MAT2A HETEROBICYCLIC INHIBITOR COMPOUNDS

Abstract

This document provides compounds according to formula (1) or formula (2) and their pharmaceutically acceptable salts, stereoisomers, and / or tautomers, as described herein. Pharmaceutical compositions and methods for using the compounds to treat cancers are also provided, including certain cancers in which the gene encoding methylthioadenosine phosphorylase (MTAP) is deleted.

Description

A mixture of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 192, 100 mg, 0.2 mmol, 1.0 equivalent), azetidine (114.0 mg, 2.0 mmol, 10.0 equivalents), Pd2(dba)a (18.0 mg, 0.02 mmol, 0.1 equivalent), Ru-Phos (18.0 mg, 0.04 mmol, 0.2 equivalent) and K3PO4 (127 mg, 0.6 mmol, 3.0 equivalents) in toluene (2.0 mL) was shaken at 100°C in a sealed tube overnight under a nitrogen atmosphere. The mixture was concentrated and the residue was purified by preparative HPLC under reduced pressure, which gave 8-(4-(azetidin-l-yl)phenyl)-6-time toxiphenyl ) -2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one (Example 204). iR NMR (400 MHz, DMSO-ds) δ 8.93 (s, 1H), 8.70 (s, 1H), 8.43 (t, J = 6.4 Hz, 1H), 7.51 (d, J= 8.4 Hz, 2H), 7.45 (d, J= 8.8 Hz, 2H), 7.09 (d, J= 8.8 Hz, 2H), 6.35 (d, J= 8.4 Hz, 2H), 4.184.04 (m, 2H), 3.84 (s, 3H), 3.82 (t, J= 7.2 Hz, 4H), 2.36-2.26 DANIEL GOYTIA - 30709700037 Digitally signed byTOF^LTRAIWffESAW^ [m+h] + . Date: 2019.04.11 14:00:42 -03:00 Reason: Digitally Signed by INPI 228 Location: Buenos Aires, Argentina Preparation of Example 205 Step A: dimethyl 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2trifluoroethyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8yl)phenyl)malonate To a solution of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (200.0 mg, 0.396 mmol, 1.0 equivalent) in toluene (5.0 mL) were added K3PO4 (168.0 mg, 0.792 mmol, 2.0 equivalents), X-Phos (40.0 mg, 0.084 mmol, 0.2 equivalents) and Pd2(dba)a (38.0 mg, 0.045 mmol, 0.1 229 equivalents). The resulting mixture was then stirred at 100 °C for 2 hours under N2. The reaction mixture was diluted with EtOAc (10.0 mL) and washed with H2O (10 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by fast chromatography (PE / EA = 3 / 1-1 / 1), yielding the desired product (130 mg, 59% yield) as a yellow solid. LC-MS: m / z 557 [M+H]+. Step B: methyl 2-(4-(6-(4-methoxphenyl)-7-oxo-2-((2,2,2trifluoroethyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8yl)phenyl)acetate A solution of 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-(2,2,2-trifluoroethylamino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)phenyl)malonate (130.0 mg, 0.234 mmol, 1.0 equivalent) in DMSO (2.0 mL) was mixed with aqueous NaCl (0.55 M, 2.0 mL, 5.0 equivalents). The resulting mixture was stirred at 150°C for 6 hours. The reaction mixture was then diluted with ethyl acetate (10.0 mL) and washed with H₂O (10.0 mL x 3), and dried on Anhydrous Na2SO4 was concentrated under reduced pressure. The residue was purified by fast column chromatography (PE / EA 230 = 1 / 1) and 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)phenyl)acetate (85.0 mg, 73% yield) was obtained as a yellow solid. LC-MS: m / z 499 [M+H]+. Step C: 8-(4-(2-hydroxyethyl)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 205) To a solution of methyl 2-(4-(6-(4-methoxyphenyl)-7-oxo-2-(2,2,2-trifluoroethylamino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)phenyl)acetate (85.0 mg, 0.170 mmol, 1.0 equivalent) in THF (3.0 mL) LiAlH4 (32.0 mg, 0.842 mmol, 5.0 equivalents) was added at 0°C. The resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was then quenched with sodium sulfate decahydrate (100 mg), filtered, and concentrated. A mixture of the residue and DDQ (57.0 mg, 0.251 mmol, 1.5 equivalents) in THF (3.0 mL) was then stirred at room temperature and subsequently concentrated under reduced pressure. The residue was purified by preparative HPLC to yield 8-(4-(2-hydroxyethyl)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2231 trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 205). 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.77 (s, 1H), 8.50 (t, J = 6.4 Hz, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 9.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 9.2 Hz, 2H), 4.64 (t, J = 5.2 Hz, 1H), 4.18-4.04 (m, 2H), 4.15-4.02 (m, 2H), 3.83 (s, 3H), 3.67-3.58 (m, 2H), 2,74 (t, J = 7.2 Hz, 2H). LC-MS: m / z 471 [M+H]+. 232 Preparación del Ejemplo 206 CO. TFA. PdJdppQCIi Tol.. MuOK lOQ^C, lÜOpsi, I6h Paso B Paso A: 8-(4-bromofenil)-6-(4-metoxifenil)-2-((2,2,2trifluoroetil)((2-(trimetilsilil)etoxi)metil)amino)pirido[4,3d]pirimidin-7(6H)-ona 233 A solution of 8-(4-bromofenil)-6-(4-metoxifenil)-2-(2,2,2trifluoroetilamino)pirido[4,3-d]pirimidin-7(6H)-ona (Ejemplo 192, 350.0 mg, 0.7 mmol, 1.0 equivalent) in anhydrous DMF (5.0 mL) was mixed with NaH (60% in oil, 57.0 mg, 1.4 mmol, 2.0 equivalents) at 0°C. The mixture was stirred at 0°C for 1 hour and then SEMC1 (141.0 mg, 0.86 mmol, 1.2 equivalents) was added. The resulting mixture was stirred at room temperature for 1 hour. The reaction was then quenched with iced aqueous NH4Cl (10.0 mL) and extracted with DCM (10.0 mL x 2). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by fast column chromatography, yielding 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one (350.0 mg, 77% yield) as a yellow solid. LC-MS: m / z 635 [M+H]+. Step B: methyl 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7dihydropyrido[4,3-d]pyrimidin-8-yl)benzoate 234 To a solution of 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one (350.0 mg, 0.55 mmol, 1.0 equivalent) in toluene / MeOH (1 / 1, v / v, 10.0 mL) TEA (167.0 mg, 1.65 mmol, 3.0 equivalents) and Pd(dppf)C12 (37.0 mg, 0.05 mmol, 0.1 equivalent) at room temperature. The resulting mixture was stirred at 100 °C under CO2 (1 atmosphere) overnight. The resulting mixture was diluted with water (20.0 mL) and extracted with EtOAc (20.0 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by fast column chromatography (PE / EA = 3 / 1-1 / 2), yielding methyl 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2—(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3d]pyrimidin-8-yl)benzoate (280.0 mg, 83% yield) as a yellow solid. LC-MS: m / z 615 [M+H]+. Step C: 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzoic acid 235 To a solution of methyl 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzoate (280.0 mg, 0.46 mmol, 1.0 equivalent) in THF (5.0 mL), LiOH (1N, aqueous, 4.6 mL, 4.6 mmol, 10.0 equivalents) was added at room temperature. The resulting mixture was stirred overnight. The reaction mixture was then poured into water (20.0 mL) and the pH was adjusted to 6.0 with a dilute HCl solution (1N). The mixture was extracted with EtOAc (20.0 mL x 3), dried over anhydrous Na2SO4, and concentrated. The residue was purified by fast column chromatography (PE / EA = 2:1 to 0:1) which yielded 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzoic acid (250.0 mg, 91% yield) as a yellow solid. LC-MS: m / z 601 [M+H]+. Step D: 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7dihydropyrido[4,3-d]pyrimidin-8-yl)benzamide 236 To a solution of 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzoic acid (250.0 mg, 0.42 mmol, 1.0 equivalent) in DMF (5 mL) were added NH4Cl (133.0 mg, 2.08 mmol, 5.0 equivalents), DIPEA (268.0 mg, 2.08 mmol, 5.0 equivalents), and HATU (316.0 mg, 0.83 mmol, 2.0 equivalents). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was then diluted with water (20 mL) and concentrated with DCM (20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by fast column chromatography (PE / EA = 1 / 1), yielding 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3d]pyrimidin-8-yl)benzamide (200 mg, 80% yield) as a yellow solid. LC-MS: m / z 600 [M+H]+. step A mixture of 4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3-d]pyrimidin-8-yl)benzamide (100.0 mg, 0.17 mmol, 1.0 equivalent) and DMF-DMA (2.0 mL) was stirred at 80°C overnight. The reaction mixture was then concentrated, and the crude product was obtained as a yellow oil. LC-MS: m / z 655 [M+H]+. Step F: 8-(4-(lH-l,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)2-( (2,2,2-trifluoroethyl) ((2 — (trimethylsilyl)ethoxy)methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)one 238 Hydrazine monohydrate (27.0 mg, 0.84 mmol, 5.0 equivalents) was added to a solution of (Z)-N-((dimethylamino)methylene)-4-(6-(4-methoxyphenyl)-7-oxo-2-((2,2,2-trifluoroethyl)((2(trimethylsilyl)ethoxy)methyl)amino)-6,7-dihydropyrido[4,3d]pyrimidin-8-yl)benzamide (120 mg, 0.17 mmol, 1.0 equivalent) in AcOH (2 mL) at room temperature. The resulting mixture was stirred at 100°C for 2 hours. The reaction was then diluted with dilute NaHCOa (aqueous saturated, 20 mL) and extracted with EtOAc (20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The residue was purified by fast column chromatography (PE / EA = 1 / 1) yielding 8-(4-(1H-1,2,4-triazol-3yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl) ((2 — (trimethylsilyl)ethoxy)methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)one (80 mg, 76% yield) as a yellow solid. LC-MS: m / z 624 [M+H]+. Step G: 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2 (2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one 239 A solution of 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)((2-(trimethylsilyl)ethoxy)methyl)amino)pyrido[4,3-d]pyrimidin-7(6H)one (80 mg, 0.13 mmol, 1.0 equivalent) in DCM (3.0 mL) was mixed with trifluoroacetic acid (1.0 mL) at room temperature. The resulting mixture was stirred for 5 hours before concentration and purification by preparative HPLC under reduced pressure to yield 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-6-(4-methoxyphenyl)-2-(2,2,2-trifluoroethylamino)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 206) . 4H NMR (400 MHz, DMSO-ds) δ 8.97 (s, 1H) , 8.84 (s, 1H) , 8.58 (t, J= 6.4 Hz, 1H) , 8.43 (br s, 1H), 7.97 (d, J= 8.4 Hz, 2H) , 7.78 (d, J = 8,4 Hz, 2H), 7,48 (d, J = 8,8 Hz, 2H), 7,10 (d, J = 8,8 Hz, 2H), 4,16-4,02 (m, 2H), 3,81 (s, 3H). LC-MS: m / z 494 [M+H]+. Preparación del Ejemplo 207 Paso A: 6-(isoxazol-4-il)-8-(4-metoxifenil)-2-((2,2,2trifluoroetil)amino)-5,6-dihidropirido[4,3-d]pirimidin-7(4aH)ona 240 OMe HOAc (42 mg, 0.7 mmol, 3.5 equivalents) was added to a solution of methyl 2-(5-formyl-2-((2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)-2-(4-methoxyphenyl) acetate (as prepared in General Procedure III, Step G) (76 mg, 0.2 mmol, 1.0 equivalent), isoxazol-4-amine (42 mg, 0.5 mmol, 2.5 equivalents) in DCE / MeOH (3 / 0.5 mL). The mixture was stirred at 45°C overnight, then cooled to 0°C. NaBHaCN (12 mg, 0.2 mmol, 1.0 equivalent) was added to the reaction mixture in one portion. The resulting mixture was then allowed to warm to room temperature and stirred for another 12 hours before being quenched with DCM (10 mL) and H₂O (10 mL). The aqueous layer was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated.The residue was purified by preparative TLC (PE:EA = 1 / 2) which gave 6-(isoxazol-4-yl)-8-(4-methoxyphenyl)2-((2,2,2-trifluoroethyl)amino)-5,6-dihydropyrido[4,3d]pyrimidin-7(4aH)-one (51 mg, 44% yield) as a white solid. LC-MS: m / z 420 [M+H]+. 241 Step B: 6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one UMe A mixture of 6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)-5,6-dihydropyrido[4,3-d]pyrimidin-7(4aH)one (51.0 mg, 0.12 mmol, 1.0 equivalent) and DDQ (40.0 mg, 0.18 mmol, 1.5 equivalent) in THF (3.0 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC under reduced pressure, which gave 6-(isoxazol-4-yl)-8-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[4,3d]pyrimidin-7(6H)-one (Example 207). iH NMR (400 MHz, DMSO-ds) δ 9.62(s,1H), 9.20(s,1H), 9.00(s,1H), 8.97(s,1H), 8.66(t,J=6.4Hz,1H)7.57(d,J=8.8Hz,2H); 6.89 (d, J= 8.8 Hz, 2H), 4.15-4.03 (m, 2H), 3.79 (s, 3H). LC-MS: m / z 418 [M+H]+. Example 208: 8-(4-methoxyphenyl)-6-(lH-pyrazol-4-yl)-2-((2,2,2trifluoroethyl)amino)pyrido[4,3-d]pyrimidin-7(6H)-one 242 OMe The title compound was synthesized from intermediate compound 1 with lH-pyrazol-4-amine as prepared in the procedure for Example 207 (Steps AB). 1HNMR (600 MHz, DMSO-ds) δ 8.95 (s, 1H), 8.93 (s, 1H), 8.51 (br s, 1H), 8.13 (s, 2H), 7.56 (d, J= 8.4 Hz, 2H), 6.88 (d, J= 8.4 Hz, 2H), 4.13–4.03 (q, J= 9.6 Hz, 2H), 3.78 (s, 3H). LC-MS: m / z 417 [M+H]+. 243 General Procedure V: Nacr.ie, e?h Step c PÜCI. toluene Step D fundamental intermediate compound I General Procedure V (sequence of R2-R3-R1) OH OH Pd(dppf)CiS1CsjCOs dioxane, H20, 1ÜQ=C Step E AiClj. Nal MeCN, 80ÜC Step G Rj.gOH OH CnjOAck, Py DCM, 40°C Step H Ν?Η, RiXH THF Step I 244 General Procedure V (sequence of R1-R3-R2}: PHY3B(OH)2 Cu(OAc)2 Fy DCM. 40*0 Step L R^ÍOHh or Rj-B |bT PrUPPMUi.CSYC] dioxane, 1GQ=C Step M General procedure V [sequence of R1-R2-R3): fundamental intermediate I compound TsOH Nal MeCN. 0DcC Step Q 245 Preparation of 8-bronno-2-chloro-7-methoxy-1,6-naphthyridine (fundamental intermediate compound I) NIS. HOAc MeCN Step A NaSMe, EtOH PüCL Step C Step D Fundamental Intermediate Compound I Step A: 3-bromo-5-iodo-2-methoxypyridin-4-amine To a solution of 3-bromo-2-methoxypyridin-4-amine (4.0 g, 19.8 mmol, 1.0 equivalent) in acetonitrile (30 mL) and acetic acid (4.1 mL), NIS (4.9 g, 21.7 mmol, 1.1 equivalent) was added, and the reaction mixture was stirred at room temperature for 16 hours. The solvent was then extracted under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (50 mL x 2). The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by rapid chromatography on silica gel (eluent: PE / EtOAc = 4 / 1), yielding 3-bromo-5-iodo-2-methoxypyridin-4 246 amine (6.0 g, 92% yield) as a white solid. LC-MS: m / z 329 [M+H]+. Step B: (E)-ethyl 3-(4-amino-5-bromo-6-methoxypyridin-3yl)acrylate A mixture of 3-bromo-5-iodo-2-methoxypyridin-4-amine (6 g, 18.3 mmol, 1.0 equivalent), trio-tolylphosphine (553 mg, 1.8 mmol, 0.1 equivalent), NaHCOa (2.7 g, 32.1 mmol, 1.8 equivalent), ethyl acrylate (2 g, 20.1 mmol, 1.1 equivalent), and Pd(OAc)2 (205 mg, 0.9 mmol, 0.05 equivalent) in DMF (30 mL) was stirred at 70°C under N2 for 16 hours. The reaction was then diluted with 10% aqueous LiCl (50 mL) and extracted with EtOAc (50 mL x 3). