-morpholin-4-yl) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (Methyl) amino) ethoxy) phenyl) propanoic acid; 3- (4- (2-((4- (dimethylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl)- 2-ethoxypropanoic acid; 3- (4- (2-((4- (isopropylamino) -6- (p-tolyloxy) -1,3,5-triazin-2-yl) (methyl) amino) ethoxy) phenyl) 2-ethoxypropanoic acid; 2-ethoxy-3- (4- (2-((4- (3-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-fluorophenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4- (4-ethoxyphenyl) -6-isopropyl-1,3,5-triazin-2-yl) (methyl) amino) ethoxy ) Phenyl) propanoic acid; 2-ethoxy-3- (4- (2-((4-ethyl-6- (3-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-methoxyphenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain; 2-ethoxy-3- (4- (2-((4-ethyl-6- (4-fluorophenyl) -1,3,5-triazin-2-yl-amino) ethoxy) phenyl) propane mountain;