Heterocyclic compounds as diacylglycerol kinase inhibitors and their uses

Abstract

The present invention relates to a heterocyclic compound represented by formula (1) which exhibits diacylglycerol kinase inhibitory activity, a pharmaceutical composition containing the compound as an active ingredient, and uses thereof.

Description

[Technical field]

[0001] The present invention relates to a heterocyclic compound represented by formula (1) which exhibits diacylglycerol kinase inhibitor activity, a pharmaceutical composition containing the same as an active ingredient, and use thereof. [Background technology]

[0002] In recent years, anti-cancer immunotherapy, especially T cell therapy, which shows great effectiveness against some tumors such as malignant melanoma, has attracted attention. However, a major obstacle to be overcome by anti-cancer T cell therapy is tumor-induced T cell immunosuppression (T cell tolerance, T cell anergy). That is, even if a large number of anti-cancer T cells approach a tumor, there is a mechanism by which the tumor neutralizes the T cells, and the effect of the T cells can be greatly reduced. Therefore, by understanding the mechanism of T cell inactivation caused by tumors and preparing measures to prevent this inactivation, it may be possible to greatly improve the therapeutic efficiency of anti-cancer T cell therapy. Diacylglycerol kinases (DGKs) have attracted great interest as an immune anti-cancer target to overcome this. DGKs are overexpressed when T cells fall into anergy, and play a role in inactivating T cell activity. Specifically, diacylglycerol kinases (DGKs) function as intracellular checkpoints by converting diacylglycerol (DAG), an important factor in signal transduction, into phosphatidic acid (PA). When DGK is inhibited, the accumulated DAG strengthens the TCR signal transduction pathway of T cells, thereby reactivating anergic T cells. Therefore, synergistic effects can be expected when DGK inhibition is used alone or in combination with cancer immunotherapy such as PD-(L)1. In addition, DGK is known to be overexpressed in various cancer cells and to cause survival, migration, and drug resistance of cancer cells. Therefore, if a substance that inhibits DGK is developed, it can be expected to have excellent anticancer effects due to its dual pharmacological effect of simultaneously exerting the role of cancer immunotherapy such as T cell reactivation and apoptotic action. Furthermore, since DGK is known to be involved in not only T cell anergy but also NK cell anergy, the development of an inhibitor may provide an additional advantage of removing cancer cells by NK cells. Summary of the Invention

[0003] An object of the present invention is to provide novel heterocyclic compounds of formula (1) which exhibit diacylglycerol kinase inhibitor activity. [Problem to be solved by the invention]

[0004] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases such as cancer associated with diacylglycerol kinase, which comprises the compound as an active ingredient.

[0005] Yet another object of the present invention is to provide a method for preventing or treating a disease associated with diacylglycerol kinase, such as cancer, in a subject using said heterocyclic compound as an active ingredient. [Means for solving the problem]

[0006] In order to achieve the above object, the present invention provides a compound represented by the following formula (1): [ka] [In the formula, m represents an integer of 0, 1, or 2; R1 represents hydrogen, halo, cyano (-CN), alkyl, alkoxy, alkylcarbonyl, or aryl; R2 represents hydrogen, halo, cyano, carboxy (-COOH), alkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, cycloalkyl, aryl, or heteroaryl; R3 represents hydrogen or alkyl; R4 represents alkyl; R5 represents alkyl, and when m is 2, they may be bonded together to form a ring; R6 is, [ka] (wherein R7 and R8 each independently represent carbocyclyl or heterocyclyl); The heteroaryl and heterocyclyl have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms; wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl and aryloxy, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0007] The compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt. The pharmaceutically acceptable salt includes an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, etc.; an organic acid 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.; a sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.; and the like. The pharmaceutically acceptable carboxylate includes an alkali metal or alkaline earth metal salt formed by, for example, lithium, sodium, potassium, calcium, magnesium, etc.; an amino acid salt such as lysine, arginine, guanidine, etc.; an organic salt such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. The compounds of formula (1) according to the present invention can be converted into their salts by conventional methods.

[0008] On the other hand, the compounds according to the present invention may have asymmetric carbon centers and asymmetric axes or planes, and therefore may exist as E or Z isomers, R or S isomers, racemates, stereoisomeric mixtures, and individual stereoisomers, all of which are within the scope of the present invention.

[0009] In this specification, unless otherwise specified, the compound of formula (1) is used to include all compounds of formula (1), pharma- ceutically acceptable salts and isomers thereof.

[0010] The concepts defined herein for substituents are used to define compounds of formula (1).

[0011] Unless otherwise indicated, the term "halo," as used herein, alone or in combination with an additional term (e.g., haloalkyl or haloalkoxy), means a radical of fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0012] As used herein, unless otherwise indicated, the term "alkyl," alone or in combination with additional terms (e.g., haloalkyl), refers to the radical of a saturated or unsaturated aliphatic hydrocarbon group, e.g., having 1 to 7 straight or branched chain carbon atoms. For example, alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl, and 1,2-dimethylpropyl, and the like.

[0013] As used herein, unless otherwise indicated, the term "alkoxy" refers to an alkyloxy having, for example, 1 to 7 carbon atoms.

[0014] As used herein, unless otherwise indicated, the term "cycloalkyl" refers to a ur-saturated cyclic aliphatic hydrocarbon having, for example, 3 to 7 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0015] As used herein, unless otherwise indicated, the term "aryl" 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, and the like.

[0016] Unless otherwise specified, the term "heteroaryl" as used herein means an aromatic hydrocarbon containing one or more heteroatoms selected from N, O and S as ring members, for example, a 5- to 10-membered aromatic hydrocarbon. Examples of heteroaryl 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 -dihydroisoquinolinyl, thiazolopyridyl, 2,3-dihydrobenzofuran, 2,3-dihydrothiophene, 2,3-dihydroindole, benzo[1,3]dioxane, chroman, thiochroman, 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]dioxin, 2,3-dihydrobenzo[1,4]dioxin, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, and the like.

[0017] As used herein, unless otherwise indicated, the term "carbocyclyl" refers to a radical of an unsaturated, partially or fully saturated hydrocarbon forming a single or fused ring, for example having 5 to 10 carbon atoms, which may include aromatic hydrocarbons such as aryls.

[0018] Unless otherwise indicated, the term "heterocyclyl" as used herein means unsaturated, or partially or fully saturated, forming a single or fused ring, and containing one or more heteroatoms, for example, 1 to 3 heteroatoms selected from the group consisting of N, O and S. Specifically, the heterocyclyl may be a 5- to 12-membered hydrocarbon having 1 to 3 heteroatoms. The unsaturated heterocyclyl may include aromatic hydrocarbons such as heteroaryls.

[0019] According to one embodiment of the present invention, in the formula (1), m represents an integer of 0, 1 or 2; R1 is hydrogen, halo, cyano, C1-C7 alkyl, C1-C7 alkoxy, C1-C7 alkylcarbonyl or C6-C 10 represents aryl; R2 is hydrogen, halo, cyano, carboxy, C1-C7 alkyl, C1-C7 alkylcarbonyl, C1-C7 alkoxycarbonyl, aminocarbonyl, C1-C7 alkylaminocarbonyl, di(C1-C7 alkyl)aminocarbonyl, di(C1-C7 alkyl)amino-C1-C7 alkylaminocarbonyl, C3-C7 cycloalkyl, C6-C 10 aryl, or a 5-10 membered heteroaryl having 1-3 heteroatoms selected from N and O; R3 represents hydrogen or C1-C7 alkyl; R4 represents C1-C7 alkyl; R5 represents C1-C7 alkyl, and when m is 2, may be bonded together to form a C2-C4 ring; R6 is, [ka] (wherein R7 and R8 are each independently C5-C 10 carbocyclyl, or a 5-12 membered heterocyclyl having 1-3 heteroatoms selected from N, O and S; The aryl, heteroaryl, carbocyclyl and heterocyclyl are unsubstituted or selected from the group consisting of halo, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, halo-C1-C7 alkoxy, C6-C 10 Aryl and C6-C 10 It may be substituted with 1 to 3 substituents selected from the group consisting of aryloxy.

[0020] According to another embodiment of the present invention, in the formula (1), m represents an integer of 0, 1 or 2; R1 represents hydrogen, halo, cyano, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 alkylcarbonyl, or C6 aryl; R2 represents hydrogen, halo, cyano, carboxy, C1-C5 alkyl, C1-C5 alkylcarbonyl, C1-C5 alkoxycarbonyl, aminocarbonyl, C1-C5 alkylaminocarbonyl, di(C1-C5 alkyl)aminocarbonyl, di(C1-C5 alkyl)amino-C1-C5 alkylaminocarbonyl, C3-C6 cycloalkyl, C6 aryl, or a 5- or 6-membered heteroaryl having 1 to 3 heteroatoms selected from N and O; R3 represents hydrogen or C1-C5 alkyl; R4 represents C1-C5 alkyl; R5 represents C1-C5 alkyl, and when m is 2, they may be bonded together to form a C2 ring; R6 is, [ka] (where R7 is C6-C 10 aryl, 6-10 membered heteroaryl having 1-3 heteroatoms selected from N and O, partially saturated C9-C 10 R represents a carbocyclyl or a partially saturated 9- or 10-membered heterocyclyl having 1 to 3 heteroatoms selected from N and O; R represents a C6-C 10 aryl; The aryl, heteroaryl, carbocyclyl and heterocyclyl are unsubstituted or selected from the group consisting of halo, C1-C5 alkyl, C1-C5 alkoxy, halo-C1-C5 alkyl, halo-C1-C5 alkoxy, C6-C 10 Aryl and C6-C 10 It may be substituted with 1 to 3 substituents selected from the group consisting of aryloxy.

[0021] Representative compounds of formula (1) according to the present invention include, but are not limited to, the following compounds: Methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Ethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Isobutyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((2-chloroquinolin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((1,2-dimethyl-1H-indol-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-((1-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(quinolin-4-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-([1,1'-biphenyl]-2-ylmethyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-Methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 4-(1-(2-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(4-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((2-methoxypyridin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((6-fluoropyridin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(4-phenoxybenzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(isoquinolin-5-ylmethyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(3-phenoxybenzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-benzylpiperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-Dimethyl-4-(1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 1-Methyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 7-Chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1-methyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1-methyl-4-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzyl)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)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1-methyl-4-(1-(quinoxalin-5-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-((5-chloronaphthalen-1-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-Methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1-methyl-4-(1-((5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 7-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Cyclopropyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-(3-chloro-4-fluorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-(3-chloro-4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Cyclopropyl-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 4-(1-(bis(3-chlorophenyl)methyl)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-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-Methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile; 7-Acetyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-4-(1-((1-isopropyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 6-Acetyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 6-Methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,8-Dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzyl)-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)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-Fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate; 1,7-Dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-Methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid; N-(2-(dimethylamino)ethyl)-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; N,N,1-trimethyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; N,1-dimethyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; 1-Methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; and 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1,7-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione.

[0022] Terms and abbreviations used herein have their original meanings unless otherwise indicated.

[0023] In order to explain the present invention, the method for producing the compound of formula (1) will be described below based on the reaction scheme. However, a person skilled in the art can produce the compound of formula (1) by various methods based on the structure of formula (1), and such methods should also be interpreted as being within the scope of the present invention. That is, the compound of formula (1) can be produced by the method described herein or by combining various methods disclosed in the prior art, and these should be interpreted as being within the scope of the present invention. Therefore, the method for producing the compound of formula (1) is not limited to the following method.

[0024] For example, the compound of formula (1) can be prepared according to the following reaction schemes 1, 2 or 3.

[0025] <Reaction Scheme 1> [ka]

[0026] <Reaction Scheme 2> [ka]

[0027] <Reaction Scheme 3> [ka]

[0028] The compound of formula (1) according to the present invention exhibits inhibitory activity against diacylglycerol kinases (DGKs). Thus, the present invention provides a pharmaceutical composition for preventing or treating a disease associated with diacylglycerol kinase, comprising the compound of formula (1) or a pharma- ceutically acceptable salt or stereoisomer thereof together with a pharma- ceutically acceptable carrier.

[0029] In one embodiment according to the present invention, the disease associated with diacylglycerol kinase is cancer. Examples of cancers that can be prevented or treated by the pharmaceutical composition according to the present invention include, but are not limited to, gastrointestinal cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain cancer, testicular cancer, laryngeal cancer, prostate cancer, neuroblastoma, kidney cancer, thyroid cancer, esophageal cancer, skin cancer, osteosarcoma, and bladder cancer.

[0030] In the present invention, the "pharmaceutical composition" may contain other ingredients such as carriers, diluents, excipients, etc., in addition to the active ingredient of the present invention. Thus, the pharmaceutical composition may contain a pharma- ceutically acceptable carrier, diluent, excipient, or a combination thereof, as necessary. The pharmaceutical composition facilitates administration of the active compound to the body. Various methods for administering the compound include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

[0031] As used herein, the term "carrier" refers to a compound that facilitates the introduction of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO) is a conventional carrier that facilitates the introduction of many organic compounds into living cells or tissues.

[0032] As used herein, "diluent" refers to a compound that is diluted in a solvent that dissolves the compound as well as stabilizing the biologically active form. In the art, salts dissolved in buffer solutions are used as diluents. The conventionally used buffer solution is phosphate buffered saline, which mimics the salt forms in body fluids. The buffer diluent does not significantly change the biological activity of the compound, since the buffer solution can control the pH of the solution at low concentrations.

[0033] As used herein, the term "pharmaceutical acceptable" refers to a property that does not impair the biological activity and physical properties of a compound.

[0034] The compound of the present invention can be formulated into various pharmaceutical dosage forms.When preparing the pharmaceutical composition according to the present invention, the active ingredient, specifically, the compound of formula (1) or its pharma- ceutically acceptable salt or stereoisomer, is mixed with a pharma- ceutically acceptable carrier selected in consideration of the dosage form to be prepared.For example, the pharmaceutical composition according to the present invention can be formulated into injections, oral preparations, etc., as necessary.