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography on silica gel (eluent: PE / EtOAc = 3 / 1), yielding (E)-ethyl 3-(4-amino-5-bromo-6-methoxypyridin-3-yl)acrylate (4.5 g, 82% yield) as a white solid. LC-MS: m / z 301 [M+H]+. Step C: 8-bromo-7-methoxy-l, 6-naphthyridin-2(1H)-one 247 A solution of (A)-ethyl 3-(4-amino-5-bromo-6-methoxypyridin-3-yl)acrylate (1.5 g, 5.0 mmol, 1.0 equivalent) in EtOH (10 mL) was mixed with 15% aqueous NaSMe (2.6 g, 5.5 mmol, 1.1 equivalent). The resulting mixture was stirred overnight at room temperature. The precipitate was collected by filtration, and the filter cake was washed with EtOAc (10 mL) and dried, yielding 8-bromo-7-methoxy-1,6-naphthyridin-2(1H)-one (1.0 g, 79% yield) as a yellow solid. LC-MS: m / z 255 [M+H]+. Step D: 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (fundamental intermediate compound I) A mixture of 8-bromo-7-methoxy-l,6-naphthyridin-2(1H)-one (2.3 g, 9.0 mmol, 1.0 equivalent) and POCl3 (12.0 mL) were stirred at 80°C for 2 hours. The reaction was then poured into cooled NaHCOa (aqueous saturated, 150 mL) and extracted with EtOAc (50 mL x 4). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography on silica gel (eluent: PE / EtOAc = 3 / 1) with the 248, which yielded 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (1.9 g, 77% yield) as a whitish solid. LC-MS: m / z 273 [M+H]+. Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2(2,2,2-trifluoroethylthio)-1,6-naphthyridin-7(6H)-one (Example 209) Pdídppf)CIE, CsíCOj tfioxane, H2Q, 100=C Step E SOCI2. DMF DCM. 40 °C Step F 41¾. Nal MeCN 00 °C Step G OH Cu(OAc)2- P? □CM. 40ÚC Step H Step E: 8-(4-chlorophenyl)-7-methoxy-l, 6-naphthyridine-2(1H)-one 249 A mixture of 8-bromo-7-methoxy-1,6-naphthyridin-2(1H)-one (10 g, 39.4 mmol, 1.0 equivalent), Pd(dppf)C12 (1.4 g, 1.9 mmol, 0.05 equivalent), CS2CO3 (25.6 g, 78.5 mmol, 2.0 equivalent), and chlorophenylboronic acid (9.2 g, 59.0 mmol, 1.5 equivalent) in dioxane / water (200 mL, 9 / 1, v / v) was stirred at 100°C under a nitrogen atmosphere for 16 hours. The reaction mixture was then diluted with water (100 mL) and extracted with EtOAc (50 mL x 5). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (eluent: PE / EtOAc = 2 / 1), yielding 8-(4-chlorophenyl)-7-methoxy-1,6-naphthiridin-2(1H)-one (10.0 g, 89% yield) as a white solid. LC-MS: m / z 287 [M+H]+. Step F: 2-chloro-8-(4-chlorophenyl)-7-methoxy-l,6-naphthyridine To a solution of 8-(4-chlorophenyl)-7-methoxy-1,6-naphthyridin2(1H)-one (8 g, 27.9 mmol, 1.0 equivalent) in DCM (100 mL), DMF (6.1 g, 83.6 mmol, 3.0 equivalents) and SOCl2 (8.2 g, 83.6 mmol, 3.0 equivalents) were added. The reaction was then stirred at 80°C for 16 hours. The resulting mixture was cooled to At room temperature (250), the solution was concentrated, quenched with ice-cooled NaHCOa (aqueous saturated, 50 mL), and extracted with EtOAc (50 mL x 2). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (eluent: PE / EtOAc = 5 / 1), yielding 2-chloro-8-(4-chlorophenyl)7-methoxy-1,6-naphthyridin (7.0 g, 83% yield) as a white solid. LC-MS: m / z 305 [M+H]+. Step G: 2-chloro-8-(4-chlorophenyl)-1,6-naphthyridin-7(6H)-one Cl To a solution of 2-chloro-8-(4-chlorophenyl)-7-methoxy-1,6-naphthyridin (2.0 g, 6.6 mmol, 1.0 equivalent) in MeCN (40.0 mL), AlCl₂ (1.8 g, 13.5 mmol, 2.0 equivalents) and Na₂ (2.2 g, 13.3 mmol, 2.0 equivalents) were added. The resulting mixture was stirred at 80°C for 8 h. The reaction mixture was then quenched with ice water (20 mL) and extracted with EtOAc (20 mL x 3). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by rapid chromatography on silica gel (eluent: 251 DCM / acetone = 2 / 1) whereby 2-chloro-8-(4 chlorophenyl)-1,6-naphthyridin-7(6H)-one (1.5 g, 79% yield) was obtained as a white solid. LC-MS: m / z 291 [M+H]+. Step H: 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)1,6-naphthyridin-7(6H)-one To a solution of 2-chloro-8-(4-chlorophenyl)-1,6-naphthiridin7(6H)-one (1.5 g, 5.2 mmol, 1.0 equivalent) in DCM (20.0 mL) Cu(OAc)2 (1.2 g, 5.6 mmol, 1.1 equivalent), pyridine (1.2 g, 15.2 mmol, 3.0 equivalent) and 2-methyl-2H-indazol-5ylboronic acid (1.4 g, 8.0 mmol, 1.5 equivalent) was added. The reaction mixture was stirred at 40°C under an O2 atmosphere for 16 hours, then concentrated under reduced pressure and purified by rapid chromatography on silica gel (eluent: PE / EtOAc = 1 / 1) yielding 2-chloro-8-(4-chlorophenyl)6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (1.4 g, 65% yield) as an orange solid. LC-MS: m / z 421 [M+H]+. Step I: 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)thio)-1,6-naphthyridin-7(6H)-one (Example 209) 252 Cl To a solution of 2,2,2-trifluoroethanethiol (124.0 mg, 1.1 mmol, 3.0 equivalents) in 2.0 mL of anhydrous THF, NaH (60% suspension in mineral oil, 43.0 mg, 1.1 mmol, 3.0 equivalents) was added in portions at 0°C. The mixture was stirred at 0°C for 0.5 hours. Then, a solution of 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)one (150.0 mg, 0.36 mmol, 1.0 equivalent) in THF (1 mL) was added. The reaction mixture was stirred at room temperature for a further 2 hours. The reaction mixture was quenched with aqueous NH4Cl (10 mL) and extracted with EtOAc (10 mL x 3). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC under reduced pressure, yielding 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)thio)-1,6-naphthyridin-7(6H)-one (Example 209). Z NMR (400 MHz, DMSO-d6) δ: 8.92 (s, 1H) , 8.51 (s, 1H) , 7.98 (d, J= 8.8 Hz, 1H), 7.92 (d, J= 2.0 Hz, 1H), 7.72 (d, J= 9.2 Hz, 1H) , 7.40 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 9.2 Hz, 2.0 Hz, 253 1H), 6.99 (d, J= 8.8 Hz, 1H), 4.23 (s, 3H) , 4.21-4.08 (m, 2H) . LC-MS: m / z 501 (M+H)+. Example 210: 8-(4-chlorophenyl)-2-cyclopropoxy-6-(2-methyl-2H indazol-5-yl)-1,6-naphthyridin-7(6H)-one Cl The title compound is synthesized from the intermediate compound 8 with cyclopropanol by the general procedure V (Step I) (NaH, THE anhydrous, 0°C at room temperature). íH NMR (400 MHz, DMSO-ch) δ: 8.78 (s, 1H), 8.50 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.70 (d, J= 2.4 Hz, 1H), 7.77 (d, J= 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 6.53 (d, J= 9.2 Hz, 1H), 4.23 (s, 3H), 4.21-4.14 (m, 2H), 0.74-0.72 (m, 4H). LC-MS: m / z 443 [M+H]+. Preparation of 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)-1,6-naphthyridin-7(6H)-one (Example 211) 254 Method A fundamental intermediate compound I H2N cf3 CsF, DMSO Step J OH Cu{OAc)s, Py DCM. 40,:C Step L aunt PdpPI^CsjCOj dioxane, 1 GOT, 2 h Step M Method A Step J: 8-bromo-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6naphthyridin-2-amine 10a 10a A mixture of 8-bromo-2-chloro-7-methoxy-1,6-naphthyridine (1.0 g, 3.8 mmol, 1.0 equivalent), CsF (860.0 mg, 5.7 mmol, 1.5 equivalent), and 2,2,2-trifluoroethanamine (1.9 g, 18.8 mmol, 5.0 equivalent) in DMSO (10.0 mL) was stirred at 100°C for 2 hours. The mixture was then poured into ice water (100 mL) and extracted with EtOAc (50 mL x 4). All organic layers combined, 255 were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (eluent: PE / EtOAc = 2 / 1) yielding 8-bromo-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthiridin-2-amine (900 mg, 71% yield) as a white solid. LC-MS: m / z 336 [M+H]+. Step K: 8-bromo-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin7(6H)-one lia 11a A mixture of 8-bromo-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthiridin-2-amine (300.0 mg, 0.8 mmol, 1.0 equivalent) and AICI3 (301.5 mg, 2.2 mmol, 3.0 equivalents) in DCE (10 mL) was stirred at 80°C for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by rapid silica gel chromatography (eluent: DCM / MeOH = 10 / 1), yielding 8-bromo-2-(2,2,2-trifluoroethylamino)-1,6-naphthiridin7(6H)-one (220.0 mg, 92% yield) as a yellow solid. LC-MS: m / z 322 [M+H]+. Step L: 8-bromo-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)-l,6-naphthyridin-7(6H)-one 12a 256 12a 8-bromo-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-1,6-naphthyridin-7(6H)-one 12a was synthesized from the intermediate compound lia with (2-methyl-2H-indazol-5-yl)boronic acid by the general procedure V (Step H). LC-MS: m / z 452 [M+H]+. Step M: 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)-8-(4-(trifluoromethoxy)phenyl)-1,6naphthyridin-7(6H)-one (Example 211) OCFj The title compound was synthesized from intermediate compound 12a with (4-(trifluoromethoxy)phenyl)boronic acid by general procedure V (Step M). iH NMR (400 MHz, DMSO-d6) δ: 8.52 (s, 1H), 8.48 (s, 1H), 8.34 (t, J= 6.4 Hz, 1H), 7.85 (dd, J= 2.0 Hz, 0.4 Hz, 1H), 7.76 (d, J = 9.2 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 9.2 Hz, 1H), 7.31 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 257 2H), 6.49 (d, J= 8.8 Hz, 1H), 4.22 (s, 3H), 4.18-4.07 (m, 2H). LC-MS: m / z 534 [M+H]+. Example 212: 8-(6-cyclopropylpyridin-3-yl)-6-(2-methyl-2Hindazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-1,6-naphthyridin7(6H)-one The title compound was synthesized from intermediate compound 12a with (6-cyclopropylpyridin-3-yl)boronic acid by general procedure V (Step M). íH NMR (400 MHz, DMSO-ds) δ: 8.61 (d, J= 1.2 Hz, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8.34 (t, J= 6.4 Hz, 1H), 7.87-7.80 (m, 2H), 7.75 (d, J= 9.2 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 7.32 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.22 (s, 3H), 4.21-4.10 (m, 2H), 2.14-2.05 (m, 1H), 0.98-0.88 (m, 4H). LC-MS: m / z 491 [M+H]+. Example 213: 6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2trifluoroethyl)amino)-8-(4-(trifluoromethyl)phenyl)-1,6naphthyridin-7(6H)-one 258 The title compound was synthesized from intermediate compound 12a with (4-(trifluoromethyl)phenyl)boronic acid by general procedure V (Step M). íH NMR (400 MHz, DMSO-ck) δ: 8.56 (s, 1H), 8.48 (s, 1H), 8.40 (t, J = 6.4 Hz, 1H), 7.89-7.80 (m, 3H), 7.78 (d, J = 9.2 Hz, 1H), 7.69 (d, J= 9.2 Hz, 1H), 7.63 (d, J= 8.4 Hz, 2H), 7.33 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 6.52 (d, J= 9.2 Hz, 1H), 4.22 (s, 3H), 4.21-4.06 (m, 2H). LC-MS: m / z 518 [M+H]+. Example 214: 8-(4-(2,2-difluoroethyl)phenyl)-6-(2-methyl-2Hindazol-5-yl)-2-((2,2,2-trifluoroethyl)amino)-1,6-naphthyridin7(6H)-one The title compound was synthesized from intermediate compound 12a with (4-(2,2-difluoroethyl)phenyl)boronic acid by general procedure V (Step M). 259 iH NMR (400 MHz, DMSO-ds) δ: 8.47 (s, 2H) , 8.31 (br s, 1H) , 7.84 (d, J= 1.6 Hz, 1H) , 7.74 (d, J= 9.2 Hz, 1H) , 7.67 (d, J= 8.8 6.24 (tt, Jhf = 56.6 Hz, 4.8 Hz, 1H), 4.22 (s, 3H), 4.23-4.10 (m, 2H), 3.18 (dt, Jhf = 18.2 Hz, 4.8 Hz, 2H). LC-MS: m / z 514 [M+H]+. Preparation of 2-etoxi-6-(2-metil-2H-indazol-5-il)-8-(4(trifluorometil)fenil)-1,6-naftiridin-7(6H)-ona (Ejemplo 215) ÓH Cu(OAc)2. Py, DCM, 40 °C Paso L Er 12b PdtPPtlsh, CsjCOj dioxano, 100=C Paso M Method B Paso N: 8-bromo-2-chloro-l,6-naftiridin-7(6H)-ona 260 Br To a solution of 8-bromo-2-chloro-7-methoxy-1,6-naphthyridin (10.1 g, 40.0 mmol, 1.0 equivalent) in DCE (180 mL) AlCl₃ (15.9 g, 120.0 mmol, 3.0 equivalents) was added at 10°C. The resulting mixture was then stirred at 80°C for 2 hours and slaked with water (19.4 mL, 1.1 mol, 27.0 equivalents) at 10°C. This slaked mixture was stirred at room temperature for 0.5 hours and then filtered. The filter cake was washed with DCM / EtOH (200 mL, 10 / 1, v / v) and the filtrate was concentrated and gave 8-bromo-2-chloro-1,6-naphthyridin-7(6H)-one (9.8 g, crude) as a yellow solid in the next step. LC-MS: m / z 261 [M+H]+. Step O: 8-bromo-2-ethoxy-l,6-naphthyridin-7(6H)-one HnZZA Er 11b To a solution of 8-bromo-2-chloro-7-methoxy-1,6-naphthyridin (9.5 g, 40.0 mmol, 1.0 equivalent) in EtOH (220.0 mL) was added NaOEt (27.2 g, 400.0 mmol, 10.0 equivalents). The resulting solution was stirred at 100°C for 5 hours. The mixture was then poured into ice-cooled NH4Cl (aqueous saturated, 200 mL) and adjusted to pH 6 with HCl (aqueous). The mixture was extracted with EtOAc (100 mL x 4) and the organic layers were combined and washed with 261 µg of brine (50 mL) were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: DCM / EtOH = 50 / 10:1), which yielded 8-bromo-2-ethoxy-1,6-naphthiridin-7(6H)one (5.3 g, 49% yield) as a brown solid. LC-MS: m / z 271, 273 [M+H]+. Preparation of 8-bromo-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)1,6-naphthyridin-7(6H)-one 8-Bromo-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-naftiridin7(6H)-one was synthesized from intermediate compound 11b with 2-methyl-2H-indazol-5-ylboroonic acid as in the procedure for Example 209 (Step H). LC-MS: m / z 399, 401 [M+H]+. Example 215: Preparation of 2-ethoxy-6-(2-methyl-2H-indazol-5yl)-8-(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-7(6H)-one 262 The title compound was synthesized from intermediate compound 12b with 4-(trifluoromethyl)phenylboronic acid by the general procedure V (Step M) (Pd(PPha)4, CS2CO3, dioxane, 100°C). iH NMR (400 MHz, DMSO-cM δ: 8.81 (s, 1H), 8.50 (s, 1H), 7.99 (d, J= 9.2 Hz, 1H), 7.91 (d, J= 1.6 Hz, 1H), 7.88 (d, J= 8.0 Hz, 2H), 7, 74-7, 67 (m, 3H), 7.