KR20230164601A - Heterocyclic compound as diacrylglycerol kinases inhibitor and use thereof - Google Patents

Abstract

The present invention relates to a heterocyclic compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity, a pharmaceutical composition containing the same as an active ingredient, and its use.

Description

Heterocycle compounds and use thereof as diacylglycerol kinase inhibitors {HETEROCYCLIC COMPOUND AS DIACRYLGLYCEROL KINASES INHIBITOR AND USE THEREOF}

The present invention relates to a heterocyclic compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity, a pharmaceutical composition containing the same as an active ingredient, and its use.

Recently, anti-cancer immunotherapy, especially T-cell therapy, has been attracting attention as it has shown great effectiveness in some tumors such as malignant melanoma. However, a major obstacle that anti-cancer T-cell therapy must overcome is the phenomenon of tumor-induced T cell suppression (T cell therapy). Tolerance, T cell anergy) exists. In other words, even if a large number of anti-cancer T cells approach the tumor, the effect may be greatly halved because the tumor has a mechanism to disable the T cells. Therefore, understanding the mechanism of T cell inactivation by tumors and developing measures to prevent it can greatly improve the treatment efficiency of anticancer T cell therapy. To overcome this, the DGK enzyme is attracting great interest as an immune-anticancer target. It is overexpressed when T cells fall into anergy and plays a role in disabling the activity of T cells. Specifically, diacylglycerol kinases (DGKs) act as intracellular checkpoints through a reaction that converts diacylglycerol (DAG), an important factor in signal transduction, into phosphatidic acid (PA). When inhibited, accumulated DAG is known to enhance the TCR signaling pathway of T cells and reactivate anergic T cells, so synergy can be expected when used alone or in combination with anticancer immunotherapy drugs such as PD-(L)1. . In addition, DGK is overexpressed in various cancer cells and is known to cause cancer cell survival, migration, and drug resistance. Therefore, if a substance that inhibits DGK is developed, it can act as an immunotherapy agent such as T cell reactivation. Excellent anticancer efficacy can be expected through the dual pharmacological effect of simultaneously exhibiting cell death effects. Additionally, since DGK is known to be involved in not only T cell anergy but also NK cell anergy, the additional benefit of eliminating cancer cells by NK cells may be obtained when developing an inhibitor.

The purpose of the present invention is to provide a novel heterocycle compound represented by Formula 1 that exhibits diacylglycerol kinase inhibitor activity.

Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diacylglycerol kinase-related diseases, such as cancer, containing the above compound as an active ingredient.

Another object of the present invention is to provide a method for preventing or treating diacylglycerol kinase-related diseases, such as cancer, in a subject using the above compound as an active ingredient.

In order to achieve the above object, the present invention provides a compound of the following formula (1), or a pharmaceutically acceptable salt or stereoisomer thereof:

[Formula 1]

In Formula 1,

m represents 0, 1 or 2;

X represents N or CH;

R ₁ represents hydrogen, halo, cyano(-CN), alkyl, alkoxy or aryl unsubstituted or substituted with halo;

R ₂ represents hydrogen, halo, alkyl, alkylcarbonyl or alkoxycarbonyl;

R ₃ represents hydrogen or alkyl;

R ₄ represents alkyl;

R ₅ represents alkyl, and when m is 2, they can combine with each other to form a ring;

R ₆ is -C(=O)-R ₇ , -S(=O) ₂ -R ₇ , -C(=O)-alkylene-R ₇ , -OR ₇ , , -C(=O)-cycloalkylene-R ₇ , -alkylene-C(=O)-R ₇ , or -NH-C(=O)-R ₇ ; where R ₇ represents cycloalkyl, aryl, aralkyl, heterocycloalkyl or heterocyclyl; R ₈ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;

The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl include halo, cyano, oxo (=O), alkyl, alkoxy, haloalkyl, haloalkoxy, alkylcarbonyl, dialkylamino, aryl, aryloxy and unsubstituted. or may be optionally substituted with one or more substituents selected from the group consisting of heteroaryl substituted with halo;

The heterocycloalkyl, heterocyclyl and heteroaryl may have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms.

The compound of Formula 1 according to the present invention can form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; Organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc.; Acid addition salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid are included. Additionally, pharmaceutically acceptable carboxylic acid salts include, for example, alkali metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc.; Amino acid salts such as lysine, arginine, and guanidine; Organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. are included. The compound of formula 1 according to the present invention can be converted into its salt by conventional methods.

Meanwhile, the compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, and therefore may exist as E or Z isomers, R or S isomers, racemates, diastereomeric mixtures, and individual diastereomers. All these isomers and mixtures are included within the scope of the present invention.

In this specification, unless otherwise specified for convenience, the compound of Formula 1 is used to include the compound of Formula 1, pharmaceutically acceptable salts and stereoisomers thereof.

In defining the compound of Formula 1 throughout this specification, the following concepts defined for substituents are used.

Unless otherwise stated, the term “halo” used herein when used alone or in combination with additional terms (e.g., haloalkyl or haloalkoxy), fluorine (F), chlorine (Cl) , represents a radical that is bromine (Br) or iodine (I).

Unless otherwise stated, the term “cyano” herein means -CN.

Unless otherwise stated, the term “oxo” herein means =O.

Unless otherwise stated, the term "alkyl" herein, when used alone or in combination with additional terms (e.g. haloalkyl), refers to a straight-chain or branched alkyl group, e.g. It refers to a radical of a group of saturated aliphatic hydrocarbons having from 7 to 7 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, It includes, but is not limited to, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl.

Unless otherwise stated, the term “alkoxy” herein means alkyloxy, eg, alkyloxy having 1 to 7 carbon atoms.

Unless otherwise stated, the term “alkylene” herein means a radical of the group of divalent straight-chain or branched, saturated aliphatic hydrocarbons, e.g., having 1 to 5 carbon atoms.

Unless otherwise stated, the term “cycloalkyl” herein refers to a radical of the group of cyclic, saturated, aliphatic hydrocarbons having, for example, 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

Unless stated otherwise, the term “cycloalkylene” herein refers to a radical of the group of divalent cyclic, saturated, aliphatic hydrocarbons having, for example, 3 to 6 carbon atoms.

Unless otherwise stated, the term “heterocycloalkyl” herein includes one or more heteroatoms selected from N, O and S, preferably 1 to 3 heteroatoms selected from N and O as reducing elements and is entirely saturated. refers to hydrocarbons.

Unless otherwise stated, the term “aryl” herein refers to an aromatic hydrocarbon, for example, an aromatic hydrocarbon having 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, etc.

Unless otherwise stated, the term “heteroaryl” herein refers to an aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S as a reducing member, for example, a 5 to 10 membered aromatic hydrocarbon. Examples of heteroaryls include pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thiazolyl, Isothiazolyl, furanyl, benzofuranyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, quinolinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl, 3,4 -Dihydroisoquinolyl, thiazolopyridyl, 2,3-dihydrobenzofuran, 2,3-dihydrothiophene, 2,3-dihydroindole, benzo[1,3]dioxane, chroman, cy. Ochroman, 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]dioxin, 2,3-dihydrobenzo[1,4]dioxin, 6,7-dihydro-5H-cyclopenta [d] Pyrimidine, etc. are included, but are not limited thereto.

Unless otherwise stated, the term “heterocyclyl” herein refers to an unsaturated or partially saturated single or fused ring having one or more heteroatoms selected from N, O and S, for example 1 to 3 heteroatoms. It refers to hydrocarbons that form a ring. Specifically, the heterocyclyl may be a 5- to 12-membered hydrocarbon having 1 to 3 heteroatoms. The unsaturated heterocyclyl may include an aromatic hydrocarbon such as heteroaryl.

According to one embodiment of the present invention, in Formula 1

m represents 0, 1 or 2;

X represents N or CH;

R ₁ represents hydrogen, halo, cyano, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy or C ₆ -C ₁₀ aryl unsubstituted or substituted with halo;

R ₂ represents hydrogen, halo, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkylcarbonyl or C ₁ -C ₇ alkoxycarbonyl;

R ₃ represents hydrogen or C ₁ -C ₇ alkyl;

R ₄ represents C ₁ -C ₇ alkyl;

R ₅ represents C ₁ -C ₇ alkyl, and when m is 2, they may combine with each other to form a C ₂ -C ₄ ring;

R ₆ is -C(=O)-R ₇ , -S(=O) ₂ -R ₇ , -C(=O)-C ₁ -C ₅ alkylene-R ₇ , -OR ₇ , , -C(=O)-C ₃ -C ₆ cycloalkylene-R ₇ , -C ₁ -C ₅ alkylene-C(=O)-R ₇ , or -NH-C(=O)-R ₇ ; Here, R ₇ is 5 to 3 heteroatoms selected from C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₇ alkyl, N and O. represents a 10-membered heterocycloalkyl, or a 5- to 12-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S; R ₈ represents hydrogen, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkyl-C ₁ -C ₇ alkyl;

The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl are unsubstituted or halo, cyano, oxo, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, halo-C ₁ -C ₇ alkyl, halo-C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkylcarbonyl, di(C ₁ -C ₇ alkyl)amino, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy and unsubstituted or halo substituted N and It may be substituted with 1 to 3 substituents selected from the group consisting of 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from O.

Representative compounds of Formula 1 according to the present invention may include, but are not limited to, the following compounds:

1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;

1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;

1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;

4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;

1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;

1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2 ,3-b]pyrazine-6-carbonitrile;

7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;

7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;

7-chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetra Hydropyrido[2,3-b]pyrazine-6-carbonitrile;

7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;

7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethoxy)phenyl)piperidine-1-carboxamide;

7-Chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;

7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyri do[2,3-b]pyrazine-2,3-dione;

7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;

7-Chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;

7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;

7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;

4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-yl)sulfonyl)benzonitrile;

4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -carbonyl)benzonitrile;

4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;

7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-carbonyl)piperidin-4-yl)-1-methyl-1,4-di hydropyrido[2,3-b]pyrazine-2,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethyl)phenyl)piperidine-1-carboxamide;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorophenyl ) piperidine-1-carboxamide;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-cyano phenyl)piperidine-1-carboxamide;

7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;

7-Chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;

7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;

7-Chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;

7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;

4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi din-1-yl)acetyl)benzonitrile;

7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione;

7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;

7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;

7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4- Dihydropyrido[2,3-b]pyrazine-2,3-dione;

7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;

7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2, 3-b]pyrazine-2,3-dione;

7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;

4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;

7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;

7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;

7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;

7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione;

7-chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl) -1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione hydrochloride;

N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl )Cyclohexyl)-4-(trifluoromethoxy)benzamide;

7-Chloro-4-(1-(5-chloropyrimidinee-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;

7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 -Dion;

7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;

4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;

6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;

7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;

4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;

6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;

7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;

7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;

7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(3-chlorophenyl ) piperidine-1-carboxamide;

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorobenzyl ) piperidine-1-carboxamide;

1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;

7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;

6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;

7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;

Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[ 2,3-b]pyrazine-7-carboxylate;

1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione; and

7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione.

Terms and abbreviations used in this specification have their original meanings unless otherwise defined.

Hereinafter, to facilitate understanding of the present invention, a method for preparing the compound of Formula 1 will be described based on an exemplary reaction scheme. However, those skilled in the art to which the present invention pertains can prepare the compound of Formula 1 by various methods based on the structure of Formula 1, and all of these methods should be interpreted as falling within the scope of the present invention. do. That is, the compound of Formula 1 can be prepared by arbitrarily combining various synthetic methods described in this specification or disclosed in the prior art, and this is understood to be within the scope of the present invention, and the method for producing the compound of Formula 1 is described below. It is not limited.

For example, the compound of Formula 1 can be prepared according to the following Schemes 1 to 5.

[Scheme 1]

[Scheme 2]

[Scheme 3]

[Scheme 4]

[Scheme 5]

In Schemes 1 to 5, R ₁ to R ₆ are as defined herein.

The compound of Formula 1 according to the present invention has diacylglycerol kinases (DGKs) inhibitor activity. Accordingly, the present invention provides a pharmaceutical composition for the prevention or treatment of diseases related to diacylglycerol kinase, comprising the compound of Formula 1, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier. do.

In one embodiment according to the present invention, the diacylglycerol kinase-related disease is cancer. Examples of cancer that can be prevented or treated with the pharmaceutical composition according to the present invention include gastrointestinal cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain tumor, testicular cancer, laryngeal cancer, and prostate cancer. Cancer includes, but is not limited to, neuroblastoma, kidney cancer, thyroid cancer, esophageal cancer, skin cancer, osteosarcoma, and bladder cancer.

In the present invention, “pharmaceutical composition” may include other chemical components such as carriers, diluents, excipients, etc. in addition to the active compound according to the present invention. Accordingly, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof, if necessary. Pharmaceutical compositions facilitate administration of the active compound into an organism. There are a variety of techniques for administering compounds, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.

As used herein, “carrier” refers to a compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism.

As used herein, “diluent” is defined as a compound diluted in water that not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer is phosphate buffered saline, which mimics the salt form of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for buffer diluents to modify the biological activity of a compound.

As used herein, “pharmaceutically acceptable” means a property that does not impair the biological activity and physical properties of a compound.

The compounds of the present invention can be formulated into various pharmaceutical dosage forms depending on the purpose. When preparing a pharmaceutical composition according to the present invention, the active ingredient, specifically the compound of Formula 1, a pharmaceutically acceptable salt or stereoisomer thereof, is mixed with various pharmaceutically acceptable salts or stereoisomers that can be selected depending on the formulation to be prepared. Mix with the carrier. For example, the pharmaceutical composition according to the present invention may be formulated into an injectable formulation, an oral formulation, etc., depending on the purpose.

The compounds of the present invention can be formulated by known methods using known pharmaceutical carriers and excipients and placed in unit dosage form or multi-dose containers. The form of the preparation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium and may contain customary dispersing, suspending or stabilizing agents. Additionally, for example, it may be in the form of a dry powder that is dissolved in sterile, pyrogen-free water before use. The compounds of the present invention may also be formulated in suppository form using conventional suppository bases such as cocoa butter or other glycerides. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules, and capsules and tablets are particularly useful. Tablets and pills are preferably manufactured as enteric coating agents. Solid dosage forms can be prepared by mixing the compounds of the present invention with one or more inert diluents such as sucrose, lactose, starch, etc. and carriers such as lubricants such as magnesium stearate, disintegrants, binders, etc.

If necessary, the compound according to the present invention or a pharmaceutical composition containing the same can be administered in combination with other drugs, for example, other anticancer immunotherapy agents.

The dosage of the compound of formula 1 of the present invention is determined according to the doctor's prescription depending on factors such as the patient's weight, age, and the specific nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 0.3 to 500 mg per day, depending on the frequency and intensity of administration. When administered intramuscularly or intravenously to adults, a total dose of approximately 1 to 300 mg per day, divided into single doses, will usually be sufficient, although higher daily doses may be desirable for some patients.

As used herein, “treatment” means stopping, delaying, or alleviating the progression of a disease when used in a subject showing symptoms of the disease.

The heterocycle compound represented by Formula 1 according to the present invention can be usefully used for the prevention or treatment of diseases related to diacylglycerol kinases, such as cancer, by inhibiting diacylglycerol kinases (DGKs).

The present invention will be described in more detail below through preparation examples and examples. However, these examples are only illustrative of the present invention, and the scope of the present invention is not limited thereto.

An explanation of the abbreviations and terms used in the following preparation examples and examples is as follows:

ACN: Acetonitrile

DCE: dichloroethane

DCM: dichloromethane

DIAD: diisopropyl azodicarboxylate

DIPEA: N,N-diisopropylethylamine

DMAP: Dimethylaminopyridine

DMF: N,N-dimethylformamide

EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EtOAc: ethyl acetate

EtOH: Ethanol

Et ₃ N: triethylamine

HATU: Hexafluorophosphate Azabenzotriazole Tetramethyl Euronium

HOBt: Hydroxybenzotriazole

IPA: Isopropyl Alcohol

MeOH: methanol

MPLC: medium pressure liquid chromatography

NaH: sodium hydride

NBS: N-bromosuccinimide

NCS: N-chlorosuccinimide

Pd ₂ (dba) ₃ : Tris(dibenzylideneacetone)dipalladium (0)

(PPh ₄ ) ₄ Pd: tetrakis(triphenylphosphine)palladium (0)

TBSCl: tert-butyldimethylsilyl chloride

TEA: triethylamine

THF: tetrahydrofuran

TLC: thin layer chromatography

Xantphos: (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane)

Preparation Example 1: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Dissolve tert-butyl 4-amidopiperidine-1-carboxylate (1.00 g, 5.00 mmol) and 2-fluoro-3-nitropyridine (0.71 g, 5.00 mmol) in DMF (15 ml) and add dia. Isopropylamine (1.75 mL, 10.00 mmol) was added and stirred at 60°C for 4 hours. The reaction was cooled to room temperature, diluted with EtOAc, washed twice with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.53 g).

¹ H-NMR (500 MHz, CHLOROFORM-D) δ 8.46~8.41 (m, 2H), 8.19 (dd, 1H), 6.68 (dd, 1H), 4.41~4.38 (m, 1H), 4.09 (br s, 2H), 3.03 (br s, 2H), 2.11~2.07 (m, 2H), 1.55~1.53 (m, 2H), 1.50 (s, 9H)

LC/MS: 267 (M+H-t-Bu)

Step B: Preparation of tert-butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.50 g, 1.55 mmol) was dissolved in MeOH (10 mL) and then dissolved in Zn (2) at 0°C. 24 g, 34.4 mmol) and ammonium chloride (0.92 g, 17.14 mmol) were slowly added and stirred under reflux at 70°C for 20 hours. After completion of the reaction, the mixture was cooled to room temperature, filtered through a Celite pad, and concentrated under reduced pressure. The mixture was diluted with DCM and extracted using saturated aqueous NaHCO ₃ solution. The organic layer was dried using anhydrous MgSO ₄ and then distilled under reduced pressure to obtain the title compound (440 mg).

LC/MS: 293 (M+H)

Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)pyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate (130 mg, 0.18 mmol) and diisopropylamine (0.23 mL, 1.33 mmol) were dissolved in dichloromethane ( After dissolving in 10 mL), ethyl oxalyl chloride (0.075 mL, 0.67 mmol) was added at 0°C and stirred at room temperature for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound (146 mg), which was used directly in the next reaction without purification.

LC/MS: 393 (M+H)

Step D: of tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate manufacturing

Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)pyridin-2-yl)amino)piperidine-1-carboxylate (70 mg, 0.18 mmol) was dissolved in EtOH (6 mL) and then added sodium ethoxide (0.35 mL, 0.89 mmol, 20 wt% in EtOH) and stirred at 70°C for 0.5 hours. The reaction was cooled to room temperature, diluted with water, acidified to pH 5 with 1 N HCl, and extracted twice with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (42 mg), which was used directly in the next reaction without purification.

