KR20140052829A - Novel compound having activity to gpr119, process of preparing thereof and pharmaceutical compositon comprising the same - Google Patents

Abstract

The present invention relates to a novel compound having GPR119 activity, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient. In particular, the novel compound: has a hypoglycemic activity and a positive effect on pancreatic beta cells; improves lipid metabolism associated with risk factors of chronic cardiovascular diseases; and thus can be used for treating and/or preventing metabolic diseases such as diabetes.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel compound having GPR119 agonistic activity, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. BACKGROUND OF THE INVENTION 1. Field of the Invention [0001]

The present invention relates to a novel compound, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient. More particularly, to a compound having GPR119 agonistic activity, a method for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

Metabolic Disease refers to a syndrome in which risk factors such as obesity, diabetes, hypertriglyceridemia, hypertension, cardiovascular disease, and blood clotting disorder occur together. According to the ATP III of the National Cholesterol Education Program (NCEP), announced in 2001, ① Abdominal obesity with a waist circumference of 40 inches (102 cm) for men and 35 inches (88 cm) for women, ② 150 mg / dL or more of hypertriglyceridemia, ③ HDL cholesterol is 40 mg / dL for male, 50 mg / dL for female, ④ hypertension for blood pressure 130/85 mmHg or more, or ⑤ fasting glucose for 110 mg / dL or more If one of the risk factors is more than three, it is judged as a metabolic disease.

The prevalence of diabetes worldwide is rapidly increasing due to increased obesity and sedentary lifestyle patterns, according to the International Diabetes Federation (IDF), the number of diabetic patients is expected to increase from 246 million in 2007 to 400 million in 2030 It is expected to show an explosive increase of 15 million people.

Glucagon-like peptide 1 (GLP1) is a short peptide hormone with a half-life of less than 2 minutes, which is secreted by stimulating L-cells of the small intestine after the meal. Glucagon-like peptide 1 (GLP1) And is one of the incretin hormones that induce insulin secretion in pancreatic beta cells. Therefore, it is suggested that intrinsic treatment of metabolic diseases such as diabetes through beta-cell function improvement which can not be performed by existing diabetes drugs is possible by using drugs acting thereon. Recently, a number of studies have been conducted on drugs that directly affect the GLP1 receptor or increase endogenous GLP1 secretion or stability.

The GLP1 receptor is a protein belonging to the G protein-coupled receptor (GPCR) class B, and its tertiary structure has not been identified. Since the receptor has a unique binding method in which the N-terminal of the receptor binds with the ligand to determine affinity, This is being recognized as a very difficult drug target.

The mechanism of glycoprotein receptor 119 (GPR119) activity that increases the secretion of GLP1 and mediates the anti-diabetic effect mediated by the action of endogenous incretin. GPR119 is a receptor belonging to GPCR class A, which is a drug target that facilitates the development of low molecular ligands as compared to class B. GPR119 agonists have been reported to promote secretion of GLP1 in the small intestine and increase insulin secretion directly or indirectly in pancreatic beta cells. Increased insulin secretion following GPR119 activation appears to be due, in part, to increased biosynthesis resulting from increased drug-induced insulin gene promoter activity.

Recently, Guo Z. et al. Reported that activation of GPR119 with a low molecular weight compound increases the proliferation of pancreatic beta cells, thereby increasing the efficacy of pancreatic islet transplantation. Apart from the function of glycemic control, GPR119 recognizes the concentration of exogenous fat in the small intestinal epithelium and plays an important role in maintaining the homeostasis of the fat in vivo. Therefore, when GPR119 is activated by a low molecular weight compound, it is suggested that GPR119 agonist may have therapeutic effect on dyslipidemia by inhibiting lipid absorption in the small intestine and improving lipid metabolism. In addition, selective low-molecular GPR119 agonists such as PSN632408 inhibit rat food intake in high-fat-fed rats and reduce weight gain and adipose tissue, GPR119 is known as a target associated with obesity and related metabolic diseases There is a bar.

In summary, low-molecular drugs that activate GPR119 have been shown to be of value as a type 2 diabetes drug that improves lipid metabolism, a risk factor for chronic cardiovascular risk, with effective blood-glucose lowering effects and positive effects on pancreatic beta cells. PSN-821 and MBX-2982 are undergoing Phase 2 clinical trials and four of them are in the early phase of clinical trials, along with two of them being in Phase 1 clinical trials.

The present invention provides novel compounds having GPR119 agonistic activity.

The present invention also provides a process for preparing a novel compound having GPR119 agonistic activity.

In addition, the present invention provides a pharmaceutical composition comprising the novel compound as an active ingredient and useful for the treatment or prevention of metabolic diseases.

The present invention provides a novel compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1, R ₁ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₂ and R ₃ are each independently hydrogen or halogen; X is -C (O) NHR ₄ , -C (O) -YC (O) NHR ₅ , -NHC (O) R ₆ , or -NHS (O) ₂ R ₇ ; R ₄ is an alkenyl having 1 to 6 carbon atoms, an alkynyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 7 carbon atoms, a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms, (CH ₂ ) m R ₈ , and -CH (R ₉ ) (CH ₂ ) n C (O) R ₁₀ , wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted divalent cycloalkyl, ≪ / RTI > m is an integer from 1 to 4; n is an integer from 0 to 3; R ₈ is a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms; R ₉ is selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, -C (O) OR ₁₁ , and - (CH ₂ ) mSR ₁₂ ; R ₁₀ is selected from the group consisting of hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, -NR ₁₃ R ₁₄ , and -YC (O) NHR ₅ ; R ₁₁ and R ₁₂ are each independently hydrogen or alkyl having 1 to 4 carbon atoms; R ₁₃ and R ₁₄ are each independently a substituted or unsubstituted alkyl having 1 to 4 carbon atoms; Y is pyrrolidine; R ₅ is hydrogen, alkyl having 1 to 4 carbon atoms, or substituted or unsubstituted aryl having 6 to 40 carbon atoms; R ₆ is selected from the group consisting of alkenyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkoxy having 3 to 7 carbon atoms, and alkenyloxy having 1 to 6 carbon atoms; R ₇ is alkenyl having 1 to 6 carbon atoms or - (CH ₂ ) mR ₁₅ ; R ₁₅ is a substituted or unsubstituted bicycloalkyl having 4 to 10 carbon atoms.

The present invention also provides a process for preparing the compound, an isomer thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition for the treatment or prevention of metabolic diseases having a G-protein coupled receptor (GPR119) agonistic activity comprising the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, a compound, a method for producing the same, and a pharmaceutical composition containing the same as an effective ingredient according to a specific embodiment of the present invention will be described in detail.

The present inventors have studied a therapeutic agent for metabolic diseases such as diabetes mellitus in which the prevalence rate is rapidly increasing globally and synthesized a low molecular weight drug that activates GPR119 to show an effective blood glucose lowering effect and a positive effect on pancreatic beta cells And confirmed the invention.

According to one embodiment of the present invention, there can be provided a novel compound represented by the following general formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1, R ₁ is hydrogen or alkyl having 1 to 6 carbon atoms; R ₂ and R ₃ are each independently hydrogen or halogen; X is -C (O) NHR ₄ , -C (O) -YC (O) NHR ₅ , -NHC (O) R ₆ , or -NHS (O) ₂ R ₇ ; R ₄ is an alkenyl having 1 to 6 carbon atoms, an alkynyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 7 carbon atoms, a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms, (CH ₂ ) m R ₈ , and -CH (R ₉ ) (CH ₂ ) n C (O) R ₁₀ , wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted divalent cycloalkyl, ≪ / RTI > m is an integer from 1 to 4; n is an integer from 0 to 3; R ₈ is a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms; R ₉ is selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, -C (O) OR ₁₁ , and - (CH ₂ ) mSR ₁₂ ; R ₁₀ is selected from the group consisting of hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, -NR ₁₃ R ₁₄ , and -YC (O) NHR ₅ ; R ₁₁ and R ₁₂ are each independently hydrogen or alkyl having 1 to 4 carbon atoms; R ₁₃ and R ₁₄ are each independently a substituted or unsubstituted alkyl having 1 to 4 carbon atoms; Y is pyrrolidine; R ₅ is hydrogen, alkyl having 1 to 4 carbon atoms, or substituted or unsubstituted aryl having 6 to 40 carbon atoms; R ₆ is selected from the group consisting of alkenyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkoxy having 3 to 7 carbon atoms, and alkenyloxy having 1 to 6 carbon atoms; R ₇ is alkenyl having 1 to 6 carbon atoms or - (CH ₂ ) mR ₁₅ ; R ₁₅ is a substituted or unsubstituted bicycloalkyl having 4 to 10 carbon atoms.

In a novel compound of this embodiment, R < ₄ > is a cycloalkyl of 3 to 7 carbon atoms, substituted or unsubstituted with oxo, a heterocyclic ring of 3 to 7 carbon atoms substituted or unsubstituted with oxo, Bicycloalkyl having 4 to 10 carbon atoms, and tricycloalkyl having 7 to 12 carbon atoms substituted or unsubstituted with a hydroxy group.

The R ₈ may be a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms. And R ₁₃ and R ₁₄ may be alkyl having 1 to 4 carbon atoms which is substituted or unsubstituted with a functional group selected from the group consisting of hydrogen, oxo, amino substituted with unsubstituted or unsubstituted aryl, and aryl.

In addition, R ₅ may be substituted or unsubstituted aryl having 6 to 40 carbon atoms.

And R ₆ may be a cycloalkoxy having 3 to 7 carbon atoms which is substituted or unsubstituted with alkyl having 1 to 4 carbon atoms.

In addition, R ₁₅ may be a bicycloalkyl having 4 to 10 carbon atoms which is substituted or unsubstituted with oxo or alkyl having 1 to 4 carbon atoms.

In addition, throughout this specification, the term " substituted or unsubstituted "for a certain functional group means that the functional group may be substituted with another functional group such as an oxo, hydroxy, alkyl, aryl or nitroaryl group, Lt; / RTI > may be further substituted or unsubstituted.

According to one embodiment of the present invention, the compound represented by Formula 1 may be a compound selected from the group consisting of the following compounds:

Yl) propoxy) -2-fluoro-N- (3- (2-oxopyrrolidin-1 -Yl) propyl) benzamide;

(1R, 3s, 5R, 7S) -3, 7-dihydroxy-4- (3- (1- (5- ethylpyrimidin- -Hydroxyadamantan-1-yl) benzamide;

Yl) propoxy) -2-fluoro-N - ((5-oxopyrrolidin-2-ylpiperidin- ) Methyl) benzamide;

(R) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin- -5-oxopentanoate;

(S) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin- -5-oxopentanoate;

(S) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 5-oxopentanolic acid;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluoro-N- (2-oxopropyl) benzamide;

(2-amino-2-oxoethyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4-yl) propoxy) -2-fluorobenzamide ;

2-fluoro-N- (prop-2-yn-1-yl) piperidine- Benzamide;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluoro-N- (2-oxocyclopentyl) benzamide;

2-fluoro-N- (2-oxotetrahydrofuran-3-yl) piperidin-4-yl) Benzamide;

(3-amino-3-oxopropyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4-yl) propoxy) -2-fluorobenzamide ;

(S) -2- (4- (3- (1- (5-Ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzamido) pentanedioic acid ;

(S) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2- fluorobenzoyl) pyrrolidin- Carboxamide;

(S) -N- (1-amino-4-methyl-1-oxopentan-2-yl) -4- Yl) propoxy) -2-fluorobenzamide;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- Yl) propoxy) -2-fluorobenzamide;

(S) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2-fluorobenzamide;

(R) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2-fluorobenzamide;

(R) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzoyl) pyrrolidin- Carboxamide carboxamide;

(S) -N- (1-amino-4- (methylthio) -1-oxobutan-2-yl) -4- (3- (1- (5-ethylpyrimidin- Yl) propoxy) -2-fluorobenzamide;

(R) -N- (1-amino-4- (methylthio) -1-oxobutan-2-yl) -4- Yl) propoxy) -2-fluorobenzamide;

(S) -N- (2- ((1-amino-1-oxo-3-phenylpropan- 2-yl) piperidin-4-yl) propoxy) -2-fluorobenzamide;

(S) -4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluoro- N- (4-nitrophenyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) benzamide;

(S) -1- (2- (4- (3- (1- (5-Ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzamido) acetyl ) -N- (4-nitrophenyl) pyrrolidine-2-carboxamide carboxamide;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidine-l- Yl) propoxy) -2-fluorobenzamide;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- Yl) propoxy) -2-fluorobenzamide;

Yl) propoxy) -2,6-difluoro-N- (prop-2-yn-1-yl) piperidin- -Yl) benzamide;

(3-amino-3-oxopropyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4- yl) propoxy) Lt; / RTI >

(2-amino-2-oxoethyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- Lt; / RTI >

Yl) propoxy) -2,6-difluoro-N- (3- (2-oxopyrrolyl) 1-yl) propyl) benzamide;

(S) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6- difluorobenzoyl) pyrrolidine -2-carboxamide;

(S) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2,6-difluorobenzamide;

(R) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2,6-difluorobenzamide;

(R) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluoro Benzamido) -5-oxopentanoate;

(R) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzene 5-oxopentanoic < / RTI >acid;

(S) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluoro Benzamido) -5-oxopentanoate;

(S) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzene 5-oxopentanoic < / RTI >acid;

N-allyl-4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide;

(S) -diethyl 2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide ) Pentane dianoate;

(S) -2- (4- (3- (1- (5-Ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzamido) pentane Dioxy acid;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluoro-N- (2-oxopropyl) benzamide;

(S) -N- (1-amino-4-methyl-1-oxopentan-2-yl) -4- Yl) propoxy) -2, 6-difluorobenzamide;

4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- Yl) propoxy) -2, 6-difluorobenzamide;

4-yl) propoxy) -2,6-difluoro-N- (4-oxocyclohexyl) benzamide ;

4-yl) propoxy) -2,6-difluoro-N- (3-oxocyclohexyl) benzamide ;

4-yl) propoxy) -2,6-difluoro-N- (2-oxocyclohexyl) benzamide ;

4-yl) propoxy) -2,6-difluoro-N- (2-oxocyclopentyl) benzamide ;

(Prop-2-yn-1-yl) piperidin-4-yl) propoxy) Benzamide;

4- (3- (l- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) -pyridin- Benzamide;

1- (7,7-Dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) -N- (4- (3- Piperidin-4-yl) propoxy) -2-fluorophenyl) methanesulfonamide;

Propoxy) -2-fluorophenyl) prop-2-en-1-sulfone Amide;

Methyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;

Pentyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;

Vinyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;

Allyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;

(5S) -2-isopropyl-5-methylcyclohexyl (4- (3- (1- (5-ethylpyrimidin- 2- yl) piperidin- 4- yl) propoxy) -2-fluoro Phenyl) carbamate;

Isobutyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;

1- (7,7-Dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) -N- (4- (3- Piperidin-4-yl) propoxy) -2, 6-difluorophenyl) methanesulfonamide;

N- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) acrylamide;

Pentyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) carbamate;

Allyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) carbamate; And

N- (2-fluoro-4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) phenyl) acrylamide.