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H) , 6.57 (d, J = 8.8 Hz, 1H) , 4.25 (q, J = 7.2 Hz, 2H) , 4.23 (s, 3H) , 1.26 (t, J= 7.2 Hz, 3H) m / z 465 [M+H]+. Example 216: 8-(6-(difluoromethyl)pyridin-3-yl)-2-ethoxy-6-(2methyl-2H-indazol-5-yl)-1, 6-naphthyridine-7(6H)-one chk The title compound was synthesized from intermediate compound 12b with 2-(difluoromethyl)-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (Step M). Η NMR (400 MHz, DMSO-cM δ: 8.95 (d, J= 1.2 Hz, 1H), 8.85 (s, 1H) , 8.51 (s, 1H) , 8.27 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 8.02 (d, J = 9.2 Hz, 6H), 7.92 (d, J= 1.2 Hz, 1H), 7.72 (d, J= 3.6 Hz, 1H), 7.70 (d, J = 2.8 Hz, 1H), 7.36 (dd, J = 9.2 Hz, 2.0 Hz, 263 1H) , 6.98 (t, Jhf = 55.2 Hz, 1H) , 6.59 (d, J= 9.2 Hz, 1H) , 4.25 (q, J = 7.2 Hz, 2H), 4.23 (s, 3H) , H 1, 7.27 (t LCMS: m / z 448 [M+H]+. Example 217: 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(4(trifluoromethoxy)phenyl)-1,6-naphthyridine-7(6H)-one ocf2 The intermediate compound was synthesized from intermediate compound 12b with (4-(trifluoromethoxy)phenyl)boronic acid by general procedure V (Step M). íH NMR (400 MHz, DMSO-ds) δ: 8.77 (s, 1H), 8.50 (s, 1H), 7.98 (d, J= 9.0 Hz, 1H), 7.89 (d, J= 2.0 Hz, 1H), 7.75 (d, J= 8.8 Hz, 2H), 7.70 (d, J = 9.0 Hz, 1H), 7.37-7.30 (m, 3H), 6.55 (d, J = 9.0 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 4.22 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). LC-MS: m / z 481 [M+H]+. Example 218: 8-(6-(difluoromethoxy)pyridin-3-yl)-2-ethoxy-6-(2 methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one 264 ou-k The title compound was synthesized from intermediate compound 12b with 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (Step M). iH NMR (400 MHz, DMSO-ds) δ: 8.77 (s, 1H), 8.51 (d, J= 2.4 Hz, 1H), 8.49 (s, 1H), 8.18 (dd, J= 4.4 Hz, 2.0 Hz, 1H), 7.99 (d, J = 8.8 Hz, 1H) , 7.89 (d, J= 2.0 Hz, 1H), 7.74 (t, Jhf = 73.2 Hz, 1H), 7.71 (d, J= 9.2 Hz, 1H), 7.35 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 9.2 Hz, 1H), 4.27 (q, J= 7.2 Hz, 2H), 4.22 (s, 3H), 1.27 (t, J= 7.2 Hz, 3H). LCMS: m / z 464 [M+H]+. Example 219: 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(6methylpyridin-3-yl)-1,6-naphthyridin-7(6H)-one 265 The title compound was synthesized from intermediate compound 12b with (6-methylpyridin-3-yl)boronic acid by general procedure V (Step M). 4H NMR (400 MHz, DMSO-ds) δ: 8.75 (s, 1H), 8.70 (br s, 1H), 8.50 (s, 1H), 7.98 (d, J= 8.8 Hz, 1H), 7.93 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.55 (d, J = 8.8 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 4.23 (s, 3H), 1.28 (t, J= 7.2 Hz, 3H). LC-MS: m / z 412 [M+H]+. Example 220: 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(6 (trifluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 12b with (6-(trifluoromethyl)pyridin-3yl)boronic acid by general procedure V (Step M). iH NMR (400 MHz, DMSO-ds) δ: 9.05 (d, J= 7.8 Hz, 1H) , 8.88 (s 1H), 8.51 (s, 1H), 8.37 (dd, J= 8.0 Hz, 2.0 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.93 (d, J= 2.0 Hz, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.6 Hz, 2.0 Hz, 266 1H) , 6.61 (d, J = 9.2 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H) , 4.23 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H) . LC-MS: m / z 466 [M+H]+. Example 221: 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(2-methyl 2H-indazole-5-yl)-1, 6-naphthyridine-7(6H)-one The title compound was synthesized from intermediate compound 12b with (6-cyclopropylpyridin-3-yl)boronic acid by general procedure V (Step M). 4H NMR (400 MHz, DMSO-ds) δ: 8.93 (s, 1H) , 8.89 (s, 1H) , 8.51 (s, 1H) , 8.04 (d, J= 9.2 Hz, 1H) 2 , 7, 7, 7.7 (d, 2) J (d, J= 9.2 Hz, 1H), 7.56 (d, J= 8.0 Hz, 1H) , 7.35 (dd, J= 9.2 Hz, 2.0 Hz, 1H) , 6.63 (d, J= 9.2 Hz, 1H), J. 4.31 (q (s, 3H), 2.36–2.25 (m, 1H), 1.31 (t, J= 6.8 Hz, 3H) , 1.27–1.20 (m, 2H) , 1.17–1.09 (m, 2H) . LC-MS: m / z 437 [M+H]+. Example 222: 8-(4-(1H-1,2,4-triazol-3-yl)phenyl)-2-ethoxy-6-(2 methyl-2H-indazol-5-yl)-1, 6-naphthyridine-7(6H)-one 267 The title compound was synthesized from intermediate compound 12b with 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-overall lugopacediol M via unprotection with ASD through general procedure I (Step F) . XH NMR (400 MHz, DMSO-cG) δ: 14.05 (br. s, 1H) , 8.75 (s, 1H) , 8.50 (s, 1H) , 8.39 (br.d, 1H) , 8.01 (H) 8 Hz, 8. J= 9.2 Hz, 1H), 7.90 (d, J= 1.6 Hz, 1H) , 7.77 (d, J= 8.4 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.35 (dd, J= 8,8 J. Hz. 5, 2,8 H. 5, 2, 1H). 9.2 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H) , 4.23 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H) . LC-MS: m / z 464 [M+H]+. Example 223: 8-(4-(lH-pyrazol-3-yl)phenyl)-2-ethoxy-6-(2-methyl2H-indazol-5-yl)-1, 6-naphthyridine-7(6H) -one 268 The title compound was synthesized from intermediate compound 12b with 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-lH-general disassembly through V via the con MFA procedure the general procedure I (Step F) iH NMR (400 MHz, DMSO-cL) δ: 12.87 (br.s, 1H), 8.70 (s, 1H), 8.49 (s, 1H) , 7.97 (d, J = 9.2 Hz, 1H) , 7, 1,89 (d, J = Hz 85–7, 69 (m, 6H) , 7.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H) , 6.73 (s, 1H) , 6.54 (d, J = 8.8 Hz, 1H), 4.27 (q H2) J s, 4.2 1.27 (t, J = 7.2 Hz, 3H) . LC-MS: m / z 463 [M+H]+. Example 224: 8-(4-(lH-imidazol-4-yl)phenyl)-2-ethoxy-6-(2-methyl2H-indazol-5-yl)-1, 6-naphthyridine-7(6H) -one The title compound was synthesized from intermediate compound 12b with 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-lH-general deprotection via V con ( TFAprocedure the general procedure I (Step F) 2694H NMR (400 MHz, from DMSO) δ: 12.14 (br s, 1H) , 8.70 (s, 1H) , 8.50 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.1 Hz, 7.89 (d 78-7, 58 (m, 7H), 7.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H) , 6.53 (d, J = 9.2 Hz, 1H), 4.27 (q, J= 7.2 Hz, 2H) .7 ( 1, 3.23 (s 7.2 Hz, 3H). LC-MS: m / z 463 [M+H]+. Preparation 8-bromo-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2H indazol-5-yl)-1,6-naphthyridine-7(6H)-one 12c Oh Br 12c 8-bromo-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2H-indazol-5-yl)- 1,6-Naphthyridin-7(6H)-one 12c was synthesized from intermediate compound 11b with 2-(2-(methylsulfonyl)ethyl)-2H-indazol5-ylboronic acid by general procedure V (Step L). LC-MS: m / z 491, 493 [M+H]+. Example 225: Preparation of 8-(4-chlorophenyl)-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one Cl 270 The title compound was synthesized from intermediate compound 12c with 4-chlorophenylboronic acid using general procedure V (Step M). Z NMR (400 MHz, DMSO-cM δ: 8.76 (s, 1H), 8.62 (s, 1H), 8,007.93 (m, 2H), 7.87 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.42-7.36 (m, 3H), 6.54 (d, J= 9.2 Hz, 1H), 4.91 (t, J = 6.8 Hz, 2H), 4.26 (q, J= 6.8 Hz, 2H), 3.80 (t, J= 6.8 Hz, 2H), 2.94 (s, 3H), 1.27 (t, J= 6.8 Hz, 3H). 523 [M+H]+. Preparation of 8-bromo-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol6-yl)-1,6-naphthyridin-7(6H)-one 12d NZ Ul Br 12d 8-bromo-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,6naphthyridin-7(6H)-one 12d was synthesized from intermediate compound 11b with (1-methyl-1H-benzo[d]imidazol-6-yl)boronic acid by general procedure V (Step L). LC-MS: m / z 399 [M+H]+. Example 226: Preparation of 2-ethoxy-6-(1-methyl-1Hbenzo[d]imidazol-6-yl)-8-(6-(trifluoromethyl)pyridin-3-yl)-1,6-naphthyridin-7(6H)-one 271 The title compound was synthesized from intermediate compound 12d with (6-(trifluoromethyl)pyridin-3yl)boronic acid by general procedure V (Step M). íH NMR (400 MHz, DMSO-ds) δ: 9.05 (d, J= 1.6 Hz, 1H), 8.88 (s, 1H), 8.37 (dd, J= 8.4 Hz, 2.0 Hz, 1H), 8.35 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.89 (d, J= 2.0 Hz, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.38 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). LC-MS: m / z 466 [M+H]+. Example 227: 2-ethoxy-6-(1-methyl-lH-benzo[d]imidazol-6-yl)-8(4-(trifluoromethyl)phenyl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 12d with (4-(trifluoromethyl)phenyl)boronic acid by general procedure V (Step M). 272 ϊΗ NMR (400 MHz, DMSO-cM δ: 8.80 (s, 1H), 8.34 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.90-7.84 (m, 3H), 7.79 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.36 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 6.57 (d, J = 8.8 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.26 (t, J= 7.2 Hz, 3H). LC-MS: m / z 465 [M+H]+. Example 228: 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6-(1-methyllH-benzo[d]imidazol-6-yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 12d with (6-cyclopropylpyridin-3-yl)boronic acid by general procedure V (Step M). XH NMR (400 MHz, DMSO-cM δ: 8.74 (s, 1H) , 8.64 (d, J = 1.6 Hz 1H) , 8.34 (s, 1H) , 7.97 (d, J= 9.2 Hz, 1H,= 8 , 8 , 7 Hz, 1H), 7.85 (d, J= 2.4 Hz, 1H) , 7.78 (d, J= 8.4 Hz, 1H) , 7.35 (dd, J = 8.8 Hz, 2.0 Hz, 1H) , 7.28 (d, Jd = 8.0) Hz 9.2 Hz, 1H), 4.26 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.16-2.06 (m, 1H), 1.28 (t, J= 7.2 Hz, 3H), 0.99-H]+8).[m LC, -H]8. 273 Example 229: 8-(6-(difluoromethoxy)pyridin-3-yl)-2-ethoxy-6-(lmethyl-lH-benzo [d]imidazol-6-yl)-1, 6-naphthyridine-7(6H)-one The title compound was synthesized from intermediate compound 12d with 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (Step M). 7H NMR (400 MHz, DMSO-cL) δ: 8.77 (s, 1H) , 8.51 (d, <7 = 1, 6 Hz, 1H), 8.34 (s, 1H), 8.19 (dd, J= 8.8 Hz, J = 2.0, 2.0 ,8, Hz 1H), 7.86 (d, J= 2.0 Hz, 1H) , 7.79 (d, J= 8.4 Hz, 1H) , 7.75 (t, Jhf = 73.2 Hz, 1H) , 7.36 (dd, J = 9.1 Hz. J, 7.1 Hz, 2.0 9.2 Hz, 1H) , 6.58 (d, J = 9.2 Hz, 1H) , 4.28 (q, J= 7.2 Hz, 2H), 3.88 (s, 3H), 1.28 (t, J= 7.2 Hz, 3H). LCMS: m / z 464 [M+H]+. Preparation of 8-bromo-2-ethoxy-6-(quinolin-6-yl)-l,6naphthyridine-7(6H)-one 12e 274 8-bromo-2-ethoxy-6-(quinolin-6-yl)-1, 6-naphthyridine-7(6H)-one 12e was synthesized from intermediate compound 11b with quinolin-6-ylboronic acid by general procedure V (Step L) . LC-MS: m / z 396 (M+H)+. Example 230: Preparation of 8-(4-(difluoromethoxy)phenyl)-2ethoxy-6-(quinolin-6-yl)-1,6-naphthyridine-7(6H)-one The title compound was synthesized from intermediate compound 12e with 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by general procedure V (Step M). !H NMR (400 MHz, DMSO-ds) δ: 9.02 (dd, <7 = 4, 4 Hz, 2.0 Hz, 1H), 8.83 (s, 1H), 8.48 (dd, J = 8.8 Hz, 1.2 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.16 (d, J= 8.8 Hz, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.94 (dd, J = 8.8 Hz, 2.0 Hz, 1H) , 7.71 (d, J = 8.8 Hz, 2H) , 7.65 (dd, J= 8.4 Hz, 4.0 Hz, 1H) , 7.28 (t, Jhf = 74.4 Hz, 1H), 7.16 (d, J= 8.8 Hz, 2H), 6.57 (d, J= 8.8 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H). LC-MS: m / z 460 [M+H]+. 275 Example 231: 8-(6-cyclopropylpyridin-3-yl)-2-ethoxy-6(quinolin-6-yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 12e with (6-cyclopropylpyridin-3-yl)boronic acid by general procedure V (Step M). iH NMR (400 MHz, DMSO-ds) δ: 9.02 (dd, J= 4.0 Hz, 2.0 Hz, 1H) , 8.84 (s, 1H) , 8.65 (d, J = 2.0 Hz, 1H) , 8.47 (dd, 2.8), J 8.24 (d, J= 2.4 Hz, 1H), 8.16 (d, J= 9.2 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H) , 7.94 (dd, J = 9.2 Hz, 2.0 Hz, JH) 8 (dd, 7, 1H) 8 , 7 Hz, 1H), 7.65 (dd, J= 8.4 Hz, 4.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.58 (d, J = 9.2 Hz, 1H), 4.27 (q, J = 7.6) - 1.2, 2H , 1.28 (t, J = 7.2 Hz, 3H), 0.98–0.91 (m, 4H). LC-MS: m / z 435 [M+H]+. Example 232: 8-(6-(difluoromethoxy)pyridin-3-yl)-2-ethoxy-6(quinoline-6-yl)-1,6-naphthyridine-7(6H) -one οαγ 276 The title compound was synthesized from intermediate compound 12e with 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyridine by general procedure V (Step M). iH NMR (400 MHz, DMSO-ds) δ: 9.02 (dd, J= 4.2 Hz, 2.0 Hz, 1H) , 8.89 (s, 1H) , 8.53 (d, J = 2.0 Hz, 1H) , 8.48 (dd, J = 8.4 Hz, 1.2 Hz, 1H), 8.25 (d, J= 2.4 Hz, 1H), 8.21 (dd, J= 8.4 Hz, 2.4 Hz, 1H), 8.17 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.96 (dd, J = 9.0 Hz, 2.0 Hz, 1H), 7.76 (t, Jhf = 73.2 Hz, 1H) , 7.66 (dd, J = 8.4 Hz, 4.2 Hz, 1H), 7.11 (dd, J= 8.4 Hz, 0.4 Hz, 1H) , 6.61 (d, J = 9.0 Hz, 1H) , 4.28 (q, J = 7.2 Hz, 2H) , 1.28 (t, J= 7.2Hz, 3H). LC-MS: m / z 461 (M+H)+. Preparation of 8-bromo-2-(cyclopropylmethoxy)-1,6-naftiridin7 ( 6H) -ona 11c 11c 8-bromo-2-(cyclopropylmethoxy)-1, 6-nafthyridin-7(6H)-ona 11c is synthesized from the intermediate compound 14 with cyclopropylmethanol by the general process V (Paso O). LC-MS: m / z 295 [M+H]+. Preparación de 8-bromo-2-(ciclopropilmetoxi)-6-(2-metil-2Hindazol-5-il)-1, 6-naftiridin-7(6H)-ona 12f 277 12th 8-bromo-2-(cyclopropylmethoxy)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one 12f was synthesized from intermediate compound 11c with 2-methyl-2H-indazol-5-ylboronic acid by general procedure V (Step L). LC-MS: m / z 425, 427 [M+H)+. Example 233: Preparation of 8-(4-chlorophenyl)-2-(cyclopropylmethoxy)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one Cl The title compound was synthesized from intermediate compound 12f with 4-chlorophenylboronic acid by general procedure V (Step M). íH NMR (400 MHz, DMSO-ds) δ: 8.75 (s, 1H), 8.49 (s, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.89 (dd, J= 2.0 Hz, 0.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.33 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 6.57 (d, J = 9.2 Hz, 278 1H), 4.22 (s, 3H), 4.08 (d, J= 7.6 Hz, 2H), 1.23-1.11 (m, 1H), 0.53–0.46 (m, 2H), 0.26–0.20 (m, 2H).LC-MS: m / z 457 [M+H]+. Example 234: Preparation of 8-(4-chlorophenyl)-6-(1-methyl-lHbenzo [ d]imidazol-6-yl)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-one Pass R Step P: 8-(4-chlorophenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6naphthyridin-2-amine 15a A mixture of naphthyridin-2-amine Pd(PPha)4 (52.0 mg, Ν'ΆΑ x AÁ A 0 NN CF3 1 H 3 0 Cl 15a 8-bromo-7-methoxy-N-(2,2,2-trifluoroethyl)-1, 6- (300.0 mg, 0.9 mmol, 1.0 equiv), 0.05 mmol, 0.05 equiv.), CS2CO3 (580.0 279 mg, 1.8 mmol, 2.0 equivalents) and 4-chlorophenylboronic acid (208.0 mg, 1.3 mmol, 1.5 equivalents) in dioxane-water (5.0 mL, 9 / 1, v / v) was stirred at 100°C under a N2 atmosphere for 16 hours. The reaction mixture was then diluted with water (20 mL) and extracted with EtOAc (20 mL x 3). All organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (eluent: PE / EA = 2 / 1), yielding 8-(4-chlorophenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthiridin-2-amine (300 mg, 92% yield) as a white solid. LC-MS: m / z 368 [M+H]+. Step Q: 8-(4-chlorophenyl)-2- (2,2,2-trifluoroethylamino)-1,6 naphthyridin-7(6H)-one 16a A mixture of 8-(4-chlorophenyl)-7-methoxy-N-(2,2,2-trifluoroethyl)-1,6-naphthiridin-2-amine (300 mg, 0.8 mmol, 1.0 equivalent), TsOH (422 mg, 2.5 mmol, 3.0 equivalents), and Nal (407.0 mg, 2.5 mmol, 3.0 equivalents) in MeCN (10 mL) was stirred at 80°C for 2 hours. The reaction mixture was then quenched with ice water (10 mL) and extracted with EtOAc (10 mL x 3). 