Compound as PARP1 inhibitor and pharmaceutical composition comprising the same

Abstract

The present invention relates to a compound represented by formula 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof as a PARP1 inhibitor and a pharmaceutical composition including the same, and a method using the same for preventing or treating PARP1 activity-related diseases and a use thereof.

Description

[0001] Specification Title COMPOUND AS PARP1 INHIBITOR AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME 5 Technical Field The present invention relates to a compound, a stereoisomer thereof, a pharmaceutically acceptable salt thereof as a PARP1 inhibitor and a pharmaceutical composition including the same, and a method for preventing or treating PARP1 10 activity-related diseases using the same and a use thereof. Background Enzymes of a poly(ADP-ribose) polymerase (PARP) family may play important roles in many cellular processes such as replication, recombination, 15 chromatin remodeling, and DNA damage repair (O'Connor MJ, Mol Cell (2015) 60(4):547-60). Examples of PARP inhibitors and their mechanisms of action are taught, for example, in WO 2004 / 080976. PARP1 and PARP2 are the most extensively studied PARPs for their roles in 20 DNA damage repair. PARP1 is activated by DNA damage break and functions to catalyze the addition of poly(ADP-ribose) (PAR) chains to a target protein. The post- translational modification, known as PARylation, mediates recruitment of additional DNA repair factors into DNA lesions.

[0002] 1 / 411

[0003] After completion of such recruitment role, PARP self-PARylation triggers release of bound PARP from DNA, thus allowing access to other DNA repair proteins to complete the repair. Thus, the binding of PARP to a damaged site, a catalytic activity thereof, and a final release thereof from DNA are all important steps in which cancer 5 cells respond to DNA damage caused by chemotherapy and radiotherapy (Bai P. Biology of poly(ADP-ribose) polymerases: the factotums of cell maintenance. Mol Cell 2015;58:947-58.). Inhibition of the PARP family enzymes was utilized as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. A 10 number of preclinical and clinical studies have demonstrated that tumor cells, including deleterious alterations of BRCA1 or BRCA2, the major tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of DNA repair enzymes in the PARP family. These tumors have a defective homologous recombination repair 15 (HRR) pathway and rely on a PARP enzyme function for survival. PARP inhibitor therapy mainly targeted BRCA-mutant cancer, but PARP inhibitors were clinically tested in non-BRCA mutant tumors exhibiting homologous recombination deficiency (HRD) (Turner N, Tutt A, Ashworth A. Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer 2004;4:814-9.). 20 It is believed that PARP inhibitors with improved selectivity for PARP1 may lead to improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is also believed that selective and potent inhibition of PARP1 may lead to the capture of PARP1 on DNA, thus leading to double-stranded DNA break (DSB)

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[0005] through the disruption of an S-phase replication fork. The PARP1-DNA capture is also regarded to be an effective mechanism for selectively killing tumor cells with HRDs. Thus, there is an unmet medical need for effective and safe PARP inhibitors, in particular, PARP inhibitors with selectivity for PARP1. 5 [Related Art References] [Non-Patent Documents] J. Med. Chem.2021, 64, 19, 14498–14512 [Patent Documents] International Unexamined Patent Publication WO 2021 / 013735 10 International Unexamined Patent Publication WO 2021 / 260092 Disclosure Technical Problem The present invention may provide a compound, a stereoisomer thereof, or a 15 pharmaceutically acceptable salt thereof as a PARP1 inhibitor. The present invention may provide a pharmaceutical composition including a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a PARP1 inhibitor. The present invention may provide a pharmaceutical composition for 20 preventing or treating PARP1 activity-related diseases, including a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a PARP1 inhibitor as an effective ingredient (active ingredient). The present invention may provide a method for preventing or treating

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[0007] PARP1 activity-related diseases, including administering a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a PARP1 inhibitor; or a pharmaceutical composition including the same. The present invention may provide a use of a compound, a stereoisomer 5 thereof, or a pharmaceutically acceptable salt thereof as a PARP1 inhibitor; or a pharmaceutical composition including the same for preventing or treating PARP1 activity-related diseases. The present invention may provide a use of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof as a PARP1 inhibitor; or a 10 pharmaceutical composition including the same in preparing a medication for preventing or treating PARP1 activity-related diseases. Technical Solution Hereinafter, the present invention will be described in more detail. All the 15 combinations of various elements disclosed in the present invention fall within the scope of the present invention. In addition, it cannot be seen that the scope of the present invention is limited to the specific description below. Compound represented by formula 1 20 The present invention may provide a compound represented by formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Formula 1]

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[0009] wherein in above formula 1, M is CRx, N, NRy, O or S, X1, X2and X3are each independently N or CRz, 5 Rx, Ryand Rzare each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, R1is H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2- C5 alkynyl or O-(C1-C5 alkyl), 10 Y1, Y2, Y3, Y4and Y5are each independently C, CH, CH2, N, NH, O or S, B is cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene or heteroarylene, L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, R2and R3are each independently H, halogen, OH, CN, C1-C5 alkyl, C1-C5 15 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl or O-(C1-C5 alkyl), RAand RBare each independently H, C1-C5 alkyl, C1-C5 haloalkyl, - C(=O)O-(C1-C5 alkyl), -S(=O)2-(C1-C5 alkyl), cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, or RAand RBare bonded to

[0010] 5 / 411

[0011] each other to form , Z is CH2, NH, O, S, C(=O) or S(=O)2, at least one H of RA, RBand formed by bonding RAand RBmay be each independently substituted with halogen, OH, CN, (=O), C1-C5 alkyl, C1- 5 C5 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, (C1-C5 alkylene)-O-(C1-C5 alkyl), O- (C1-C5 alkyl), -C(=O)O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, 10 provided that a and b; c and d; e and f; and g and h may not be 0 at the same time, and halogen is F, Cl, Br or I. In one embodiment, it may be provided that in above formula 1, M is CRx, N, NRy, O or S, 15 X1, X2and X3are each independently N or CRz, Rx, Ryand Rzare each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, R1is H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2- C5 alkynyl or O-(C1-C5 alkyl),

[0012] 6 / 411

[0013] , Y1, Y2, Y3, Y4and Y5are each independently C, CH, CH2, N, NH, O or S, B is three- to seven-membered cycloalkylene, three- to seven-membered cycloalkenylene, three- to seven-membered heterocycloalkylene including one to three 5 heteroatoms independently selected from the group consisting of N, O and S, three- to seven-membered heterocycloalkenylene including one to three heteroatoms independently selected from the group consisting of N, O and S, C6-C12 arylene, or five- to 12-membered heteroarylene including one to three heteroatoms independently selected from the group consisting of N, O and S, 10 L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, R2and R3are each independently H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl or O-(C1-C5 alkyl), RAand RBare each independently H, C1-C5 alkyl, C1-C5 haloalkyl, - C(=O)O-(C1-C5 alkyl), -S(=O)2-(C1-C5 alkyl), three- to seven-membered cycloalkyl, 15 three- to seven-membered cycloalkenyl, three- to seven-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S, three- to seven-membered heterocycloalkenyl including one to three heteroatoms independently selected from the group consisting of N, O and S, C6-C12 aryl, or five- to 12-membered heteroaryl including one to three heteroatoms 20 independently selected from the group consisting of N, O and S, or RAand RBare

[0014] 7 / 411

[0015] bonded to each other to form , Z is CH2, NH, O, S, C(=O) or S(=O)2, at least one formed by bonding RAand RBmay be each independently substituted with halogen, OH, CN, (=O), C1-C5 alkyl, C1- 5 C5 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, (C1-C5 alkylene)-O-(C1-C5 alkyl), O- (C1-C5 alkyl), -C(=O)O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, 10 provided that a and b; c and d; e and f; and g and h may not be 0 at the same time, and halogen may be F, Cl, Br or I. In one embodiment, it may be provided that in above formula 1, M is CRx, N, O or S, 15 X1, X2and X3are each independently N or CRz, Rxand Rzare each independently H or halogen, R1is C1-C5 alkyl,

[0016] 8 / 411

[0017] Y1, Y2, Y3, Y4and Y5are each independently C, CH, CH2, N or O, B is C6-C12 arylene or five- to 12-membered heteroarylene including one to three heteroatoms independently selected from the group consisting of N, O and S, L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, 5 R2and R3are each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, RAand RBare each independently H, C1-C5 alkyl, -C(=O)O-(C1-C5 alkyl), three- to seven-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S, C6-C12 aryl, or five- to 12-membered heteroaryl including one to three heteroatoms independently selected 10 from the group consisting of N, O and S, or RAand RBare bonded to each other to form formed by bonding RAand RBmay be each independently substituted with halogen, (=O), C1-C5 alkyl, C1-C5 15 haloalkyl, (C1-C5 alkylene)-O-(C1-C5 alkyl), O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, 20 provided that a and b; c and d; e and f; and g and h may not be 0 at the same time, and

[0018] 9 / 411

[0019] halogen may be F or Cl. In one embodiment, it may be provided that in above formula 1, M is CRx, N, O or S, 5 X1, X2and X3are each independently N or CRz, Rxand Rzare each independently H or halogen, R1is C1-C5 alkyl, , Y1, Y4and Y5are each independently N, 10 Y2is C, CH or N, Y3is each independently CH2or O, B is phenylene or five- to six-membered heteroarylene including one to two heteroatoms independently selected from the group consisting of N, O and S L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, 15 R2and R3are each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, RAand RBare each independently H, C1-C5 alkyl, -C(=O)O-(C1-C5 alkyl), four- to five-membered heterocycloalkyl including one O, phenyl or five- to six- membered heteroaryl including one to two Ns, or RAand RBare bonded to each other to form ,

[0020] 10 / 411

[0021] Z is CH2, NH, O, C(=O) or S(=O)2, at least one H of RA, RBand formed by bonding RAand RBmay be each independently substituted with halogen, (=O), C1-C5 alkyl, C1-C5 haloalkyl, (C1-C5 alkylene)-O-(C1-C5 alkyl), O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, provided that a and b; c and d; e and f; and g and h may not be 0 at the same time, and 10 halogen may be F or Cl. In the present invention, "Cm-Cn" (in which m and n are each independently an integer of 1 or more) may mean the number of carbons and, for example, "C1-C5 alkyl" may represent alkyl having one to five carbon atoms. 15 In the present invention, “alkyl” may mean a linear or branched saturated hydrocarbon group. In the present invention, alkyl may have one to five carbon atoms. In one embodiment, alkyl may have one to four carbon atoms. In one embodiment, alkyl may have one to three carbon atoms. Examples of alkyl may include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, sec-pentyl, tert- 20 pentyl, isopentyl, sec-isopentyl, neo-pentyl, etc., but are not limited thereto.

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[0023] In the present invention, "alkenyl" may mean a linear or branched unsaturated hydrocarbon group including one or more double bonds. In the present invention, alkenyl may have two to five carbon atoms. In one embodiment, alkenyl may have two to four carbon atoms. Examples of alkenyl may include ethenyl, allyl, propenyl, etc., 5 but are not limited thereto. In the present invention, "alkynyl" may mean a linear or branched unsaturated hydrocarbon group including one or more triple bonds. In the present invention, alkynyl may have two to five carbon atoms. In one embodiment, alkynyl may have two to four carbon atoms. Examples of alkynyl may include ethynyl, propynyl, butynyl, etc., but 10 are not limited thereto. In the present invention, "haloalkyl" may mean alkyl substituted with one or more halogens such as F, Cl, Br, I. The meaning of alkyl may be as defined above. For example, C1 haloalkyl may mean alkyl in which at least one H of C1 alkyl is substituted with halogen such as F, Cl, Br, I, specifically, -CFH2, -CF2H or -CF3. 15 In the present invention, "cycloalkyl" may mean a saturated hydrocarbon ring having three or more carbon atoms, which may include both monocyclic and polycyclic ring structures. As one example, in the present invention, cycloalkyl may be a ring having three to 12, three to ten, three to eight, or three to seven carbon atoms. Examples of cycloalkyl may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 20 cycloheptyl, cyclooctyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, bicyclooctyl, bicyclononyl, spiropentyl, spirohexyl, spiroheptyl, spirooctyl, spirononyl, etc., but are

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[0025] not limited thereto. In the present invention, "cycloalkenyl" may mean an unsaturated hydrocarbon ring having three or more carbon atoms including one or more double bonds, which may include both monocyclic and polycyclic ring structures. In other 5 words, in the present invention, cycloalkenyl may mean a ring structure including one or more carbon-carbon double bonds in the cycloalkyl ring as defined above. In the present invention, cycloalkenyl may be a ring having three to 12, three to ten, three to eight, or three to seven carbon atoms. Examples of cycloalkenyl may include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc., but are not limited 10 thereto. In the present invention, "heterocycloalkyl" may mean a cyclic functional group in which at least one or more carbon atoms constituting the cycloalkyl ring as defined above are substituted with a heteroatom. Examples of the heteroatom may include nitrogen (N), oxygen (O) or sulfur (S). In this case, the heteroatoms included in 15 the ring of heterocycloalkyl may be one type or two or more types, one or one or more of one type of heteroatom may be included therein, and at least one or more of the two or more types of heteroatoms may be included therein, respectively. As one example, in the present invention, heterocycloalkyl may be a three- to 12-membered ring. As one example, in the present invention, heterocycloalkyl may be a three- to seven-membered 20 ring including one to three heteroatoms. As one example, in the present invention, heterocycloalkyl may be a four- to six-membered ring including one or two heteroatoms.

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[0027] Examples of heterocycloalkyl may include oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, etc., but are not limited thereto. 5 In the present invention, "heterocycloalkenyl" may mean a cyclic functional group in which at least one or more carbon atoms constituting the cycloalkenyl ring as defined above are substituted with a heteroatom. Examples of the heteroatom may include nitrogen (N), oxygen (O) or sulfur (S). In this case, the heteroatoms included in the ring of heterocycloalkenyl may be one type or two or more types, one or one or 10 more of one type of heteroatom may be included therein, and at least one or more of the two or more types of heteroatoms may be included therein, respectively. In the present invention, "aryl" may mean a monocyclic or polycyclic aromatic hydrocarbon ring. As one example, in the present invention, aryl may have six to 20 carbon atoms. As one example, in the present invention, aryl may have six to 12 15 carbon atoms. Examples of aryl may include phenyl, biphenyl, naphthalenyl, etc., but are not limited thereto. In the present invention, "heteroaryl" may mean a monocyclic or polycyclic aromatic hydrocarbon ring including at least one or more of heteroatom such as nitrogen (N), oxygen (O) or sulfur (S). As one example, in the present invention, heteroaryl may 20 be a five- to 12-membered ring. As one example, in the present invention, heteroaryl may be a five- to 12-membered ring including one to three heteroatoms. As one example,

[0028] 14 / 411

[0029] in the present invention, heteroaryl may be a five- to eight-membered ring including one to three heteroatoms. As one example, in the present invention, heteroaryl may be a five- or six-membered ring including one or two heteroatoms. As one example, in the present invention, heteroaryl may be a five- or six-membered ring including one or two 5 Ns. When heteroaryl includes two or more heteroatoms, the types of heteroatoms may be the same as or different from each other. For example, a case in which heteroaryl includes two or more heteroatoms selected from nitrogen, oxygen, and sulfur may refer to various combinations such as a case of including two nitrogen atoms, a case of including one nitrogen atom and one oxygen atom, a case of including two oxygen 10 atoms and one nitrogen atom, and the like. Examples of heteroaryl may include pyridinyl, thiophenyl, triazolyl, tetrazolyl, benzothiazolyl, benzothiophenyl, quinolinyl, indolyl, isoindolyl, benzofuranyl, benzopyrroyl, furanyl, pyrrolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyrimidinyl, isoquinolinyl, benzoxazolyl, benzoimidazolyl, dihydrobenzothiophenyl, 15 purinyl, indolizinyl, chromenyl, pyrrolopyridinyl, pyrazolopyridinyl, thiadiazolopyridinyl, triazinyl, triazolopyrimidinyl, triazolopyridinyl, triazolopyridazinyl, indazolyl, imidazopyridinyl, imidazopyridazinyl, oxadiazolopyridinyl, benzothiadiazolyl, benzotriazolyl, benzoxadiazole, isomers thereof, and the like, but are not limited thereto. 20 In the present invention, cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene, heteroarylene or phenylene may mean a divalent

[0030] 15 / 411

[0031] functional group which is further free of one hydrogen in cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl or phenyl. The present invention may provide compounds described in a table below, 5 stereoisomers thereof, or pharmaceutically acceptable salts thereof.

[0032] 16 / 411

[0033]

[0034] 17 / 411

[0035]

[0036]

[0037]

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[0039]

[0040] 24 / 411

[0041]

[0042] 25 / 411

[0043]

[0044] 26 / 411

[0045]

[0046] 27 / 411

[0047] In the present invention, “stereoisomer” may include a diastereomer and an optical isomer, which may include all of the followings: a single enantiomer, a mixture of enantiomers including a racemate, a single diastereomer, and a mixture of 5 diastereomers. Such isomer may be separated by resolution according to conventional techniques, for example, column chromatography, HPLC or the like. Alternatively, the isomer may be stereospecifically synthesized by using a known array of optically pure starting materials and / or reagents. Specifically, the isomer may be an optical isomer. In the present invention, “pharmaceutically acceptable salts” may mean salts 10 conventionally used in a pharmaceutical field, for example, inorganic ion salts prepared

[0048] 28 / 411

[0049] from calcium, potassium, sodium, magnesium and the like; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, 5 tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbric acid, carbonic acid, vanillic acid, etc.; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like; amino acid salts prepared from glycine, arginine, 10 lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but are not limited to those listed salts. The compound represented by formula 1 of the present invention may include a pharmaceutically acceptable isotopically labeled compound which is the same as the compound listed in the present specification, but in which at least one or more of atoms 15 having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number predominant in nature are replaced. Examples of isotopes which may be included in the compound of the present invention may include isotopes of hydrogen,2H,3H; isotopes of carbon,11C,13C,14C; isotopes of chlorine, 36Cl; isotopes of fluorine,18F; isotopes of iodine,123I,125I; isotopes of nitrogen,13N,15N; 20 isotopes of oxygen,15O,17O,18O; isotopes of phosphorus,32P; and isotopes of sulfur, 35S, etc. Certain isotopically labeled compounds of the present invention, e.g., compounds incorporating radioisotopes, may be useful in drug and / or substrate tissue distribution studies (e.g., assays). Radioisotopes tritium, that is,3H, and carbon-14, that

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[0051] is,14C, may be useful in view of their ease of incorporation and immediate detection means. Substitution with heavier isotopes, for example, substitution of hydrogen (1H) with deuterium (2H) may exhibit excellent effects on disease treatment by enhancing metabolic stability, such as increasing half-life in vivo or reducing dosage. Substitution 5 with positron-emitting isotopes, for example,11C,15F,18F,15O,13N, etc., may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention may be generally prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the reaction formulas and / or examples and preparation 10 examples described in the present specification, by using the appropriate isotopically labeled reagents in place of the non-labeled reagents used herein. Compounds represented by formula 1 in the present specification may include isotopically labeled compounds, for example, compounds including, but not limited to, isotopes such as deuterium and tritium, and all other isotopes discussed above. 15 In the present invention, “prevention” may refer to all the acts, which inhibit or delay the occurrence of a disease by administering the compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof. 20 In the present invention, “treatment” may refer to all the acts, by which a symptom of an individual likely to develop or suffering from a disease gets better or takes a favorable turn by administering the compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt

[0052] 30 / 411

[0053] thereof. The compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof may be advantageously used for preventing or treating PARP1 activity-related diseases. 5 The compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof may inhibit PARP1 activity. The compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof may show an effect 10 of preventing or treating PARP1 activity-related diseases at a level similar to, substantially the same as, or higher than that of a conventionally known drug for preventing or treating the PARP1 activity-related diseases. Method for preparing compound represented by formula 1 15 The present invention may provide a method for preparing a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: The compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof may be prepared 20 according to a method of any one of reaction formulas 1 to 11, and the reaction formulas 1 to 11 may be modified to levels apparent to those skilled in the art. In the following reaction formulas 1 to 11, halo may mean F, Cl, Br or I, and each of R1, R2, R3, RA, RB, A, B, K, L, M, X1, X2and X3may be substantially the same

[0054] 31 / 411

[0055] as defined in formula 1 unless specifically defined. [Reaction Formula 1] According to above reaction formula 1, a compound of formula 1-3 may be 5 prepared from a compound of formula 1-1 and a compound of formula 1-2 through a palladium catalyst cross-coupling reaction, and a protecting group (PG) may be removed to prepare a compound of formula 1-4. [Reaction Formula 2] 10 According to above reaction formula 2, a compound of formula 2-2 may be prepared from a compound of formula 2-1 and the compound of formula 1-2 through a suzuki reaction, and a compound of formula 2-3 may be prepared through a hydrogenation reaction, and a protecting group (PG) may be removed to prepare a compound of formula 2-4. 15 [Reaction Formula 3]

[0056] 32 / 411

[0057] According to above reaction formula 3, a compound of formula 3-1 may be prepared from the compound of formula 1-3 through a hydrolysis reaction, a compound of formula 3-2 may be prepared through a reaction with an amine compound, and a protecting group (PG) may be removed to prepare a compound of formula 3-3. 5 [Reaction Formula 4] According to above reaction formula 4, a compound of formula 4-1 may be prepared from the compound of formula 3-2 through a reaction with Lawesson's reagent, and a protecting group (PG) may be removed to prepare a compound of formula 4-2. 10 [Reaction Formula 5] According to above reaction formula 5, a compound of formula 5-2 may be prepared from a compound of formula 5-1 and the compound of formula 1-2 through a substitution reaction, and a compound of formula 5-3 may be prepared through a 15 hydrolysis reaction. A compound of formula 5-4 may be prepared through a reaction with an amine compound, and a protecting group (PG) may be removed to prepare a

[0058] 33 / 411

[0059] compound of formula 5-5. [Reaction Formula 6] According to above reaction formula 6, a compound of formula 6-2 may be 5 prepared from the compound of formula 1-1 and a compound of formula 6-1 through a substitution reaction or a reductive amination reaction, and a compound of formula 6-3 may be prepared through a hydrolysis reaction. A compound of formula 6-4 may be prepared through a reaction with an amine compound, and a protecting group (PG) may be removed to prepare a compound of formula 6-5. 10 [Reaction Formula 7] According to above reaction formula 7, a compound of formula 7-2 may be prepared from a compound of formula 7-1 and the compound of formula 1-4 through a

[0060] 34 / 411

[0061] substitution reaction, and a compound of formula 7-3 may be prepared through a hydrolysis reaction. A compound of formula 7-4 may be prepared through a reaction with an amine compound. [Reaction Formula 8] 5 According to above reaction formula 8, a compound of formula 8-1 may be prepared from a compound of formula 7-1 and the compound of formula 2-4 through a substitution reaction, and a compound of formula 8-2 may be prepared through a hydrolysis reaction. A compound of formula 8-3 may be prepared through a reaction 10 with an amine compound. [Reaction Formula 9]

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[0063] According to above reaction formula 9, a compound of formula 9-1 may be prepared from the compound of formula 7-1 and the compound of formula 3-3 or the compound of formula 4-2 through a substitution reaction. [Reaction Formula 10] 5 According to above reaction formula 10, a compound of formula 10-1 may be prepared from the compound of formula 7-1 and the compound of formula 5-5 through a substitution reaction. [Reaction Formula 11] 10 According to above reaction formula 11, a compound of formula 11-1 may be prepared from the compound of formula 7-1 and the compound of formula 6-5 through a substitution reaction. In the present invention, the compounds prepared in above reaction formulas 15 1 to 11 may include Example Compounds 1 to 197. Pharmaceutical Compositions, Methods and Uses The present invention may provide a pharmaceutical composition including a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically

[0064] 36 / 411

[0065] acceptable salt thereof. The present invention may provide a pharmaceutical composition for preventing or treating PARP1 activity-related diseases, including the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable 5 salt thereof an effective ingredient (active ingredient). In other words, the pharmaceutical composition including the compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof as an effective ingredient may be advantageously used for preventing or treating PARP1 activity-related diseases. 10 The PARP1 activity-related disease may be cancer or inflammatory disease. The cancer may be at least one selected from the group consisting of breast cancer, ovary cancer, pancreas cancer, prostate cancer, hematological cancer, gastrointestinal cancer such as gastric cancer or colorectal cancer, lung cancer such as small cell lung cancer or non-small cell lung cancer, and brain cancer such as glioma or 15 glioblastoma. The brain cancer may be metastatic cancer caused by tumors in other parts of the body such as breast cancer, ovary cancer, pancreas cancer, prostate cancer, hematological cancer, gastrointestinal cancer such as gastric cancer or colorectal cancer, or lung cancer such as small cell lung cancer or non-small cell lung cancer. 20 The inflammatory disease may be at least one selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colonitis, ulcerative colitis, Graft-versus-host disease (GVHD), systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin-dependent diabetes