Compounds belonging to the category of Formula 1 can exhibit excellent GPR119 agonistic activity and thus exhibit a hypoglycemic effect and a positive effect on pancreatic beta cells and thus can be more effectively used for treating various metabolic diseases.

The compound represented by Formula 1 may have an asymmetric carbon center and may exist as an optical isomer, a partial optical isomer or a racemate when it has an asymmetric carbon center, and all isomers including all isomer May be included in the category of compounds according to one embodiment of.

The salt of the compound represented by the formula (1) or the salt of the isomer of the compound represented by the formula (1) may also be included in the category of the compound of the above-mentioned embodiment. For example, specific examples of the compound represented by Formula 1 or a pharmaceutically acceptable salt of the isomer thereof include salts with inorganic acids such as hydrochloric acid, bromic acid, phosphoric acid or sulfuric acid; Salts with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, or sulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid ; Salts with alkali metals such as sodium, potassium or lithium; Or salts with various acids known to be capable of forming other pharmaceutically acceptable salts and the like.

According to another embodiment of the present invention, there is provided a process for preparing a compound of formula (I), comprising: reacting a compound of formula (II) and a compound of formula (VII) Introducing LG (leaving group) into the compound of Formula 3 to form a compound of Formula 4; There can be provided a process for the preparation of a compound of one embodiment as described above, which comprises reacting a compound of formula (IV) and a compound of formula (VIII) and converting X 'to X to form a compound of formula (1).

(2)

(3)

[Chemical Formula 4]

(7)

[Chemical Formula 1]

[Chemical Formula 8]

In the above formula, R ₁ to R ₃ And X is as defined for formula (1), and X 'is an amine group, a carboxyl group or an ester group in which a protecting group is introduced or not introduced; Z is halogen; LG is a leaving group.

The leaving group means an atom or an atomic group which is likely to fall off from the reaction substrate by a substitution reaction or a elimination reaction and specifically includes methanesulfonate, halogen, tosylate, triflate, phosphate Phosphate, and diazonium salt.

The formation of the compound of Formula 3 may be carried out in the presence of a base, and specific examples of the base include potassium carbonate (K ₂ CO ₃ ) and triethylamine (TEA).

The step of forming the compound of Formula 4 may be carried out using at least one selected from the group consisting of methanesulfonyl chloride, carbon tetrabromide, and N-bromosuccinimide. These compounds can be used to form a compound of formula (IV) in which an appropriate eliminator is introduced, and the compound of formula (IV) can be appropriately prepared according to one embodiment of the present invention.

Meanwhile, after the compound of formula (4) is formed, the reaction between the compound of formula (8) and the compound of formula (8) is carried out, Can be prepared. When X is -C (O) NHR ₄ or -C (O) -YC (O) NHR _{5 according} to an embodiment, X 'is R ₁₆ -COO- Can be appropriately reacted with the compound of the formula (4). Subsequent conversion of X 'into X may include hydrolyzing the reaction products of Formulas 4 and 8 to form a compound of Formula 1-a; And amidating the carboxyl group of Formula 1-a.

[Chemical Formula 1-a]

In the above formulas, R ₁ to R ₅ are as defined for formula (1); R ₁₆ may be selected from the group consisting of hydrogen, alkyl of 1 to 7 carbon atoms, alkenyl, alkynyl, and allyl.

That is, X is -C (O) NHR ₄ , or -C (O) -YC (O) NH ₂ , by suitably amidating such a carboxy group after obtaining a compound of formula 1-a converted to a carboxyl group by hydrolysis of X ' O) NHR < ₅ >. Depending on the kind of X, a reaction product for progressing the amidation may be suitably selected by those skilled in the art, and the progress of the amidation reaction may be according to the known amidation reaction conditions. In addition, specific progress conditions of the amidation reaction are described in the following examples.

An example of the overall reaction for preparing a compound of formula (1) wherein X is -C (O) NHR ₄ , -C (O) -YC (O) NHR _{5 according} to one embodiment is as described in Scheme 1 below. However, this Scheme 1 shows only one example of the above production method, and the production method of other embodiments is not limited thereto.

 [Reaction Scheme 1]

In the above Reaction Scheme 1, R _{1 ,} to R _{5 ,} R _{16 ,} and X are as defined for Formula (1).

On the other hand, when preparing a compound wherein X is -NHC (O) R ₆ or -NHS (O) ₂ R ₇ according to another embodiment, X 'is a protected amine group of PG-NH- Which can be suitably reacted with the compound of formula (IV). The step of converting X 'to X in the subsequent step may include deprotonating the reaction product of the above formulas (4) and (8) to form a compound of formula (1-b); And reacting the amine group of Formula 1-b with at least one member selected from the group consisting of acid chloride, sulfonyl chloride, and chloroformate in the presence of a base.

 [Chemical Formula 1-b]

In the above formula, R ₁ To R _{3 ,} R ₆ , and R ₇ are as defined for formula 1; PG is an amino protecting group.

That is, the X 'is deprotected to obtain a compound of the formula 1-b converted to an amine group, and then the amine group is reacted with an acid chloride, chloroformate or the like in the presence of a suitable base to obtain a compound wherein X is -NHC (O) R ₆ And can be reacted with a sulfonyl chloride or the like to obtain a compound represented by the formula -NHS (O) ₂ R ₇ . The deprotection can be carried out in the presence of trifluoroacetic acid (TFA), hydrochloric acid (HCl), or acetic acid, and specific examples of the base include triethylamine (TEA). Specific progress conditions of this reaction are described in the following examples.

Specific examples of the amino protecting group PG include t-butoxycarbonyl group (Boc), benzyloxycarbonyl (cbz), and triphenylmethyl (trityl). The use of an amino protecting group makes it possible to temporarily protect an amino group having high reactivity, and thus it is easy to prepare the compound of formula (1).

An example of the overall reaction for preparing a compound of formula (1) wherein X is -NHC (O) R ₆ or -NHS (O) ₂ R _{7 according} to one embodiment is as set forth in Scheme 2 below. However, this Scheme 2 shows only one example of the above production method, and the production method of other embodiments is not limited thereto.

 [Reaction Scheme 2]

In the above Reaction Scheme 2, R _{1 ,} to R _{3 ,} PG, and X are as defined for Formula (1).

According to another embodiment of the present invention, there is provided a pharmaceutical composition for treating or preventing a metabolic disease comprising the compound represented by the formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .

As described above, the present inventors have newly synthesized the compound of Formula 1 having GPR119 agonistic activity. In the case of a pharmaceutical composition having a G-protein coupled receptor (GPR119) agonistic activity, it has been found that effective blood glucose lowering action and pancreatic β- And has the effect of improving the lipid metabolism, which is a risk factor of chronic cardiovascular disease, and is effective for the treatment and / or prevention of metabolic diseases.

The metabolic disease may be diabetes, obesity, hypertension, cardiovascular disease, hypercoagulability or dyslipidemia. Action activity against GPR119 increases the secretion of glucagon-like peptide (GLP1) or the secreted GLP1, mediates the action of endogenous incretin, And can exhibit drug efficacy.

The pharmaceutical composition containing the compound represented by the formula (1), an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient may be used in the form of a general pharmaceutical preparation. The pharmaceutical preparations can be administered in various forms of oral and parenteral administration at the time of administration, and the formulations can be variously determined depending on the method of use.

When formulating into various formulations of oral and parenteral formulations, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like generally used.

The solid preparation for oral administration may include tablets, pills, powders, granules, capsules and the like. Such solid preparations may contain at least one compound selected from the group consisting of the compound represented by the formula (1), the isomer thereof or the pharmaceutically acceptable salt thereof For example, starch, calcium carbonate, sucrose or lactose, gelatin and the like can be prepared by mixing the above excipients, for example, starch, calcium carbonate, sucrose or lactose. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. The liquid preparations for oral administration include suspensions, solutions, emulsions and syrups. In addition to water and liquid paraffin which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like May be included.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used as the non-aqueous solvent and suspension agent. Examples of suppository bases include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like.

In addition, the pharmaceutical composition containing the compound represented by the formula (1) of the present invention, an isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient may exhibit an effective amount in a dosage range of about 0.1 to about 1,000 mg. The dose or the dose may be administered in one dose or several times a day depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, It is possible.

The novel compounds, isomers thereof, or pharmaceutically acceptable salts thereof of the present invention exhibit GPR119 agonistic activity and can be usefully used for the treatment and / or prevention of metabolic diseases such as diabetes. More specifically, GPR119 agonistic activity can improve lipid metabolism, which is a risk factor for chronic cardiovascular disease, with effective hypoglycemic action and a positive effect on pancreatic beta cells.

Hereinafter, preferred embodiments and experimental examples are provided to facilitate understanding of the present invention. However, the following examples and experimental examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited thereto.

Analysis of the synthesized compounds according to the present invention was confirmed with an Agilent (TM) 1100 series LC / MSD and a nuclear magnetic resonance apparatus.

< Manufacturing example : Formula 2 to  6, 1-a and 1-b>

< Manufacturing example  1> 3- (Piperidin-4-yl) propan-1-ol (Formula 2)

(10 g, 41 mmol) was dissolved in methylene chloride (MC, 12 ml) as a solvent and then TFA (9.3 ml) was added to the solution. Was added. After reaction at room temperature for 12 hours, the reaction was concentrated. MC (50 ml) and 2N-NaOH were added to the reaction to adjust the pH to 3 and extracted. Water was removed from the separated organic layer using MgSO ₄ , filtered and reduced in pressure to give the desired compound 3- (piperidin-4-yl) propan-1-ol in 91% yield.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 145.2 (M ⁺

^{1 H NMR (600 MHz, DMSO} ) ppm 8.80 (br s, 1H) 8.53 (br s, 1H) 4.42 (m, 2H) 3.35 (br s, 1H) 3.19 (m, 2H) 2.78 (m, 2H) 1.77 (m, 2 H) 1.49 (m, 1 H) 1.46 (m, 2 H) 1.23 (m,

< Manufacturing example  2 > 3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) propan-1-ol (Formula 3)

(5.4 g, 38 mmol) synthesized in Preparation Example 1 and 2-chloro-5-ethylpyrimidine (5.4 g, 38 mmol) were dissolved in N, N-dimethylformamide K ₂ CO ₃ (4.3 g, 38 mmol) was added with N-dimethylformamide (DMF, 10 ml) as a solvent, and the mixture was reacted at 80 ^° C for 12 hours. To the reaction was added water and ethyl acetate (EA, 50 ml) to extract the organic layer. The organic layer was washed with brine (30 ml × 2), the separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. Purification by silica gel column chromatography using hexane and EA as a developing solvent gave the desired compound 3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propane- 1-ol.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 250.0 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.15 (s, 2H) 4.67 (m, 2H) 3.64 (m, 2H) 2.84 (m, 2H) 2.41 (m, 2H) 1.68 (m, 4H) 1.49 (m , 1 H) 1.40 (m, 4 H) 1.12 (m, 3 H)

< Manufacturing example  3 > 3- (1- (5- Ethylpyrimidine 2-yl) piperidin-4-yl) propyl Methane sulfonate  (Formula 4)

(7 g, 21 mmol) synthesized in Production Example 2 (3- (1- (5-ethylpyrimidin-2-yl) piperidin- It was lowered and the reaction was used as a 0 ^o C. Methanesulfonyl chloride (4.7 ml, 42 mmol) was slowly added dropwise, followed by stirring at room temperature for 2 hours. The organic layer was extracted with water and EA (50 ml), and the separated organic layer was washed with brine (30 ml × 2). The separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA . (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propyl methanesulfonate in a yield of 95%.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 328.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.24 (s, 2H) 4.65 (m, 2H) 4.19 (t, J = 12.8 Hz, 2H) 3.65 (m, 2H) 2.98 (s, 3H) 2.90 (m, 2H), 2.46 (m, 2H) 1.79 (m, 4H) 1.49 (m,

< Manufacturing example  4> methyl  4- (3- (1- (5- Ethylpyrimidine -2 days) Pepperidine Yl) Propoxy ) -2-fluorobenzoate (Formula 5)