LC/MS: 347 (M+H), 369 (M+Na)

Step E: Tert-Butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

Tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (42 mg, 0.12 mmol) was dissolved in DMF (5 mL), cesium carbonate (158 mg, 0.49 mmol) and idomethane (0.011 mL, 0.18 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. The reaction was diluted with water and extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by Preparatory TLC to obtain the title compound (19 mg).

¹ H-NMR (500 MHz, CHLOROFORM-D) δ 8.27~8.26 (m, 1H), 7.53~7.51 (m, 1H), 7.25~7.23 (m, 1H), 5.58 (s, 1H), 4.29 (br s, 2H), 3.64 (s, 3H), 2.91~2.87 (m, 4H), 1.65 (br s, 2H), 1.51 (s, 9H)

LC/MS: 383 (M+Na)

Step F: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (19 mg, 0.053 mmol) was dissolved in dichloromethane (4 mL), HCl (0.26 mL, 1.05 mmol, 4 M in 1,4-dioxane) was added, and the mixture was stirred at room temperature for 16 hours. The mixture was distilled under reduced pressure and extracted using 10% MeOH/DCM (v/v) solution and 0.3 N NaOH aqueous solution. The organic layer was dried using anhydrous MgSO ₄ and then distilled under reduced pressure to obtain the title compound (18 mg).

LC/MS: 261 (M+H)

Preparation Example 2: Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

The title compound (1.61 g) was obtained by using 2-fluoro-6-methyl-3-nitropyridine (0.781 g, 5.00 mmol) in the same manner as Step A of Preparation Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.31 (d, J = 8.5 Hz, 1H), 8.24 (d, J = 7.0 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.45- 4.40 (m, 1H), 4.07 (s, 2H), 3.07-3.02 (m, 2H), 2.48 (s, 3H), 2.08 (d, J = 10.4 Hz, 2H), 1.58-1.52 (m, 2H) , 1.50 (s, 9H)

LC/MS: 337 (M+H)

Step B: Preparation of 6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (800 mg, 2.38 mmol) was prepared in the same manner as Step B of Preparation Example 1. The title compound (720 mg) was obtained.

LC/MS: 307 (M+H), 329 (M+Na)

Step C: Tert-Butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate

6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (720 mg, 2.35 mmol) was prepared in the same manner as Step C of Preparation Example 1. The title compound (898 mg) was obtained using

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.43 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.28 (s, 2H), 6.53 (d, J = 7.9 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.28 (d, J = 7.0 Hz, 1H), 4.18-4.12 (m, 2H), 4.06 (s, 1H), 2.98 (t, J = 11.3 Hz, 2H) ), 2.41 (s, 4H), 2.09-2.05 (m, 4H), 1.49 (s, 9H)

LC/MS: 408 (M+H).

Step D: Tert-Butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (898 mg, 2.21 mmol) The title compound (781 mg) was obtained using the same method as Step D of Preparation Example 1.

LC/MS: 383 (M+Na), 743 (2M+Na)

Step E: Tert-Butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate

Tert-Butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (660 mg, 1.83 mmol) was obtained using the same method as Step E of Preparation Example 1 to obtain the title compound (322 mg).

1H-NMR (500 MHz, DMSO-D6) δ 7.71 (d, J = 8.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 5.47 (s, 1H), 4.09 (s, 2H), 3.50-3.43 (m, 3H), 2.85 (s, 1H), 2.66-2.60 (m, 2H), 2.48-2.35 (m, 4H), 1.60 (d, J = 9.5 Hz, 2H), 1.50-1.24 ( m, 9H)

LC/MS: 375 (M+H)

Step F: Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Carboxylate (300 mg, 0.83 mmol) was reacted using the same method as Step F of Preparation Example 1 to obtain the title compound (256 mg).

LC/MS: 275 (M+H)

Preparation Example 3: 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6- Manufacture of carbonitrile

Step A: Preparation of tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Preparation Example 1 using tert-butyl 4-amidopiperidine-1-carboxylate (4.21 g, 21.0 mmol) and 2,6-dichloro-3-nitropyridine (4.20 g, 20.0 mmol) The title compound (6.21 g) was obtained in the same manner as A.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.37 (d, J = 8.5 Hz, 1H), 8.30 (d, J = 7.5 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 4.37~ 4.33 (m, 1H), 4.09 (br s, 2H), 3.04 (br s, 2H), 2.08 (d, J = 10.0 Hz, 2H), 1.57-1.52 (m, 2H), 1.50 (s, 9H)

LC/MS: 379 (M+Na)

Step B: Preparation of tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (2.0 g, 5.61 mmol), Zn(CN) ₂ (0.987 g, 8.41 mmol), (PPh ₄ ) ₄ Pd (0.648 g, 0.561 mmol) was dissolved in DMF (50 mL) and stirred at 100°C for 1 hour. The reaction was cooled to room temperature, diluted with EtOAc, and washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.84 g).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.55 (d, J = 8.5 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 4.39~ 4.33 (m, 1H), 4.17~4.12 (m, 2H), 3.06~3.01 (m, 2H), 2.10~2.08 (m, 2H), 1.57-1.52 (m, 2H), 1.51 (s, 9H)

LC/MS: 370 (M+Na)

Step C: of tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate manufacturing

After dissolving tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.04 g, 2.99 mmol) in THF (34 mL), 0 NaH (179 mg, 4.48 mmol, 60% in dispersion oil) was slowly added at ℃ and stirred for 30 minutes. Ethyl oxalyl chloride (0.66 mL, 5.97 mmol) was added to the reaction at 0°C and stirred at room temperature for 1 hour. The reaction was terminated by slowly adding water to the reaction product, diluted with EtOAc, and washed with 0.5 N aqueous NaOH solution, aqueous sodium bicarbonate solution, and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.02 g).

LC/MS: 470 (M+Na)

Step D: Tert-Butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1 -Manufacture of carboxylates

tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.51 g, 1.14 mmol) was dissolved in EtOH (10 mL), water (10 mL), iron (0.77 g, 13.9 mmol), and ammonium chloride (1.35 g, 25 mmol) were added at room temperature and stirred at 70°C for 4 hours. . The reaction product was cooled to room temperature, filtered under reduced pressure with Celite, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound (0.39 g), which was used directly in the next reaction without purification.

LC/MS: 394 (M+Na)

Step E: tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate

Tert-Butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl Rate (0.388 g, 1.045 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.368 g).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 5.50~5.47 (m, 1H), 4.37~4.29 (m , 2H), 3.67 (s, 3H), 2.91 (m, 2H), 2.84~2.80 (m, 2H), 1.68-1.65 (m, 2H), 1.53 (s, 9H)

LC/MS: 408 (M+Na)

Step F: 1-Methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-car Manufacturing of Bonitrile

tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-Carboxylate (0.300 g, 0.778 mmol) was prepared in the same manner as Step F of Preparation Example 1 to obtain the title compound (250 mg).

LC/MS: 286 (M+H), 308 (M+Na)

Preparation Example 4: Preparation of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Preparation Example 1 using tert-butyl 4-amidopiperidine-1-carboxylate (5.96 g, 29.7 mmol) and 5-chloro-2-fluoro-3-nitropyridine (5.00 g, 28.3 mmol) The title compound (10.0 g) was obtained in the same manner as step A.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.40 (d, J = 2.3 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H), 4.30 ( tt, J = 10.7, 3.5 Hz, 1H), 4.18-3.95 (m, 2H), 2.98 (t, J = 12.1 Hz, 2H), 2.05 (d, J = 10.5 Hz, 2H), 1.53-1.48 (2H) ), 1.46 (s, 9H)

LC/MS: 357 (M+H), 379 (M+Na)

Step B: Preparation of tert-butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetoamido)piperidine-1-carboxylate

The same as step C of Preparation Example 3 using tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (3.20 g, 8.97 mmol) The title compound (1.32 g) was obtained through this method.

LC/MS: 479 (M+Na)

Step C: Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

Tert-butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetoamido)piperidine-1-carboxylate (1.90 g, 4.16 mmol) ) was used to obtain the title compound (1.28 g) in the same manner as Step D of Preparation Example 3.

LC/MS: 325 (M+H-t-Bu)

Step D: Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate

Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (1.28 g, 3.36 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (1.08 g).

LC/MS: 417 (M+Na)

Step E: Preparation of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Carboxylate (1.08 g, 2.74 mmol) was prepared using the same method as Step F of Preparation Example 1 to obtain the title compound (1,000 mg).

1H-NMR (400 MHz, METHANOL-D4) δ 8.23 (d, J = 1.8 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 5.72 (t, J = 11.7 Hz, 1H), 3.59 ( s, 4H), 3.54 (d, J = 12.3 Hz, 2H), 3.22-3.02 (m, 3H), 1.97 (d, J = 15.6 Hz, 2H)

LC/MS: 295 (M+H)

Preparation Example 5: 7-Chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 -Manufacture of dione

Step A: Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate

Tert-butyl 4-amido-3,3-dimethylpiperidine-1-carboxylate (0.951 g, 4.16 mmol) and 5-chloro-2-fluoro-3-nitropyridine (0.700 g, 3.97 mmol) The title compound (1.36 g) was obtained in the same manner as Step A of Preparation Example 1 using mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.44 (d, J = 2.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 8.28 (d, J = 8.5 Hz, 1H), 4.36~ 4.31 (m, 1H), 4.19~4.06 (m, 1H), 3.88~3.76 (m, 1H), 2.95 (br s, 1H), 2.78~2.74 (m, 1H), 1.84 (br s, 1H), 1.68-1.61 (m, 1H), 1.50 (s, 9H), 1.04 (s, 3H), 0.96 (s, 3H)

LC/MS: 407 (M+Na)

Step B: Tert-Butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine- Preparation of 1-carboxylate

Prepared using tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (1.01 g, 2.62 mmol) The title compound (0.120 g) was obtained in the same manner as Step C of Example 3.

LC/MS: 507 (M+Na)

Step C: Tert-Butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3-di Preparation of methylpiperidine-1-carboxylate

Tert-Butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine-1-car The title compound (0.161 g) was obtained in the same manner as Step D of Preparation Example 3 using boxylate (0.23 g, 0.474 mmol), and was used directly in the next reaction without purification.

LC/MS: 431 (M+Na)

Step D: Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3 , Preparation of 3-dimethylpiperidine-1-carboxylate

Tert-butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3-dimethylpiperi Dean-1-carboxylate (0.161 g, 0.394 mmol) was obtained using the same method as Step E of Preparation Example 1, and the residue was purified by MPLC to obtain the title compound (0.100 g).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.48 (dd, J = 7.5, 2.0 Hz, 1H), 5.68~5.32 (2 dd, 1H), 4.42~ 4.29 (m, 1H), 3.96~3.81 (m, 1H), 3.64 (s, 3H), 3.49~3.37 (m, 1H), 2.84~2.74 (m, 2H), 1.58~1.52 (m, 1H), 1.50 (s, 9H), 1.12~1.05 (2 s, 3H), 0.94~0.83 (2 s, 3H)

LC/MS: 445 (M+Na)

Step E: 7-Chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Manufacturing of dione

Tert-Butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-3,3- The title compound (0.094 g) was obtained from dimethylpiperidine-1-carboxylate (0.100 g, 0.236 mmol) using the same method as Step F of Preparation Example 1, and was used directly in the next reaction without purification.

LC/MS: 323 (M+H)

Preparation Example 6: 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,Manufacture of 3-dione

Step A: tert-butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-car Preparation of boxylate

5-Chloro-2-fluoro-3-nitropyridine (5.00 g, 28.3 mmol) and tert-butyl (1R,3s,5S)-3-amino-8-azabicyclo[3.2.1]octane-8 -Carboxylate (6.41 g, 28.30 mmol) was prepared using the same method as Step A of Preparation Example 1 to obtain the title compound (10.71 g).

1H-NMR (500 MHz, DMSO-D6) δ 8.67 (d, J = 6.7 Hz, 1H), 8.56 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.4 Hz, 1H), 4.44 ( q, J = 6.4 Hz, 1H), 4.13 (s, 2H), 2.15 (d, J = 12.2 Hz, 2H), 1.98 (s, 4H), 1.82 (d, J = 13.7 Hz, 2H), 1.43 ( s, 9H)

LC/MS: 405 (M+Na)

Step B: Tert-Butyl (1R,3s,5S)-3-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-8- Preparation of azabicyclo[3.2.1]octane-8-carboxylate

tert-Butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate ( The title compound (1.17 g) was obtained using the same method as Step C of Preparation Example 3 (3.20 g, 8.36 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.68 (s, 1H), 8.36 (d, J = 2.4 Hz, 1H), 4.29 (d, J = 29.6 Hz, 2H), 4.16-4.12 (m, 2H) ), 3.94 (t, J = 8.5 Hz, 1H), 2.56 (d, J = 27.2 Hz, 1H), 1.98 (s, 2H), 1.72-1.65 (m, 3H), 1.52-1.49 (m, 1H) , 1.46 (s, 9H), 1.33-1.24 (m, 4H)

LC/MS: 483 (M+H), 505 (M+Na)

Step C: tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) Preparation of -8-azabicyclo[3.2.1]octane-8-carboxylate

tert-butyl (1R,3s,5S)-3-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-8-azabicyclo [3.2.1] Octane-8-carboxylate (1.17 g, 2.42 mmol) was prepared using the same method as Step D of Preparation Example 3 to obtain the title compound (0.77 g).

1H-NMR (500 MHz, DMSO-D6) δ 12.14 (br s, 1H), 8.14 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 5.27 (q, J = 9.6 Hz, 1H), 4.22 (d, J = 34.2 Hz, 2H), 2.26-2.18 (m, 4H), 1.95 (d, J = 39.7 Hz, 2H), 1.85 (s, 2H), 1.47 (s, 9H)

LC/MS: 407 (M+H)

Step D: tert-butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4 Preparation of (1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)- 8-azabicyclo[3.2.1]octane e-8-carboxylate (0.72 g, 1.78 mmol) was prepared using the same method as Step E of Preparation Example 1 to obtain the title compound (0.75 g).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 2.1 Hz, 1H), 5.59-5.51 (m, 1H), 4.36 (d, J = 58.0 Hz, 1H), 3.64 (s, 3H), 2.37 (m, 3H), 2.27-2.19 (m, 2H), 2.12-1.98 (m, 4H), 1.56 (s, 9H)

LC/MS: 443 (M+Na)

Step E: 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, Preparation of 3-dione

Tert-Butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H) -I)-8-azabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.40 mmol) was prepared using the same method as Step F of Preparation Example 1 to obtain the title compound (440 mg). .

LC/MS: 321 (M+H)

Preparation Example 7: Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

The title compound (1.80 g) was synthesized in the same manner as Step A of Preparation Example 1 using 2-chloro-6-methoxy-3-nitropyridine (1.00 g, 5.30 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.66 (d, J = 7.0 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 6.09 (d, J = 9.2 Hz, 1H), 4.33- 4.26 (m, 1H), 4.07 (br s, 2H), 3.97 (s, 3H), 3.04 (t, J = 11.3 Hz, 2H), 2.09 (d, J = 10.1 Hz, 2H), 1.62-1.57 ( m, 2H), 1.50 (s, 9H)

LC/MS: 375 (M+Na)

Step B: Preparation of tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate

Step B of Preparation Example 1 using tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.80 g, 5.11 mmol) The title compound (1.65 g) was obtained in a similar manner and used directly in the next reaction without purification.

LC/MS: 345 (M+Na)

Step C: Tert-Butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates

Tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.21 g, 3.72 mmol) was dissolved in DCE (50 mL). Ethyl 2-chloro-2-oxoacetate (0.625 mL, 5.60 mmol) and DIPEA (1.95 mL, 2.57 mmol) were added and stirred at room temperature for 12 hours and then at 70°C for 2 days. The reaction was terminated by adding water to the reactant, and then extracted three times with DCM. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (750 mg), which was immediately used in the next reaction.

LC/MS: 399 (M+Na)

Step D: tert-butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate

Tert-Butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl The title compound (600 mg) was synthesized in a manner similar to Step E of Preparation Example 1 using 750 mg, 3.72 mmol.

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.50 (d, J = 8.9 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 5.49-5.44 (m, 1H), 4.33 (d, J = 61.0 Hz, 2H), 3.94 (s, 3H), 3.63 (s, 3H), 2.99-2.82 (m, 4H), 1.71 (d, J = 10.1 Hz, 2H), 1.49 (s, 9H)

LC/MS: 335 (M+Na-tBu), 413 (M+Na)

Step E: Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- The title compound (450 mg) was obtained in a manner similar to Step F of Preparation Example 1 using 1-carboxylate (600 mg, 1.54 mmol).

LC/MS: 291 (M+H)

Preparation Example 8: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

The title compound (3.32 g) was synthesized in the same manner as Step A of Preparation Example 1 using 2-fluoro-4-methyl-3-nitropyridine (1.56 g, 9.99 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 4.31~ 4.28 (m, 1H), 4.06 (br s, 2H), 3.04~2.99 (m, 2H), 2.56 (s, 3H), 2.08~2.06 (m, 2H), 1.52 (s, 9H), 1.51~1.44 (m, 2H)

LC/MS: 337 (M+H)

Step B: Preparation of tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Similar to step B of Preparation Example 1 using tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.46 mmol) The title compound (1.35 g) was obtained by this method, and was used directly in the next reaction without purification.

LC/MS: 307 (M+H)

Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Similar method to Step C of Preparation Example 1 using tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (1.35 g, 4.41 mmol) The title compound (1.67 g) was obtained.

LC/MS: 407 (M+H)

Step D: Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (930 mg, 2.29 mmol) The title compound (34 mg) was obtained in a similar manner to Step D of Preparation Example 1.

LC/MS: 305 (M+H-t-Bu)

Step E: Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate

Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate The title compound (35 mg) was synthesized in a similar manner to Step E of Preparation Example 1 using (34 mg, 0.094 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 5.74 (br s, 1H), 4.31~4.22 (m, 2H), 4.13 (s, 3H), 2.96~2.94 (m, 4H), 2.61 (s, 3H), 1.65~1.62 (m, 2H), 1.52 (s, 9H)

LC/MS: 397 (M+Na)

Step F: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- The title compound (29 mg) was synthesized in a manner similar to Step F of Preparation Example 1 using carboxylate (35 mg, 0.093 mmol).

LC/MS: 275 (M+H)

Preparation Example 9: 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione manufacturing

Step A: Preparation of tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

2,6-Difluoro-3-nitropyridine (2 g, 12.49 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.502 g, 12.49 mmol) were dissolved in IPA, and DIPEA ( 4.36 ml, 24.99 mmol) was added and stirred at 70°C for 4 hours. The reaction product was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (3.78 g) using MPLC.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.28 (d, J = 9.1 Hz, 1H), 6.00 (d, J = 9.1 Hz, 1H), 5.25 (t, J = 6.2 Hz, 1H), 3.85- 4.45 (4H), 3.01 (s, 2H), 2.03 (q, J = 4.1 Hz, 2H), 1.46 (s, 9H), 1.35 (d, 6H)

LC/MS: 381 (M+H)

Step B: Preparation of tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate

Step B of Preparation Example 1 using tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (3.76 g, 9.87 mmol) The title compound (1.07 g) was synthesized in a similar manner.