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[0067] mellitus. The pharmaceutical composition of the present invention may further include at least one pharmaceutically acceptable carrier in addition to the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof 5 for administration. The pharmaceutically acceptable carrier may be one which is conventionally used in the art, specifically including, but not limited thereto, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidine, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, 10 magnesium stearate, or mineral oil. The pharmaceutical composition of the present invention may further include lubricants, humectants, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, dispersing agents, stabilizing agents, etc., in addition to the above ingredients. In addition, the pharmaceutical composition of the present invention may be formulated into an oral dosage form such 15 as tablet, powder, granule, pill, capsule, suspension, emulsion, liquid for internal use, emulsion, syrup, etc., as well as a form of external preparation, suppository or sterile solution for injection by using a pharmaceutically acceptable carrier and an excipient, and thus may be prepared in a unit dose form or prepared by being inserted into a multi- dose container. The preparations may be prepared according to a conventional method 20 used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19thed., 1995), and may be formulated into various preparations depending on each disease or ingredient. The pharmaceutical composition of the present invention may be orally or

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[0069] parenterally administered (for example, applied intravenously, hypodermically, intraperitoneally or locally) according to an intended method, in which a dosage thereof varies depending on a patient’s weight, age, gender, health condition, diet, an administration time, an administration method, an excretion rate, a severity of a disease 5 and the like. The compound represented by formula 1 of the present invention may be administered at one time or several divided times a day, but is not necessarily limited thereto. The daily dosage of the compound represented by formula 1 of the present invention, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof may 10 be specifically about 0.1 to about 10,000 mg / kg, about 1 to about 8,000 mg / kg, about 5 to about 6,000 mg / kg, or about 10 to about 4,000 mg / kg, and more specifically about 50 to about 2,000 mg / kg, but is not limited thereto. In addition to the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof, the pharmaceutical composition 15 of the present invention may further include at least one ingredient which may exhibit the same or similar medicinal effects or may bring synergy to medicinal effects in combination. The pharmaceutical composition of the present invention may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. 20 The present invention may provide a method for preventing or treating PARP1 activity-related diseases, including administering the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof; or

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[0071] the pharmaceutical composition including the same. In the administering, the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof; or the pharmaceutical composition including the same may be administered to an individual 5 in need thereof. In the present invention, “administration” may refer to introducing a predetermined substance into an individual by an appropriate method. In the present invention, “individual” may refer to all the animals such as rats, mice, livestock, etc., including humans, who have already developed or are likely to 10 develop the diseases, and specifically may refer to mammals including humans, but is not limited thereto. The method for preventing or treating PARP1 activity-related diseases of the present invention may refer to administering a therapeutically effective amount of the 15 compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof; or the pharmaceutical composition including the same. In the present invention, “therapeutically effective amount” may refer to an amount enough to treat a disease at a reasonable risk / benefit ratio applicable to medical treatment and not to cause a side effect, and may be determined by those skilled in the 20 art according to factors including a patient’s gender, age, weight and health condition, a type of disease, severity, activity of a drug, sensitivity to a drug, an administration method, an administration time, an administration route, an excretion rate, a treatment period, a drug combined or concurrently used, as well as other factors well known in a

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[0073] pharmaceutical field. It may be preferable to differently apply a specific therapeutically effective amount for a certain patient depending on various factors including a type and degree of reaction to be achieved therefrom, a specific composition including a presence of other preparations used in some cases, a patient’s age, weight, general health 5 condition, gender and diet, an administration time, an administration route, a secretion rate of the composition, a treatment period and a drug used together with the specific composition or simultaneously therewith, as well as other similar factors well known in a pharmaceutical field. 10 The present invention may provide a use of the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof for preventing or treating PARP1 activity-related diseases. The present invention may provide a use of the compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof in 15 preparing a medication for preventing or treating PARP1 activity-related diseases. The present invention may provide a use of the pharmaceutical composition according to the present invention for preventing or treating PARP1 activity-related diseases. The present invention may provide a use of the pharmaceutical composition 20 according to the present invention in preparing a medication for preventing or treating PARP1 activity-related diseases. Matters mentioned in the compound represented by formula 1, the pharmaceutical composition, the method and the use of the present invention may be

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[0075] applied the same, if not contradictory to each other. Advantageous Effects The compound represented by formula 1, the stereoisomer thereof, or the 5 pharmaceutically acceptable salt thereof of the present invention may exhibit an inhibitory effect on PARP1, and may be advantageously used for preventing or treating PARP1 activity-related diseases. Mode for Invention 10 Hereinafter, the present invention will be described in more detail through preparation examples and exemplary examples. However, the following preparation examples and exemplary examples are provided for the purpose of illustrating the present invention, and thus the present invention is not limited to the preparation examples and exemplary examples. 15 <Preparation Example> The compounds of the present invention were synthesized as follows. In order to prepare the compound of the present invention, the reactants used in each reaction were each purchased from Sigma Aldrich Corporation and the like, or 20 synthesized using an organic synthesis method apparent to those skilled in the art, and used without a separate purification process. The compounds of each Example were identified by1H-NMR (Bruker, avance II 400) and Mass (Waters, SQD2) analysis.

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[0077] Preparation of intermediate compound Synthesis of intermediate compound 1: Methyl 5-piperazin-1-ylpyridin- 2-carboxylate hydrochloride [Step 1] Synthesis of tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazin-1- 5 carboxylate Methyl 5-bromopyridin-2-carboxylate (100.00%, 2.160 g, 9.999 mmol), tert- butyl piperazin-1-carboxylate (100.00%, 2.200 g, 11.812 mmol), RuPhos Pd G3 (100.00%, 0.420 g, 0.502 mmol), and cesium carbonate (100.00%, 6.500 g, 19.950 10 mmol) were mixed in 1,4-dioxane (50 mL) at room temperature, and the resulting mixture was stirred at 100°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified 15 by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazin-1- carboxylate (3.000 g, 93.35%) in the form of a yellowish solid. [Step 2] Synthesis of intermediate compound 1

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[0079] Tert-butyl 4-(6-methoxycarbonyl-3-pyridyl)piperazin-1-carboxylate (100.00%, 3.000 g, 9.334 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2.6 mL, 10.400 mmol) were mixed in dichloromethane (40 mL) at room temperature, 5 and the resulting mixture was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 1, methyl 5-piperazin-1- ylpyridin-2-carboxylate hydrochloride, 2.400 g, 99.77%, yellowish solid). 10 Synthesis of intermediate compound 1A: 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate 15 Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate hydrochloride (100.00%, 1.000 g, 3.880 mmol), 7-(bromomethyl)-3-ethyl-1H-1,5- naphthyridin-2-one (100.00%, 1.100 g, 4.118 mmol), and N,N-diisopropylethylamine

[0080] 44 / 411

[0081] (100.00% solution, 3.4 mL, 19.466 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5- 5 [4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2- carboxylate (1.100 g, 69.57%) in the form of a white solid. [Step 2] Synthesis of intermediate compound 1A Methyl 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1- 10 yl]pyridin-2-carboxylate (100.00%, 1.100 g, 2.699 mmol) and sodium hydroxide (5.00 M solution in water, 1.1 mL, 5.500 mmol) were mixed in tetrahydrofuran (3 mL) / methanol (3 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further15 purification (intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 1.060 g, 99.82%, white solid). Synthesis of intermediate compound 1B: 5-[4-[(5-fluoro-2-methyl-3-oxo- 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid 20 [Step 1] Synthesis of methyl 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-

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[0083] 6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylate Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate hydrochloride (100.00%, 0.600 g, 2.328 mmol), 7-(bromomethyl)-8-fluoro-3-methyl- 5 1H-quinoxalin-2-one (100.00%, 0.700 g, 2.582 mmol), and N,N-diisopropylethylamine (100.00% solution, 1.6 mL, 9.161 mmol) were mixed in acetonitrile (10 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, and then the resulting 10 concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain methyl 5-[4-[(5- fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2- carboxylate (0.950 g, 99.19%) in the form of a yellowish solid. [Step 2] Synthesis of intermediate compound 1B 15 Methyl 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (100.00%, 0.950 g, 2.309 mmol) and sodium hydroxide (5.00 M solution in water, 3 mL, 15.000 mmol) were mixed in

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[0085] tetrahydrofuran (3 mL) / methanol (3 mL) at room temperature, and the resulting mixture was stirred at 50°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further 5 purification (intermediate compound 1B, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 0.910 g, 99.16%, light brown solid). Synthesis of intermediate compound 1C: 5-[4-[(2-ethyl-5-fluoro-3-oxo- 10 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate 15 hydrochloride (100.00%, 1.000 g, 3.880 mmol), N,N-diisopropylethylamine (100.00% solution, 3.4 mL, 19.466 mmol), and 7-(bromomethyl)-3-ethyl-8-fluoro-1H- quinoxalin-2-one (100.00%, 1.100 g, 3.858 mmol) were mixed in acetonitrile (20 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. 20 The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl

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[0087] 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2- carboxylate (1.180 g, 71.47%) in the form of a yellowish solid. [Step 2] Synthesis of intermediate compound 1C 5 Methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]pyridin-2-carboxylate (100.00%, 1.180 g, 2.773 mmol) and sodium hydroxide (5.00 M solution in water, 1.1 mL, 5.500 mmol) were mixed in tetrahydrofuran (3 mL) / methanol (3 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for three days. After removing the solvent from the 10 reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 1C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin- 6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 1.100 g, 96.42%, light brown solid). 15 Synthesis of intermediate compound 1D: 5-[4-[(3-ethyl-2-oxo-1H- pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylate

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[0089] Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate hydrochloride (100.00%, 0.260 g, 1.009 mmol), N,N-diisopropylethylamine (100.00 % solution, 0.9 mL, 5.153 mmol), and 7-(bromomethyl)-3-ethyl-1H-pyrido[2,3- 5 b][1,4]oxazin-2-one (100.00 %, 0.280 g, 1.033 mmol) were mixed in acetonitrile (4 mL) at room temperature, and the resulting mixture was stirred at 80°C for three days, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin- 10 2-carboxylate (0.275 g, 66.26%) in the form of a white solid. [Step 2] Synthesis of intermediate compound 1D Methyl 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (100.00%, 0.275 g, 0.668 mmol) and 15 sodium hydroxide (5.00 M solution in water, 0.27 mL, 1.350 mmol) were mixed in tetrahydrofuran (1 mL) / methanol (1 mL) / water (0.7 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was

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[0091] used without further purification (intermediate compound 1D, 5-[4-[(3-ethyl-2-oxo-1H- pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 0.260 g, 97.88%, white solid). 5 Synthesis of intermediate compound 2: Methyl 6-fluoro-5-piperazin-1- yl-pyridin-2-carboxylate hydrochloride [Step 1] Synthesis of tert-butyl 4-(2-fluoro-6-methoxycarbonyl-3- pyridyl)piperazin-1-carboxylate 10 Methyl 5-bromo-6-fluoro-pyridin-2-carboxylate (100.00%, 1.900 g, 10.023 mmol), tert-butyl piperazin-1-carboxylate (100.00%, 2.200 g, 11.812 mmol), RuPhos Pd G3 (100.00%, 0.420 g, 0.502 mmol), and cesium carbonate (100.00%, 7.000 g, 21.484 mmol) were mixed in 1,4-dioxane (40 mL) at room temperature, and the resulting mixture was stirred at 100°C for 18 hours, after which the reaction was 15 terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 10% to 50%) and concentrated to obtain tert-butyl 4-(2-fluoro-6-methoxycarbonyl-3- 20 pyridyl)piperazin-1-carboxylate (3.000 g, 88.19%) in the form of a yellow solid.

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[0093] [Step 2] Synthesis of intermediate compound 2 Tert-butyl 4-(2-fluoro-6-methoxycarbonyl-3-pyridyl)piperazin-1- carboxylate (100.00%, 3.000 g, 8.839 mmol) and hydrogen chloride (4.00 M solution 5 in 1,4-dioxane, 11 mL, 44.000 mmol) were mixed in dichloromethane (40 mL) at room temperature, and the resulting mixture was stirred at 40°C for three hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2, methyl 6- 10 fluoro-5-piperazin-1-yl-pyridin-2-carboxylate hydrochloride, 2.400 g, 98.48%, yellowish solid). Synthesis of intermediate compound 2A: 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid15 [Step 1] Synthesis of methyl 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2-

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[0095] carboxylate hydrochloride (100.00%, 1.000 g, 3.627 mmol), 7-(bromomethyl)-3-ethyl- 1H-1,5-naphthyridin-2-one (100.00%, 1.000 g, 3.744 mmol), and N,N- diisopropylethylamine (100.00% solution, 3.3 mL, 18.894 mmol) were mixed in acetonitrile (15 mL) at room temperature, and the resulting mixture was stirred at 80°C 5 for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate (1.000 g, 62.78%) in the form of a white solid. 10 [Step 2] Synthesis of intermediate compound 2A Methyl 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1- yl]-6-fluoro-pyridin-2-carboxylate (100.00%, 1.000 g, 2.350 mmol) and sodium hydroxide (5.00 M solution in water, 1 mL, 5.000 mmol) were mixed in tetrahydrofuran 15 (3 mL) / methanol (3 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid, 0.960 g, 99.29%, white 20 solid).

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[0097] Synthesis of intermediate compound 2B: 6-fluoro-5-[4-[(5-fluoro-2- methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid 5 [Step 1] Synthesis of methyl 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylate Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2- carboxylate hydrochloride (100.00%, 0.800 g, 2.902 mmol), 7-(bromomethyl)-8-10 fluoro-3-methyl-1H-quinoxalin-2-one (100.00%, 0.800 g, 2.951 mmol), and N,N- diisopropylethylamine (100.00% solution, 2.5 mL, 14.313 mmol) were mixed in acetonitrile (15 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and15 dried to obtain methyl 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (1.020 g, 81.87%) in the form of a white solid. [Step 2] Synthesis of intermediate compound 2B

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[0099] Methyl 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (100.00%, 1.020 g, 2.375 mmol) and sodium hydroxide (5.00 M solution in water, 1 mL, 5.000 mmol) were mixed in 5 tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro- 2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 10 0.980 g, 99.32%, gray solid). Synthesis of intermediate compound 2C: 5-[4-[(2-ethyl-5-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- 15 yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2- carboxylate hydrochloride (100.00%, 0.800 g, 2.902 mmol), 7-(bromomethyl)-3-ethyl-

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[0101] 8-fluoro-1H-quinoxalin-2-one (100.00%, 0.830 g, 2.911 mmol), and N,N- diisopropylethylamine (100.00% solution, 2.6 mL, 14.886 mmol) were mixed in acetonitrile (10 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to 5 room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate (0.780 g, 60.63%) in the form of a yellowish solid. [Step 2] Synthesis of intermediate compound 2C 10 Methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.780 g, 1.759 mmol) and sodium hydroxide (5.00 M solution in water, 0.7 mL, 3.500 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the 15 resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro- 3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid, 0.750 g, 99.29%, yellowish solid). 20

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[0103] Synthesis of intermediate compound 2D: 5-[4-[(2-ethyl-7-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate 5 Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2- carboxylate hydrochloride (100.00%, 0.500 g, 1.814 mmol), 7-(bromomethyl)-3-ethyl- 6-fluoro-1H-quinoxalin-2-one hydrobromide (100.00%, 0.670 g, 1.831 mmol), and N,N-diisopropylethylamine (100.00% solution, 1.6 mL, 9.161 mmol) were mixed in 10 acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate (0.600 g, 74.62%) in the form 15 of a white solid. [Step 2] Synthesis of intermediate compound 2D Methyl 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-

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[0105] 1-yl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.600 g, 1.353 mmol) and sodium hydroxide (5.00 M solution in water, 0.55 mL, 2.750 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the 5 solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2D, 5-[4-[(2-ethyl-7-fluoro- 3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid, 0.580 g, 99.82%, yellowish solid). 10 Synthesis of intermediate compound 2E: 5-[4-[(2-ethyl-8-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate 15 Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2- carboxylate hydrochloride (100.00%, 0.300 g, 1.088 mmol), 7-(bromomethyl)-3-ethyl- 5-fluoro-1H-quinoxalin-2-one (100.00%, 0.310 g, 1.087 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.95 mL, 5.440 mmol) were mixed in acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred overnight 20 at 80°C, after which the reaction was terminated by lowering the temperature to room

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[0107] temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-pyridin-2-carboxylate (0.200 g, 41.45%) in the form of a brown solid. [Step 2] Synthesis of intermediate compound 2E 5 Methyl 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin- 1-yl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.200 g, 0.451 mmol) and sodium hydroxide (5.00 M solution, 0.18 mL, 0.900 mmol) were mixed in tetrahydrofuran (3 mL) / water (3 mL) at room temperature, and the resulting mixture was stirred at the same 10 temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2E, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-pyridin-2-carboxylic acid, 0.180 g, 92.93%, brown solid). 15 Synthesis of intermediate compound 2F: 5-[4-[(3-ethyl-2-oxo-1H- pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2- carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate

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[0109] Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2- carboxylate hydrochloride (100.00%, 0.440 g, 1.596 mmol), 7-(bromomethyl)-3-ethyl- 1H-pyrido[2,3-b][1,4]oxazin-2-one (100.00%, 0.450 g, 1.660 mmol), and N,N- 5 diisopropylethylamine (100.00% solution, 1.4 mL, 8.016 mmol) were mixed in acetonitrile (8 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- 10 yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate (0.500 g, 72.96%) in the form of a white solid. [Step 2] Synthesis of intermediate compound 2F Methyl 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- 15 yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.500 g, 1.164 mmol) and sodium hydroxide (5.00 M solution in water, 0.47 mL, 2.350 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (1.5 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After

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[0111] removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2F, 5-[4-[(3- ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro- pyridin-2-carboxylic acid, 0.480 g, 99.24%, yellowish solid). 5 Synthesis of intermediate compound 2G: 5-[4-[(2-ethyl-7-fluoro-3-oxo- 4H-1,4-benzoxazin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate 10 Intermediate compound 2, methyl 6-fluoro-5-piperazin-1-yl-pyridin-2- carboxylate hydrochloride (100.00%, 0.300 g, 1.088 mmol), 6-(bromomethyl)-2-ethyl- 7-fluoro-4H-1,4-benzoxazin-3-one (100.00%, 0.313 g, 1.086 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.95 mL, 5.440 mmol) were mixed in 15 acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred overnight at 80°C, after which the reaction was terminated by lowering the temperature to room temperature. The resulting mixture was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain methyl 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin-1-yl]-6- 20 fluoro-pyridin-2-carboxylate (0.480 g, 98.82%) in the form of a brown solid.

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[0113] [Step 2] Synthesis of intermediate compound 2G Methyl 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.480 g, 1.075 5 mmol) and sodium hydroxide (5.00 M solution, 0.43 mL, 2.150 mmol) were mixed in tetrahydrofuran (3 mL) / water (3 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 2G, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- 10 benzoxazin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid, 0.450 g, 96.79%, brown solid). Synthesis of intermediate compound 3: Methyl 5-(4-piperidyl)pyridin-2- carboxylate hydrochloride 15 [Step 1] Synthesis of methyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H- pyridin-4-yl)pyridin-2-carboxylate Methyl 5-bromopyridin-2-carboxylate (100.00%, 2.200 g, 10.184 mmol),

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[0115] tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1- carboxylate (100.00%, 3.700 g, 11.970 mmol), Pd(dtbpf)Cl2(100.00%, 0.400 g, 0.614 mmol), and potassium carbonate (100.00%, 2.800 g, 20.260 mmol) were mixed in 1,4- dioxane (30 mL) / water (10 mL) at room temperature, and the resulting mixture was 5 stirred at 50°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 10%) and 10 concentrated to obtain the product, which was then purified again by chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 2%) and concentrated to obtain methyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyridin-2- carboxylate (1.300 g, 40.09%) in the form of a yellowish solid. [Step 2] Synthesis of methyl 5-(1-tert-butoxycarbonyl-4-piperidyl)pyridin-2- 15 carboxylate Methyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)pyridin-2- carboxylate (100.00%, 1.400 g, 4.397 mmol) was mixed in methanol (50 mL) and stirred at room temperature, and then 10%-Pd / C (0.300 g) was slowly added at the same 20 temperature and stirred at the same temperature for three days by attaching a hydrogen

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[0117] balloon. The reaction mixture was filtered through a plastic filter to remove a solid therefrom, and the solvent was removed from the resulting filtrate under reduced pressure. Then, the resulting product was used without further purification (methyl 5- (1-tert-butoxycarbonyl-4-piperidyl)pyridin-2-carboxylate, 1.376 g, 97.67%, yellowish 5 oil) Methyl 5-(1-tert-butoxycarbonyl-4-piperidyl)pyridin-2-carboxylate (100.00%, 1.376 g, 4.295 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 10 5.4 mL, 21.600 mmol) were mixed in dichloromethane (15 mL) at room temperature, and the resulting mixture was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 3, methyl 5-(4- 15 piperidyl)pyridin-2-carboxylate hydrochloride, 1.100 g, 99.77%, yellowish solid). Synthesis of intermediate compound 3A: 5-[1-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- 20 yl)methyl]-4-piperidyl]pyridin-2-carboxylate

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[0119] Intermediate compound 3, methyl 5-(4-piperidyl)pyridin-2-carboxylate hydrochloride (100.00%, 0.600 g, 2.337 mmol), 7-(bromomethyl)-3-ethyl-1H-1,5- naphthyridin-2-one (100.00%, 0.700 g, 2.621 mmol), and N,N-diisopropylethylamine 5 (100.00% solution, 1.6 mL, 9.161 mmol) were mixed in acetonitrile (8 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5- [1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]pyridin-2- 10 carboxylate (0.800 g, 84.21%) in the form of a light brown solid. [Step 2] Synthesis of intermediate compound 3A Methyl 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4- piperidyl]pyridin-2-carboxylate (100.00%, 0.800 g, 1.968 mmol) and sodium hydroxide 15 (5.00 M solution in water, 0.8 mL, 4.000 mmol) were mixed in tetrahydrofuran (3 mL) / methanol (3 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further

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[0121] purification (intermediate compound 3A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]-4-yl]pyridin-2-carboxylic acid, 0.770 g, 99.71%, light brown solid). 5 Synthesis of intermediate compound 3B: 5-[1-[(5-fluoro-2-methyl-3-oxo- 4H-quinoxalin-6-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]-4-piperidyl]pyridin-2-carboxylate 10 Intermediate compound 3, methyl 5-(4-piperidyl)pyridin-2-carboxylate hydrochloride (100.00%, 0.600 g, 2.337 mmol), 7-(bromomethyl)-8-fluoro-3-methyl- 1H-quinoxalin-2-one (100.00%, 0.700 g, 2.582 mmol), and N,N-diisopropylethylamine (100.00% solution, 1.6 mL, 9.161 mmol) were mixed in acetonitrile (8 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the 15 reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5- [1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]pyridin-2- carboxylate (0.800 g, 83.41%) in the form of a light brown solid. [Step 2] Synthesis of intermediate compound 3B

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[0123] Methyl 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-4- piperidyl]pyridin-2-carboxylate (100.00%, 0.800 g, 1.949 mmol) and sodium hydroxide (5.00 M solution in water, 0.8 mL, 4.000 mmol) were mixed in tetrahydrofuran (3 5 mL) / methanol (3 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 3B, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid, 0.770 g, 99.65%, 10 brown solid). Synthesis of intermediate compound 4: Methyl 6-fluoro-5-(4- piperidyl)pyridin-2-carboxylate hydrochloride [Step 1] Synthesis of methyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H- 15 pyridin-4-yl)-6-fluoro-pyridin-2-carboxylate Methyl 5-bromo-6-fluoro-pyridin-2-carboxylate (100.00%, 1.900 g, 10.023 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-

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[0125] pyridin-1-carboxylate (100.00%, 3.700 g, 11.970 mmol), Pd(dtbpf)Cl2(100.00%, 0.400 g, 0.614 mmol), and potassium carbonate (100.00%, 3.000 g, 21.707 mmol) were mixed in 1,4-dioxane (30 mL) / water (10 mL) at room temperature, and the resulting mixture was stirred at 50°C for 18 hours, after which the reaction was terminated by lowering 5 the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain methyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)- 10 6-fluoro-pyridin-2-carboxylate (1.500 g, 44.49%) in the form of a yellowish solid. [Step 2] Synthesis of methyl 5-(1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro- pyridin-2-carboxylate Methyl 5-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-6-fluoro- 15 pyridin-2-carboxylate (100.00%, 1.500 g, 4.459 mmol) was mixed in methanol (50 mL) and stirred at room temperature, and then 10%-Pd / C (0.300 g) was slowly added at the same temperature and stirred at the same temperature for 18 hours by attaching a hydrogen balloon. The reaction mixture was filtered through a plastic filter to remove a solid therefrom, and the solvent was removed from the resulting filtrate under reduced20 pressure. Then, the resulting product was used without further purification (methyl 5-