(2 g, 6 mmol) synthesized in Production Example 3 and 3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propylmethanesulfonate (1.1 g, 6 mmol) was added K ₂ CO ₃ (1.4 g, 12 mmol) with DMF (5 ml) as a solvent and reacted at 80 ^° C. for 12 hours, and then the reaction was cooled to room temperature. Water and EA (50 ml) were added to the reaction mixture to extract the organic layer. The organic layer was washed with brine (30 ml × 2), the separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. Purification by silica gel column chromatography using hexane and EA as a developing solvent gave the desired compound in the form of methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) ) Propoxy) -2-fluorobenzoate. &Lt; / RTI &gt;

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 402.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.19 (s, 2H) 7.86 (m, 1H) 6.72 (m, 1H) 6.51 (m, 1H) 4.68 (m, 2H) 4.02 (m, 2H) 3.90 (s 2H), 1.18 (m, 3H), 2.47 (m, 2H), 2.47 (m,

< Manufacturing example  5> 4- (3- (1- (5- Ethylpyrimidine -2 days) Pepperidine Yl) Propoxy )-2- Fluorobenzanide  (Formula 1-a)

2-yl) propoxy) -2-fluorobenzoate (1.5 g, 0.15 mmol) of the formula 5 synthesized in Preparation Example 4, 3.7 mmol) was used as a solvent in a ratio of 4: 1 in 1,4-dioxane (12 ml) and water (3 ml). 2N-NaOH (6 ml) was added and the mixture was reacted at room temperature for 5 hours, and then the reaction product was concentrated. EA (20 ml) and 2N-HCl were added to the reaction mixture to adjust the pH to 3, and the organic layer was extracted. The separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. Recrystallization from hexanes afforded the desired compound of formula 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzoic acid in 78% .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 388.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.19 (s, 2H) 7.96 (m, 1H) 6.72 (m, 1H) 6.62 (m, 1H) 4.68 (m, 2H) 4.02 (m, 2H) 2.87 (m 2H), 2.47 (m, 2H) 1.87 (m, 4H) 1.56 (m,

< Manufacturing example  6> methyl  4- (3- (1- (5- Ethylpyrimidine -2 days) Pepperidine Yl) Propoxy ) -2,6- Difluorobenzoate (Formula 5)

Ethyl) piperidin-4-yl) propylmethanesulfonate (2 g, 6 mmol) synthesized in Preparation Example 3 and methyl 2,6-difluoro (1.3 g, 6 mmol) was added K ₂ CO ₃ (1.4 g, 12 mmol) in DMF (5 ml) as a solvent, and the mixture was reacted at 80 ^° C. for 12 hours. Lt; / RTI &gt; Water and EA (50 ml) were added to the reaction mixture to extract the organic layer. The organic layer was washed with brine (30 ml × 2), the separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. The residue was purified by silica gel column chromatography using hexane and EA as eluent to obtain the desired compound, methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 2,6-difluorobenzoate was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 420.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 7.98 (m, 1H) 6.46 (d, J HF = 3.2 Hz, 1H) 4.68 (m, 2H) 3.93 (m, 2H) 3.87 (m (M, 3H), 2.85 (m, 2H), 1.45 (m, 2H)

< Manufacturing example  7> 4- (3- (1- (5- Ethylpyrimidine -2 days) Pepperidine Yl) Propoxy ) -2,6- Difluorobenzoic acid  (Formula 1-a)

(5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzoate ( 1.5 g, 3.7 mmol) was used as a solvent in a ratio of 4: 1 in 1,4-dioxane (12 ml) and water (3 ml). 2N-NaOH (6 ml) was added and the mixture was reacted at room temperature for 5 hours, and then the reaction product was concentrated. EA (20 ml) and 2N-HCl were added to the reaction mixture to adjust the pH to 3, and the organic layer was extracted. The separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. Recrystallization from hexane gave the desired compound 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzoic acid .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 406.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.15 (s, 2H) 7.93 (m, 1H) 6.65 (m, 1H) 4.65 (m, 2H) 3.97 (m, 2H) 3.87 (m, 2H) 2.84 (t , J = 24.8 Hz, 2H) 2.41 (q, J = 22.4 Hz, 2H) 1.80 (m, 4H) 1.52 (m, 1H) 1.39 (m, 2H) 1.18 (m, 3H)

< Manufacturing example  8 > t-Butyl (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorophenyl ) Carbamate  (Formula 6)

4-yl) propylmethanesulfonate (2 g, 6 mmol) of the formula 4 synthesized in Preparation Example 3 and N-Boc-4-amino 3-fluorophenol (1.4 g, 6 mmol) was added K ₂ CO ₃ (1.4 g, 12 mmol) in DMF (5 ml) as a solvent, reacted at 80 ^° C. for 12 hours and the reaction was cooled to room temperature . Water and EA (50 ml) were added to the reaction mixture to extract the organic layer. The organic layer was washed with brine (30 ml × 2), the separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. Purification by silica gel column chromatography using hexane and EA as eluent gave the desired compound t-butyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- Propoxy) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 459.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.17 (s, 2H) 6.72 (m, 1H) 6.58 (m, 1H) 6.53 (m, 1H) 4.68 (m, 2H) 3.86 (m, 4H) 2.83 (m (M, 3H), 1.45 (m, 2H), 2.74 (m,

< Manufacturing example  9> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoroaniline  (Formula 1-b)

(4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) Carbamate (2.5 g, 5.4 mmol) was dissolved in MC (5 ml) as a solvent and TFA (2 ml) was added. After reaction at room temperature for 12 hours, the reaction was concentrated. MC (20 ml) and 2N-NaOH were added to the reaction to adjust to pH 3 and extracted. Water was removed from the separated organic layer using MgSO ₄ , filtered and reduced in pressure to obtain the desired compound, 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- ) -2-fluoroaniline.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 359.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.17 (s, 2H) 6.72 (m, 1H) 6.58 (m, 1H) 6.53 (m, 1H) 4.68 (m, 2H) 3.86 (m, 2H) 2.83 (m 2H), 2.72 (m, 2H), 2.44 (m, 2H) 1.98 (m,

< Manufacturing example  10> t-Butyl (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorophenyl ) Carbamate  (Formula 6)

Except that N-Boc-4-amino-3,5-difluorophenol (1.5 g, 6 mmol) was used in place of N-Boc-4-amino-3-fluorophenol (1.4 g, 8) to give the desired form of the compound t-butyl (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- Difluorophenyl) carbamate. &Lt; / RTI &gt;

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 477.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 6.38 (m, 2H) 4.65 (m, 2H) 4.08 (br s, 1H) 3.81 (m, 2H) 3.38 (s, 2H) 2.84 ( (m, 3H), 1.24 (m, 2H), 2.40 (m, 2H)

< Manufacturing example  11 > 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoroaniline  (Formula 1-b)

propoxy) -2-fluorophenyl) carbamate (2.5 g, 5.4 mmol) was added to a solution of tert-butyl 4- (3- (1- (5- ethylpyrimidin- Instead of t-butyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6-difluorophenyl ) Carbamate (2 g, 5.3 mmol) was used to carry out the same procedure as in PREPARATION 9 to obtain the desired compound of 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidine Yl) propoxy) -2,6-difluoroaniline.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 377.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 6.38 (m, 2H) 4.65 (m, 2H) 3.91 (m, 2H) 3.35 (s, 2H) 2.84 (m, 2H) 2.40 (m 2H) 1.73 (m, 4 H) 1.52 (m, 1 H) 1.37 (m,

< Manufacturing example  12> 3- (1- (5- Pentylpyrimidine Yl) piperidin-4-yl) propan-1-ol (Formula 3)

The same procedure as in Production Example 2 was carried out except that 2-chloro-5-pentylpyrimidine (7.84 ml, 46.08 mmol) was used instead of 2-chloro-5-ethylpyrimidine (5.4 g, 38 mmol) Compound 3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propan-1-ol was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 292.2 (M ⁺

^{1 H NMR (400 MHz, CDCl3} ) ppm 8.24 (s, 2H), 4.64 (d, J = 15.2Hz, 2H), 3.66-3.61 (m, 3H) 2.86-2.79 (m, 2H), 2.38-2.35 ( (m, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.63-1.56 (m, 4H), 1.53-1.50 2H), 0.86-0.84 (m, 3H)

< Manufacturing example  13> 3- (1- (5- Pentylpyrimidine 2-yl) piperidin-4-yl) propyl Methane sulfonate  (Formula 4)

3- (1- (2-pyridyl) pyrimidin-4-yl) propanoate synthesized in Production Example 12, instead of 3- (1- (5- ethylpyrimidin- Propyl-1-ol (12.2 g, 41.86 mmol) was used in place of the compound 3 - (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propylmethanesulfonate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 370.2 (M ⁺

^{1 H NMR (400 MHz, CDCl3} ) ppm 8.24 (s, 2H), 4.64 (d, J = 15.2Hz, 2H), 3.66-3.61 (m, 2H), 3.16 (s, 3H), 2.86-2.79 (m (M, 2H), 2.38-2.35 (m, 2H), 1.75 (d, J = 12.4 Hz, 2H), 1.63-1.56 ), 1.18-1.11 (m, 2H), 0.86-0.84 (m, 3H)

< Manufacturing example  14> methyl  4- (3- (1- (5- Pentylpyrimidine -2 days) Pepperidine Yl) Propoxy ) -2- Luoro benzoi (Formula 5)

(3- (1- (5-ethylpiperidin-4-yl) piperidin-4-yl) propyl methanesulfonate The same procedure as in Preparation Example 4 was carried out, except that methyl (4-methylphenyl) piperidin-4-yl) propylmethanesulfonate (1.2 g, (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzoate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 444.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.90-8.00 (m, 1H), 6.58-6.74 (m, 2H), 4.65-4.68 (m, 2H), 3.98 (m, 2H 2H), 1.76-1.83 (m, 4H), 1.10-1.60 (m, 11H), 0.86 (m, 3H)

< Manufacturing example  15> 4- (3- (1- (5- Pentylpyrimidine -2 days) Pepperidine Yl) Propoxy )-2- Fluorobenzanide  (Formula 1-a)

Was obtained in the same manner as in Preparation Example 14, except that methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2- fluorobenzoate (1.5 g, (1.4 g, 3.2 mmol) of methyl 4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluorobenzoate The title compound was prepared in the same manner as in Production Example 5 except that 4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) I got a Robbie Rice Eshid.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 430.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.90-8.00 (m, 1H), 6.58-6.74 (m, 2H), 4.65-4.68 (m, 2H), 3.98 (m, 2H ), 2.84 (m, 2H), 2.36-2.42 (m, 2H), 1.76-1.83 (m, 4H), 1.10-1.60

< Manufacturing example  16> t-Butyl (2- Fluoro -4- (3- (1- (5- Pentylpyrimidine Yl) piperidin-4-yl) Propoxy ) Phenyl ) Carbamate  (Formula 6)

(3- (1- (5-ethylpiperidin-4-yl) piperidin-4-yl) propyl methanesulfonate Propylmethanesulfonate (3.68 g, 11.26 mmol) was used in place of the compound of Preparation Example 8 to give the desired compound of t-butyl (4-methylpiperazin- (2-fluoro-4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) phenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 500.8 (M ⁺

^{1 H NMR (400 MHz, CDCl3} ) ppm 8.11 (s, 2H), 7.83 (s, 1H), 6.62-6.60 (m, 2H), 6.43 (s, 1H), 4.66 (d, J = 12Hz, 2H) (M, 2H), 1.43-1. 24 (m, 2H) 10H), 0.86-0.84 (m, 3H)

< Manufacturing example  17> 2- Fluoro -4- (3- (1- (5- Pentylpyrimidine Yl) piperidin-4-yl) Propoxy ) Aniline (formula (I-b)

propoxy) -2-fluorophenyl) carbamate (2.5 g, 5.4 mmol) was added to a solution of tert-butyl 4- (3- (1- (5- ethylpyrimidin- Instead of t-butyl (2-fluoro-4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin- ) Carbamate (2.0 g, 3.99 mmol) was used to carry out the same procedure as in PREPARATION 9 to obtain the desired compound 2-fluoro-4- (3- (1- (5-pentylpyrimidin- Yl) piperidin-4-yl) propoxy) aniline.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 400.9 (M ⁺

^{1 H NMR (400 MHz, CDCl3} ) ppm 8.11 (s, 2H), 6.76-6.40 (m, 3H), 6.27 (s, 2H), 4.66 (d, J = 12.8Hz, 2H), 3.86-3.83 (m 2H), 3.40 (m, 1H), 2.81-2.78 (m, 2H), 2.39-2.35 (m, 2H), 1.75-1.37 (m, 3H)

< Example  1 > 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- (3- (2- Oxopyrrolidine -1-yl) propyl) Benzamide

Yl) propoxy) -2-fluorobenzoic acid (30 mg, 0.08 mmol) synthesized in Production Example 5 was dissolved in tetra EDC (24.5 mg, 0.16 mmol) and hydrobenzotriazole (HOBT, 14 mg, 0.12 mmol) were added to the reaction mixture at room temperature for 30 minutes using hydrofuran (THF, 2 ml) as a solvent. To the reaction mixture was added 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) and TEA (0.04 ml, 0.32 mmol) and the mixture was reacted at room temperature for 12 hours. ) Was added to extract the organic layer. The organic layer was washed with brine (30 ml × 2), and the separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. Purification by silica gel column chromatography using hexane and EA as eluent gave the desired compound of formula 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- ) Propoxy) -2-fluoro-N- (3- (2-oxopyrrolidin-1-yl) propyl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 511.7 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.20 (s, 2H) 8.05 (m, 1H) 7.94 (m, 1H) 7.61 (m, 1H) 6.84 (m, 2H) 4.60 (d, J = 12.8 Hz, 2H (M, 4H), 1.00 (m, 4H), 1.00 (m, 4H), 3.99 (m, (m, 3H)