1H-NMR (400 MHz, CHLOROFORM-D) δ 6.87 (d, J = 7.8 Hz, 1H), 5.87 (d, J = 8.2 Hz, 1H), 5.07-5.00 (m, 1H), 4.29 (s, 1H) ), 4.00 (d, J = 10.5 Hz, 3H), 2.94 (t, J = 11.4 Hz, 2H), 2.74 (s, 1H), 2.06 (q, J = 4.1 Hz, 2H), 1.46 (s, 9H) ), 1.38 (d, J = 9.1 Hz, 2H), 1.34-1.30 (m, 6H)

LC/MS: 351 (M+H)

Step C: Tert-Butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- Preparation of 1-carboxylate

Step C of Preparation Example 7 using tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.07 g, 3.05 mmol) The title compound (1.2 g) was synthesized in a similar manner.

LC/MS: 405 (M+H)

Step D: Tert-Butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) Preparation of piperidine-1-carboxylate

Tert-Butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-car The title compound (870 mg) was synthesized in a manner similar to Step E of Preparation Example 1 using boxylate (1.256 g, 3.11 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.48 (d, J = 8.9 Hz, 1H), 6.64-6.62 (m, 1H), 5.43 (s, 1H), 5.17-5.13 (m, 1H), 4.29 (d, J = 29.3 Hz, 2H), 3.62 (s, 3H), 2.89 (d, J = 11.0 Hz, 4H), 1.67 (d, J = 20.8 Hz, 2H), 1.51 (s, 9H), 1.40 (d, J = 6.1 Hz, 6H)

LC/MS: 419 (M+H)

Step E: Preparation of 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine The title compound (668 mg) was synthesized in a manner similar to Step F of Preparation Example 1 using -1-carboxylate (870 mg, 2.079 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 7.44 (d, J = 8.7 Hz, 1H), 6.59 (dd, J = 8.7, 0.9 Hz, 1H), 5.41 (d, J = 7.8 Hz, 1H), 5.18 (q, J = 6.1 Hz, 1H), 3.69 (d, J = 0.9 Hz, 2H), 3.59 (s, 3H), 3.27 (d, J = 10.1 Hz, 2H), 2.80-2.70 (m, 4H) ), 1.67 (d, J = 9.6 Hz, 2H), 1.40-1.39 (m, 6H)

LC/MS: 319 (M+H)

Preparation Example 10: Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Preparation Example 1 using 2,6-difluoro-3-nitropyridine (2 g, 12.49 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.502 g, 12.49 mmol) The title compound (4.2 g) was synthesized in a manner similar to Step A.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.35 (d, J = 3.2 Hz, 1H), 8.18 (dd, J = 8.0, 3.0 Hz, 1H), 8.02 (d, J = 6.9 Hz, 1H), 4.31-4.27 (m, 1H), 4.05 (d, J = 11.0 Hz, 2H), 2.98 (t, J = 11.9 Hz, 2H), 2.04 (d, J = 10.5 Hz, 2H), 1.52-1.49 (m , 2H), 1.46 (s, 9H)

LC/MS: 341 (M+H)

Step B: Preparation of tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate

Step B of Preparation Example 1 using tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.2 g, 12.34 mmol) The title compound (2.67 g) was synthesized in a similar manner.

1H-NMR (400 MHz, CHLOROFORM-D) δ 7.56 (d, J = 2.7 Hz, 1H), 6.67 (dd, J = 8.9, 2.5 Hz, 1H), 4.00 (d, J = 11.9 Hz, 2H), 3.70 (s, 1H), 3.32 (s, 2H), 2.94 (t, J = 12.1 Hz, 2H), 2.08-2.03 (m, 2H), 1.45 (s, 9H), 1.35-1.29 (m, 2H)

LC/MS: 311 (M+H)

Step C: Tert-Butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates

Similar to Step C of Preparation Example 7 using tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate (2.67 g, 8.60 mmol) The title compound (3.0 g) was synthesized using this method.

LC/MS: 365 (M+H)

Step D: tert-butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate

Tert-Butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl The title compound (1.92 g) was synthesized in a manner similar to Step E of Preparation Example 1 using nitrate (3 g, 8.23 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.09 (d, J = 2.7 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 5.46 (s, 1H), 4.28 (s, 2H), 3.59 (s, 3H), 2.88-2.80 (m, 4H), 1.62 (s, 2H), 1.47 (d, J = 15.1 Hz, 9H)

LC/MS: 379 (M+H)

Step E: Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- The title compound (1.27 g) was synthesized in a similar manner to Step F of Preparation Example 1 using 1-carboxylate (1.915 g, 5.06 mmol).

LC/MS: 279 (M+H)

Preparation Example 11: Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7 -Manufacture of carboxylates

Step A: Preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate

The title compound (17.56 g, 98%) was synthesized in the same manner as Step A of Preparation Example 1 using methyl 6-chloro-5-nicotinate (10.00 g, 46.20 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 9.01 (d, J = 10.1 Hz, 2H), 8.47 (d, J = 7.0 Hz, 1H), 4.47 (br s, 1H), 4.12 (br s, 2H) ), 3.95 (s, 3H), 3.03 (t, J = 11.1 Hz, 2H), 2.10 (d, J = 12.2 Hz, 2H), 1.61-1.51 (m, 2H), 1.50 (s, 9H)

LC/MS: 325 (M-tBu+2H), 403.2 (M+Na)

Step B: Preparation of methyl 5-amino-6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)nicotinate

Similar to step B of Preparation Example 1 using methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate (17.20 g, 45.20 mmol) This method gave the title compound (15.84 g, 99%).

LC/MS: 351 (M+H)

Step C: Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3- b]Preparation of pyrazine-7-carboxylate

Similar to Step C of Preparation Example 7 using methyl 5-amino-6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)nicotinate (15.84 g, 45.20 mmol) The title compound (8.50 g, 46%) was synthesized using this method.

LC/MS: 427 (M+Na)

Step D: Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[ Preparation of 2,3-b]pyrazine-7-carboxylate

Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine The title compound (4.51 g, 51%) was synthesized in a similar manner to Step E of Preparation Example 1 using -7-carboxylate (8.50 g, 21.02 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.82 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 5.55 (br s, 1H), 4.27 (br s, 2H) ), 3.98 (s, 3H), 3.66 (s, 3H), 2.86-2.81 (m, 4H), 1.67-1.59 (m, 2H), 1.49 (s, 9H)

LC/MS: 431 (M+Na)

Step E: Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7- Preparation of carboxylates

Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3 -b] The title compound (3.8 g) was synthesized in a similar manner to Step F of Preparation Example 1 using pyrazine-7-carboxylate (4.50 g, 10.75 mmol).

LC/MS: 319 (M+H)

Preparation Example 12: Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

The title compound (4.21 g) was obtained in a similar manner to Step A of Preparation Example 1 using 2-chloro-5-methyl-3-nitropyridine (10 g, 57.9 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 8.5 Hz, 2H), 8.05 (d, J = 6.4 Hz, 1H), 4.36-4.35 (m, 1H), 4.08 (br s, 2H), 3.03 (t, J = 11.4 Hz, 2H), 2.29 (s, 3H), 2.12-2.04 (m, 2H), 1.54-1.50 (m, 11H)

LC/MS: 403.2 (M+Na), 325.1 (M-tbu+2H)

Step B: Preparation of tert-butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Similar method to step B of Preparation Example 1 using tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.21 g, 12.52 mmol) The title compound (3.64 g) was obtained.

LC/MS: 307.2 (M+H)

Step C: Tert-Butyl 4-(7-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

In a similar manner to Step C of Preparation Example 7 using tert-butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate (3.64 g, 11.88 mmol) The title compound (2.1 g) was obtained and used in the next reaction without further purification.

LC/MS: 361.2 (M+H)

Step D: Tert-Butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Manufacture of 1-carboxylate

Tert-butyl 4-(7-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate ( The title compound (1.8 g) was obtained in a similar manner to Step E of Preparation Example 1 using 2.1 g, 5.83 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.08 (s, 1H), 7.32 (s, 1H), 5.55 (br s, 1H), 4.43-4.12 (m, 3H), 3.63 (s, 3H), 2.95-2.81 (m, 5H), 2.44 (s, 3H), 1.52 (s, 9H)

LC/MS: 397.2 (M+Na)

Step E: Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- The title compound (1.2 g) was obtained in a similar manner to Step F of Preparation Example 1 using carboxylate (1.8 g, 4.81 mmol).

LC/MS: 275.1 (M+H)

Preparation Example 13: Preparation of 7-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

_NBS ( 0.552 g, 3.10 mmol) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with EtOAc and washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.23 g).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.53 (d, J = 2.4 Hz, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 7.2 Hz, 1H), 4.31~ 4.28 (m, 1H), 4.10-4.04 (m, 2H), 3.01~2.95 (m, 2H), 2.05~2.03 (m, 2H), 1.52-1.48 (2H), 1.46 (s, 9H)

LC/MS: 433, 435 (M+Na)

Step B: of tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate manufacturing

Step C of Preparation Example 3 using tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.23 g, 3.07 mmol) The title compound (0.880 g) was obtained in the same manner.

LC/MS: 523, 525 (M+Na)

Step C: Tert-Butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -Manufacture of carboxylates

Tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.880 g, The title compound (0.480 g) was obtained in the same manner as Step D of Preparation Example 3 using 1.755 mmol) and used directly in the next reaction without purification.

LC/MS: 447, 449 (M+Na)

Step D: Tert-Butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)- Preparation of 3,3-dimethylpiperidine-1-carboxylate

Tert-Butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxyl Rate (0.480 g, 1.129 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.335 g).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.29 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 5.51~5.49 (m, 1H), 4.31~4.27 (m , 2H), 3.63 (s, 3H), 2.87~2.83 (m, 4H), 1.65 (br s, 2H), 1.52 (s, 9H)

LC/MS: 461, 463 (M+Na)

Step E: Preparation of 7-bromo-4-(piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

tert-butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-Carboxylate (0.335 g, 0.763 mmol) was prepared using the same method as Step F of Preparation Example 1 to obtain the title compound (0.314 g).

LC/MS: 338, 340 (M+H)

Preparation Example 14: Preparation of 7-chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of 4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-one

Similar to step A of Preparation Example 1 using 5-chloro-2-fluoro-3-nitropyridine (6 g, 34.0 mmol) and 4-aminocyclohexan-1-one hydrochloride (5.09 g, 34.0 mmol) The title compound (8.9 g) was obtained by this method.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.44 (d, J = 2.4 Hz, 1H), 8.39 (d, J = 2.4 Hz, 1H), 8.19 (d, J = 6.1 Hz, 1H), 4.64- 4.62 (m, 1H), 2.54-2.51 (m, 4H), 2.40-2.37 (m, 2H), 1.94-1.89 (m, 2H)

LC/MS: 270.0 (M+H)

Step B: Preparation of 4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexan-1-one

4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-one (8.5 g, 31.5 mmol) was used to prepare the title compound (5.1 g) was obtained.

LC/MS: 240.1 (M+H)

Step C: Preparation of 7-chloro-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

The title compound (4.39 g) was prepared in a manner similar to Step C of Preparation Example 7 using 4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexane-1-one (5 g, 20.86 mmol). ) was obtained.

LC/MS: 294.1 (M+H), 316.1 (M+Na)

Step D: Preparation of 7-chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Preparation Example 1 using 7-chloro-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (4.4 g, 14.98 mmol) The title compound (2.55 g) was obtained in a similar manner to step E of .

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 5.86-5.81 (m, 1H), 3.62 (d, J = 7.6 Hz, 3H), 3.07 (qd, J = 12.3, 5.5 Hz, 2H), 2.61-2.51 (m, 4H), 2.04-2.01 (m, 2H)

LC/MS: 308.0 (M+H), 330.0 (M+Na)

Preparation Example 15: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl 4-((3-amino-6-chloropyridin-2-yl)amino)piperidine-1-carboxylate

Using tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (7.86 g, 22.03 mmol) obtained in Step A of Preparation Example 3 The title compound (4.4 g) was synthesized in a manner similar to Step B of Preparation Example 1.

LC/MS: 271 (M+H-t-Bu), 349 (M+Na)

Step B: Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

Similar method to Step C of Preparation Example 7 using tert-butyl 4-((3-amino-6-chloropyridin-2-yl)amino)piperidine-1-carboxylate (4.4 g, 13.46 mmol) The title compound (5.13 g) was synthesized and used directly in the next reaction.

LC/MS: 281 (M+H-t-Bu)

Step C: Tert-Butyl 4-(6-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate

Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate The title compound (3.91 g, 74%) was synthesized in a similar manner to Step E of Preparation Example 1 using (5.13 g, 13.47 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.47~5.42 (m, 1H), 4.36~4.26 (m , 2H), 3.64 (s, 3H), 2.91~2.84 (m, 4H), 1.66~1.65 (m, 2H), 1.52 (s, 9H)

LCMS: 417 (M+Na)

Step D: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Tert-Butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate (500 mg, 1.27 mmol) was obtained in the same manner as Step F of Preparation Example 1 to obtain the title compound (450 mg, 99%).

LC/MS: 337 (M+H)

Preparation Example 16: 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2 ,3-b] Production of pyrazine-2,3-dione

Step A: tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-car Preparation of boxylate

5-chloro-2-fluoro-3-nitropyridine (1.00 g, 5.66 mmol) and tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (1.41 g, The title compound (2.11 g) was synthesized in the same manner as Step A of Preparation Example 1 using 6.23 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 4.74- 4.69 (m, 1H), 4.31 (br s, 2H), 2.04-2.01 (m, 4H), 1.80 (q, J = 7.0 Hz, 2H), 1.71-1.60 (m, 2H), 1.48 (s, 9H) )

LC/MS: 383 (M+H)

Step B: tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxyl Manufacture of rate

tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate ( The title compound (1.88 g) was obtained in a similar manner to Step B of Preparation Example 1 using 2.11 g, 5.49 mmol), and was used directly in the next reaction without purification.

LC/MS: 375 (M+Na)

Step C: tert-butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4 Preparation of (1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate

tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.88 g, 5.33 mmol) and DIPEA (5.58 mL, 32.00 mmol) were dissolved in DCM (300 mL) and then ethyl 2-chloro-2-oxoacetate (1.79 mL, 15.98 mmol) was slowly added while maintaining the temperature at 0°C. Next, it was heated to 50°C and stirred for 18 hours. After completion of the reaction, the mixture was extracted using a saturated NH ₄ Cl aqueous solution, and the organic layer was dried using MgSO ₄ and then distilled under reduced pressure to obtain a concentrated mixture. The obtained mixture was synthesized in a similar manner to Step E of Preparation Example 1 to obtain the title compound (1.50 g).

1H-NMR (500 MHz, DMSO-D6) δ 8.20 (s, 1H), 7.95 (d, J = 1.8 Hz, 1H), 5.83 (br s, 1H), 4.16 (br s, 2H), 3.48 (s) , 3H), 2.81-2.72 (m, 2H), 2.01-1.98 (m, 2H), 1.81-1.68 (m, 2H), 1.49 (s, 9H)

LC/MS: 421 (M+H)

Step D: 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2, 3-b] Preparation of pyrazine-2,3-dione

Tert-Butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H) The title compound (1.25 g) was obtained in a similar manner to Step F of Preparation Example 1 using -yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 3.56 mmol).

LC/MS: 321 (M+H)

Preparation Example 17: Preparation of 4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Step A: Preparation of tert-butyl (4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexyl)carbamate

Step A of Preparation Example 1 using 5-chloro-2-fluoro-3-nitropyridine (1 g, 5.66 mmol) and tert-butyl (4-aminocyclohexyl) carbamate (1.214 g, 5.66 mmol) The title compound (1.92 g) was synthesized in a similar manner.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (d, J = 2.3 Hz, 1H), 8.32 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 7.3 Hz, 1H), 4.40 ( s, 1H), 3.49 (s, 1H), 2.13 (dd, J = 32.0, 16.9 Hz, 4H), 1.44 (s, 10H), 1.35 (dd, J = 24.0, 10.7 Hz, 4H)

LC/MS: 371 (M+H)

Step B: Preparation of tert-butyl (4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexyl)carbamate

Tert-butyl (4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexyl)carbamate (1.21 g, 3.26 mmol) was used in a similar manner to Step B of Preparation Example 1. Compound (717 mg) was synthesized.

1H-NMR (400 MHz, CHLOROFORM-D) δ 7.65 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.40 (d, J = 6.9 Hz, 1H), 3.89- 3.82 (m, 2H), 3.46 (s, 1H), 3.19 (s, 2H), 2.17-2.14 (m, 2H), 2.03 (t, J = 3.9 Hz, 2H), 1.43 (s, 9H)

LC/MS: 341 (M+H)

Step C: tert-butyl (4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carbamate manufacture of

The title compound was prepared in a manner similar to Step C of Preparation Example 7 using tert-butyl (4-((3-amino-5-chloropyridin-2-yl)amino)cyclohexyl)carbamate (717 mg, 2.104 mmol). (630 mg) was synthesized.

1H-NMR (400 MHz, METHANOL-D4) δ 8.16 (d, J = 2.3 Hz, 1H), 7.54-7.50 (m, 1H), 5.31 (s, 1H), 3.46-3.38 (m, 1H), 2.74 (d, J = 11.9 Hz, 2H), 2.01 (d, J = 11.0 Hz, 2H), 1.71 (d, J = 10.1 Hz, 2H), 1.42 (s, 10H), 1.37 (d, J = 12.3 Hz) , 2H)

LC/MS: 395 (M+H)

Step D: tert-butyl (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclo Preparation of hexyl)carbamate

Tert-butyl (4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carbamate (630 mg , 1.596 mmol), the title compound (1.92 g) was synthesized in a similar manner to Step E of Preparation Example 1.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.16 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 5.27 (s, 1H), 4.41 (s, 1H), 3.59 (s,3H) ), 2.82-2.77 (m, 2H), 2.13 (d, J = 12.8 Hz, 2H), 1.68 (d, J = 11.4 Hz, 2H), 1.45 (s, 9H), 1.33-1.27 (m, 2H)

LC/MS: 409 (M+H)

Step E: Preparation of 4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

tert-butyl (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)carba The title compound (635 mg) was synthesized in a manner similar to Step F of Preparation Example 1 using mate (720 mg, 1.761 mmol).