280 organic layers were combined, washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (DCM / MeOH = 20 / 1), yielding 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthiridin-7(6H)-one (280 mg, 97% yield) as a white solid. LC-MS: m / z 354 [M+H]+. Example 234, Step R: 8-(4-chlorophenyl)-6-(1-methyl-lHbenzo[ d]imidazol-6-yl)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-one A mixture of 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethylamino)1,6-naphthyridin-7(6H)-one (50.0 mg, 0.14 mmol, 1.0 equivalent), Cul (26.6 mg, 0.14 mmol, 1.0 equivalent), CsF (63.8 mg, 0.4 mmol, 3.0 equivalent), Ni,ife-dimethylcyclohexan-l,2-diamine (29.8 mg, 0.2 mmol, 1.5 equivalent) and 6-bromo-l-methyl-lHbenzo[d]imidazole (44.3 mg, 0.2 mmol, 1.5 equivalent) in MeCN (3 mL) was stirred at 100°C under an atmosphere of N2 for 3h. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The organic layers were combined, and 281 were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC under reduced pressure which yielded 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6yl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one (Example 234). iH NMR (400 MHz, DMSO-cG) δ: 8.50 (s, 1H) , 8.40-8.28 (m, 2H) , 7.82 (s, 1H) , 7.75 (d, J = 9.2 Hz, 2H) , 7.64 (d, J = 8.4 Hz, 2H), 7.37-7.28 (m, 3H), 6.51 (d, J= 8.8 Hz, 1H), 4.22-4.10 (m, 2H), 3.87 (s, 3H). LC-MS: m / z 484 [M+H]+. Example 235: 8-(4-chlorophenyl)-6-(1-methyl-1Hbenzo [ d][l,2,3]triazol-6-i)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-ona The stock compound is synthesized from the intermediate compound 16a with 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazol by the general process V (Paso R). ΧΗ NMR (400 MHz, DMSO-ds) δ: 8.53 (s, 1H) , 8.41 (t, J= 6.0 Hz, 1H) , 8.17 (d, J = 3.6 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.75 (d, J= 9.2 Hz, 1H), 7.64 (d, J= 8.4 Hz, 2H), 7.54 (dd, J= 9.2 282 Hz, 1.6 Hz, 1H), 7.34 (d, J= 8.4 Hz, 2H), 6.52 (d, J= 9.2 Hz, 1H), 4.35 (s, 3H), 4.23-4.10 (m, 2H). LC-MS: m / z 485 [M+H]+. Example 236: 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16a with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). 4H NMR (400 MHz, DMSO-ds) δ: 8.51 (s, 1H), 8.47 (s, 1H), 8.36 (t, J= 6.4 Hz, 1H), 7.84 (d, J= 1.2 Hz, 1H), 7.75 (d, J= 8.8 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.31 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 6.50 (d, J = 9.2 Hz, 1H), 4.22 (s, 3H), 4.09-4.06 (m, 2H). LC-MS: m / z 484 [M+H]+. Example 237: 8-(4-chlorophenyl)-6-(2,3-dimethyl-2H-indazol-5-yl)2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one 283 The title compound was synthesized from intermediate compound 16a with 5-bromo-2,3-dimethyl-2H-indazole by general procedure V (Step R). iR NMR (400 MHz, DMSO-ds) δ: 8.50 (s, 1H) , 8.34 (br s, 1H) , 7.84 (d, J= 2.0 Hz, 1H), 7.76 (d, J= 8.4 Hz, 1H) , 7.65 (d, J= 8.8 Hz, 2H) , 7.58 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.8 Hz, 1H), 6.50 (d, J = 8.8 Hz, 1H), 4.18-4.03 (m, 2H), 4.10 (s, 3H), 2.64 (s, 3H). LC-MS: m / z 498 [M+H]+. Example 238: 8-(4-chlorophenyl)-6-(4-methoxyphenyl)-2-(2,2,2trifluoroethylamino)-1,6-naphthyridin-7(6H)-ona The title compound is synthesized from the intermediate compound 16a with 1-bromo-4-methoxybencene by the general process V (Paso R). íR NMR (400 MHz, DMSO-ds) δ: 8.41 (s, 1H) , 8.34 (t, J= 6.0 Hz, 1H) , 7.74 (d, J = 9.2 Hz, 1H) , 7.62 (d, J = 8.4 Hz, 2H) , 7.43 284 (d, J= 8.8 Hz, 2H), 7.33 (d, J= 8.4 Hz, 2H), 7.07 (d, J= 8.8 Hz, 2H), 6.49 (d, J= 9.2 Hz, 1H), 4.20-4.07 (m, 2H), 3.83 (s, 3H). LC-MS: m / z 460 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-7-methoxy-N-(2,2,2trifluoroethyl)-1,6-naphthyridine-2-amine 15b 8-(4-(difluoromethoxy)phenyl)-7-methoxy-N- (2,2,2-trifluoroethyl) - 1,6-Naphthyridin-2-amine 15b was synthesized from intermediate compound 10a with 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by general procedure V (Step P). LC-MS: m / z 400 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one 16b 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylamino)-1,6naphthyridin-7(6H)-one 16b was synthesized from intermediate compound 15b by general procedure V (Step Q). LC-MS: m / z 386 [M+H]+. 285 Example 239: 8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazole 5-yl)-2-(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16b with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). iR NMR (400 MHz, DMSO-ds) δ: 8.49 (s, 1H), 8.48 (s, 1H), 8.31 (t, J= 6.0 Hz, 1H), 7.84 (d, J= 1.6 Hz, 1H), 7.75 (d, J= 9.2 Hz, 1H), 7.71-7.64 (m, 3H), 7.31 (dd, J= 9.2 Hz, 1.6 Hz, 1H) , 7.25 (t, Jhf = 74.4Hz, 1H) , 7.09 (d, J= 8.8 Hz, 2H) , 6.49 (d, J= 9.2 Hz, 1H), 4.22 (s, 3H), 4.21-4.09 (m, 2H). LC-MS: m / z 516 [M+H]+. Example 240: 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-lH benzo[ d]imidazol-6-yl)-2-(2,2,2-trifluoroethylamino)-1,6 naphthyridin-7(6H)-one CCHK 286 The title compound was synthesized from intermediate compound 16b with 6-bromo-l-methyl-lH-benzo[d]imidazole by general procedure V (Step R). 4H NMR (400 MHz, DMSO-ds) δ: 8.49 (s, 1H) , 8.33 (br s, 1H) , 8.32 (s, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.78-7.72 (m, 2H) , 7.66 (d, J = 8.8 Hz, 2H) , 7.31 (dd, J = 8.4 Hz, 2.0 Hz, 1H) , 7.25 (t, Jhf= 74.4Hz, 1H) , 7.09 (d, J= 8.8 Hz, 2H) , 6.51 (d, J= 9.2 Hz, 1H), 4.22-4.10 (m, 2H), 3.87 (s, 3H) . LC-MS: m / z 516 [M+H]+. Example 241: 8-(4-(difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2(2,2,2-trifluoroethylamino)-1,6-naphthyridin-7(6H)-ona The composition of the title is synthesized starting from the intermediate composition 16b with 1-bromo-4-methoxybenceno by means of the general procedure V (Paso R). 4H NMR (400 MHz, DMSO-ds) δ: 8.40 (s, 1H) , 8.30 (t, J= 5.6 Hz, 1H) , 7.73 (d, J = 9.2 Hz, 1H) , 7.63 (d, J = 8.8 Hz, 2H) , 7.43 (d, J = 9.2 Hz, 2H), 7.24 (t, Jhf = 74.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 9.2 Hz, 2H), 6.48 (d, J = 9.2 Hz, 1H), 4.20-4.07 (m, 2H), 3.82 (s, 3H). LC-MS: m / z 492 [M+H]+. 287 Preparation of 8-bromo-7V-cyclopropyl-7-methoxy-l,6-naph thyridin-2 amine 10b O γ N Br 8-bromo-7V-cyclopropyl-7-methoxy-l, 6-naf thyridin-2-amine 10b was synthesized from the fundamental intermediate compound I with cyclopropanamine by the general procedure V (Step J). LC-MS: m / z 294 [M+H]+. Preparation of N-cyclopropyl-8-(4-(difluoromethoxy)phenyl)-7-methoxy-1,6-naphthyridin-2-amine 15c OCHF215c N-cyclopropyl-8-(4-(difluoromethoxy)phenyl)-7-methoxy-1,6-naphthyridin-2-amine 15c was synthesized from intermediate compound 10b with 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by general procedure V (Step P). LC-MS: m / z 358 [M+H]+. Preparation of 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-1,6-naphthyridin-7(6H)-one 16c 288 CChR 16c 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-1, 6-naphthyridin-7(6H)-one 16c was synthesized from intermediate compound 15c by general procedure V (Step Q). LC-MS: m / z 344 [M+H]+. Example 242: Preparation of 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16c with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). 4H NMR (400 MHz, DMSO-ds) δ: 8.46 (s, 1H), 8.37 (br s, 1H), 7.90 (br s, 1H), 7.84-7.81 (m, 2H), 7.87 (d, J= 9.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 9.2, 2.0 Hz, 1H), 7.23 (t, Jhf = 74.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.31 (t, J = 8.8 Hz, 1H), 4.22 (s, 3H), 2.80-2.70 (m, 1H), 0.80-0.61 (m, 2H), 0.55-0.42 (m, 2H). LC-MS: m / z 474 [M+H]+. 289 Preparation of 8-bromo-2-ethoxy-7-methoxy-l,6-naphthyridine 10c be 10c 8-bromo-2-ethoxy-7-methoxy-l,6-naphthyridine 10c was synthesized from the fundamental intermediate compound I with EtONa / EtOH by the general procedure V (Step J). LC-MS: m / z 283 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-ethoxy-7-methoxy-l,6naphthyridine 15d 8-(4-chlorophenyl)-2-ethoxy-7-methoxy-l,6-naphthyridine 15d was synthesized from 10c with 4-chlorophenylboronic acid by the general procedure V (Step P). LC-MS: m / z 315 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-ethoxy-l, 6-naphthyridin-7(6H)one 16d A mixture of 8-(4-chlorophenyl)-2-ethoxy-7-methoxy-l,6-naphthyridine (550.0 mg, 1.8 mmol, 1.0 equivalent), TsOH (958.0 mg, 5.3 mmol, 290 3.0 equivalents), LiCl (115.0 mg, 5.3 mmol, 3.0 equivalents) in DMF (12.0 mL) was stirred at 120°C for 5 hours. The mixture was poured into iced aqueous NH4Cl (10 mL). The mixture was extracted with EA (10 mL x 3) and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography on silica gel (PE : EA = 4 : 1 to 0 : 1) yielding 8-(4-chlorophenyl)-2-ethoxy-1,6-naphthiridin-7(6H)-one (180 mg, 34% yield) as a yellow solid. LC-MS: m / z 301 [M+H]+. Example 243: Preparation of 8-(4-chlorophenyl)-2-ethoxy-6-(quinolin-6-yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16d with 6-bromoquinoline using general procedure V (Step R). íR NMR (400 MHz, DMSO-cJ) δ: 9.02 (dd, <7 = 8.0, 1.6 Hz, 1H) , 8.85 (s, 1H) , 8.48 (d, J= 7.2 Hz d 1H), 8.24 (d, 1.4 (d) J= Hz J = 8.8 Hz, 1H) , 7.98 (d, J = 9.2 Hz, 1H) , 7.95 (dd, J = 8.8, 2.4 Hz, 1H) , 7.68 (d, J= 8.4 Hz, 2H) , 7, 4.65 (dd 7.41 (d, J= 8.4 Hz, 2H), 6.57 (d, J= 9.2 Hz, 1H) , 291 4.27 (q, J= 7.2 Hz, 2H) , 1.28 (t, J= 7.2 Hz , 3H) . LC-MS: m / z 428 [M+H]+. Example 244: 8-(4-chlorophenyl)-2-ethoxy-6-(quinoxalin-6-yl)-1,6naphthyridine-7(6H)-one Cl The title compound was synthesized from intermediate compound 16d with 6-bromoquinoxaline by general procedure V (Step R). XH NMR (400 MHz, DMSO-ds) δ: 9,06 (dd, <7 = 4, 4 Hz, 2,0 Hz, 2H) , 8,88 (s, 1H), 8,38 (d, J = 2,4 Hz, 1H), 8,25 (d, J = 8,8 Hz, 1H) , 8,09 (dd, J = 9.0 Hz, 2.0 Hz, 1H) , 7.98 (d, J = 9.0 Hz, 1H) , 7.69 (d, J = 8.8 Hz, 2H) , 7.42 (d, J = 8.8 Hz, 2H) , 6.58 (d, J= 9.0 Hz, 1H) , 4.27 (q, J= 7.2Hz, 2H) , 1.28 (t, J= 7.2 Hz, 3H). LC-MS: m / z 429 [M+H]+. Example 245: 8-(4-chlorophenyl)-6-(cinolin-6-yl)-2-ethoxi-l,6 naftiridin-7(6H)-ona 292 The title compound is synthesized from the intermediate compound 16d with 6-bromocinoline by the general process V (Paso R). íR NMR (400 MHz, DMSO-ds) δ: 9.49 (d, J= 6.0 Hz, 1H) , 8.87 (s, 1H) , 8.62 (d, J = 9.2 Hz, 1H) , 8.37 (d, J = 2.0 Hz, 1H) , 8.33 (d, J= 6.0 Hz, 1H), 8.18 (d, J= 6.4 Hz, 1H) , 8.16 (d, J= 2.0 Hz, 1H) , 7.98 (d, J = 9.2 Hz, 1H) , 7.69 (d, J = 8.6 Hz, 2H) , 7.42 (d, J= 8.6 Hz, 2H) , 6.59 (d, J= 9.2 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H). LC-MS: m / z 429 [M+H]+. Example 246: 8-(4-chlorophenyl)-2-ethoxi-6- (quinazolin-6-yl)-1,6 naftiridin-7(6H)-ona Cl The title compound is synthesized from the intermediate compound 16d with 6-bromoquinazoline by the general procedure V (Paso R). 293 iH NMR (400 MHz, DMSO-ds) δ: 9.71 (s, 1H) , 9.42 (s, 1H) , 8.86 (s, 1H) , 8.44 (d, J = 2.0 Hz, 1H) , 8 J = Hz (dd 1H), 8.17 (d, J= 8.8 Hz, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.68(d, J = 8.4 Hz, 2H), 7.41 (d, J= 8.4 Hz, 2H), 6,4, J= 8 8 (d, 8 = 7.2 Hz, 2H), 1.28 (t, J= 7.2 Hz, 3H). LC-MS: m / z 429 [M+H]+. Example 247: 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5 il)-1,6-naphthyridine-7(6H)-ona OI The title compound was synthesized from intermediate compound 16d with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). iH NMR (400 MHz, DMSO-ds) δ: 8.75 (s, 1H) , 8.50 (s, 1H) , 7.97 (d, J= 9.1 Hz, IH), 7.89 (d, J= 2.0 Hz, 1H,6), 7.6 J, 70 (d (d, J = 8.6 Hz, 2H) , 7.40 (d, J = 8.6 Hz, 2H), 7.33 (dd, J = 9.2 Hz, 2.4 Hz, 1H), 6.54 (d, J= 9.2 Hz, 1H) 2), 4,25 = 6,25 (q, J (s, 3H) , 1.27 (t, J= 6.8 Hz, 3H) . LC-MS: m / z 431 [M+H]+. 294 Example 248: 8-(4-chlorophenyl)-2-ethoxy-6-(1-methyl-lHbenzo[d]imidazol-6-yl)-1,6-naphthyridine-7(6H)-one Cl The title compound was synthesized from intermediate compound 16d with 6-bromo-l-methyl-lH-benzo[d]imidazole by general procedure V (Step R). íR NMR (400 MHz, DMSO-d6) δ: 8.74 (s, 1H) , 8.34 (s, 1H) , 7.97 (d, J= 9.0 Hz, 1H), 7.85 (d, J= 2.0 Hz, J=H) 8 , 7 (7 , 7.67 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.34 (dd, J = 8.5 Hz, 2.0 Hz, 1H) , 6.55 (d, J = 9.0 Hz, 7, 1,2 = 2) 3.87 (s, 3H), l.27(t, J= 7.2 Hz, 3H). LC-MS: m / z 431 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-methoxy 1,6-use 15e OCHF215e 8- (4-(difluoromethoxy)phenyl)-2-ethoxy-7-methoxy-l,6-naphthyridine 15e was synthesized from the intermediate compound 10c with 2—(4—(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane 295 using the general procedure V (Step P). LC-MS: m / z 347 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-l,6naphthyridin-7(6H)-one 16e OCHF216e 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-l,6-naphthyridin-7(6H)-one 16e is prepared from intermediate compound 16d by general procedure V (Step Q). LC-MS: m / z 333 [M+H]+. Example 249: Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6-dihydropyridin-3yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16e with 5-bromo-l-(2-(methylsulfonyl)ethyl)pyridin2(lH)-one by general procedure V (Step R). 4H NMR (400 MHz, DMSO-cG) δ: 8.61 (s, 1H) , 8.17 (d, J= 2.8 Hz, 1H) , 7.93 (d, J = 9.2 Hz, 1H) , 7.69 (dd, J. Hz, 9.6 Hz, 2.2.2 1H) , 7.65 (d, J = 8.8 Hz, 2H) , 7.28 (t, Jhf = 74.4 Hz, 1H) , 6.55 (d, J = 9.2 Hz, 1H) , 6.52 (d, J = 9.6) Hz (1,4 Hz, 2H) , 4.24 (q, J = 7.2 Hz, 2H) , 3.61 (t, J = 7.2 Hz, 2H) , 3.08 (s, 3H) , 1.26 (t, J = 7.2 Hz, 3H) . LC-MS: m / z 532 [M+H]+. Example 250: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(4methoxyphenyl)-1,6-naphthyridine-7(6H)-one The title compound was synthesized from intermediate compound 16e with l -bromo-4-methoxybenzene by general procedure V (Step R). iH NMR (400 MHz, DMSO-ds) δ: 8.64 (s, 1H) , 7.94 (d, J = 9.2 Hz, 1H) , 7.67 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.8 Hz), JfH7 (J = 27, 4, 4, Hz Hz, 1H) , 7.15 (d, J = 8.8 Hz, 2H) , 7.09 (d, J = 8.8 Hz, 2H), 6.52 (d, J= 9.2 Hz, 1H), 4.24 (q, J= 7.2 Hz, 36H, 3H), 3 7.2 Hz, 3H). LC-MS: m / z 439 [M+H]+. Example 251: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl2H-indazol-5-yl)-1, 6-naphthyridine-7(6H) -one 297 cchi-2 The title compound was synthesized from intermediate compound 16e with l -bromo-4-methoxybenzene by general procedure V (Step R). 