< Example  2 > 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N - ((1 R, 3S, 5R, 7S) -3- Hydroxyadamantane -1 day) Benzamide

(54 mg, 0.32 mmol) was used instead of (lr, 3s, 5R, 7S) -3-aminoadamantan-l-ol (54 mg, 0.32 mmol) instead of 1- (3- aminopropyl) pyrrolidin- Yl) propoxy) -2- (4-methylpiperazin-2-yl) piperidine was prepared by the same method as in Example 1, Fluoro-N - ((lr, 3s, 5R, 7S) -3-hydroxyadamantan-l-yl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 536.7 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.21 (s, 2H) 7.47 (m, 1H) 7.21 (m, 1H) 6.80 (m, 1H) 4.58 (m, 2H) 4.52 (m, 2H) 3.99 (m, 2H), 2.32 (m, 2H), 2.13 (m, 2H) 1.89 (m, 1.03 (m, 2 H) 1.00 (m, 3 H)

< Example  3 > 4- (3- (1- (5- Ethylpyrimidine  Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N - ((5- Oxopyrrolidine -2 days) methyl ) Benzamide

The procedure of Example 1 was repeated except for using 5- (aminomethyl) pyrrolidin-2-one (37 mg, 0.32 mmol) instead of 1- (3-aminopropyl) pyrrolidin- 4-yl) propoxy) -2-fluoro-N - (((2- 5-oxopyrrolidin-2-yl) methyl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 483.7 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.21 (s, 2H) 8.11 (m, 1H) 7.70 (m, 1H) 7.62 (m, 1H) 6.84 (m, 2H) 4.60 (m, 2H) 4.02 (m, 2H), 3.73 (m, 2H), 3.73 (m, 2H), 2.78 (m, 1.25 (m, 2 H) 1.02 (m, 3 H)

< Example  4 > (R) - methyl  5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide ) -5- Oxopentanonate

The procedure of Example 1 was repeated except that D-glutamine methyl ester (51 mg, 0.32 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) (R) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2-fluorobenzene Amino) -5-oxopentanoate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 529.7 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.45 (s, 1H) 8.20 (s, 2H) 7.59 (m, 1H) 7.32 (s, 1H) 6.85 (br s, 2H) 4.60 (m, 2H) 4.02 (m 2H), 1.88 (m, 2H), 1.73 (m, 2H), 3.88 (m, 1.54 (m, 1 H) 1.33 (m, 2 H) 1.01 (m, 3 H)

< Example  5> (S) - methyl  5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide ) -5- Oxopentanonate

The procedure of Example 1 was repeated except that L-glutamine methyl ester (51 mg, 0.32 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (S) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2-fluorobenzene Amino) -5-oxopentanoate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 529.7 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.45 (s, 1H) 8.20 (s, 2H) 7.59 (m, 1H) 7.32 (s, 1H) 6.85 (br s, 2H) 4.60 (m, 2H) 4.02 (m 2H), 1.88 (m, 2H), 1.73 (m, 2H), 3.88 (m, 1.54 (m, 1 H) 1.33 (m, 2 H) 1.01 (m, 3 H)

< Example  6> (S) -5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) propoxy) -2- Fluorobenzamide ) -5- Oxopentanoic Acid

(1.5 g, 3.7 mmol) instead of methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzoate (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzamide (S) -5-Amino-2- (4- (3- (((S) -2-methyl- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzamino) -5-oxopentanoic acid was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 515.7 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.45 (s, 1H) 8.20 (s, 2H) 7.59 (m, 1H) 7.32 (s, 1H) 6.85 (br s, 2H) 4.60 (m, 2H) 4.02 (m 2H), 1.74 (m, 2H), 1.74 (m, 2H), 1.88 (m, 1.33 (m, 2 H) 1.01 (m, 3 H)

< Example  7> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- (2- Oxopropyl ) Benzamide

The same procedure as in Example 1 was carried out except that 1-aminopropane-2-one (23 mg, 0.32 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin- To give the desired form of the compound 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluoro- Amide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 442.8 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.70 (m, 1H) 8.18 (s, 2H) 7.63 (m, 1H) 7.21 (br s, 1H) 6.70 (m, 1H) 4.49 (m, 2H) 4.21 (m 2H), 2.79 (m, 2H), 2.79 (m, 2H), 2.79 (m, )

< Example  8 > N- (2-amino-2- Oxoethyl ) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The same procedure as in Example 1 was repeated, except that glycinamide (24 mg, 0.32 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) - (2-amino-2-oxoethyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4- yl) propoxy) -2-fluorobenzamide .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 444.0 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.70 (m, 1H) 8.18 (s, 2H) 7.63 (m, 1H) 7.32 (br s, 1H) 6.86 (m, 1H) 6.17 (br s, 2H) 4.50 ( (m, 2H), 1.35 (m, 2H), 2.39 (m, 2H) 2H), 0.85 (m, 3H)

< Example  9> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- ( Professional 2-yn-1-yl) Benzamide

The same procedure as in Example 1 was followed except that propargylamine (7.7 mg, 0.15 mmol) was used in place of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) The compound 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluoro- ) Benzamide. &Lt; / RTI &gt;

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 425.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H), 8.02 (t, J = 8.8Hz, 1H), 6.73-6.83 (m, 2H) 6.58 (m, 1H) 4.67 (m, 2H) , 4.23 (br s, 2H), 3.96 (t, J = 6.4 Hz, 2H), 2.79-2.85 (m, 2H), 2.42 ), 1.51-1.57 (m, 1 H), 1.37-1.42 (m, 2H), 1.13-1.22 (m, 5H)

< Example  10> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- (2- Oxocyclopentyl ) Benzamide

Step 1: 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- (trans-2- Hydroxycyclopentyl ) Benzamide  Produce

The same procedure as in Example 1 was conducted except that trans-2-aminocyclopentanol hydrochloride (44 mg, 0.32 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one 4-yl) propoxy) -2-fluoro-N- (trans-2-hydroxycyclohexyl) / RTI &gt; cyclopentyl) benzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 471.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 8.01 (m, 1H), 6.77-6.80 (m, 2H), 6.57-6.60 (m, 1H), 4.68 (m, 2H), 2H), 2.20 (br s, 1H), 2.03-2.06 (m, 1H) ), 1.72-1.82 (m, 7H), 1.53-1.56 (m, 2H), 1.32-1.41 (m, 2H), 1.02-1.22

Step 2: 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- (2-ox Small cycle Pentyl) Benzamide  Produce

Example 1 Step 1 To a solution of the compound 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluoro- ( 40 mg, 0.06375 mmol) was dissolved in 3 ml of MC, followed by addition of des-martin periodine (40.5 mg, 1.5 eq) at 0 ° C, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, water was added to the reaction product and extracted with EA. The organic layer was washed with water and brine and then separated. The separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. The residue was purified by silica gel column chromatography using hexane and EA as eluent to give the desired compound, 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 2-fluoro-N- (2-oxocyclopentyl) benzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 469.3 (M ⁺

¹ H NMR (400 MHz, CDCl ₃ ) ppm 8.14 (s, 2H), 8.00 (m, 1H), 7.00-7.15 ), 4.68 (m, 2H) , 4.21-4.35 (m, 1H), 3.97 (t, J = 6.4Hz, 2H), 2.65-2.83 (m, 3H), 2.40-2.46 (m, 3H), 2.01- 2H), 1.72-1.86 (m, 7H), 1.38-1.44 (m, 2H), 1.14-1.26 (m, 5H)

< Example  11 > 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluoro -N- (2- Oxotetrahydrofuran -3 days) Benzamide

The same procedure as in Example 1 was repeated except that alpha-amino-gamma-butyrolactone bromate (25.4 mg, 0.15 mmol) was used in place of 1- (3-aminopropyl) pyrrolidin- Method to give the desired form of compound 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluoro- Tetrahydrofuran-3-yl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 471.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H), 8.00 (m, 1H), 7.13-7.18 (m, 1H), 6.73-6.76 (m, 1H), 6.57-6.61 (m, 1H ), 4.65-4.70 (m, 3H), 4.51 (m, IH), 4.28-4.35 (m, IH), 3.96 (t, J = 6.4Hz, 2H), 2.79-2.91 2H), 1.12-1.23 (m, 5H), 1.45-1.40 (m, 3H)

< Example  12 > N- (3-amino-3- Oxopropyl ) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The same procedure as in Example 1 was repeated except that beta-alanine amide hydrochloride (19.3 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2- Propyl) -4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluoro Lt; / RTI &gt;

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 458.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.98 (m, 1H), 7.24-7.35 (m, 1H), 6.72-6.75 (m, 1H), 6.57-6.61 (m, 1H ), 4.66-4.69 (m, 2H) , 3.96 (t, J = 6.4Hz, 2H), 3.73-3.75 (m, 2H), 2.77-2.90 (m, 2H), 2.57 (t, J = 6.0Hz, 2H), 1.14-1.23 (m, 2H), 2.40-2.46 (m, 2H), 1.76-1.84 (m, 4H), 1.49-1.58

< Example  (S) -2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamido ) Pentane Dioki Acid

Step 1: (S) - Diethyl  2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamido ) Pentanedioate  Produce

The procedure of Example 1 was repeated except that L-glutamic acid diethyl ester hydrochloride (35.9 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (S) -diethyl 2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluorobenzene Amido) pentane &lt; / RTI &gt;

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 573.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.98 (m, 1H), 7.22-7.27 (m, 1H), 6.72-6.75 (m, 1H), 6.58-6.62 (m, 1H 2H), 4.06-4.11 (m, 2H), 3.97 (t, J = 6.4 Hz, 2H), 4.81-4.83 (m, 2H), 2.28-2.46 (m, 5H), 2.09-2.12 (m, 1H), 1.76-1.86 (m, 4H), 1.52-1.58 (m, 1H), 1.38-1.43 , &Lt; / RTI &gt; 2H), 1.14-1.30 (m, 11H)

Step 2: (S) -2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2-fluorobenzamido) Pentane Dioki Acid  Produce

Example 1 Step 1 Compound (S) -diethyl 2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluoro Benzamido) pentane Ioate (20 mg, 0.03492 mmol) was dissolved in 1.5 ml of dioxane. 2N NaOH (0.35 ml, 20 eq) was added at 0 ° C and the mixture was stirred at room temperature for 15 hours. After the completion of the reaction, water was added to the reaction mixture, neutralized with 2N-HCl, and extracted with EA. The organic layer was washed with water and brine and then separated. The separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. (S) -2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4 - yl) propoxy) -2-fluorobenzamido) pentane dioxy acid.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 517.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.20 (s, 2H), 7.97 (m, 1H), 7.41-7.46 (m, 1H), 6.73-6.75 (m, 1H), 6.58-6.62 (m, 1H 2H), 2.85-2.91 (m, 2H), 2.29-2.54 (m, 6H), 1.78-1.81 (m, , 4H), 1.52-1.65 (m, 1H), 1.39-1.41 (m, 2H), 1.15-1.23 (m, 5H)

< Example  14 (S) -1- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzoyl ) Pyrrolidine -2- Carboxamide

The procedure of Example 1 was repeated except that L-proline amide (17.7 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (S) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzoyl) pyrrolidine- 2-carboxamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 484.3 (M ⁺

¹ H NMR (400 MHz, CDCl ₃ ) ppm 8.13 (s, 2H), 7.32 (m, IH), 6.87 (br s, IH), 6.69 - 6.72 , 5.56 (br s, IH), 4.74-4.77 (m, IH), 4.65-4.70 (m, 2H), 3.92-3.96 (M, 2H), 2.39-2.45 (m, 2H), 1.76-2.12 (m, 8H), 1.52-1.55

< Example  15> (S) -N- (1-Amino-4- methyl -One- Oxopentane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The procedure of Example 1 was repeated except that L-leucine amide (25.8 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (S) -N- (1-amino-4-methyl-1-oxopentan-2-yl) -4- (3- (1- (5-ethylpyrimidin- Yl) propoxy) -2-fluorobenzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 500.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.98 (m, 1H), 6.88-6.93 (m, 1H), 6.74-6.77 (m, 1H), 6.57-6.61 (m, 1H ), 6.30 (br s, IH), 5.41 (br s, IH), 4.64-4.70 (m, 3H), 3.97 (m, 2H), 2.79-2.86 ), 1.52-1.86 (m, 8H), 1.38-1.43 (m, 2H), 1.09-1.23 (m, 5H), 0.93-0.97

< Example  16> (R) -N- (1-Amino-4- methyl -One- Oxopentane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The procedure of Example 1 was repeated except that D-leucine amide (25.8 mg, 0.15 mmol) was used in place of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- Yl) propoxy) -2-fluorobenzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 500.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.98 (m, 1H), 6.88-6.93 (m, 1H), 6.74-6.77 (m, 1H), 6.57-6.61 (m, 1H ), 6.30 (br s, IH), 5.41 (br s, IH), 4.64-4.70 (m, 3H), 3.97 (m, 2H), 2.79-2.86 ), 1.52-1.86 (m, 8H), 1.38-1.43 (m, 2H), 1.09-1.23 (m, 5H), 0.93-0.97