1H-NMR (400 MHz, METHANOL-D4) δ 8.21 (d, J = 2.3 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 5.22-5.57 (1H), 3.64 (s, 4H), 3.57 (d, J = 3.7 Hz, 3H), 3.20 (s, 1H), 2.76 (d, J = 11.0 Hz, 2H), 2.16 (d, J = 12.3 Hz, 2H), 1.84 (d, J = 10.5 Hz, 2H), 1.58 (dd, J = 12.6, 3.9 Hz, 2H)

LC/MS: 309 (M+H)

Preparation Example 18: 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine Preparation of -2,3-dione hydrochloride

Step A: Preparation of tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.20 mmol) obtained in step A of Preparation Example 3 was reacted with CH ₃ After dissolving in CN (50 mL), NCS (0.842 g, 6.31 mmol) was added and stirred at 50°C for 5 hours. The reaction was concentrated under reduced pressure, diluted with EtOAc, and washed with aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (1.57 g).

LC/MS: 413, 415 (M+Na)

Step B: Tert-Butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxyl Manufacture of rate

Step C of Preparation Example 3 using tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.920 g, 2.351) The title compound (1.05 g) was obtained in the same manner.

LC/MS: 513, 515 (M+Na)

Step C: Tert-Butyl 4-(6,7-dichloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate

Tert-Butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (220 mg, 0.448 mol) to obtain the title compound (0.186 g) in the same manner as Step D of Preparation Example 3 and used directly in the next reaction without purification.

LC/MS: 437, 439 (M+Na)

Step D: Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Preparation of piperidine-1-carboxylate

Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Dean-1-carboxylate (0.186 g, 0.448 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.121 g).

LC/MS: 451. 453 (M+Na)

Step E: Tert-Butyl 4-(7-chloro-6-(2-fluorophenyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine Preparation of -4(1H)-yl)piperidine-1-carboxylate

Tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Dean-1-carboxylate (0.090 g, 0.210 mmol), (2-fluorophenyl)boronic acid (44 mg, 0.314), 2M sodium carbonate aqueous solution (0.314 mL) and tetrakistriphenylphosphinepalladium (24 mg) , 0.02 mmol) was dissolved in 1,4-dioxane (5 mL) and stirred at 90°C for 3 hours. The reaction was cooled to room temperature, filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (89 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.62 (s, 1H), 7.49~7.46 (m, 2H), 7.32~7.28(m, 1H), 7.24~7.20 (m, 2H), 5.48~5.45 ( m, 1H), 4.30~4.20 (m, 2H), 3.67 (s, 3H), 2.81 (br s, 4H), 1.67 (br s, 2H), 1.44 (s, 9H)

LC/MS: 511 (M+Na)

Step F: 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- Preparation of 2,3-dione hydrochloride

Tert-butyl 4-(7-chloro-6-(2-fluorophenyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4( 1H)-yl)piperidine-1-carboxylate (0.089 g, 0.182 mmol) was obtained in the same manner as Step F of Preparation Example 1 to obtain the title compound (80 mg) and used directly in the next reaction without purification. .

LC/MS: 389 (M+H)

Preparation Example 19: 7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b ]Preparation of pyrazine-6-carbonitrile 2 hydrochloride

Step A: Preparation of tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.00 g, 2.80 mmol) obtained in Step A of Preparation Example 3 and NBS The title compound (1.08 g) was obtained in the same manner as Step A of Preparation Example 18.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.62 (s, 1H), 8.16 (d, J = 5.6 Hz, 1H), 4.33~4.27 (m, 1H), 4.15-4.09 (m, 2H), 3.06 ~3.01 (m, 2H), 2.09~2.07 (m, 2H), 1.55-1.52 (m, 2H), 1.50 (s, 9H)

LC/MS: 457, 459 (M+Na)

Step B: Preparation of tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Preparation Example 3 using tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.500 g, 1.148 mmol) The title compound (0.201 g) was obtained in the same manner as step B.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.69 (s, 1H), 8.05 (d, J = 7.5 Hz, 1H), 4.33~4.28 (m, 1H), 4.17-4.12 (m, 2H), 3.05 ~3.00 (m, 2H), 2.09~2.07 (m, 2H), 1.55-1.52 (m, 2H), 1.50 (s, 9H)

LC/MS: 523, 525 (M+Na)

Step C: Tert-Butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1 -Manufacture of carboxylates

Preparation example using tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.370 g, 0.868 mmol) The title compound (0.251 g) was obtained in the same manner as Step C of 3.

LC/MS: 548, 550 (M+Na)

Step D: tert-Butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) Preparation of piperidine-1-carboxylate

Tert-Butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxyl The title compound (0.215 g) was obtained in the same manner as in Step D of Preparation Example 3 using a rate (0.251 g, 0.477 mmol) and used directly in the next reaction without purification.

LC/MS: 472, 474 (M+Na)

Step E: tert-butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H )-yl) Preparation of piperidine-1-carboxylate

Tert-Butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -1-Carboxylate (0.215 g, 0.477 mmol) was obtained using the same method as Step E of Preparation Example 1. The residue was purified by MPLC to obtain the title compound (0.114 g).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.29 (d, J = 1.2 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 5.51~5.49 (m, 1H), 4.31~4.27 (m , 2H), 3.63 (s, 3H), 2.87~2.83 (m, 4H), 1.65 (br s, 2H), 1.52 (s, 9H)

LC/MS: 486, 488 (M+Na)

Step F: 7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b] Preparation of pyrazine-6-carbonitrile 2 hydrochloride

Tert-Butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Piperidine-1-carboxylate (0.114 g, 0.246 mmol) was used in the same manner as Step F of Preparation Example 1 to obtain the title compound (0.107 g), which was used directly in the next reaction without purification.

LC/MS: 364, 366 (M+H)

Preparation Example 20: 7-Chloro-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Manufacturing of dione

Step A: Preparation of (1r,4r)-4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol

5-Chloro-2-fluoro-3-nitropyridine (3.53 g, 20.0 mmol) and trans-4-aminocyclohexane-1-ol (2.30 g, 20.00 mmol) were prepared in a manner similar to Step A of Preparation Example 1. The title compound (5.3 g) was obtained using .

Step B: Preparation of N-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-nitropyridin-2-amine

(1r,4r)-4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol (1.0 g, 3.68 mmol) was dissolved in TBSCl (0.832 g) in CH ₂ Cl ₂ solvent. , 5.52 mmol), Et ₃ N (1.54 mL, 11.0 mmol), and DMAP (0.045 g, 0.368 mmol) were added and stirred at room temperature for 18 hours. The reaction product was diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.35 g).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.41 (d, J =2.5 Hz, 1H), 8.38 (d, J = 2.5 Hz, 1H), 8.12 (d, J = 7.0 Hz, 1H), 4.19~ 4.16 (m, 1H), 3.73~3.69 (m, 1H), 2.16~2.13 (m, 2H), 1.94~1.91 (m, 2H), 1.55~1.49 (m, 2H), 1.45~1.38 (m, 2H) ), 0.91 (s, 9H), 0.08 (s, 3H), 0.02 (s, 3H)

LC/MS: 386 (M+H)

Step C: Ethyl 2-(((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)(5-chloro-3-nitropyridin-2-yl)amino)-2- Manufacture of oxoacetate

Prepared using N-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-5-chloro-3-nitropyridin-2-amine (1.0 g, 2.59 mmol) The title compound (0.72 g) was obtained in the same manner as Step C of Example 3.

Step D: 4-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3- b] Preparation of pyrazine-2,3-dione

Ethyl 2-(((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)(5-chloro-3-nitropyridin-2-yl)amino)-2-oxoacetate ( The title compound (0.228 g) was obtained in the same manner as Step C of Preparation Example 7 using 0.72 g, 1.48 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J =2.0 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 5.38~5.33 (m, 1H), 3.79~3.73 (m , 1H), 3.62 (s, 3H), 2.76~2.67 (m, 2H), 2.02~2.00 (m, 2H), 1.69~1.67 (m, 2H), 1.55~1.50 (m, 2H), 0.92 (s) , 9H), 0.11 (s, 3H), 0.02 (s, 3H)

LC/MS: 424 (M+H), 446 (M+Na)

Step E: 7-Chloro-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da Preparation of ions

4-((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione (0.140 g, 0.33 mmol) was added with 1N HCl (2 mL) in THF solvent and stirred at room temperature for 3 hours. The reaction solution was adjusted to pH 9 with 1N NaOH and extracted with EtOAc. The organic layer was dried over Na ₂ SO ₄ and distilled under reduced pressure, and the residue was purified by MPLC to obtain the title compound (96 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J =2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.40~5.34 (m, 1H), 3.85~3.81 (m , 1H), 3.63 (s, 3H), 2.81~2.73 (m, 2H), 2.15~2.13 (m, 2H), 1.73~1.71 (m, 2H), 1.54~1.49 (m, 2H)

LC/MS: 310 (M+H), 332 (M+Na)

Preparation Example 21: 7-chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Preparation of pyrazine-2,3-dione 2 hydrochloride

Step A: Preparation of tert-butyl (2R,5S)-4-((5-chloro-3-nitropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate

5-Chloro-2-fluoro-3-nitropyridine (306 mg, 1.73 mmol) with tert-butyl (2R,5S)-4-amino-2,5-dimethylpiperidine-1-carboxylate Acetate (500 mg, 1.73 mmol) was dissolved in DMF (20 mL), then DIPEA (0.606 mL, 3.47 mmol) was added and stirred for 3 hours. The reaction was terminated by adding water to the reactant, and then extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (500 mg, 75%).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (d, J = 6.4 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 4.59~ 4.55 (m, 1H), 4.39~4.33 (m, 1H), 3.98~3.95 (m, 1H), 2.87~2.81 (m, 1H), 2.13~2.08 (m, 1H), 1.99~1.96 (m, 2H) ), 1.50 (s, 9H), 1.22 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.4 Hz, 3H)

LC/MS: 329 (M+H-t-Bu)

Step B: Preparation of tert-butyl (2R,5S)-4-((3-amino-5-chloropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate

Tert-Butyl (2R,5S)-4-((5-chloro-3-nitropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate (330 mg, 0.857 mmol) was dissolved in MeOH (10 mL), Zn (1.12 g, 17.2 mmol) and ammonium chloride (0.460 g, 8.57 mmol) were added, and then stirred at 70°C for 3 hours. After filtering with a Celite pad and concentrating under reduced pressure, the title compound (304 mg) was obtained and used immediately in the next reaction.

LC/MS: 355 (M+H)

Step C: tert-butyl (2R,5S)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H )-yl)-2,5-dimethylpiperidine-1-carboxylate Preparation

Tert-butyl (2R,5S)-4-((3-amino-5-chloropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate (304 mg, 0.857 mmol ) was dissolved in DCE (10 mL), then ethyl 2-chloro-2-oxoacetate (0.144 mL, 1.29 mmol) and DIPEA (0.449 mL, 2.57 mmol) were added, stirred at room temperature for 12 hours, and then stirred at 70°C. Stirred over the weekend. The reaction was terminated by adding water to the reactant, and then extracted three times with DCM. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (209 mg), which was immediately used in the next reaction.

LC/MS: 309 (M+H-t-Bu)

Step D: tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) -Preparation of 2,5-dimethylpiperidine-1-carboxylate

tert-butyl (2R,5S)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl The title compound (81 mg, 38%) was synthesized in a similar manner to Step E of Preparation Example 1 using )-2,5-dimethylpiperidine-1-carboxylate (209 mg, 0.511 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.36~5.31 (m, 1H), 4.04~3.93 (m , 2H), 3.64 (s, 3H), 3.07~2.95 (m, 2H), 2.76~2.69 (m, 1H), 1.85~1.80 (m, 1H), 1.52 (s, 9H), 1.25 (d, J = 6.0 Hz, 3H), 0.78 (d, J = 6.4 Hz, 3H)

LC/MS: 367 (M+H-t-Bu), 445 (M+Na)

Step E: 7-Chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] Preparation of pyrazine-2,3-dione 2 hydrochloride

tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-2, The title compound (68 mg, 99%) was synthesized in a similar manner to Step F of Preparation Example 1 using 5-dimethylpiperidine-1-carboxylate (81 mg, 0.192 nnol).

LC/MS: 323 (M+H)

Preparation Example 22: 7-chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 Preparation of hydrochloride salt

Step A: Preparation of tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.15 g, 3.42 mmol) obtained in Step A of Preparation Example 2 was reacted with CH ₃ After dissolving in CN (30 mL), NCS was added and stirred at 60°C for 72 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and an aqueous sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to synthesize the title compound (770 mg, 61%).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.38 (s, 1H), 8.14 (d, J = 7.0 Hz, 1H), 4.40~4.35 (m, 1H), 4.08 (br s, 2H), 3.03 ( d, J = 10.5 Hz, 2H), 2.57 (s, 3H), 2.08~2.06 (m, 2H), 1.55~1.51 (m, 2H), 1.50 (s, 9H)

LC/MS: 393 (M+H)

Step B: Preparation of tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Preparation Example 1 using tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (310 mg, 0.836 mmol) The title compound (271 mg, 95%) was synthesized in a manner similar to Step B.

LC/MS: 341 (M+H)

Step C: Tert-Butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi Preparation of dine-1-carboxylate

Step of Preparation Example 7 using tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (271 mg, 0.795 mmol) The title compound (314 mg, 99%) was synthesized in a similar manner to C.

LC/MS: 339 (M+H-t-Bu)

Step D: Tert-Butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl ) Preparation of piperidine-1-carboxylate

Tert-Butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 The title compound (271 mg, 83%) was synthesized in a similar manner to Step E of Preparation Example 1 using -carboxylate (314 mg, 0.795 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.46 (s, 1H), 5.50 (s, 1H), 4.35~4.24 (m, 2H), 3.61 (s, 3H), 2.87~2.85 (m, 4H) , 2.61 (s, 3H), 1.65 (br s, 2H), 1.52 (s, 9H)

LC/MS: 431 (M+Na), 353 (M+H-t-Bu)

Step E: 7-Chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 Preparation of hydrochloride salt

Tert-Butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi The title compound (221 mg, 97%) was synthesized in a manner similar to Step F of Preparation Example 1 using dine-1-carboxylate (271 mg, 0.663 mmol).

LC/MS: 309 (M+H)

Preparation Example 23: 7-bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 hydrochloride manufacturing

Step A: Preparation of tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

Tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.90 g, 14.57 mmol) obtained in Step A of Preparation Example 2 was reacted with CH ₃ After dissolving in CN (146 mL), NBS was added and stirred at room temperature for 18 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and an aqueous sodium bicarbonate solution, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to synthesize the title compound (6.05 g, 92%).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.52 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 4.37 (m, 1H), 4.08 (br s, 2H), 3.03 (t, J = 11.9 Hz, 2H), 2.61 (s, 3H), 2.08-2.06 (m, 2H), 1.58 (s, 3H), 1.53 (dd, J = 12.8, 4.0 Hz, 2H), 1.50 (s, 9H) )

LC/MS: 437 (M+Na)

Step B: Preparation of tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Preparation Example 1 using tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1000 mg, 2.41 mmol) The title compound (811 mg, 87%) was synthesized in a manner similar to step B of .

LC/MS: 385, 387 (M+H)

Step C: Tert-Butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Preparation of peridine-1-carboxylate

Preparation Example 7 using tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (811 mg, 2.11 mmol) The title compound (925 mg, 99%.) was synthesized in a manner similar to Step C.

LC/MS: 439, 441 (M+H)

Step D: Tert-Butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) Preparation of piperidine-1-carboxylate

Tert-butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- The title compound (732 mg, 77%) was synthesized in a similar manner to Step E of Preparation Example 1 using 1-carboxylate (925 mg, 2.11 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.61 (s, 1H), 5.49 (s, 1H), 4.35~4.24 (m, 2H), 3.61 (s, 3H), 2.87~2.85 (m, 4H) , 2.65 (s, 3H), 1.64 (br s, 2H), 1.52 (s, 9H)

LC/MS: 475, 477 (M+Na)

Step E: 7-Bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione 2 Preparation of hydrochloride salt

tert-butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p The title compound (631 mg, 100%) was synthesized in a similar manner to Step F of Preparation Example 1 using peridine-1-carboxylate (732 mg, 1.62 mmol).

LC/MS: 353, 355 (M+H)

Preparation Example 24: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride

Step A: Preparation of tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate

The title compound (3.32 g, 99%) was synthesized in the same manner as Step A of Preparation Example 1 using 2-fluoro-4-methyl-3-nitropyridine (1.56 g, 9.99 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 5.0 Hz, 1H), 7.45 (d, J = 7.0 Hz, 1H), 6.50 (d, J = 5.0 Hz, 1H), 4.31~ 4.28 (m, 1H), 4.06 (br s, 2H), 3.04~2.99 (m, 2H), 2.56 (s, 3H), 2.08~2.06 (m, 2H), 1.52 (s, 9H), 1.51~1.44 (m, 2H)

LC/MS: 337 (M+H)

Step B: Preparation of tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Similar to step B of Preparation Example 1 using tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.46 mmol) The title compound (1.35 g, 99%) was obtained through this method, and was used directly in the next reaction without purification.

LC/MS: 307 (M+H)

Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate

Similar method to Step C of Preparation Example 1 using tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (1.35 g, 4.41 mmol) The title compound (1.67 g, 93%) was obtained.

LC/MS: 407 (M+H)

Step D: Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- Preparation of carboxylates

Tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (930 mg, 2.29 mmol) and DIPEA (2.0 mL, 11.4 mmol) were dissolved in DCE (15 mL) and stirred at 70°C for 24 hours. The reaction product was cooled to room temperature and concentrated under reduced pressure to obtain the title compound (34 mg, 4%) using MPLC.

LC/MS: 305 (M+H-t-Bu)

Step E: Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine -Preparation of 1-carboxylate

Tert-Butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1-carboxylate The title compound (35 mg, 99%) was synthesized in a similar manner to Step E of Preparation Example 1 using (34 mg, 0.094 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 5.74 (br s, 1H), 4.31~4.22 (m, 2H), 4.13 (s, 3H), 2.96~2.94 (m, 4H), 2.61 (s, 3H), 1.65~1.62 (m, 2H), 1.52 (s, 9H)

LC/MS: 397 (M+Na)

Step F: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride

Tert-Butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidin-1- The title compound (29.2 mg, 100%) was synthesized in a manner similar to Step F of Preparation Example 1 using carboxylate (35 mg, 0.093 mmol).