4H NMR (400 MHz, DMSO-ds) δ: 8.73 (s, 1H) , 8.50 (s, 1H) , 7.96 (d, J = 9.2 Hz, 1H) , 7.89 (d, J = 1.6 Hz, 453 (7, 7), 7 (dd, J = 9.2 Hz, 2.0 Hz, 1H) , 7.28 (t, Jhf = 74.4 Hz, 1H) , 7.15 (d, J = 8.8 Hz, 2H), 6.54 (d, J= 8.8 Hz, J, 1,2 = 2) . 4.22 (s, 3H) , 1.27 (t, J = 7.2 Hz, 3H) . LC-MS: m / z 4 63 [M+H]+. Example 252: 8-(4- (difluoromethoxy)phenyl)-2-ethoxy-6-(1-methylH-benzo[d][l,2,3]triazol-6-yl)-l,6-naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16e with 6-bromo-l-methyl-lH-benzo[d][1,2,3]triazole by general procedure V (Step R). 298 Z NMR (400 MHz, DMSO-ds) δ: 8.76 (s, 1H) , 8.22-8.17 (m, 2H) , 7.96 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H, 58), 7.69 (d, J = 8.8 Hz, 2H. Hz, 1H) , 8.28 (t, Jhf = 74.4 Hz, 1H) , 7.16 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 9.2 Hz, 1H), 4.35 (s, 3H), J = 7.2 Hz, 3H). LC-MS: m / z 464 [M+H]+. Example 253: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methylH-benzo[d]imidazol-6-yl)-1,6-naphthyridin-7(6H) -one ochf2 The title compound was synthesized from intermediate compound 16e with 6-bromo-l-methyl-lH-benzo[d]imidazole by general procedure V (Step R). iH NMR (400 MHz, DMSO-ds) δ: 8.79 (s, 1H), 8.45 (br s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.94 (br s, 1H), 7.88 (br s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 6.0 Hz, 1H), 7.34 (t, Jhf = 74.4 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 8.8 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 3.94(s, 3H), 1.33 (t, J= 7.2 Hz, 3H). LC-MS: m / z 463 [M+H]+. Preparation of 8-bromo-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6 naphthyridine lOd 299 Br 10d 8-bromo-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridine lOd was synthesized from the fundamental intermediate compound I with 2,2,2-trifluoroethanol by general procedure V (Step J). LC-MS: m / z 337 [M+H]+. Preparation of 8-(4-chlorophenyl)-7-methoxy-2-(2,2,2trifluoroethoxy)-1,6-naphthyridine 15f 8-(4-chlorophenyl)-7-methoxy-2-(2,2,2-trifluoroethoxy)-1,6 naphthyridine 15f was synthesized from lOd with 4 chlorophenylboronic acid by general procedure V (Step P). LC-MS: m / z 369 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethoxy)-1,6 naphthiridin-7(6H)-one 16f Cl I6f 300 8-(4-chlorophenyl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthiridin7(6H)-one 16f was synthesized from 15f by general procedure V (Step Q). LC-MS: m / z 355 [M+H]+. Example 254: Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2-hindazol-5-yl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6H)one Cl The title compound was synthesized from intermediate compound 16f with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). 4H NMR (400 MHz, DMSO-ds) δ: 8.86 (s, 1H) , 8.50 (s, 1H) , 8.10 (d, J= 9.2 Hz, 1H) , 7.91 (d, J= 2.0 Hz, 1H) , 7.71(d, J= 9.2 Hz, 1H) , 7.68 (d, J = 8.8 Hz, 2H) , 7.41 (d, J = 8.8 Hz, 2H) , 7.35 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 6.71 (d, J= 9.2 Hz, 1H), 4.93 (q, J= 9.2 Hz, 2H) , 4.23 (s, 3H) . LC-MS: m / z 485 [M+H]+. Example 255: 8-(4-chlorophenyl)-6-(1-methyl-1H-benzo[d]imidazol-6yl)-2-(2,2,2-trifluoroethoxy)-1,6-naftiridin-7(6H)-ona 301 Cl The stock compound is synthesized from the intermediate compound 16f with 6-bromo-1-methyl-1H-benzo[d]imidazole by the general process V (Paso R). íH NMR (400 MHz, DMSO-ds) δ: 8.85 (s, 1H) , 8.34 (s, 1H) , 8.10 (d, J= 9.2 Hz, 1H) , 7.87 (d, J= 2.0 Hz, 1H) , 7.79 (d, J= 8.4 Hz, 1H) , 7.68 (d, J = 8.8 Hz, 2H) , 7.42 (d, J = 8.8 Hz, 2H) , 7.35 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 6.71 (d, J= 8.8 Hz, 1H), 4.93 (q, J= 9.2 Hz, 2H), 3.87 (s, 3H). LC-MS: m / z 485 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-7-methoxy-2-(2,2,2 trifluoroethoxy)-1,6-naphthyridine 15g ochf2i5g 8-(4-(difluoromethoxy)phenyl)-7-methoxy-2-(2,2,2-trifluoroethoxy) 1,6-Naphthyridine 15g was synthesized from 10d with 2-(4(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane by the general procedure V (Step P). LC-MS: m / z 401 [M+H]+. 302 Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6H)-one 16g 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)-1, 6-naphthyridin-7(6H)-one 16g was synthesized from 15g by general procedure V (Step Q). LC-MS: m / z 387 [M+H]+. Example 256: Preparation of 8-(4-(difluoromethoxy)phenyl)-6-(2methyl-2H-indazol-5-yl)-2-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-7(6H)-one QCHF; The title compound was synthesized from intermediate compound 16g with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). iR NMR (400 MHz, DMSO-ds) δ: 8.85 (s, 1H), 8.51 (s, 1H), 8.10 (d, J = 9.2 Hz, 1H), 7.91 (d, J = 2.0 Hz, 1H), 7.73-7, 67 (m, 3H), 7.35 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.28 (t, Jhf = 74.4 Hz, 1H), 7.17 (d, J= 8.8 Hz, 2H), 6.70 (d, J= 9.2 Hz, 1H), 4.92 (q, J = 8.8 Hz, 2H), 4.23 (s, 3H). LC-MS: m / z 517 [M+H]+. 303 Example 257: 8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-lHbenzo[d]imidazol-6-yl)-2-(2,2,2-trifluoroethoxy)-1,6naphthyridin-7(6H)-one The title compound was synthesized from intermediate compound 16g with 6-bromo-l-methyl-lH-benzo[d]imidazole by general procedure V (Step R). iR NMR (400 MHz, DMSO-ds) δ: 8.84 (s, 1H) , 8.34 (s, 1H) , 8.10 (d, J = 9.2 Hz, 1H) , 7.87 (d, J = 2.0 Hz, 189, H = 7,7 7.71 (d, J = 8.8 Hz, 2H) , 7.36 (dd, J = 8.8 Hz, 2.0 Hz, 1H) , 7.28 (t, Jhf = 74.4 Hz, 1H) , 7.17 (d, J= 8.7) Hz (2.71) Hz, Hz, 1H), 4.93 (q, J= 8.8 Hz, 2H), 3.88 (s, 3H). LCMS: m / z 517 [M+H]+. Example 258: 8-(4-(difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2(2,2,2-trifluoroethoxy)-1,6-naphthyridine-7(6H)-one 304 The title compound was synthesized from intermediate compound 16g with l -bromo-4-methoxybenzene by general procedure V (Step R). íH NMR (400 MHz, DMSO-ds) δ: 8.81 (s, 1H) , 8.13 (d, J = 9.2 Hz, 1H) , 7.74 (d, J = 8.8 Hz, 2H) , 7.54 (d, J = 8.3 = 8.3) 74.4 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H) , 7.16 (d, J = 8.8 Hz, 2H) , 6.74 (d, J= 8.8 Hz, 1H), 4.97 (q, J= 3.8) Hz). LC-MS: m / z 493 [M+H]+. Preparation of 8-bromo-2-(ethylthio)-7-methoxy-l,6-naphthyridine lOe 8-bromo-2-(ethylthio)-7-methoxy-1,6-naphthyridine lOe was synthesized from intermediate compound I with sodium ethanethiolate by general procedure V (Step J). LC-MS: m / z 299, 301 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-(ethylthio)-7-methoxy-l,6 naphthyridine 15h 305 8-(4-chlorophenyl)-2-(ethylthio)-7-methoxy-1,6-naphthyridine 15h was synthesized from 10e with 4-chlorophenylboronic acid by the general procedure V (Step P). LC-MS: m / z 331 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-(ethylthio)-1,6-naphthyridin7(6H)-one 16h 8-(4-chlorophenyl)-2-(ethylthio)-1,6-naphthyridin-7(6H)-one 16h was synthesized from 15h by general procedure V (Step Q). LC-MS: m / z 317 [M+H]+. Example 259: Preparation of 8-(4-chlorophenyl)-2-(ethylthio)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one The title compound was synthesized from the intermediate compound 16h with 5-bromo-2-methyl-2H-indazole by general procedure V (Step R). íR NMR (400 MHz, DMSO-ck) δ: 8.82 (s, 1H) , 8.50 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.84 (d, J= 8.8 Hz, 1H), 7.2, 71 (d 306 1H) , 7.64 (d, J = 8.6 Hz, 2H) , 7.42 (d, J = 8.6 Hz, 2H) , 7.35 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 6,84 (d, J= 33 (Hs), 4, Hz 2.99 (q, J= 7.2 Hz, 2H) , 1.16 (t, J= 7.2 Hz, 3H) . LC-MS: m / z 4 4 7 [M+H]+. Preparation of 8-bromo-7-methoxy-2-propyl-l,6-naphthyridine lOf ο from Br 10Í To a mixture of 8-bromo-2-chloro-7-methoxy-1, 6-naphthiridine (300.0 mg, 1.1 mmol, 1.0 equivalent) and Fe(acac)a (387.0 mg, 1.1 mmol, 1.0 equivalent) in THF / NMP (5.0 mL / 0.5 mL) 11.0 mL of propylmagnesium bromide (IM solution in diethyl ether, 11.0 mmol, 10.0 equivalents) was slowly added at room temperature. The mixture was stirred at room temperature for 1 hour and carefully quenched with water. The mixture was diluted with EtOAc, washed with water and then with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid chromatography on silica gel (PE / EtOAc = 5 / 1) which gave 8-bromo-7-methoxy-2-propyl-1,6-naphthiridine (180 mg, 59% yield) as a yellow solid. LC-MS: m / z 281, 283 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-7-methoxy-2-propyl 1,6-naphthyridine 15i 307 8-(4-(difluoromethoxy)phenyl)-7-methoxy-2-propyl-l,6-naphthyridine 15i was synthesized from 10f with 2-(4-(difluoromethoxy)phenyl)4,4,5,5-tetramethyl-l,3,2-dioxaborolane by general procedure V (Step P). LC-MS: m / z 345 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-propyl-1,6-naphthyridin-7(6H)-one 16i OCHK 16Í 8-(4-(difluoromethoxy)phenyl)-2-propyl-l,6-naphthyridin-7(6H)-one 16i was synthesized from 15i using the general procedure V (Q step). LC-MS: m / z 331 (M+H)+. Example 260: Preparation of 8-(4-(difluoromethoxy)phenyl)-6-time til-lH-benzo[d]imidazol-6-yl)-2-propyl-l,6-naphthyridin-7(6H)one 308 The title compound was synthesized from intermediate compound 16i with 6-bromo-l-methyl-lH-benzo[d]imidazole by general procedure V (Step R). íR NMR (400 MHz, DMSO-d6) δ: 8.87 (s, 1H), 8.34 (s, 1H), 7.99 (d, J= 8.8Hz, 1H), 7.87 (d, J= 2.0 Hz, 1H) , H 7, 79 (d 7.65 (d, J = 8.6 Hz, 2H) , 7.36 (dd, J = 8.8 Hz, 2.0 Hz, 1H) , 7.29 (t, Jhf = 74.4 Hz, 1H) , 7.16 (d, J= 6.93 Hz) 8, 8, H = 6.6 Hz ( Hz, 1H), 3.88 (s, 3H) , 2.70–2.66 (m, 2H) , 1.73–1.62 (m, 2H), 0.92 (t, J= 7.2 Hz, 3H) . LC-MS: m / z 461 [M+H]+. The following compounds were synthesized using the General Procedure V (steps J, P, Q and R) : / NXX 0 LC-MS (ESI) : m / z 459 [M+H]+. XH NMR (400 MHz, DMSO- Cl de) δ 8.73 (s, 1H) , 104-A 8- (4-chlorophenyl)-2- 8.57 (d, J = 0.9 Hz, ethoxy-6-(2-isopropyl- 1H), J =96 (d 2H-indazole-5-yl)-1, 6- naphthyridine-7(6H)-ona Hz, 1H), 7.87 (dd, J =2.1, 0.8 Hz, 1H), 309 (sintetizada desde 8(4-chlorofenil)-2-etoxi1,6-naftiridin-7(6H)ona y 5-bromo-2isopropyl-2H-indazol (Ref: Organic Letters, 16 (11), 3114-3117; 2014)) 7.72 (dt, J = 9.1, 0.9 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.43 7.38 (m, 2H), 7.33 (dd, J = 9.1, 2.1 Hz, 1H), 6, 54 (d, J = 9.0 Hz, 1H), 4.89 (hept, J = 6.6 Hz, 1H), 4.26 (q, J = 7.0 Hz, 2H), 1.58 (d, J = 6.6 Hz, 6H), 1.27 (t, J = 7.1 Hz, 3H). 105-A NZ-, NJ Λ N YY 0 c 8- (4-chlorofenil)-6- (2,3-dimethyl-2H-indazol-5-il)-2-etoxi- 1,6-naftiridin-7(6H)ona LC-MS (ESI): m / z 445 [M+H]+. 2H NMR (400 MHz, DMSOdg) δ 8.74 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 1.9 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.60 (d, J = 9.1 Hz, 1H), 7,447.37 (m, 2H), 7.29 (dd, J = 9.1, 2.0 Hz, 1H), 6, 54 (d, J = 9.0 310 Hz, IH), 4.25 (q, J = 7.0 Hz, 2H), 4.10 (s, 3H), 2.64 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). Ab c LC-MS (ESI): m / z 432 [M+H]+. ΧH NMR (400 MHz, DMSO- UI d6) δ 8.79 (s, IH), 8-(4-chlorofenil)-2- 8.20 (dd, J = 2.0, etoxi-6-(2-methyl-2H- 0.7 Hz, IH), 8.05 (d, benzo[d][1,2,3]triazol- J = 9.0 Hz, IH), 7.97 5-il)-1,6-naftiridin- (d, J = 9.2 Hz, IH), 106-A 7(6H)-ona 7.67 (d, J = 8.5 Hz, 2H), 7.58 (dd, J = (synthetic desde 8- 9.0, 2.0 Hz, IH) , (4-chlorofenil)-2-etoxi- 7.41 (d, J = 8.6 Hz, 1,6-naftiridin-7 (6H)- 2H), 6.56 (d, J = 9.0 ona y 5-bromo-2-methyl- Hz, IH), 4.56 (s, 2H- 3H), 4.26 (q, J = 7.1 benzo[d] [ 1,2,3]triazol Hz, 2H), 1.27 (t, J = (Ref: WO 2007 / 84451) 7.0 Hz, 3H). 311 LC-MS (ESI): m / z 532 107-A □. 1 1 JJ Horse; o O 8- (4- (difluoromethoxy)phenyl)- [M+H]+. 4H NMR (400 MHz, DMSOd6) 5 8.62 (s, 1H) , 8.17 (d, J = 2.9 Hz, (1H) , 7, 94 (d, J = 9.1 Hz, 1H), 7.69 (dd, J = 7.6. Hz) 9, 2.7, 2.2 8.6 Hz, 1H), 7,41 (d, J = 8.6 2-ethoxy-6-(1-(2- (methylsulfonyl)ethyl)-6oxo-1,6-dihydropyridine3-yl)-1,6-naphthyridine- 7(6H)-ona Hz, 2H (2, H), J = 6,6 (d, J = 9.7 Hz, 1H), 4.34 (t, J = 7.1 Hz, 2H) , 4.24 (q, J = 7.1 Hz, 2H), 3.61 (t, J = 7.1 Hz, 2H), 3.08 (s, 371 (H = 1,2). The following compounds were synthesized by General Procedure V (Method B) : el 312 108-A c C ,1 Z'Y / c''' ó ochf2 8- (4- (difluoromethoxy) phenyl)-2-ethoxy-6- (2- (2- (methylsulfonyl)ethyl )-2H-indazol-5-yl) m - 1,6-naphthyridine / MS (ESI5)- ona 7(6H [M+H]+. XH NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.63 (d, J = 0.9 Hz, 1H), 7.96 (d, J = 9, 1 Hz, 1H), 7.93 (dd, J = 2.1, 7.7 = Hz) 9.2, 0.9 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.38 (dd, J = 9.1, 2.1 Hz, 1H) , 7.27 (t, JHF = 74.4 Hzd, 1H), 7.6, J = 2.8 (d, = 9, 0 Hz, 1H), 4.94 (t, J = 6.8 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.91 (t, J = 6.8 Hz, 2H), 2.95 313 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). LC-MS (ESI): m / z 475 [M+H]+. 2H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.50 (s, 1H), 7.97 (d, J = 9.1 μg 1 Hz, 1H), 7.92 - 0 7.87 (m, 1H), 7.70 μg (d, J = 9.1 Hz, 109-A 8-(4-bromofenil)-2- 1H), 7.61 (d, J = etoxi-6-(2-methyl- 8.6 Hz, 2H), 7.53 2H-indazol-5-il)- (d, J = 8.6 Hz, 1,6-naftiridin- 2H), 7.34 (dd, J = 7(6H)-ona 9.1 2.0 Hz, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4,304.21 (m, 5H), 1.27 (t, J = 7.1 Hz, 3H). 314 110-A tz —ν Ί 1 (γι °CHF; 8-(6- (difluoromethoxy) pyridine-3-yl)-6-time til-2H-inda zol-5yl)-2- (2,2,2trifluoroethoxy) 1,6-naphthyridine-one (ESI 7(LC6H)-z [M+H]+. 4H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.57 − 8.47 (m, 2H), 8.20 (dd, J = 8.6, 2.4 Hz, 1H), 8.13 (d, J = 71.9) Hz, 3 2.0 Hz, 1H), 7.76 (t, JHF = 73.1 Hz, 1H), 7.72 (d, J = 9, 1 Hz, 1H), 7.37 (dd, J = 9.1, 2.0 Hz, 1H) , 7.11 (d, J = 6, = 1.1). 9.0 Hz, 1H), 4.94 (q, J = 9, 0 Hz, 2H), 4.23 (s, 3H). 111-AA rem a ) LC-MS (ESI): m / z 427 [M+H]+. 4H NMR (400 MHz, DMSO-d6) δ 8, 61 (s, 315 2-ethoxy-6-(1-methyl- 1H-benzo[d]imidazol-6-yl)-8- (6- (methylamino)pyridine -3-yl)-1,6- naphthyridine-7(6H)- ona 1H), 8,37 – 8,29 (m, 2H), J (7, 8,19), 9.1 Hz, 1H), 7.83 (d, J = 1, 9 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 8.7, 2.4 Hz, 1H), 7,32 (dd, J = 1.5, Hz), J = 8,6, 2 8.9 Hz, 1H), 6.44 (d, J = 8.7 Hz, 1H), 6.39 (t, J = 4.9 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 2, 309 (d = Hz), J = 1 7.0 Hz, 3H). 