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[0127] (1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro-pyridin-2-carboxylate, 1.370 g, 90.79%, black oil) [Step 3] Synthesis of intermediate compound 4 5 Methyl 5-(1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro-pyridin-2- carboxylate (100.00%, 1.370 g, 4.048 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 5 mL, 20.000 mmol) were mixed in dichloromethane (15 mL) at room temperature, and the resulting mixture was stirred at 40°C for three hours, after which the reaction was terminated by lowering the temperature to room temperature. After 10 removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 4, methyl 6- fluoro-5-(4-piperidyl)pyridin-2-carboxylate hydrochloride, 1.100 g, 98.90%, black solid). 15 Synthesis of intermediate compound 4A: 5-[1-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate

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[0129] Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2- carboxylate hydrochloride (100.00%, 0.550 g, 2.002 mmol), 7-(bromomethyl)-3-ethyl- 1H-1,5-naphthyridin-2-one (100.00%, 0.550 g, 2.059 mmol), and N,N- 5 diisopropylethylamine (100.00% solution, 1.8 mL, 10.306 mmol) were mixed in acetonitrile (8 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4- 10 piperidyl]-6-fluoro-pyridin-2-carboxylate (0.570 g, 67.07%) in the form of a gray solid. [Step 2] Synthesis of intermediate compound 4A Methyl 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]- 6-fluoro-pyridin-2-carboxylate (100.00%, 0.570 g, 1.343 mmol) and sodium hydroxide 15 (5.00 M solution in water, 0.54 mL, 2.700 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (1.5 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further

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[0131] purification (intermediate compound 4A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 0.550 g, 99.81%, gray solid). 5 Synthesis of intermediate compound 4B: 5-[1-[(2-ethyl-5-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of 5-(1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro-pyridin- 2-carboxylic acid 10 Methyl 5-(1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro-pyridin-2- carboxylate (100.00%, 0.350 g, 1.034 mmol) and lithium hydroxide monohydrate (100.00% solution, 0.1437 mL, 5.171 mmol) were dissolved in methanol (10 mL) / tetrahydrofuran (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction 15 mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain 5-(1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro-pyridin-2- carboxylic acid (0.255 g, 76.00%) in the form of a white solid. [Step 2] Synthesis of 6-fluoro-5-(4-piperidyl)pyridin-2-carboxylic acid 20 hydrochloride

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[0133] 5-(1-tert-butoxycarbonyl-4-piperidyl)-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.520 g, 1.603 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2 mL, 8.000 mmol) were mixed in dichloromethane (5 mL) at room temperature, and 5 the resulting mixture was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with dichloromethane, and dried to obtain 6-fluoro-5-(4- piperidyl)pyridin-2-carboxylic acid hydrochloride (0.392 g, 93.81%) in the form of a white solid. 10 [Step 3] Synthesis of intermediate compound 4B 6-fluoro-5-(4-piperidyl)pyridin-2-carboxylic acid hydrochloride (100.00%, 0.050 g, 0.192 mmol), 7-(bromomethyl)-3-ethyl-8-fluoro-1H-quinoxalin-2-one (100.00%, 0.060 g, 0.210 mmol), and N,N-diisopropylethylamine (100.00% solution, 15 0.17 mL, 0.973 mmol) were mixed in acetonitrile (1 mL) at room temperature, and the resulting mixture was stirred at 85°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain intermediate compound 4B, 5-[1-

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[0135] [(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2- carboxylic acid (0.050 g, 60.85%) in the form of a yellowish solid. Synthesis of intermediate compound 4C: 5-[1-[(2-ethyl-7-fluoro-3-oxo- 5 4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2-10 carboxylate hydrochloride (100.00%, 0.500 g, 1.820 mmol), 7-(bromomethyl)-3-ethyl- 6-fluoro-1H-quinoxalin-2-one hydrobromide (100.00%, 0.670 g, 1.831 mmol), and N,N-diisopropylethylamine (100.00% solution, 1.6 mL, 9.161 mmol) were mixed in acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to 15 room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylate (0.600 g, 74.50%) in the form of a white solid. [Step 2] Synthesis of intermediate compound 4C

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[0137] Methyl 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.600 g, 1.356 mmol) and sodium hydroxide (5.00 M solution in water, 0.55 mL, 2.750 mmol) were mixed in 5 tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 4C, 5-[1-[(2-ethyl-7-fluoro- 3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 10 0.580 g, 99.85%, yellowish solid). Synthesis of intermediate compound 4D: 5-[1-[(2-ethyl-8-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6- 15 yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2- carboxylate hydrochloride (100.00%, 0.500 g, 2.000 mmol), 7-(bromomethyl)-3-ethyl-

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[0139] 5-fluoro-1H-quinoxalin-2-one hydrobromide (100.00%, 0.664 g, 1.814 mmol), and N,N-diisopropylethylamine (100.00% solution, 1.584 mL, 9.070 mmol) were mixed in acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to 5 room temperature. After removing the solvent from the reaction mixture under reduced pressure, the precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6- fluoro-pyridin-2-carboxylate (320.000 mg, 40.00%) in the form of a brown solid. [Step 2] Synthesis of intermediate compound 4D 10 Methyl 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylate (100.00%, 320.000 mg, 0.723 mmol) and sodium hydroxide (5.00 M solution, 0.289 mL, 1.445 mmol) were mixed in acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, 15 after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 4D, 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 0.310 g, 100.10%, brown solid). 20

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[0141] Synthesis of intermediate compound 4E: 5-[1-[(2-ethyl-5-fluoro-3-oxo- 4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate 5 Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2- carboxylate hydrochloride (100.00%, 0.850 g, 3.094 mmol), 6-(bromomethyl)-2-ethyl- 5-fluoro-4H-1,4-benzoxazin-3-one (100.00%, 1.000 g, 3.471 mmol), and N,N- diisopropylethylamine (100.00% solution, 2.7 mL, 15.458 mmol) were mixed in 10 acetonitrile (12 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]- 4-piperidyl]-6-fluoro-pyridin-2-carboxylate (0.900 g, 65.29%) in the form of a 15 yellowish solid. [Step 2] Synthesis of intermediate compound 4E Methyl 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazine-6-yl)methyl]-4-

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[0143] piperidyl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.900 g, 2.020 mmol) and sodium hydroxide (5.00 M solution in water, 0.43 mL, 2.150 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the 5 solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 4E, 5-[1-[(2-ethyl-5-fluoro- 3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 0.870 g, 99.83%, yellowish solid). 10 Synthesis of intermediate compound 4F: 5-[1-[(2-ethyl-7-fluoro-3-oxo- 4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate 15 Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2- carboxylate hydrochloride (100.00%, 0.850 g, 3.094 mmol), 6-(bromomethyl)-2-ethyl- 7-fluoro-4H-1,4-benzoxazin-3-one (100.00%, 1.000 g, 3.471 mmol), and N,N- diisopropylethylamine (100.00% solution, 2.7 mL, 15.458 mmol) were mixed in acetonitrile (12 mL) at room temperature, and the resulting mixture was stirred at 80°C 20 for 18 hours, after which the reaction was terminated by lowering the temperature to

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[0145] room temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column 5 chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain methyl 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate (1.300 g, 94.31%) in the form of a yellowish solid. [Step 2] Synthesis of intermediate compound 4F 10 Methyl 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazine-6-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylate (100.00%, 1.300 g, 2.918 mmol) and sodium hydroxide (5.00 M solution in water, 0.43 mL, 2.150 mmol) were mixed in tetrahydrofuran (3 mL) / methanol (3 mL) / water (3 mL) at room temperature, and the 15 resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 4F, 5-[1-[(2-ethyl-7-fluoro- 3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 1.200 g, 95.32%, white solid). 20

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[0147] Synthesis of intermediate compound 4G: 5-[1-[(2-ethyl-8-fluoro-3-oxo- 4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid [Step 1] Synthesis of methyl 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate 5 Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2- carboxylate hydrochloride (100.00%, 0.850 g, 3.094 mmol), 6-(bromomethyl)-2-ethyl- 8-fluoro-4H-1,4-benzoxazin-3-one (100.00%, 1.000 g, 3.471 mmol), and N,N- diisopropylethylamine (100.00% solution, 2.7 mL, 15.458 mmol) were mixed in 10 acetonitrile (12 mL) at room temperature, and the resulting mixture was stirred at 80°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]- 4-piperidyl]-6-fluoro-pyridin-2-carboxylate (0.650 g, 47.16%) in the form of a pink 15 solid. [Step 2] Synthesis of intermediate compound 4G Methyl 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4-benzoxazine-6-yl)methyl]-4-

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[0149] piperidyl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.650 g, 1.459 mmol) and sodium hydroxide (5.00 M solution in water, 0.43 mL, 2.150 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the 5 solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 4G, 5-[1-[(2-ethyl-8-fluoro- 3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 0.620 g, 98.50%, yellowish solid). 10 Synthesis of intermediate compound 5: 3-fluoro-4-piperazin-1-yl-N- pyrrolidin-1-yl-benzamide dihydrochloride [Step 1] Synthesis of tert-butyl 4-(2-fluoro-4-methoxycarbonyl- phenyl)piperazin-1-carboxylate 15 Methyl 4-bromo-3-fluoro-benzoate (100.00%, 0.930 g, 3.991 mmol), tert- butyl piperazin-1-carboxylate (100.00%, 0.900 g, 4.832 mmol), RuPhos Pd G3 (100.00%, 0.150 g, 0.179 mmol), and cesium carbonate (100.00%, 2.600 g, 7.980 mmol) were mixed in 1,4-dioxane (10 mL) at room temperature, and the resulting mixture was stirred at 100°C for 18 hours, after which the reaction was terminated by lowering the 20 temperature to room temperature. The reaction mixture was filtered through a celite pad

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[0151] to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 10%) and concentrated to obtain tert-butyl 4-(2-fluoro-4-methoxycarbonyl-phenyl)piperazin-1-carboxylate 5 (1.200 g, 88.85%) in the form of a white solid. [Step 2] Synthesis of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-3-fluoro- benzoic acid Tert-butyl 4-(2-fluoro-4-methoxycarbonyl-phenyl)piperazin-1-carboxylate 10 (100.00%, 1.200 g, 3.546 mmol) and sodium hydroxide (5.00 M solution in water, 1.42 mL, 7.100 mmol) were mixed in tetrahydrofuran (4 mL) / methanol (4 mL) / water (4 mL) at room temperature, and the resulting mixture was stirred at the same temperature for three hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (4-(4-tert- 15 butoxycarbonylpiperazin-1-yl)-3-fluoro-benzoic acid, 1.140 g, 99.10%, white solid). [Step 3] Synthesis of tert-butyl 4-[2-fluoro-4-(pyrrolidin-1- ylcarbamoyl)phenyl]piperazin-1-carboxylate

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[0153] 4-(4-tert-butoxycarbonylpiperazin-1-yl)-3-fluoro-benzoic acid (100.00%, 1.140 g, 3.514 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 2.000 g, 5.260 mmol), N,N-diisopropylethylamine (100.00% solution, 1.8 mL, 10.300 mmol), and pyrrolidin- 5 1-amine dihydrochloride (100.00%, 0.840 g, 5.281 mmol) were mixed in N,N- dimethylformamide (20 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The 10 organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[2-fluoro-4-(pyrrolidin-1-ylcarbamoyl)phenyl]piperazin-1- 15 carboxylate (1.000 g, 72.50%) in the form of a white solid. [Step 4] Synthesis of intermediate compound 5 Tert-butyl 4-[2-fluoro-4-(pyrrolidin-1-ylcarbamoyl)phenyl]piperazin-1- carboxylate (100.00%, 1.000 g, 2.548 mmol) and hydrogen chloride (4.00 M solution 20 in 1,4-dioxane, 2.4 mL, 9.600 mmol) were mixed in dichloromethane (5 mL) at room

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[0155] temperature, and the resulting mixture was stirred at the same temperature for three days. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 5, 3- fluoro-4-piperazin-1-yl-N-pyrrolidin-1-yl-benzamide dihydrochloride, 0.900 g, 5 96.70%, white solid). Synthesis of intermediate compound 6: 2-fluoro-4-piperazin-1-yl-N- pyrrolidin-1-yl-benzamide dihydrochloride [Step 1] Synthesis of tert-butyl 4-(3-fluoro-4-methoxycarbonyl- 10 phenyl)piperazin-1-carboxylate Methyl 4-bromo-2-fluoro-benzoate (100.00%, 0.930 g, 3.991 mmol), tert- butyl piperazin-1-carboxylate (100.00%, 0.900 g, 4.832 mmol), RuPhos Pd G3 (100.00%, 0.150 g, 0.179 mmol), and cesium carbonate (100.00%, 2.600 g, 7.980 mmol) 15 were mixed in 1,4-dioxane (10 mL) at room temperature, and the resulting mixture was stirred at 100°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column 20 chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 10 % 50%) and

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[0157] concentrated to obtain tert-butyl 4-(3-fluoro-4-methoxycarbonyl-phenyl)piperazin-1- carboxylate (1.100 g, 81.45%) in the form of a white solid. [Step 2] Synthesis of 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-fluoro- benzoic acid 5 Tert-butyl 4-(3-fluoro-4-methoxycarbonyl-phenyl)piperazin-1-carboxylate (100.00%, 1.100 g, 3.251 mmol) and sodium hydroxide (5.00 M solution in water, 1.3 mL, 6.500 mmol) were mixed in tetrahydrofuran (4 mL) / methanol (4 mL) / water (4 mL), and the resulting mixture was stirred at room temperature for three hours and stirred at 10 40℃ for two hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (4- (4-tert-butoxycarbonylpiperazin-1-yl)-2-fluoro-benzoic acid, 1.050 g, 99.57%, white solid). 15 [Step 3] Synthesis of tert-butyl 4-[3-fluoro-4-(pyrrolidin-1- ylcarbamoyl)phenyl]piperazin-1-carboxylate 4-(4-tert-butoxycarbonylpiperazin-1-yl)-2-fluoro-benzoic acid (100.00%,

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[0159] 1.050 g, 3.237 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 1.800 g, 4.734 mmol), N,N-diisopropylethylamine (100.00% solution, 1.7 mL, 9.760 mmol), and pyrrolidin- 1-amine dihydrochloride (100.00%, 0.770 g, 4.841 mmol) were mixed in N,N- 5 dimethylformamide (20 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, 10 dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[3-fluoro-4-(pyrrolidin-1-ylcarbamoyl)phenyl]piperazin-1- carboxylate (1.000 g, 78.71%) in the form of light yellow oil. 15 [Step 4] Synthesis of intermediate compound 6 Tert-butyl 4-[3-fluoro-4-(pyrrolidin-1-ylcarbamoyl)phenyl]piperazin-1- carboxylate (100.00%, 1.000 g, 2.548 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 2.4 mL, 9.600 mmol) were mixed in dichloromethane (5 mL) at room 20 temperature, and the resulting mixture was stirred at the same temperature for three days.

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[0161] After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 6, 2- fluoro-4-piperazin-1-yl-N-pyrrolidin-1-yl-benzamide dihydrochloride, 0.900 g, 96.70%, yellowish solid). 5 Synthesis of intermediate compound 7: 6-piperazin-1-yl-N-pyrrolidin-1- yl-pyridazin-3-carboxamide hydrochloride [Step 1] Synthesis of methyl 6-(4-tert-butoxycarbonylpiperazin-1- yl)pyridazin-3-carboxylate 10 Methyl 6-bromopyridazin-3-carboxylate (100.00%, 1.000 g, 4.608 mmol), tert-butyl piperazin-1-carboxylate (100.00%, 1.030 g, 5.530 mmol), cesium carbonate (100.00 % solution, 0.7378 mL, 9.217 mmol), and RuPhos Pd G3 (100.00%, 0.385 g, 0.460 mmol) were mixed in 1,4-dioxane (12 mL) at room temperature, and the resulting 15 mixture was stirred at 100°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%)20 and concentrated to obtain methyl 6-(4-tert-butoxycarbonylpiperazin-1-yl)pyridazin-3-

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[0163] carboxylate (386.000 mg, 25.98%) in the form of a yellow solid. [Step 2] Synthesis of 6-(4-tert-butoxycarbonylpiperazin-1-yl)pyridazin-3- carboxylic acid 5 Methyl 6-(4-tert-butoxycarbonylpiperazin-1-yl)pyridazin-3-carboxylate (100.00%, 386.000 mg, 1.197 mmol) and sodium hydroxide (5.00 M solution, 0.479 mL, 2.395 mmol) were mixed in tetrahydrofuran (5 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the10 resulting product was used without further purification (6-(4-tert- butoxycarbonylpiperazin-1-yl)pyridazin-3-carboxylic acid, 0.369 g, 99.97%, yellow solid). [Step 3] Synthesis of tert-butyl 4-[6-(pyrrolidin-1-ylcarbamoyl)pyridazin-3- yl]piperazin-1-carboxylate 15 6-(4-tert-butoxycarbonylpiperazin-1-yl)pyridazin-3-carboxylic acid (100.00%, 0.300 g, 0.973 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.740 g,

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[0165] 1.946 mmol), N,N-diisopropylethylamine (100.00% solution, 0.425 mL, 2.434 mmol), and pyrrolidin-1-amine dihydrochloride (100.00%, 0.186 g, 1.169 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. The solvent was removed from the reaction 5 mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[6-(pyrrolidin-1-ylcarbamoyl)pyridazin-3- yl]piperazin-1-carboxylate (94.000 mg, 25.66%) in the form of a white solid. [Step 4] Synthesis of intermediate compound 7 10 Tert-butyl 4-[6-(pyrrolidin-1-ylcarbamoyl)pyridazin-3-yl]piperazin-1- carboxylate (100.00%, 94.000 mg, 0.250 mmol) and hydrogen chloride (4.00 M solution, 0.631 mL, 2.524 mmol) were mixed in dichloromethane (12 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. 15 After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 7, 6- piperazin-1-yl-N-pyrrolidin-1-yl-pyridazin-3-carboxamide hydrochloride, 0.075 g, 96.01%, white solid). 20 Synthesis of intermediate compound 8: 5-piperazin-1-yl-N-pyrrolidin-1- yl-pyrazin-2-carboxamide hydrochloride

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[0167] [Step 1] Synthesis of methyl 5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazin- 2-carboxylate Methyl 5-bromopyrazin-2-carboxylate (100.00%, 1.000 g, 4.608 mmol), tert- 5 butyl piperazin-1-carboxylate (100.00%, 1.030 g, 5.530 mmol), cesium carbonate (100.00 %, 3.003 g, 9.217 mmol), and RuPhos Pd G3 (100.00%, 0.385 g, 0.460 mmol) were mixed in 1,4-dioxane (12 mL) at room temperature, and the resulting mixture was stirred at 100°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad 10 to remove a solid therefrom. The solvent was removed from the resulting filtrate under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain methyl 5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazin-2- carboxylate (1.080 g, 72.70%) in the form of a yellow solid. 15 [Step 2] Synthesis of 5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazin-2- carboxylic acid Methyl 5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazin-2-carboxylate

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[0169] (100.00%, 1.080 g, 3.350 mmol) and sodium hydroxide (5.00 M solution, 1.34 mL, 6.700 mmol) were mixed in tetrahydrofuran (4 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was 5 used without further purification (5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazin-2- carboxylic acid, 1.033 g, 100.00%, white solid). [Step 3] Synthesis of tert-butyl 4-[5-(pyrrolidin-1-ylcarbamoyl)pyrazin-2- yl]piperazin-1-carboxylate 10 5-(4-tert-butoxycarbonylpiperazin-1-yl)pyrazin-2-carboxylic acid (100.00%, 0.500 g, 1.622 mmol), pyrrolidin-1-amine dihydrochloride (100.00%, 0.310 g, 1.949 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 1.233 g, 3.243 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.708 mL, 4.054 mmol) were mixed in N,N- 15 dimethylformamide (5 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. The solvent was removed from the reaction mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[5-(pyrrolidin-1-ylcarbamoyl)pyrazin-2- 20 yl]piperazin-1-carboxylate (70.000 mg, 11.47%) in the form of a white solid.

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[0171] [Step 4] Synthesis of intermediate compound 8 Tert-butyl 4-[5-(pyrrolidin-1-ylcarbamoyl)pyrazin-2-yl]piperazin-1- carboxylate (100.00%, 70.000 mg, 0.186 mmol) and hydrogen chloride (4.00 M 5 solution, 0.465 mL, 1.860 mmol) were mixed in dichloromethane (5 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 8, 5- piperazin-1-yl-N-pyrrolidin-1-yl-pyrazin-2-carboxamide hydrochloride, 58.000 mg, 10 99.70%, white solid). Synthesis of intermediate compound 9: 6-fluoro-5-(4-fluoro-4-piperidyl)- N-pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2-trifluoroacetic acid [Step 1] Synthesis of ethyl 5-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)-6- 15 fluoro-pyridin-2-carboxylate Ethyl 5-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)pyridin-2-carboxylate (100.00%, 1.500 g, 4.257 mmol) and silver(II) fluoride (100.00%, 5.000 equiv., 21.280 mmol) were dissolved in acetonitrile (10 mL) at room temperature, and the resulting

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[0173] solution was stirred at 50°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium 5 sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 50%) and concentrated to obtain ethyl 5-(1-tert-butoxycarbonyl-4-fluoro-4- piperidyl)-6-fluoro-pyridin-2-carboxylate (0.820 g, 52.01%) in the form of a white solid. [Step 2] Synthesis of 5-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)-6-fluoro- 10 pyridin-2-carboxylic acid Ethyl 5-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)-6-fluoro-pyridin-2- carboxylate (100.00%, 0.820 g, 2.214 mmol) and lithium hydroxide monohydrate (100.00% solution, 0.3076 mL, 11.070 mmol) were dissolved in tetrahydrofuran (20 15 mL) / water (5 mL) at room temperature, and the resulting solution was stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, 1 M-hydrochloric acid aqueous solution (10 mL) was added to the resulting concentrate and stirred to filter the precipitated solid, washed with water, and dried to obtain 5-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)-6-fluoro-pyridin-2-carboxylic 20 acid (0.700 g, 92.37%) in the form of a white solid. [Step 3] Synthesis of tert-butyl 4-fluoro-4-[2-fluoro-6-(pyrrolidin-1- ylcarbamoyl)-3-pyridyl]piperidin-1-carboxylate

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[0175] 5-(1-tert-butoxycarbonyl-4-fluoro-4-piperidyl)-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.550 g, 1.607 mmol), pyrrolidin-1-amine dihydrochloride (100.00%, 1.000 equiv., 1.607 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- 5 b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 3.000 equiv., 4.820 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.8396 mL, 4.820 mmol) were dissolved in N,N-dimethylformamide (10 mL) at room temperature, and the resulting solution was stirred at the same temperature. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a 10 saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain tert-butyl 4-fluoro- 4-[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3-pyridyl]piperidin-1-carboxylate (0.650 g, 15 98.55%) in the form of a white solid. [Step 4] Synthesis of intermediate compound 9 Tert-butyl 4-fluoro-4-[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3- pyridyl]piperidin-1-carboxylate (100.00%, 0.795 g, 1.937 mmol) was dissolved in 20 dichloromethane (15 mL) at room temperature, and 2,2,2-trifluoroacetic acid (100.00%

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[0177] solution, 4.446 mL, 58.100 mmol) was added to the resulting solution and stirred at the same temperature for five hours. The solvent was removed from the reaction mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 20%) and 5 concentrated to obtain intermediate compound 9, 6-fluoro-5-(4-fluoro-4-piperidyl)-N- pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2-trifluoroacetic acid (0.500 g, 47.95%) in the form of a yellow solid. Synthesis of intermediate compound 10: 5-(azetidin-3-yloxy)-6-fluoro-N- 10 pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2-trifluoroacetic acid [Step 1] Synthesis of methyl 5-(1-tert-butoxycarbonylazetidin-3- yl)oxypyridin-2-carboxylate Tert-butyl 3-hydroxyazetidin-1-carboxylate (100.00%, 2.000 g, 11.547 mmol) 15 and sodium hydride (60.00% solution, 0.70277 mL, 16.165 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL) at 0℃, and methyl 5-fluoropyridin-2- carboxylate (100.00%, 1.200 equiv., 13.856 mmol) was added to the resulting solution and stirred at room temperature for three hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated 20 aqueous ammonium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was