LC/MS: 275 (M+H)

Example 1: 1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione (1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of

1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg, 0.10 mmol) obtained in Preparation Example 1 ), EDC (42 mg, 0.20 mmol), HOBt (31 mg, 0.20 mmol), and 4-(trifluoromethoxy)benzoic acid (40 mg, 0.2 mmol) were dissolved in DMF (1 mL) and then added to TEA (42 μL, 0.30 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours, diluted with EtOAc, and washed three times with saturated NH ₄ Cl aqueous solution. The organic layer was dried over anhydrous MgSO ₄ and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (31 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (d, J = 4.6 Hz, 1H), 7.53 (dd, J = 8.5, 2.1 Hz, 3H), 7.28-7.24 (m, 3H), 5.71 (br s, 2H), 4.91 (br s, 1H), 3.87 (br s, 1H), 3.64 (s, 3H), 3.21 (br s, 1H), 2.97 (br s, 3H), 1.81 (br s, 1H) )

LC/MS: 449.1 (M+H)

Example 2: 1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)

1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg) obtained in Preparation Example 2 , 0.01 mmol) to obtain the title compound (29 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54-7.52 (m, 2H), 7.41 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.07 (d, J = 8.2 Hz, 1H), 5.73 (br s, 2H), 4.91 (br s, 1H), 3.87 (br s, 1H), 3.61 (s, 3H), 3.23 (br s, 1H), 3.00 (dd, J = 20.3, 11.4 Hz, 2H), 2.57 (s, 3H), 1.74 (d, J = 58.6 Hz, 2H)

LC/MS: 463.1 (M+H)

Example 3: 1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione ( Preparation of 1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg) obtained in Preparation Example 2 , 0.01 mmol) and DIPEA (0.057 mL, 0.318 mmol) were dissolved in DCM (0.9 mL), and then 4-methylbenzenesulfonyl chloride (28 mg, 0.15 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 3 hours, then diluted with DCM and extracted using brine. The organic layer was dried with anhydrous MgSO ₄ and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (38 mg).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (d, J = 5.9 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 6.9 Hz, 1H), 7.55 ( t, J = 7.5 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H), 5.48-5.43 (m, 1H), 3.59 (s, 3H), 3.11-3.04 (m, 4H), 2.54 (d, J = 14.2 Hz, 3H), 2.36-2.29 (m, 2H), 1.74-1.49 (m, 2H), 1.43 (s, 3H)

LC/MS: 429.1 (M+H)

Example 4: 4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) manufacture of

1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20 mg, 0.067 mmol) obtained in Preparation Example 1 ) and 3-chlorobenzenesulfonyl chloride (16 mg, 0.074 mmol) were used to obtain the title compound (11 mg) in a similar manner to Example 3.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.37-7.33 (m, 1H), 7.26-7.21 (m , 2H), 7.15 (dd, J = 7.3, 6.4 Hz, 1H), 7.04 (t, J = 9.1 Hz, 1H), 5.53-5.46 (m, 1H), 4.85 (d, J = 11.9 Hz, 1H) , 4.03 (d, J = 13.7 Hz, 1H), 3.78 (d, J = 5.0 Hz, 2H), 3.59 (s, 3H), 2.75-2.65 (m, 2H), 1.70-1.63 (m, 2H)

LC/MS: 435.0 (M+H), 436.0 (M+2H)

Example 5: 4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] Pyrazine-2,3-dione (4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2 ,3-dione) production

1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20 mg, 0.067 mmol) obtained in Preparation Example 1 ) and 3,4-dichlorobenzenesulfonyl chloride (18 mg, 0.074 mmol) to obtain the title compound (20 mg) in a similar manner to Example 3.

LC/MS: 469.0 (M+H)

Example 6: 1-Methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione (1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of

1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20 mg, 0.067 mmol) obtained in Preparation Example 1 ) and 4-phenoxybenzenesulfonyl chloride (20 mg, 0.074 mmol) to obtain the title compound (1 mg) in a similar manner to Example 3.

LC/MS:493.1 (M+H), 515.1(M+Na)

Example 7: 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydro Pyrido[2,3-b]pyrazine-6-carbonitrile (1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2 Manufacture of ,3,4-tetrahydropyrid[2,3-b]pyrazine-6-carbonitrile)

1-Methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6 obtained in Preparation Example 3 The title compound (52 mg) was obtained in the same manner as in Example 8 using -carbonitrile (50 mg, 0.155 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.029 ml, 0.186 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.67 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.31 ( d, J = 2.0 Hz, 2H), 5.67~5.62 (m, 1H), 4.97~4.95 (m, 1H), 3.91 (br s, 1H), 3.68 (s, 3H), 3.23 (br s, 1H) , 2.95~2.87 (m, 3H), 1.82~1.70 (d, 2H)

LC/MS: 474 (M+H)

Example 8: 7-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (800) obtained in Preparation Example 4 mg, 2.73 mmol) and DIPEA (2.1 mL, 12.08 mmol) were dissolved in DCM (20 mL), and then 4-(trifluoromethoxy)benzoyl chloride (0.571 ml, 3.62 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 6 hours, diluted with DCM, and extracted using a saturated NH ₄ Cl aqueous solution. The organic layer was dried using anhydrous MgSO ₄ and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (860 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 1.5 Hz, 1H), 7.27 ( d, J = 8.2 Hz, 2H), 5.62 (t, J = 11.6 Hz, 1H), 4.91 (br s, 2H), 3.88 (br s, 1H), 3.62 (br s, 3H), 3.20 (br s , 1H), 2.93 (br s, 2H), 1.90-1.52 (m, 2H)

LC/MS: 483.1 (M+H)

Example 9: 7-Chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione Preparation of (7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (23) obtained in Preparation Example 4 mg, 0.078 mmol) and 4-methylbenzenesulfonyl chloride (14.88 mg, 0.078 mmol) to obtain the title compound (13 mg) in a similar manner to Example 3.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12 (d, J = 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 1.8 Hz, 1H), 7.34 ( d, J = 7.8 Hz, 2H), 5.16 (tt, J = 12.1, 3.7 Hz, 1H), 3.95 (d, J = 11.9 Hz, 2H), 3.57 (t, J = 15.1 Hz, 3H), 3.04 ( qd, J = 12.3, 4.1 Hz, 2H), 2.47 (d, J = 15.1 Hz, 4H), 2.40 (dd, J = 11.9, 1.8 Hz, 2H), 1.66 (d, J = 11.9 Hz, 3H)

LC/MS: 449 (M+H)

Example 10: 7-Chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydro Pyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1- Preparation of methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 obtained in Preparation Example 5, The title compound (51 mg) was obtained in the same manner as in Example 8 using 3-dione (47 mg, 0.119 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.022 ml, 0.143 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (s, 1H), 7.51~7.50 (m, 3H), 7.29 (d, J = 8.5 Hz, 2H), 5.78, 5.45 (2s, 1H), 4.91 , 4.53 (2s, 1H), 3.93~2.85 (m, 3H), 3.65 (s, 3H), 1.72~1.63 (m, 2H), 1.28~0.78 (m, 6H)

LC/MS: 511 (M+H)

Example 11: 7-Chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octane-3 -1)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1R,3s,5S)-8-( Preparation of 4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (20) obtained in Preparation Example 4 mg, 0.056 mmol) to obtain the title compound (24 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.23 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 2.1 Hz, 1H), 7.32- 7.27 (m, 2H), 5.74 (t, J = 9.6 Hz, 1H), 4.99 (br s, 1H), 4.13 (br s, 1H), 3.62 (s, 3H), 2.53 (d, J = 9.2 Hz) , 1H), 2.46-2.36 (m, 2H), 2.29 (t, J = 9.0 Hz, 1H), 2.13-2.04 (m, 4H)

LC/MS: 509.1 (M+H), 531.1 (M+Na)

Example 12: 7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3 ,4-Tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile (7-bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin Preparation of -4-yl)-1,2,3,4-tetrahydropyrid[2,3-b]pyrazine-6-carbonitrile)

7-Bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-] obtained in Preparation Example 19 b] The title compound (59 mg) was prepared in the same manner as in Example 8 using pyrazine-6-carbonitrile (52 mg, 0.119 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.022 ml, 0.143 mmol). got it

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.74 (s, 1H), 7.56 (d, J = 8.5Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 5.58~5.53 (m, 1H) ), 4.94 (br s, 1H), 3.91 (br s, 1H), 3.67 (s, 3H), 3.22 (br s, 1H), 2.97~2.83 (m, 3H), 1.81~1.70 (m, 2H)

LC/MS: 552, 554 (M+H)

Example 13: 7-Chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1 ,Manufacture of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(4-(trifluoromethoxy)phenyl)acetic acid (24 mg, 0.11 mmol) to obtain the title compound (30 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.1 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 2H), 7.20 ( d, J = 8.2 Hz, 2H), 5.54-5.50 (m, 1H), 4.85 (d, J = 11.6 Hz, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.79 (s, 2H), 3.60 (s, 3H), 3.20-3.15 (m, 1H), 2.84-2.65 (m, 3H), 1.71 (d, J = 12.8 Hz, 1H), 1.65 (d, J = 11.9 Hz, 1H)

LC/MS: 497.1 (M+H)

Example 14: 7-Chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da Preparation of ion (7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione)

Step A: Preparation of 4-((5-chloro-3-nitropyridin-2-yl)amino)cyclohexan-1-ol

The same method as Step A of Preparation Example 1 using 5-chloro-2-fluoro-3-nitropyridine (1 g, 5.66 mmol) and 4-aminocyclohexan-1-ol (0.652 g, 5.66 mmol) The title compound (1.49 g) was obtained.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.39 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 4.18- 4.11 (m, 1H), 3.72 (dt, J = 14.5, 5.1 Hz, 1H), 2.17-2.14 (m, 2H), 2.04 (d, J = 11.4 Hz, 2H), 1.51-1.34 (m, 5H)

LC/MS: 272 (M+H)

Step B: Preparation of 5-chloro-N-(4-(3-chlorophenoxy)cyclohexyl)-3-nitropyridin-2-amine

4-((5-Chloro-3-nitropyridin-2-yl)amino)cyclohexane-1-ol (500 mg, 1.840 mmol) was dissolved in THF (5 ml) and 3-chlorophenol (214 μl, 2.024 μl) mmol), TEA (513 μl, 3.68 mmol) and triphenylphosphine (965 mg, 3.68 mmol) were added, DIAD (716 μl, 3.68 mmol) was slowly added, and the mixture was stirred at room temperature for 4 hours. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (174 mg), which was used directly in the next reaction without purification.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.40 (d, J = 2.7 Hz, 1H), 8.34 (d, J = 2.7 Hz, 1H), 8.20 (d, J = 7.3 Hz, 1H), 7.19 ( t, J = 8.0 Hz, 1H), 6.93-6.91 (m, 2H), 6.83-6.80 (m, 1H), 4.50 (q, J = 2.3 Hz, 1H), 4.29-4.25 (m, 1H), 2.08 -2.03 (m, 2H), 1.94-1.90 (m, 2H), 1.86-1.73 (m, 4H)

LC/MS: 383 (M+H)

Step C: Preparation of ethyl 2-((5-chloro-3-nitropyridin-2-yl)(4-(3-chlorophenoxy)cyclohexyl)amino)-2-oxoacetate

5-Chloro-N-(4-(3-chlorophenoxy)cyclohexyl)-3-nitropyridin-2-amine (28 mg, 0.073 mmol) was used in the same manner as Step C of Preparation Example 3. Compound (15 mg) was obtained.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.75 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.3 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.89 ( d, J = 8.2 Hz, 1H), 6.80 (s, 1H), 6.70 (d, J = 8.2 Hz, 1H), 4.54 (s, 1H), 4.45 (s, 1H), 4.12 (q, J = 6.9 Hz, 2H), 2.08 (dd, J = 23.6, 12.6 Hz, 2H), 1.72-1.59 (m, 4H), 1.24 (t, J = 6.9 Hz, 3H)

LC/MS: 482 (M+H)

Step D: Preparation of 7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione

Prepared using ethyl 2-((5-chloro-3-nitropyridin-2-yl)(4-(3-chlorophenoxy)cyclohexyl)amino)-2-oxoacetate (15 mg, 0.031 mmol) The title compound (2 mg) was obtained in the same manner as Step D of Example 3 and used directly in the next reaction without purification.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.23 (s, 1H), 7.69 (s, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.92-6.90 (m, 2H), 5.43 (s, 1H), 4.61 (s, 1H), 3.10 (d, J = 10.1 Hz, 2H), 2.22 (d, J = 12.8 Hz, 2H), 1.71 (t , J = 14.0 Hz, 3H), 1.52 (d, J = 11.4 Hz, 4H)

LC/MS: 407 (M+H)

Step E: 7-Chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione manufacture of

7-Chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (5 mg, 0.012 mmol) The title compound (2 mg) was obtained in the same manner as Step F of Preparation Example 1.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.00 ( t, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.2, 2.3 Hz, 2H), 5.39 (d, J = 3.7 Hz, 1H), 4.60 (s, 1H), 3.60 (s, 3H), 3.09 (dd, J = 13.0, 3.0 Hz, 2H), 2.22-2.19 (m, 2H), 1.70 (t, J = 14.0 Hz, 2H), 1.50 (d, J = 12.3 Hz, 3H)

LC/MS: 421 (M+H)

Example 15: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin Preparation of -4(1H)-yl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)

4-(Trifluoromethoxy)aniline (46 mg, 0.257 mmol) and DIPEA (0.064 mL, 0.37 mmol) were dissolved in anhydrous THF (2.5 mL), and triphosgene (27 mg, 0.09 mmol) was added at 0°C. Stirred for 30 minutes. Afterwards, 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3 obtained in Preparation Example 4 was added to the reaction mixture. -Dione (90 mg, 0.25 mmol) and DIPEA (0.064 mL, 0.37 mmol) were added and stirred for an additional 3 hours. The mixture was concentrated by distillation under reduced pressure, diluted with DCM, and extracted with brine. The organic layer was dried over anhydrous MgSO ₄ and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (100 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.51 (s, 1H), 7.46-7.33 (m, 3H), 7.05 (d, J = 7.9 Hz, 2H), 5.55 (s) , 1H), 4.30 (d, J = 12.2 Hz, 2H), 3.59 (s, 3H), 2.99 (t, J = 12.5 Hz, 2H), 2.84 (d, J = 11.6 Hz, 2H), 1.69 (d) , J = 11.0 Hz, 2H)

LC/MS: 498.1 (M+H)

Example 16: 7-Chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrid[ Preparation of 2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(pyridin-2-yl)acetic acid (13 mg, 0.10 mmol) to obtain the title compound (31 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.53 (d, J = 4.6 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.71 (td, J = 7.8, 1.4 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.18 (dd, J = 7.3, 5.2 Hz, 1H), 5.53-5.49 (m, 1H), 4.84 (d , J = 11.0 Hz, 1H), 4.27 (d, J = 13.7 Hz, 1H), 4.00 (s, 2H), 3.60 (s, 3H), 3.15 (td, J = 13.1, 2.2 Hz, 1H), 2.79 -2.59 (m, 3H), 1.69 (d, J = 12.2 Hz, 1H), 1.62 (d, J = 11.9 Hz, 1H)

LC/MS: 414.1 (M+H)

Example 17: 7-Chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2, 3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrid Preparation of [2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(thiophen-2-yl)acetic acid (14 mg, 0.10 mmol) to obtain the title compound (28 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.15 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 4.9 Hz, 1H), 6.98- 6.94 (m, 2H), 5.55-5.50 (m, 1H), 4.84 (d, J = 11.6 Hz, 1H), 4.09-4.01 (m, 1H), 3.97 (d, J = 3.1 Hz, 2H), 3.60 (s, 3H), 3.20 (td, J = 13.2, 2.1 Hz, 1H), 2.82-2.76 (m, 1H), 2.74-2.69 (m, 2H), 1.72-1.65 (m, 2H)

LC/MS: 419.1 (M+H)

Example 18: 7-Chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b] pyrazine-2,3-dione (7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-(2-fluorophenyl)acetic acid (15 mg, 0.10 mmol) to obtain the title compound (31 mg) in a similar manner to Example 1.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.15 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.37 (td, J = 7.5, 1.7 Hz, 1H), 7.28-7.23 (m, 1H), 7.16 (dd, J = 7.3, 6.4 Hz, 1H), 7.06 (t, J = 9.1 Hz, 1H), 5.55-5.49 (m, 1H), 4.86 (d, J = 11.9 Hz, 1H), 4.05 (d, J = 13.7 Hz, 1H), 3.80 (d, J = 5.0 Hz, 2H), 3.60 (s, 3H), 3.22-3.16 (m, 1H), 2.83-2.69 ( m, 3H), 1.72-1.64 (m, 2H)

LC/MS: 431.1 (M+H)

Example 19: 7-Chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[ Preparation of 2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 The title compound (27 mg) was obtained in a similar manner to Example 1 using mg, 0.10 mmol) and 2-(furan-2-yl)acetic acid (12 mg, 0.10 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.35 ( q, J = 1.6 Hz, 1H), 6.25 (d, J = 3.4 Hz, 1H), 5.56-5.51 (m, 1H), 4.85-4.83 (m, 1H), 4.14-4.09 (m, 1H), 3.82 (d, J = 3.7 Hz, 2H), 3.61 (s, 3H), 3.22 (td, J = 13.3, 2.3 Hz, 1H), 2.81-2.72 (m, 3H), 1.72-1.68 (m, 2H)

LC/MS: 431.1 (M+H)

Example 20: 7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4 -Dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl) Preparation of piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b] obtained in Preparation Example 18 The title compound (41 mg) was prepared in the same manner as in Example 8 using pyrazine-2,3-dione (35 mg, 0.082 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.016 ml, 0.099 mmol). got it

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.65 (s, 1H), 7.51 (dd, J = 14.5, 7.0, Hz, 2H), 7.36~7.19 (m, 6H), 5.61~5.56 (m, 1H) ), 4.86 (br s, 1H), 3.77 (br s, 1H), 3.69 (s, 3H), 3.14~3.12 (m, 1H), 3.01~2.89 (m, 3H), 1.83~1.68 (m, 2H) )

LC/MS: 557 (M+H)

Example 21: 7-Chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2-phenylacetic acid (12 mg, 0.10 mmol) to obtain the title compound (26 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.13 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.30 ( s, 1H), 7.28-7.23 (m, 2H), 5.49 (t, J = 3.7 Hz, 1H), 4.87 (d, J = 11.6 Hz, 1H), 4.02 (d, J = 13.7 Hz, 1H), 3.81 (s, 2H), 3.59 (s, 3H), 3.12 (td, J = 13.1, 1.9 Hz, 1H), 2.81-2.59 (m, 3H), 1.69 (d, J = 12.2 Hz, 1H), 1.58 (d, J = 12.2 Hz, 1H)

LC/MS: 413.1 (M+H)

Example 22: 7-Chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 Preparation of -b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 1-phenylcyclopropane-1-carboxylic acid (15 mg, 0.10 mmol) to obtain the title compound (30 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.14 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.21 ( d, J = 7.9 Hz, 3H), 5.46 (t, J = 11.7 Hz, 1H), 4.85 (br s, 1H), 4.25 (br s, 1H), 3.59 (s, 3H), 2.91 (br s, 1H), 2.87-2.66 (m, 2H), 2.50 (br s, 1H), 1.70 (br s, 1H), 1.44 (br s, 1H), 1.30-1.26 (m, 2H), 1.22 (brs, 2H) )