112-A = 8 / =\ V? c LC-MS (ESI): m / z 536 [M+H]+. XH NMR (400 MHz, DMSO-d6) δ 8, 94 (s, 316 6- (1-metil-lHbenzo[d]imidazol-6- il)-2- (2,2,2- trifluoroetoxi)-8- (6- 1H), 8,64 (d, J = 2,3 Hz, 1H), 8,36 (s, 1H), 8,29 (dd, J = 8,5, 2,4 Hz, 1H), 8,14 (d, J = (trifluorometoxi) 9,0 Hz, 1H), 7,90 piridin-3-il)-1,6- (d, J = 2,0 Hz, naftiridin-7(6H)- 1H), 7,80 (d, J = ona 8,5 Hz, 1H), 7,39 (dd, J = 8,5, 2,1 Hz, 1H), 7,32 (d, J = 8,5 Hz, 1H), 6,76 (d, J = 9, 0 Hz, 1H), 4 .95 (q, J = 9.0 Hz, 2H), 3.88 (s, 3H). LC-MS (ESI) : m / z f j 492 [M+H]+. 113-A 4H NMR (400 MHz, DMSO-d6) δ 8,85 (s, 8-(6- 1H), 8,65 (dd, J = ciclopropilpiridin- 2,2, 0,8 Hz, 1H) , 3-il)-6-(2-metil- 8,51 (s, 1H), 8,10 2H-indazol-5-il)-2- (d, J = 9, 0 Hz, 317 (2,2,2-trifluoroetoxi) - 1,6-naftiridin- 7(6H)-ona 1H), 7.93 - 7.87 (m, 2H), 7.72 (dt, J = 9, 2, 0, 9 Hz, 1H), 7.35 (dd, J = 9.1, 2.0 Hz, 1H), 7.30 (dd, J = 8.1, 0.8 Hz, 1H), 6.71 (d, J = 9, 0 Hz, 1H), 4.93 (q, J = 9.1 Hz, 2H), 4.23 (s, 3H), 2.12 (tt, J = 7.6, 5.2 Hz, 1H), 0.95 (ddd, J = 7.3, 5.5, 2.3 Hz, 4H). Il 1 LC-MS (ESI): m / z 388 [M+H]+. \ H 2H NMR (400 MHz, Yn DMSO-d6) δ 8.68 114-A 2-etoxi-6-(4- (dd, J = 2,2, 0,8 metoxifenil)-8-(6- Hz, 1H), 8.66 (s, metilpiridin-3-il)- 1H), 7.95 (d, J = 1,6-naftiridin- 9,1 Hz, 1H), 7.90 7(6H)-ona (dd, J = 8,0, 2,3 318 Hz, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.24 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 9, 0 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.83 (s, 3H), 2.48 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H). 115-AN Ί 1 0 U'CD3 2- (2,2-difluoroetoxi)-8- (4-(metoxi- d3)fenil)-6-ti- me til-2H-inda zol-5- il)-1,6-naftiridin- 7(6H)-ona LC-MS (ESI): m / z 466 [M+H]+. 2H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.50 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.89 (s, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 9.1, 2.1 Hz, 1H), 6, 92 (d, J = 8.8 319 Hz, 2H), 6.63 (d, J = 9.0 Hz, 1H), 6.35 (t, JHF = 54.7 Hz, 1H), 4.50 (td, JHF = 15.0, J = 3.6 Hz, 2H), 4.23 (s, 3H). 116-A —n Ί Ί A 0 ugd3 8-(4-(metoxi- d3)fenil)-6-ti- me til -2H- inda zol-5- il)-2- (2,2,2- trifluoroetoxi)- 1,6-naftiridin- 7(6H)-ona LC-MS (ESI): m / z 484 [M+H]+. 4H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.50 (s, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.90 (s, 1H), 7.71 (d, J = 9.1 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 9.1, 2.1 Hz, 1H), 6, 92 (d, J = 8.4 Hz, 2H), 6.67 (d, J = 8.9 Hz, 1H), 4.94 (q, J = 9.1 Hz, 2H), 4.22 (s, 3H). 320 117-A —N 1 I 0 ocd3 2-etoxi-8-(4- (metoxi-d3)fenil)6- (2-methyl-2H-indazol-5-il)-1, 6naftiridin-7(6H)ona LC-MS (ESI): m / z 430 [M+H]+. X-H 2H), 7.33 (d, J = 9.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 6.51 (d, J = 9.0 Hz, 1H), 4.35 4.08 (m, 5H), 1.26 (q, J = 7.4 Hz, 3H). 118-A —N 1 1 N^O^CFg pH ghf2 8-(6- (difluorometil) piridin-3-il)-6-(2- LC-MS (ESI): m / z 502 [M+H]+.2H NMR (400 MHz, DMSO-d6) δ 8.96 (br s, 2H), 8.52 (s, 1H), 8,29 (dd, J = 321 metil-2H-indazol-5- 8,1, 2,1 Hz, 1H), il)-2- (2,2,2- 8,15 (d, J = 9,0 trifluoroetoxi) - Hz, 1H), 7,94 (dd, 1,6-naftiridin- J = 2,1, 0.8 Hz, 7(6H)-ona 1H), 7.75 - 7.73 (m, 1H), 7.71 (dd, J = 2.2, 1.3 Hz, 1H), 7.38 (dd, J = 9.1, 2.1 Hz, 1H), 6.99 (t, JHF = 55.1 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 4,94 (q, J = 9.0 Hz, 2H), 4.23 (s, 3H). tí z 1 LC-MS (ESI): m / z (γXή^Ό^ 467 [M+H]+. Xil NyN 2H NMR (400 MHz, cf2 DMSO-d6) δ 9.41 (s, 119-A 2-etoxi-6-(2-methyl- 2H), 8.96 (s, 1H), 2H-indazol-5-il)-8- 8.52 (s, 1H), 8.07 (2-(trifluorometil) (d, J = 9, 1 Hz, pirimidin-5-il)- 1H), 7.94 (dd, J = 1,6-naftiridin- 2,0, 0,8 Hz, 1H), 7(6H)-ona 7.77 - 7.69 (m, 322 IH), 7.38 (dd, J = 9.1, 2.1 Hz, IH), 6.66 (d, J = 9.0 Hz, IH), 4.33 (q, J = 7.1 Hz, 2H), 4.23 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 120-A 7Tb Tn 8-(6-ciclopropilpiridin3-il)-6-(1-methyl-1H-benzo[d]imidazol-6il)-2-(2,2,2trifluoroetoxi)-1,6-naftiridin-7(6H)-ona LC-MS (ESI): m / z 492 [M+H]+. ΧΗ NMR (400 MHz, DMSO-d6) δ 8.85 (s, IH), 8.65 (d, J = 2.1 Hz, IH), 8.34 (s, IH), 8.10 (d, J = 9.0 Hz, IH), 7.94 - 7.88 (m, IH), 7.87 (d, J = 2.0 Hz, IH), 7.79 (d, J = 8.6 Hz, IH), 7.36 (dd, J = 8.6, 2.0 Hz, IH), 7.30 (d, J = 8.0 Hz, IH), 6.72 (d, J = 9, 0 Hz, IH), 4.94 (q, J = 323 9.0 Hz, 2H), 3.87 (s, 3H), 2.12 (dq, J = 12.8, 7.9, 6.7 Hz, 1H), 0.96 (dt, J = 10.0, 3.3 Hz, 4H). 121-ATI ίγΝ %f3 2-etoxi-6-(4-metoxifenil)-8-(6(trifluorometoxi)pyridin-3-il)-1,6naftiridin-7(6H)ona LC-MS (ESI): m / z 458 [M+H]+. X-H 8.9 Hz, 2H), 7.30 (dd, J = 8.5, 0.7 Hz, 1H), 7.10 (d, J = 9.0 Hz, 2H), 6.57 (d, J = 9, 0 Hz, 1H), 4.26 (q, J = 7.0 Hz, 2H), 3.84 324 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). z 1 rj Cl 8-(4-chlorofenil)-2etoxi-4-methyl-6-(2methyl-2H-indazol-5il)-1,6-naftiridin-7(6H)-ona LC-MS (ESI): m / z 445 [M+H]+. 2H NMR (400 MHz, DMSO-d6) δ 8.56 (s 1H), 8.49 (s, 1H), 7.89 (d, J = 1, 9 Hz, 1H), 7.69 (d, r J 122-A (sintetizada a partir de 3-bromo5-yodo-2metoxipiridin-4amina y etil (E)but-2-enoato mediante un general procedimiento V (secuencia de Rl- = 9.1 Hz, 1H), 7.65 - 7.59 (m, 2H), 7.43 - 7.37 (m, 2H), 7.34 (dd, J = 9.1, 2.0 Hz, 1H), 6.42 (d, J = 1.3 Hz, 1H), 4,284,16 (m, 5H), 2,43 (s, 3H), 1,25 (t, J = 7.0 Hz, 3H). R3-R2, Method B, Steps BD and L-0)) 325 123-A —n 1 | '^ A All An °XHF2 2- (2,2- difluoroetoxi)-8- (6- (difluorometoxi) piridin-3-il)-6-time til-2H-inda zol-5il)-1,6-naftiridin7(6H)-ona LC-MS (ESI): m / z 500 [M+H]+. 4H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.55 - 8.49 (m, 2H), 8.19 (dd, J = 8.5, 2.4 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7, 92 (dd, J = 2.1, 0.8 Hz, 1H), 7.76 (t, JHF = 73.1 Hz, 1H), 7.72 (dt, J = 9.2, 0.9 Hz, 1H), 7.36 (dd, J = 9.1, 2.0 Hz, 1H), 7.10 (dd, J = 8, 6, 0, 7 Hz, 1H), 6,69 (d, J = 9,0 (Hz, 1H), 6.36 (tt, JHF = 54.6, J = 3.4 Hz, 1H), 4.53 (td, JHF = 15.1, J = 3.4 Hz, 2H), 4.23 (s, 3H). 326 124-A Ν / <· —μ Ί 1 N^O^C Fa βγΝ CFa 6- (2-metil-2Hindazol-5-il)-2(2,2,2- trifluoroetoxi)-8(6- (trifluorometil) piridin-3-il)-1,6naftiridin-7(6H)- ona LC-MS (ESI): m / z 520 [M+H]+. XH NMR (400 MHz, DMSO-d6) δ 9,06 (d, J = 2,0 Hz, 1H) , 9,00 (s, 1H), 8,53 (s, 1H), 8,39 (dd, J = 8,2, 2,0 Hz, 1H), 8,17 (d, J = 9,1 Hz, 1H), 7,96 (dd, J = 2,1, 0,8 Hz, 1H), 7,92 (dd, J = 8,3, 0.8 Hz, 1H), 7,73 (dd, J = 9,2, 0,9 Hz, 1H), 7,39 (dd, J = 9,1, 2,0 Hz, 1H), 6,78 (d, J = 9, 0 Hz, 1H), 4,95 (q, J = 9,0 Hz, 2H), 4,24 (s, 3H). 327 125-A —ri Ί 1 (Ϊ1 ^n uxf3 2- (2,2-difluoroetoxi)-6- (2-methyl-2H-indazol-5-il)-8-(6(trifluorometoxi)pyridin-3-il)-1,6naftiridin-7(6H)ona LC-MS (ESI): m / z 518 [M+H]+. XH NMR (400 MHz, DMSO-d6) δ 8,91 (s, 1H), 8,63 (dd, J = 2,4, 0,6 Hz, 1H), 8,52 (s, 1H), 8,29 (dd, J = 8,5, 2,4 Hz, 1H), 8,10 (d, J = 9,1 Hz, 1H), 7,93 (dd, J = 2.0, 0.8 Hz, 1H), 7.72 (dt, J = 9.1, 0.9 Hz, 1H), 7.37 (dd, J = 9.1, 2.1 Hz, 1H), 7.31 (dd, J = 8.4, 0.7 Hz, 1H), 6.70 (d, J = 9, 0 Hz, 1H), 6.35 (tt, JHF = 54.6, J = 3.5 Hz, 1H), 4.52 (td, JHF = 15.0, J = 3.6 Hz, 2H), 4.23 (s, 3H). 328 LC-MS (ESI): m / z N 1 1 499 [M+H]+. ... 2- (2,2- (m, 3H), 7,35 (dd, 126-A difluoroetoxi)-8- J = 9,1, 2,0 Hz, (4- (difluorometoxi) 1H), 7,28 (t, JHF = fenil)-6-(2-metil- 74,3 Hz, 1H), 7,17 2H-indazol-5-il)-(d, J = 8.7 Hz, 1,6-naftiridin- 2H), 6.66 (d, J = 7(6H)-ona 9.0 Hz, 1H), 6.35 (tt, JHF = 54.7, J = 3.5 Hz, 1H), 4.51 (td, J = 15.0, 3.5 Hz, 2H), 4.23 (s, 3H). 329 LC-MS (ESI): m / z O^A^N^'O^CF. C^N OCHF; 8-(6- (difluorometoxi) 518 [M+H]+. 4H NMR (400 MHz, DMSO-d6) δ 8, 90 (s, 1H), 8,53 (d, J = 2,4 Hz, 1H), 8,35 (s, 1H), 8,20 (dd, J = 8,5, 2,4 Hz, 1H), 8,13 (d, J = 9,0 Hz, 1H), 7,89 127-A piridin-3-il)-6-(1- metil-lH- (t, J = 2,0 Hz, 1H), 7,76 (t, JHF = benzo[d]imidazol-6- il)-2- (2,2,2- trifluoroetoxi) - 1,6-naftiridin- 7(6H)-ona 73,1 Hz, 1H), 7,80 (d, J = 8,5 Hz, 1H), 7,38 (dd, J = 8,5, 2,1 Hz, 1H), 7,11 (d, J = 8,5 Hz, 1H), 6,75 (d, J = 9,0 Hz, 1H), 4,94 (q, J = 9, 0 Hz, 2H), 3.88 (s, 3H). 330 128-A C^N cf3 6- (1-metil-lH- benzo[d]imidazol-6il)-2- (2,2,2- trifluoroetoxi)-8(6- (trifluorometil) piridin-3-il)-1,6naftiridin-7(6H)ona LC-MS (ESI): m / z 520 [M+H]+. XH NMR (400 MHz, DMSO-d6) δ 9,06 (s, 1H), 8,99 (s, 1H) , 8,39 (d, J = 8,7 Hz, 1H), 8,36 (s, 1H), 8,17 (d, J = 9,0 Hz, 1H), 7,967,89 (m, 2H) , 7,81 (d, J = 8,5 Hz, 1H), 7,40 (dd, J = 8,7, 2,0 Hz, 1H), 6,79 (d, J = 9,0 Hz, 1H), 4,95 (q, J = 9,0 Hz, 2H), 3,88 (s, 3H). 129-A °chf2 8-(6- (difluorometoxi) LC-MS (ESI) : m / z 440 [M+H]+. XH NMR (400 MHz, DMSO-d6) δ 8,70 (s, 1H), 8,50 (dd, J = 2,3, 0,7 Hz, 1H), 8,16 (dd, J = 8,5, 331 piridin-3-il)-2-etoxi-6-(4-metoxfenil)-1,6naftiridin-7 (6H)ona 2.4 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.76 (t, JHF = 73.1 Hz, 1H), 7.48 (d, J = 8.9 Hz, 2H), 7.13 - 7.07 (m, 3H), 6.56 (d, J = 9.0 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H). 130-A TA —n Ί 1 ΓΗ 'YN 6- (2-methyl-2H- indazol-5-il)-8-(6- metilpiridin-3-il) - 2-(2,2,2- trifluoroetoxi) - 1,6-naftiridin- 7(6H)-ona LC-MS (ESI): m / z 466 [M+H]+. 2H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.52 (s, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.98 - 7, 90 (m, 2H), 7.72 (d, J = 9.1 Hz, 1H), 7.37 (dd, J = 9.1, 2.0 Hz, 332 1H), 7,27 (d, J = 8,0 Hz, 1H) , 6,72 (d, J = 9, 0 Hz, 1H), 4 ,94 (q, J = 9,0 Hz, 2H), 4,23 (s, 3H), 2,51 (s , 3H - buried). LC-MS (ESI): m / z 536 [M+H]+. ñ z 1 XH NMR (400 MHz, DMSO-d6) δ 8, 95 (s, 1H), 8,64 (d, J = 2,4 Hz, 1H), 8,52 6- (2-metil-2H- (s, 1H), 8,29 (dd, indazol-5-il)-2- J = 8,5, 2,4 Hz, 131-A (2,2,2- 1H), 8,14 (d, J = trifluoroetoxi)-8- 9,0 Hz, 1H), 7,94 (6- (dd, J = 2,1, 0,8 (trifluorometoxi) Hz, 1H), 7,76- piridin-3-il)-1,6- 7,69 (m, 1H), 7,37 naftiridin-7(6H)- (dd, J = 9,1, 2,0 ona Hz, 1H), 7,31 (d, J = 8,5 Hz, 1H), 6,75 (d, J = 9, 0 Hz, 333 1H), 4 ,94 (q, J = 9,1 Hz, 2H), 4,23 (s, 3H). ( o LC-MS (ESI) : m / z 412 [M+H]+. 2H NMR (400 MHz, DMSO-d6) δ 8,75 (s, 1H), 8,70 (d, J = 2,2 Hz, 1H), 8,34 (s, 1H), 7,98 (d, J = 9,1 Hz, 1H), 7,93 (dd, J = 8,0, 2,3 2-etoxi-6-(1-metil- Hz, 1H), 7.86 (d, J 132-A 1H- benzo[d]imidazol-6- il)-8-(6- metilpiridin-3-il) - 1,6-naftiridin- 7(6H)-ona = 2,0 Hz, 1H), 7,79 (d, J = 8,5 Hz, 1H), 7,35 (dd, J= 8,5, 2,0 Hz, 1H), 7.25 (d, J = 8,0 Hz, 1H), 6,56 (d, J =9,0 Hz, 1H), 4,27 (q, J = 7,0 Hz, 2H), 3,88 (s, 3H), 1,28 (t, J = 7,0 Hz, 3H). 334 LC-MS (ESI): m / z 482 [M+H]+. 4H NMR (400 MHz, DMSO-d6) δ 8.83 (s 1H), 8.62 (d, J = r ί z 1 2.3 Hz, 1H), 8.51 (s, 1H), 8.28 (dd, (¡1 J = 8,5, J = 2.4, CF = 1Hz 2-ethoxy-6-(2-methyl- 9.0 Hz, 1H), 7,91 133-A 2H-indazol-5-yl)-8- (d, J = 2.0 Hz, (6- 1H), 7,72 (d, J = (trifluoromethoxy) 36-H) -din-7, (dd, J = 9.1, 2.0 naphthyridine-7(6H)- Hz, 1H), 7.31 (d, J ona = 8.5 Hz, 1H), 6.59 (d, J = 9, 0 Hz, 1H), 4.28), (q, J = 7.2, J 4, 2H3), = 7.1 Hz, 3H). 335 —n Ί 1 0 Cl 8-(4-chlorophenyl)-2ethoxy-3-methyl-6-(2methyl-2H-indazol-5- LC-MS (ESI): m / z 445 [M+H]+.4H NMR (400 MHz, DMSO-d6) δ 8, 62 (s, 1H) , 8.49 (s, 1H) , 7.86 (dd, J = 2.0, 134-A il)-1,6-naphthyridin- 7(6H)-one 0.8 Hz, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.71 - 7, 65 (synthesized from (m, 3H), 7.39 (d,J 3-bromo-5-iodo-2- methoxypyridin-4- = 8.5 Hz, 2H), 7, (dd, J = 9.1, 2.1 32 amine and methacrylate Hz, 1H), 4.28 (q, J of ethyl through = 7.0 Hz, 2H), 4, 22 the procedure (s, 3H), 2.12 (d, General J V (sequence of Rl- R3-R2, Method B, Steps BD and L-0)) = 1.2 Hz, 3H), 1, (t, J = 7.0 Hz, 3H) . 29 General Procedure VI: 336 General Procedure VI: AlkyPSH Alkyl—OH NaH, THF Step A NHjÜAc Tol., HOAc. 100 °C Step C Aryl—BfOHjj Cij(OAc)z ΐ eq pirkfina 4 eq DCM. 02, 40=C Step D Preparation for Example 261: NH^ÓAc TdL, HOAc. 100'JC Step C Step A: methyl 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-(2,2,2trifluoroethoxy)pyrimidin-4-yl)acetate 337 To a solution of 2,2,2-trifluoroethanol (150 mg, 1.5 mmol, 3 equivalents) in THF (3 mL) NaH (60% in mineral oil, 60 mg, 1.5 mmol, 3 equivalents) was added at 0°C. The mixture was stirred at 0°C for 30 minutes. Then 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4-yl) methyl acetate (l) (prepared by General Procedure III using 2-(4-bromophenyl) methyl acetate (Steps AC)) (230 mg, 0.5 mmol, 1.0 equivalents) was added and the mixture was stirred at room temperature (25°C) for another 3 hours. The reaction mixture was then poured into cooled (saturated, aqueous) NH4CI and the aqueous layer was extracted with EtOAc (10 mL x 3).The combined organic layers were dried over Na2SO4 and concentrated, yielding a brown oil, which was purified by silica gel chromatography (PE : EA =20: 1-10: 1) giving 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl) methyl acetate (150 mg, 62% yield) as a white solid. LC-MS: m / z 479, 481 [M+H]+. Step B: methyl 2-(4-bromophenyl)-2-(5-formyl-2-(2,2,2trifluoroethoxy)pyrimidin-4-yl)acetate 338 ΒΓ To a solution of methyl 2-(4-bromophenyl)-2-(5-(dimethoxymethyl)2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate (120 mg, 0.25 mmol, 1.0 equivalent) in acetone (1.5 mL) and H2O (1.5 mL) p-TSA (10 mg, 0.075 mmol, 0.3 equivalent) was added. The resulting mixture was stirred at 70°C for 1 hour. The reaction mixture was then extracted with EtOAc (5 mL x 3), dried over anhydrous Na2SO4, and concentrated, yielding 2-(4-bromophenyl)-2-(5-formyl-2(2,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate (86 mg, crude) as a white solid. LC-MS: m / z 433, 435 [M+H]+. Step C: 8-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidin-7(6H)-one Br To a solution of 2-(4-bromophenyl)-2-(5-formyl-2-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)acetate (86 mg, 0.20 mmol, 1.0 equivalent) in AcOH (1 mL) and toluene (1 mL) was added NH4OAC (512 mg, 6.4 mmol, 320 equivalents). The resulting mixture was stirred at 100°C for 1.5 hours, then the reaction was quenched by adding aqueous NaHCO3. The reaction mixture was extracted. 