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[0179] purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain methyl 5-(1-tert-butoxycarbonylazetidin-3- yl)oxypyridin-2-carboxylate (3.310 g, 92.98%) in the form of a white solid. [Step 2] Synthesis of methyl 5-(1-tert-butoxycarbonylazetidin-3-yl)oxy-6- 5 fluoro-pyridin-2-carboxylate Methyl 5-(1-tert-butoxycarbonylazetidin-3-yl)oxypyridin-2-carboxylate (100.00%, 3.350 g, 10.870 mmol) and silver(II) fluoride (100.00%, 5.000 equiv., 54.330 mmol) were dissolved in acetonitrile (30 mL) at room temperature, and the resulting 10 solution was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate 15 was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate / hexane = 0% to 100%) and concentrated to obtain methyl 5-(1-tert-butoxycarbonylazetidin-3- yl)oxy-6-fluoro-pyridin-2-carboxylate (1.275 g, 35.96%) in the form of a white solid. [Step 3] Synthesis of 5-(1-tert-butoxycarbonylazetidin-3-yl)oxy-6-fluoro- pyridin-2-carboxylic acid

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[0181] Methyl 5-(1-tert-butoxycarbonylazetidin-3-yl)oxy-6-fluoro-pyridin-2- carboxylate (100.00%, 0.275 g, 0.843 mmol) and lithium hydroxide monohydrate (100.00% solution, 0.1171 mL, 4.214 mmol) were dissolved in tetrahydrofuran (8 5 mL) / water (2 mL) at room temperature, and the resulting solution was stirred at the same temperature for three hours. After removing the solvent from the reaction mixture under reduced pressure, 1 N-hydrochloric acid aqueous solution (20 mL) was added to the resulting concentrate and stirred to filter the precipitated solid, washed with water, and dried to obtain 5-(1-tert-butoxycarbonylazetidin-3-yl)oxy-6-fluoro-pyridin-2- 10 carboxylic acid (0.251 g, 95.36%) in the form of a white solid. [Step 4] Synthesis of tert-butyl 3-[[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3- pyridyl]oxy]azetidin-1-carboxylate 5-(1-tert-butoxycarbonylazetidin-3-yl)oxy-6-fluoro-pyridin-2-carboxylic 15 acid (100.00%, 0.252 g, 0.807 mmol), pyrrolidin-1-amine dihydrochloride (100.00%, 1.020 equiv., 0.823 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 3.000 equiv., 2.421 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.4216 mL, 2.421 mmol)

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[0183] were dissolved in dichloromethane (8 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dehydrated with anhydrous magnesium 5 sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain tert-butyl 3-[[2- fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3-pyridyl]oxy]azetidin-1-carboxylate (0.301 g, 98.06%) in the form of a white solid. 10 [Step 5] Synthesis of intermediate compound 10 Tert-butyl 3-[[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3- pyridyl]oxy]azetidin-1-carboxylate (100.00%, 0.310 g, 0.815 mmol) and 2,2,2- trifluoroacetic acid (100.00% solution, 1.871 mL, 24.450 mmol) were dissolved in 15 dichloromethane (10 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain intermediate compound 10, 5-(azetidin-3-yloxy)-6-fluoro-N- 20 pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2-trifluoroacetic acid (0.287 g, 69.29%) in

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[0185] the form of a yellow solid. Synthesis of intermediate compound 11: 5-(piperazin-1-ylmethyl)-N- pyrrolidin-1-yl-pyridin-2-carboxamide dihydrochloride 5 [Step 1] Synthesis of tert-butyl 4-[(6-methoxycarbonyl-3- pyridyl)methyl]piperazin-1-carboxylate Methyl 5-formylpyridin-2-carboxylate (100.00%, 1.000 g, 6.055 mmol), tert- butyl piperazin-1-carboxylate (100.00%, 1.300 g, 6.980 mmol), and sodium 10 triacetoxyborohydride (100.00%, 2.000 g, 9.437 mmol) were mixed in dichloromethane (30 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with 15 anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 30% to 100%) and concentrated to obtain tert-butyl 4-[(6- methoxycarbonyl-3-pyridyl)methyl]piperazin-1-carboxylate (2.000 g, 98.48%) in the form of a white solid. 20 [Step 2] Synthesis of 5-[(4-tert-butoxycarbonylpiperazin-1- yl)methyl]pyridin-2-carboxylic acid

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[0187] Tert-butyl 4-[(6-methoxycarbonyl-3-pyridyl)methyl]piperazin-1-carboxylate (100.00%, 2.000 g, 5.963 mmol) and sodium hydroxide (5.00 M solution in water, 2.4 mL, 12.000 mmol) were mixed in tetrahydrofuran (7 mL) / methanol (7 mL) / water (7 5 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (5-(4-tert- butoxycarbonylpiperazin-1-yl)methyl]pyridin-2-carboxylic acid, 1.900 g, 99.14%, white solid). 10 [Step 3] Synthesis of tert-butyl 4-[[6-(pyrrolidin-1-ylcarbamoyl)-3- pyridyl]methyl]piperazin-1-carboxylate 5-[(4-tert-butoxycarbonylpiperazine1-yl)methyl]pyridin-2-carboxylic acid (100.00%, 1.000 g, 3.111 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- 15 triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 1.800 g, 4.734 mmol), N,N-diisopropylethylamine (100.00% solution, 1.63 mL, 9.360 mmol), and pyrrolidin-1-amine dihydrochloride (100.00%, 0.700 g, 4.401 mmol) were mixed in dichloromethane (8 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the

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[0189] temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under 5 reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[[6-(pyrrolidin-1-ylcarbamoyl)-3-pyridyl]methyl]piperazin-1- carboxylate (0.177 g, 14.61%) in the form of light yellow oil. [Step 4] Synthesis of intermediate compound 11 10 Tert-butyl 4-[[6-(pyrrolidin-1-ylcarbamoyl)-3-pyridyl]methyl]piperazin-1- carboxylate (100.00%, 0.177 g, 0.454 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 0.7 mL, 2.800 mmol) were mixed in dichloromethane (2 mL) at room temperature, and the resulting mixture was stirred at 40°C for two hours, after which 15 the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 11, 5-(piperazin- 1-ylmethyl)-N-pyrrolidin-1-yl-pyridin-2-carboxamide dihydrochloride, 0.160 g, 97.18%, white solid). 20 Synthesis of intermediate compound 12: 5-(piperazin-1-ylmethyl)-N-

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[0191] pyrrolidin-1-yl-thiophen-2-carboxamide dihydrochloride [Step 1] Synthesis of tert-butyl 4-[(5-methoxycarbonyl-2- thienyl)methyl]piperazin-1-carboxylate 5 Methyl 5-formylthiophen-2-carboxylate (100.00%, 1.000 g, 5.876 mmol), tert-butyl piperazin-1-carboxylate (100.00%, 1.300 g, 6.980 mmol), and sodium triacetoxyborohydride (100.00%, 2.000 g, 9.437 mmol) were mixed in dichloromethane (30 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was 10 poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 20% to 30%) and concentrated to obtain tert-butyl 4-[(5- 15 methoxycarbonyl-2-thienyl)methyl]piperazin-1-carboxylate (1.900 g, 94.99%) in the form of a yellowish solid. [Step 2] Synthesis of 5-[(4-tert-butoxycarbonylpiperazin-1- yl)methyl]thiophen-2-carboxylic acid 20 Tert-butyl 4-[(5-methoxycarbonyl-2-thienyl)methyl]piperazin-1-carboxylate (100.00%, 1.900 g, 5.582 mmol) and sodium hydroxide (5.00 M solution in water, 2.2

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[0193] mL, 11.000 mmol) were mixed in tetrahydrofuran (6 mL) / methanol (6 mL) / water (6 mL) at room temperature, and the resulting mixture was stirred at 50 ℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced 5 pressure, the resulting product was used without further purification (5-(4-tert- butoxycarbonylpiperazin-1-yl)methyl]thiophen-2-carboxylic acid, 1.800 g, 98.80%, white solid). [Step 3] Synthesis of tert-butyl 4-[[5-(pyrrolidin-1-ylcarbamoyl)-2- thienyl]methyl]piperazin-1-carboxylate 10 5-[(4-tert-butoxycarbonylpiperazine1-yl)methyl]thiophen-2-carboxylic acid (100.00%, 1.000 g, 3.064 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 1.800 g, 4.734 mmol), N,N-diisopropylethylamine (100.00% solution, 1.63 mL, 9.360 mmol), 15 and pyrrolidin-1-amine dihydrochloride (100.00%, 0.700 g, 4.401 mmol) were mixed in N,N-dimethylformamide (8 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The 20 organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under

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[0195] reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 24 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[[5-(pyrrolidin-1-ylcarbamoyl)-2-thienyl]methyl]piperazin-1- carboxylate (0.870 g, 71.98%) in the form of white foam solid. 5 [Step 4] Synthesis of intermediate compound 12 Tert-butyl 4-[[5-(pyrrolidin-1-ylcarbamoyl)-2-thienyl]methyl]piperazin-1- carboxylate (100.00%, 0.870 g, 2.205 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 3.3 mL, 13.200 mmol) were mixed in dichloromethane (8 mL) at room 10 temperature, and the resulting mixture was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 12, 5-(piperazin- 1-ylmethyl)-N-pyrrolidin-1-yl-thiophen-2-carboxamide dihydrochloride, 0.800 g, 15 98.76%, white solid). Synthesis of intermediate compound 13: 2-(piperazin-1-ylmethyl)-N- pyrrolidin-1-yl-oxazol-4-carboxamide dihydrochloride [Step 1] Synthesis of methyl 2-[(4-tert-butoxycarbonylpiperazin-1- 20 yl)methyl]oxazol-4-carboxylate

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[0197] Methyl 2-(chloromethyl)oxazol-4-carboxylate (100.00%, 1.000 g, 5.696 mmol), tert-butyl piperazin-1-carboxylate (100.00%, 1.200 g, 6.443 mmol), and N,N- diisopropylethylamine (100.00 % solution, 3 mL, 17.176 mmol) were mixed in 5 dimethylsulfoxide (10 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column 10 chromatography (SiO2, 24 g cartridge; ethyl acetate / hexane = 10% to 100%) and concentrated to obtain methyl 2-[(4-tert-butoxycarbonylpiperazin-1-yl)methyl]oxazol- 4-carboxylate (0.670 g, 36.15%) in the form of colorless oil. [Step 2] Synthesis of 2-[(4-tert-butoxycarbonylpiperazin-1- yl)methyl]oxazol-4-carboxylic acid 15 Methyl 2-[(4-tert-butoxycarbonylpiperazin-1-yl)methyl]oxazol-4- carboxylate (100.00%, 0.670 g, 2.059 mmol) and sodium hydroxide (5.00 M solution in water, 0.83 mL, 4.150 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the resulting mixture was stirred at 40℃ 20 for 18 hours, after which the reaction was terminated by lowering the temperature to

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[0199] room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (2-[(4-tert- butoxycarbonylpiperazin-1-yl)methyl]oxazol-4-carboxylic acid, 0.640 g, 99.85%, white solid). 5 [Step 3] Synthesis of tert-butyl 4-[[4-(pyrrolidin-1-ylcarbamoyl)oxazol-2- yl]methyl]piperazin-1-carboxylate 2-[(4-tert-butoxycarbonylpiperazine1-yl)methyl]oxazol-4-carboxylic acid (100.00%, 0.640 g, 2.056 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- 10 triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 1.800 g, 4.734 mmol), N,N-diisopropylethylamine (100.00% solution, 1.63 mL, 9.360 mmol), and pyrrolidin-1-amine dihydrochloride (100.00%, 0.700 g, 4.401 mmol) were mixed in N,N-dimethylformamide (5 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the 15 temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography 20 (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain tert-butyl 4-[[4-(pyrrolidin-1-ylcarbamoyl)oxazol-2-yl]methyl]piperazin-1-

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[0201] carboxylate (0.350 g, 44.87%) in the form of light yellow oil. [Step 4] Synthesis of intermediate compound 13 Tert-butyl 4-[[4-(pyrrolidin-1-ylcarbamoyl)oxazol-2-yl]methyl]piperazin-1- 5 carboxylate (100.00%, 0.350 g, 0.923 mmol) and hydrogen chloride (4.00 M solution in 1,4-dioxane, 1.4 mL, 5.600 mmol) were dissolved in dichloromethane (4 mL) at room temperature, and the resulting solution was stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (intermediate compound 13, 2-(piperazin- 10 1-ylmethyl)-N-pyrrolidin-1-yl-oxazol-4-carboxamide dihydrochloride, 0.320 g, 98.46%, white solid). Synthesis of intermediate compound 14: 6-fluoro-5-piperazin-1-yl-N- pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2-trifluoroacetic acid 15 [Step 1] Synthesis of tert-butyl 4-[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3- pyridyl]piperazin-1-carboxylate 5-(4-tert-butoxycarbonylpiperazin-1-yl)-6-fluoro-pyridin-2-carboxylic acid (100.00 %, 0.300 g, 0.922 mmol), pyrrolidin-1-amine dihydrochloride (100.00 %, 1.050

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[0203] equiv., 0.968 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00 %, 2.500 equiv., 2.306 mmol) and N,N-diisopropylethylamine (100.00 % solution, 0.4016 mL, 2.306 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature, and the 5 resulting solution was stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge;10 methanol / dichloromethane = 0% to 20%) and concentrated to obtain tert-butyl 4-[2- fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3-pyridyl]piperazin-1-carboxylate (0.360 g, 99.20 %) in the form of a yellow solid. [Step 2] Synthesis of intermediate compound 14 15 Tert-butyl 4-[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3-pyridyl]piperazin-1- carboxylate (100.00 %, 0.360 g, 0.915 mmol) was dissolved in dichloromethane (5 mL) at room temperature, and 2,2,2-trifluoroacetic acid (100.00% solution, 2.100 mL, 27.450 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced 20 pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to

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[0205] obtain 6-fluoro-5-piperazin-1-yl-N-pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2- trifluoroacetic acid (0.320 g, 67.08 %) in the form of a white solid. Synthesis of intermediate compound 15: 6-fluoro-5-[(2R,3S)-2- 5 methylazetidin-3-yl]oxy-N-pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2- trifluoroacetic acid [Step 1] Synthesis of methyl 5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl- azetidin-3-yl]oxypyridin-2-carboxylate 10 Tert-butyl (2R,3S)-hydroxy-2-methyl-azetidin-1-carboxylate (100.00 %, 2.000 g, 10.681 mmol), sodium hydride (100.00 % solution, 0.41793 mL, 16.022 mmol) and methyl 5-fluoropyridin-2-carboxylate (100.00 %, 1.050 equiv., 11.216 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature, and the resulting solution was stirred at the same temperature for 18 hours. Water was poured into the 15 reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 40 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain methyl 5-[(2R,3S)- 20 1-tert-butoxycarbonyl-2-methyl-azetidin-3-yl]oxypyridin-2-carboxylate (2.730 g, 79.28 %) in the form of a yellow solid. [Step 2] Synthesis of methyl 5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl-

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[0207] azetidin-3-yl]oxy-6-fluoro-pyridin-2-carboxylate Methyl 5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl-azetidin-3- yl]oxypyridin-2-carboxylate (100.00 %, 2.730 g, 8.468 mmol) and silver(II) fluoride 5 (100.00 %, 4.000 equiv., 33.870 mmol) were dissolved in acetonitrile (30 mL) at room temperature, and the resulting solution was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a celite pad to remove a solid therefrom, and then, the resulting filtrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl10 acetate / hexane = 0% to 80%) and concentrated to obtain methyl 5-[(2R,3S)-1-tert- butoxycarbonyl-2-methyl-azetidin-3-yl]oxy-6-fluoro-pyridin-2-carboxylate (0.300 g, 10.41%) in the form of a yellow solid. [Step 3] Synthesis of 5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl-azetidin-3- yl]oxy-6-fluoro-pyridin-2-carboxylic acid 15 Methyl 5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl-azetidin-3-yl]oxy-6- fluoro-pyridin-2-carboxylate (100.00 %, 0.300 g, 0.881 mmol) and lithium hydroxide monohydrate (100.00 % solution, 0.09796 mL, 3.525 mmol) were dissolved in tetrahydrofuran (8 mL) / water (2 mL) at room temperature, and the resulting solution

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[0209] was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl-azetidin-3-yl]oxy-6-fluoro- pyridin-2-carboxylic acid, 0.240 g, 83.46 %, white solid). 5 [Step 4] Synthesis of tert-butyl (2R,3S)-3-[[2-fluoro-6-(pyrrolidin-1- ylcarbamoyl)-3-pyridyl]oxy]-2-methyl-azetidin-1-carboxylate 5-[(2R,3S)-1-tert-butoxycarbonyl-2-methyl-azetidin-3-yl]oxy-6-fluoro- pyridin-2-carboxylic acid (100.00 %, 0.250 g, 0.766 mmol), pyrrolidin-1-amine10 dihydrochloride (100.00 %, 1.050 equiv., 0.805 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00 %, 2.500 equiv., 1.915 mmol), and N,N- diisopropylethylamine (100.00 % solution, 0.3336 mL, 1.915 mmol) were dissolved in N,N-dimethylformamide (15 mL) at room temperature, and the resulting solution was 15 stirred at the same temperature for 18 hours. Water was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%)20 and concentrated to obtain tert-butyl (2R,3S)-3-[[2-fluoro-6-(pyrrolidin-1- ylcarbamoyl)-3-pyridyl]oxy]-2-methyl-azetidin-1-carboxylate (0.233 g, 77.11 %) in the form of a yellow solid.

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[0211] [Step 5] Synthesis of intermediate compound 15 Tert-butyl (2R,3S)-3-[[2-fluoro-6-(pyrrolidin-1-ylcarbamoyl)-3- pyridyl]oxy]-2-methyl-azetidin-1-carboxylate (100.00 %, 0.400 g, 1.014 mmol) was 5 dissolved in dichloromethane (5 mL) at room temperature, and 2,2,2-trifluoroacetic acid (100.00 % solution, 2.328 mL, 30.430 mmol) was added to the resulting solution and stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 20%)10 and concentrated to obtain 6-fluoro-5-[(2R,3S)-2-methylazetidin-3-yl]oxy-N- pyrrolidin-1-yl-pyridin-2-carboxamide 2,2,2-trifluoroacetic acid (0.220 g, 41.52 %) in the form of a yellow oil. Preparation of example compound 15 Synthesis of example compound 1, N'-ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2-carbohydrazide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 20 ethylhydrazine oxalate (100.00%, 0.110 g, 0.733 mmol), triethylamine (100.00%

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[0213] solution, 0.27 mL, 1.940 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.45 mL, 0.764 mmol) were mixed in dichloromethane (3 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. 5 Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain example10 compound 1, N'-ethyl-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carbohydrazide (0.036 g, 21.68%) in the form of a white solid. 1H-NMR (400 MHz, CDCl3) δ 11.84 (s, 1H), 8.52 (d, J = 1.5 Hz, 1H), 8.21 (s, 1H), 7.83 (s, 2H), 7.66 (s, 1H), 7.24 – 7.13 (m, 1H), 3.88 – 3.64 (m, 4H), 3.39 (s, 15 4H), 2.87 – 2.60 (m, 6H), 1.34 – 1.17 (m, 6H).; LRMS (ES) m / z 436.7 (M++ 1). Synthesis of example compound 2, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(2-oxooxazolidin-3-yl)pyridin-2- carboxamide 20 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-

[0214] 111 / 411

[0215] yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.080 g, 0.203 mmol), 3- aminooxazolidin-2-one (100.00%, 0.030 g, 0.294 mmol), triethylamine (100.00% solution, 0.1 mL, 0.717 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.24 mL, 0.407 mmol) were mixed in dichloromethane (1 mL) at 5 room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced 10 pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 2, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N-(2-oxooxazolidin-3-yl)pyridin-2-carboxamide (0.034 g, 35.01%) in the form of a white solid. 151H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.56 (s, 1H), 8.42 (s, 1H), 8.32 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.43 (d, J = 7.1 Hz, 1H), 4.41 (s, 2H), 3.79 – 3.60 (m, 4H), 3.40 (s, 4H), 3.10 (s, 2H), 2.56 (s, 4H), 1.19 (t, J = 7.0 Hz, 3H).; LRMS (ES) m / z 478.3 (M++ 1). 20 Synthesis of example compound 3, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(4-methylpiperazin-1-yl)pyridin-2- carboxamide

[0216] 112 / 411

[0217] Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.080 g, 0.203 mmol), 1- amino-4-methylpiperazine (100.00% solution, 0.04 mL, 0.344 mmol), triethylamine 5 (100.00% solution, 0.1 mL, 0.717 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.24 mL, 0.407 mmol) were mixed in dichloromethane (1 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into 10 the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 3, 5-[4-[(7-ethyl-6-oxo-5H-1,5-15 naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(4-methylpiperazin-1-yl)pyridin-2- carboxamide (0.041 g, 41.10%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.21 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.25 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.39 (dd, J = 8.8, 2.9 Hz, 1H), 3.65 (s, 2H), 2.84 (t, J = 4.8 Hz, 4H), 2.60 – 20 2.53 (m, 6H), 2.47 – 2.24 (m, 6H), 2.22 – 2.13 (m, 5H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 491.4 (M++ 1).

[0218] 113 / 411

[0219] Synthesis of example compound 4, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-(2-pyridyl)pyridin-2- carbohydrazide 5 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.080 g, 0.203 mmol), 2- hydrazinopyridine (100.00% solution, 0.03 mL, 0.330 mmol), triethylamine (100.00% solution, 0.1 mL, 0.717 mmol), and propylphosphonic anhydride solution (50.00% 10 solution in EtOAc, 0.24 mL, 0.407 mmol) were mixed in dichloromethane (1 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid 15 residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 4, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N'-(2-pyridyl)pyridin-2-carbohydrazide (0.035 g, 35.52%) in the form of a yellowish 20 solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.19 (d, J = 2.4 Hz, 1H),

[0220] 114 / 411

[0221] 8.50 – 8.40 (m, 2H), 8.34 (d, J = 2.8 Hz, 1H), 8.10 – 7.99 (m, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.54 – 7.46 (m, 1H), 7.42 (dd, J = 8.9, 2.9 Hz, 1H), 6.68 (dd, J = 6.7, 5.3 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 3.67 (s, 2H), 3.38 (d, J = 4.8 Hz, 4H), 2.63 – 2.52 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 485.3 5 (M++ 1). Synthesis of example compound 5, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2-carbohydrazide 10 Intermediate compound 1B, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.070 g, 0.176 mmol), 1,1-dimethylhydrazine (100.00% solution, 0.03 mL, 0.395 mmol), triethylamine (100.00% solution, 0.08 mL, 0.574 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.16 mL, 0.272 mmol) were mixed in dichloromethane (1 15 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated 20 under reduced pressure. The resulting concentrate was purified by column

[0222] 115 / 411

[0223] chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain example compound 5, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2-carbohydrazide (0.028 g, 36.17%) in the form of a yellowish solid. 51H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.17 (s, 1H), 8.24 (s, 1H), 7.80 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 3.71 (s, 2H), 3.14 – 2.93 (m, 3H), 2.67 – 2.53 (m, 9H), 2.42 (s, 3H), 1.19 (t, J = 7.2 Hz, 2H).; LRMS (ES) m / z 440.3 (M++ 1). 10 Synthesis of example compound 6, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(2-oxooxazolidin-3-yl)pyridin-2- carboxamide Intermediate compound 1B, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 15 6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.070 g, 0.176 mmol), 3-aminooxazolidin-2-one (100.00 %, 0.030 g, 0.294 mmol), triethylamine (100.00% solution, 0.08 mL, 0.574 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.16 mL, 0.272 mmol) were mixed in dichloromethane (1 mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after 20 which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction

[0224] 116 / 411

[0225] mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain 5 example compound 6, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-(2-oxooxazolidin-3-yl)pyridin-2-carboxamide (0.013 g, 15.33%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.55 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.9, 2.9 Hz, 10 1H), 7.34 – 7.25 (m, 1H), 4.41 (t, J = 7.8 Hz, 2H), 3.78 – 3.65 (m, 4H), 3.44 – 3.36 (m, 4H), 2.63 – 2.54 (m, 4H), 2.42 (s, 3H).; LRMS (ES) m / z 482.3 (M++ 1). Synthesis of example compound 7, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(4-methylpiperazin-1-yl)pyridin-2- 15 carboxamide Intermediate compound 1B, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.070 g, 0.176 mmol), 1-amino-4-methylpiperazine (100.00% solution, 0.04 mL, 0.344 mmol), triethylamine 20 (100.00% solution, 0.08 mL, 0.574 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.16 mL, 0.272 mmol) were mixed in dichloromethane (1

[0226] 117 / 411

[0227] mL) at room temperature, and the resulting mixture was stirred at 40℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to 5 remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 15%) and concentrated to obtain example compound 7, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(4-methylpiperazin-1-yl)pyridin-2- 10 carboxamide (0.035 g, 40.17%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.23 (s, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.38 (dd, J = 8.9, 2.9 Hz, 1H), 7.29 (dd, J = 12.8, 4.6 Hz, 1H), 3.69 (s, 2H), 3.60 (s, 1H), 3.18 (s, 2H), 3.06 – 2.98 (m, 1H), 2.85 (t, J = 4.8 Hz, 4H), 2.57 (s, 4H), 2.48 – 2.44 (m, 3H), 2.42 (s, 4H), 2.21 15 (s, 3H).; LRMS (ES) m / z 495.4 (M++ 1). Synthesis of example compound 8, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2- carbohydrazide 20 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-

[0228] 118 / 411

[0229] yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.254 mmol), 1.1-dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol), triethylamine (100.00% solution, 0.1 mL, 0.717 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.23 mL, 0.390 mmol) were mixed in dichloromethane (2 5 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column 10 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 8, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2-carbohydrazide (0.020 g, 18.07%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.18 (s, 1H), 8.41 (d, J = 1.7 15 Hz, 1H), 8.24 (d, J = 2.9 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.39 (dd, J = 8.9, 2.9 Hz, 1H), 3.66 (s, 2H), 3.33 – 3.26 (m, 4H), 2.62 – 2.53 (m, 12H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 436.4 (M++ 1). Synthesis of example compound 9, 5-[4-[(7-ethyl-6-oxo-5H-1,5-20 naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N',N'-dimethyl-pyridin-2- carbohydrazide

[0230] 119 / 411

[0231] Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.243 mmol), 1.1-dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol), 5 triethylamine (100.00% solution, 0.1 mL, 0.717 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.22 mL, 0.373 mmol) were mixed in dichloromethane (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with dichloromethane, filtered 10 through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 9, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N',N'-dimethyl-pyridin-2- 15 carbohydrazide (0.010 g, 9.07%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.26 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.57 (dd, J = 10.6, 8.2 Hz, 1H), 3.66 (s, 2H), 3.17 (d, J = 5.0 Hz, 4H), 2.63 – 2.53 (m, 12H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 454.3 (M++ 1). 20 Synthesis of example compound 10, 5-[4-[(7-ethyl-6-oxo-5H-1,5-

[0232] 120 / 411

[0233] naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-phenyl-pyridin-2-carbohydrazide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.254 mmol), 5 phenylhydrazine hydrochloride (100.00%, 0.060 g, 0.415 mmol), triethylamine (100.00% solution, 0.1 mL, 0.717 mmol), and propylphosphonic anhydride solution (50.00% solution in EtOAc, 0.23 mL, 0.390 mmol) were mixed in dichloromethane (2 mL) at room temperature, and the resulting mixture was stirred at 45°C for 18 hours to lower the temperature to room temperature, after which sodium hydrogen carbonate (2 mL) 10 was added to the reaction mixture at room temperature and stirred for five minutes to terminate the reaction. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 10, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- 15 yl)methyl]piperazin-1-yl]-N'-phenyl-pyridin-2-carbohydrazide (0.009 g, 7.32%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.16 (d, J = 2.6 Hz, 1H), 8.42 (s, 1H), 8.34 (s, 1H), 7.88 – 7.72 (m, 3H), 7.64 (s, 1H), 7.42 (d, J = 6.6 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H), 6.71 (dd, J = 17.9, 7.5 Hz, 3H), 3.67 (s, 2H), 2.65 – 2.53 (m, 20 10H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 484.3 (M++ 1).