LC/MS: 439.1 (M+H)

Example 23: 7-Chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydro Pyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl Preparation of -1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (60) obtained in Preparation Example 4 mg, 0.17 mmol) and 2-(2-fluorophenyl)-2-methylpropanoic acid (33 mg, 0.18 mmol) to obtain the title compound (26 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.34 (td, J = 7.8, 1.2 Hz, 1H), 7.24-7.20 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.14-7.10 (m, 1H), 5.41-5.36 (m, 1H), 4.96 (br s, 1H), 3.62 (d) , J = 5.5 Hz, 1H), 3.60 (s, 3H), 2.81-2.65 (m, 3H), 2.31 (s, 1H), 1.74-1.65 (m, 1H), 1.61-1.57 (m, 6H), 1.27-1.22 (m, 1H)

LC/MS: 459.1 (M+H)

Example 24: 7-Chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione )Manufacture of

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-chlorobenzoyl chloride (20 mg, 0.11 mmol) to obtain the title compound (19 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.8 Hz, 1H), 7.52-7.51 (m, 1H), 7.44-7.39 (m, 4H), 5.60 (d, J = 11.3 Hz) , 1H), 4.89 (br s, 1H), 3.87 (br s, 1H), 3.62 (s, 3H), 3.18 (br s, 1H), 2.91 (br s, 3H), 1.75 (d, J = 44.9 Hz, 2H)

LC/MS: 433.1 (M+H)

Example 25: 7-Chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-(trifluoromethyl)benzoyl chloride (21 mg, 0.11 mmol) to obtain the title compound (26 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.51 ( d, J = 1.8 Hz, 1H), 5.63 (t, J = 11.4 Hz, 1H), 4.94 (s, 1H), 3.80-3.75 (m, 1H), 3.62 (s, 3H), 3.20 (s, 1H) ), 2.93 (s, 3H), 1.82 (s, 1H), 1.65 (s, 1H)

LC/MS: 467.1 (M+H)

Example 26: 4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl) piperidin-1-yl) sulfonyl) benzonitrile (4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin- Preparation of 4(1H)-yl)piperidin-1-yl)sulfonyl)benzonitrile)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-cyanobenzenesulfonyl chloride (22.3 mg, 0.111 mmol) to obtain the title compound (42 mg) in a similar manner to Example 3.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.50 ( d, J = 2.0 Hz, 1H), 5.30~5.25 (m, 1H), 4.06~4.04 (m, 2H), 3.62 (s, 3H), 3.11~3.04 (m, 2H), 2.61~2.56 (m, 2H), 1.75~1.73 (m, 2H)

LC/MS: 482 (M+Na)

Example 27: 4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)p Peridine-1-carbonyl)benzonitrile (4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)piperidine-1-carbonyl)benzonitrile)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-(trifluoromethyl)benzoyl chloride (18 mg, 0.11 mmol) to obtain the title compound (1 mg) in a similar manner to Example 8.

LC/MS: 424.1 (M+H)

Example 28: 4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione (4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4 Preparation of -dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (37) obtained in Preparation Example 4 mg, 0.10 mmol) and 4-(tert-butyl)benzenesulfonyl chloride (26 mg, 0.111 mmol) to obtain the title compound (43 mg) in a similar manner to Example 3.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 1.5 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.49 ( d, J = 2.0 Hz, 1H), 5.23~5.18 (m, 1H), 4.01~3.99 (m, 2H), 3.62 (s, 3H), 3.14~3.10 (m, 2H), 2.51~2.46 (m, 2H), 1.73~1.70 (m, 2H), 1.40 (s, 9H)

LC/MS: 491 (M+H), 513 (M+Na)

Example 29: 7-Chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-carbonyl)piperidin-4-yl)-1-methyl-1 ,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxine-6- Preparation of carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.10 mmol) and 2,3-dihydrobenzo[b][1,4]dioxin-6-carboxylic acid (32 mg, 0.11 mmol) to prepare the title compound (35 mg) in a similar manner to Example 1. got it

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 3.7 Hz, 1H), 7.51 (s, 1H), 6.95-6.80 (m, 3H), 5.59 (t, J = 11.3 Hz, 1H) ), 4.99 (d, J = 9.5 Hz, 1H), 4.45-4.23 (m, 4H), 3.75-3.72 (m, 1H), 3.61 (s, 3H), 2.94-2.80 (m, 3H), 1.77 ( d, J = 7.9 Hz, 2H), 1.59 (d, J = 11.6 Hz, 1H)

LC/MS: 457.1 (M+H)

Example 30: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-(trifluoromethyl)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin Preparation of -4(1H)-yl)-N-(4-(trifluoromethyl)phenyl)piperidine-1-carboxamide)

4-(trifluoromethyl)aniline (18 mg, 0.11 mol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido obtained in Preparation Example 4 The title compound (28 mg) was obtained in a similar manner to Example 15 using [2,3-b]pyrazine-2,3-dione (30 mg, 0.10 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.50-7.42 (m, 4H), 7.11 (s, 1H) ), 5.60-5.55 (m, 1H), 4.30 (d, J = 13.4 Hz, 2H), 3.61 (s, 3H), 3.05 (td, J = 12.8, 1.7 Hz, 2H), 2.88 (qd, J = 12.3, 4.0 Hz, 2H), 1.75-1.72 (m, 2H)

LC/MS: 482.1 (M+H)

Example 31: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-Chlorophenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)-N-(4-chlorophenyl)piperidine-1-carboxamide)

4-chloroaniline (14 mg, 0.11 mol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-] obtained in Preparation Example 4 b] The title compound (31 mg) was obtained in a similar manner to Example 15 using pyrazine-2,3-dione (30 mg, 0.10 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 2.1 Hz, 1H), 7.35-7.32 (m, 2H), 7.18 (dd, J = 11.6, 3.1 Hz, 2H), 7.06 (s, 1H), 5.58-5.53 (m, 1H), 4.29 (d, J = 13.4 Hz, 2H), 3.60 (s, 3H), 3.04-2.99 (m, 2H), 2.86 (qd, J = 12.3, 3.9 Hz, 2H), 1.83-1.71 (m, 2H)

LC/MS: 448.0 (M+H)

Example 32: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-Cyanophenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H )-yl)-N-(4-cyanophenyl)piperidine-1-carboxamide) Preparation

4-Aminobenzonitrile (13 mg, 0.11 mol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido [2, [3-b] The title compound (19 mg) was obtained in a similar manner to Example 15 using pyrazine-2,3-dione (30 mg, 0.10 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 1.8 Hz, 1H), 7.61 (s, 1H), 7.53 (dd, J = 5.5, 3.7 Hz, 3H), 7.51-7.43 (m , 2H), 5.62-5.57 (m, 1H), 4.33 (d, J = 13.7 Hz, 2H), 3.61 (d, J = 3.1 Hz, 3H), 3.02 (t, J = 12.1 Hz, 2H), 2.89 -2.81 (m, 2H), 1.72 (d, J = 9.8 Hz, 2H)

LC/MS: 439.1 (M+H)

Example 33: 7-Chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione (7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) manufacturing

2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (32 mg) was synthesized in a manner similar to Example 8 using hydrochloride (30 mg, 0.082 mmol) and cyclohexanecarbonyl chloride (14.36 mg, 0.098 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.51-7.47 (m, 1H), 5.57-5.53 (m, 1H), 4.84 (d, J = 10.5 Hz) , 1H), 4.08 (d, J = 15.1 Hz, 1H), 3.60 (s, 3H), 3.16 (t, J = 13.3 Hz, 1H), 2.89-2.75 (m, 2H), 2.67-2.49 (m, 2H), 1.81 (s, 2H), 1.72 (d, J = 16.9 Hz, 3H), 1.26 (d, J = 9.1 Hz, 4H)

LC/MS: 405 (M+H)

Example 34: 7-Chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)

2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 Dissolve hydrochloride (30 mg, 0.082 mmol) in ACN (5 ml) and add 2-bromo-1-phenylethan-1-one (19.49 mg, 0.098 mmol) and K ₂ CO ₃ (33.8 mg, 0.245 mmol). After adding it, it was stirred at room temperature for 2 hours. NaHCO ₃ was added and extracted with DCM. The organic layer was dried using anhydrous MgSO4 and then distilled under reduced pressure. The residue was purified by MPLC to give the title compound (19 mg).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.51-7.45 (m, 4H), 5.35 (s, 1H), 3.92 (s, 2H), 3.60 (s, 4H), 3.18-3.09 (m, 4H), 2.49 (d, J = 12.8 Hz, 2H) , 1.24 (s, 1H)

LC/MS: 413 (M+H)

Example 35: 7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2, 3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrid[2 ,3-b]pyrazine-2,3-dione) production

7-Chloro-1-methyl-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine obtained in Preparation Example 20 -2,3-Dione (20 mg, 0.065 mmol), 4-(trifluoromethoxy)phenol (17.3 mg, 0.097 mmol) and triphenylphosphine (33.9 mg, 0.129) were dissolved in THF (6 mL). Then DIAD (0.025 ml, 0.129 mmol) was added. The reaction solution was stirred at room temperature for 16 hours, diluted with H ₂ O and EtOAc, and the extracted organic layer was dried over anhydrous Na ₂ CO ₃ and distilled under reduced pressure. The residue was purified by MPLC to give the title compound (15 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 9.0 Hz, 2H), 7.04 ( d, J = 9.0 Hz, 2H), 5.47-5.42 (m, 1H), 4.63 (s, 1H), 3.64 (s, 3H), 3.17-3.09 (m, 2H), 2.25-2.22 (m, 2H) , 1.76~1.71 (m, 2H), 1.55~1.52 (m, 2H)

LC/MS: 470 (M+H)

Example 36: 7-Chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (7-chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b] Preparation of pyrazine-2,3-dione)

2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (32 mg) was obtained in a similar manner to Example 3 using hydrochloride (30 mg, 0.082 mmol) and 4-chlorobenzenesulfonyl chloride (17.22 mg, 0.082 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.73 (dt, J = 8.8, 2.3 Hz, 2H), 7.53 (dt, J = 8.8, 2.1 Hz, 2H) ), 7.46 (d, J = 1.8 Hz, 1H), 5.20 (qd, J = 8.1, 4.0 Hz, 1H), 3.97 (dd, J = 9.8, 2.1 Hz, 2H), 3.58 (s, 3H), 3.04 (qd, J = 12.5, 4.1 Hz, 2H), 2.48 (td, J = 12.3, 2.3 Hz, 2H), 1.69 (d, J = 11.9 Hz, 2H)

LC/MS: 470 (M+H)

Example 37: 7-Chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[ 2,3-b] pyrazine-2,3-dione (7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (21 mg) was prepared in a manner similar to Example 34 using hydrochloride (30 mg, 0.082 mmol) and 2-bromo-1-(4-chlorophenyl)ethan-1-one (22.86 mg, 0.098 mmol). was obtained.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.21-8.19 (m, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.46-7.41 (m, 3H), 5.36 (t, J = 12.6 Hz) , 1H), 3.88 (s, 2H), 3.60 (s, 3H), 3.15-3.04 (m, 4H), 2.50 (d, J = 11.4 Hz, 2H), 1.62 (d, J = 11.0 Hz, 2H)

LC/MS: 448 (M+H)

Example 38: 4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)- 1) piperidin-1-yl) acetyl) benzonitrile (4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b ]Preparation of pyrazin-4(1H)-yl)piperidin-1-yl)acetyl)benzonitrile)

2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title compound (10 mg) was obtained in a similar manner to Example 34 using hydrochloride (30 mg, 0.082 mmol) and 4-(2-bromoacetyl)benzonitrile (21.94 mg, 0.098 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.3 Hz, 1H), 8.16 (t, J = 4.1 Hz, 2H), 7.81-7.76 (m, 2H), 7.46 (d, J = 1.8 Hz, 1H), 5.39-5.33 (m, 1H), 3.88 (s, 2H), 3.59 (d, J = 5.0 Hz, 3H), 3.12-3.01 (m, 4H), 2.50-2.44 (m, 2H), 1.62 (d, J = 13.3 Hz, 2H)

LC/MS: 438 (M+H)

Example 39: 7-Chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4- Dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl) Preparation of piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

2 of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 4 The title was prepared in a similar manner to Example 34 using hydrochloride (30 mg, 0.082 mmol) and 2-bromo-1-(4-(trifluoromethyl)phenyl)ethan-1-one (26.1 mg, 0.098 mmol). Compound (5 mg) was obtained.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.46 ( d, J = 1.8 Hz, 1H), 5.21-5.44 (1H), 3.88 (s, 2H), 3.60 (s, 3H), 3.09 (dd, J = 19.9, 11.7 Hz, 4H), 2.45 (t, J = 11.2 Hz, 2H), 1.64 (s, 2H)

LC/MS: 481 (M+H)

Example 40: 7-Chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b] Pyrazine-2,3-dione (7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)

7-Chloro-1-methyl-4-(4-oxocyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (50 mg, 0.16 mmol), 4-(trifluoromethoxy)aniline (86 mg, 0.487 mmol), and sodium triacetoxyborohydride (172 mg, 0.812 mmol) were dissolved in DCE (1.7 mL) and then added to acetic acid (14 μL, 0.244 mmol) was added at room temperature. The reaction mixture was stirred at 60° C. for 25 hours. The reaction mixture was cooled, distilled under reduced pressure, and diluted with DCM. The mixture was extracted using saturated aqueous NaHCO ₃ solution. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure, and then purified by MPLC to obtain the title compound (13 mg).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.22 (t, J = 1.8 Hz, 1H), 7.49 (dd, J = 5.9, 1.8 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.69-6.56 (m, 2H), 5.51-5.37 (m, 1H), 4.34 (br s, 1H), 3.78 (br s, 1H), 3.62 (d, J = 3.7 Hz, 3H), 2.87-2.74 ( m, 2H), 2.07 (d, J = 16.0 Hz, 2H), 1.77-1.67 (m, 2H), 1.57 (t, J = 6.2 Hz, 2H)

LCMS: 469.1 (M+H), 470.1 (M+2H) 471.1 (M+3H)

Example 41: 7-Chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1 ,Manufacture of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-((1r,4r)-4-hydroxycyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine obtained in Preparation Example 20 -2,3-dione (45 mg, 0.145 mmol), 2-chloro-5-methylpyrimidine, Cs ₂ CO ₃ (142 mg, 0.436 mmol), xantphos (8.4 mg, 0.015 mmol), Pd ₂ (dba ) ₃ (6.7 mg, 0.0073 mmol) was stirred at 110°C for 6 hours in 1,4-dioxane (6 mL) solvent. The reaction solution was cooled to room temperature, filtered through Celite, and the filtrate was distilled under reduced pressure. The residue was purified by MPLC to give the title compound (11 mg).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.34 (s, 2H), 8.23 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 5.47~5.43 (m, 1H) ), 5.14~5.09 (m, 1H), 3.64 (s, 3H), 2.94~2.87 (m, 2H), 2.38~2.36 (m, 2H), 2.25 (s, 3H), 1.80~1.72 (m, 4H) )

LC/MS: 424 (M+Na)

Example 42: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3 -b] Preparation of pyrazin-4(1H)-yl)-N-methyl-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 The title compound (20 mg) was obtained in a similar manner to Step E of Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (25 mg, 0.05 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.5 Hz, 2H), 7.20 ( d, J = 8.9 Hz, 2H), 5.41 (t, J = 12.1 Hz, 1H), 4.01 (d, J = 12.8 Hz, 2H), 3.61 (s, 3H), 3.27 (s, 3H), 2.80- 2.75 (m, 2H), 2.67 (qd, J = 12.2, 3.4 Hz, 2H), 1.51 (d, J = 11.6 Hz, 2H)

LC/MS: 512.1 (M+H), 534.1 (M+Na)

Example 43: 7-Chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy )benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) Preparation

7-Chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3- obtained in Preparation Example 21 b] The title compound (39 mg) was prepared in the same manner as in Example 1 using pyrazine-2,3-dione (34 mg, 0.095 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.018 ml, 0.114 mmol). ) got

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.25 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.30 ( d, J = 8.5 Hz, 2H), 5.48~5.43 (m, 1H), 4.40 (br s, 1H), 3.68~3.65 (m, 1H), 3.63 (s, 3H), 3.32~3.27 (m, 1H) ), 3.17~3.10 (m, 1H), 2.74~2.70 (m, 1H), 2.03~1.99 (m, 1H), 1.38 (d, J = 6.5 Hz, 3H), 0.79 (d, J = 7.0 Hz, 3H)

LC/MS: 511 (M+H)

Example 44: 7-Chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (50) obtained in Preparation Example 4 mg, 0.170 mmol) was dissolved in DMF (3 mL) and 4-fluoro-3-(trifluoromethyl)benzoic acid (35.3 mg, 0.170 mmol), DIPEA (74.1 μl, 0.424 mmol) and HATU (77 mg, 0.204 mmol) were dissolved in DMF (3 mL). mmol) was added and stirred at room temperature for 12 hours. It was diluted with EtOAc and washed several times with brine. The organic layer was dried over anhydrous MgSO ₄ and distilled under reduced pressure, and then purified by MPLC to obtain the title compound (55 mg).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.70-7.66 (m, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 9.1 Hz, 1H), 7.24 (s, 0H), 5.61 (d, J = 11.4 Hz, 1H), 4.66-5.07 (1H), 3.65-3.97 (1H) ), 3.61 (s, 3H), 3.04-3.34 (1H), 2.91 (s, 3H), 1.79-1.59 (m, 2H)

LC/MS: 485 (M+H)

Example 45: 7-Chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyri [2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1 ,Manufacture of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.13 mmol) and 4-(trifluoromethyl)cyclohexane-1-carboxylic acid (31 mg, 0.16 mmol) to obtain the title compound (51 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 2.1 Hz, 1H), 5.61-5.56 (m, 1H), 4.84 (d, J = 12.2 Hz, 1H), 4.01 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.21 (t, J = 12.1 Hz, 1H), 2.90-2.56 (m, 4H), 2.13-1.91 (m, 5H), 1.74-1.68 (m, 4H), 1.64-1.59 (m, 2H)

LC/MS: 473.1 (M+H), 495.1 (M+Na)

Example 46: 7-Chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-fluoro-2-(trifluoromethyl)benzoic acid (28.2 mg, 0.136 mmol) to obtain the title compound (35 mg) in a similar manner to Example 45.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.18 (dd, J = 6.9, 1.8 Hz, 1H), 7.75-7.69 (m, 1H), 7.48 (dd, J = 7.3, 2.3 Hz, 1H), 7.21 -7.03 (m, 2H), 5.62-5.50 (m, 1H), 4.98-4.91 (m, 1H), 3.60 (d, J = 3.7 Hz, 3H), 3.49 (dd, J = 35.0, 13.5 Hz, 1H) ), 3.26-3.13 (m, 1H), 3.02-2.80 (m, 3H), 1.82-1.77 (m, 1H), 1.61-1.54 (m, 2H)