[0035] The compounds of the present invention can be formulated by known methods using known pharmaceutical carriers and excipients and filled into unit dose forms or multi-dose containers. The formulations can be in the form of solutions, suspensions or emulsions in oily or aqueous media, and can contain conventional dispersing, suspending or stabilizing agents. They can also be in the form of dry powders, for example, to be dissolved in sterile, pyrogen-free water before use. The compounds of the present invention can also be formulated into suppositories by using conventional suppository bases, such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are particularly preferred. Tablets and pills are preferably enteric coated. Solid forms can be prepared by mixing the compounds of the present invention with one or more inert diluents, such as sucrose, lactose, starch, and at least one carrier selected from lubricants, disintegrants, binders, and the like, such as magnesium stearate.

[0036] The compound according to the present invention or a pharmaceutical composition containing it can be administered in combination with other drugs, for example other immunological anti-cancer drugs, if necessary.

[0037] The dosage of the compound of formula (1) of the present invention is determined by a doctor's prescription, taking into consideration the patient's weight, age and medical condition. The usual dosage for adults ranges from about 0.3 to 500 mg per day, depending on the frequency and strength of administration. The typical daily dose for intramuscular or intravenous administration for adults ranges from about 1 to 300 mg per day, which can be administered in divided unit doses. In some cases, higher daily doses are required.

[0038] As used herein, "treatment" means arresting, slowing or alleviating the progression of a disease in a subject who exhibits symptoms of the disease. Effect of the Invention

[0039] The heterocyclic compound represented by formula (1) according to the present invention can be usefully used for the prevention or treatment of diseases associated with diacylglycerol kinases (DGKs), such as cancer, by inhibiting diacylglycerol kinases (DGKs). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0040] The present invention will be described in more detail with reference to the following Preparation Examples and Examples, however, it should be understood that the scope of the present invention is not limited to these Examples.

[0041] The abbreviations and terms used in the following Production Examples and Examples are as follows. CH3CN:Acetonitrile DIPEA: N,N-diisopropylethylamine DME: Dimethoxyethane DMF: N,N-dimethylformamide EtOAc: ethyl acetate EtOH: Ethanol MEOH: Methanol MPLC: Medium pressure liquid chromatography NaH: Sodium hydride NBS: N-bromosuccinimide NCS: N-chlorosuccinimide Pd(OAc)2: Palladium(II) acetate (PPh4)4Pd: Tetrakis(triphenylphosphine)palladium(0) THF: tetrahydrofuran TLC: Thin Film Chromatography Zn(CN)2: Zinc cyanide

[0042] Preparation Example 1: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Step A: Preparation of tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] tert-Butyl 4-amidopiperidine-1-carboxylate (1.00 g, 5.00 mmol) and 2-fluoro-3-nitropyridine (0.71 g, 5.00 mmol) were dissolved in DMF (15 mL), diisopropylamine (1.75 mL, 10.00 mmol) was added, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture 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+Ht-Bu)

[0043] Step B: Preparation of tert-butyl 4-((3-aminopyridin-2-yl)amino)piperidine-1-carboxylate [ka] tert-Butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.50 g, 1.55 mmol) and 10% palladium on carbon (49.5 mg, 0.047 mmol) were added to methanol (40 mL) and stirred at room temperature under a hydrogen balloon for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound (440 mg), which was used immediately in the next reaction without purification. LC / MS: 293 (M+H)

[0044] Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)pyridin-2-yl)amino)piperidine-1-carboxylate [ka] 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 (10 mL), and ethyl oxalyl chloride (0.075 mL, 0.67 mmol) was added at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (146 mg). This was used immediately in the next reaction without purification. LC / MS: 393 (M+H)

[0045] Step D: Preparation of tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] 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), sodium ethoxide (0.35 mL, 0.89 mmol, 20 wt % in EtOH) was added and stirred at 70° C. for 0.5 h. The reaction mixture was cooled at room temperature, diluted with water, acidified to about pH 5 with 1N HCl, and extracted twice with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (42 mg), which was used immediately in the next reaction without purification. LC / MS: 347 (M+H), 369 (M+Na)

[0046] Step E: Preparation of tert-butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] tert-Butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (42 mg, 0.12 mmol) was dissolved in DMF (5 mL), and cesium carbonate (158 mg, 0.49 mmol) and iodomethane (0.011 mL, 0.18 mmol) were added and stirred at room temperature for 0.5 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC to give 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)

[0047] Step F: Preparation of 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] tert-Butyl 4-(1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (19 mg, 0.053 mmol) was dissolved in dichloromethane (4 mL), HCl (0.26 mL, 1.05 mmol, 4M in 1,4-dioxane) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (18 mg), which was used immediately in the next reaction without purification. LC / MS: 261 (M+H)

[0048] Preparation Example 2: 7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (10.0 g) was obtained in the same manner as in Production Example 1, Step A, 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). 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)

[0049] Step B: Preparation of tert-butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate [ka] tert-Butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (3.20 g, 8.97 mmol) was dissolved in THF (100 mL) and NaH (538 mg, 13.45 mmol, 60% in oil dispersion) was added slowly at 0° C., followed by stirring for 30 min. Ethyl oxalyl chloride (1.99 mL, 17.94 mmol) was added to the reaction mixture at 0° C. and stirred at room temperature for 1 h. Water was added slowly to the reaction mixture to quench the reaction. The reaction mixture was diluted with EtOAc, washed with 0.5N aqueous NaOH, aqueous sodium bicarbonate and brine, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.32 g). LC / MS: 479 (M+Na)

[0050] Step C: Preparation of tert-butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] tert-Butyl 4-(N-(5-chloro-3-aminopyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (1.90 g, 4.16 mmol) was dissolved in EtOH (30 mL), and water (30 mL), iron (2.32 g, 41.6 mmol) and ammonium chloride (4.05 g, 76 mmol) were added at room temperature and stirred at 0° C. for 4 hours. The reaction mixture was cooled to room temperature, filtered under reduced pressure using Celite, and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.28 g). This was used immediately in the next reaction without purification. LC / MS: 325 (M+Ht-Bu)

[0051] Step D: Preparation of tert-butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The residue obtained by the same method as in Preparation Example 1, Step E, of tert-butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (1.28 g, 3.36 mmol) was purified by MPLC to give the title compound (1.08 g). LC / MS: 417 (M+Na)

[0052] Step E: Preparation of 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (1.08 g, 2.74 mmol), the title compound (1,000 mg) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. 1 H-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)

[0053] Preparation Example 3: Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.61 g) was obtained in the same manner as in Step A of Production Example 1 using 2-fluoro-6-methyl-3-nitropyridine (0.781 g, 5.00 mmol). 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)

[0054] Step B: Preparation of 6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (720 mg) was obtained in the same manner as in Production Example 1, Step B, using tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (800 mg, 2.38 mmol). LC / MS: 307 (M+H), 329 (M+Na)

[0055] Step C: tert-Butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (898 mg) was obtained in the same manner as in Production Example 1, Step C, using 6-tert-butyl 4-((3-amino-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (720 mg, 2.35 mmol). 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).

[0056] Step D: Preparation of tert-butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (781 mg) was obtained in the same manner as in Production Example 1, Step D, using tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (898 mg, 2.21 mmol). LC / MS: 383 (M+Na), 743 (2M+Na)

[0057] Step E: Preparation of tert-butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (322 mg) was obtained from tert-butyl 4-(6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (660 mg, 1.83 mmol) in a manner similar to that of Production Example 1, Step E. 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)

[0058] Step F: Preparation of 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] The title compound (256 mg) was obtained from tert-butyl 4-(1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (300 mg, 0.83 mmol) in a manner similar to that of Production Example 1, Step F. LC / MS: 275 (M+H)

[0059] Preparation Example 4: Preparation of 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (6.21 g) was obtained in the same manner as in Production Example 1, Step A, 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). 1 H-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)

[0060] Step B: Preparation of tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] 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), (PPh4)4Pd (0.648 g, 0.561 mmol) were dissolved in DMF (50 mL) and stirred at 100° C. for 1 h. The reaction mixture was cooled at room temperature, diluted with EtOAc, and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to give 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)

[0061] Step C: Preparation of tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate [ka] The title compound (1.02 g) was obtained in the same manner as in Step B of Production Example 2 using tert-butyl 4-((6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.04 g, 2.99 mmol). LC / MS: 470 (M+Na)

[0062] Step D: Preparation of tert-butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] Using tert-butyl 4-(N-(6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.51 g, 1.14 mmol), the title compound (0.388 g) was obtained in the same manner as in Step C of Preparation 2. This was used immediately in the next reaction without purification. LC / MS: 394 (M+Na)

[0063] Step E: Preparation of tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The residue obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.388 g, 1.045 mmol) was purified by MPLC to give the title compound (0.368 g). 1 H-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)

[0064] Step F: Preparation of 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile hydrochloride [ka] Using tert-butyl 4-(6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.300 g, 0.778 mmol), the title compound (250 mg) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 286 (M+H), 308 (M+Na)

[0065] Preparation Example 5: Preparation of 7-chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate [ka] The title compound (1.36 g) was obtained in the same manner as in Production Example 1, Step A, using 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). 1 H-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)

[0066] Step B: Preparation of tert-butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine-1-carboxylate [ka] The title compound (0.120 g) was obtained in the same manner as in Production Example 2, Step B using tert-butyl 4-((5-chloro-3-nitropyridin-2-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (1.01 g, 2.62 mmol). LC / MS: 507 (M+Na)

[0067] Step C: Preparation of tert-butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-3,3-dimethylpiperidine-1-carboxylate [ka] Using tert-butyl 4-(N-(5-chloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)-3,3-dimethylpiperidine-1-carboxylate (0.23 g, 0.474 mmol), the title compound (0.161 g) was obtained in the same manner as in Step C of Preparation 2. This was used immediately in the next reaction without purification. LC / MS: 431 (M+Na)

[0068] Step D: Preparation of tert-butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-3,3-dimethylpiperidine-1-carboxylate [ka] The residue obtained in the same manner as in Step E of Production Example 1 was purified by MPLC using tert-butyl 4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-3,3-dimethylpiperidine-1-carboxylate (0.161 g, 0.394 mmol) to give 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 (2s, 3H), 0.94-0.83 (2s, 3H) LC / MS: 445 (M+Na)

[0069] Step E: Preparation of 7-chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-3,3-dimethylpiperidine-1-carboxylate (0.100 g, 0.236 mmol), the title compound (0.094 g) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 323 (M+H)

[0070] Preparation Example 6: Preparation of 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Using 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), the title compound (10.71 g) was obtained in the same manner as in Step A of Production Example 2. 1 H-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)

[0071] Step B: Preparation of 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 [ka] The title compound (1.17 g) was obtained in the same manner as in Production Example 2, Step B, using tert-butyl (1R,3s,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (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)

[0072] Step C: Preparation of tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Using 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), the title compound (0.77 g) was obtained in the same manner as in Step C of Production Example 2. 1 H-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)

[0073] Step D: Preparation of tert-butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Using tert-butyl (1R,3s,5S)-3-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-8-azabicyclo[3.2.1]octane e-8-carboxylate (0.72 g, 1.78 mmol), the title compound (0.75 g) was obtained in the same manner as in Production Example 2, Step D. 1 H-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)

[0074] Step E: Preparation of 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl (1R,3s,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.40 mmol), the title compound (440 mg) was obtained in the same manner as in Step E of Production Example 2. LC / MS: 321 (M+H)

[0075] Preparation Example 7: Preparation of 7-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-((3-nitropyridin-2-yl)amino)amido piperidine-1-carboxylate (1.00 g, 3.10 mmol) dissolved in CH3CN (20 mL), 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, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (1.23 g). 1 H-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)

[0076] Step B: Preparation of tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate [ka] The title compound (0.880 g) was obtained in the same manner as in Step B of Production Example 2 using tert-butyl 4-((5-bromo-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.23 g, 3.07 mmol). LC / MS: 523, 525 (M+Na)

[0077] Step C: Preparation of tert-butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] Using tert-butyl 4-(N-(5-bromo-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.880 g, 1.755 mmol), the title compound (0.480 g) was obtained in the same manner as in Step C of Preparation 2. This was used immediately in the next reaction without purification. LC / MS: 447, 449 (M+Na)

[0078] Step D: Preparation of tert-butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-3,3-dimethylpiperidine-1-carboxylate [ka] The residue obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(7-bromo-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.480 g, 1.129 mmol) was purified by MPLC to give 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)

[0079] Step E: Preparation of 7-bromo-4-(piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(7-bromo-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.335 g, 0.763 mmol), the title compound (0.314 g) was obtained in the same manner as in Production Example 1, Step F. This was used immediately in the next reaction without purification. LC / MS: 338, 340 (M+H)

[0080] Preparation Example 8: Preparation of 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile dihydrochloride [ka] Step A: Preparation of tert-butyl 4-(7-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (0.098 g) was obtained in the same manner as in Step B of Production Example 4 using 7-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (0.120 g, 0.273 mmol) obtained in Production Example 7. 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.52 (d, J = 1.5 Hz, 1H), 7.73 (d, J = 1.5 Hz, 1H), 5.55-5.50 (m, 1H), 4.31-4.30 (m, 2H), 3.67 (s, 3H), 2.84-2.77 (m, 4H), 1.67-1.65 (m, 2H), 1.51 (s, 9H) LC / MS: 408 (M+Na)

[0081] Step B: Preparation of 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile dihydrochloride [ka] Using tert-butyl 4-(7-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.098 g, 0.254 mmol), the title compound (0.091 g) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 286 (M+H)