[0234] 121 / 411

[0235] Synthesis of example compound 11, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-morpholino-pyridin-2-carboxamide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- 5 yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.254 mmol), morpholin-4-amine (100.00% solution, 0.05 mL, 0.520 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- 10 dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and 15 concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 11, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N-morpholino-pyridin-2-carboxamide (0.025 g, 20.59%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.37 (s, 1H), 8.41 (d, J = 1.7 20 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 1.1 Hz, 1H), 7.40 (dd, J = 8.9, 2.9 Hz, 1H), 3.66 (t, J = 4.4 Hz, 6H), 2.92 – 2.77 (m, 4H),

[0236] 122 / 411

[0237] 2.62 – 2.52 (m, 10H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 478.3 (M++ 1). Synthesis of example compound 12, N-(1,1-dioxo-1,4-thiazinan-4-yl)-5- [4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2- 5 carboxamide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.254 mmol), 1,1-dioxo-1,4-thiazinan-4-amine (100.00%, 0.080 g, 0.533 mmol), 1- 10 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (1 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the 15 temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example20 compound 12, N-(1,1-dioxo-1,4-thiazinan-4-yl)-5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2-carboxamide (0.030 g, 22.45%) in

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[0239] the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.90 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.27 (t, J = 3.4 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.40 (dd, J = 8.8, 2.9 Hz, 1H), 4.05 (s, 1H), 3.66 (s, 2H), 3.25 (s, 4H), 2.62 – 2.53 (m, 5 13H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 526.3 (M++ 1). Synthesis of example compound 13, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxooxazolidin-3- yl)pyridin-2-carboxamide 10 Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.243 mmol), 3-aminooxazolidin-2-one (100.00%, 0.040 g, 0.392 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide15 hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (5 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture 20 under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and

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[0241] concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 13, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- 6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin-2-carboxamide (0.024 g, 19.93%) in the 5 form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.65 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.76 (s, 1H), 7.68 – 7.55 (m, 2H), 4.41 (t, J = 7.8 Hz, 2H), 3.79 – 3.60 (m, 4H), 3.28 – 3.10 (m, 4H), 2.64 – 2.52 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 496.3 (M++ 1). 10 Synthesis of example compound 14, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N'-(2-pyridyl)pyridin-2- carbohydrazide 15 Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.243 mmol), 2-hydrazinopyridine, 98% (100.00% solution, 0.04 mL, 0.440 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), and N,N-20 diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred

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[0243] at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and 5 concentrated to obtain example compound 14, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N'-(2-pyridyl)pyridin-2- carbohydrazide (0.020 g, 16.37%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 10.26 (s, 1H), 8.44 (d, J = 14.9 Hz, 2H), 8.04 (d, J = 3.8 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 7.67 – 10 7.55 (m, 2H), 7.51 (t, J = 6.9 Hz, 1H), 6.72 – 6.64 (m, 1H), 6.58 (d, J = 8.4 Hz, 1H), 3.67 (s, 2H), 3.26 – 3.10 (m, 4H), 2.65 – 2.53 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 503.3 (M++ 1). Synthesis of example compound 15, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-15 oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2- carbohydrazide Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g,20 0.241 mmol), 1,1-dimethylhydrazine (100.00% solution, 0.03 mL, 0.395 mmol), 1-

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[0245] [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.150 g, 0.395 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (5 mL) at room temperature, and the resulting mixture was stirred 5 at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred 10 to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 15, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2-carbohydrazide (0.029 g, 26.33%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.26 (s, 1H), 7.82 (d, J = 8.0 15 Hz, 1H), 7.61 – 7.43 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 3.70 (s, 2H), 3.16 (s, 4H), 2.59 (s, 4H), 2.55 (s, 6H), 2.42 (s, 3H).; LRMS (ES) m / z 458.3 (M++ 1). Synthesis of example compound 16, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(2-oxooxazolidin-3-yl)pyridin- 20 2-carboxamide

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[0247] Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.241 mmol), 3-aminooxazolidin-2-one (100.00%, 0.040 g, 0.392 mmol), 1- 5 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.140 g, 0.368 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the 10 temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example15 compound 16, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-(2-oxooxazolidin-3-yl)pyridin-2-carboxamide (0.016 g, 13.31%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.65 (s, 1H), 7.88 (dd, J = 8.1, 1.1 Hz, 1H), 7.59 (dd, J = 10.5, 8.2 Hz, 1H), 7.51 (s, 1H), 7.34 – 7.25 (m, 1H), 4.41 20 (t, J = 7.8 Hz, 2H), 3.71 (dd, J = 9.3, 6.1 Hz, 4H), 3.22 (s, 4H), 2.60 (s, 4H), 2.42 (s,

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[0249] 3H).; LRMS (ES) m / z 500.3 (M++ 1). Synthesis of example compound 17, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N'-(2-pyridyl)pyridin-2- 5 carbohydrazide Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.241 mmol), 2-hydrazinopyridine, 98% (100.00% solution, 0.04 mL, 0.440 mmol), 1- 10 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.140 g, 0.368 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the 15 temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example20 compound 17, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N'-(2-pyridyl)pyridin-2-carbohydrazide (0.009 g, 7.38%) in

[0250] 129 / 411

[0251] the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 10.29 (s, 1H), 8.82 – 8.51 (m, 1H), 8.04 (d, J = 3.9 Hz, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.67 – 7.46 (m, 3H), 7.32 (t, J = 7.7 Hz, 1H), 6.76 – 6.67 (m, 1H), 6.61 (d, J = 8.0 Hz, 1H), 3.95 – 3.66 (m, 2H), 3.28 5 – 3.08 (m, 4H), 2.82 – 2.55 (m, 4H), 2.43 (s, 3H).; LRMS (ES) m / z 507.3 (M++ 1). Synthesis of example compound 18, N',N'-dimethyl-5-[4-[(3-methyl-2- oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2- carbohydrazide 10 [Step 1] Synthesis of methyl 5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylate Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate hydrochloride (100.00%, 0.260 g, 1.009 mmol), N,N-diisopropylethylamine (100.00 %15 solution, 0.9 mL, 5.153 mmol), and 7-(bromomethyl)-3-methyl-1H-pyrido[2,3- b][1,4]oxazin-2-one (100.00 %, 0.280 g, 1.022 mmol) were mixed in acetonitrile (4 mL) at room temperature, and the resulting mixture was stirred at 80°C for three days, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl20 5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1- yl]pyridin-2-carboxylate (0.285 g, 68.17%) in the form of a white solid.

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[0253] [Step 2] Synthesis of 5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid Methyl 5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- 5 yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (100.00%, 0.240 g, 0.604 mmol) and sodium hydroxide (5.00 M solution in water, 0.25 mL, 1.250 mmol) were mixed in tetrahydrofuran (1 mL) / methanol (1 mL) / water (0.7 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was10 used without further purification (5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin- 7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 0.230 g, 99.33%, yellowish solid). [Step 3] Synthesis of example compound 18 15 5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin- 1-yl]pyridin-2-carboxylic acid (100.00%, 0.230 g, 0.600 mmol), 1,1-dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol), 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.150

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[0255] g, 0.395 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the 5 solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 18, N',N'-dimethyl-5-[4-[(3-methyl-2-oxo-1H-pyrido[2,3- 10 b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carbohydrazide (0.016 g, 6.27%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.17 (s, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.9, 2.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 4.90 (q, J = 6.8 Hz, 1H), 3.48 (s, 2H), 3.32 – 3.26 (m, 15 4H), 2.54 (d, J = 8.8 Hz, 10H), 1.47 (d, J = 6.8 Hz, 3H).; LRMS (ES) m / z 426.3 (M++ 1). Synthesis of example compound 19, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2- 20 carbohydrazide

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[0257] Intermediate compound 1D, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.260 g, 0.654 mmol), 1,1-dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide 5 hexafluorophosphate (HATU, 100.00%, 0.150 g, 0.395 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture 10 under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 19, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- 15 yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2-carbohydrazide (0.024 g, 8.35%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 9.17 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.22 (s, 1H), 4.83 – 4.68 (m, 1H), 3.47 (s, 2H), 3.32 – 3.27 (m, 4H), 2.60 – 2.52 (m, 10H), 1.98 – 1.73 (m, 2H), 20 1.00 (t, J = 7.3 Hz, 3H).; LRMS (ES) m / z 440.3 (M++ 1). Synthesis of example compound 20, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-isopropyl-pyridin-2-carbohydrazide

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[0259] Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), isopropylhydrazine (100.00% solution, 0.07 mL, 0.796 mmol), 1- 5 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the 10 temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example15 compound 20, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N'-isopropyl-pyridin-2-carbohydrazide (0.040 g, 23.33%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.62 (s, 1H), 8.41 (d, J = 1.5 Hz, 1H), 8.27 (d, J = 2.6 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.40 (dd, J = 8.8, 2.8 Hz, 1H), 3.66 (s, 2H), 3.33 – 3.22 (m, 4H), 3.13 – 3.00 (m, 1H), 20 2.62 – 2.52 (m, 7H), 1.19 (t, J = 7.4 Hz, 3H), 0.99 (d, J = 6.3 Hz, 6H).; LRMS (ES) m / z 450.3 (M++ 1).

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[0261] Synthesis of example compound 21, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-(oxetan-3-yl)pyridin-2- carbohydrazide 5 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), oxalic acid oxetane-3-ylhydrazine (100.00%, 0.130 g, 0.730 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide10 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture 15 under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which acetonitrile (2 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 21, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- 20 N'-(oxetan-3-yl)pyridin-2-carbohydrazide (0.043 g, 24.33%) in the form of a white solid.

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[0263] 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.93 (d, J = 6.4 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.40 (dd, J = 8.9, 2.9 Hz, 1H), 5.52 (t, J = 6.0 Hz, 1H), 4.56 (t, J = 6.8 Hz, 2H), 4.48 (t, J = 6.2 Hz, 2H), 4.22 – 4.11 (m, 1H), 3.66 (s, 2H), 3.37 (s, 4H), 5 2.56 (t, J = 7.1 Hz, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 464.4 (M++ 1). Synthesis of example compound 22, 5-[4-[(5-fluoro-2-methyl-3-oxo-4H- 1,4-benzoxazin-6-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2- carbohydrazide 10 [Step 1] Synthesis of methyl 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-1,4- benzoxazine-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylate Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate hydrochloride (100.00%, 0.260 g, 1.009 mmol), N,N-diisopropylethylamine (100.00 %15 solution, 0.9 mL, 5.153 mmol), and 6-(bromomethyl)-5-fluoro-2-methyl-4H-1,4- benzoxazin-3-one (100.00 %, 0.280 g, 1.022 mmol) were mixed in acetonitrile (4 mL) at room temperature, and the resulting mixture was stirred at 80°C for three days, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl20 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin-1-

[0264] 136 / 411

[0265] yl]pyridin-2-carboxylate (0.285 g, 68.17%) in the form of a white solid. [Step 2] Synthesis of 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-1,4-benzoxazine-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid 5 Methyl 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (100.00%, 0.285 g, 0.688 mmol) and sodium hydroxide (5.00 M solution in water, 0.28 mL, 1.400 mmol) were mixed in tetrahydrofuran (1 mL) / methanol (1 mL) / water (0.7 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the 10 solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (5-[4-[(5-fluoro-2-methyl-3-oxo-4H-1,4-benzoxazin- 6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 0.270 g, 98.05%, white solid). [Step 3] Synthesis of example compound 22 15 5-[4-[(5-fluoro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin- 1-yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.250 mmol), 1,1-dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol), 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.150

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[0267] g, 0.395 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the 5 solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which saturated aqueous sodium hydrogen carbonate solution (10 mL) was added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound 22, 5-[4-[(5-10 fluoro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin-1-yl]-N',N'- dimethyl-pyridin-2-carbohydrazide (0.070 g, 63.34%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.18 (s, 1H), 8.23 (d, J = 2.8 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.9, 2.9 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 4.71 (q, J = 6.7 Hz, 1H), 3.53 (s, 2H), 3.33 – 3.23 (m, 15 4H), 2.59 – 2.52 (m, 10H), 1.44 (d, J = 6.8 Hz, 3H).; LRMS (ES) m / z 443.3 (M++ 1). Synthesis of example compound 23, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]piperazin-1-yl]-N',N'-dimethyl-pyridin-2- carbohydrazide 20 [Step 1] Synthesis of methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylate

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[0269] Intermediate compound 1, methyl 5-piperazin-1-ylpyridin-2-carboxylate hydrochloride (100.00%, 0.260 g, 1.009 mmol), N,N-diisopropylethylamine (100.00 % solution, 0.9 mL, 5.153 mmol), and 6-(bromomethyl)-2-ethyl-5-fluoro-4H-1,4- 5 benzoxazin-3-one (100.00 %, 0.300 g, 1.041 mmol) were mixed in acetonitrile (4 mL) at room temperature, and the resulting mixture was stirred at 80°C for three days, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with acetonitrile, and dried to obtain methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin-1-yl]pyridin- 10 2-carboxylate (0.315 g, 72.87%) in the form of a white solid. [Step 2] Synthesis of 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid Methyl 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6- 15 yl)methyl]piperazin-1-yl]pyridin-2-carboxylate (100.00%, 0.315 g, 0.735 mmol) and sodium hydroxide (5.00 M solution in water, 0.3 mL, 1.500 mmol) were mixed in tetrahydrofuran (1 mL) / methanol (1 mL) / water (0.7 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the

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[0271] solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid, 0.300 g, 98.48%, white solid). [Step 3] Synthesis of example compound 23 5 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin-1- yl]pyridin-2-carboxylic acid (100.00%, 0.100 g, 0.241 mmol), 1,1-dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol), 1-[bis(dimethylamino)methylene]-1H- 1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.150 10 g, 0.395 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.13 mL, 0.746 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was 15 purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which saturated aqueous sodium hydrogen carbonate solution (10 mL) was added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound 23, 5-[4-[(2- ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]piperazin-1-yl]-N',N'-dimethyl- 20 pyridin-2-carbohydrazide (0.030 g, 27.23%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.17 (s, 1H), 8.23 (d, J = 2.8

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[0273] Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.38 (dd, J = 8.9, 2.9 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 4.61 – 4.51 (m, 1H), 3.53 (s, 2H), 3.31 (d, J = 5.3 Hz, 4H), 2.59 – 2.52 (m, 10H), 1.91 – 1.70 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 457.3 (M++ 1). 5 Synthesis of example compound 24, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-[(2R)-2-(methoxymethyl)pyrrolidin- 1-yl]pyridin-2-carboxamide 10 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), (2R)-2-(methoxymethyl)pyrrolidin-1-amine (100.00% solution, 0.1 mL, 0.761 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), and N,N-15 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 20 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which saturated aqueous sodium hydrogen

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[0275] carbonate solution (10 mL) was added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound 24, 5-[4-[(7-ethyl-6-oxo-5H- 1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-[(2R)-2-(methoxymethyl)pyrrolidin- 1-yl]pyridin-2-carboxamide (0.110 g, 57.06%) in the form of a yellowish solid. 51H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.24 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.40 (dd, J = 8.9, 2.8 Hz, 1H), 3.66 (s, 2H), 3.41 – 3.35 (m, 4H), 3.23 – 3.13 (m, 4H), 3.12 – 3.02 (m, 1H), 2.88 (q, J = 8.3 Hz, 1H), 2.63 – 2.52 (m, 8H), 1.98 – 1.85 (m, 1H), 1.82 – 1.65 (m, 2H), 1.53 (dt, J = 12.0, 6.3 Hz, 1H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS 10 (ES) m / z 506.4 (M++ 1). Synthesis of example compound 25, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-[(2S)-2-(methoxymethyl)pyrrolidin- 1-yl]pyridin-2-carboxamide 15 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), (2S)-2-(methoxymethyl)pyrrolidin-1-amine (100.00% solution, 0.1 mL, 0.761 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide20 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), and N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol) were mixed in N,N-

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[0277] dimethylformamide (5 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 5 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which saturated aqueous sodium hydrogen carbonate solution (10 mL) and ethyl acetate (10 mL) were added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound 25, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-[(2S)-2- 10 (methoxymethyl)pyrrolidin-1-yl]pyridin-2-carboxamide (0.070 g, 36.31%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.40 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.40 (dd, J = 8.9, 2.8 Hz, 1H), 3.65 (s, 2H), 3.36 (d, J = 5.5 Hz, 4H), 3.22 – 3.16 (m, 4H), 3.11 – 3.03 (m, 15 1H), 2.88 (q, J = 8.3 Hz, 1H), 2.56 (t, J = 7.0 Hz, 8H), 2.02 – 1.89 (m, 1H), 1.83 – 1.65 (m, 2H), 1.59 – 1.45 (m, 1H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 506.4 (M++ 1). Synthesis of example compound 26, 5-[1-[(7-ethyl-6-oxo-5H-1,5- 20 naphthyridin-3-yl)methyl]-4-piperidyl]-N',N'-dimethyl-pyridin-2-carbohydrazide

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[0279] Intermediate compound 3A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.382 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- 5 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1,1- dimethylhydrazine (100.00% solution, 0.05 mL, 0.658 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture 10 under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (15 mL) were added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound15 26, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-N',N'- dimethyl-pyridin-2-carbohydrazide (0.056 g, 33.72%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 9.50 (s, 1H), 8.51 (d, J = 1.6 Hz, 1H), 8.40 (d, J = 1.6 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 8.0, 2.0 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 3.62 (s, 2H), 2.94 (d, J = 8.7 Hz, 2H), 2.68 (t, J = 11.7 20 Hz, 1H), 2.55 (d, J = 10.7 Hz, 8H), 2.13 (t, J = 10.5 Hz, 2H), 1.83 – 1.63 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 435.4 (M++ 1). Synthesis of example compound 27, 5-[1-[(7-ethyl-6-oxo-5H-1,5-

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[0281] naphthyridin-3-yl)methyl]-4-piperidyl]-N-(2-oxooxazolidin-3-yl)pyridin-2- carboxamide Intermediate compound 3A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- 5 yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.382 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- aminooxazolidin-2-one (100.00%, 0.060 g, 0.588 mmol) were mixed in N,N- 10 dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and 15 concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (15 mL) were added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound 27, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-N-(2- oxooxazolidin-3-yl)pyridin-2-carboxamide (0.089 g, 48.86%) in the form of a white 20 solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 1.7 Hz, 1H), 8.41 (d, J = 1.7

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[0283] Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.92 (dd, J = 8.1, 2.0 Hz, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 4.42 (t, J = 7.8 Hz, 2H), 3.75 (t, J = 7.8 Hz, 2H), 3.63 (s, 2H), 2.95 (d, J = 11.4 Hz, 2H), 2.80 – 2.64 (m, 1H), 2.60 – 2.52 (m, 2H), 2.14 (t, J = 10.5 Hz, 2H), 1.85 – 1.66 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 477.3 (M++ 1). 5 Synthesis of example compound 28, 5-[1-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]-4-piperidyl]-N'-phenyl-pyridin-2-carbohydrazide Intermediate compound 3A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-10 yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.382 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and phenylhydrazine hydrochloride (100.00%, 0.090 g, 0.622 mmol) were mixed in N,N-dimethylformamide 15 (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the 20 product, to which acetonitrile (4 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 28, 5-[1-[(7-

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[0285] ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-N'-phenyl-pyridin-2- carbohydrazide (0.066 g, 35.78%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.48 (s, 1H), 8.58 (d, J = 14.7 Hz, 2H), 7.98 (d, J = 7.8 Hz, 1H), 7.89 (s, 2H), 7.78 (d, J = 13.9 Hz, 2H), 7.14 (t, 5 J = 7.6 Hz, 2H), 6.72 (dd, J = 18.6, 7.6 Hz, 3H), 4.65 – 3.76 (m, 2H), 3.02 – 2.76 (m, 2H), 2.63 – 2.52 (m, 4H), 2.10 – 1.77 (m, 5H), 1.20 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 483.3 (M++ 1). Synthesis of example compound 29, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H- 10 quinoxalin-6-yl)methyl]-4-piperidyl]-N',N'-dimethyl-pyridin-2-carbohydrazide Intermediate compound 3B, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.378 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide15 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1,1- dimethylhydrazine (100.00% solution, 0.05 mL, 0.658 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the 20 temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column

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[0287] chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound 5 29, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-N',N'- dimethyl-pyridin-2-carbohydrazide (0.060 g, 36.16%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.50 (s, 1H), 8.51 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.86 (dd, J = 8.2, 2.1 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.33 – 7.24 (m, 1H), 3.66 (s, 2H), 3.02 – 2.90 (m, 2H), 2.71 – 2.61 (m, 1H), 2.56 10 (s, 6H), 2.42 (s, 3H), 2.20 – 2.09 (m, 2H), 1.82 – 1.62 (m, 4H).; LRMS (ES) m / z 439.3 (M++ 1). Synthesis of example compound 30, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]-4-piperidyl]-N-(2-oxooxazolidin-3-yl)pyridin-2- 15 carboxamide Intermediate compound 3B, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.378 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide20 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3-

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[0289] aminooxazolidin-2-one (100.00%, 0.060 g, 0.588 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture 5 under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain example compound10 30, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-N-(2- oxooxazolidin-3-yl)pyridin-2-carboxamide (0.032 g, 17.60%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.88 (s, 1H), 8.59 (d, J = 1.6 Hz, 1H), 7.94 (dt, J = 8.2, 5.0 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 7.30 (t, J = 7.7 Hz, 15 1H), 4.42 (t, J = 7.8 Hz, 2H), 3.74 (t, J = 7.8 Hz, 2H), 3.69 (s, 2H), 3.09 – 2.90 (m, 2H), 2.77 – 2.63 (m, 1H), 2.42 (s, 3H), 2.28 – 2.06 (m, 2H), 1.86 – 1.64 (m, 4H).; LRMS (ES) m / z 481.3 (M++ 1). Synthesis of example compound 31, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H- 20 quinoxalin-6-yl)methyl]-4-piperidyl]-N'-phenyl-pyridin-2-carbohydrazide

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[0291] Intermediate compound 3B, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.378 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- 5 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and phenylhydrazine hydrochloride (100.00%, 0.090 g, 0.622 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced 10 pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which acetonitrile (4 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 31, 5-[1-[(5- fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-N'-phenyl-pyridin-2- 15 carbohydrazide (0.027 g, 14.67%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.65 (s, 1H), 10.49 (s, 1H), 8.59 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.94 – 7.77 (m, 2H), 7.68 – 7.55 (m, 2H), 7.17 – 7.09 (m, 2H), 6.78 – 6.67 (m, 3H), 4.42 (s, 2H), 3.60 – 3.41 (m, 2H), 3.15 – 2.91 (m, 3H), 2.45 (s, 3H), 2.07 (t, J = 10.0 Hz, 4H).; LRMS (ES) m / z 487.3 (M++ 1). 20 Synthesis of example compound 32, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(4-ethylpiperazin-1-yl)pyridin-2- carboxamide

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[0293] Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 4- ethylpiperazin-1-amine (100.00% solution, 0.08 mL, 0.598 mmol), N,N- 5 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the 10 temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain example compound 32, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(4-ethylpiperazin-1-yl)pyridin-2- 15 carboxamide (0.110 g, 57.17%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.21 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 1.3 Hz, 1H), 7.40 (dd, J = 8.9, 2.9 Hz, 1H), 3.66 (s, 2H), 3.06 – 2.96 (m, 1H), 2.92 (s, 1H), 2.85 (t, J = 4.8 Hz, 4H), 2.63 – 2.53 (m, 6H), 2.49 – 2.40 (m, 3H), 2.39 – 2.23 (m, 4H), 20 1.19 (t, J = 7.4 Hz, 3H), 1.06 – 0.94 (m, 4H).; LRMS (ES) m / z 505.4 (M++ 1).