339 with EtOAc (5 mL x 3), was dried over anhydrous Na2SO4 and concentrated. The resulting crude product was purified by silica gel chromatography, which yielded 8-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (60 mg, 75% yield) as a brown solid. LC-MS: m / z 400, 402 [M+H]+. Step D: 8-(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one To a solution of 8-(4-bromophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (60 mg, 0.15 mmol, 1.0 equivalent) in DCM (3 mL) were added (4-methoxyphenyl)boronic acid (32 mg, 0.3 mmol, 2.0 equivalents), Cu(OAc)2 (54 mg, 0.3 mmol, 2.0 equivalents) and pyridine (48 mg, 0.6 mmol, 4.0 equivalents). The mixture was then stirred at 40°C under an atmosphere of O2 (1 atmosphere) overnight. The crude mixture was concentrated under reduced pressure which gave a brown oil, then the resulting residue was purified by preparative HPLC under reduced pressure which gave 8(4-bromophenyl)-6-(4-methoxyphenyl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 261). 340 iH NMR (400 MHz, DMSO-cM δ: 9.22 (s, 1H), 9.19 (s, 1H), 7.63 (d, J= 8.4 Hz, 2H), 7.57 (d, J= 8.4 Hz, 2H), 7.52 (d, J= 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 4.95 (q, J = 8.8 Hz, 2H), 3.84 (s, 3H): m / z 506, 508 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-(2,2,2 trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one 4b 46 8- (4-chlorophenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidin-7(6H)-one 4b was synthesized from methyl 2-(4chlorophenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4yl)acetate by general procedure VI (AC steps) LCMS: m / z 356 [M+H]+. Example 262: Preparation of 8-(4-chlorophenyl)-6-(2-methyl-2-hindazol-5-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-(6H)-one Cl 341 The title compound was synthesized from intermediate compound 4b with 2-methyl-2H-indazol-5-ylboronic acid by general procedure VI (Step D) (Cu(0Ac)2, pyridine, O2 atmosphere, DCM, 40°C). iH NMR (400 MHz, DMSO-ds) δ: 9.28 (s, 1H), 9.23 (s, 1H), 8.54 (s, 1H) , 7.96 (d, J= 2.0 Hz, 1H) , 7.74 (d, J= 9.2 Hz, 1H) , 7.70 (d, J = 8.8 Hz, 2H), 7.44 (d, J= 8.8 Hz, 2H) , 7.38 (dd, J= 2.0 Hz, 2.9 Hz Hz, 1H) , 4.95 (q, J= 9.2 Hz, 2H) , 4.23 (s, 3H) LC-MS: m / z 486 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one 4c 4c 8- (4 - (difluchromethoxy)phenyl)-2-(2,2,2- trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one 4c was synthesized from methyl 2-(4-(difluoromethoxy)phenyl)-2-(5-(dimethoxymethyl)-2(methylsulfonyl)pyrimidin-4-yl)acetate by General Procedure VI (Steps AC). LC-MS: m / z 388 [M+H]+ Example 263: Preparation of 8-(4-(difluoromethoxy)phenyl)-6-(1methyl-lH-benzo[d]imidazol-6-yl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one 342 oghf2 The title compound was synthesized from intermediate compound 4c with 1-methyl-1H-benzo[d]imidazol-6-ylboronic acid by general procedure VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C). iR NMR (400 MHz, DMSO-ds) δ: 9.26 (s, 1H) , 9.24 (s, 1H) , 8.37 (s, 1H) , 7.91 (d, J = 2.0 Hz, 1H) , 7.82 (d, J = 8.8 Hz, 1H) , 7.73 (d, J= 8.8 Hz, 2H), 7.40 (dd, J= 8.8 Hz, 2.0 Hz, 1H), 7.29 (t, Jhf = 74.2 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 4.96 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H). LC-MS: m / z 518 [M+H]+. Example 264: 8-(4-(difluoromethoxy)phenyl)-6-(quinolin-6-yl)-2(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one The title compound was synthesized from intermediate compound 4c with quinolin-6-ylboronic acid by general procedure VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 4 0°C). 3434H NMR (400 MHz, DMSO-ds) δ: 9.40 (s, 1H) , 9.29 (s, 1H), 9.09 (dd, J = 4.2, 1.7 Hz, 1H) , 8.55 (d, J = 8.3 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H) , 8.24 (d, J = 9.0 Hz, 1H) , 8.02 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H) , 7.72 (dd, J = 8.3 Hz, 4.2 Hz, 1H) , 7.34 (t, Jhf = 74.2) Hz, 1H) , 7.23 (d, J= 8.8 Hz, 2H) , 5.01 (q, J = 8.9 Hz, 2H) . LC-MS: m / z 515 [M+H]+. Example 265: 8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol5-11)-2-(2,2,2-trifluoroethoxy) pyrido[4,3-d]pyrimidin-7(6H)-ona oghf2 The title compound is synthesized from the intermediate compound 4c with 2-methyl-2H-indazol-5-ylboronic acid by the general procedure VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C). 4H NMR (400 MHz, DMSO-ds) δ: 9.26 (s, 1H), 9.23 (s, 1H), 8.54 (s, 1H), 7.96 (d, J= 2.0 Hz, 1H), 7.75-7.70 (m, 3H), 7.38 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.29 (t, Jhf = 74.4 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 4.96 (q, J= 9.0 Hz, 2H), 4.23 (s, 3H). LC-MS: m / z 518 [M+H]+. 344 Example 266: 6-(lH-benzo[d]imidazol-6-yl)-8-(4(difluchromethoxy)phenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidin-7(6H)-one OCHF2 The title compound was synthesized from intermediate compound 4c with 1-((2-(trimethylsilyl)ethoxy)methyl)-1H benzo[d]imidazol-6-ylboronic acid by general procedure VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C) and then deprotected with TFA by general procedure I (Step F). Y NMR (400 MHz, DMSO-dg) δ: 9.26 (s, 1H) , 9.23 (s, 1H) , 8.45 (br s, 1H), 8.38 (s, 1H), 7.85 (br s, 1H), 7.73 (d, 8.8 Hz, 7.3 Hz), s, 1H) , 7.29 (t, Jhf = 74.0 Hz, 1H) , 7.18 (d, J = 8.8 Hz, 2H), 4.96 (q, J= 9.2 Hz, 2H). LC-MS: m / z 504 [M+H]+. Preparation of 8- (4-cyclopropylphenyl)-2-(2,2,2trifluoroethoxy)pyrido[4,3-d]pyrimidine-7(6H)-one 4d 345 8- (4-cyclopropylphenyl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3- d]pyrimidine-7(6H)-one 4d was synthesized from methyl 2-(4cyclopropylphenyl)-2-(5-(dimethoxymethyl)-2(methylsulfonyl)pyrimidin-4-yl)acetate by general procedure VI (Steps AC). LC-MS: m / z 362 [M+H]+ Example 267: Preparation of 8-(4-cyclopropylphenyl)-6-(quinolin6-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3-d]pyrimidin-7(6H)-one The title compound was synthesized from intermediate compound 4d with quinolin-6-ylboronic acid by general procedure VI (Step D) (Cu(0Ac)2, pyridine, 02 atmosphere, DCM, 40°C) 4H NMR (400 MHz, DMSO-ds) δ: 9.31 (s, 1H) , 9.23 (s, 1H) , 9.04 (dd, J= 4.4 Hz, 1.6 Hz, 1H), 8.49 (d, J= 7.2), J = 7.2 ( Hz ,8, 1 = 1 1H), 8.19 (d, J= 9.0 Hz, 1H), 7.97 (d, J= 9.0 Hz, 2.4 Hz, 1H), 7.66 (dd, J= 8.4 Hz, 4.4 Hz, 1H), 7.56 (d, J, 4 J= 8.4 =) 8 Hz, 2H) , 4.97 (q, J = 9.2 Hz, 2H) , 1.99–1.90 (m, 1H), 1.01–0.93 (m, 2H), 0.73–0.67 (m, 2H). LC-MS: m / z 489 [M+H]+. 346 Preparation of 2-(2,2,2-trifluoroethoxy)-8-(4-(1-( flit rimethyl sil il) ethoxy)methyl)-lH-l,2,4-triazol-3yl)phenyl)pyrido[4,3-d]pyrimidine-7(6H)-ona 4e NSEM 4e 2-(2,2,2-trifluoroethoxy)-8-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3yl)phenyl)pyrido[4,3-d]pyrimidin-7(6H)-one 4e was synthesized from methyl 2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4-yl)-2(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3yl)phenyl)acetate by general procedure VI (Steps AC). LC-MS: m / z 519 [M+H]+ Example 268: Preparation of 8-(4-(1H-1,2,4-triazol-3-yl)phenyl) 6-(quinolin-6-yl)-2-(2,2,2-trifluoroethoxy)pyrido[4,3d]pyrimidin-7(6H)-one The title compound was synthesized from the intermediate compound 4e with quinolin-6-ylboronic acid by means of 347 general procedure VI (Step D) (Cu(0Ac)2, pyridine, O2 atmosphere, DCM, 40°C) and then deprotection with TFA by means of general procedure I (Step F). XH NMR (400 MHz, DMSO-ds) δ: 14.20 (br s, 1H) , 9.38 (s, 1H) , 9.27 (s, IH), 9.05 (dd, J= 8.0 Hz, 1.6 Hz, 1H), 8.51 (d, J, 8.0 Hz, IH) 7.91 (s, IH) , 8.31 (d, J= 2.0 Hz, 1H), 8.21 (d, J= 8.8 Hz, IH), 8.05 (d, J = 8.4 Hz, 2H) , 8.00 (dd, J= 9.2 Hz, 2.0, IH, J = 7.8) 8.4 Hz, 1H) , 7.68 (dd, J = 8.4 Hz, 4.0 Hz, IH), 4.99 (q, J= 8.8 Hz, 2H) LC-MS: m / z 516 [M+H]+. Preparation of 8-(4-chlorophenyl)-2-ethoxypyrido[4,3-d]pyrimidin7(6H)-one 4f 8- (4-chlorophenyl)-2-ethoxypyrido[4,3-d]pyrimidin-7(6H)-one 4f was synthesized from methyl 2-(4-chlorophenyl)-2-(5-(dimethoxymethyl)-2(methylsulfonyl)pyrimidin-4-yl)acetate via the general procedure of EVI( AC). LC-MS: m / z 302 [M+H]+ Preparation of 8-(4-chlorophenyl)-2-ethoxy-6-(1-methyl-lHbenzo[d]imidazol-6-yl)pyrido[4,3-d]pyrimidin-7(6H)-one (Example 269) 348 The title compound was synthesized from intermediate compound 4f with 1-methyl-1H-benzo[d]imidazol-6-ylboronic acid by general procedure VI (Step D) (Cu(0Ac)2, pyridine, O2 atmosphere, DCM, 40°C). íH NMR (400 MHz, DMSO-ds) δ: 9.17 (s, 2H), 8.36 (s, 1H), 7.89 (d, J= 2.0 Hz, 1H), 7.81 (d, J= 8.4 Hz, 1H), 7.70 (d, J= 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 7.38 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H). LC-MS: m / z 432 [M+H]+. Example 270: 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[4,3-d]pyrimidin-7(6H)-one you The title compound was synthesized from intermediate compound 4f with 2-methyl-2H-indazol-5-ylboronic acid by general procedure VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C). 349 iH NMR (400 MHz, DMSO-cM δ: 9.17 (s, 1H), 9.15 (s, 1H), 8.53 (s, 1H) , 7.94 (d, J= 2.0 Hz, 1H) , 7.73 (9,9,6 (H) J= Hz J= 8.4 Hz, 2H), 7.43 (d, J= 8.4 Hz, 2H) , 7.36 (dd, J= 9.2 Hz, 2.0 Hz, 1H) , 4.29 (q, J = 7.2 Hz, 2H) , (2.3=H0) (s Hz, 3H). LC-MS: m / z 432 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[4,3d]pyrimidine-7(6H)-one 4g 8- (4-(difluoromethoxy)phenyl)-2-ethoxypirido[4,3-d]pyrimidine- 7(6H)-one 4g was synthesized from methyl 2—(4— (difluoromethoxy)phenyl)-2-(5-(dimethoxymethyl)-2(methylsulfonyl)pyrimidine-4-yl)acetate with EtOH by general procedure VI (Step AC). LC-MS: m / z 334 [M+H]+ Example 271: Preparation of 8-(4-(difluoromethoxy)phenyl)-2 ethoxy-6-(quinolin-6-yl)pyrido[4,3-d]pyrimidine-7(6H)-one 350 The title compound was synthesized from the intermediate compound 4g with quinolin-6-ylboronic acid by general procedure VI (Step D) (Cu(0Ac)2, pyridine, O2 atmosphere, DCM, 4 0°C). iH NMR (400 MHz, DMSO-ds) δ: 9.30 (s, 1H), 9.22 (s, 1H), 9.08 (dd, J = 4.3 Hz, 1.6 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.23 ​​(d, J = 9.0 Hz, 1H), 8.01 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.71 (dd, J = 8.8 Hz, 4.3 Hz, 1H), 7.34 (t, Jhf = 74.4 Hz, 1H), 7.23 (d, J= 8.8 Hz, 2H), 4.35 (q, J= 7.2 Hz, 2H), 1.36 (t, J= 7.2 Hz, 3H). LC-MS: m / z 461 [M+H]+. Example 272: 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-2Hindazol-5-yl)pyrido[4,3-d]pyrimidin-7(6H)-one The title compound was synthesized from the intermediate compound 4g with 2-methyl-2H-indazol-5-ylboronic acid by general procedure VI (Step D) (Cu(OAc)2, pyridine, O2 atmosphere, DCM, 40°C). 4H NMR (400 MHz, DMSO-ds) δ: 9.16 (s, 1H) , 9.15 (s, 1H) , 8.53 (s, 1H), 7.95 (d, J= 2.0 Hz, 1H), 7.75-7.70 (m, J= 2.0 Hz, 1H), 7.75-7.70 (m, 3, 3, JH) 351 9.2 Hz, 2.0 Hz, 1H) , 7.29 (t, Jhf = 74.4 Hz, 1H) , 7.17 (d, J = 8.4 Hz, 2H), 4.30 (q, J= 7.2 Hz, 2H) , 4.23 (s, 3H) , 1.31 (t, J = 7.2 Hz, 3H). LC-MS: m / z 464 [M+H]+. Preparation of 2-cyclopropoxy-8-(4(difluoromethoxy)phenyl)pyrido[4 ,3-d]pyrimidin-7(6H)-one 4h hAAn . UCHFü 4h 2-cyclopropoxy-8- (4-(difluoromethoxy)phenyl)pyrido[4,3d]pyrimidine-7(6H)-one 4h was synthesized from methyl 2-(4(difluoromethoxy)phenyl)-2-(5-(dimethoxymethyl)-2(methylsulfonyl)-pyrimidine-4-propanol conjugate) by general procedure VI (AC Steps). LC-MS: m / z 346 [M+H]+ Example 273: Preparation of 2-cyclopropoxy-8-(4 (difluoromethoxy)phenyl)-6-(quinolin-6-yl)pyrido[4,3 d]pyrimidine-7(6H)-one ochf2 352 The title compound is synthesized after the intermediate compound 4h with quinoline-6-ylboronic acid using the general procedure VI (Step D) (Cu(0Ac)2, pyridine, 02 atmosphere, DCM, 4 0°C). iH NMR (400 MHz, DMSO-ds) δ: 9.28 (s, 1H) , 9.17 (s, 1H) , 9.04 (dd, J= 4.4 Hz, 1.6 Hz, 1H), 8.49 (d, J= 8.4 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 (d, J= 9.0 Hz, 1H), 7.97 (dd, J= 9.0 Hz, 2.4 Hz, 1H), 7.82 (d, J= 8.8 Hz, 2H), 7.67 (dd, J= 8.4 Hz, 4.4 Hz, 1H) , 7.28 (t, Jhf = 74.4 Hz, 1H) , 7.19 (d, J= 8.8 Hz, 2H) , 4.28-4.19 (m, 1H), 0.80-0.73 (m, 4H) . LC-MS: m / z 473 [M+H]+. Preparation of 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2 trifluoroethylthio)pyrido[4,3-d]pyrimidin-7(6H)-ona 4i 8-(4-(difluoromethoxy)phenyl)-2-(2,2,2-trifluoroethylthio)pyrido[4,3-d]pyrimidin-7(6H)-one 4i was synthesized from methyl 2-(4-(difluoromethoxy)phenyl)-2-(5-(dimethoxymethyl)-2-(methylsulfonyl)pyrimidin-4-yl)acetate with 2,2,2-trifluoroethanethiol by general procedure VI (Steps AC). LC-MS: m / z 404 [M+H]+ 353 Example 274: Preparation of 8-(4-(difluoromethoxy)phenyl)-6 (quinolin-6-yl)-2-(2,2,2-trifluoroethylthio)pyrido[4,3d]pyrimidin-7(6H)-one The title compound was synthesized from intermediate compound 4i with quinolin-6-ylboronic acid by general procedure VI (Step D) (Cu(0Ac)2, pyridine, O2 atmosphere, DCM, 4 0°C). iH NMR (400 MHz, DMSO-ds) δ: 9.36 (s, 1H), 9.12 (s, 1H), 9.08 (dd, J = 4.3 Hz, 1.6 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 9.0 Hz, 1H), 8.01 (dd, J = 9.0 Hz, 2.4 Hz, 1H), 7.71 (dd, J = 8.4 Hz, 4.3 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.29 (t, Jhf = 74.0 Hz, 1H), 7.19 (d, J= 8.8 Hz, 2H), 4.11 (q, J = 10.4 Hz, 2H). LC-MS: m / z 531 [M+H]+. Ejemplo 135-A: 8-(4-chlorofenil)-6-(2-metil-2H-indazol-5-il)-2 ((metilsulfonil)metil)-1,6-naftiridin-7(6H)-ona 354 Paso A. metil 2-(8-(4-chlorofenil)-6-(2-metil-2H-indazol-5-il) 7-oxo-6,7-dihidro-1,6-naftiridin-2-il)-2(metilsulfonil)acetato To a solution of 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2-hindazol-5-yl)-1,6-naphthyridin-7(6H)-one (200 mg, 0.47 mmol, 1.0 equivalent, as synthesized in Example 209) in DMSO (3.0 mL) Cs3CO3 (308 mg, 0.95 mmol, 2.0 equivalents) and methyl 2-(methylsulfonyl)acetate (144 mg, 0.95 mmol, 2.0 equivalents) were added at room temperature. The reaction mixture was stirred at 100°C for 14 hours. The resulting mixture was poured into ice water, the reaction mixture was extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, yielding 2-(8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-7-oxo-6,7-dihydro-1,6-naphthiridin-2-yl)-2-(methylsulfonyl)acetate (70 mg, 23% yield) as a yellow solid. LC-MS (ESI): m / z 537 [M+H]+. Step B. 