< Example  17> (S) -N- (1-amino-1- Oxopropane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The procedure of Example 1 was repeated except that L-alanine amide (19.3 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) Propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 458.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H), 7.96 (m, 1H), 7.11-7.16 (m, 1H), 6.73-6.75 (m, 1H), 6.57-6.61 (m, 1H ), 6.42 (br s, IH), 5.58 (br s, IH), 4.65-4.73 (m, 3H), 3.96 (m, 2H), 2.79-2.86 ), 1.75-1.86 (m, 4H), 1.37-1.57 (m, 6H), 1.08-1.23 (m, 5H)

< Example  18> (R) -N- (1-amino-1- Oxopropane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The procedure of Example 1 was repeated except that D-alanine amide (19.3 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) Propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 458.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H), 7.96 (m, 1H), 7.11-7.16 (m, 1H), 6.73-6.75 (m, 1H), 6.57-6.61 (m, 1H ), 6.42 (br s, IH), 5.58 (br s, IH), 4.65-4.73 (m, 3H), 3.96 (m, 2H), 2.79-2.86 ), 1.75-1.86 (m, 4H), 1.37-1.57 (m, 6H), 1.08-1.23 (m, 5H)

< Example  (R) -1- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzoyl ) Pyrrolidine -2- Carboxamide carboxamide

The procedure of Example 1 was repeated except that D-proline amide (23.3 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one Yl) propoxy) -2-fluorobenzoyl) pyrrolidine-2-carboxylic acid (R) -1- (4- 2-carboxamide carboxamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 484.3 (M ⁺

¹ H NMR (400 MHz, CDCl ₃ ) ppm 8.13 (s, 2H), 7.32 (m, IH), 6.87 (br s, IH), 6.69 - 6.72 , 5.56 (br s, IH), 4.74-4.77 (m, IH), 4.65-4.70 (m, 2H), 3.92-3.96 (M, 2H), 2.39-2.45 (m, 2H), 1.76-2.12 (m, 8H), 1.52-1.55

< Example  20> (S) -N- (1-amino-4- ( Methyl thio )-One- Oxobutane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The same procedure as in Example 1 was carried out except that L-methionine amide (28.6 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) (S) -N- (1-amino-4- (methylthio) -1-oxobutan-2-yl) -4- Piperidin-4-yl) propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 518.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.97 (m, 1H), 7.22-7.27 (m, 1H), 6.73-6.76 (m, 1H), 6.58-6.62 (m, 1H ), 6.40 (br s, 1 H), 5.53 (br s, 1 H), 4.82-4.87 (m, 2H), 2.18-2.27 (m, 1H), 2.11-2.03 (m, 4H), 1.75-1.86 (m, 4H), 1.50-1.57 (m, 1H), 1.37-1.43 (m, 2H), 1.14-1.24 (m, 5H)

< Example  (R) -N- (1-amino-4- ( Methyl thio )-One- Oxobutane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The same procedure as in Example 1 was followed except that D-methionine amide (28.6 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (R) -N- (1-amino-4- (methylthio) -1-oxobutan-2-yl) -4- ) Piperidin-4-yl) propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 518.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.97 (m, 1H), 7.22-7.27 (m, 1H), 6.73-6.76 (m, 1H), 6.58-6.62 (m, 1H ), 6.40 (br s, 1 H), 5.53 (br s, 1 H), 4.82-4.87 (m, 2H), 2.18-2.27 (m, 1H), 2.11-2.03 (m, 4H), 1.75-1.86 (m, 4H), 1.50-1.57 (m, 1H), 1.37-1.43 (m, 2H), 1.14-1.24 (m, 5H)

< Example  (S) -N- (2 - ((1-amino-1-oxo-3- Phenylpropane Yl) amino) -2- Oxoethyl ) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The same procedure as in Example 1 was repeated except that glycine phenylalanine amide (43.6 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) (S) -N- (2- ((1-amino-1-oxo-3-phenylpropan- Pyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 591.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 7.92-7.96 (m, 1H), 7.13-7.29 (m, 6H), 6.74-6.78 (m, 2H), 6.59-6.63 (m (M, 2H), 2.80-2.86 (m, 2H), 6.20 (br s, (m, 2H), 2.40-2.46 (m, 2H), 1.55-1.88 (m, 5H), 1.38-1.44

< Example  (S) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2-fluoro-N- (2 - ((1 - ((4- Nitrophenyl ) Amino) -1-oxo-3- Phenylpropane Yl) amino) -2-oxoethyl) Benzamide

The same procedure as in Example 1 was repeated except that glycine phenylalanine nitrophenylamide (53.0 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one 2-fluoro-N- (2 - (((R) -2-fluoro-4- 1 - ((4-nitrophenyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 712.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.98 (s, 1H), 8.11-8.15 (m, 4H), 7.81-7.89 (m, 3H), 7.05-7.30 (m, 6H), 6.60-6.78 (m 2H), 2.41-2.88 (m, 2H), 2.41-2.42 (m, 2H) 2H), 1.14-1.25 (m, 4H), 1.52-1.60 (m, 1H), 1.39-1.45

< Example  (S) -1- (2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamido ) Acetyl) -N- (4- Nitrophenyl ) Pyrrolidine -2- Carboxamide carboxamide

The same procedure as in Example 1 was repeated except that glycine proline nitrophenylamide (50.9 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (S) -1- (2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluorobenzamide ) Acetyl) -N- (4-nitrophenyl) pyrrolidine-2-carboxamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 662.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 9.88 (s, 1H), 8.13 (s, 2H), 8.06-8.08 (m, 2H), 7.99 (m, 1H), 7.55-7.66 (m, 3H), (M, 2H), 3.96 (m, 2H), 4.76-4.68 (m, ), 3.69-3.73 (m, 1H), 3.51-3.58 (m, 1H), 2.79-2.85 (m, 2H), 2.39-2.45 (m, 1H), 1.33-1.46 (m, 2H), 1.12-1.25 (m, 5H)

< Example  25> N - ((2R, 3R) -1-amino-3- methyl -One- Oxopentane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The procedure of Example 1 was repeated except that D-isoleucine amide (37.8 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin-2-one (45 mg, 0.32 mmol) 2-yl) -4- (3- (1- (5-ethylpyrimidin-2-yl) piperidine Pyridin-4-yl) propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 500.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.15 (s, 2H), 7.97 (m, 1H), 7.11-7.17 (m, 1H), 6.74-6.77 (m, 1H), 6.59-6.63 (m, 1H ), 6.23 (br s, 1 H), 5.66 (br s, 1 H), 4.67-4.71 (m, 2H), 4.54-4.57 ), 2.41-2.47 (m, 2H), 1.98-2.06 (m, 1H), 1.77-1.91 (m, 5H), 1.51-1.67 (m, 5 H), 0.92 - 1.02 (m, 6 H)

< Example  26> N - ((2S, 3S) -1-amino-3- methyl -One- Oxopentane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorobenzamide

The same procedure as in Example 1 was repeated except that L-isoleucine amide (37.8 mg, 0.15 mmol) was used instead of 1- (3-aminopropyl) pyrrolidin- 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidine-2-carboxylic acid Pyridin-4-yl) propoxy) -2-fluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 500.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.15 (s, 2H), 7.97 (m, 1H), 7.11-7.17 (m, 1H), 6.74-6.77 (m, 1H), 6.59-6.63 (m, 1H ), 6.23 (br s, 1 H), 5.66 (br s, 1 H), 4.67-4.71 (m, 2H), 4.54-4.57 ), 2.41-2.47 (m, 2H), 1.98-2.06 (m, 1H), 1.77-1.91 (m, 5H), 1.51-1.67 (m, 5 H), 0.92 - 1.02 (m, 6 H)

< Example  27> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- ( Professional 2-yn-1-yl) Benzamide

(30 mg, 0.08 mmol) and 1- (3-aminopropyl) -2-fluorobenzoic acid (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -pyrrolidine- -2,3-difluorobenzoic acid (30 mg, 0.07 mmol) and propargylamine (18 mg, 0.32 mmol) were used in the same manner as in Example 1 to obtain the desired compound 4- (3 (Prop-2-yn-1-yl) benzoic acid methyl ester, Amide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 443.2 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.99 (br s, 1H) 8.20 (s, 2H) 6.77 (m, 2H) 4.59 (m, 2H) 4.00 (m, 2H) 3.15 (s, 1H) 2.78 (m 2H), 1.41 (m, 2H), 1.41 (m, 4H) 1.54 (m,

< Example  28 > N- (3-amino-3- Oxopropyl ) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

(3-Amino-3-oxo-thiophen-2-yl) -methanone was prepared in the same manner as in Example 27, except that 3-aminopropanamide (28 mg, 0.32 mmol) Propyl) -4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 476.2 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.55 (br s, 1H) 8.20 (s, 2H) 7.34 (m, 1H) 6.84 (m, 1H) 6.74 (t, J = 9.6 Hz, 2H) 4.59 (m, 2H), 1.31 (m, 2H), 1.31 (m, 2H), 3.31 (m, ) 1.22 (m, 1H) 1.11 (m, 2H) 1.01 (m, 3H)

< Example  29> N- (2-Amino-2- Oxoethyl ) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

(2-Amino-2-oxoethyl) - (2-amino-2-oxoethyl) -piperidine was prepared following the same procedure as in Example 27, except that glycine amide (24 mg, 0.32 mmol) To obtain 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 462.2 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.63 (br s, 1H) 8.20 (s, 2H) 7.26 (m, 1H) 7.08 (m, 1H) 6.75 (m, 2H) 4.59 (m, 2H) 4.00 (m 2H), 3.79 (m, 2H), 2.79 (m, 2H), 1.41 (m, 2H) ) 1.02 (m, 3 H)

< Example  30> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (3- (2- Oxopyrrolidine Yl) propyl) Benzamide

The same procedure as in Example 27 was followed, except that 1- (3-aminopropyl) pyrrolidin-2-one (46 mg, 0.32 mmol) was used instead of propargylamine (18 mg, 0.32 mmol) Yl) propoxy) -2,6-difluoro-N- (3- (2-oxopyrrolyl) Yl) propyl) benzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 530.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.12 (s, 2H) 6.44 (m, 2H) 6.14 (m, 1H) 4.65 (m, 2H) 4.20 (m, 2H) 3.90 (m, 2H) 2.81 (t , J = 25.6 Hz, 2H) 2.41 (m, 4H) 2.43 (m, 4H) 1.75 (m, 4H) 1.54 (m, 4H) 1.38 (m, 4H) 1.22 (m, 1H) 1.15 (m, 3H)

< Example  (S) -1- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzoyl ) Pyrrolidine -2- Carboxamide

(S) -1- (4- (3, 3-dihydroxy-phenyl) -propan-2-ol was obtained by carrying out the same procedure as in Example 27, with the exception that L-proline amide (37 mg, 0.32 mmol) - (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzoyl) pyrrolidine-2-carboxamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 502.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 6.43 (m, 2H) 4.68 (m, 2H) 4.26 (m, 1H) 3.91 (m, 2H) 2.84 (m, 2H) 2.42 (m 2H), 2.21 (m, 2H) 2.04 (m, 2H) 1.91 (m, 2H) 1.80 (m, 2H) 1.69 )

< Example  (S) -N- (1-amino-1- Oxopropane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

(S) -N- (1-amino-2-methylpyridin-2-yl) -methanone was carried out in the same manner as in Example 27, except that L-alanine amide (18.4 mg, 0.15 mmol) Yl) propoxy) -2, 6-difluorobenzene (prepared according to the method of Example 1, Amide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 476.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.60-6.62 (m, 1H), 6.43-6.47 (m, 2H), 6.28 (br s, 1H), 5.43 (br s, 1H ), 4.66-4.75 (m, 3H), 3.92 (t, J = 6.4,2H), 2.79-2.86 (m, 2H), 2.40-2. -1.57 (m, 6H), 1.14 - 1.25 (m, 5H)

< Example  33> (R) -N- (1-amino-1- Oxopropane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

(R) -N- (1-amino-4-methylpiperazin-1-yl) -methanone was carried out in the same manner as in Example 27 except that D-alanine amide (18.4 mg, 0.15 mmol) Yl) propoxy) -2, 6-difluorobenzene (prepared according to the method of Example 1, Amide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 476.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.60-6.62 (m, 1H), 6.43-6.47 (m, 2H), 6.28 (br s, 1H), 5.43 (br s, 1H ), 4.66-4.75 (m, 3H), 3.92 (t, J = 6.4,2H), 2.79-2.86 (m, 2H), 2.40-2. -1.57 (m, 6H), 1.14 - 1.25 (m, 5H)

< Example  34 > (R) - methyl  5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide ) -5- Oxopenanoate

(R) -methyl 5-amino-2 (4-methyl-2-pyrrolidinone) was carried out in the same manner as in Example 27, except that D-glutamine methyl ester (51 mg, 0.32 mmol) - (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6- difluorobenzamido) -5- Eight.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 548.3 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.92 (m, 1H) 6.48 (m, 2H) 6.09 (br s, 1H) 5.35 (br s, 1H) 4.83 (m, 1H) 4.71 (m, 2H), 3.95 (m, 2H), 3.79 (s, 3H), 2.87 , [Delta] H) 1.25 (m, 2H) 1.18 (m, 3H)

< Example  (R) -5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) propoxy) -2,6- Difluorobenzamide ) -5- Oxopentanoic acid

(1.5 g, 3.7 mmol) instead of methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzoate (R) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) (R) -5-amino-2- (4-fluorophenyl) -5-oxopentanoate was obtained in the same manner as in Production Example 5, (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamido) -5-oxopentanoic acid was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 534.2 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.91 (m, 1H) 6.48 (m, 2H) 6.09 (br s, 1H) 5.35 (br s, 1H) 4.88 (m, 1H) 4.73 (m, 2H), 3.95 (m, 2H), 2.87 (m, 2H), 2.44 , &Lt; / RTI &gt; 2H) 1.18 (m, 3H)