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[0295] Synthesis of example compound 33, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-methyl-pyridin-2-carbohydrazide dihydrochloride [Step 1] Synthesis of tert-butyl N-[[5-[4-[(7-ethyl-6-oxo-5H-1,5- 5 naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2-carbonyl]amino]-N-methyl- carbamate Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.200 g, 0.508 mmol), 10 tert-butyl N-amino-N-methyl-carbamate (100.00% solution, 0.11 mL, 0.774 mmol), N,N-diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred 15 at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated 20 aqueous sodium hydrogen carbonate solution (10 mL) were added and stirred to filter the precipitated solid, washed with ethyl acetate, and dried to obtain tert-butyl N-[[5-

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[0297] [4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2- carbonyl]amino]-N-methyl-carbamate (0.240 g, 90.51%) in the form of a yellowish solid. [Step 2] Synthesis of example compound 33 5 Tert-butyl N-[[5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carbonyl]amino]-N-methyl-carbamate (100.00%, 0.100 g, 0.192 mmol) and hydrogen chloride (1.00 M solution in EtOAc, 2 mL, 2.000 mmol) were mixed in dichloromethane (4 mL) at room temperature, and the resulting 10 mixture was stirred at 40°C for three days, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with dichloromethane, and dried to obtain example compound 33, 5-[4-[(7- ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-methyl-pyridin-2- carbohydrazide dihydrochloride (0.094 g, 99.17%) in the form of a yellowish solid. 151H-NMR (400 MHz, MeOD) δ 9.03 (d, J = 1.7 Hz, 1H), 8.66 (d, J = 1.3 Hz, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.12 (d, J = 8.9 Hz, 1H), 7.99 (s, 1H), 7.69 (dd, J = 9.0, 2.9 Hz, 1H), 4.82 (s, 2H), 4.02 – 3.39 (m, 6H), 3.08 (s, 3H), 3.02 (s, 1H), 2.83 – 2.74 (m, 2H), 2.02 (d, J = 8.7 Hz, 1H), 1.34 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 422.3 (M++ 1). 20

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[0299] Synthesis of example compound 34, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-pyrrolidin-1-yl-pyridin-2- carboxamide 5 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), pyrrolidin-1-amine dihydrochloride (100.00 %, 0.090 g, 0.566 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide10 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 15 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and concentrated to obtain the product, to which acetonitrile (4 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 34, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.037 g, 21.02%) in the form of a white solid. 201H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.16 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 2.7 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H),

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[0301] 7.40 (dd, J = 8.9, 2.8 Hz, 1H), 3.66 (s, 2H), 3.41 – 3.34 (m, 4H), 2.97 – 2.80 (m, 4H), 2.63 – 2.52 (m, 6H), 1.82 – 1.67 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 462.3 (M++ 1). 5 Synthesis of example compound 35, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-(3-fluorophenyl)pyridin-2- carbohydrazide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-10 yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and (3- fluorophenyl)hydrazine hydrochloride (100.00%, 0.080 g, 0.492 mmol) were mixed in 15 N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 10%) and 20 concentrated to obtain the product, to which acetonitrile (4 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example

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[0303] compound 35, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N'-(3-fluorophenyl)pyridin-2-carbohydrazide (0.051 g, 26.67%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.27 (s, 1H), 8.44 (s, 1H), 5 8.34 (s, 1H), 8.11 (s, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.44 (d, J = 6.8 Hz, 1H), 7.14 (dd, J = 15.0, 7.9 Hz, 1H), 6.56 (d, J = 8.2 Hz, 1H), 6.45 (dd, J = 16.1, 10.1 Hz, 2H), 3.69 (s, 2H), 3.38 (s, 4H), 2.70 – 2.53 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 502.3 (M++ 1). 10 Synthesis of example compound 36, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-(4-fluorophenyl)pyridin-2- carbohydrazide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-15 yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and (4- fluorophenyl)hydrazine hydrochloride (100.00%, 0.080 g, 0.492 mmol) were mixed in 20 N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by lowering the

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[0305] temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (4 mL) was added and stirred 5 to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 36, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- N'-(4-fluorophenyl)pyridin-2-carbohydrazide (0.014 g, 7.32%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.22 (s, 1H), 8.44 (s, 1H), 10 8.34 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.77 (s, 2H), 7.66 (s, 1H), 7.44 (s, 1H), 6.97 (t, J = 8.8 Hz, 2H), 6.80 – 6.66 (m, 2H), 3.67 (s, 2H), 3.49 – 3.34 (m, 4H), 2.69 – 2.52 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 502.3 (M++ 1). Synthesis of example compound 37, 5-[4-[(7-ethyl-6-oxo-5H-1,5-15 naphthyridin-3-yl)methyl]piperazin-1-yl]-N'-(4-methylsulfonylphenyl)pyridin-2- carbohydrazide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- 20 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-

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[0307] diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and (4- methylsulfonylphenyl)hydrazine hydrochloride (100.00%, 0.100 g, 0.449 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at 50℃ for 18 hours, after which the reaction was terminated by 5 lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (4 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain10 example compound 37, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-N'-(4-methylsulfonylphenyl)pyridin-2-carbohydrazide (0.019 g, 8.87%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.44 (d, J = 1.6 Hz, 1H), 8.68 (d, J = 1.6 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H), 7.85 (d, J = 15 8.8 Hz, 1H), 7.77 (s, 1H), 7.69 – 7.60 (m, 3H), 7.43 (dd, J = 8.9, 2.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 3.69 (s, 2H), 3.47 – 3.35 (m, 4H), 3.07 (s, 3H), 2.68 – 2.52 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 562.3 (M++ 1). Synthesis of example compound 38, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- 20 quinoxalin-6-yl)methyl]piperazin-1-yl]-N'-(oxetan-3-yl)pyridin-2-carbohydrazide

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[0309] Intermediate compound 1C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- 5 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and oxalic acid oxetan-3-ylhydrazine (100.00%, 0.100 g, 0.561 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for two days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 10 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 38, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N'-(oxetan-3-yl)pyridin-2-carbohydrazide (0.025 g, 14.24%) in the form of a white 15 solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.92 (d, J = 6.3 Hz, 1H), 8.27 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.39 (dd, J = 8.9, 2.9 Hz, 1H), 7.34 – 7.23 (m, 1H), 5.52 (t, J = 6.0 Hz, 1H), 4.56 (t, J = 6.8 Hz, 2H), 4.48 (t, J = 6.2 Hz, 2H), 4.22 – 4.10 (m, 1H), 3.70 (s, 2H), 3.38 – 3.34 (m, 4H), 20 2.83 (q, J = 7.4 Hz, 2H), 2.63 – 2.53 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 482.3 (M++ 1). Synthesis of example compound 39, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-

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[0311] quinoxalin-6-yl)methyl]piperazin-1-yl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide Intermediate compound 1C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 mmol), 1- 5 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.090 g, 0.566 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred 10 at the same temperature for two days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example15 compound 39, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.067 g, 38.31%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.16 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.39 (d, J = 6.7 Hz, 1H), 20 7.31 (t, J = 7.4 Hz, 1H), 3.72 (s, 2H), 3.40 – 3.35 (m, 2H), 2.96 – 2.76 (m, 6H), 2.60 (s, 4H), 1.76 (s, 4H), 1.22 (t, J = 7.3 Hz, 3H).; LRMS (ES) m / z 480.3 (M++ 1).

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[0313] Synthesis of example compound 40, tert-butyl N-[[5-[4-[(2-ethyl-5- fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2- carbonyl]amino]carbamate 5 Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- 10 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and tert-butyl carbazate (100.00%, 0.080 g, 0.605 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for two days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g 15 cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 40, tert-butyl N-[[5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carbonyl]amino]carbamate (0.071 g, 37.39%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 10.04 (s, 1H), 8.83 (s, 1H), 20 7.85 (d, J = 7.7 Hz, 1H), 7.63 – 7.49 (m, 2H), 7.38 – 7.24 (m, 1H), 3.71 (s, 2H), 3.26 – 3.09 (m, 4H), 2.83 (q, J = 7.3 Hz, 2H), 2.66 – 2.54 (m, 4H), 1.42 (s, 9H), 1.23 (t, J = 7.4

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[0315] Hz, 3H).; LRMS (ES) m / z 544.3 (M++ 1). Synthesis of example compound 41, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N',N'-dimethyl-pyridin-2- 5 carbohydrazide Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide10 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1,1- dimethylhydrazine (100.00% solution, 0.04 mL, 0.527 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for two days. After removing the solvent from the reaction 15 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 41, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- 20 yl]-6-fluoro-N',N'-dimethyl-pyridin-2-carbohydrazide (0.068 g, 41.29%) in the form of

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[0317] a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.26 (s, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.63 – 7.50 (m, 2H), 7.30 (t, J = 7.7 Hz, 1H), 3.71 (s, 2H), 3.24 – 3.03 (m, 4H), 2.83 (q, J = 7.3 Hz, 2H), 2.65 – 2.57 (m, 4H), 2.55 (s, 6H), 1.22 (t, J = 7.4 Hz, 3H).; 5 LRMS (ES) m / z 472.3 (M++ 1). Synthesis of example compound 42, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N'-(oxetan-3-yl)pyridin-2- carbohydrazide 10 Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- 15 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and oxalic acid oxetan-3-ylhydrazine (100.00%, 0.100 g, 0.561 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for two days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 20 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred

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[0319] to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 42, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-N'-(oxetan-3-yl)pyridin-2-carbohydrazide (0.048 g, 27.51%) in the form of a yellowish solid. 51H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.03 (s, 1H), 7.83 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 – 7.52 (m, 2H), 7.37 – 7.19 (m, 1H), 5.56 (s, 1H), 4.56 (t, J = 6.8 Hz, 2H), 4.47 (t, J = 6.2 Hz, 2H), 4.16 (s, 1H), 3.71 (s, 2H), 3.25 – 3.06 (m, 4H), 2.82 (q, J = 7.4 Hz, 2H), 2.68 – 2.54 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 500.3 (M++ 1). 10 Synthesis of example compound 43, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide 15 Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-1-20 amine dihydrochloride (100.00%, 0.090 g, 0.566 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred

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[0321] at the same temperature for two days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred 5 to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 43, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.062 g, 35.68%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.23 (s, 1H), 7.82 (d, J = 7.4 10 Hz, 1H), 7.55 (s, 2H), 7.30 (s, 1H), 3.73 (s, 2H), 3.25 – 3.05 (m, 4H), 3.01 – 2.74 (m, 6H), 2.72 – 2.53 (m, 4H), 1.84 – 1.63 (m, 4H), 1.32 – 1.14 (m, 3H).; LRMS (ES) m / z 498.3 (M++ 1). Synthesis of example compound 44, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- 15 quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carbohydrazide dihydrochloride Example compound 40, tert-butyl N-[[5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carbonyl]amino]carbamate 20 (100.00%, 0.030 g, 0.055 mmol) and hydrogen chloride (1.00 M solution in EtOAc, 0.6

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[0323] mL, 0.600 mmol) were mixed in dichloromethane (1 mL) at room temperature, and the resulting mixture was stirred at 40°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The precipitated solid was filtered, washed with dichloromethane, and dried to obtain example compound 44, 5- 5 [4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro- pyridin-2-carbohydrazide dihydrochloride (0.022 g, 77.20%) in the form of a yellowish solid. 1H-NMR (400 MHz, MeOD) δ 8.09 – 8.01 (m, 1H), 7.79 – 7.65 (m, 2H), 7.62 – 7.52 (m, 1H), 4.67 (s, 2H), 4.01 – 3.36 (m, 8H), 2.96 (q, J = 7.4 Hz, 2H), 1.34 (t, J = 10 7.4 Hz, 3H).; LRMS (ES) m / z 444.3 (M++ 1). Synthesis of example compound 45, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(2-oxooxazolidin-3-yl)pyridin-2- carboxamide 15 Intermediate compound 1C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-20 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- aminooxazolidin-2-one (100.00%, 0.060 g, 0.588 mmol) were dissolved in

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[0325] dichloromethane (5 mL) at room temperature, and the resulting solution was stirred at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to 5 obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 45, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(2- oxooxazolidin-3-yl)pyridin-2-carboxamide (0.018 g, 9.96%) in the form of a white solid. 101H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.55 (s, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.41 (dd, J = 8.9, 2.9 Hz, 1H), 7.34 – 7.25 (m, 1H), 4.41 (t, J = 7.8 Hz, 2H), 3.78 – 3.65 (m, 4H), 3.43 – 3.35 (m, 4H), 2.83 (q, J = 7.4 Hz, 2H), 2.63 – 2.54 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 496.3 (M++ 1). 15 Synthesis of example compound 46, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin- 2-carboxamide 20 Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349

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[0327] mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- aminooxazolidin-2-one (100.00%, 0.060 g, 0.588 mmol) were mixed in N,N- 5 dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for three days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred 10 to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 46, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin-2-carboxamide (0.028 g, 15.61%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.65 (s, 1H), 7.88 (dd, J = 15 8.1, 1.2 Hz, 1H), 7.64 – 7.50 (m, 2H), 7.37 – 7.23 (m, 1H), 4.41 (t, J = 7.8 Hz, 2H), 3.72 (t, J = 7.8 Hz, 4H), 3.27 – 3.08 (m, 4H), 2.83 (q, J = 7.4 Hz, 2H), 2.66 – 2.53 (m, 4H), 1.23 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 514.3 (M++ 1). Synthesis of example compound 47, 5-[4-[(7-ethyl-6-oxo-5H-1,5-20 naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide

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[0329] Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.200 g, 0.486 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide 5 hexafluorophosphate (HATU, 100.00%, 0.280 g, 0.736 mmol), N,N- diisopropylethylamine (100.00% solution, 0.25 mL, 1.440 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.120 g, 0.754 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction 10 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (4 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 47, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]- 15 6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.040 g, 17.16%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.23 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 7.88 – 7.79 (m, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.59 – 7.50 (m, 1H), 3.66 (s, 2H), 3.24 – 3.07 (m, 4H), 2.99 – 2.84 (m, 4H), 2.65 – 2.53 (m, 6H), 1.81 – 1.67 (m, 4H), 20 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 480.3 (M++ 1).

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[0331] Synthesis of example compound 48, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(7- ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2- carboxamide 5 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3,3- 10 difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for four days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) 15 and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 48, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2-carboxamide (0.015 g, 8.14%) in the form of a white solid. 201H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.04 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s,

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[0333] 1H), 7.40 (dd, J = 8.9, 2.8 Hz, 1H), 4.20 (t, J = 12.3 Hz, 4H), 3.67 (s, 2H), 3.44 – 3.34 (m, 4H), 2.65 – 2.53 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 484.3 (M++ 1). 5 Synthesis of example compound 49, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(1-piperidyl)pyridin-2-carboxamide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- 10 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and piperidin-1-amine (100.00% solution, 0.06 mL, 0.571 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature 15 for four days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 49, 5-[4-[(7-20 ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(1-piperidyl)pyridin- 2-carboxamide (0.019 g, 10.48%) in the form of a yellowish solid.

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[0335] 1H-NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.10 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (s, 1H), 7.46 – 7.32 (m, 1H), 3.66 (s, 2H), 3.60 – 3.42 (m, 1H), 3.26 (s, 4H), 2.83 – 2.70 (m, 3H), 2.63 – 2.53 (m, 6H), 1.66 – 1.51 (m, 4H), 1.50 – 1.31 (m, 2H), 1.19 (t, J = 7.4 Hz, 5 3H).; LRMS (ES) m / z 476.3 (M++ 1). Synthesis of example compound 50, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(7- ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2- carboxamide 10 Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-15 diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3,3- difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for four days. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by 20 column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and

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[0337] stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 50, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxamide (0.033 g, 18.05%) in the form of a white solid. 51H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.09 (s, 1H), 8.41 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.57 (dd, J = 10.6, 8.3 Hz, 1H), 4.19 (t, J = 12.3 Hz, 4H), 3.66 (s, 2H), 3.26 – 3.05 (m, 4H), 2.65 – 2.53 (m, 6H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 502.3 (M++ 1). 10 Synthesis of example compound 51, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-pyrrolidin-1-yl-pyridin-2- carboxamide Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- 15 quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.100 g, 0.629 mmol) were mixed in N,N- 20 dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction

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[0339] mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example 5 compound 51, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.050 g, 28.64%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.23 (s, 1H), 7.89 – 7.76 (m, 1H), 7.63 – 7.46 (m, 2H), 7.36 – 7.23 (m, 1H), 3.70 (s, 2H), 3.23 – 3.07 (m, 4H), 2.98 10 – 2.81 (m, 4H), 2.65 – 2.54 (m, 4H), 2.42 (s, 3H), 1.83 – 1.68 (m, 4H).; LRMS (ES) m / z 484.3 (M++ 1). Synthesis of example compound 52, 5-[1-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]-4-piperidyl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide 15 Intermediate compound 3A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.200 g, 0.510 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N-20 diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.130 g, 0.817 mmol) were mixed in N,N-

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[0341] dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and 5 concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 52, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-N- pyrrolidin-1-yl-pyridin-2-carboxamide (0.070 g, 29.82%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 9.49 (s, 1H), 8.51 (s, 2H), 10 7.95 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.71 (s, 1H), 3.99 (s, 2H), 3.30 – 3.02 (m, 4H), 2.97 – 2.74 (m, 5H), 2.63 – 2.53 (m, 2H), 1.97 – 1.80 (m, 4H), 1.81 – 1.64 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 461.3 (M++ 1). Synthesis of example compound 53, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-15 quinoxalin-6-yl)methyl]-4-piperidyl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide Intermediate compound 3B, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin- 6-yl)methyl]-4-piperidyl]pyridin-2-carboxylic acid (100.00%, 0.200 g, 0.505 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide20 hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and pyrrolidin-1-

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[0343] amine dihydrochloride (100.00%, 0.130 g, 0.817 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 5 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 53, 5-[1-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]-4- piperidyl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.080 g, 34.14%) in the form of a 10 yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (s, 1H), 9.50 (s, 1H), 8.51 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.56 – 7.42 (m, 1H), 4.36 (s, 2H), 3.48 – 3.35 (m, 4H), 3.01 – 2.79 (m, 5H), 2.45 (s, 3H), 2.06 – 1.87 (m, 4H), 1.82 – 1.69 (m, 4H).; LRMS (ES) m / z 465.3 (M++ 1). 15 Synthesis of example compound 54, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-N-pyrrolidin-1-yl-pyridin-2- carboxamide 20 Intermediate compound 1D, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.200 g,

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[0345] 0.503 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.130 g, 0.817 mmol) were mixed in N,N- 5 dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred 10 to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 54, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- yl)methyl]piperazin-1-yl]-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.080 g, 34.14%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.22 (s, 1H), 8.27 (s, 1H), 15 7.91 – 7.72 (m, 2H), 7.42 (d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 4.78 (s, 1H), 3.62 – 3.36 (m, 4H), 2.99 – 2.79 (m, 5H), 2.68 – 2.52 (m, 4H), 1.96 – 1.68 (m, 7H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 466.3 (M++ 1). Synthesis of example compound 55, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(7-20 ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2- carboxamide

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[0347] Intermediate compound 4A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.366 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide 5 hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 3,3- difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the 10 reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 55, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(7-ethyl-6-oxo-5H-1,5- 15 naphthyridin-3-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxamide (0.050 g, 27.33%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.32 (s, 1H), 8.65 (s, 1H), 8.07 – 7.89 (m, 2H), 7.87 – 7.73 (m, 2H), 4.45 (s, 2H), 4.20 (t, J = 12.3 Hz, 4H), 3.61 – 3.39 (m, 2H), 3.25 – 2.99 (m, 3H), 2.57 (q, J = 7.5 Hz, 2H), 2.18 – 1.88 (m, 4H), 1.20 20 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 501.3 (M++ 1).