[0082] Preparation Example 9: Preparation of 7-acetyl-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-(7-(1-ethoxyvinyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] 7-Bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (0.150 g, 0.341 mmol) obtained in Production Example 7, tributyl(1-ethoxyvinyl)stenene (148 mg, 0.410), and tetrakis(triphenylphosphine)palladium (40 mg, 0.034) were added to 1,4-dioxane (10 mL) and stirred at 100° C. for 3 hours. The reaction mixture was cooled to room temperature and filtered through Celite, the filtrate was concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (0.134 g). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.50 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 5.64-5.60 (m, 1H), 4.73 (d, J = 3.0 Hz, 1H), 4.36 (d, J = 3.0 Hz, 1H), 4.30-4.28 (m, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.67 (s, 3H), 2.91-2.89 (m, 4H), 1.67-1.65 (m, 2H), 1.52 (s, 9H), 1.47 (t, J = 7.0 Hz, 3H) LC / MS: 453 (M+Na)

[0083] Step B: Preparation of 7-acetyl-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(7-(1-ethoxyvinyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.134 g, 0.311 mmol), the title compound (0.111 g) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 303 (M+H)

[0084] Preparation Example 10: Preparation of 7-bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.08 g) was obtained in the same manner as in Step A of Production Example 5 using tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.00 g, 2.80 mmol) synthesized in Step A of Production Example 3. 1 H-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)

[0085] Step B: Preparation of tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (0.201 g) was obtained in the same manner as in Production Example 4, Step B using tert-butyl 4-((5-bromo-6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.500 g, 1.148 mmol). 1 H-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)

[0086] Step C: Preparation of tert-butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate [ka] The title compound (0.251 g) was obtained in the same manner as in Step B of Production Example 2 using tert-butyl 4-((5-bromo-6-cyano-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.370 g, 0.868 mmol). LC / MS: 548, 550 (M+Na)

[0087] Step D: Preparation of tert-butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] Using tert-butyl 4-(N-(5-bromo-6-cyano-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (0.251 g, 0.477 mmol), the title compound (0.215 g) was obtained in the same manner as in Step C of Preparation 2. This was used immediately in the next reaction without purification. LC / MS: 472, 474 (M+Na)

[0088] Step E: Preparation of tert-butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The residue obtained in the same manner as in Step E of Production Example 1 was purified by MPLC using tert-butyl 4-(7-bromo-6-cyano-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.215 g, 0.477 mmol) to give the title compound (0.114 g). 1 H-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)

[0089] Step F: Preparation of 7-bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride [ka] Using tert-butyl 4-(7-bromo-6-cyano-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.114 g, 0.246 mmol), the title compound (0.107 g) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 364, 366 (M+H)

[0090] Preparation Example 11: Preparation of 7-chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Step A: Preparation of tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] tert-Butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine e-1-carboxylate (1.5 g, 4.20 mmol) obtained in Step A of Preparation 4 was dissolved in CH3CN (50 mL), NCS (0.842 g, 6.31 mmol) was added, and the mixture was stirred at 50° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc, and washed with aqueous sodium bicarbonate 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)

[0091] Step B: Preparation of tert-butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate [ka] The title compound (1.05 g) was obtained in the same manner as in Production Example 2, Step B using tert-butyl 4-((5,6-dichloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (0.920 g, 2.351). LC / MS: 513, 515 (M+Na)

[0092] Step C: Preparation of tert-butyl 4-(6,7-dichloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] Using tert-butyl 4-(N-(5,6-dichloro-3-nitropyridin-2-yl)-2-ethoxy-2-oxoacetamido)piperidine-1-carboxylate (220 mg, 0.448 mol), the title compound (0.186 g) was obtained in the same manner as in Step C of Preparation 2. This was used immediately in the next reaction without purification. LC / MS: 437, 439 (M+Na)

[0093] Step D: Preparation of tert-butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The residue obtained in the same manner as in Step E of Production Example 1 was purified by MPLC using tert-butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.186 g, 0.448 mmol) to give the title compound (0.121 g). LC / MS: 451. 453 (M+Na)

[0094] Step E: Preparation of 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 [ka] tert-Butyl 4-(6,7-dichloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (0.090 g, 0.210 mmol), (2-fluorophenyl)boronic acid (44 mg, 0.314), 2M aqueous sodium carbonate solution (0.314 mL) and tetrakistriphenylphosphine palladium (24 mg, 0.02 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 90° C. for 3 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by MPLC to give the title compound (89 mg). 1 H-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)

[0095] Step F: Preparation of 7-chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Using 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), the title compound (80 mg) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 389 (M+H)

[0096] Preparation Example 12: Preparation of 1-ethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-(1-ethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (50 mg) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (50 mg, 0.144 mmol) obtained in Step D of Production Example 1 and iodoethane (17.50 μL, 0.217 mmol). LC / MS: 375 (M+H)

[0097] Step B: Preparation of 1-ethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(1-ethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (50 mg, 0.134 mmol), the title compound (36 mg) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 275 (M+H)

[0098] Preparation Example 13: Preparation of 1-isobutyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-(1-isobutyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (26 mg) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (50 mg, 0.144 mmol) obtained in Step D of Production Example 1 and 1-bromo-2-methylpropane (29.7 mg, 0.217 mmol). LC / MS: 403 (M+H)

[0099] Step B: Preparation of 1-isobutyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] The title compound (19 mg) was obtained in the same manner as in Production Example 1, Step F, using tert-butyl 4-(1-isobutyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (26 mg, 0.065 mmol). LC / MS: 303 (M+H)

[0100] Preparation Example 14: Preparation of 1,2-dimethyl-1H-indole-3-carbaldehyde [ka] The title compound (100 mg) was obtained in the same manner as in Step E of Production Example 1 using 2-methyl-1H-indole-3-carbaldehyde (100 mg, 0.628 mmol). LC / MS: 174 (M+H) Preparation Example 15: Preparation of 1-methyl-1H-indole-5-carbaldehyde [ka] The title compound (109 mg) was obtained in the same manner as in Step E of Production Example 1 using 1H-indole-5-carbaldehyde (100 mg, 0.689 mmol). LC / MS: 160 (M+H)

[0101] Preparation Example 16: Preparation of 6-(1-chloroethyl)quinoxaline [ka] Step A: Preparation of 1-(quinoxalin-6-yl)ethan-1-ol [ka] 1-(Quinoxalin-6-yl)ethan-1-one (500 mg, 2.90 mmol) was dissolved in MEOH (5,808 μL), and sodium borohydride (165 mg, 4.36 mmol) was added at 0° C. and stirred for 1 hour. Water was added to the reaction mixture to quench the reaction, and the mixture was 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 (312 mg). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.81 (dd, J = 3.9, 1.1 Hz, 2H), 8.16-7.99 (m, 2H), 7.82 (dd, J = 8.7, 1.8 Hz, 1H), 5.15 (q, J = 6.4 Hz, 1H), 1.60 (d, J = 6.9 Hz, 3H) LC / MS: 175 (M+H)

[0102] Step B: Preparation of 6-(1-chloroethyl)quinoxaline [ka] 1-(Quinoxalin-6-yl)ethan-1-ol (312 mg, 1.791 mmol) was dissolved in DCM, and SOCl2 (196 μL, 2.69 mmol) was added at 0° C. and stirred for 1 hour. The reaction mixture was quenched by adding water, and then extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (300 mg). LC / MS: 193 (M+H)

[0103] Preparation Example 17: Preparation of 7-chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl (2R,5S)-4-((5-chloro-3-nitropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate [ka] 5-Chloro-2-fluoro-3-nitropyridine (306 mg, 1.73 mmol) and tert-butyl (2R,5S)-4-amino-2,5-dimethylpiperidine-1-carboxylate acetate (500 mg, 1.73 mmol) were dissolved in DMF (20 mL), DIPEA (0.606 mL, 3.47 mmol) was added, and the mixture was stirred for 3 hours. The reaction mixture was quenched by adding water, 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 give the title compound (500 mg, 75%). 1 H-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+Ht-Bu)

[0104] Step B: Preparation of tert-butyl (2R,5S)-4-((3-amino-5-chloropyridin-2-yl)amino)-2,5-dimethylpiperidine-1-carboxylate [ka] 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), and Zn (1.12 g, 17.2 mmol) and ammonium chloride (0.460 g, 8.57 mmol) were added and stirred at 70° C. for 3 h. After filtration through a pad of Celite, the reaction mixture was concentrated under reduced pressure to give the title compound (304 mg), which was used immediately in the next reaction. LC / MS: 355 (M+H)

[0105] Step C: Preparation of 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 [ka] 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) and ethyl 2-chloro-2-oxoacetate (0.144 mL, 1.29 mmol) and DIPEA (0.449 mL, 2.57 mmol) were added and stirred at room temperature for 12 h and at 70° C. over the weekend. The reaction mixture was quenched with water and extracted three times with DCM. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (209 mg), which was used immediately in the next reaction. LC / MS: 309 (M+Ht-Bu)

[0106] Step D: Preparation of tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-2,5-dimethylpiperidine-1-carboxylate [ka] Using 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 (209 mg, 0.511 mmol), the title compound (81 mg, 38%) was obtained in the same manner as in Step E of Production Example 1. 1 H-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+Ht-Bu), 445 (M+Na)

[0107] Step E: Preparation of 7-chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] The title compound (68 mg, 99%) was obtained in the same manner as in Step F of Production Example 1 using tert-butyl (2R,5S)-4-(7-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-2,5-dimethylpiperidine-1-carboxylate (81 mg, 0.192 mmol). LC / MS: 323 (M+H)

[0108] Preparation Example 18: Preparation of 7-chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] tert-Butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.15 g, 3.42 mmol) obtained in Step A of Production Example 3 was dissolved in CH3CN (30 mL), NCS was added, and the mixture was stirred at 60° C. for 72 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and an aqueous solution of sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (770 mg, 61%). 1 H-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)

[0109] Step B: Preparation of tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (271 mg, 95%) was obtained in the same manner as in Step B of Preparation 17 using tert-butyl 4-((5-chloro-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (310 mg, 0.836 mmol). LC / MS: 341 (M+H)

[0110] Step C: Preparation of tert-butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (314 mg, 99%) was obtained in the same manner as in Step C of Preparation 17 using tert-butyl 4-((3-amino-5-chloro-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (271 mg, 0.795 mmol). LC / MS: 339 (M+Ht-Bu)

[0111] Step D: Preparation of tert-butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (271 mg, 83%) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(7-chloro-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (314 mg, 0.795 mmol). 1 H-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+Ht-Bu)

[0112] Step E: Preparation of 7-chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] The title compound (221 mg, 97%) was obtained in the same manner as in Step F of Example 1 using tert-butyl 4-(7-chloro-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (271 mg, 0.663 mmol). LC / MS: 309 (M+H)

[0113] Preparation Example 19: Preparation of 7-bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] tert-Butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.90 g, 14.57 mmol) obtained in Step A of Production Example 3 was dissolved in CH3CN (146 mL), NBS was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with EtOAc and aqueous sodium bicarbonate, the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by MPLC to obtain the title compound (6.05 g, 92%). 1 H-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)

[0114] Step B: Preparation of tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (811 mg, 87%) was obtained in the same manner as in Step B of Production Example 17 using tert-butyl 4-((5-bromo-6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1000 mg, 2.41 mmol). LC / MS: 385, 387 (M+H)

[0115] Step C: Preparation of tert-butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (925 mg, 99%) was obtained in the same manner as in Step C of Preparation 17 using tert-butyl 4-((3-amino-5-bromo-6-methylpyridin-2-yl)amino)piperidine-1-carboxylate (811 mg, 2.11 mmol). LC / MS: 439, 441 (M+H)

[0116] Step D: Preparation of tert-butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (732 mg, 77%) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(7-bromo-6-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (925 mg, 2.11 mmol). 1 H-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)

[0117] Step E: Preparation of 7-bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] The title compound (631 mg, 100%) was obtained in the same manner as in Step F of Production Example 1 using tert-butyl 4-(7-bromo-1,6-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (732 mg, 1.62 mmol). LC / MS: 353, 355 (M+H)

[0118] Preparation Example 20: Preparation of 6-acetyl-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Step A: Preparation of tert-butyl 4-((3-amino-6-chloropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (4.4 g, 61%) was obtained in the same manner as in Step B of Production Example 17 using tert-butyl 4-((6-chloro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (7.86 g, 22.03 mmol) synthesized in Step A of Production Example 4. LC / MS: 271 (M+Ht-Bu), 349 (M+Na)

[0119] Step B: Preparation of tert-butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] 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 obtained in a similar manner to Step C of Preparation 17. It was used immediately in the next reaction. LC / MS: 281 (M+Ht-Bu)

[0120] Step C: Preparation of tert-butyl 4-(6-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (3.91 g, 74%) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(6-chloro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (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)

[0121] Step D: Preparation of tert-butyl 4-(6-(1-ethoxyvinyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (143 mg, 87%) was obtained in the same manner as in Step A of Production Example 9 using tert-butyl 4-(6-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (150 mg, 0.38 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 7.62 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 5.52 (br s, 1H), 5.32 (d, J = 1.5 Hz, 1H), 4.41-4.34 (m, 3H), 4.01 (q, J = 7.0 Hz, 2H), 3.65 (s, 3H), 3.00-2.93 (m, 4H), 1.71-1.69 (m, 2H), 1.52 (s, 9H) LC / MS: 375 (M+Ht-Bu), 453 (M+Na)

[0122] Step E: Preparation of 6-acetyl-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Using tert-butyl 4-(6-(1-ethoxyvinyl)-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (143 mg, 0.332 mmol), the title compound (113 mg) was obtained in the same manner as in Step F of Production Example 1. This was used immediately in the next reaction without purification. LC / MS: 303 (M+H)

[0123] Preparation Example 21: Preparation of 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] The title compound (450 mg, 99%) was obtained by treating tert-butyl 4-((6-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (500 mg, 1.27 mmol) obtained in Step C of Preparation Example 20 in the same manner as in Step F of Preparation Example 1, and was used immediately in the next reaction without purification. LC / MS: 337 (M+H)