LC/MS: 485 (M+H)

Example 47: 4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 4-bromo-2-(trifluoromethyl)benzoic acid (36.5 mg, 0.136 mmol) to obtain the title compound (35 mg) in a similar manner to Example 45.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.18 (dd, J = 6.6, 2.1 Hz, 1H), 7.85 (d, J = 13.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.51-7.47 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 5.67-5.49 (m, 1H), 4.98-4.91 (m, 1H), 3.60 (d, J = 3.7 Hz, 3H), 3.53- 3.41 (m, 1H), 3.23-3.09 (m, 1H), 3.02-2.81 (m, 3H), 1.81-1.76 (m, 1H), 1.58 (s, 2H)

LC/MS:456 (M+H)

Example 48: 7-Chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-fluoro-2-methylbenzoic acid (20.92 mg, 0.136 mmol) to obtain the title compound (30 mg) in a similar manner to Example 45.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.17 (d, J = 19.2 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 13.0, 7.5 Hz, 1H), 7.04-6.86 (m, 2H), 5.59 (s, 1H), 4.98 (s, 1H), 3.60 (t, J = 16.7 Hz, 4H), 3.18-3.12 (m, 1H), 2.96-2.82 (m, 3H), 2.34 (d, J = 77.8 Hz, 3H), 1.80 (d, J = 11.4 Hz, 1H), 1.58 (d, J = 14.6 Hz, 2H)

LC/MS:431 (M+H)

Example 49: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3 -b] Preparation of pyrazin-4(1H)-yl)-N-ethyl-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 A method similar to Step E of Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (40 mg, 0.08 mmol) and bromoethane (7.80 μL, 0.10 mmol) The title compound (15 mg) was obtained.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.19- 7.16 (m, 2H), 5.38 (t, J = 11.9 Hz, 1H), 3.96 (d, J = 13.1 Hz, 2H), 3.71 (q, J = 7.0 Hz, 2H), 3.60 (s, 3H), 2.73 (dd, J = 13.0, 11.4 Hz, 2H), 2.62 (qd, J = 12.3, 3.4 Hz, 2H), 1.46 (dd, J = 11.6, 2.1 Hz, 2H), 1.17 (t, J = 7.0 Hz) , 3H)

LC/MS:526.1 (M+H), 548.1 (M+Na)

Example 50: 7-Chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione (7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[ Preparation of 2,3-b]pyrazine-2,3-dione)

7-Chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da obtained in Preparation Example 21 The title compound (43 mg) was obtained in the same manner as in Example 8 using ion (47 mg, 0.136 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.026 ml, 0.163 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 9.0 Hz, 2H), 7.49 (s, 1H), 7.29 (d, J = 8.5 Hz, 2H), 5.66 (br s, 1H) , 4.93 (br s, 1H), 3.88 (br s, 1H), 3.62 (s, 3H), 3.23 (br s, 1H), 2.96 (br s, 3H), 2.65 (s, 3H), 1.83~1.67 (m, 2H)

LC/MS: 497 (M+H)

Example 51: 7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione (7-bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid Preparation of [2,3-b]pyrazine-2,3-dione)

7-Bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- obtained in Preparation Example 23 The title compound (59 mg) was obtained in the same manner as in Example 8 using dione (49 mg, 0.126 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.024 ml, 0.151 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.64 (s, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 5.65 (br s, 1H) , 4.93 (br s, 1H), 3.89 (br s, 1H), 3.62 (s, 3H), 3.22 (br s, 1H), 2.96 (br s, 3H), 2.68 (s, 3H), 1.82~1.67 (m, 2H)

LC/MS: 541, 543 (M+H)

Example 52: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( Cyclopropylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid Preparation of [2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (50 mg, 0.10 mmol) and (bromomethyl)cyclopropane (15 mg, 0.11 mmol) The title compound (31 mg) was obtained in a similar manner to E.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (s, 1H), 7.48 (s, 1H), 7.28-7.19 (m, 4H), 5.39 (s, 1H), 4.00 (d, J = 12.5 Hz , 2H), 3.60 (s, 3H), 3.54 (d, J = 6.4 Hz, 2H), 2.74 (t, J = 12.5 Hz, 2H), 2.64 (t, J = 10.7 Hz, 2H), 1.48 (d , J = 11.0 Hz, 2H), 1.13 (s, 1H), 0.45 (d, J = 7.3 Hz, 2H), 0.15 (d, J = 4.0 Hz, 2H)

LC/MS: 552.2 (M+H), 574.2 (M+Na)

Example 53: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( Cyclohexylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid Preparation of [2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (50 mg, 0.10 mmol) and (bromomethyl)cyclohexane (20 mg, 0.11 mmol) The title compound (11 mg) was obtained in a similar manner to E.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.16 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.16 ( d, J = 8.9 Hz, 2H), 5.40 (s, 1H), 4.02 (d, J = 13.1 Hz, 2H), 3.61 (s, 3H), 3.51 (d, J = 7.0 Hz, 2H), 2.76 ( t, J = 12.2 Hz, 2H), 2.65 (dd, J = 12.1, 9.3 Hz, 2H), 1.81-1.69 (m, 6H), 1.49 (d, J = 10.1 Hz, 2H), 1.28-1.18 (m , 3H), 1.04-0.97 (m, 2H)

LC/MS: 594.2 (M+H), 595.2 (M+2H)

Example 54: 7-Chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-di Hydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin Preparation of -4-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid (29.3 mg, 0.145 mmol) to obtain the title compound (22 mg) in a similar manner to Example 1.

LC/MS: 480.0 (M+H)

Example 55: 7-Chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidine- 4-yl)-1-methyl-1,4-dihydropyrido [2,3-b] pyrazine-2,3-dione (7-chloro-4-(1-(1-(5-chloropyridin- 2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione) manufacture of

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (42.3 mg, 0.145 mmol). The title compound (39 mg) was obtained in a similar manner.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.48 (s, 1H), 8.19 (s, 1H), 7.87 (dd, J = 2.3, 8.7 Hz, 1H), 7.82 (s, 1H), 7.75 (d) , J = 8.7 Hz, 1H), 7.49 (s, 1H), 5.64-5.56 (m, 1H), 4.96 (d, J = 10.4 Hz, 1H), 3.88 (d, J = 14.2 Hz, 1H), 3.62 (s, 3H), 3.33-3.24 (m, 1H), 3.00-2.88 (m, 3H), 1.81 (d, J = 11.6 Hz, 1H), 1.67 (d, J = 11.9 Hz, 1H)

LC/MS: 569.4 (M+H)

Example 56: 7-Chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione hydrochloride (7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b] Preparation of pyrazine-2,3-dione hydrochloride)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione of Preparation Example 4 (300 mg , 0.906 mmol) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (208 mg, 0.906 mmol) were used to obtain a mixture (257 mg) in a similar manner to Example 1 and then purified. The title compound (224 mg) was synthesized in a manner similar to Step F of Preparation Example 1.

1H-NMR (500 MHz, METHANOL-D4) δ 8.24 (s, 1H), 7.90 (s, 1H), 5.72 (br. s., 1H), 4.71 (d, J = 13.0 Hz, 1H), 4.24 ( d, J = 13.3 Hz, 1H), 3.63-3.57 (m, 3H), 3.45 (t, J = 13.6 Hz, 2H), 3.19-3.04 (m, 3H), 2.85-2.63 (m, 4H), 2.06 -1.88 (m, 4H), 1.85 (d, J = 12.8 Hz, 1H), 1.78 (d, J = 11.1 Hz, 1H)

LC/MS: 443.4 (M+H)

Example 57: N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4( 1H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide (N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3- Preparation of dihydropyrido[2,3-b]pyrazin-4(1H)-yl)cyclohexyl)-4-(trifluoromethoxy)benzamide)

4-(4-aminocyclohexyl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione of Preparation Example 17 (50 mg, 0.162 mmol) and 4-(trifluoromethoxy)benzoyl chloride (43.6 mg, 0.194 mmol) to obtain the title compound (25 mg) in a similar manner to Example 8.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12-8.26 (1H), 7.72-7.88 (2H), 7.39-7.49 (1H), 7.26-7.36 (2H), 5.81-5.97 (1H), 5.25-5.41 (1H), 4.11-4.23 (1H), 3.52-3.68 (3H), 2.83-3.02 (2H), 2.18-2.35 (2H), 1.71-1.86 (2H), 1.45-1.51 (2H)

LC/MS: 497 (M+H)

Example 58: 7-Chloro-4-(1-(5-chloropyrimidinee-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2, 3-b] pyrazine-2,3-dione (7-chloro-4-(1-(5-chloropyrimidine-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 5-chloropyrimidine-2-carboxylic acid (23.67 mg, 0.149 mmol) to obtain the title compound (44 mg) in a similar manner to Example 44.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.78 (s, 2H), 8.21 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 5.56 (d, J = 11.4 Hz, 1H), 4.95 (d, J = 9.1 Hz, 1H), 3.72 (d, J = 13.3 Hz, 1H), 3.60 (s, 3H), 3.26 (td, J = 13.2, 2.9 Hz, 1H), 3.04-2.95 (m, 3H), 1.82 (d, J = 8.7 Hz, 1H), 1.64 (d, J = 11.0 Hz, 1H)

LC/MS: 436 (M+H)

Example 59: 7-Chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione (7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 Manufacture of -dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (40) obtained in Preparation Example 4 mg, 0.136 mmol) and 6-chloronicotinic acid (23.52 mg, 0.149 mmol) to obtain the title compound (53 mg) in a similar manner to Example 44.

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.50 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.79 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 5.61 (d, J = 11.4 Hz, 1H), 4.89 (s, 1H), 3.82 (d, J = 27.0 Hz, 1H), 3.61 (s, 3H), 3.26 (s, 1H), 2.96-2.83 (m, 3H), 1.75 (d, J = 38.9 Hz, 2H)

LC/MS: 435 (M+H)

Example 60: 7-Chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2 ,3-b]pyrazine-2,3-dione) production

7-Chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-obtained in Example 56 b] The title compound was prepared in a manner similar to Step E of Preparation Example 1 using pyrazine-2,3-dione hydrochloride (30 mg, 0.068 mmol) and 1-bromo-2-methylpropane (9 mg, 0.081 mmol). (7.7 mg) was obtained.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.17 (s, 1H), 7.49 (s, 1H), 5.57 (br. s., 1H), 4.84 (d, J = 12.7 Hz, 1H), 4.21 ( br. s., 2H), 4.08 (d, J = 12.8 Hz, 1H), 3.87 (d, J = 5.0 Hz, 2H), 3.61 (s, 3H), 3.22 (t, J = 12.4 Hz, 1H) , 2.91-2.66 (m, 6H), 1.94 (tt, J = 6.8, 13.3 Hz, 1H), 1.82-1.67 (m, 6H), 0.94 (d, J = 6.7 Hz, 6H)

LC/MS: 463.0 (M+H),

Example 61: 4-(1-(1-acetylpiperidin-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2, 3-b] pyrazine-2,3-dione (4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-obtained in Example 56 b] The title compound (17.6 mg) was obtained in a similar manner to Example 8 using pyrazine-2,3-dione hydrochloride (30 mg, 0.068 mmol) and acetyl chloride (0.015 ml, 0.203 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (br. s., 1H), 7.49 (s, 1H), 5.60 (br. s., 1H), 4.84 (d, J = 11.7 Hz, 1H) , 4.61 (t, J = 14.3 Hz, 1H), 4.08 (d, J = 11.9 Hz, 1H), 3.90 (br. s., 1H), 3.61 (s, 3H), 3.23 (t, J = 13.0 Hz) , 1H), 3.18-3.07 (m, 1H), 2.89 (br. s., 1H), 2.83- 2.74 (m, 2H), 2.74-2.65 (m, 2H), 2.11 (s, 3H), 1.90- 1.71 (m, 6H)

LC/MS: 449.0 (M+H),

Example 62: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( Cyclobutylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid Preparation of [2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl)-N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide)

4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N- obtained in Example 15 Preparation Example 1 using (4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide (50 mg, 0.10 mmol) and (bromomethyl)cyclobutane (17 mg, 0.11 mmol) The title compound (10 mg) was obtained in a similar manner to E.

LC/MS:526.1 (M+H), 548.1 (M+Na)

Example 63: 6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)

6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione of Preparation Example 7 (30 mg, 0.103 mmol) to obtain the title compound (35 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.50 (t, J = 7.5 Hz, 3H), 7.28 (d, J = 7.0 Hz, 2H), 6.70 (d, J = 8.9 Hz, 1H), 5.59 ( t, J = 11.4 Hz, 1H), 4.92 (s, 1H), 3.98 (br s, 4H), 3.62 (br s, 3H), 3.21 (s, 1H), 3.02-2.90 (m, 3H), 1.80 (d, J = 53.1 Hz, 2H)

LC/MS: 479.1 (M+H), 480.2 (M+2H)

Example 64: 6-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione (6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)

6-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 15 mg, 0.102 mmol) to obtain the title compound (30 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.54 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H), 7.25 ( d, J = 8.5 Hz, 1H), 5.57 (br s, 1H), 4.91 (br s, 1H), 3.86 (br s, 1H), 3.63 (s, 3H), 3.22 (br s, 1H) 3.01- 2.83 (m, 3H), 1.82 (br s, 1H), 1.68 (br s, 1H)

LC/MS: 483.1 (M+H), 505.1 (M+Na)

Example 65: 7-Chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] Pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (150 mg, 0.453 mmol) and 4-(tert-butoxycarbonyl)piperazine-1-carboxylic acid (104 mg, 0.r453 mmol) to obtain the title compound (38 mg) in a similar manner to Example 57.

1H-NMR (500 MHz, METHANOL-D4) δ 8.24 (s, 1H), 7.90 (s, 1H), 5.62 (br. s., 1H), 3.92 (d, J = 13.0 Hz, 2H), 3.61 ( s, 3H), 3.47 (br. s., 4H), 3.21 (br. s., 4H), 3.03 (t, J = 12.7 Hz, 2H), 2.88-2.78 (m, 2H), 1.74 (d, J = 11.0 Hz, 2H)

LC/MS: 444.4 (M+H)

Example 66: 4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrid[2,3-b ]Manufacture of pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30) obtained in Preparation Example 4 mg, 0.091 mmol) and 1H-indole-3-carboxylic acid (17.52 mg, 0.109 mmol) to obtain the title compound (3.4 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.40 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 5.61 (br. s., 1H), 4.61 (br. s., 1H), 3.74 (br. s., 1H), 3.61 (s, 3H), 3.49 (d, J = 5.6 Hz, 1H), 3.09 (d, J = 11.1 Hz, 2H), 2.98 (d, J = 8.4 Hz, 2H), 1.72 (d, J = 12.2 Hz) , 2H)

LC/MS: 438.9 (M+H)

Example 67: 6-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3 Preparation of -b]pyrazine-2,3-dione)

6-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (200) obtained in Preparation Example 15 mg, 0.604 mmol) and 4-oxocyclohexane-1-carboxylic acid (86 mg, 0.604 mmol) to obtain the title compound (53 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 7.47 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 5.58-5.50 (m, 1H), 4.87 (d, J = 11.0 Hz, 1H), 4.14 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.30 (t, J = 13.0 Hz, 1H), 3.05-2.95 (m, 2H), 2.81-2.69 (m, 2H), 2.61 (t, J = 4.3 Hz, 1H), 2.58 (t, J = 4.0 Hz, 1H), 2.41-2.34 (m, 2H), 2.22-2.12 (m, 2H), 2.09 (br. s., 2H), 1.82 (d, J = 11.6 Hz, 1H), 1.75 (d, J = 11.9 Hz, 1H)

LC/MS: 419.9 (M+H)

Example 68: 7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3 Preparation of -b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (200 mg, 0.604 mmol) and 4-oxocyclohexane-1-carboxylic acid (86 mg, 0.604 mmol) to obtain the title compound (112 mg) in a similar manner to Example 1.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.49 (s, 1H), 5.60 (t, J = 11.9 Hz, 1H), 4.85 (d, J = 12.8 Hz, 1H), 4.13 (d, J = 11.7 Hz, 1H), 3.61 (s, 3H), 3.27 (t, J = 12.9 Hz, 1H), 2.99 (dt, J = 4.7, 9.2 Hz, 1H), 2.96-2.87 (m , 1H), 2.78 (d, J = 9.6 Hz, 1H), 2.74-2.65 (m, 1H), 2.56 (d, J = 13.1 Hz, 2H), 2.38 (d, J = 7.9 Hz, 2H), 2.14 (d, J = 8.7 Hz, 2H), 2.11-2.01 (m, 2H), 1.79 (d, J = 11.3 Hz, 1H), 1.73 (d, J = 11.3 Hz, 1H)

LC/MS: 419.9 (M+H)

Example 69: 6-Chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

6-Chloro-1-methyl-4-(1-(4-oxocyclohexanee-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2 ,3-b]pyrazine-2,3-dione (20 mg, 0.048 mmol) and dimethylamine (3.23 mg, 0.072 mmol) were used to obtain the title compound (4.5 mg) in a similar manner to Example 41.

LC/MS: 449.0 (M+H)

Example 70: 7-Chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione (7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1, Preparation of 4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2, [3-b] The title compound (3.4 mg) was obtained in a similar manner to Example 41 using pyrazine-2,3-dione (20 mg, 0.048 mmol) and dimethylamine (3.23 mg, 0.072 mmol).