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[0349] Synthesis of example compound 56, 5-[1-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide 5 Intermediate compound 4A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.366 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and pyrrolidin-1-10 amine dihydrochloride (100.00%, 0.130 g, 0.817 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and 15 concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 56, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-6- fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.065 g, 37.16%) in the form of a white solid. 201H-NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 9.47 (s, 1H), 8.64 – 8.37 (m, 1H), 8.17 – 7.96 (m, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 4.01 (s,

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[0351] 2H), 3.27 – 3.04 (m, 4H), 3.02 – 2.83 (m, 5H), 2.56 (q, J = 7.9 Hz, 2H), 2.03 – 1.82 (m, 4H), 1.81 – 1.63 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 479.6 (M++ 1). Synthesis of example compound 57, 5-[1-[(7-ethyl-6-oxo-5H-1,5- 5 naphthyridin-3-yl)methyl]-4-piperidyl]-6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin- 2-carboxamide Intermediate compound 4A, 5-[1-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.366 10 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 3- aminooxazolidin-2-one (100.00%, 0.050 g, 0.490 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred 15 at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) and sodium hydrogen carbonate (15 mL) were added and filtered through a plastic filter to obtain the organic20 layer, which was then concentrated to obtain example compound 57, 5-[1-[(7-ethyl-6- oxo-5H-1,5-naphthyridin-3-yl)methyl]-4-piperidyl]-6-fluoro-N-(2-oxooxazolidin-3-

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[0353] yl)pyridin-2-carboxamide (0.085 g, 47.03%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 10.90 (s, 1H), 8.40 (d, J = 1.8 Hz, 1H), 8.16 – 8.06 (m, 1H), 7.95 (dd, J = 7.6, 1.3 Hz, 1H), 7.75 (s, 1H), 7.62 (d, J = 1.3 Hz, 1H), 4.42 (t, J = 7.8 Hz, 2H), 3.74 (t, J = 7.8 Hz, 2H), 3.63 (s, 2H), 2.96 (dd, 5 J = 14.2, 5.5 Hz, 2H), 2.88 – 2.74 (m, 1H), 2.59 – 2.52 (m, 2H), 2.21 – 2.09 (m, 2H), 1.88 – 1.65 (m, 4H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 495.5 (M++ 1). Synthesis of example compound 58, N-(3,3-difluoroazetidin-1-yl)-5-[1- [(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro- 10 pyridin-2-carboxamide Intermediate compound 4B, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.350 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide15 hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 3,3- difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the 20 reaction mixture under reduced pressure, the resulting concentrate was purified by

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[0355] column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 58, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(2-ethyl-5-fluoro-3-oxo- 5 4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxamide (0.014 g, 7.71%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.29 (s, 1H), 8.25 – 7.98 (m, 1H), 7.96 – 7.74 (m, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.41 – 7.21 (m, 1H), 4.20 (t, J = 12.3 Hz, 4H), 3.67 (s, 2H), 2.96 (d, J = 11.5 Hz, 2H), 2.87 – 2.72 (m, 3H), 2.16 (t, J = 10 10.0 Hz, 2H), 1.82 – 1.65 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 519.5 (M++ 1). Synthesis of example compound 59, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-15 carboxamide Intermediate compound 4B, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.200 g, 0.467 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide20 hexafluorophosphate (HATU, 100.00%, 0.270 g, 0.710 mmol), N,N- diisopropylethylamine (100.00% solution, 0.25 mL, 1.440 mmol), and pyrrolidin-1-

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[0357] amine dihydrochloride (100.00%, 0.120 g, 0.754 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture and extracted with ethyl acetate. The 5 organic layer was washed with a saturated aqueous sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 59, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- 10 yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.090 g, 38.82%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.45 (s, 1H), 8.10 – 8.00 (m, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.29 (t, J = 7.7 Hz, 1H), 3.67 (s, 2H), 2.96 (d, J = 11.4 Hz, 2H), 2.93 – 2.86 (m, 4H), 2.86 – 2.71 (m, 4H), 2.16 (t, J = 9.8 15 Hz, 2H), 1.84 – 1.64 (m, 7H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 497.5 (M++ 1). Synthesis of example compound 60, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin-2-20 carboxamide

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[0359] Intermediate compound 4B, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.350 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N- 5 diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 3- aminooxazolidin-2-one (100.00%, 0.050 g, 0.490 mmol) were mixed in N,N- dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 10 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) and sodium hydrogen carbonate (15 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain example compound 60, 5-[1-[(2-ethyl-5- fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-(2-oxooxazolidin- 15 3-yl)pyridin-2-carboxamide (0.090 g, 50.15%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.88 (s, 1H), 8.13 (dd, J = 9.5, 7.8 Hz, 1H), 7.94 (dd, J = 7.7, 1.3 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.37 – 7.22 (m, 1H), 4.43 (t, J = 7.8 Hz, 2H), 3.73 (t, J = 7.8 Hz, 2H), 3.67 (s, 2H), 3.02 – 2.91 (m, 2H), 2.86 – 2.71 (m, 3H), 2.23 – 2.09 (m, 2H), 1.84 – 1.63 (m, 4H), 1.22 (t, J = 7.4 Hz, 20 3H).; LRMS (ES) m / z 513.6 (M++ 1). Synthesis of example compound 61, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(3- ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-

[0360] 184 / 411

[0361] pyridin-2-carboxamide Intermediate compound 2F, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid 5 (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N-diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 3,3-difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting 10 mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain15 example compound 61, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(3-ethyl-2-oxo-1H- pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxamide (0.060 g, 32.87%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 10.11 (s, 1H), 7.89 – 7.68 (m, 2H), 7.67 – 7.54 (m, 1H), 7.29 (s, 1H), 4.85 – 4.69 (m, 1H), 4.19 (t, J = 12.3 Hz, 20 4H), 3.80 – 2.96 (m, 8H), 2.88 – 2.56 (m, 2H), 1.98 – 1.74 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 506.5 (M++ 1).

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[0363] Synthesis of example compound 62, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide 5 Intermediate compound 2F, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 10 0.789 mmol), N,N-diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and pyrrolidin-1-amine dihydrochloride (100.00%, 0.130 g, 0.817 mmol) were mixed in N,N-dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by 15 column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 62, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- yl)methyl]piperazin-1-yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.064 g, 20 36.66%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.16 – 10.76 (m, 1H), 9.26 (s, 1H), 8.06 –

[0364] 186 / 411

[0365] 7.67 (m, 2H), 7.66 – 7.11 (m, 2H), 4.78 (s, 1H), 3.82 – 2.98 (m, 10H), 2.70 – 2.53 (m, 4H), 1.98 – 1.79 (m, 2H), 1.79 – 1.64 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 484.5 (M++ 1). 5 Synthesis of example compound 63, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxooxazolidin-3- yl)pyridin-2-carboxamide Intermediate compound 2F, 5-[4-[(3-ethyl-2-oxo-1H-pyrido[2,3- 10 b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.300 g, 0.789 mmol), N,N-diisopropylethylamine (100.00% solution, 0.27 mL, 1.550 mmol), and 3-aminooxazolidin-2-one (100.00%, 0.050 g, 0.490 mmol) were mixed in N,N- 15 dimethylformamide (2 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and sodium hydrogen 20 carbonate (15 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain example compound 63, 5-[4-[(3-ethyl-2-

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[0367] oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2- oxooxazolidin-3-yl)pyridin-2-carboxamide (0.100 g, 55.44%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.65 (s, 1H), 7.89 (dd, J = 5 8.1, 1.2 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.64 – 7.53 (m, 1H), 7.22 (d, J = 2.0 Hz, 1H), 4.83 – 4.69 (m, 1H), 4.41 (t, J = 7.8 Hz, 2H), 4.10 (q, J = 5.3 Hz, 1H), 3.72 (t, J = 7.8 Hz, 2H), 3.48 (s, 2H), 3.26 – 3.19 (m, 4H), 2.61 – 2.53 (m, 3H), 1.99 – 1.74 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 500.1 (M++ 1). 10 Synthesis of example compound 64, N-(azetidin-1-yl)-5-[4-[(7-ethyl-6- oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2-carboxamide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- 15 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and azetidin-1-amine dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred 20 at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column

[0368] 188 / 411

[0369] chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and sodium hydrogen carbonate (10 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain example compound 64, N-(azetidin-1-yl)- 5 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]pyridin-2- carboxamide (0.030 g, 17.58%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.25 (s, 1H), 7.76 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.54 – 7.24 (m, 2H), 5.42 (s, 1H), 3.86 (s, 1H), 3.66 (s, 2H), 3.51 (s, 1H), 3.32 – 3.21 (m, 4H), 3.05 – 2.74 (m, 3H), 2.63 – 2.52 10 (m, 5H), 2.07 – 1.92 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 448.3 (M++ 1). Synthesis of example compound 65, N-(azetidin-1-yl)-5-[4-[(7-ethyl-6- oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-15 carboxamide Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide20 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and azetidin-1-amine

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[0371] dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column 5 chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 65, N-(azetidin-1-yl)-5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxamide (0.013 g, 7.66%) in the form 10 of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.45 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 7.58 – 7.38 (m, 2H), 5.39 (s, 1H), 4.03 – 3.59 (m, 2H), 3.58 – 3.39 (m, 2H), 3.26 – 3.02 (m, 4H), 2.98 – 2.70 (m, 3H), 2.71 – 2.52 (m, 5H), 1.98 (s, 2H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 466.2 (M++ 1). 15 Synthesis of example compound 66, N-(azetidin-1-yl)-6-fluoro-5-[4-[(5- fluoro-2-methyl-3-oxo-4H-quinoxaline-6-yl)methyl]piperazin-1-yl]pyridin-2- carboxamide 20 Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g,

[0372] 190 / 411

[0373] 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and azetidin-1-amine dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- 5 dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred 10 to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 66, N-(azetidin-1-yl)-6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxamide (0.040 g, 23.59%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.60 – 7.38 (m, 3H), 7.35 – 15 7.24 (m, 1H), 5.36 (s, 1H), 3.94 – 3.40 (m, 4H), 3.23 – 3.01 (m, 4H), 2.99 – 2.70 (m, 2H), 2.67 – 2.54 (m, 4H), 2.42 (s, 3H), 2.05 – 1.91 (m, 2H).; LRMS (ES) m / z 470.2 (M++ 1). Synthesis of example compound 67, N-(azetidin-1-yl)-5-[1-[(2-ethyl-5-20 fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2- carboxamide

[0374] 191 / 411

[0375] Intermediate compound 4E, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- 5 b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and azetidin-1- amine dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction 10 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain15 example compound 67, N-(azetidin-1-yl)-5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxamide (0.060 g, 35.54%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.99 – 7.85 (m, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 5.33 (t, J = 8.5 Hz, 20 1H), 4.60 – 4.48 (m, 1H), 3.57 – 3.39 (m, 3H), 3.03 – 2.84 (m, 3H), 2.84 – 2.65 (m, 3H), 2.14 – 2.05 (m, 2H), 2.03 – 1.93 (m, 2H), 1.91 – 1.60 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H).;

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[0377] LRMS (ES) m / z 486.2 (M++ 1). Synthesis of example compound 68, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(2- ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro- 5 pyridin-2-carboxamide Intermediate compound 4E, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- 10 b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3,3- difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the 15 reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain20 example compound 68, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(2-ethyl-5-fluoro-3-oxo-

[0378] 193 / 411

[0379] 4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxamide (0.030 g, 16.54%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.72 – 10.32 (m, 2H), 8.11 – 8.01 (m, 1H), 7.91 – 7.81 (m, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 4.56 – 4.47 (m, 5 1H), 4.19 (t, J = 12.3 Hz, 4H), 3.56 – 3.44 (m, 2H), 3.01 – 2.85 (m, 2H), 2.83 – 2.69 (m, 1H), 2.09 (t, J = 10.2 Hz, 2H), 1.91 – 1.61 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 522.2 (M++ 1). Synthesis of example compound 69, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-10 benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide Intermediate compound 4E, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%,15 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin- 1-amine dihydrochloride (100.00%, 0.130 g, 0.817 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred 20 at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column

[0380] 194 / 411

[0381] chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain 5 example compound 69, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.080 g, 46.05%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.44 (s, 1H), 8.12 – 7.99 (m, 1H), 7.86 (dd, J = 7.6, 1.3 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 10 4.55 (dd, J = 7.8, 4.6 Hz, 1H), 3.57 – 3.40 (m, 2H), 3.02 – 2.82 (m, 6H), 2.81 – 2.68 (m, 1H), 2.16 – 2.01 (m, 2H), 1.93 – 1.61 (m, 10H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 500.2 (M++ 1). Synthesis of example compound 70, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-15 benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin-2- carboxamide Intermediate compound 4E, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%,20 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol),

[0382] 195 / 411

[0383] N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- aminooxazolidin-2-one (100.00%, 0.050 g, 0.490 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction 5 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (10 mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain10 example compound 70, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4-benzoxazin-6- yl)methyl]-4-piperidyl]-6-fluoro-N-(2-oxooxazolidin-3-yl)pyridin-2-carboxamide (0.080 g, 44.63%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.83 (s, 1H), 8.17 – 8.06 (m, 1H), 7.94 (dd, J = 7.6, 1.2 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 15 4.58 – 4.50 (m, 1H), 4.43 (t, J = 7.8 Hz, 2H), 3.73 (t, J = 7.8 Hz, 2H), 3.56 – 3.42 (m, 2H), 3.04 – 2.69 (m, 3H), 2.19 – 2.03 (m, 2H), 1.91 – 1.61 (m, 6H), 1.18 (t, J = 7.1 Hz, 3H).; LRMS (ES) m / z 516.2 (M++ 1). Synthesis of example compound 71, N-(azetidin-1-yl)-5-[4-[(2-ethyl-5-20 fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2- carboxamide

[0384] 196 / 411

[0385] Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide 5 hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N- diisopropylethylamine (100.00% solution, 0.19 mL, 1.090 mmol), and azetidin-1-amine dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction 10 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 71, N-(azetidin-1-yl)-5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- 15 yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxamide (0.030 g, 17.76%) in the form of a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.61 – 7.40 (m, 3H), 7.34 – 7.23 (m, 1H), 5.46 – 5.24 (m, 1H), 3.91 – 3.40 (m, 4H), 3.24 – 3.03 (m, 4H), 2.98 – 2.71 (m, 4H), 2.64 – 2.54 (m, 4H), 2.05 – 1.92 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS 20 (ES) m / z 484.2 (M++ 1).

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[0387] Synthesis of example compound 72, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(2- ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin- 2-carboxamide 5 Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N- diisopropylethylamine (100.00% solution, 0.19 mL, 1.090 mmol), and 3,3- 10 difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) 15 and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 72, N-(3,3-difluoroazetidin-1-yl)-5-[4-[(2-ethyl-5-fluoro-3-oxo- 4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxamide (0.060 g, 33.06%) in the form of a yellow solid. 201H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.08 (s, 1H), 7.86 – 7.77

[0388] 198 / 411

[0389] (m, 1H), 7.61 – 7.49 (m, 2H), 7.35 – 7.25 (m, 1H), 4.18 (t, J = 12.3 Hz, 4H), 3.71 (s, 2H), 3.26 – 3.07 (m, 4H), 2.82 (q, J = 7.4 Hz, 2H), 2.66 – 2.54 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 520.1 (M++ 1). 5 Synthesis of example compound 73, N-(azetidin-1-yl)-5-[1-[(2-ethyl-7- fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2- carboxamide Intermediate compound 4F, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- 10 benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and azetidin-1- amine dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- 15 dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified 20 by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 73, N-(azetidin-1-yl)-5-[1-[(2-

[0390] 199 / 411

[0391] ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin- 2-carboxamide (0.080 g, 47.39%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.98 – 7.85 (m, 1H), 7.42 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 10.3 Hz, 1H), 5.34 (t, J = 8.6 Hz, 5 1H), 4.61 – 4.46 (m, 1H), 3.57 – 3.48 (m, 2H), 3.48 – 3.39 (m, 2H), 3.03 – 2.87 (m, 2H), 2.85 – 2.69 (m, 3H), 2.17 – 2.05 (m, 2H), 2.04 – 1.93 (m, 2H), 1.88 – 1.62 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 486.2 (M++ 1). Synthesis of example compound 74, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(2-10 ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro- pyridin-2-carboxamide Intermediate compound 4F, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%,15 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3,3- difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was 20 stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with ethyl acetate,

[0392] 200 / 411

[0393] filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 74, N-(3,3-difluoroazetidin- 5 1-yl)-5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6- fluoro-pyridin-2-carboxamide (0.100 g, 55.15%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.30 (s, 1H), 8.10 – 8.01 (m, 1H), 7.89 (dd, J = 7.6, 1.3 Hz, 1H), 6.92 (d, J = 7.3 Hz, 1H), 6.87 (d, J = 10.3 Hz, 1H), 4.58 – 4.51 (m, 1H), 4.20 (t, J = 12.3 Hz, 4H), 3.45 (s, 2H), 3.00 – 2.84 (m, 2H), 10 2.84 – 2.70 (m, 1H), 2.10 (t, J = 11.6 Hz, 2H), 1.90 – 1.58 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 522.2 (M++ 1). Synthesis of example compound 75, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- 15 carboxamide Intermediate compound 4F, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- 20 b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-

[0394] 201 / 411

[0395] 1-amine dihydrochloride (100.00%, 0.080 g, 0.503 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with ethyl acetate, filtered 5 through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain example compound 75, 5-[1-[(2-ethyl-7-fluoro-3-oxo- 4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- 10 carboxamide (0.100 g, 57.57%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 9.45 (s, 1H), 8.09 – 7.99 (m, 1H), 7.88 (dd, J = 7.6, 1.3 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.88 (d, J = 10.3 Hz, 1H), 4.59 – 4.48 (m, 1H), 3.46 (s, 2H), 3.00 – 2.84 (m, 6H), 2.83 – 2.70 (m, 1H), 2.19 – 2.01 (m, 2H), 1.89 – 1.61 (m, 10H), 0.98 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 500.2 (M++ 15 1). Synthesis of example compound 76, N-(azetidin-1-yl)-5-[1-[(2-ethyl-8- fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2- carboxamide 20 Intermediate compound 4G, 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4-

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[0397] benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and azetidin-1- 5 amine dihydrochloride (100.00%, 0.100 g, 0.690 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, 10 and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 76, N-(azetidin-1-yl)-5-[1-[(2- ethyl-8-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin- 2-carboxamide (0.110 g, 65.16%) in the form of a white solid. 151H-NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.97 – 7.86 (m, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 11.2 Hz, 1H), 6.72 (s, 1H), 5.34 (t, J = 8.5 Hz, 1H), 4.66 – 4.53 (m, 1H), 3.57 – 3.47 (m, 2H), 3.41 (s, 2H), 3.05 – 2.85 (m, 2H), 2.84 – 2.63 (m, 3H), 2.17 – 1.94 (m, 4H), 1.91 – 1.64 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 486.2 (M++ 1). 20 Synthesis of example compound 77, N-(3,3-difluoroazetidin-1-yl)-5-[1-[(2- ethyl-8-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro- pyridin-2-carboxamide

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[0399] Intermediate compound 4G, 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- 5 b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol), N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3,3- difluoroazetidin-1-amine hydrochloride (100.00%, 0.080 g, 0.553 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen 10 carbonate solution was poured into the reaction mixture, extracted with ethyl acetate, filtered through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 77, N-(3,3-difluoroazetidin-15 1-yl)-5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6- fluoro-pyridin-2-carboxamide (0.100 g, 55.15%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.30 (s, 1H), 8.12 – 8.00 (m, 1H), 7.89 (dd, J = 7.6, 1.3 Hz, 1H), 6.83 (dd, J = 11.3, 1.6 Hz, 1H), 6.71 (s, 1H), 4.65 – 4.56 (m, 1H), 4.20 (t, J = 12.3 Hz, 4H), 3.41 (s, 2H), 3.00 – 2.85 (m, 2H), 2.85 – 20 2.69 (m, 1H), 2.16 – 1.97 (m, 2H), 1.91 – 1.64 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 522.2 (M++ 1).

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[0401] Synthesis of example compound 78, 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide 5 Intermediate compound 4G, 5-[1-[(2-ethyl-8-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.348 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.200 g, 0.526 mmol),10 N,N-diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin- 1-amine dihydrochloride (100.00%, 0.080 g, 0.503 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, extracted with ethyl acetate, filtered 15 through a plastic filter to remove solid residues and an aqueous solution layer therefrom, and then concentrated under reduced pressure. The resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 78, 5-[1-[(2-ethyl-8-fluoro-3-oxo- 4H-1,4-benzoxazin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- 20 carboxamide (0.110 g, 63.32%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.45 (s, 1H), 8.12 – 8.00 (m,

[0402] 205 / 411

[0403] 1H), 7.88 (dd, J = 7.6, 1.3 Hz, 1H), 6.83 (dd, J = 11.3, 1.6 Hz, 1H), 6.71 (s, 1H), 4.66 – 4.53 (m, 1H), 3.41 (s, 2H), 3.02 – 2.83 (m, 6H), 2.82 – 2.69 (m, 1H), 2.16 – 1.97 (m, 2H), 1.94 – 1.59 (m, 10H), 1.00 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 500.2 (M++ 1). 5 Synthesis of example compound 79, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(2-oxopyrrolidin-1-yl)pyridin-2- carboxamide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-10 yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1- aminopyrrolidin-2-one hydrochloride (100.00%, 0.080 g, 0.586 mmol) were mixed in 15 N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and 20 stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 79, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-

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[0405] yl)methyl]piperazin-1-yl]-N-(2-oxopyrrolidin-1-yl)pyridin-2-carboxamide (0.060 g, 33.09%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.33 (s, 1H), 8.42 (s, 1H), 8.32 (d, J = 2.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J 5 = 8.9, 2.8 Hz, 1H), 3.66 (s, 2H), 3.50 (t, J = 7.1 Hz, 2H), 3.45 – 3.35 (m, 4H), 2.65 – 2.53 (m, 6H), 2.31 (t, J = 8.0 Hz, 2H), 2.10 – 1.97 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 476.2 (M++ 1). Synthesis of example compound 80, 5-[4-[(7-ethyl-6-oxo-5H-1,5-10 naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxopyrrolidin-1- yl)pyridin-2-carboxamide Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 15 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1- aminopyrrolidin-2-one hydrochloride (100.00%, 0.080 g, 0.586 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was 20 stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by

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[0407] column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain example compound 80, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxopyrrolidin-1-yl)pyridin-2- carboxamide (0.120 g, 66.69%) in the form of a white solid. 51H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 10.43 (s, 1H), 8.45 – 8.34 (m, 1H), 7.87 (dd, J = 8.1, 1.3 Hz, 1H), 7.76 (s, 1H), 7.67 – 7.61 (m, 1H), 7.61 – 7.53 (m, 1H), 4.10 (q, J = 5.3 Hz, 1H), 3.67 (s, 2H), 3.49 (t, J = 7.1 Hz, 2H), 3.22 (d, J = 4.6 Hz, 4H), 2.64 – 2.57 (m, 4H), 2.56 – 2.52 (m, 1H), 2.31 (t, J = 8.0 Hz, 2H), 2.11 – 1.97 (m, 2H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 494.3 (M++ 1). 10 Synthesis of example compound 81, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(2-oxopyrrolidin-1-yl)pyridin- 2-carboxamide 15 Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1- 20 aminopyrrolidin-2-one hydrochloride (100.00%, 0.080 g, 0.586 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was

[0408] 208 / 411

[0409] stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and 5 stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 81, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-(2-oxopyrrolidin-1-yl)pyridin-2-carboxamide (0.030 g, 16.70%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 10.43 (s, 1H), 7.86 (dd, J = 10 8.1, 1.2 Hz, 1H), 7.63 – 7.55 (m, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 – 7.22 (m, 1H), 3.72 (s, 2H), 3.48 (t, J = 7.0 Hz, 2H), 3.27 – 3.09 (m, 4H), 2.71 – 2.54 (m, 4H), 2.42 (s, 3H), 2.30 (t, J = 8.0 Hz, 2H), 2.09 – 1.98 (m, 2H).; LRMS (ES) m / z 498.2 (M++ 1). Synthesis of example compound 82, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-15 quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxopyrrolidin-1-yl)pyridin- 2-carboxamide Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 20 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N-

[0410] 209 / 411

[0411] diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 1- aminopyrrolidin-2-one hydrochloride (100.00%, 0.080 g, 0.586 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the 5 reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 2% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 82, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- 10 yl)methyl]piperazin-1-yl]-6-fluoro-N-(2-oxopyrrolidin-1-yl)pyridin-2-carboxamide (0.045 g, 25.18%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 10.42 (s, 1H), 7.93 – 7.77 (m, 1H), 7.66 – 7.49 (m, 2H), 7.39 – 7.20 (m, 1H), 3.71 (s, 2H), 3.48 (t, J = 7.0 Hz, 2H), 3.27 – 3.07 (m, 4H), 2.83 (q, J = 7.4 Hz, 2H), 2.67 – 2.55 (m, 4H), 2.30 (t, J = 8.0 Hz, 15 2H), 2.10 – 1.97 (m, 2H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 512.3 (M++ 1). Synthesis of example compound 83, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-(3-fluoropyrrolidin-1-yl)pyridin-2- carboxamide 20 Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-

[0412] 210 / 411

[0413] yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- 5 fluoropyrrolidin-1-amine (100.00% solution, 0.06 mL, 0.645 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) 10 and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 83, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-N-(3-fluoropyrrolidin-1-yl)pyridin-2-carboxamide (0.056 g, 30.62%) in the form of a white solid. 151H-NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.41 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.63 (d, J = 1.2 Hz, 1H), 7.40 (dd, J = 8.9, 2.9 Hz, 1H), 5.25 (dt, J = 55.2, 5.7 Hz, 1H), 3.66 (s, 2H), 3.42 – 3.33 (m, 4H), 3.28 – 3.08 (m, 3H), 2.96 – 2.84 (m, 1H), 2.63 – 2.53 (m, 6H), 2.35 – 2.16 (m, 1H), 2.03 – 1.84 (m, 1H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 20 480.2 (M++ 1). Synthesis of example compound 84, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-(3-fluoropyrrolidin-1-

[0414] 211 / 411

[0415] yl)pyridin-2-carboxamide Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 5 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- fluoropyrrolidin-1-amine (100.00% solution, 0.06 mL, 0.645 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was 10 stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain15 example compound 84, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-N-(3-fluoropyrrolidin-1-yl)pyridin-2-carboxamide (0.027 g, 14.88%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.48 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 7.87 – 7.80 (m, 1H), 7.76 (s, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.60 – 7.50 (m, 20 1H), 5.37 – 5.12 (m, 1H), 3.66 (s, 2H), 3.30 – 3.06 (m, 7H), 2.94 – 2.82 (m, 1H), 2.66 – 2.53 (m, 6H), 2.34 – 2.14 (m, 1H), 2.02 – 1.82 (m, 1H), 1.19 (t, J = 7.4 Hz, 3H).;

[0416] 212 / 411

[0417] LRMS (ES) m / z 498.2 (M++ 1). Synthesis of example compound 85, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-(3-fluoropyrrolidin-1- 5 yl)pyridin-2-carboxamide Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-10 oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- fluoropyrrolidin-1-amine (100.00% solution, 0.06 mL, 0.645 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the 15 reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 30%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 85, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- 20 yl)methyl]piperazin-1-yl]-N-(3-fluoropyrrolidin-1-yl)pyridin-2-carboxamide (0.022 g, 12.15%) in the form of a white solid.