[0124] Preparation Example 22: Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.80 g, 96%) was obtained using 2-chloro-6-methoxy-3-nitropyridine (1.00 g, 5.30 mmol) in a manner similar to that of Production Example 4, Step A. 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)

[0125] Step B: Preparation of tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.65 g, 73%) was obtained in a similar manner to Step B of Preparation 17 using tert-butyl 4-((6-methoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.80 g, 5.11 mmol), which was used immediately in the next reaction without purification. LC / MS: 345 (M+Na)

[0126] Step C: Preparation of tert-butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] Using tert-butyl 4-((3-amino-6-methoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.21 g, 3.72 mmol), the title compound (750 mg, 54%) was obtained in a similar manner to Step C of Preparation 17. It was immediately used in the next reaction. LC / MS: 399 (M+Na)

[0127] Step D: Preparation of tert-butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (600 mg, 77%) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(6-methoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (750 mg, 3.72 mmol). 1 H-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)

[0128] Step E: Preparation of 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(6-methoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (600 mg, 1.54 mmol), the title compound (550 mg, 90%) was obtained in the same manner as in Step F of Preparation 1. The compound was used immediately in the next reaction. LC / MS: 291 (M+H)

[0129] Preparation Example 23: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Step A: Preparation of tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (3.32 g, 99%) was obtained using 2-fluoro-4-methyl-3-nitropyridine (1.56 g, 9.99 mmol) in a manner similar to that of Production Example 4, Step B. 1 H-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)

[0130] Step B: Preparation of tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.35 g, 99%) was obtained in the same manner as in Step B of Preparation 17 using tert-butyl 4-((4-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (1.5 g, 4.46 mmol), and was used immediately in the next reaction without purification. LC / MS: 307 (M+H)

[0131] Step C: Preparation of tert-butyl 4-((3-(2-ethoxy-2-oxoacetamido)-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.67 g, 93%) was obtained in the same manner as in Production Example 1, Step C using tert-butyl 4-((3-amino-4-methylpyridin-2-yl)amino)piperidine-1-carboxylate (1.35 g, 4.41 mmol). LC / MS: 407 (M+H)

[0132] Step D: Preparation of tert-butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] A mixture of 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) was dissolved in DCE (15 mL) and stirred at 70° C. for 24 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and purified by MPLC to give the title compound (34 mg, 4%). LC / MS: 305 (M+Ht-Bu)

[0133] Step E: Preparation of tert-butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (35 mg, 99%) was obtained in the same manner as in Step E of Production Example 1 using tert-butyl 4-(8-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (34 mg, 0.094 mmol). 1 H-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)

[0134] Step F: Preparation of 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] The title compound (29.2 mg, 100%) was obtained in the same manner as in Step F of Production Example 1 using tert-butyl 4-(1,8-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (35 mg, 0.093 mmol). LC / MS: 275 (M+H) Preparation Example 24: Preparation of 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] The title compound (2.11 g, 97%) was obtained in the same manner as in Step A of Production Example 4 using 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, 6.23 mmol). 1 H-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)

[0135] Step B: Preparation of tert-butyl (1R,3r,5S)-3-((3-amino-5-chloropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] Using tert-butyl (1R,3r,5S)-3-((5-chloro-3-nitropyridin-2-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (2.11 g, 5.49 mmol), the title compound (1.88 g, 97%) was obtained in the same manner as in Step B of Preparation 17. This was used immediately in the next reaction without purification. LC / MS: 375 (M+Na)

[0136] Step C: Preparation of tert-butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] 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 ethyl 2-chloro-2-oxoacetate (1.79 mL, 15.98 mmol) was slowly added while maintaining the temperature at 0°C. After heating to 50°C, the reaction mixture was stirred for 18 hours. After the reaction was completed, the mixture was extracted with a saturated aqueous solution of NH4Cl, the organic layer was dried over MgSO4, and distilled under reduced pressure to obtain a concentrated mixture. The obtained mixture was treated in the same manner as in Step E of Production Example 1 to obtain the title compound (1.50 g, 67%). 1 H-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)

[0137] Step D: Preparation of 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride [ka] Using tert-butyl (1R,3r,5S)-3-(7-chloro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (1.50 g, 3.56 mmol), the title compound (1.25 g, 98%) was obtained in the same manner as in Step F of Preparation 1. The compound was used immediately in the next reaction. LC / MS: 321 (M+H)

[0138] Preparation Example 25: Preparation of 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] 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, DIPEA (4.36 mL, 24.99 mmol) was added, and the mixture was stirred for 4 hours at 70° C. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and subjected to MPLC to give the title compound (3.775 g). 1 H-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)

[0139] Step B: Preparation of tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (1.07 g) was obtained in the same manner as in Step B of Production Example 17 using tert-butyl 4-((6-isopropoxy-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (3.755 g, 9.87 mmol). 1 H-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)

[0140] Step C: Preparation of tert-butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (1.2 g) was obtained in the same manner as in Step C of Production Example 17 using tert-butyl 4-((3-amino-6-isopropoxypyridin-2-yl)amino)piperidine-1-carboxylate (1.07 g, 3.05 mmol). LC / MS: 405 (M+H)

[0141] Step D: Preparation of tert-butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (870 mg) was obtained in the same manner as in Step D of Production Example 17 using tert-butyl 4-(6-isopropoxy-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (1.256 g, 3.11 mmol). 1 H-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)

[0142] Step E: Preparation of 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(6-isopropoxy-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (870 mg, 2.079 mmol), the title compound (668 mg) was obtained in the same manner as in Step E of Production Example 17. 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)

[0143] Preparation Example 26: Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (4.2 g) was obtained in the same manner as in Step A of Production Example 25 using 2,6-difluoro-3-nitropyridine (2 g, 12.49 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (2.502 g, 12.49 mmol). 1 H-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)

[0144] Step B: Preparation of tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (2.67 g) was obtained in the same manner as in Step B of Production Example 17 using tert-butyl 4-((5-fluoro-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.2 g, 12.34 mmol). 1 H-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)

[0145] Step C: Preparation of tert-butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (3.0 g) was obtained in the same manner as in Step C of Preparation 17 using tert-butyl 4-((3-amino-5-fluoropyridin-2-yl)amino)piperidine-1-carboxylate (2.67 g, 8.60 mmol). LC / MS: 365 (M+H)

[0146] Step D: Preparation of tert-butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] The title compound (1.92 g) was obtained in the same manner as in Step D of Production Example 17 using tert-butyl 4-(7-fluoro-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (3 g, 8.23 ​​mmol). 1 H-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)

[0147] Step E: Preparation of 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(7-fluoro-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (1.915 g, 5.06 mmol), the title compound (1.27 g) was obtained in the same manner as in Step E of Production Example 17. LC / MS: 279 (M+H)

[0148] Preparation Example 27: Preparation of methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate dihydrochloride [ka] Step A: Preparation of methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate [ka] The title compound (17.56 g, 98%) was obtained using methyl 6-chloro-5-nicotinate (10.00 g, 46.20 mmol) in a manner similar to that of Step A of Production Example 4. 1 H-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)

[0149] Step B: Preparation of methyl 5-amino-6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)nicotinate [ka] Using methyl 6-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-5-nitronicotinate (17.20 g, 45.20 mmol), the title compound (15.84 g, 99%) was obtained in the same manner as in Step B of Example 17, and was used immediately in the next reaction without purification. LC / MS: 351 (M+H)

[0150] Step C: Preparation of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate [ka] 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 obtained in the same manner as in Step C of Preparation 17. It was immediately used in the next reaction. LC / MS: 427 (M+Na)

[0151] Step D: Preparation of methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate [ka] The title compound (4.51 g, 51%) was obtained in the same manner as in Step E of Production Example 1 using methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (8.50 g, 21.02 mmol). 1 H-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)

[0152] Step E: Preparation of methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate dihydrochloride [ka] Using methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (4.50 g, 10.75 mmol), the title compound (35 mg, 99%) was obtained in the same manner as in Step F of Preparation 1. The compound was used immediately in the next reaction. LC / MS: 319 (M+H)

[0153] Preparation Example 28: Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Step A: Preparation of tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate [ka] 2-Chloro-5-methyl-3-nitropyridine (10.00 g, 57.90 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (12.19 g, 60.80 mmol) were dissolved in DMF (300 mL), TEA (12.12 mL) was added, and the mixture was stirred at 100° C. for 20 hours. The reaction mixture was cooled to room temperature and concentrated by distillation under reduced pressure. The concentrated mixture was dissolved in diethyl ether and extracted with a saturated aqueous solution of ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The concentrated mixture was purified by MPLC to give the title compound (4.21 g, 22%). 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)

[0154] Step B: Preparation of tert-butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate [ka] The title compound (3.64 g, 95%) was obtained in the same manner as in Step B of Preparation 17 using tert-butyl 4-((5-methyl-3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (4.21 g, 12.52 mmol), which was used immediately in the next reaction without purification. LC / MS: 307.2 (M+H)

[0155] Step C: Preparation of tert-butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] tert-Butyl 4-((3-amino-5-methylpyridin-2-yl)amino)piperidine-1-carboxylate (3.64 g, 11.88 mmol) and TEA (6.62 mL, 47.50 mmol) were dissolved in DCE (150 mL), and ethyl 2-chloro-2-oxoacetate (2.65 mL, 23.76 mmol) was slowly added at 0° C. and stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature and then extracted with a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate to obtain a concentrated mixture. The concentrated mixture was used in the same manner as in Step E of Production Example 1 to obtain the title compound (1.80 g, 41%). 1 H-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)

[0156] Step D: Preparation of 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride [ka] Using tert-butyl 4-(1,7-dimethyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (1.80 g, 4.81 mmol), the title compound (1.65 g, 99%) was obtained in the same manner as in Step F of Preparation 1. The compound was used immediately in the next reaction. 1H-NMR (400 MHz, DMSO-D6) δ 9.14 (d, J = 9.6 Hz, 1H), 8.52 (d, J = 9.6 Hz, 1H), 8.02 (s, 1H), 7.65 (s, 1H), 5.52 (t, J = 11.9 Hz, 1H), 3.45 (s, 3H), 3.34 (d, J = 11.9 Hz, 2H), 3.03 (q, J = 12.3 Hz, 2H), 2.88 (dd, J = 22.4, 12.3 Hz, 2H), 2.34 (s, 3H), 1.76 (d, J = 12.8 Hz, 2H) LC / MS: 275.1 (M+H)

[0157] Production Example 29: Production of N,1-dimethyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide dihydrochloride [ka] Step A: Preparation of 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [ka] Methyl 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (3.90 g, 9.32 mmol) obtained in step D of Preparation Example 27 and LiBr (4.05 g, 46.60 mmol) were dissolved in THF (90 mL) and distilled water (10 mL), TEA (6.50 mL, 46.60 mmol) was added, and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, concentrated by distillation under reduced pressure, and extracted with EA and distilled water. The aqueous layer was acidified to pH 2-3 using 1N HCl aqueous solution, and then extracted as an organic layer through a DCM solution containing 10% MEOH. The obtained organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain the title compound (2.48 g). 1 H-NMR (500 MHz, DMSO-D6) δ 13.49 (br s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 5.51 (s, 1H), 4.10 (br s, 2H), 3.55 (s, 3H), 2.88 (br s, 2H), 2.58 (d, J = 12.5 Hz, 2H), 1.63 (d, J = 11.9 Hz, 2H), 1.45 (s, 9H) LC / MS: 403.1 (MH)

[0158] Step B: Preparation of tert-butyl 4-(1-methyl-7-(methylcarbamoyl)-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.247 mmol) was dissolved in DCM, DIPEA (130 μL, 0.742 mmol) and HATU (282 mg, 0.742 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the mixture was extracted with EA and distilled water. The obtained organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain the title compound (100 mg). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.52 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 1.8 Hz, 1H), 6.43 (d, J = 4.6 Hz, 1H), 5.44-5.62 (1H), 4.15-4.38 (1H), 3.66 (s, 3H), 3.06 (d, J = 5.0 Hz, 3H), 2.81 (t, J = 10.3 Hz, 4H), 1.64-1.53 ​​(m, 8H), 1.49 (d, J = 3.2 Hz, 9H), 1.44 (d, J = 6.9 Hz, 8H) LC / MS: 418 (MH)

[0159] Step C: Preparation of N,1-dimethyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide dihydrochloride [ka] Using tert-butyl 4-(1-methyl-7-(methylcarbamoyl)-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (100 mg, 0.240 mmol), the title compound (75 mg) was obtained in the same manner as in Step F of Preparation 1. The compound was used immediately in the next reaction. LC / MS: 318 (M+H)

[0160] Preparation Example 30: Preparation of 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide dihydrochloride [ka] Step A: Preparation of tert-butyl 4-(7-carbamoyl-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate [ka] 4-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (200 mg, 0.495 mmol) obtained in step A of Production Example 29 was dissolved in DCM, thionyl chloride (54.1 μL, 0.742 mmol) was added, and the mixture was stirred at 75° C. for 5 hours. After completion of the reaction, the mixture was distilled under reduced pressure, and the reaction mixture was dissolved in anhydrous THF. Ammonium hydroxide (553 μL, 14.19 mmol) was slowly added at 0° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with EA and distilled water. The obtained organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to obtain the title compound (75 mg). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.90 (d, J = 1.8 Hz, 1H), 8.43-8.40 (m, 1H), 5.97-6.95 (2H), 5.86 (s, 1H), 4.63 (s, 2H), 4.00 (s, 3H), 3.18 (d, J = 8.7 Hz, 4H), 1.96 (d, J = 10.1 Hz, 2H), 1.81 (s, 9H) LC / MS: 404 (MH)

[0161] Step B: Preparation of 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide dihydrochloride [ka] Using tert-butyl 4-(7-carbamoyl-1-methyl-2,3-dioxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-yl)piperidine-1-carboxylate (75 mg, 0.186 mmol), the title compound (56 mg) was obtained in the same manner as in Step F of Preparation 1. This was used immediately in the next reaction. LC / MS: 304 (MH)