< Example  36> (S) - methyl  5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide ) -5- Oxopenanoate

(S) -methyl 5-amino-2 (4-methyl-2-pyrrolidinone) was prepared in the same manner as in Example 27, except that L-glutamine methyl ester (51 mg, 0.32 mmol) - (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6- difluorobenzamido) -5- Eight.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 548.3 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.92 (m, 1H) 6.48 (m, 2H) 6.09 (br s, 1H) 5.35 (br s, 1H) 4.83 (m, 1H) 4.71 (m, 2H), 3.95 (m, 2H), 3.79 (s, 3H), 2.87 , [Delta] H) 1.25 (m, 2H) 1.18 (m, 3H)

< Example  (S) -5-Amino-2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) propoxy) -2,6- Difluorobenzamide ) -5- Oxopentanoic acid

Methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2-fluorobenzoate

(5-ethylpyrimidin-2-yl) piperidin-4-one synthesized in Example 36 instead of 2- (4- (3- -Propoxy) -2,6-difluorobenzamajido) -5-oxopentanoate (30 mg, 0.055 mmol) was used to carry out the same procedure as in Production Example 5 to obtain the desired form of compound (S) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzene 5-oxopentanoic &lt; / RTI &gt; acid.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 534.2 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.91 (m, 1H) 6.48 (m, 2H) 6.09 (br s, 1H) 5.35 (br s, 1H) 4.88 (m, 1H) 4.73 (m, 2H), 3.95 (m, 2H), 2.87 (m, 2H), 2.44 , &Lt; / RTI &gt; 2H) 1.18 (m, 3H)

< Example  38> N-Allyl-4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

Allyl-4- (3- (1- ((2-pyridinyl) pyrimidin-2-ylamino) -thiazole was obtained in the same manner as in Example 27, except that allylamine (18 mg, 0.32 mmol) Ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 445.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 6.43 (m, 2H) 5.99 (br s, 1H) 5.96 (m, 1H) 5.25 (d, J = 17.2 Hz) 5.16 (d, J (M, 2H), 1.65 (m, 2H), 1.65 (m, 2H) m, 2 H) 1.14 (m, 3 H)

< Example  (S) - Diethyl  2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) propoxy) -2,6- Difluorobenzamide ) Pentanedioate

(S) -diethyl 2- (trifluoromethyl) benzyl chloride was carried out in the same manner as in Example 27 except that L-glutamic acid diethyl ester hydrochloride (65 mg, 0.32 mmol) was used in place of propargylamine (18 mg, 0.32 mmol) (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamido) pentane diioate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 591.3 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.70 (m, 1H) 6.45 (m, 2H) 4.83 (m, 1H) 4.71 (m, 2H) 4.24 (m, 2H) 4.13 (m 2H), 3.94 (m, 2H), 2.87 (m, 2H), 2.47 (m, 4H) ) 1.40 (m, 2H) 1.30 (t, J = 13.8 Hz, 3H) 1.24 (t, J = 14.4 Hz, 3H) 1.19 (m, 3H)

< Example  (S) -2- (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide ) Pentane Dioki Acid

(1.5 g, 3.7 mmol) instead of methyl 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzoate (S) -diethyl 2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6-difluorobenzene (S) -2- (4- (3- (1- (5-Ethyl-2-oxo-ethyl) Pyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamido) pentanedioic acid.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 535.2 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.72 (m, 1H) 6.45 (m, 2H) 4.85 (m, 1H) 4.71 (m, 2H) 4.24 (m, 2H) 4.14 (m 2H), 3.94 (m, 2H), 2.88 (m, 2H), 2.47 (m, 4H) ) 1.40 (m, 2 H) 1.19 (m, 3 H)

< Example  4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro  -N- (2- Oxopropyl ) Benzamide

(23 mg, 0.32 mmol) was used in place of propionaldehyde (18 mg, 0.32 mmol) to give the desired form of compound 4- (3- (1 - (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluoro-N- (2-oxopropyl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 461.2 (M ⁺

^{1 H NMR (600 MHz, CDCl} 3) ppm 8.16 (s, 2H) 6.79 (br s, 1H) 6.48 (m, 2H) 4.71 (m, 2H) 4.35 (m, 2H) 3.95 (m, 2H) 2.84 ( (m, 2H), 1.41 (m, 2H), 1.41 (m, 2H)

< Example  (S) -N- (1-amino-4- methyl -One- Oxopentane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

(S) -N- (1-amino (2-aminoethyl) amino] propanoic acid was prepared in the same manner as in Example 27, except that L- leucine amide (24.7 mg, 0.15 mmol) Yl) propoxy) -2, 6-dihydro-2H-pyran-2- Difluorobenzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 518.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.39-6.45 (m, 3H), 6.31 (br s, 1H), 5.45 (br s, 1H), 4.66-4.69 (m, 3H ), 3.92 (m, 2H), 2.79-2.85 (m, 2H), 2.40-2.46 (m, 2H), 1.51-1.85 (m, 8H), 1.36-1.41 , 5H), 0.95-0.96 (m, 6H)

< Example  (R) -N- (1-amino-4- methyl -One- Oxopentane Yl) -4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluorobenzamide

(R) -N- (1-amino-4-methylpiperazin-1-yl) -methanone was carried out in the same manner as in Example 27 except that D- leucine amide (24.7 mg, 0.15 mmol) Yl) propoxy) -2, 6-dihydro-2H-pyran-2- Difluorobenzamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 518.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.39-6.45 (m, 3H), 6.31 (br s, 1H), 5.45 (br s, 1H), 4.66-4.69 (m, 3H ), 3.92 (m, 2H), 2.79-2.85 (m, 2H), 2.40-2.46 (m, 2H), 1.51-1.85 (m, 8H), 1.36-1.41 , 5H), 0.95-0.96 (m, 6H)

< Example  4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (4- Oxocyclohexyl ) Benzamide

Step 1: 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (trans-4- Hydroxycyclohexyl ) Benzamide  Produce

The title compound was prepared in the same manner as in Example 27, except that trans-4-aminocyclohexanol hydrochloride (22.4 mg, 0.15 mmol) was used instead of propargylamine (18 mg, 0.32 mmol) - (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluoro-N- (trans-4-hydroxycyclohexyl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 503.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.41-6.43 (m, 2H), 5.70-5.72 (m, 1H), 4.66-4.69 (m, 2H), 3.89-3.98 (m (M, 4H), 1.75-1.84 (m, 4H), 1.14 (m, 2H), 3.60-3.65 -1.59 (m, 12H)

Step 2: 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (4- Oxocyclohexyl ) Benzamide  Produce

(3- (1- (5-Ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-dioxaborolanilide synthesized in the above Step 1 (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) -Yl) propoxy) -2,6-difluoro-N- (4-oxocyclohexyl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 501.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.43-6.45 (m, 2H), 5.91 (m, 1H), 4.66-4.69 (m, 2H), 4.43-4.45 (m, 1H ), 3.90-3.94 (m, 2H), 2.79-2.86 (m, 2H), 2.32-2.53 (m, 6H), 1.52-2.02 (m, 5H)

< Example  45> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (3- Oxocyclohexyl ) Benzamide

The same procedure as in Example 44 was followed, except that 3-amino-cyclohexanol (21.3 mg, 0.18 mmol) was used instead of trans 4-aminocyclohexanol hydrochloride (22.4 mg, 0.15 mmol) - (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6-difluoro-N- (3-oxocyclohexyl) .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 501.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.41-6.45 (m, 2H), 5.95-5.96 (m, 1H), 4.65-4.69 (m, 2H), 4.42-4.46 (m (M, 3H), 1.35 (m, 3H), 1.45 (m, -1.43 (m, 2H), 1.12-1.24 (m, 5H)

< Example  46> 4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (2- Oxocyclohexyl ) Benzamide

The same procedure as in Example 44 was followed except that 2-amino-cyclohexanol hydrochloride (28.0 mg, 0.18 mmol) was used instead of trans 4-aminocyclohexanol hydrochloride (22.4 mg, 0.15 mmol) 4-yl) propoxy) -2,6-difluoro-N- (2-oxocyclohexyl) benzamide .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 501.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H), 6.99-7.00 (m, 1H), 6.42-6.45 (m, 2H), 4.61-4.69 (m, 3H), 3.90-3.93 (m 2H), 2.79-2.85 (m, 2H), 2.38-2.57 (m, 4H), 2.14-2.20 (m,

< Example  4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Difluoro -N- (2- Oxocyclopentyl ) Benzamide

The same procedure as in Example 44 was followed, except that 2-amino-cyclopentanol hydrochloride (32 mg, 0.32 mmol) was used instead of trans 4-aminocyclohexanol hydrochloride (22.4 mg, 0.15 mmol) - (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6-difluoro-N- (2- oxocyclopentyl) .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 487.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 6.45 (m, 2H) 4.68 (m, 2H) 4.26 (m, 1H) 3.91 (m, 2H) 2.81 (m, 2H) 2.42 (m 2H), 2.20 (m, 1H), 2.08 (m, 1H) 1.89 (m, 1H) 1.78 (m, 3H) 1.68 ) &Lt; / RTI &gt; 1.13 (m, 3H)

< Example  48> 2- Fluoro -4- (3- (1- (5- Pentylpyrimidine Yl) piperidin-4-yl) Propoxy ) -N- ( Professional 2-yn-1-yl) Benzamide

(15 mg, 0.07 mmol) instead of 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzoic acid Except that the 4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorobenzoic acid salt (30 mg, 0.07 mmol) Fluoro-4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) -pyridine was prepared by the same method as in Example 27, -N- (prop-2-yn-1-yl) benzamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 467.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.12 (s, 2H), 8.03 (t, J = 9.2Hz, 1H), 6.74-6.83 (m, 2H), 6.57-6.61 (m, 1H), 4.65- 4.72 (m, 2H), 4.23-4.25 (m, 2H), 3.97 (t, J = 6.4, 2H), 2.82 (m, 2H), 2.38 (t, J = 7.6, 2H), 2.25 (m, 1H ), 1.76-1.83 (m, 4H), 1.17-1.57 (m, 11H), 0.86 (t, J = 7.2,

< Example  49> 2- Fluoro -N- (2- Oxotetrahydrofuran Yl) -4- (3- (1- (5- Pentylpyrimidine Yl) piperidin-4-yl) Propoxy ) Benzamide

The same procedure as in Example 48 was followed, except that alpha-amino gamma -butyrolactone hydrobromide (25.4 mg, 0.14 mmol) was used instead of propargylamine (7.7 mg, 0.14 mmol) to give the desired compound 2-fluoro (2-oxotetrahydrofuran-3-yl) -4- (3- (1- (5-pentylpyrimidin-2- yl) piperidin-4- yl) propoxy) .

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 513.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.11 (s, 2H), 7.99 (m, 1H), 7.13-7.18 (m, 1H), 6.73-6.76 (m, 1H), 6.57-6.61 (m, 1H ), 4.65-4.70 (m, 3H), 4.48-4.52 (m, IH), 4.29-4.33 (m, IH), 3.96 (t, J = 6.4Hz, 2H), 2.79-2.89 (M, 3H), 1.75-1.84 (m, 4H), 1.13-1.51 (m, 11H), 0.83-0.87

< Example  50> 1- (7,7- Dimethyl -2- Oxobicyclo [2.2.1] heptane Yl) -N- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- Propoxy )-2- Fluorophenyl ) Methanesulfonamide

Propoxy) -2-fluoroaniline (30 mg, 0.08 mmol) synthesized in Production Example 9 was dissolved in MC (2 ml) as a solvent, and TEA (25 ml) was added. (-) - 10-camphorsulfonyl chloride (47 mg, 0.16 mmol) was added dropwise thereto, followed by reaction at room temperature for 12 hours. Water and EA (20 ml) were added to extract the organic layer. The organic layer was washed with brine (30 ml × 2), the separated organic layer was washed with water using MgSO ₄ , filtered and reduced in pressure to remove EA. The residue was purified by silica gel column chromatography using hexane and EA as eluent to obtain the desired compound, 1- (7,7-dimethyl-2-oxobicyclo [2.2.1] heptan- - (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) methanesulfonamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 573.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.21 (s, 2H) 8.11 (m, 1H) 6.55 (d, J HF = 9.2 Hz, 1 H) 6.47 (d, J _HF = 9.2 Hz, 1 H) 4.66 (m, 2 H) 3.92 (m, 2 H) 3.77 (m, 2H), 1.79 (m, 2H), 1.79 (m, 2H) 1.67 (m, 2H)

< Example  51. N- (4- (3- (1- (5- Ethylpyrimidine  Yl) piperidin-4-yl) Propoxy ) -2-fluorophenyl) Professional -2-en-1- Sulfonamide

Ene-1-sulfonyl chloride (19 mg, 0.16 mmol) was used instead of (-) - 10-camphorsulfonyl chloride (47 mg, 0.16 mmol) 2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) prop- 2-ene-1-sulfonamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 463.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H) 7.45 (d, J HF = 18.4 Hz, 1H) 6.47 (m, 1H) 5.84 (m, 1H) 5.55 (m, 1H) 5.43 (m , 1H) 5.31 (m, 1H ) 4.67 (m, 2H) 3.91 (m, 2H) 3.73 (m, 2H) 2.83 (m, 2H) 2.42 (q, J = 22.4 Hz, 2H) 1.97 (m, 1H) 1.78 (m, 4 H) 1.41 (m, 2 H) 1.18 (m, 3 H)

< Example  52> methyl  (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorophenyl ) Carbamate