[0418] 213 / 411

[0419] 1H-NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.47 (s, 1H), 7.83 (d, J = 7.1 Hz, 1H), 7.60 – 7.46 (m, 2H), 7.35 – 7.21 (m, 1H), 5.37 – 5.11 (m, 1H), 3.70 (s, 2H), 3.29 – 3.05 (m, 7H), 2.94 – 2.82 (m, 1H), 2.65 – 2.54 (m, 4H), 2.42 (s, 3H), 2.34 – 2.14 (m, 1H), 2.02 – 1.82 (m, 1H).; LRMS (ES) m / z 502.1 (M++ 1). 5 Synthesis of example compound 86, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-(3-fluoropyrrolidin-1- yl)pyridin-2-carboxamide 10 Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- 15 fluoropyrrolidin-1-amine (100.00% solution, 0.06 mL, 0.645 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) 20 and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain

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[0421] example compound 86, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-N-(3-fluoropyrrolidin-1-yl)pyridin-2-carboxamide (0.035 g, 19.44%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 9.68 (s, 1H), 8.16 – 7.99 (m, 5 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.37 – 7.21 (m, 1H), 5.38 – 5.11 (m, 1H), 3.67 (s, 2H), 3.31 – 3.08 (m, 3H), 3.03 – 2.86 (m, 3H), 2.85 – 2.69 (m, 3H), 2.35 – 2.09 (m, 3H), 2.04 – 1.85 (m, 1H), 1.82 – 1.64 (m, 3H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 515.2 (M++ 1). 10 Synthesis of example compound 87, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-N-[3-(trifluoromethyl)pyrrolidin-1- yl]pyridin-2-carboxamide Intermediate compound 1A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-15 yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.381 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- (trifluoromethyl)pyrrolidin-1-amine (100.00%, 0.070 g, 0.454 mmol) were mixed in 20 N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the

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[0423] reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain 5 example compound 87, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-N-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-2- carboxamide (0.035 g, 17.33%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.49 (s, 1H), 8.43 (s, 1H), 8.27 (s, 1H), 7.98 – 7.59 (m, 3H), 7.47 – 7.25 (m, 1H), 3.83 – 3.45 (m, 2H), 3.41 – 3.33 10 (m, 4H), 3.26 – 3.11 (m, 2H), 3.11 – 2.95 (m, 3H), 2.69 – 2.51 (m, 6H), 2.14 – 2.02 (m, 1H), 1.89 – 1.77 (m, 1H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 530.2 (M++ 1). Synthesis of example compound 88, 5-[4-[(7-ethyl-6-oxo-5H-1,5- naphthyridin-3-yl)methyl]piperazin-1-yl]-6-fluoro-N-[3- 15 (trifluoromethyl)pyrrolidin-1-yl]pyridin-2-carboxamide Intermediate compound 2A, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.365 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide20 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3-

[0424] 216 / 411

[0425] (trifluoromethyl)pyrrolidin-1-amine (100.00%, 0.070 g, 0.454 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by 5 column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 88, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3- yl)methyl]piperazin-1-yl]-6-fluoro-N-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-2- 10 carboxamide (0.060 g, 30.05%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.54 (s, 1H), 8.41 (d, J = 1.8 Hz, 1H), 7.83 (dd, J = 8.1, 1.2 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.59 – 7.51 (m, 1H), 3.66 (s, 2H), 3.25 – 3.06 (m, 7H), 3.02 (t, J = 6.9 Hz, 2H), 2.64 – 2.53 (m, 6H), 2.13 – 2.02 (m, 1H), 1.87 – 1.76 (m, 1H), 1.19 (t, J = 7.4 Hz, 3H).; LRMS (ES) 15 m / z 548.1 (M++ 1). Synthesis of example compound 89, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl]-N-[3-(trifluoromethyl)pyrrolidin- 1-yl]pyridin-2-carboxamide 20 Intermediate compound 2B, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-

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[0427] quinoxalin-6-yl)methyl]piperazin-1-yl]pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.361 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- 5 (trifluoromethyl)pyrrolidin-1-amine (100.00%, 0.070 g, 0.454 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) 10 and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 89, 6-fluoro-5-[4-[(5-fluoro-2-methyl-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-N-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-2- carboxamide (0.004 g, 2.01%) in the form of a yellowish solid. 151H-NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 9.53 (s, 1H), 7.88 – 7.77 (m, 1H), 7.61 – 7.45 (m, 2H), 7.34 – 7.23 (m, 1H), 3.70 (s, 2H), 3.25 – 3.05 (m, 7H), 3.02 (t, J = 6.9 Hz, 2H), 2.65 – 2.54 (m, 4H), 2.42 (s, 3H), 2.15 – 2.02 (m, 1H), 1.88 – 1.75 (m, 1H).; LRMS (ES) m / z 552.1 (M++ 1). 20 Synthesis of example compound 90, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-[3- (trifluoromethyl)pyrrolidin-1-yl]pyridin-2-carboxamide

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[0429] Intermediate compound 2C, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide 5 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and 3- (trifluoromethyl)pyrrolidin-1-amine (100.00%, 0.070 g, 0.454 mmol) were mixed in N,N-dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the 10 reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which ethyl acetate (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL) were added and filtered through a plastic filter to obtain the organic layer, which was then concentrated to obtain example15 compound 90, 5-[4-[(2-ethyl-5-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-N-[3-(trifluoromethyl)pyrrolidin-1-yl]pyridin-2-carboxamide (0.020 g, 10.12%) in the form of a yellowish solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.43 (s, 1H), 9.74 (s, 1H), 8.16 – 8.00 (m, 1H), 7.92 – 7.80 (m, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.37 – 7.21 (m, 1H), 3.67 (s, 2H), 20 3.25 – 3.11 (m, 2H), 3.11 – 3.01 (m, 2H), 2.99 – 2.89 (m, 2H), 2.86 – 2.70 (m, 3H), 2.26 – 2.02 (m, 3H), 1.86 – 1.61 (m, 5H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z

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[0431] 565.1 (M++ 1). Synthesis of example compound 91, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- 5 carboxamide Intermediate compound 2D, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.349 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide10 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.080 g, 0.503 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction 15 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 91, 5-[4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- 20 yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.050 g, 28.77%) in the form of a yellowish solid.

[0432] 220 / 411

[0433] 1H-NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.24 (s, 1H), 7.83 (dd, J = 8.1, 1.1 Hz, 1H), 7.63 – 7.50 (m, 2H), 7.38 (d, J = 6.9 Hz, 1H), 3.69 (s, 2H), 3.26 – 3.07 (m, 4H), 2.96 – 2.85 (m, 4H), 2.81 (q, J = 7.4 Hz, 2H), 2.68 – 2.55 (m, 4H), 1.81 – 1.67 (m, 4H), 1.22 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 498.2 (M++ 1). 5 Synthesis of example compound 92, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide 10 Intermediate compound 4C, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid(100.00%, 0.150 g, 0.350 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-1-15 amine dihydrochloride (100.00%, 0.080 g, 0.503 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and 20 concentrated to obtain the product, to which ethyl acetate (5 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL) were added and filtered through a plastic

[0434] 221 / 411

[0435] filter to obtain the organic layer, which was then concentrated to obtain example compound 92, 5-[1-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]-4-piperidyl]- 6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.050 g, 28.76%) in the form of a yellowish solid. 51H-NMR (400 MHz, DMSO-d6) δ 12.28 (s, 1H), 9.45 (s, 1H), 8.09 – 7.98 (m, 1H), 7.89 (dd, J = 7.6, 1.3 Hz, 1H), 7.53 (d, J = 10.4 Hz, 1H), 7.38 (d, J = 6.9 Hz, 1H), 3.64 (s, 2H), 3.03 – 2.94 (m, 2H), 2.94 – 2.85 (m, 4H), 2.84 – 2.73 (m, 3H), 2.25 – 2.12 (m, 2H), 1.86 – 1.64 (m, 8H), 1.21 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 497.2 (M++ 1). 10 Synthesis of example compound 93, 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-7-yl)methyl]-4-piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide [Step 1] Synthesis of methyl 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3- 15 b][1,4]oxazin-7-yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylate Intermediate compound 4, methyl 6-fluoro-5-(4-piperidyl)pyridin-2- carboxylate hydrochloride (100.00%, 0.500 g, 1.820 mmol), 7-(bromomethyl)-3-ethyl- 1H-pyrido[2,3-b][1,4]oxazin-2-one hydrobromide (100.00%, 0.650 g, 1.847 mmol), 20 and N,N-diisopropylethylamine (100.00% solution, 1.6 mL, 9.161 mmol) were mixed in acetonitrile (6 mL) at room temperature, and the resulting mixture was stirred at 80°C

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[0437] for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure, and then the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 1% to 5%) and concentrated to 5 obtain methyl 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylate (0.770 g, 98.73%) in the form of a yellowish solid. [Step 2] Synthesis of 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid 10 Methyl 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylate (100.00%, 0.770 g, 1.797 mmol) and sodium hydroxide (5.00 M solution in water, 0.72 mL, 3.600 mmol) were mixed in tetrahydrofuran (2 mL) / methanol (2 mL) / water (2 mL) at room temperature, and the 15 resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction mixture under reduced pressure, the resulting product was used without further purification (5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7- yl)methyl]-4-piperidyl]-6-fluoro-pyridin-2-carboxylic acid, 0.740 g, 99.37%, yellowish solid). 20 [Step 3] Synthesis of example compound 93

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[0439] 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]-4- piperidyl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.150 g, 0.362 mmol), 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide 5 hexafluorophosphate (HATU, 100.00%, 0.220 g, 0.579 mmol), N,N- diisopropylethylamine (100.00% solution, 0.2 mL, 1.150 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.120 g, 0.754 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred at the same temperature for 18 hours. After removing the solvent from the reaction 10 mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 1% to 10%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with acetonitrile, and dried to obtain example compound 93, 5-[1-[(3-ethyl-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-7-yl)methyl]-4- 15 piperidyl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (0.050 g, 28.62%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 10.54 (s, 1H), 9.50 (s, 1H), 8.04 – 7.89 (m, 3H), 7.44 (s, 1H), 4.90 – 4.75 (m, 1H), 4.29 (s, 2H), 3.62 – 3.39 (m, 2H), 3.19 – 2.99 (m, 3H), 2.99 – 2.81 (m, 4H), 2.06 – 1.96 (m, 3H), 1.94 – 1.80 (m, 2H), 20 1.80 – 1.69 (m, 4H), 1.01 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 483.2 (M++ 1).

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[0441] Synthesis of example compound 94, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H- quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-(3-fluoropyrrolidin-1- yl)pyridin-2-carboxamide 5 Intermediate compound 2E, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.110 g, 0.256 mmol), N,N-diisopropylethylamine (100.00% solution, 0.134 mL, 0.767 mmol), 3- fluoro-1-pyrrolidinamine (100.00%, 0.040 g, 0.384 mmol), and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide10 hexafluorophosphate (HATU, 100.00%, 0.146 g, 0.384 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and 15 concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with diethyl ether, and dried to obtain example compound 94, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-N-(3-fluoropyrrolidin-1-yl)pyridin-2-carboxamide (8.000 mg, 6.06%) in the form of a white solid. 201H-NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.47 (s, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.57 (q, J = 6.2 Hz, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 5.24 (q, J = 19.3 Hz, 1H),

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[0443] 3.61 (s, 2H), 3.18 – 3.12 (m, 5H), 2.89 – 2.8769 (m, 1H), 2.81 (q, J = 7.3 Hz, 2H), 2.57 (s, 4H), 2.41 – 2.19 (m, 4H), 1.21 (t, J = 5.2 Hz, 3H).; LRMS (ES) m / z 516.6 (M++ 1). Synthesis of example compound 95, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H- 5 quinoxalin-6-yl)methyl]piperazin-1-yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide Intermediate compound 2E, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6- yl)methyl]piperazin-1-yl]-6-fluoro-pyridin-2-carboxylic acid (100.00%, 0.110 g, 0.260 10 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 100.00%, 0.146 g, 0.384 mmol), N,N- diisopropylethylamine (100.00% solution, 0.134 mL, 0.767 mmol), and pyrrolidin-1- amine dihydrochloride (100.00%, 0.033 g, 0.383 mmol) were mixed in N,N- dimethylformamide (3 mL) at room temperature, and the resulting mixture was stirred 15 overnight at the same temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 12 g cartridge; methanol / dichloromethane = 0% to 5%) and concentrated to obtain the product, to which acetonitrile (10 mL) was added and stirred to filter the precipitated solid, washed with diethyl ether, and dried to obtain example20 compound 95, 5-[4-[(2-ethyl-8-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1- yl]-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-carboxamide (15.000 mg, 12.00%) in the form

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[0445] of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.22 (s, 1H), 7.82 (q, J = 3.0 Hz, 1H), 7.57 (q, J = 6.3 Hz, 1H), 7.11 (s, 1H), 7.09 (s, 1H), 3.61 (s, 2H), 3.18 (s, 4H), 2.89 (s, 4H), 2.81 (d, J = 7.4 Hz, 2H), 2.57 (s, 4H), 1.78 (s, 4H), 1.21 (t, J = 5.2 Hz, 5 3H).; LRMS (ES) m / z 498.0 (M++ 1). Synthesis of example compound 96, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H-1,4- benzoxazin-6-yl)methyl]azetidin-3-yl]oxy-6-fluoro-N-pyrrolidin-1-yl-pyridin-2- carboxamide 10 Intermediate compound 10, 5-(azetidin-3-yloxy)-6-fluoro-N-pyrrolidin-1-yl- pyridin-2-carboxamide 2,2,2-trifluoroacetic acid (100.00%, 0.050 g, 0.098 mmol), 6- (bromomethyl)-2-ethyl-5-fluoro-4H-1,4-benzoxazin-3-one (100.00%, 1.000 equiv., 0.098 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.06853 mL, 0.394 15 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and the resulting solution was stirred at 70°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the resulting concentrate was purified by column chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 30%)20 and concentrated to obtain example compound 96, 5-[1-[(2-ethyl-5-fluoro-3-oxo-4H- 1,4-benzoxazin-6-yl)methyl]azetidin-3-yl]oxy-6-fluoro-N-pyrrolidin-1-yl-pyridin-2-

[0446] 227 / 411

[0447] carboxamide (0.022 g, 45.88%) in the form of a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.31 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = 10.1, 8.3 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 4.98 - 4.95 (m, 1H), 4.54 - 4.51 (m, 1H), 3.74 - 3.71 (m, 2H), 3.61 (s, 2H), 3.15 - 5 3.11 (m, 2H), 2.88 (s, 4H), 1.83 - 1.72 (m, 6H), 0.91 (t, J = 7.4 Hz, 3H).; LRMS (ES) m / z 488.2 (M++ 1). Synthesis of example compound 97, 6-fluoro-5-[1-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]azetidin-3-yl]oxy-N-pyrrolidin-1-yl-pyridin-2- 10 carboxamide Intermediate compound 10, 5-(azetidin-3-yloxy)-6-fluoro-N-pyrrolidin-1-yl- pyridin-2-carboxamide 2,2,2-trifluoroacetic acid (100.00%, 0.050 g, 0.098 mmol), 7- (bromomethyl)-8-fluoro-3-methyl-1H-quinoxalin-2-one (100.00%, 1.000 equiv., 0.098 15 mmol), and N,N-diisopropylethylamine (100.00% solution, 0.06853 mL, 0.394 mmol) were dissolved in acetonitrile (5 mL) at room temperature, and the resulting solution was stirred at 70°C for 18 hours, after which the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture and extracted with dichloromethane. The organic layer was washed with a saturated aqueous 20 sodium chloride solution, dehydrated with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified by column

[0448] 228 / 411

[0449] chromatography (SiO2, 4 g cartridge; methanol / dichloromethane = 0% to 20%) and concentrated to obtain example compound 97, 6-fluoro-5-[1-[(5-fluoro-2-methyl-3- oxo-4H-quinoxalin-6-yl)methyl]azetidin-3-yl]oxy-N-pyrrolidin-1-yl-pyridin-2- carboxamide (0.014 g, 30.25%) in the form of a white solid. 51H-NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 9.31 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.56 (dd, J = 10.4, 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H), 5.01 - 4.98 (m, 1H), 3.80 - 3.76 (m, 4H), 3.21 - 3.18 (m, 2H), 2.88 (s, 4H), 2.40 (s, 3H), 1.74 (s, 4H).; LRMS (ES) m / z 471.1 (M++ 1). 10 Synthesis of example comp...

Claims

【Claims】

1. A compound represented by formula 1 below, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: 5 [Formula 1]wherein in above formula 1, M is CRx, N, NRy, O or S, X1, X2and X3are each independently N or CRz, 10 Rx, Ryand Rzare each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, R1is H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2- C5 alkynyl or O-(C1-C5 alkyl),, 15 Y1, Y2, Y3, Y4and Y5are each independently C, CH, CH2, N, NH, O or S, B is cycloalkylene, cycloalkenylene, heterocycloalkylene, heterocycloalkenylene, arylene or heteroarylene, L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond,389 / 411R2and R3are each independently H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl or O-(C1-C5 alkyl), RAand RBare each independently H, C1-C5 alkyl, C1-C5 haloalkyl, - C(=O)O-(C1-C5 alkyl), -S(=O)2-(C1-C5 alkyl), cycloalkyl, cycloalkenyl, 5 heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl, or RAand RBare bonded to each other to form, Z is CH2, NH, O, S, C(=O) or S(=O)2, at least oneformed by bonding RAand RBis each independently substituted with halogen, OH, CN, (=O), C1-C5 alkyl, C1-C510 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, (C1-C5 alkylene)-O-(C1-C5 alkyl), O-(C1- C5 alkyl), -C(=O)O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, 15 provided that a and b; c and d; e and f; and g and h are not 0 at the same time, and halogen is F, Cl, Br or I.

2. The compound represented by formula 1, the stereoisomer thereof, or the 20 pharmaceutically acceptable salt thereof of claim 1, wherein in above formula 1,390 / 411M is CRx, N, NRy, O or S, X1, X2and X3are each independently N or CRz, Rx, Ryand Rzare each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, 5 R1is H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2- C5 alkynyl or O-(C1-C5 alkyl),, Y1, Y2, Y3, Y4and Y5are each independently C, CH, CH2, N, NH, O or S, B is three- to seven-membered cycloalkylene, three- to seven-membered 10 cycloalkenylene, three- to seven-membered heterocycloalkylene including one to three heteroatoms independently selected from the group consisting of N, O and S, three- to seven-membered heterocycloalkenylene including one to three heteroatoms independently selected from the group consisting of N, O and S, C6-C12 arylene, or five- to 12-membered heteroarylene including one to three heteroatoms independently 15 selected from the group consisting of N, O and S, L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, R2and R3are each independently H, halogen, OH, CN, C1-C5 alkyl, C1-C5 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl or O-(C1-C5 alkyl), RAand RBare each independently H, C1-C5 alkyl, C1-C5 haloalkyl, - 20 C(=O)O-(C1-C5 alkyl), -S(=O)2-(C1-C5 alkyl), three- to seven-membered cycloalkyl, three- to seven-membered cycloalkenyl, three- to seven-membered heterocycloalkyl391 / 411including one to three heteroatoms independently selected from the group consisting of N, O and S, three- to seven-membered heterocycloalkenyl including one to three heteroatoms independently selected from the group consisting of N, O and S, C6-C12 aryl, or five- to 12-membered heteroaryl including one to three heteroatoms 5 independently selected from the group consisting of N, O and S, or RAand RBare bonded to each other to form, Z is CH2, NH, O, S, C(=O) or S(=O)2, at least oneformed by bonding RAand RBis each independently substituted with halogen, OH, CN, (=O), C1-C5 alkyl, C1-C510 haloalkyl, C2-C5 alkenyl, C2-C5 alkynyl, (C1-C5 alkylene)-O-(C1-C5 alkyl), O-(C1- C5 alkyl), -C(=O)O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, 15 provided that a and b; c and d; e and f; and g and h are not 0 at the same time, and halogen is F, Cl, Br or I.

3. The compound represented by formula 1, the stereoisomer thereof, or the 20 pharmaceutically acceptable salt thereof of claim 1 or 2, wherein in above formula 1,392 / 411M is CRx, N, O or S, X1, X2and X3are each independently N or CRz, Rxand Rzare each independently H or halogen, R1is C1-C5 alkyl, 5, Y1, Y2, Y3, Y4and Y5are each independently C, CH, CH2, N or O, B is C6-C12 arylene or five- to 12-membered heteroarylene including one to three heteroatoms independently selected from the group consisting of N, O and S, L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, 10 R2and R3are each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, RAand RBare each independently H, C1-C5 alkyl, -C(=O)O-(C1-C5 alkyl), three- to seven-membered heterocycloalkyl including one to three heteroatoms independently selected from the group consisting of N, O and S, C6-C12 aryl, or five- to 12-membered heteroaryl including one to three heteroatoms independently selected 15 from the group consisting of N, O and S, or RAand RBare bonded to each other to format east one oA,Ban formed by bonding RAand RBis393 / 411each independently substituted with halogen, (=O), C1-C5 alkyl, C1-C5 haloalkyl, (C1- C5 alkylene)-O-(C1-C5 alkyl), O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, 5 a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, provided that a and b; c and d; e and f; and g and h are not 0 at the same time, and halogen is F or Cl.

4. 10 The compound represented by formula 1, the stereoisomer thereof, or the pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein in above formula 1, M is CRx, N, O or S, X1, X2and X3are each independently N or CRz, 15 Rxand Rzare each independently H or halogen, R1is C1-C5 alkyl,, Y1, Y4and Y5are each independently N, Y2is C, CH or N, 20 Y3is each independently CH2or O, B is phenylene or five- to six-membered heteroarylene including one to two394 / 411heteroatoms independently selected from the group consisting of N, O and S L is -O-, -(C1-C3 alkylene)-, -(C1-C3 alkylene)-NH- or a single bond, R2and R3are each independently H, halogen, C1-C5 alkyl or C1-C5 haloalkyl, RAand RBare each independently H, C1-C5 alkyl, -C(=O)O-(C1-C5 alkyl), 5 four- to five-membered heterocycloalkyl including one O, phenyl or five- to six- membered heteroaryl including one to two Ns, or RAand RBare bonded to each other to form, Z is CH2, NH, O, C(=O) or S(=O)2, at least one H of RA, RBand formed by bonding RAand RBis10 each independently substituted with halogen, (=O), C1-C5 alkyl, C1-C5 haloalkyl, (C1- C5 alkylene)-O-(C1-C5 alkyl), O-(C1-C5 alkyl) or -S(=O)2-(C1-C5 alkyl), K is O or S, is a single bond or a double bond, a, b, c, d, e, f, g and h are each independently an integer of 0, 1, 2, 3 or 4, 15 provided that a and b; c and d; e and f; and g and h are not 0 at the same time, and halogen is F or Cl.

5. A compound described in a table below, a stereoisomer thereof, or a 20 pharmaceutically acceptable salt thereof:395 / 411396 / 411H O N N397 / 411402 / 411403 / 411404 / 411405 / 411406 / 411407 / 411

6. A pharmaceutical composition for preventing or treating PARP1 activity- related diseases, comprising a compound, a stereoisomer thereof, or a pharmaceutically 5 acceptable salt thereof according to any one of claims 1 to 5 as an active ingredient.

7. The pharmaceutical composition of claim 6, wherein the PARP1 activity- related disease is cancer or inflammatory disease. 10

8. The pharmaceutical composition of claim 7, wherein the cancer is at least one selected from the group consisting of breast cancer, ovary cancer, pancreas cancer, prostate cancer, hematological cancer, gastrointestinal cancer, lung cancer, and brain408 / 411cancer.

9. The pharmaceutical composition of claim 7, wherein the inflammatory 5 disease is at least one selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colonitis, ulcerative colitis, Graft-versus- host disease (GVHD), systemic lupus erythematosus, toxic shock syndrome, osteoarthritis, and insulin-dependent diabetes mellitus. 10

10. A method for preventing or treating PARP1 activity-related diseases, the method comprising: administering a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5; or a pharmaceutical composition according to any one of claims 6 to 15 9.

11. A use of a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5; or a 20 pharmaceutical composition according to any one of claims 6 to 9 for preventing or treating PARP1 activity-related diseases.409 / 411

12. A use of a compound represented by formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5; or a pharmaceutical composition according to any one of claims 6 to 9 in preparing a 5 medication for preventing or treating PARP1 activity-related diseases.410 / 411

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