[0162] Example 1: Preparation of methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] 1-Methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (18 mg, 0.054 mmol) obtained in Preparation Example 1, diisopropyl (0.019 mL, 0.11 mmol), and 4-(trifluoromethoxy)benzaldehyde (0.015 mL, 0.11) were dissolved in dichloromethane (5 mL), sodium triacetoxyborohydride (57 mg, 0.27 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with an aqueous sodium bicarbonate solution and extracted three times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC to obtain the title compound (22 mg). 1 H NMR (500 MHz, CHLOROFORM-D) δ 8.30-8.29 (m, 1H), 7.51 (d, 1H), 7.43 (d, 2H), 7.24-7.19 (m, 3H), 5.47-5.43 (m, 1H), 3.65 (s, 3H), 3.62 (s, 2H), 3.10-3.03 (m, 4H), 2.28-2.24 (m, 2H), 1.65-1.63 (m, 2H) LC / MS: 435 (M+H), 457 (M+Na)

[0163] Example 2: Preparation of 1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (42 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (34 mg, 0.109 mmol) obtained in Production Example 3 and 4-(trifluoromethoxy)benzaldehyde (41.6 mg, 0.19 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 7.44 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.5 Hz, 1H), 5.49-5.45 (m, 1H), 3.62 (s, 3H), 3.62 (s, 2H), 3.11-3.02 (m, 4H), 2.60 (s, 3H), 2.30-2.25 (m, 2H), 1.63-1.61 (m, 2H) LC / MS: 449 (M+H)

[0164] Example 3: Preparation of ethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (22 mg) was obtained in the same manner as in Example 1 using 1-ethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (36 mg, 0.104 mmol) obtained in Production Example 12. 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.24 (dd, J = 4.6, 1.4 Hz, 1H), 7.57-7.47 (m, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.22-7.14 (m, 3H), 5.44 (t, J = 12.1 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.64 (s, 2H), 3.25-3.00 (m, 4H), 2.29 (t, J = 13.3 Hz, 2H), 1.62 (d, J = 8.7 Hz, 2H), 1.35 (t, J = 7.3 Hz, 3H) LC / MS: 449 (M+H)

[0165] Example 4: Preparation of isobutyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (22 mg) was obtained in the same manner as in Example 1 using 1-isobutyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (19 mg, 0.051 mmol) obtained in Production Example 13. 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.24 (dd, J = 4.6, 1.4 Hz, 1H), 7.45 (dd, J = 8.2, 0.9 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.16 (q, J = 4.3 Hz, 3H), 5.50-5.35 (1H), 4.02 (d, J = 7.3 Hz, 2H), 3.58 (s, 2H), 3.13-2.91 (m, 4H), 2.32-2.12 (m, 3H), 1.70-1.53 ​​(m, 2H), 1.02 (q, J = 6.9Hz, 6H) LC / MS: 477 (M+H)

[0166] Example 5: Preparation of 1,6-dimethyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (9.7 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 1-naphthylaldehyde (0.012 mL, 0.086 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.49-8.35 (1H), 7.89-7.81 (1H), 7.81-7.70 (1H), 7.49 (d, J = 7.8 Hz, 3H), 7.45-7.37 (1H), 7.34 (d, J = 8.2 Hz, 1H), 7.02 (s, 1H), 5.55-5.37 (1H), 4.01 (s, 2H), 3.58 (s, 3H), 3.07 (s, 4H), 2.55 (s, 3H), 2.31 (s, 2H), 1.66-1.48 (2H) LC / MS: 415 (M+H)

[0167] Example 6: Preparation of 4-(1-((2-chloroquinolin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (12.2 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 2-chloroquinoline-3-carbaldehyde (16.55 mg, 0.086 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.38 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.78-7.62 (m, 1H), 7.55 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.2 Hz, 1H), 5.63-5.42 (m, 1H), 3.82 (s, 2H), 3.70-3.52 (m, 3H), 3.24-3.00 (m, 4H), 2.58 (s, 3H), 2.52-2.34 (2H), 1.74-1.55 (m, 2H) LC / MS: 450 (M+H)

[0168] Example 7: Preparation of 4-(1-((1,2-dimethyl-1H-indol-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (1.5 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 1,2-dimethyl-1H-indole-3-carbaldehyde (14.97 mg, 0.086 mmol) obtained in Production Example 14. 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.63 (d, J = 7.3 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.8 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.12 (t, J = 7.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 5.32 (d, J = 30.2 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 3.73 (d, J = 23.8 Hz, 3H), 3.60 (d, J = 15.6 Hz, 3H), 3.45-3.18 (m, 4H), 1.66 (d, J = 8.7 Hz, 2H) LC / MS: 432 (M+H)

[0169] Example 8: Preparation of 1,6-dimethyl-4-(1-((1-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (23.6 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 1-methyl-1H-indole-5-carbaldehyde (13.75 mg, 0.086 mmol) obtained in Production Example 15. 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.58 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 9.1 Hz, 2H), 7.10-6.95 (m, 2H), 6.45 (d, J = 3.2 Hz, 1H), 5.52-5.31 (m, 1H), 3.89-3.77 (m, 3H), 3.76 (s, 2H), 3.59 (t, J = 6.6 Hz, 3H), 3.19-2.94 (m, 4H), 2.56 (t, J = 12.8 Hz, 3H), 2.41-2.10 (m, 2H), 1.57 (d, J = 10.5Hz, 2H) LC / MS: 418 (M+H)

[0170] Example 9: Preparation of 1,6-dimethyl-4-(1-(quinolin-4-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (20 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and quinoline-4-carbaldehyde (0.011 mL, 0.086 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.87 (d, J = 4.1 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 8.7 Hz, 1H), 7.80-7.62 (m, 1H), 7.62-7.53 (m, 1H), 7.51 (d, J = 4.1 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.10-6.95 (1H), 5.47 (t, J = 11.9 Hz, 1H), 4.02 (s, 2H), 3.59 (s, 3H), 3.21-2.96 (m, 4H), 2.55 (d, J = 14.2 Hz, 3H), 2.47-2.26 (m, 2H), 1.64-1.48 (2H) LC / MS: 416 (M+H)

[0171] Example 10: Preparation of 4-(1-([1,1'-biphenyl]-2-ylmethyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (23 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and [1,1'-biphenyl]-2-carbaldehyde (0.014 mL, 0.086 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.59 (d, J = 7.3 Hz, 1H), 7.52-7.37 (4H), 7.37-7.32 (m, 3H), 7.29 (d, J = 7.3 Hz, 1H), 7.25 (t, J = 3.4 Hz, 2H), 7.00 (d, J = 8.2 Hz, 1H), 5.46-5.25 (m, 1H), 3.58 (s, 3H), 3.43 (s, 2H), 3.09-2.84 (m, 4H), 2.61-2.46 (3H), 2.08 (t, J = 11.4 Hz, 2H), 1.80-1.59 (m, 2H), 1.54 (d, J = 11.0 Hz, 2H) LC / MS: 441 (M+H)

[0172] Example 11: Preparation of 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile [ka] The title compound (26 mg) was obtained in the same manner as in Example 1 using 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride (36 mg, 0.100 mmol) obtained in Production Example 4 and 4-(trifluoromethoxy)benzaldehyde (41.6 mg, 0.19 mmol). 1H NMR (500 MHz, CHLOROFORM-D) δ 7.64 (d, J = 8.5 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.5 Hz, 1H), 5.38-5.31 (m, 1H), 3.67 (s, 3H), 3.61 (s, 2H), 3.05-2.93 (m, 4H), 2.28-2.24 (m, 2H), 1.64-1.62 (m, 2H) LC / MS: 460 (M+H)

[0173] Example 12: Preparation of 4-(1-(2-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (21 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 2-chlorobenzaldehyde (18 mg, 0.13 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 7.63 (d, J = 7.3 Hz, 1H), 7.38 (q, J = 8.3 Hz, 2H), 7.30-7.27 (m, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 5.51-5.47 (m, 1H), 3.73 (s, 2H), 3.62 (s, 3H), 3.12-3.06 (m, 4H), 2.60 (s, 3H), 2.40-2.34 (m, 2H), 1.92 (s, 1H), 1.62 (d, J = 11.9 Hz, 2H) LC / MS: 399 (M+H)

[0174] Example 13: Preparation of 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (18 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 3-chlorobenzaldehyde (18 mg, 0.13 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 7.41-7.38 (m, 2H), 7.29-7.24 (m, 3H), 7.06 (d, J = 8.2 Hz, 1H), 5.48-5.43 (m, 1H), 3.62 (s, 3H), 3.59 (s, 2H), 3.06-3.01 (m, 3H), 2.62 (d, J = 14.6 Hz, 3H), 2.28-2.06 (m, 2H), 1.94 (s, 1H), 1.70-1.61 (m, 2H) LC / MS: 399 (M+H)

[0175] Example 14: Preparation of 4-(1-(4-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] 1,6-Dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (30 mg, 0.086 mmol) obtained in Preparation 3, 1-(bromomethyl)-4-chlorobenzene (0.018 mg, 0.86 mmol) and DIPEA (0.02 mL, 0.11 mmol) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 6 hours. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (31 mg). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 7.34-7.28 (m, 5H), 7.05 (d, J = 7.9 Hz, 1H), 5.45 (d, J = 11.3 Hz, 1H), 3.62 (s, 3H), 3.58 (s, 2H), 3.04 (q, J = 12.3 Hz, 4H), 2.58 (d, J = 17.1 Hz, 3H), 2.26-2.22 (m, 2H), 1.92 (s, 1H), 1.70-1.60 (m, 2H) LC / MS: 399 (M+H)

[0176] Example 15: Preparation of 4-(1-((2-methoxypyridin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (15 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 2-methoxynicotinaldehyde (26 mg, 0.19 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.09 (d, J = 3.4 Hz, 1H), 7.80 (d, J = 6.7 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.93 (dd, J = 7.2, 5.0 Hz, 1H), 5.48 (t, J = 11.7 Hz, 1H), 3.99 (s, 3H), 3.62 (s, 5H), 3.12-3.06 (m, 4H), 2.61 (d, J = 11.6 Hz, 3H), 2.37-2.33 (m, 2H), 1.63 (d, J = 10.4 Hz, 2H) LC / MS: 396 (M+H)

[0177] Example 16: Preparation of 4-(1-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (21 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 6-fluoropicolinaldehyde (36 mg, 0.29 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.18 (s, 1H), 7.93-7.89 (m, 1H), 7.41-7.39 (m, 1H), 7.06 (d, J = 4.0 Hz, 1H), 6.95 (dd, J = 8.2, 2.7 Hz, 1H), 5.50-5.45 (m, 1H), 3.62 (s, 4H), 3.61 (s, 2H), 3.06-3.00 (m, 5H), 2.59 (s, 3H), 2.30-2.25 (m, 2H) LC / MS: 384 (M+H), 406 (M+Na)

[0178] Example 17: Preparation of 4-(1-((6-fluoropyridin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (11 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 6-fluoronicotinaldehyde (36 mg, 0.29 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.19-8.11 (m, 1H), 7.49-7.39 (m, 1H), 7.10-7.00 (m, 3H), 5.54-5.43 (m, 1H), 3.64 (s, 2H), 3.63-3.48 (m, 3H), 3.10 (qd, J = 12.3, 3.7 Hz, 2H), 3.00 (d, J = 11.6 Hz, 2H), 2.63-2.58 (m, 3H), 2.34-2.19 (m, 2H), 1.65-1.45 (m, 2H) LC / MS: 384 (M+H)

[0179] Example 18: Preparation of 1,6-dimethyl-4-(1-(4-phenoxybenzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (28 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 4-phenoxybenzaldehyde (17.13 mg, 0.086 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.37-7.29 (m, 5H), 7.10-7.06 (m, 1H), 7.03-6.99 (m, 3H), 6.96 (dt, J = 9.1, 2.4 Hz, 2H), 5.43 (t, J = 11.9 Hz, 1H), 3.59 (s, 2H), 3.58 (s, 3H), 3.10-3.00 (m, 4H), 2.60-2.54 (m, 3H), 2.27-2.21 (m, 2H), 1.60-1.57 (m, 2H) LC / MS: 457 (M+H)

[0180] Example 19: Preparation of 1,6-dimethyl-4-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (15 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 2-naphthaldehyde (13.49 mg, 0.086 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 7.83-7.78 (m, 4H), 7.56 (dd, J = 8.7, 1.4 Hz, 1H), 7.51-7.42 (m, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.01 (t, J = 8.9 Hz, 1H), 5.48-5.42 (m, 1H), 3.76 (s, 2H), 3.62 (d, J = 28.8 Hz, 3H), 3.10-3.02 (m, 4H), 2.58 (d, J = 9.6 Hz, 3H), 2.30-2.24 (m, 2H), 1.59 (d, J = 11.4 Hz, 2H) LC / MS: 415 (M+H)

[0181] Example 20: Preparation of 4-(1-(isoquinolin-5-ylmethyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (35 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and isoquinoline-5-carbaldehyde (46 mg, 0.29 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 9.27 (s, 1H), 8.59 (d, J = 5.8 Hz, 1H), 8.23 ​​(d, J = 5.8 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 5.48 (t, J = 11.9 Hz, 1H), 4.00 (s, 2H), 3.61 (s, 3H), 3.10-3.06 (m, 3H), 2.58 (s, 3H), 2.37-2.32 (m, 2H), 1.84 (s, 2H), 1.63-1.60 (m, 2H) LC / MS: 438 (M+Na)