The same procedure as in Example 50 was followed, except that methyl chloroformate (0.006 ml, 0.075 mmol) was used instead of (-) - 10- camphorsulfonyl chloride (47 mg, 0.16 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 417.3 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.14 (s, 2H) 7.81 (s, 1H) 6.71-6.57 (m, 3H) 4.68-4.65 (m, 2H) 3.90-3.77 (m, 2H) 3.76 (s, 3H) 2.82 (t, J = 23.6 Hz, 2H), 2.46-2.40 (m, 2H), 1.83-1.75 (m, 4H), 1.58 (s, 1H), 1.42-1.35 (m, 2H), 1.31- 1.21 (m, 2 H) 1.18 - 1.00 (m, 3 H)

< Example  53> Pentyl  (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2- Luo Lope Neil) Carbamate

The same procedure as in Example 50 was followed, except that pentyl chloroformate (0.01 g, 0.075 mmol) was used in place of (-) - 10- camphorsulfonyl chloride (47 mg, 0.16 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 473.3 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.14 (s, 2H) 7.82 (s, 1H) 6.64-6.60 (m, 3H) 4.68-4.65 (m, 2H) 4.15-4.12 (m, 2H) 3.90-3.87 ( m, 2H) 2.82 (t, J = 24 Hz, 2H), 2.42 (q, J = 20.8Hz, 2H), 1.82-1.75 (m, 3H), 1.67-1.54 (m, 6H), 1.42-1.00 ( m, 9H), 1.00-0.88 (m, 3H)

< Example  Vinyl (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2- Luo Lope Neil) Carbamate

The procedure of Example 50 was followed except that vinyl chloroformate (0.007 ml, 0.075 mmol) was used instead of (-) - 10-camphorsulfonylolide (47 mg, 0.16 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 429.2 (M ⁺

¹ H NMR (400 MHz, DMSO) ppm 8.14 (s, 2H) 8.04-7.99 (m, 1H) 7.99 (s, 1H) 6.70-6.60 (m, 3H) 5.36-5.23 m, 2H) 3.93-3.87 (m, 2H) 2.82 (t, J = 24 Hz, 2H), 2.42 (m, 2H) 1.84-1.75 (m, 4H), 1.66 (s, 1H), 1.58-1.49 ( m, 2H), 1.42-1.31 (m, 2H), 1.01-0.93 (m, 3H)

< Example  Allyl (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2- Luo Lope Neil) Carbamate

The same procedure as in Example 50 was followed except that allyl chloroformate (0.008 ml, 0.075 mmol) was used instead of (-) - 10- camphorsulfonylolide (47 mg, 0.16 mmol) 4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 443.3 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.14 (s, 2H) 7.84 (s, 1H) 6.70-6.60 (m, 3H) 5.98-5.91 (m, 1H) 5.34-5.23 (m, 2H) 4.69-4.59 ( m, 4H), 3.93-3.87 (m , 2H), 2.82 (t, J = 24Hz, 2H), 2.42 (q, J = 22.4 Hz, 2H), 1.84-1.75 (m, 4H), 1.66 (s, 1H) 1.56-1.49 (m, 2H) 1.31-1.17 (m, 2H) 1.01-0.93 (m, 3H)

< Example  56> (5S) -2-Isopropyl-5- Methylcyclohexyl  (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorophenyl ) Carbamate

The procedure of Example 50 was repeated except that (1R) - (-) - menthyl chloroformate (0.02 ml, 0.075 mmol) was used in place of (-) - 10-camphorsulfonylolide (47 mg, 0.16 mmol) (5S) -2-isopropyl-5-methylcyclohexyl (4- (3- (1- (5-ethylpyrimidin- ) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 541.4 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.13 (s, 2H) 7.88 (s, 1H) 6.64-6.59 (m, 3H) 4.68-4.60 (m, 3H) 3.87 (m, 2H) 3.38 (m, 2H) 2H), 2.84-2.78 (m, 2H), 2.65-2.54 (q, J = 47.6 Hz, m, 6H) 1.37-1.25 (m, 2H) 1.20-1.03 (m, 4H) 0.99-0.61 (m, 9H)

< Example  Isobutyl (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy )-2- Fluorophenyl ) Carbamate

The same procedure as in Example 50 was followed, except that isobutyl chloroformate (0.01 ml, 0.075 mmol) was used instead of (-) - 10- camphorsulfonylolide (47 mg, 0.16 mmol) Butyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 459.3 (M ⁺

^{1 H NMR (400 MHz, DMSO} ) ppm 8.14 (s, 2H) 7.84 (s, 1H) 6.65-6.60 (m, 3H) 4.67 (d, J = 13.2 Hz, 2H) 3.93-3.87 (m, 4H), (M, 2H), 2.42 (m, 2H), 1.94 (m, 1H) 1.78 (m, 2H), 1.58-1.50 9H)

< Example  58> 1- (7,7- Dimethyl -2- Oxobicyclo [2.2.1] heptane Yl) -N- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- Propoxy ) -2,6- Difluorophenyl ) Methanesulfonamide

Was obtained in the same manner as in Example 11, except that 4 (4-benzyloxyphenyl) propionamide synthesized in Production Example 11 was used instead of 4- (3- (1- (5-ethylpyrimidin- - (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluoroaniline (30 mg, 0.16 mmol) (7,7-dimethyl-2-oxobicyclo [2.2.1] heptan-l-yl) -N- (4- (3- - (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) methanesulfonamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 591.3 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H) 7.62 (s, 1H) 6.55 (d, J HF = 9.2 Hz, 1 H) 6.47 (d, J _HF = 9.2 Hz, 1 H) 4.66 (m, 2 H) 3.92 (m, 2 H) 3.77 (m, 2H), 1.79 (m, 2H), 1.79 (m, 2H) 1.67 (m, 2H)

< Example  (I) N- (4- (3- (1- (5- Ethylpyrimidine  Yl) piperidin-4-yl) Propoxy ) -2,6- Effluo Phenyl) Acrylamide

The same procedure as in Example 58 was followed, except that acryloyl chloride (14 mg, 0.16 mmol) was used instead of (-) - 10- camphorsulfonyl chloride (47 mg, 0.16 mmol) (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) acrylamide was obtained.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 431.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.14 (s, 2H) 6.72 (br s, 1H) 6.46 (m, 2H) 6.40 (m, 1H) 6.29 (m, 1H) 5.78 (m, 1H) 4.68 ( (m, 2H), 3.83 (m, 2H), 2.83 (m, 2H) 2H) 1.50 (m, 3H)

< Example  60> Pentyl  (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Effluo Phenyl) Carbamate

(24 mg, 0.16 mmol) was used in the place of (-) - 10- camphorsulfonylolide (47 mg, 0.16 mmol) instead of pentyl chloroformate - (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 491.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.13 (s, 2H) 6.44 (m, 2H) 4.67 (m, 2H) 4.17 (m, 2H) 4.00 (m, 1H) 3.84 (m, 2H) 3.52 (m 2H), 1.24 (m, 4H), 1.13 (m, 2H), 1.24 (m, ) 0.89 (m, 3H)

< Example  61> Allyl (4- (3- (1- (5- Ethylpyrimidine Yl) piperidin-4-yl) Propoxy ) -2,6- Effluo Phenyl) Carbamate

The same procedure as in Example 58 was followed, except that allyl chloroformate (19 mg, 0.16 mmol) was used instead of (-) - 10- camphorsulfonylolide (47 mg, 0.16 mmol) - (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) carbamate.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 461.2 (M ⁺

^{1 H NMR (400 MHz, CDCl} 3) ppm 8.21 (s, 2H) 6.46 (d, J HF 2H), 2.48 (m, 2H), 2.46 (m, 2H), 1.79 (m, m, 4 H) 1.40 (m, 3 H) 1.23 (m, 2 H) 1.16 (m, 3 H)

< Example  62> N- (2- Fluoro -4- (3- (1- (5- Pentylpyrimidine Yl) piperidin-4-yl) Propoxy ) Phenyl ) Acrylamide

(30 mg, 0.08 mmol) and (-) - 10-camphor (2-fluoroaniline Fluoro-4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxypropionate synthesized in Production Example 17 instead of 4- ) Aniline (7.5 mg, 0.038 mmol) and acryloyl chloride (0.006 ml, 0.075 mmol) were used in the same manner as in Example 50 to give the desired compound N- (2-fluoro- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) phenyl) acrylamide.

MS (ESI ^& lt ^{; +} & gt ^; ) m / z 454.8 (M ⁺

^{1 H NMR (400 MHz, CDCl3} ) ppm 8.11 (s, 2H), 8.02 (s, 1H), 7.16 (s, 1H), 6.64-6.62 (m, 2H), 6.48 (m, 1H), 6.01 (m , 1H), 5.50 (m, 1H), 4.67 (d, J = 12Hz, 2H), 3.89-3.88 (m, 2H), 2.82 (m, 2H), 2.37-2.36 (m, 2H), 1.78-1.75 (m, 4H), 1.57-1.38 (m, 5H), 1.28-1.15 (m, 6H), 0.86-0.84

< Experimental Example 1 > People Ability to activate GPR119  black

The amount of cyclic adenosine 3 ', 5'-phosphate (cAMP), which is increased by temporarily expressing human GPR119 in a cell and activating the receptor by the compound of the present invention, is measured by HTRF (homogeneous time resolved fluorescence) Was used as a measure of efficacy for GPR119 receptor activation.

Human GPR119 expression vector was transfected into hamster kidney epithelial cells (HEK293) and cultured for 24 hours for expression. To a buffer solution of KRBH (Krebs-Ringer Bicarabonate HEPES; Mol Cell Endocrinol, 2008 (291): 71-78), 11.1 mM glucose, 0.1% bovine serum albumin and 0.5 mM IBMX -isobutyl-1-methylxanthine) was pre-treated for 10 minutes. Subsequently, the drug was diluted in the same solution, treated with cells for 60 minutes, and the supernatant was removed. The intracellular cAMP level was quantitated using a Cysbio cAMP HiRange kit.

The active potency of the receptor is determined by performing multiple concentration assays on the compounds of the present invention to determine the concentration of compound of the present invention causing 50% activation of the maximum effect of oleoylethanolamide (OEA), an endogenous ligand of GPR119 (OEA 50%) were calculated using linear regression analysis.

The results are shown in Table 1, indicating that the compounds of the present invention exhibited activity in all of the compounds of the Examples and exhibited high activity in most of the compounds.

Person GPR119 Activation ability  Drug search results Example hGPR119 activation ability (nM) Example hGPR119 activation ability (nM) One 6.2 32 0.5 2 40.4 33 1.1 3 24.5 34 20.7 4 20.3 35 7.5 5 18.2 36 6.5 6 1,626 37 169.6 7 2.8 38 1.3 8 4.9 39 0.7 9 0.8 40 11.9 10 2.2 41 <1 11 6.7 42 1.1 12 23.8 43 1.5 13 52.5 44 1.2 14 5.6 45 1.2 15 2.5 46 1.7 16 4.3 47 1.2 17 1.8 48 1.5 18 7.5 49 <10 19 67.6 50 0.4 20 2.1 51 40.4 21 6.4 52 10.5 22 72.1 53 5.6 23 270.7 54 11 24 > 1,000 55 0.9 25 19.9 56 633.8 26 5.5 57 1.6 27 0.1 58 1.9 28 1.1 59 0.6 29 0.7 60 13.4 30 1.0 61 0.2 31 1.6 62 0.5

< Experimental Example 2 > Insulin secretion activity assay in hamster beta cells

HIT-T15 cells, a hamster beta cell line, were stabilized for 72 hours and left in KRBH buffer containing 1% bovine serum albumin for 1 hour to deplete glucose. Then, 11.1 mM glucose and phosphodiesterase inhibitor 100 μm Ro-20-1724 were diluted in the same buffer, and insulin was quantitated using a rat insulin ELISA kit in ALPCO medium. In order to correct the deviation between the wells, the supernatant was removed, the cells were treated with 0.1 N hydrochloric acid solution for 10 minutes, neutralized with 10% (w / v) potassium hydrogen carbonate solution and quantified with Pierce's Bicinchoninic acid reagent The amount of secreted insulin was expressed as the amount of insulin per unit cell protein divided by the total protein amount.

Insulin secretory activity was assessed in multiple concentrations for the compounds of the present invention in the same manner as in Experimental Example 1 to determine the concentration of the compound of the present invention causing 50% activation of the maximum effect of OEA, the endogenous ligand of GPR119 %) Were calculated using linear regression analysis.

The results are shown in Table 2, and it was confirmed that a high activity of insulin secretion ability was obtained in a large number of compounds tested.

Results of insulin secretion activity in hamster beta cells Example Insulin secretion ability (nM) Example Insulin secretion ability (nM) One > 1,000 39 15 7 33 45 4.3 8 103 46 0.60 9 183 47 10 10 <1,000 41 0.20 14 209 42 9.3 17 91 43 2.2 27 3.1 35 0.80 29 1.0 37 <10 32 344 40 3.5 33 > 1,000 50 145 34 73 55 3.2 36 > 1,000 62 22 38 1.4

< Experimental Example 3 > From the mouse Improve my ability  Effect Black

 One of the indicators of antidiabetic effect was evaluated as a meaning of improving the postprandial blood glucose control ability of the compound in 7 week old male mice (C57BL / 6 mouse).