LC/MS: 449.0 (M+H)

Example 71: 7-Chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2, 3-b] pyrazine-2,3-dione (7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrid[2, Preparation of 3-b]pyrazine-2,3-dione)

7-Chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] obtained in Example 66 ] The title compound (9.6) was prepared in a manner similar to Step E of Preparation Example 1 using pyrazine-2,3-dione (20 mg, 0.045 mmol) and 1-bromo-2-methylpropane (7 mg, 0.054 mmol). mg) was obtained.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (s, 1H), 7.48 (s, 1H), 5.53-5.43 (m, 1H), 3.90-3.81 (m, 3H), 3.61 (s, 3H) , 3.53-3.50 (m, 2H), 3.33-3.30 (m, 1H), 3.29-3.26 (m, 2H), 2.97-2.85 (m, 4H), 2.39 (br. s., 1H), 2.09 (d) , J = 7.3 Hz, 1H), 1.94 (td, J = 6.7, 13.4 Hz, 1H), 1.68 (d, J = 13.3 Hz, 2H), 1.31-1.23 (m, 3H), 0.94 (d, J = 6.7 Hz, 4H), 0.90 (d, J = 6.6 Hz, 2H)

LC/MS: 464.0 (M+H)

Example 72: 7-Chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine Preparation of -2,3-dione)

7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (25) obtained in Preparation Example 4 mg, 0.075 mmol) and pyrrolidine-1-carbonyl chloride (58.1 mg, 0.435 mmol) to obtain the title compound (20.2 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (s, 1H), 7.47 (s, 1H), 5.52-5.44 (m, 1H), 3.93 (d, J = 8.4 Hz, 2H), 3.61 (s , 3H), 3.41 (t, J = 6.4 Hz, 4H), 2.94-2.82 (m, 5H), 1.87-1.82 (m, 4H), 1.67 (m, 2H)

LC/MS: 392.9 (M+H)

Example 73: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 3-Chlorophenyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)-N-(3-chlorophenyl)piperidine-1-carboxamide)

3-chloroaniline (0.016 ml, 0.149 mmol) and 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido [2,3- obtained in Preparation Example 4 b] The title compound (35 mg) was obtained in a similar manner to Example 15 using pyrazine-2,3-dione (0.04 g, 0.136 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.19 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.24 (d, J = 8.2 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 5.57-5.52 (m, 1H), 4.26 (d, J = 13.1 Hz, 2H), 3.60 (s, 3H), 3.03 (t, J = 12.1 Hz, 2H), 2.88 (qd, J = 12.3, 3.9 Hz, 2H), 1.73 (d, J = 9.8 Hz, 2H) )

LC/MS: 448.1 (M+H)

Example 74: 4-(7-Chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-( 4-Chlorobenzyl)piperidine-1-carboxamide (4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrid[2,3-b]pyrazin-4(1H) Preparation of -yl)-N-(4-chlorobenzyl)piperidine-1-carboxamide)

(4-Chlorophenyl)methanamine (0.019 ml, 0.149 mmol) 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido [2 ,3-b]pyrazine-2,3-dione (0.04 g, 0.136 mmol) was used to obtain the title compound (28 mg) in a similar manner to Example 15.

1H-NMR (500 MHz, DMSO-D6) δ 8.26 (d, J = 1.8 Hz, 1H), 7.96 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.32 ( d, J = 8.5 Hz, 2H), 7.19 (t, J = 5.6 Hz, 1H), 5.41 (br s, 1H), 4.25 (d, J = 5.8 Hz, 2H), 4.15 (d, J = 13.7 Hz) , 2H), 3.49 (s, 3H), 2.81 (t, J = 12.7 Hz, 2H), 2.59-2.56 (m, 2H), 1.59 (d, J = 9.8 Hz, 2H)

LC/MS: 462.1 (M+H) 484.1 (M+Na)

Example 75: 1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)

1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (14 mg) obtained in Preparation Example 24 , 0.045 mmol) and 4-(trifluoromethoxy)benzoyl chloride (0.015 mg, 0.068 mmol) to obtain the title compound (19 mg) in the same manner as in Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.28 (d, J = 4.5 Hz, 1H), 7.56 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.16 ( d, J = 4.5 Hz, 1H), 5.90 (br s, 1H), 4.94 (br s, 1H), 4.13 (s, 3H), 3.89 (br s, 1H), 3.24~2.99 (m, 4H), 2.63 (s, 3H), 1.81~1.67 (m, 2H)

LC/MS: 463 (M+H), 485 (M+Na)

Example 76: 7-Chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octane-3 -1)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (7-chloro-1-methyl-4-((1R,3r,5S)-8-( Preparation of 4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrid[2,3-b]pyrazine-2,3-dione)

4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[ The title compound (38 mg) was obtained in a similar manner to Example 8 using 2,3-b]pyrazine-2,3-dione (30 mg, 0.094 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.22 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 1.8 Hz, 1H), 7.27 ( d, J = 7.9 Hz, 2H), 56.08-5;94 (m, 1H), 4.99 (br s, 1H), 4.21-4.06 (m, 1H), 3.61 (s, 3H), 3.12 (br s, 1H), 3.00 (br s, 1H), 2.15 (br s, 2H), 1.97 (br s, 1H), 1.71 (br s, 1H), 1.57 (br s, 2H)

LC/MS: 509.1 (M+H), 522.1 (M+Na)

Example 77: 6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2, 3-b]pyrazine-2,3-dione (6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3 Preparation of -b]pyrazine-2,3-dione)

6-Isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione obtained in Preparation Example 9 The title compound (38 mg) was obtained in a similar manner to Example 8 using (30 mg, 0.094 mmol) and 4-(trifluoromethoxy)benzoyl chloride (23.28 mg, 0.104 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 7.49 (dd, J = 6.9, 1.8 Hz, 2H), 7.46 (d, J = 8.7 Hz, 1H), 7.27 (s, 2H), 6.62 (d, J = 8.7 Hz, 1H), 5.54 (s, 1H), 5.15 (t, J = 6.2 Hz, 1H), 4.53-5.04 (1H), 3.64-4.23 (1H), 3.60 (s, 3H), 2.94 (s) , 4H), 1.61-1.99 (2H), 1.39 (d, J = 6.4 Hz, 6H)

LC/MS: 507 (M+H)

Example 78: 7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)

7-Fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (obtained in Preparation Example 10) The title compound (23 mg) was obtained in a similar manner to Example 8 using 30 mg, 0.108 mmol) and 4-(trifluoromethoxy)benzoyl chloride (26.6 mg, 0.119 mmol).

1H-NMR (400 MHz, CHLOROFORM-D) δ 8.12 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.28 ( dd, J = 8.7, 2.3 Hz, 1H), 5.62 (t, J = 11.4 Hz, 1H), 4.93 (s, 1H), 3.78 (s, 1H), 3.62 (d, J = 15.1 Hz, 3H), 3.17 (d, J = 11.4 Hz, 1H), 2.92 (s, 3H), 1.80-1.59 (m, 2H)

LC/MS: 467 (M+H)

Example 79: Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetra Hydropyrido [2,3-b] pyrazine-7-carboxylate (methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1, Preparation of 2,3,4-tetrahydropyrid[2,3-b]pyrazine-7-carboxylate)

Methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine- obtained in Preparation Example 11 The title compound (159 mg) was obtained in a similar manner to Example 8 using 7-carboxylate 2 hydrochloride (200 mg, 0.511 mmol).

1H-NMR (500 MHz, DMSO-D6) δ 8.78 (s, 1H), 8.08 (s, 1H), 7.58 (d, J = 7.9 Hz, 2H), 7.48 (d, J = 7.9 Hz, 2H), 5.61 (br s, 1H), 4.66 (br s, 1H), 3.93 (s, 3H), 3.67 (br s, 1H), 3.55 (s, 3H), 3.28 (br s, 1H), 2.94 (br s , 1H), 2.78-2.56 (m, 2H), 1.80 (br s, 1H), 1.67 (br s, 1H)

LC/MS: 507.2 (M+H), 529.1 (M+Na)

Example 80: 1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione (1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3-b]pyrazine- Preparation of 2,3-dione)

1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (100 mg) obtained in Preparation Example 12 , 0.365 mmol) to obtain the title compound (119 mg) in a similar manner to Example 8.

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.10 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.34 (s, 1H), 7.32-7.27 (m, 2H), 5.70 (br s, 1H), 4.94 (br s, 1H), 3.89 (br s, 1H), 3.64 (s, 3H), 3.22 (br s, 1H), 2.99 (s, 3H), 2.46 (s, 3H), 1.91-1.63 (m, 2H)

LC/MS: 463.1 (M+H)

Example 81: 7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione (7-bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrid[2,3- b]Manufacture of pyrazine-2,3-dione)

7-Bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (obtained in Preparation Example 13) The title compound (165 mg) was obtained in a similar manner to Example 8 using 250 mg, 0.737 mmol).

1H-NMR (500 MHz, CHLOROFORM-D) δ 8.30 (s, 1H), 7.63 (s, 1H), 7.53 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 5.62 (br s, 1H), 4.92 (br s, 1H), 3.79-3.96 (m, 1H), 3.62 (s, 3H), 3.20 (br s, 1H), 2.92 (br s, 3H), 1.60- 1.90 (m, 2H)

LC/MS: 529.1 (M+Na)

Experimental example: Measurement of DGKα enzyme inhibition effect

_{First ,} 1 40), a 3X OAG (3mM)/ATP (0.45mM) substrate solution was prepared and thoroughly vortexed for 3 minutes to induce the formation of detergent-lipid micelles. Then, a 3X DGKα (7.5 nM) enzyme solution was prepared in 2X enzyme assay buffer (80 mM MOPS (pH 7.2), 2 mM DTT, 200 mM NaCl, 0.2 mg/mL BSA) and vortexed briefly.

After preparing the two solutions, a half-area opaque 96-well assay plate was prepared, and 10 μL of 3X diluted compound solution (30 μM to 0 μM) was transferred to each well. Next, 10 μL of 3X DGKα enzyme solution was transferred to the same plate, mixed by pipetting, and then 10 μL of 3X OAG/ATP substrate solution was added to the assay plate and mixed well. The plate was incubated for 20 minutes at room temperature for the enzyme reaction. Next, 15 μL of ADP-Glo reagent was added to each well, mixed by pipetting, and then incubated the plate for 40 min at room temperature to deplete the remaining ATPs. After this step, 30 μL of Kinase Detection Reagent was added, mixed, incubated for an additional 20 minutes at room temperature, and luminescence was measured in Envision to calculate the IC ₅₀ value for each compound.

The measurement results are shown in Table 1 (+: IC ₅₀ >1 μM, ++: 1 μM> IC ₅₀ >300 nM, +++: IC ₅₀ <300 nM).

[Table 1]

Claims (6)

A compound of formula 1 below, or a pharmaceutically acceptable salt or stereoisomer thereof:
[Formula 1]


In Formula 1,
m represents 0, 1 or 2;
X represents N or CH;
R ₁ represents hydrogen, halo, cyano(-CN), alkyl, alkoxy or aryl unsubstituted or substituted with halo;
R ₂ represents hydrogen, halo, alkyl, alkylcarbonyl or alkoxycarbonyl;
R ₃ represents hydrogen or alkyl;
R ₄ represents alkyl;
R ₅ represents alkyl, and when m is 2, they can combine with each other to form a ring;
R ₆ is -C(=O)-R ₇ , -S(=O) ₂ -R ₇ , -C(=O)-alkylene-R ₇ , -OR ₇ , , -C(=O)-cycloalkylene-R ₇ , -alkylene-C(=O)-R ₇ , or -NH-C(=O)-R ₇ ; where R ₇ represents cycloalkyl, aryl, aralkyl, heterocycloalkyl or heterocyclyl; R ₈ represents hydrogen, alkyl, cycloalkyl or cycloalkyl-alkyl;
The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl include halo, cyano, oxo (=O), alkyl, alkoxy, haloalkyl, haloalkoxy, alkylcarbonyl, dialkylamino, aryl, aryloxy and unsubstituted. or may be optionally substituted with one or more substituents selected from the group consisting of heteroaryl substituted with halo;
The heterocycloalkyl, heterocyclyl and heteroaryl have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms. According to paragraph 1,
m represents 0, 1 or 2;
X represents N or CH;
R ₁ represents hydrogen, halo, cyano, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy or C ₆ -C ₁₀ aryl unsubstituted or substituted with halo;
R ₂ represents hydrogen, halo, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkylcarbonyl or C ₁ -C ₇ alkoxycarbonyl;
R ₃ represents hydrogen or C ₁ -C ₇ alkyl;
R ₄ represents C ₁ -C ₇ alkyl;
R ₅ represents C ₁ -C ₇ alkyl, and when m is 2, they may combine with each other to form a C ₂ -C ₄ ring;
R ₆ is -C(=O)-R ₇ , -S(=O) ₂ -R ₇ , -C(=O)-C ₁ -C ₅ alkylene-R ₇ , -OR ₇ , , -C(=O)-C ₃ -C ₆ cycloalkylene-R ₇ , -C ₁ -C ₅ alkylene-C(=O)-R ₇ , or -NH-C(=O)-R ₇ ; Here, R ₇ is 5 to 3 heteroatoms selected from C ₃ -C ₇ cycloalkyl, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryl-C ₁ -C ₇ alkyl, N and O. represents a 10-membered heterocycloalkyl, or a 5- to 12-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O and S; R ₈ represents hydrogen, C ₁ -C ₇ alkyl, C ₃ -C ₇ cycloalkyl or C ₃ -C ₇ cycloalkyl-C ₁ -C ₇ alkyl;
The cycloalkyl, aryl, heterocycloalkyl and heterocyclyl are unsubstituted or halo, cyano, oxo, C ₁ -C ₇ alkyl, C ₁ -C ₇ alkoxy, halo-C ₁ -C ₇ alkyl, halo-C ₁ -C ₇ alkoxy, C ₁ -C ₇ alkylcarbonyl, di(C ₁ -C ₇ alkyl)amino, C ₆ -C ₁₀ aryl, C ₆ -C ₁₀ aryloxy and unsubstituted or halo substituted N and A compound characterized by being substituted with 1 to 3 substituents selected from the group consisting of 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from O, or a pharmaceutically acceptable salt or stereoisomer thereof. The compound according to claim 1, wherein the compound of formula 1 is selected from the following group, or a pharmaceutically acceptable salt or stereoisomer thereof:
1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;
1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
1,6-dimethyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
4-(1-((3-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
4-(1-((3,4-dichlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
1-methyl-4-(1-((4-phenoxyphenyl)sulfonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3- Dion;
1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2 ,3-b]pyrazine-6-carbonitrile;
7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
7-chloro-1-methyl-4-(1-tosylpiperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;
7-chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetra Hydropyrido[2,3-b]pyrazine-6-carbonitrile;
7-chloro-1-methyl-4-(1-(2-(4-(trifluoromethoxy)phenyl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-chloro-4-(4-(3-chlorophenoxy)cyclohexyl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethoxy)phenyl)piperidine-1-carboxamide;
7-Chloro-1-methyl-4-(1-(2-(pyridin-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-chloro-1-methyl-4-(1-(2-(thiophen-2-yl)acetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-chloro-4-(1-(2-(2-fluorophenyl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-chloro-4-(1-(2-(furan-2-yl)acetyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-Chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyri do[2,3-b]pyrazine-2,3-dione;
7-chloro-1-methyl-4-(1-(2-phenylacetyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
7-Chloro-1-methyl-4-(1-(1-phenylcyclopropane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-chloro-4-(1-(2-(2-fluorophenyl)-2-methylpropanoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2 ,3-b]pyrazine-2,3-dione;
7-chloro-4-(1-(4-chlorobenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
4-((4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine- 1-yl)sulfonyl)benzonitrile;
4-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperidine-1 -carbonyl)benzonitrile;
4-(1-((4-(tert-butyl)phenyl)sulfonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
7-chloro-4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-carbonyl)piperidin-4-yl)-1-methyl-1,4-di hydropyrido[2,3-b]pyrazine-2,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-(tri fluoromethyl)phenyl)piperidine-1-carboxamide;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorophenyl ) piperidine-1-carboxamide;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-cyano phenyl)piperidine-1-carboxamide;
7-chloro-4-(1-(cyclohexanecarbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-da ion;
7-Chloro-1-methyl-4-(1-(2-oxo-2-phenylethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
7-chloro-1-methyl-4-((1s,4s)-4-(4-(trifluoromethoxy)phenoxy)cyclohexyl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-Chloro-4-(1-((4-chlorophenyl)sulfonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
7-chloro-4-(1-(2-(4-chlorophenyl)-2-oxoethyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
4-(2-(4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)piperi din-1-yl)acetyl)benzonitrile;
7-chloro-1-methyl-4-(1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethyl)piperidin-4-yl)-1,4-dihydropyrido [2,3-b]pyrazine-2,3-dione;
7-chloro-1-methyl-4-(4-((4-(trifluoromethoxy)phenyl)amino)cyclohexyl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
7-chloro-1-methyl-4-((1r,4r)-4-((5-methylpyrimidin-2-yl)oxy)cyclohexyl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-methyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1-methyl-1,4- Dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-chloro-4-(1-(4-fluoro-3-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-chloro-1-methyl-4-(1-(4-(trifluoromethyl)cyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido [2, 3-b]pyrazine-2,3-dione;
7-chloro-4-(1-(5-fluoro-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
4-(1-(4-bromo-2-(trifluoromethyl)benzoyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-chloro-4-(1-(5-fluoro-2-methylbenzoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-ethyl-N-( 4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3- b]pyrazine-2,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclopropylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclohexylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
7-chloro-1-methyl-4-(1-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[ 2,3-b]pyrazine-2,3-dione;
7-chloro-4-(1-(1-(5-chloropyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carbonyl)piperidin-4-yl) -1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
7-chloro-1-methyl-4-(1-(piperidine-4-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione hydrochloride;
N-((1r,4r)-4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl )Cyclohexyl)-4-(trifluoromethoxy)benzamide;
7-Chloro-4-(1-(5-chloropyrimidinee-2-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-chloro-4-(1-(6-chloronicotinoyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3 -Dion;
7-chloro-4-(1-(1-isobutylpiperidine-4-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b ]Pyrazine-2,3-dione;
4-(1-(1-acetylpiperidine-4-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(cyclobutylmethyl) -N-(4-(trifluoromethoxy)phenyl)piperidine-1-carboxamide;
6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine- 2,3-dione;
7-chloro-1-methyl-4-(1-(piperazine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2, 3-dione;
4-(1-(1H-indole-3-carbonyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
6-chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
7-Chloro-1-methyl-4-(1-(4-oxocyclohexane-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
6-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-chloro-4-(1-(4-(dimethylamino)cyclohexane-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3 -b]pyrazine-2,3-dione;
7-chloro-4-(1-(4-isobutylpiperazine-1-carbonyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-chloro-1-methyl-4-(1-(pyrrolidine-1-carbonyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(3-chlorophenyl ) piperidine-1-carboxamide;
4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazin-4(1H)-yl)-N-(4-chlorobenzyl ) piperidine-1-carboxamide;
1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione;
7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzoyl)-8-azabicyclo[3.2.1]octan-3-yl)- 1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione;
6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b] pyrazine-2,3-dione;
7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione;
Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[ 2,3-b]pyrazine-7-carboxylate;
1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2 ,3-dione; and
7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzoyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine -2,3-dione. Diacylglycerol kinase comprising the compound of formula 1 as defined in any one of claims 1 to 3 as an active ingredient, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier. Pharmaceutical composition for preventing or treating diseases related to (DGKs). The pharmaceutical composition according to claim 4, wherein the disease related to diacylglycerol kinases (DGKs) is cancer. The method of claim 5, wherein the cancer is gastrointestinal cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain tumor, testicular cancer, laryngeal cancer, prostate cancer, neuroblastoma, kidney cancer, A pharmaceutical composition selected from the group consisting of thyroid cancer, esophageal cancer, skin cancer, osteosarcoma, and bladder cancer.