[0182] Example 21: Preparation of 1,6-dimethyl-4-(1-(3-phenoxybenzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (28 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and 3-phenoxybenzaldehyde (0.015 mL, 0.086 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 7.37-7.26 (m, 4H), 7.14-7.05 (m, 3H), 7.01 (dt, J = 8.7, 1.3 Hz, 3H), 6.89 (dd, J = 7.8, 1.8 Hz, 1H), 5.43-5.36 (m, 1H), 3.59 (s, 2H), 3.58 (s, 3H), 3.08-3.02 (m, 4H), 2.56 (d, J = 23.3 Hz, 3H), 2.23 (t, J = 11.7 Hz, 2H), 1.58 (d, J = 8.7Hz, 2H) LC / MS: 457 (M+H)

[0183] Example 22: Preparation of 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (20 mg) was obtained in the same manner as in Example 1 using 1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (30 mg, 0.10 mmol) obtained in Production Example 1 and 3-chlorobenzaldehyde (43 mg, 0.30 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.30 (d, J = 4.3 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.40 (s, 1H), 7.28-7.22 (m, 4H), 5.43 (t, J = 12.1 Hz, 1H), 3.64 (s, 3H), 3.59 (s, 2H), 3.06 (q, J = 12.3 Hz, 4H), 2.27-2.23 (m, 2H), 1.63 (d, J = 11.0 Hz, 2H) LC / MS: 385 (M+H)

[0184] Example 23: Preparation of 4-(1-benzylpiperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (8 mg) was obtained in the same manner as in Example 1 using 1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Production Example 3 and benzaldehyde (31 mg, 0.29 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 7.41-7.27 (m, 6H), 7.05 (d, J = 8.2 Hz, 1H), 5.45 (t, J = 12.1 Hz, 1H), 3.63 (d, J = 14.0 Hz, 5H), 3.11-3.05 (m, 3H), 2.60 (s, 3H), 2.28-2.24 (m, 3H), 1.61 (d, J = 11.0 Hz, 2H) LC / MS: 365 (M+H)

[0185] Example 24: Preparation of 1,6-dimethyl-4-(1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] 1,6-Dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.086 mmol) obtained in Preparation 3 and 6-(1-chloroethyl)quinoxaline (23.17 mg, 0.086 mmol) obtained in Preparation 16 were dissolved in DMF (2 mL), potassium carbonate (45 mg, 0.33 mmol) was added, and the mixture was stirred at 90° C. for 16 hours. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (22 mg). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.85 (d, J = 4.3 Hz, 2H), 8.22-8.12 (m, 1H), 8.04-8.02 (m, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 5.44 (t, J = 12.2 Hz, 1H), 3.91-3.87 (m, 1H), 3.69-3.59 (m, 4H), 3.18 (d, J = 10.7 Hz, 1H), 3.12-2.90 (m, 3H), 2.64-2.60 (m, 3H), 2.34-2.29 (m, 2H), 1.53 (d, J = 6.7 Hz, 3H) LC / MS: 431 (M+H)

[0186] Example 25: Preparation of 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile [ka] The title compound (31 mg) was obtained in the same manner as in Example 1 using 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride (50 mg, 0.155) obtained in Production Example 4 and 3-chlorobenzaldehyde (33 mg, 0.27 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 8.64 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (s, 1H), 7.32-7.28 (m, 3H), 5.39-5.33 (m, 1H), 3.67 (s, 3H), 3.67 (s, 2H), 3.12-2.98 (m, 4H), 2.37-2.32 (m, 2H), 1.66-1.64 (m, 2H) LC / MS: 410 (M+H)

[0187] Example 26: Preparation of 1-methyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile [ka] The title compound (33 mg) was obtained in the same manner as in Example 1 using 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride (40 mg, 0.124) obtained in Production Example 4 and 1-naphthaldehyde (19 mg, 0.12 mmol). 1H NMR (500 MHz, CHLOROFORM-D) δ 8.43 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.63-7.51 (m, 5H), 7.46-7.43 (m, 1H), 5.40-5.35 (m, 1H), 4.06 (s, 2H), 3.66 (s, 3H), 3.15-3.13 (m, 2H), 3.032-2.95 (m, 2H), 2.38-2.34 (m, 2H), 1.64-1.62 (m, 2H) LC / MS: 426 (M+H)

[0188] Example 27: Preparation of 7-chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (15 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (40 mg, 0.109 mmol) obtained in Production Example 2 and 3-chlorobenzaldehyde (0.012 mL, 0.109 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.36 (s, 1H), 7.25-7.20 (m, 3H), 5.30 (qd, J = 7.9, 4.1 Hz, 1H), 3.59 (s, 3H), 3.54 (s, 2H), 3.01-2.92 (m, 4H), 2.22-2.16 (m, 2H), 1.61-1.58 (m, 2H) LC / MS: 420 (M+H)

[0189] Example 28: Preparation of 7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (22 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (40 mg, 0.109 mmol) obtained in Production Example 2 and 4-(trifluoromethoxy)benzaldehyde (0.016 mL, 0.109 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 5.34-5.29 (m, 1H), 3.59 (s, 3H), 3.56 (s, 2H), 3.01-2.92 (m, 4H), 2.22-2.16 (m, 2H), 1.58 (s, 2H) LC / MS: 469 (M+H)

[0190] Example 29: Preparation of 7-chloro-1-methyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (48 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.170 mmol) obtained in Production Example 2 and 1-naphthaldehyde (0.023 mL, 0.170 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.34 (d, J = 8.2 Hz, 1H), 8.19 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.2 Hz, 1H), 7.55-7.39 (m, 5H), 5.34 (tt, J = 12.1, 3.9 Hz, 1H), 3.98 (s, 2H), 3.59 (d, J = 12.8 Hz, 3H), 3.09 (d, J = 11.4 Hz, 2H), 2.97 (qd, J = 12.3, 3.8 Hz, 2H), 2.28 (dd, J = 11.9, 10.1 Hz, 2H), 1.58 (d, J = 10.1 Hz, 2H) LC / MS: 435 (M+H)

[0191] Example 30: Preparation of 7-chloro-1-methyl-4-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (56.7 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.170 mmol) obtained in Production Example 2 and 3-(trifluoromethyl)benzaldehyde (0.018 mL, 0.136 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.8 Hz, 1H), 7.60-7.42 (m, 5H), 5.31 (d, J = 3.7 Hz, 1H), 3.62 (s, 2H), 3.59 (s, 3H), 3.02-2.94 (m, 4H), 2.21 (dd, J = 13.0, 11.2 Hz, 2H), 1.61-1.57 (m, 2H) LC / MS: 453 (M+H)

[0192] Example 31: Preparation of 7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (49 mg) was obtained in the same manner as in Example 1 using 7-chloro-4-(3,3-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (47 mg, 0.119) obtained in Production Example 5 and 4-(trifluoromethoxy)benzaldehyde (68 mg, 0.36 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.0 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.55-5.20 (m, 1H), 3.64 (s, 3H), 3.62-3.44 (m, 3H), 3.10-3.03 (m, 1H), 2.51-2.49 (m, 1H), 2.21-2.04 (m, 2H), 1.58-1.52 (m, 2H), 1.24-1.17 (2s, 3H), 0.86-0.70 (2s, 3H) LC / MS: 497 (M+H)

[0193] Example 32: Preparation of 7-chloro-1-methyl-4-((1R,3s,5S)-8-(4-(trifluoromethoxy)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (32 mg) was obtained in the same manner as in Example 1 using 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (40 mg, 0.10 mmol) obtained in Production Example 6 and 4-(trifluoromethoxy)benzaldehyde (58 mg, 0.31 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.26 (d, J = 4.6 Hz, 1H), 7.50-7.46 (m, 4H), 7.19 (d, J = 6.1 Hz, 1H), 5.94 (t, J = 9.6 Hz, 1H), 3.62 (s, 3H), 3.51 (s, 2H), 3.35 (s, 2H), 2.33 (dd, J = 21.4, 9.5 Hz, 2H), 2.18-2.06 (m, 4H), 1.94 (d, J = 7.6 Hz, 2H) LC / MS: 495 (M+H)

[0194] Example 33: Preparation of 7-chloro-1-methyl-4-(1-(quinoxalin-5-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (20 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.170 mmol) obtained in Production Example 2 and quinoxaline-5-carbaldehyde (23.66 mg, 0.150 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.84 (s, 2H), 8.21 (d, J = 1.8 Hz, 1H), 8.01 (q, J = 3.8 Hz, 2H), 7.80 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 5.34 (tt, J = 12.2, 4.0 Hz, 1H), 4.32 (s, 2H), 3.60 (d, J = 9.6 Hz, 3H), 3.14 (d, J = 11.4 Hz, 2H), 3.05 (qd, J = 12.2, 3.9 Hz, 2H), 2.40-2.31 (m, 2H), 1.62 (d, J = 9.1 Hz, 2H) LC / MS: 437 (M+H)

[0195] Example 34: Preparation of 7-bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (296 mg) was obtained in the same manner as in Example 1 using 7-bromo-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (314 mg, 0.762) obtained in Production Example 7 and 4-(trifluoromethoxy)benzaldehyde (290 mg, 1.524 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 8.33 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.36-5.32 (m, 1H), 3.63 (s, 3H), 3.60 (s, 2H), 3.04-2.97 (m, 4H), 2.25-2.20 (m, 2H), 1.64-1.61 (m, 2H) LC / MS: 512, 514 (M+H)

[0196] Example 35: Preparation of 7-chloro-4-(1-((5-chloronaphthalen-1-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (48 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.170 mmol) obtained in Production Example 2 and 5-chloro-1-naphthaldehyde (32.3 mg, 0.170 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.31 (d, J = 8.7 Hz, 1H), 8.26-8.22 (m, 1H), 8.19 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 7.3, 0.9 Hz, 1H), 7.53 (dd, J = 14.0, 6.2 Hz, 2H), 7.44 (dd, J = 8.9, 7.1 Hz, 2H), 5.38-5.32 (m, 1H), 3.98 (s, 2H), 3.58 (s, 3H), 3.06 (d, J = 11.4 Hz, 2H), 2.96 (qd, J = 12.3, 4.2 Hz, 2H), 2.32-2.27 (m, 2H), 1.58 (d, J = 11.4 Hz, 2H) LC / MS: 470 (M+H)

[0197] Example 36: Preparation of 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] 7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg, 0.058 mmol) obtained in Example 35 and 1-methyl-4-(3,3,4,4-tetramethylboron-1-yl)-1H-pyrazole (11.93 mg, 0.058 mmol) were dissolved in DME, and aqueous sodium carbonate solution (88 μL, 0.175 mmol) and tetrakis (6.75 mg, 5.84 μmol) were added, and the mixture was stirred at 110 ° C. for 12 hours under nitrogen. After the reaction was completed, the reaction mixture was filtered through Celite and extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (2 mg). 1 H-NMR (400 MHz, METHANOL-D4) δ 8.46 (d, J = 2.1 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.86 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.54 (s, 1H), 4.48 (s, 1H), 3.93 (s, 3H), 3.72 (d, J = 21.5 Hz, 2H), 3.65 (s, 3H), 3.63 (s, 1H), 3.12 (d, J = 13.7 Hz, 3H), 2.40 (s, 1H), 1.71 (t, J = 10.3 Hz, 2H) LC / MS: 515 (M+H)

[0198] Example 37: Preparation of 7-chloro-1-methyl-4-(1-((5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (41 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.170 mmol) obtained in Production Example 2 and 5,6,7,8-tetrahydronaphthalene-1-carbaldehyde (0.025 mL, 0.170 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.3 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 7.05 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H), 5.32 (tt, J = 12.0, 4.0 Hz, 1H), 3.59 (s, 3H), 3.45 (s, 2H), 3.02-2.88 (m, 4H), 2.81 (dt, J = 15.6, 6.3 Hz, 4H), 2.21-2.12 (m, 2H), 1.86-1.74 (m, 4H), 1.57 (d, J = 15.6 Hz, 2H) LC / MS: 439 (M+H)

[0199] Example 38: Preparation of 7-bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile [ka] The title compound (57 mg) was obtained in the same manner as in Example 1 using 7-bromo-1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile dihydrochloride (55 mg, 0.126 mmol) obtained in Production Example 10 and 4-(trifluoromethoxy)benzaldehyde (68 mg, 0.36 mmol). 1H NMR (500 MHz, CHLOROFORM-D) δ 7.70 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 5.29-5.23 (m, 1H), 3.65 (s, 3H), 3.61(s, 2H), 3.05-2.89 (m, 4H), 2.28-2.23 (m, 2H), 1.63-1.61 (m, 2H) LC / MS: 538, 540 (M+H)

[0200] Example 39: Preparation of 7-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (21 mg) was obtained in the same manner as in Example 38 using 7-bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg, 0.058 mmol) obtained in Example 35 and (2-fluorophenyl)boronic acid (9.81 mg, 0.070 mmol). 1 H-NMR (400 MHz, METHANOL-D4) δ 8.43 (t, J = 1.6 Hz, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.65-7.58 (m, 4H), 7.55-7.51 (m, 2H), 7.48 (d, J = 8.7 Hz, 2H), 7.45-7.41 (m, 1H), 7.33-7.27 (m, 2H), 7.23 (d, J = 8.2 Hz, 3H), 5.52 (s, 1H), 3.28 (m, 3H), 3.06-2.97 (m, 4H), 2.27 (t, J = 11.7 Hz, 2H), 1.70 (d, J = 10.5Hz, 2H) LC / MS: 529 (M+H)

[0201] Example 40: Preparation of 7-cyclopropyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] 7-Bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg, 0.058 mmol) obtained in Example 35 and cyclopropylboronic acid (6.02 mg, 0.070 mmol) were dissolved in toluene, potassium phosphate tribasic (37.2 mg, 0.175 mmol), tricyclohexylphosphine (5.84 μL, 3.51 μmol) and Pd(OAc)2 (0.787 mg, 3.51 μmol) were added, and the mixture was stirred at 100° C. for 12 hours under nitrogen gas. After the reaction was completed, the reaction mixture was filtered through Celite and extracted three times with EtOAc. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (4.2 mg). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.04 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 1.8 Hz, 1H), 5.36 (s, 1H), 3.59 (s, 3H), 3.56 (s, 2H), 3.05-2.98 (m, 4H), 2.23-2.16 (m, 2H), 1.99-1.93 (m, 1H), 1.10-1.05 (m, 2H), 0.74 (td, J = 5.7, 4.6Hz, 2H) LC / MS: 475 (M+H)