The experimental mice were fasted for 16-17 hours from the day before the experiment. The compound of the present invention was orally administered 30 minutes before the glucose administration and 30 minutes later, the glucose solution (2 g / kg / 10 ml) was orally administered. The drug was suspended in 0.5% methylcellulose solution. Immediately prior to administration of the drug, immediately before the administration of the glucose solution, and at 15, 30, 60, 90 and 120 minutes after the administration of the glucose, the blood obtained by cutting the vein was collected using a glucose meter (AccuChek Active, Roche Diagnostics) And the area under the curve of the blood glucose curve over time was calculated. The area under the calculated blood glucose curve was determined by limiting the area under the blood glucose curve of the negative control group to which the glucose solution was not administered and then calculating the inhibitory activity against the increase in blood glucose of the control group administered with 0.5% methylcellulose solution and the glucose solution as a percentage The drug efficacy improvement effect of the drug was evaluated.

The results are shown in Table 3. As shown in Table 3, a significant improvement in resistance to potency was confirmed in a number of compounds tested.

From the mouse Improve my ability  Drug search results Example Improvement of my ability (Inhibition% @ 10 mg / kg) 7 40.6% 8 24.6% 9 28.6% 14 47.8% 17 47.8% 27 36.8% 29 34.0% 32 51.1% 62 30.6%

As shown in Tables 1 to 3, it was confirmed that the novel compounds synthesized in Examples 1 to 62, isomers thereof, or pharmaceutically acceptable salts thereof have a therapeutic activity against the GPR119 receptor. In addition, the effect of insulin secretion activity and excellent resistance to endurance in beta cells was confirmed in a number of example compounds tested. Accordingly, the compounds of the above examples are expected to have a high therapeutic effect or preventive effect against metabolic diseases such as obesity, diabetes, hypertension, cardiovascular diseases, hypercoagulable disorder, and dyslipidemia.

Claims (16)

Claims 1. A compound represented by the following formula (1), an isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,
R ₁ is hydrogen or alkyl having 1 to 6 carbon atoms;
R ₂ and R ₃ are each independently hydrogen or halogen;
X is -C (O) NHR ₄ , -C (O) -YC (O) NHR ₅ , -NHC (O) R ₆ , or -NHS (O) ₂ R ₇ ;
R ₄ is an alkenyl having 1 to 6 carbon atoms, an alkynyl having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl having 3 to 7 carbon atoms, a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms, (CH ₂ ) m R ₈ , and -CH (R ₉ ) (CH ₂ ) n C (O) R ₁₀ , wherein R is selected from the group consisting of hydrogen, substituted or unsubstituted divalent cycloalkyl, &Lt; / RTI &gt;
m is an integer from 1 to 4;
n is an integer from 0 to 3;
R ₈ is a substituted or unsubstituted heterocyclic group having 3 to 7 carbon atoms;
R ₉ is selected from the group consisting of hydrogen, alkyl having 1 to 4 carbon atoms, -C (O) OR ₁₁ , and - (CH ₂ ) mSR ₁₂ ;
R ₁₀ is selected from the group consisting of hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, -NR ₁₃ R ₁₄ , and -YC (O) NHR ₅ ;
R ₁₁ and R ₁₂ are each independently hydrogen or alkyl having 1 to 4 carbon atoms;
R ₁₃ and R ₁₄ are each independently a substituted or unsubstituted alkyl having 1 to 4 carbon atoms;
Y is pyrrolidine;
R ₅ is hydrogen, alkyl having 1 to 4 carbon atoms, or substituted or unsubstituted aryl having 6 to 40 carbon atoms;
R ₆ is selected from the group consisting of alkenyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, substituted or unsubstituted cycloalkoxy having 3 to 7 carbon atoms, and alkenyloxy having 1 to 6 carbon atoms;
R ₇ is alkenyl having 1 to 6 carbon atoms or - (CH ₂ ) mR ₁₅ ;
R ₁₅ is a substituted or unsubstituted bicycloalkyl having 4 to 10 carbon atoms.
The method according to claim 1,
R ₄ is a substituted or unsubstituted cycloalkyl having 3 to 7 carbon atoms substituted with oxo, a substituted or unsubstituted heterocyclic having 3 to 7 carbon atoms substituted with oxo, a substituted or unsubstituted bicycloalkyl having 4 to 10 carbon atoms substituted with oxo And tricycloalkyl having 7 to 12 carbon atoms substituted or unsubstituted with a hydroxy group, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein R ₈ is a heterocyclic group having 3 to 7 carbon atoms which is unsubstituted or substituted with oxo, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein R ₁₃ and R ₁₄ are alkyl having 1 to 4 carbon atoms which is substituted or unsubstituted with a functional group selected from the group consisting of hydrogen, oxo, amino substituted with unsubstituted or substituted nitroaryl, and aryl, an isomer thereof, A pharmaceutically acceptable salt thereof.
The method according to claim 1,
And R &lt; ₅ &gt; is aryl having 6 to 40 carbon atoms substituted or unsubstituted with nitro, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
And R &lt; ₆ &gt; is a cycloalkoxy having 3 to 7 carbon atoms which is unsubstituted or substituted with alkyl having 1 to 4 carbon atoms, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein R &lt; ₁₅ &gt; is an oxo or bicycloalkyl having 4 to 10 carbon atoms which is unsubstituted or substituted with alkyl having 1 to 4 carbon atoms, an isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
Wherein the compound is selected from the group consisting of the following compounds, isomers thereof, or pharmaceutically acceptable salts thereof:
Yl) propoxy) -2-fluoro-N- (3- (2-oxopyrrolidin-1 -Yl) propyl) benzamide;
(1R, 3s, 5R, 7S) -3, 7-dihydroxy-4- (3- (1- (5- ethylpyrimidin- -Hydroxyadamantan-1-yl) benzamide;
Yl) propoxy) -2-fluoro-N - ((5-oxopyrrolidin-2-ylpiperidin- ) Methyl) benzamide;
(R) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin- -5-oxopentanoate;
(S) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin- -5-oxopentanoate;
(S) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 5-oxopentanolic acid;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluoro-N- (2-oxopropyl) benzamide;
(2-amino-2-oxoethyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4-yl) propoxy) -2-fluorobenzamide ;
2-fluoro-N- (prop-2-yn-1-yl) piperidine- Benzamide;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluoro-N- (2-oxocyclopentyl) benzamide;
2-fluoro-N- (2-oxotetrahydrofuran-3-yl) piperidin-4-yl) Benzamide;
(3-amino-3-oxopropyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4-yl) propoxy) -2-fluorobenzamide ;
(S) -2- (4- (3- (1- (5-Ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzamido) pentanedioic acid ;
(S) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2- fluorobenzoyl) pyrrolidin- Carboxamide;
(S) -N- (1-amino-4-methyl-1-oxopentan-2-yl) -4- Yl) propoxy) -2-fluorobenzamide;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- Yl) propoxy) -2-fluorobenzamide;
(S) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2-fluorobenzamide;
(R) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2-fluorobenzamide;
(R) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzoyl) pyrrolidin- Carboxamide carboxamide;
(S) -N- (1-amino-4- (methylthio) -1-oxobutan-2-yl) -4- (3- (1- (5-ethylpyrimidin- Yl) propoxy) -2-fluorobenzamide;
(R) -N- (1-amino-4- (methylthio) -1-oxobutan-2-yl) -4- Yl) propoxy) -2-fluorobenzamide;
(S) -N- (2- ((1-amino-1-oxo-3-phenylpropan- 2-yl) piperidin-4-yl) propoxy) -2-fluorobenzamide;
(S) -4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluoro- N- (4-nitrophenyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) benzamide;
(S) -1- (2- (4- (3- (1- (5-Ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2-fluorobenzamido) acetyl ) -N- (4-nitrophenyl) pyrrolidine-2-carboxamide carboxamide;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidine-l- Yl) propoxy) -2-fluorobenzamide;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin- Yl) propoxy) -2-fluorobenzamide;
Yl) propoxy) -2,6-difluoro-N- (prop-2-yn-1-yl) piperidin- -Yl) benzamide;
(3-amino-3-oxopropyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin-4- yl) propoxy) Lt; / RTI &gt;
(2-amino-2-oxoethyl) -4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- Lt; / RTI &gt;
Yl) propoxy) -2,6-difluoro-N- (3- (2-oxopyrrolyl) 1-yl) propyl) benzamide;
(S) -1- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- yl) propoxy) -2,6- difluorobenzoyl) pyrrolidine -2-carboxamide;
(S) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2,6-difluorobenzamide;
(R) -N- (1-amino-1-oxopropan-2-yl) -4- (3- (1- (5-ethylpyrimidin- ) -2,6-difluorobenzamide;
(R) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluoro Benzamido) -5-oxopentanoate;
(R) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzene 5-oxopentanoic &lt; / RTI &gt;acid;
(S) -methyl 5-amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluoro Benzamido) -5-oxopentanoate;
(S) -5-Amino-2- (4- (3- (1- (5-ethylpyrimidin-2- yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzene 5-oxopentanoic &lt; / RTI &gt;acid;
N-allyl-4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide;
(S) -diethyl 2- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorobenzamide ) Pentane dianoate;
(S) -2- (4- (3- (1- (5-Ethylpyrimidin-2-yl) piperidin- 4- yl) propoxy) -2,6-difluorobenzamido) pentane Dioxy acid;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluoro-N- (2-oxopropyl) benzamide;
(S) -N- (1-amino-4-methyl-1-oxopentan-2-yl) -4- Yl) propoxy) -2, 6-difluorobenzamide;
4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4- Yl) propoxy) -2, 6-difluorobenzamide;
4-yl) propoxy) -2,6-difluoro-N- (4-oxocyclohexyl) benzamide ;
4-yl) propoxy) -2,6-difluoro-N- (3-oxocyclohexyl) benzamide ;
4-yl) propoxy) -2,6-difluoro-N- (2-oxocyclohexyl) benzamide ;
4-yl) propoxy) -2,6-difluoro-N- (2-oxocyclopentyl) benzamide ;
(Prop-2-yn-1-yl) piperidin-4-yl) propoxy) Benzamide;
4- (3- (l- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) -pyridin- Benzamide;
1- (7,7-Dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) -N- (4- (3- Piperidin-4-yl) propoxy) -2-fluorophenyl) methanesulfonamide;
Propoxy) -2-fluorophenyl) prop-2-en-1-sulfone Amide;
Methyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;
Pentyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;
Vinyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;
Allyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;
(5S) -2-isopropyl-5-methylcyclohexyl (4- (3- (1- (5-ethylpyrimidin- 2- yl) piperidin- 4- yl) propoxy) -2-fluoro Phenyl) carbamate;
Isobutyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2-fluorophenyl) carbamate;
1- (7,7-Dimethyl-2-oxobicyclo [2.2.1] heptan-1-yl) -N- (4- (3- Piperidin-4-yl) propoxy) -2, 6-difluorophenyl) methanesulfonamide;
N- (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) acrylamide;
Pentyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) carbamate;
Allyl (4- (3- (1- (5-ethylpyrimidin-2-yl) piperidin-4-yl) propoxy) -2,6-difluorophenyl) carbamate; And
N- (2-fluoro-4- (3- (1- (5-pentylpyrimidin-2-yl) piperidin-4-yl) propoxy) phenyl) acrylamide.
Reacting a compound of Formula 2 and a compound of Formula 7 to form a compound of Formula 3;
Introducing LG (leaving group) into the compound of Formula 3 to form a compound of Formula 4;
Reacting a compound of formula 4 and a compound of formula 8 and converting X 'to X to form a compound of formula 1:
(2)

(3)

[Chemical Formula 4]

(7)

[Chemical Formula 1]

[Chemical Formula 8]

In the above formulas, R ₁ to R ₃ and X are as defined for formula (1), and X is an amine group, a carboxyl group or an ester group in which a protecting group is introduced or not introduced; Z is halogen; LG is a leaving group.
10. The method of claim 9,
Wherein the step of forming the compound of Formula 3 proceeds in the presence of a base.
10. The method of claim 9,
Wherein the compound of Formula 4 is formed using at least one compound selected from the group consisting of methanesulfonyl chloride, carbon tetrabromide, and N-bromosuccinimide.
10. The method of claim 9,
Wherein X is -C (O) NHR ₄ or -C (O) -YC (O) NHR ₅ ;
X 'is an ester group of R ₁₆ -COO-;
The step of converting X 'into X may include the steps of: hydrolyzing the reaction products of Formulas 4 and 8 to form a compound of Formula 1-a; And
And amidating the carboxyl group of Formula 1-a.
[Chemical Formula 1-a]

In the above formula, R ₁ To R &lt; ₅ &gt; are as defined for formula (1);
R ₁₆ is selected from the group consisting of hydrogen, alkyl having 1 to 7 carbon atoms, alkenyl, alkynyl, and allyl.
. 10. The method of claim 9,
Wherein X is -NHC (O) R ₆ , or -NHS (O) ₂ R ₇ ;
X 'is a protected amine group of PG-NH-;
Converting the X 'to X is a step of deprotecting the reaction product of the above formulas (4) and (8) to form a compound of the formula (1-b); And
Reacting the amine group of Formula 1-b with at least one member selected from the group consisting of acid chloride, sulfonyl chloride, and chloroformate in the presence of a base.
[Chemical Formula 1-b]

In the above formula, R ₁ To R _{3 ,} R ₆ and R ₇ are as defined for formula 1;
PG is an amino protecting group.
14. The method of claim 13,
Wherein the deprotection is carried out in the presence of at least one member selected from the group consisting of trifluoroacetic acid (TFA), hydrochloric acid (HCl), and acetic acid.
A pharmaceutical composition for treating or preventing a metabolic disease comprising the compound of claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
16. The pharmaceutical composition according to claim 15, wherein the metabolic disease is selected from the group consisting of diabetes, obesity, hypertension, cardiovascular disease, hypercoagulability, and dyslipidemia.