[0202] Example 41: Preparation of 7-chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (49 mg) was obtained in the same manner as in Example 1 using 7-chloro-6-(2-fluorophenyl)-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (45 mg, 0.106 mmol) obtained in Production Example 11 and 4-(trifluoromethoxy)benzaldehyde (68 mg, 0.36 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 7.62 (s, 1H), 7.56-7.52 (m, 2H), 736-7.33(m, 3H), 7.28-7.24 (m, 1H), 7.15 (d, J = 8.5 Hz, 2H), 5.36-5.32 (m, 1H), 3.67 (s, 3H), 3.54(s, 2H), 3.04-2.95 (m, 4H), 2.24-2.19 (m, 2H), 1.68-1.61 (m, 2H) LC / MS: 563 (M+H)

[0203] Example 42: Preparation of 7-chloro-4-(1-(3-chloro-4-fluorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (34 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (40 mg, 0.109 mmol) obtained in Production Example 2 and 3-chloro-4-fluorobenzaldehyde (0.013 mL, 0.109 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.35 (s, 1H), 8.20 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 7.1, 2.1 Hz, 1H), 7.28 (qd, J = 4.4, 2.3 Hz, 1H), 7.11 (t, J = 8.5 Hz, 1H), 5.41-5.34 (m, 1H), 3.72 (s, 2H), 3.59 (s, 3H), 3.15-3.03 (m, 4H), 2.45-2.39 (m, 2H), 1.64 (d, J = 11.4 Hz, 2H) LC / MS: 438 (M+H)

[0204] Example 43: Preparation of 7-chloro-4-(1-(3-chloro-4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (45 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (40 mg, 0.109 mmol) obtained in Production Example 2 and 3-chloro-4-(trifluoromethoxy)benzaldehyde (0.017 mL, 0.109 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.46 (d, J = 1.8 Hz, 1H), 7.29 (qd, J = 8.8, 1.6 Hz, 2H), 5.37-5.31 (m, 1H), 3.59 (d, J = 1.8 Hz, 5H), 3.06-2.96 (m, 4H), 2.30-2.24 (m, 2H), 1.63-1.59 (m, 2H) LC / MS: 504 (M+H)

[0205] Example 44: Preparation of 7-cyclopropyl-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile [ka] The title compound (14 mg) was obtained in the same manner as in Example 1 using 7-bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile (30 mg, 0.058 mmol) obtained in Example 40. 1 H-NMR (400 MHz, METHANOL-D4) δ 7.47 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 7.3 Hz, 3H), 5.30 (s, 1H), 3.62 (d, J = 5.0 Hz, 2H), 3.58 (d, J = 5.5 Hz, 3H), 3.02 (d, J = 11.4 Hz, 2H), 2.93-2.90 (m, 2H), 2.29-2.23 (m, 3H), 1.66 (d, J = 11.9 Hz, 2H), 1.24-1.19 (m, 2H), 0.96 (t, J = 5.0Hz, 2H) LC / MS: 500 (M+H)

[0206] Example 45: Preparation of 4-(1-(bis(3-chlorophenyl)methyl)piperidin-4-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] 7-Chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (40 mg, 0.11 mmol) obtained in Preparation 2, 3,3'-(chloromethylene)bis(chlorobenzene) (44 mg, 0.16 mmol) and potassium carbonate (45 mg, 0.33 mmol) were dissolved in acetonitrile (2 mL), refluxed at 85° C. and stirred for 4 hours. The reaction mixture was diluted with EtOAc, washed with brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by MPLC to obtain the title compound (30 mg). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.24 (s, 1H), 7.49-7.28 (m, 8H), 5.36 (t, J = 11.4 Hz, 1H), 4.42 (s, 1H), 3.62 (s, 3H), 3.02-2.96 (m, 4H), 2.14-2.07 (m, 3H), 1.56 (d, J = 9.8 Hz, 2H) LC / MS: 529 (M+H)

[0207] Example 46: Preparation of 7-chloro-4-(1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (28 mg) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.08 mmol) obtained in Production Example 2 and 2,3-dihydrobenzo[b][1,4]dioxin-6-carbaldehyde (80 mg, 0.49 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 1.5 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 7.0 Hz, 1H), 6.85-6.79 (m, 2H), 5.32-5.27 (m, 1H), 4.28 (d, J = 3.1 Hz, 4H), 3.67 (s, 2H), 3.62 (d, J = 10.7 Hz, 3H), 3.50 (s, 2H), 3.12-3.00 (m, 4H), 2.31 (t, J = 11.4 Hz, 2H), 1.61 (d, J = 11.6 Hz, 2H) LC / MS: 443 (M+H)

[0208] Example 47: Preparation of 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile [ka] The title compound (32 mg) was obtained in the same manner as in Example 1 using 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile dihydrochloride (40 mg, 0.112 mmol) obtained in Production Example 8 and 4-(trifluoromethoxy)benzaldehyde (42.5 mg, 0.223 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 8.56 (d, J = 1.5 Hz, 2H), 7.68 (d, J = 1.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 1H), 5.39-5.35 (m, 1H), 3.66 (s, 3H), 3.60 (s, 2H), 3.05-2.97 (m, 4H), 2.25-2.20 (m, 2H), 1.65-1.62 (m, 2H) LC / MS: 460 (M+H)

[0209] Example 48: Preparation of 7-acetyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (62 mg) was obtained in the same manner as in Example 1 using 7-acetyl-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (65 mg, 0.173 mmol) obtained in Production Example 9 and 4-(trifluoromethoxy)benzaldehyde (42.5 mg, 0.223 mmol). 1 H NMR (500 MHz, CHLOROFORM-D) δ 8.85 (d, J = 1.5 Hz, 2H), 8.06 (d, J = 1.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1H), 5.47-5.42 (m, 1H), 3.70 (s, 3H), 3.62 (s, 2H), 3.06-3.04(m, 4H), 2.71 (s, 3H), 2.28-2.23 (m, 2H), 1.66-1.65 (m, 2H) LC / MS: 477 (M+H)

[0210] Example 49: Preparation of 7-chloro-4-((2R,5S)-2,5-dimethyl-1-(4-trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (34 mg, 72%) was obtained in the same manner as in Example 1 using 7-chloro-4-((2R,5S)-2,5-dimethylpiperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (34 mg, 0.095 mmol) obtained in Production Example 17 and 4-(trifluoromethoxy)benzaldehyde (42.5 mg, 0.223 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.20 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.42 (d, J 8.5 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 5.35-5.31 (m, 1H), 4.19 (d, J = 14.0 Hz, 1H), 3.62 (s, 3H), 3.48-3.41 (m, 1H), 3.07-3.04 (m, 1H), 2.66-2.64 (m, 1H), 2.41-2.34 (m, 2H), 2.28-2.26 (m, 1H), 1.69-1.66 (m, 1H), 1.27 (d, J = 6.0 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H) LC / MS: 497 (M+H)

[0211] Example 50: Preparation of 7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (58 mg, 83%) was obtained in the same manner as in Example 1 using 7-chloro-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (50 mg, 0.145 mmol) obtained in Production Example 18 and 4-(trifluoromethoxy)benzaldehyde (83 mg, 0.435 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 7.45 (s, 1H), 7.43 (d, J 8.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.39-5.35 (m, 1H), 3.61 (s, 3H), 3.60 (s, 2H), 3.05-2.99 (m, 4H), 2.65 (s, 3H), 2.26-2.21 (m, 2H), 1.62-1.60 (m, 2H) LC / MS: 483 (M+H)

[0212] Example 51: Preparation of 7-bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (54 mg, 81%) was obtained in the same manner as in Example 1 using 7-bromo-1,6-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (49 mg, 0.126 mmol) obtained in Production Example 19 and 4-(trifluoromethoxy)benzaldehyde (72 mg, 0.377 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 7.60 (s, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.39-5.34 (m, 1H), 3.61 (s, 3H), 3.60 (s, 2H), 3.06-3.01 (m, 4H), 2.69 (s, 3H), 2.25-2.21 (m, 2H), 1.65-1.60 (m, 2H) LC / MS: 527, 529 (M+H)

[0213] Example 52: Preparation of 7-chloro-4-(1-((1-isopropyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (42 mg, 68%) was obtained in the same manner as in Example 1 using 7-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (49 mg, 0.148 mmol) obtained in Production Example 2 and 1-isopropyl-1H-pyrazole-4-carbaldehyde (51 mg, 0.370 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.21 (d, J = 2.0 Hz, 1H), 7.520-7.41 (m, 4H), 5.31-5.26 (m, 1H), 4.52-4.47 (m, 1H), 3.62 (s, 3H), 3.53 (s, 2H), 3.09-2.97 (m, 4H), 2.20-2.15 (m, 2H), 1.64-1.62 (m, 2H), 1.52 (t, J = 5.0 Hz, 6H) LC / MS: 417 (M+H)

[0214] Example 53: Preparation of 6-acetyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (19 mg, 28%) was obtained in the same manner as in Example 1 using 6-acetyl-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (48 mg, 0.142 mmol) obtained in Production Example 20 and 4-(trifluoromethoxy)benzaldehyde (67 mg, 0.354 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.01 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.0 Hz, 2H), 5.43-5.37 (m, 1H), 3.69 (s, 3H), 3.58 (s, 2H), 3.14-3.06 (m, 4H), 2.83 (s, 3H), 2.25-2.21 (m, 2H), 1.73-1.71 (m, 2H) LC / MS: 477 (M+H)

[0215] Example 54: Preparation of 6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (15 mg, 31%) was obtained in the same manner as in Example 1 using 6-chloro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (30 mg, 0.10 mmol) obtained in Production Example 21 and 4-(trifluoromethoxy)benzaldehyde (39 mg, 0.21 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 7.42 (m, J = 8.4 Hz, 3H), 7.25-7.15 (m, 3H), 5.30-5.24 (m, 1H), 3.60 (s, 3H), 3.58 (s, 2H), 3.00-2.92 (m, 4H), 2.27-2.08 (m, 2H), 1.60-1.57 (m, 2H) LC / MS: 469.1 (M+H), 470.1 (M+2H), 471.1 (M+3H)

[0216] Example 55: Preparation of 6-methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (21 mg, 44%) was obtained in the same manner as in Example 1 using 6-methoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.10 mmol) obtained in Production Example 22 and 4-(trifluoromethoxy)benzaldehyde (39 mg, 0.21 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 7.45 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 6.65 (d, J = 8.7 Hz, 1H), 5.32-5.26 (m, 1H), 4.02 (s, 3H), 3.58 (d, J = 5.9 Hz, 4H), 3.53 (s, 2H), 3.10-2.97 (m, 3H), 2.16 (t, J = 11.9 Hz, 2H), 1.64 (d, J = 11.4Hz, 2H) LC / MS: 465.1 (M+H)

[0217] Example 56: Preparation of 1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (18 mg, 83%) was obtained in the same manner as in Example 1 using 1,8-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (15 mg, 0.048 mmol) obtained in Production Example 23 and 4-(trifluoromethoxy)benzaldehyde (18 mg, 0.097 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.29 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.12 (d, J = 4.5 Hz, 1H), 5.60 (br s, 1H), 4.11 (s, 3H), 3.63 (s, 2H), 3.15-3.13 (m, 2H), 3.05-3.03 (m, 2H), 2.61 (s, 3H), 2.30-2.26 (m, 2H), 1.64-1.61 (m, 2H), LC / MS: 449 (M+H)

[0218] Example 57: Preparation of 7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (42 mg, 84%) was obtained in the same manner as in Example 1 using 4-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-chloro-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione hydrochloride (30 mg, 0.084 mmol) obtained in Production Example 24 and 4-(trifluoromethoxy)benzaldehyde (48 mg, 0.25 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.27 (s, 1H), 7.54 (d, J = 7.0 Hz, 2H), 7.51 (s, 1H), 7.18 (d, J = 8.2 Hz, 2H), 5.94-5.90 (m, 1H), 4.10 (s, 2H), 3.63 (d, J = 12.8 Hz, 3H), 3.37 (s, 2H), 3.01-2.96 (m, 2H), 2.12 (s, 2H), 1.83 (d, J = 7.6 Hz, 2H), 1.34-1.29 (m, 2H) LC / MS: 495.1 (M+H), 517.1 (M+Na)

[0219] Example 58: Preparation of 6-isopropoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (28 mg) was obtained in the same manner as in Example 1 using 6-isopropoxy-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (30 mg, 0.094 mmol) obtained in Production Example 25 and 4-(trifluoromethoxy)benzaldehyde (19.71 mg, 0.104 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 7.43 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 7.8 Hz, 2H), 6.58 (d, J = 8.7 Hz, 1H), 5.29 (dd, J = 11.4, 5.0 Hz, 2H), 3.58 (s, 3H), 3.53 (s, 2H), 3.04-2.98 (m, 4H), 2.18-2.12 (m, 2H), 1.64-1.61 (m, 2H), 1.40 (d, J = 5.9 Hz, 6H) LC / MS: 493 (M+H)

[0220] Example 59: Preparation of 7-fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (38 mg) was obtained in the same manner as in Example 1 using 7-fluoro-1-methyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione (30 mg, 0.108 mmol) obtained in Production Example 26 and 4-(trifluoromethoxy)benzaldehyde (22.55 mg, 0.119 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.13 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.24 (dd, J = 9.1, 2.3 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 5.35-5.29 (m, 1H), 3.58 (s, 3H), 3.56 (s, 2H), 3.03-2.93 (m, 4H), 2.22-2.16 (m, 2H), 1.58 (s, 2H) LC / MS: 453 (M+H)

[0221] Example 60: Preparation of methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate [ka] The title compound (261 mg, 69%) was obtained in the same manner as in Example 1 using methyl 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate dihydrochloride (300 mg, 0.77 mmol) obtained in Production Example 27 and 4-(trifluoromethoxy)benzaldehyde (292 mg, 1.53 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.89 (d, J = 5.5 Hz, 1H), 8.07 (d, J = 6.1 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 5.44 (t, J = 11.4 Hz, 1H), 4.01 (s, 3H), 3.69 (s, 3H), 3.60 (s, 2H), 3.04-2.99 (m, 4H), 2.24 (t, J = 11.9 Hz, 2H), 1.64 (d, J = 9.2 Hz, 2H) LC / MS: 493.2 (M+H)

[0222] Example 61: Preparation of 1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (58 mg, 90%) was obtained in the same manner as in Example 1 using 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.14 mmol) obtained in Production Example 28 and 4-(trifluoromethoxy)benzaldehyde (82 mg, 0.43 mmol). 1H-NMR (500 MHz, CHLOROFORM-D) δ 8.08 (s, 1H), 7.45 (d, J = 7.9 Hz, 2H), 7.30 (s, 1H), 7.20 (d, J = 7.9 Hz, 2H), 5.43 (t, J = 11.6 Hz, 1H), 3.68 (s, 2H), 3.63 (s, 3H), 3.13-3.07 (m, 4H), 2.43 (s, 3H), 2.33 (t, J = 12.1 Hz, 2H), 1.64 (d, J = 11.3 Hz, 2H) LC / MS: 449.2 (M+H), 450.2 (M+2H)

[0223] Example 62: Preparation of 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid [ka] Using methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate (230 mg, 0.47 mmol) obtained in Example 60, the title compound (65 mg, 29%) was obtained in the same manner as in Step A of Production Example 29. 1 H-NMR (500 MHz, DMSO-D6) δ 8.73 (s, 1H), 8.05 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H), 5.33 (s, 1H), 3.58 (s, 2H), 3.54 (s, 3H), 2.95 (d, J = 10.1 Hz, 2H), 2.77 (d, J = 11.9 Hz, 2H), 2.13 (t, J = 11.9 Hz, 2H), 1.60 (d, J = 11.0 Hz, 2H) LC / MS: 479.1 (M+H), 480.2 (M+2H)

[0224] Example 63: Preparation of N-(2-(dimethylamino)ethyl)-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide [ka] 1-Methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (15 mg, 0.031 mmol) obtained in Example 62, HATU (18 mg, 0.047 mmol) and N1,N1-dimethylethane-1,2-diamine (8 mg, 0.094 mmol) were dissolved in DCM (1 mL), DIPEA (12 mg, 0.094 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After extraction with DCM and distilled water, the organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by MPLC to obtain the title compound (10 mg, 58%). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.62 (d, J = 1.4 Hz, 1H), 8.07 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.35 (br s, 1H), 7.16 (d, J = 8.2 Hz, 2H), 5.38 (t, J = 11.7 Hz, 1H), 3.66 (s, 3H), 3.61-3.56 (m, 4H), 3.04-2.99 (m, 4H), 2.65-2.52 (m, 2H), 2.35 (s, 6H), 2.19 (t, J = 11.9 Hz, 2H), 1.60 (d, J = 8.7Hz, 2H) LC / MS: 549.3 (M+H), 550.3 (M+2H)

[0225] Example 64: Preparation of N,N,1-trimethyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide [ka] The title compound (32 mg, 87%) was obtained in the same manner as in Example 63 using 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid (35 mg, 0.073 mmol) obtained in Example 62. 1 H-NMR (400 MHz, CHLOROFORM-D) d 8.30 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.8 Hz, 2H), 5.42-5.36 (m, 1H), 3.61 (s, 3H), 3.57 (s, 2H), 3.12 (d, J = 11.4 Hz, 6H), 3.00-2.94 (m, 4H), 2.21 (t, J = 12.1 Hz, 2H), 1.62 (d, J = 11.0Hz, 2H) LC / MS: 506.2 (M+H), 507.2 (M+2H)

[0226] Example 65: Preparation of N,1-dimethyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide [ka] The title compound (19 mg, 41%) was obtained in the same manner as in Example 1 using N,1-dimethyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide dihydrochloride (30 mg, 0.095 mmol) obtained in Production Example 29 and 4-(trifluoromethoxy)benzaldehyde (0.016 mL, 0.104 mmol). 1 H-NMR (400 MHz, CHLOROFORM-D) δ 8.51 (d, J = 1.8 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.23 (s, 1H), 5.39 (d, J = 12.3 Hz, 1H), 3.65 (s, 3H), 3.58 (s, 2H), 3.07 (d, J = 4.6 Hz, 3H), 3.02-2.95 (m, 4H), 2.24-2.19 (m, 2H), 1.61 (d, J = 8.2 Hz, 2H) LC / MS: 492 (M+H)

[0227] Example 66: Preparation of 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide [ka] The title compound (20 mg, 42%) was obtained in the same manner as in Example 1 using 1-methyl-2,3-dioxo-4-(piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide dihydrochloride (30 mg, 0.099 mmol) obtained in Production Example 30 and 4-(trifluoromethoxy)benzaldehyde (0.016 mL, 0.109 mmol). 1H-NMR (400 MHz, CHLOROFORM-D) δ 8.57 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 1.8 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.2 Hz, 2H), 5.38 (s, 1H), 3.66 (s, 3H), 3.57 (s, 2H), 3.00 (d, J = 11.0 Hz, 4H), 2.23-2.16 (m, 2H), 1.44 (dd, J = 27.0, 6.4 Hz, 2H) LC / MS: 478 (M+H)

[0228] Example 67: Preparation of 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1,7-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione [ka] The title compound (43 mg, 75%) was obtained in the same manner as in Example 1 using 1,7-dimethyl-4-(piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione dihydrochloride (50 mg, 0.14 mmol) obtained in Production Example 28 and 3-chlorobenzaldehyde (61 mg, 0.43 mmol). 1 H-NMR (500 MHz, CHLOROFORM-D) δ 8.11 (s, 1H), 7.41 (s, 1H), 7.31-7.24 (m, 4H), 5.40 (t, J = 11.6 Hz, 1H), 3.63 (s, 3H), 3.60 (s, 2H), 3.12-3.01 (m, 4H), 2.44 (s, 3H), 2.26 (t, J = 11.4 Hz, 2H), 1.62 (d, J = 11.3 Hz, 2H) LC / MS: 399.2 (M+H)

[0229] Experimental example: Measurement of inhibitory effect on DGKα enzyme First, a 3X OAG (3 mM) / ATP (0.45 mM) substrate solution was prepared in 1X substrate assay buffer (40 mM MOPS (pH 7.2), 20 mM MgCl2, 1 mM DTT, 0.4 mM CaCl2, 3 mM sodium deoxycholate, 100 mM NaCl, 0.1 mg / mL BSA, 0.12% NP-40) and thoroughly vortexed for 3 min to induce the formation of detergent-lipid micelles. Next, a 3X DGKα (7.5 nM) enzyme solution was prepared in 2X enzyme assay buffer (80 mM MOPS (pH 7.2), 2 mM MDTT, 200 mM NaCl, 0.2 mg / mL BSA) and briefly vortexed.

[0230] After preparing the two solutions, a half-area opaque 96-well assay plate was prepared, and 10 μL of 3-fold 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 10 μL of 3X OAG / ATP substrate solution was added to the assay plate and mixed well. The plate was incubated at room temperature for 20 minutes for the enzyme reaction. Next, 15 μL of ADP-Glo ​​reagent was added to each well, mixed by pipetting, and the plate was incubated at room temperature for 40 minutes to deplete the remaining ATPs. After this step, 30 μL of kinase detection reagent was added and mixed, the plate was incubated at room temperature for another 20 minutes, and the luminescence was measured by Envision to determine the IC of each compound. 50 values ​​were calculated.

[0231] The measurement results are shown in Table 1 (+: IC 50 >5μM, ++:5μM>IC 50 >300nM, +++:IC 50 <300nM). [Table 1]

Claims

1. The following formula (1) 【Chemistry 1】 [In the formula, m represents an integer of 0, 1 or 2; R 1 represents hydrogen, halo, cyano (-CN), alkyl, alkoxy, alkylcarbonyl, or aryl; R 2 represents hydrogen, halo, cyano, carboxy (-COOH), alkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, cycloalkyl, aryl, or heteroaryl; R 3 represents hydrogen or alkyl; R 4 represents alkyl; R 5 represents alkyl, and when m is 2, they may be bonded together to form a ring; R 6 teeth, 【Chemistry 2】 (Here, R 7 and R 8 each independently represents a carbocyclyl or a heterocyclyl; The heteroaryl and heterocyclyl have one or more heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S) atoms; wherein the aryl, heteroaryl, carbocyclyl and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl and aryloxy, or a pharma- ceutically acceptable salt or stereoisomer thereof.

2. m represents an integer of 0, 1 or 2; R 1 is hydrogen, halo, cyano, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, C 1 -C 7 Alkylcarbonyl or C 6 -C 10 represents aryl; R 2 is hydrogen, halo, cyano, carboxy, C 1 -C 7 Alkyl, C 1 -C 7 Alkylcarbonyl, C 1 -C 7 Alkoxycarbonyl, aminocarbonyl, C 1 -C 7 Alkylaminocarbonyl, di(C 1 -C 7 alkyl)aminocarbonyl, di(C 1 -C 7 Alkyl)amino-C 1 -C 7 Alkylaminocarbonyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 aryl, or a 5-10 membered heteroaryl having 1 to 3 heteroatoms selected from N and O; R 3 is hydrogen or C 1 -C 7 represents alkyl; R 4 is C 1 -C 7 represents alkyl; R 5 is C 1 -C 7 When m is 2, they are bonded to each other to form C 2 -C 4 may form a ring; R 6 teeth, 【Chemistry 3】 (Here, R 7 and R 8 are each independently 5 -C 10 carbocyclyl, or a 5- to 12-membered heterocyclyl having 1 to 3 heteroatoms selected from N, O, and S; The aryl, heteroaryl, carbocyclyl and heterocyclyl are unsubstituted or substituted with halo, C 1 -C 7 Alkyl, C 1 -C 7 Alkoxy, halo-C 1 -C 7 Alkyl, halo-C 1 -C 7 Alkoxy, C 6 -C 10 Aryl and C 6 -C 10 The compound according to claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof, which is substituted with 1 to 3 substituents selected from the group consisting of aryloxy.

3. The compound according to claim 1, characterized in that the compound of formula (1) is selected from the following group: or a pharma- ceutically acceptable salt or stereoisomer thereof: Methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Ethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Isobutyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((2-chloroquinolin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((1,2-dimethyl-1H-indol-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-((1-methyl-1H-indol-5-yl)methyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(quinolin-4-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-([1,1'-biphenyl]-2-ylmethyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 4-(1-(2-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(4-chlorobenzyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((2-methoxypyridin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-((6-fluoropyridin-3-yl)methyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(4-phenoxybenzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(isoquinolin-5-ylmethyl)piperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(3-phenoxybenzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-benzylpiperidin-4-yl)-1,6-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,6-dimethyl-4-(1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 1-methyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-2,3-dioxo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 7-chloro-4-(1-(3-chlorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1-methyl-4-(1-(naphthalen-1-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1-methyl-4-(1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(3,3-dimethyl-1-(4-(trifluoromethoxy)benzyl)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)benzyl)-8-azabicyclo[3.2.1]octan-3-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1-methyl-4-(1-(quinoxalin-5-ylmethyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-bromo-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-((5-chloronaphthalen-1-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-methyl-7-(1-methyl-1H-pyrazol-4-yl)-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1-methyl-4-(1-((5,6,7,8-tetrahydronaphthalen-1-yl)methyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-bromo-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 7-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-cyclopropyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-6-(2-fluorophenyl)-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-(3-chloro-4-fluorobenzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-(3-chloro-4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-cyclopropyl-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-6-carbonitrile; 4-(1-(bis(3-chlorophenyl)methyl)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-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carbonitrile; 7-acetyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-((2R,5S)-2,5-dimethyl-(1-(4-trifluoromethoxy)benzyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-bromo-1,6-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-4-(1-((1-isopropyl-1H-pyrazol-4-yl)methyl)piperidin-4-yl)-1-methyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 6-acetyl-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 6-chloro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 6-Methoxy-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1,8-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-chloro-1-methyl-4-((1R,3r,5S)-8-(4-(trifluoromethoxy)benzyl)-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)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 7-fluoro-1-methyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; Methyl 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylate; 1,7-dimethyl-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione; 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxylic acid; N-(2-(dimethylamino)ethyl)-1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; N,N,1-trimethyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; N,1-dimethyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; 1-methyl-2,3-dioxo-4-(1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-7-carboxamide; and 4-(1-(3-chlorobenzyl)piperidin-4-yl)-1,7-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-2,3-dione.

4. A pharmaceutical composition for preventing or treating a disease associated with diacylglycerol kinases (DGKs), comprising as an active ingredient a compound of formula (1) according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt or stereoisomer thereof, together with a pharma- ceutically acceptable carrier.

5. The pharmaceutical composition according to claim 4, wherein the disease associated with diacylglycerol kinases (DGKs) is cancer.

6. The pharmaceutical composition according to claim 5, characterized in that the cancer is selected from the group consisting of digestive system cancer, pancreatic cancer, breast cancer, colon cancer, retinoblastoma, liver cancer, lung cancer, ovarian cancer, cervical cancer, endometrial cancer, brain cancer, testicular cancer, laryngeal cancer, prostate cancer, neuroblastoma, kidney cancer, thyroid cancer, esophageal cancer, skin cancer, osteosarcoma and bladder cancer.

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