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2((methylsulfonyl)methyl)-1,6-naphthyridin-7(6H)-one (135-A) A solution of methyl 2-(8-(4-chlorophenyl)-6-(2-methyl-2-hindazol-5-yl)-7-oxo-6,7-dihydro-1,6-naphthyridin-2-yl)-2-(methylsulfonyl)acetate (30 mg, 0.05 mmol, 1.0 equivalent) in 355 THF (3 mL) was added to 6N aqueous HCl (1 mL) at room temperature. The reaction mixture was stirred at 100°C for 14 hours. The reaction mixture was extracted with EtOAc (20 mL x 3), the combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by preparative HPLC under reduced pressure and gave 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2((methylsulfonyl)methyl)-1,6-naphthyridin-7(6H)-one. Y NMR (400 MHz, DMSO-dí) (relation of 5:2) δ (ppm): 9.04 (s, 1H), 8.56 (d, J = 8.1 Hz, 0.4H), 8.52 (s, 1H), 8.42 (s, 0.4H), 8.15 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.1 Hz, 0.4H), 7.72 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 8.9 Hz, 0.4H), 7.60 (d, J = 8.6 Hz, 2H), 7,50 (d, J = 8,7 Hz, 0.8H), 7.40 (m, 3H), 7.08 (d, J = 8.7 Hz, 1H), 4.77 (s, 0.8H), 4.66 (s, 2H), 4.23 (s, 3H), 4.20 (s, 1.2H), 3.01 (s, 3H), 2.84 (s, 1,2H). LC-MS (ESI): m / z 479 [M+H]+. Ejemplo 136-A: Preparation of: 8-(4-chlorofenil)-2(metoximetil)-6-(2-metil-2H-indazol-5-il)-1, 6-naftiridin (6H)-ona 356 Paso A: 8-(4-chlorofenil)-2-(metoximetil)-6-(2-metil-2H-indazol5-il)-1,6-naftiridin-7(6H)-ona A solution of 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2H-indazol5-yl)-1,6-naphthyridin-7(6H)-one (100 mg, 0.24 mmol, 1.0 equivalent, as synthesized in Example 209), tributyl(methoxymethyl)stannane (159 mg, 0.48 mmol, 2.0 equivalents), and Pd(PPha)4 (24 mg, 0.024 mmol, 0.1 equivalent) in dioxane (5 mL) was stirred at 50°C for 14 hours under a nitrogen atmosphere. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC under reduced pressure, which yielded 8-(4-chlorophenyl)-2-(methoxymethyl)-6-(2-methyl-2H-indazol-5yl)-1,6-naphthyridin-7(6H)-one (136-A). LC-MS (ESI): m / z 431 [M+H]+. Example 137-A: Preparation of: 2-ethoxy-8-(6(fluoromethyl)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)-1,6 naphthiridin-7(6H)-one 357 Paso A: 2-ethoxy-8-(6-(fluoromethyl)pyridin-3-yl)-6-(2-methyl-2Hindazol-5-yl)-1,6-naftiridin-7(6H)-one To a solution of 2-ethoxy-8-(6-(hydroxymethyl)pyridin-3-yl)-6(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (synthesized from 8-bromo-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (as synthesized in Example 215) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid by General Procedure V (Step M) ) (150 mg, 0.35 mmol, 1.0 equivalent) in DCM (4 mL) DAST (161 mg, 0.70 mmol, 2.0 equivalent) was added at 0oC under N2. The resulting mixture was stirred at 0°C for 1 hour before the reaction was quenched by adding ice-cold water (3 mL). The resulting mixture was extracted with EtOAc (10 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by preparative HPLC under reduced pressure, which yielded 2-ethoxy-8-(6-(fluoromethyl)pyridin-3-yl)-6-(2-methyl-2H-indazol-5-yl)-1,6-naphthyridin-7(6H)-one (137-A). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.86 (d, J = 2.1 Hz, 1H), 8.81 (s, 1H), 8.51 (s, 1H), 8.15 (dd, J = 8.0, 2.1 Hz (d ,8, 1H), 1H J = 9.1 Hz, 1H), 7.92 (dd, J = 2.1, 0.8 Hz, 1H), 7.72 (dt, J = 9.1, 0.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.1 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 5.50 (d, J hf = 47.2 Hz, 358 2H) , 4.27 (q, J = 7.2 Hz, 2H) , 4.23 (s, 3H) , 1.28 (t, J = 7.1 Hz, 3H). LC-MS (ESI): m / z 431 [M+H]+. Example 138-A: Preparation of: 8-(4-chlorophenyl)-6-(2-methyl-2H indazol-5-yl)-2-(3,3,3-trifluoropropyl)-1,6-naphthyridine-7(6H) ona in Step A: (3,3,3-trifluoropropyl) magnesium bromide Magnesium castings (136 mg, 5.65 mmol, 1.0 equivalent) were suspended in dry THF (4 mL), and then 3-bromo-1,1,1-trifluoropropane (1.0 g, 5.65 mmol, 1.0 equivalent) was added dropwise at room temperature. The flask was gently heated using a heat gun until bubbling was observed on the surface of the magnesium castings. The resulting mixture was stirred at 70°C for 1 hour, and then the flask was allowed to cool to room temperature, resulting in a pale gray solution. The Grignard reagent was used in the next step without any further purification or isolation. Step B: 8-(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(3,3,3 trifluoropropyl)-1,6-naphthyridin-7(6H)-one 359 To a solution of 2-chloro-8-(4-chlorophenyl)-6-(2-methyl-2-hindazol-5-yl)-1,6-naphthyridin-7(6H)-one (100 mg, 0.24 mmol, 1.0 equivalent, as synthesized in Example 209) and Fe(acac)3 (85 mg, 0.24 mmol, 1.0 equivalent) in a THF / NMP mixture (4.4 mL, 10 / 1, v / v), crude (3,3,3-trifluoropropyl)magnesium bromide solution (2 mL, 2.4 mmol, 10 equivalent) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 14 hours, then the reaction was quenched by adding aqueous saturated NH4Cl (5 mL) at 0°C. The mixture was extracted with EtOAc (10 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by preparative HPLC under reduced pressure, which yielded 8(4-chlorophenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(3,3,3-trifluoropropyl)-1,6-naphthyridin-7(6H)-one (138-A). 1H NMR (400 MHz, DMSO-de) δ (ppm) 8,94 (s, 1H), 8,51 (s, 1H), 8,04 (d, J = 8,7 Hz, 1H), 7,93 (dd, J = 2,1, 0,8 Hz, 1H), 7,72 (dt, J = 9,0, 0,9 Hz, 1H), 7,67 - 7,60 (m, 2H), 7,41 (d, J = 8,6 Hz, 2H), 7,37 (dd, J = 9,1, 2,0 Hz, 1H), 7,00 (d, J = 8,7 Hz, 1H), 4,23 (s, 3H), 3,03 (t, J = 7,6 Hz, 2H), 2,77 - 2,60 (m, 2H). LC-MS (ESI): m / z 483 [M+H]+. 360 Procedimiento General VII pocij Solvente The compounds of structure 10.11 were obtained by General Procedure VII. The substituted pyridine 10.1 was treated with NBS to generate bromopyridine 10.2, reacted with NaOMe to generate methoxypyridine 10.3, and was then reduced to generate diaminopyridine 10.4. Compound 10.4 reacted with ethyl bromoacetate to give compound 10.5 and was then treated with a base to generate the bicyclic structure 10.6. After treatment with POCla to generate compound 10.7 and demethylation to generate compound 10.8, the desired R groups could be sequentially installed. The desired Ri group was introduced via an aromatic substitution reaction to obtain the compounds of structure 10.9. The desired R3 group was introduced via a copper-mediated Chan-Lam coupling to obtain the 361 compounds of structure 10.10. The desired R2 group was introduced via palladium-mediated Suzuki coupling, thereby obtaining the final compounds of structure 10.11. Example 139-A: Preparation of 139-A using Procedure General VII NBCS, DMF, Step A MaONa Meoh Step B Fs, MK,α EIOH.Hsd Step C Et / J, toluene Step D Toluene, DBU HC'ZHFj CSjCCFj. DMF Step E POCij toluene, DCE Step F DCE Step G Step H Step A: 3-bromo-2-chloro-5-nitropiridine-4-amine To a solution of 2-chloro-5-nitropiridine-4-amine (5.0 g, 28.8 mmol, 1.0 equivalent) in DMF (20 mL) NBS (6.16 g, 34.6 mmol, 1.2 equivalent) was added in several parts. After stirring at room temperature for 4 hours, most of 362 of the solvent was extracted under reduced pressure, the residue was suspended in cold water (30 mL) and the solid was filtered and dried under reduced pressure and gave 3-bromo-2-chloro-5-nitropiridine-4-amine (6.2 g, 85% yield) as a whitish solid. LCMS (ESI): m / z 252, 254 [M+H]+. Step B: 3-bromo-2-methoxy-5-nitropyridin-4-amine A suspension of 3-bromo-2-chloro-5-nitropiridine-4-amine (6.0 g, 23.8 mmol, 1.0 equivalent) in methanol (50 mL) was mixed with a freshly prepared NaOMe solution (658 mg, 28.6 mmol, 1.2 equivalent) in 5 mL of anhydrous MeOH). The reaction mixture was refluxed for 12 hours. The methanol was extracted under reduced pressure, the residue was resuspended in cold water (50 mL), and the resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum, yielding 3-bromo-2-methoxy-5-nitropiridine-4-amine (5.8 g, 98% yield) as a whitish solid. LC-MS (ESI): m / z 248, 250 [M+H]+ Step C: 5-bromo-6-methoxypyridine-3,4-diamine Iron powder (5.22 g, 93.2 mmol, 4.0 equivalents) was added to a solution of 3-bromo-2-methoxy-5-nitropiridine-4-amine (5.8 g, 23.3 mmol, 1.0 equivalent) and NH4Cl (6.35 g, 116.5 mmol, 5.0 equivalents) in EtOH / H2O (40 mL, 3 / 1, v / v), and the resulting mixture was heated to 80°C for 4 hours. The mixture was The sample was cooled to room temperature, filtered through a short Celite® stopper, and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, and the residue was purified by gel chromatography, yielding 5-bromo-6-methoxypyridine-3,4-diamine (4.0 g, 79% yield) as a brown solid, which should be used as soon as possible in the next step. LC-MS (ESI): m / z 218, 220 [M+H]+ Step D: Ethyl (4-amino-5-bromo-6-methoxypyridin-3-yl)glycinate. To a mixture of 5-bromo-6-methoxypyridine-3,4-diamine (3.6 g, 16.4 mmol, 1.0 equivalent) and TEA (2.5 mL, 18.0 mmol, 1.1 equivalent) in dry toluene (30 mL), ethyl 2-bromoacetate (3.0 g, 18.0 mmol, 1.1 equivalent) was added dropwise at 0°C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for a further 4 hours. The reaction was then quenched by adding NH4Cl (aqueous saturated) (20 mL), the resulting mixture was extracted with EtOAc (30 mL x 3), the combined organic layers were dried over Na2SO4 and then concentrated under reduced pressure and gave a crude mixture (5.2 g, crude oil), which was used in the next step without further purification. Step E: 8-bromo-7-methoxypyrido[3,4-b]pyrazin-2(1H)-one 364 A mixture containing ethyl(4-amino-5-bromo-6-methoxypyridin-3-yl)glycinate (5.2 g) and DBU (2.74 g, 18.0 mmol, 1.1 equivalents) in toluene (20 mL) was refluxed for 14 hours. The resulting mixture was concentrated under reduced pressure and purified by fast column chromatography on silica gel, yielding 8-bromo-7-methoxypyrido[3,4-b]pyrazin2(1H)-one (2.1 g, two steps, 50% overall yield) as a whitish solid. LC-MS (ESI): m / z 256, 258 [M+H]+. Step F: 8-bromo-2-chloro-7-methoxypyrido[3,4-b]pyrazine POCl3 (2.70 g, 17.6 mmol, 3.0 equivalents) was added to a solution of 8-bromo-7-methoxy-1H,2H-pyrido[3,4-b]pyrazin2-one (1.5 g, 5.85 mmol, 1.0 equivalent) in toluene / DCE (40 mL, 1 / 1, v / v), and the reaction mixture was stirred at 90°C for 15 hours. The reaction mixture was then concentrated under reduced pressure, the residue was diluted with ice water (50 mL), made basic to pH 7–8 with aqueous saturated Na3CO3, and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated under reduced pressure, and purified by fast column chromatography on silica gel, yielding 8-bromo-2-chloro-7-methoxypyrido[3,4-b]pyrazine (1 g, 3.64 mmol, 62%) as a pale yellow oil. LC-MS (ESI): m / z 274, 276 [M+H]+. 365 Step G: 8-bromo-2-chloropyrido[3,4-b]pyrazin-7-ol To a solution of 8-bromo-2-chloro-7-methoxypyrido[3,4-b]pyrazine (1 g, 3.64 mmol, 1.0 equivalent) in DCE (15 mL) anhydrous AlCl3 (0.73 g, 5.46 mmol, 1.5 equivalent) was added and the reaction mixture was stirred at 70°C for 2 hours. The reaction mixture was cooled to 0°C, quenched with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by fast column chromatography on silica gel, yielding 8-bromo-2-chloropyrido[3,4-b]pyrazin-7-ol (700 mg, 74% yield) as a pale yellow solid. LC-MS (ESI): m / z 260, 262 [M+H]+. Step H: 8-bromo-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-7-ol. To a solution of 8-bromo-2-chloropyrido[3,4-b]pyrazin-7-ol (390 mg, 1.5 mmol, 1.0 equivalent) in 2,2-difluoroethan-1-ol (5 mL), Cs2CO3 (978 mg, 3.0 mmol, 2.0 equivalents) was added, and the reaction mixture was stirred at 90°C for 3 hours. The reaction mixture was cooled to 0°C, quenched with ice water (30 mL), adjusted to pH = 6 with dilute HCl (1N, aqueous), and extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated under reduced pressure, and the residue was purified by chromatography 366 by rapid column on silica gel, producing 8bromo-2-(2,2-difluoroethoxy)pyrido[3,4-b]pyrazin-7-ol (30 mg, 7%) as a pale yellow solid. LC-MS (ESI): m / z 306, 308 [M+H]+. Step I: 8-bromo-2-(2,2-difluoroethoxy)-6-(2-methyl-2H-indazol-5yl)pyrido[3,4-b]pyrazin-7(6H)-one A mixture of 8-bromo-2-(2,2-difluoroethoxy)pyrido[3,4b]pyrazin-7-ol (30 mg, 0.1 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (35 mg, 0.2 mmol), Cu(OAc)2 (29 mg, 0.15 mmol, 1.5 equivalents), pyridine (24 L, 0.3 mmol, 0.3 equivalents), and TEA (42 L, 0.3 mmol, 0.3 equivalents) in DCM (0.5 mL) was stirred under an O2 atmosphere at 40°C for 15 hours. The reaction mixture was diluted with H2O (5 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and the residue was purified by fast column chromatography on silica gel, which yielded 8-bromo-2-(2,2-difluoroethoxy)-6-(2-methyl-2H-indazol-5yl)pyrido[3,4-b]pyrazin-7(6H)-one (20 mg, 46%) as a yellow solid. LC-MS (ESI): m / z 436, 438 [M+H]+. Step J: 2-(2,2-difluoroethoxy)-8-(4-(difluoromethox)phenyl)-6-(2methyl-2H-indazol-5-yl)pyrido[3,4-b]pyrazin-7(6H)-one 367 A mixture of 8-bromo-2-(2,2-difluoroethoxy)-6-(2-methyl-2H indazol-5-yl)pyrido[3,4-b]pyrazin-7(6H)-one (20 mg, 0.046 mmol, 1.0 equivalent), (4-(difluoromethoxy)phenyl)boronic acid (17 mg, 0.092 mmol, 2.0 equivalent), Pd(dppf)Cl2 (6.8 mg, 0.009 mmol, 0.2 equivalent) and Cs2CO3 (50 mg, 0.138 mmol, 3.0 equivalent) in a dioxane / H2O mixture (0.5 mL, 9 / 1, v / v) was stirred at 100oC under an N2 atmosphere for 15 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC under reduced pressure which yielded 2-(2,2-difluoroethoxy)-8-(4-(difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)pyrido[3,4b]pyrazin-7(6H)-one (139-A). 1H NMR (400 MHz, DMSO-d6) δ: 8.85 (s, 1H), 8.51 (s, 1H), 8.26(s, 1H), 7.93 (d, J = 1.2 Hz, 1H), 7.73-7.67 (m, 3H), 7.35 (dd,J = 9.2 Hz, 2.0 Hz, 1H), 7.29 (t, JHF = 74.2 Hz, 1H), 7.18 (d,J = 8.8 Hz, 2H), 6.41 (tt, JHF = 54.2 Hz, J = 3.2 Hz, 1H), 4.57 (td, Jhf = 14.8 Hz, J = 3.2 Hz, 2H), 4.23 (s, 3H). LC-MS (ESI): m / z 500 [M+H]+. The project introduces the interior to the General Proceedimiento VII and we use it to send the same components used to use the materials from the propiados: 368 Ejemplo Estructura Caracterización 140-A n 9 OMe 2-etoxi-8-(4- metoxifenil)-6- (2-metil-2H- indazol-5- il)pirido[3,4- b]pirazin-7(6H) - on LC-MS (ESI): m / z 428 [M+H]+. !H NMR (400 MHz, DMSOd6) δ 8.71 (s, IH), 8.50 (s, IH), 8.11 (s, IH), 7.91 (d, J = 2.0 Hz, IH), 7.70 (d, <7=9.1 Hz, IH), 7.60 - 7.54 (m, 2H), 7.34 (dd, J = 9.1, 2.1 Hz, IH), 6.94 (d, J = 8.8 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 4.23 (s, 3H), 3.79 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H). 369 141-A —NF 9 2- (2,2- difluoroethoxy)-8(4-methoxyphenyl) 6- (2-methyl-2Hindazol-5- il)pyrido[3,4b]pyrazine-7(6H) ona LC-MS (ESI): m / z 464 [M+H]+. XH NMR (4 00 MHz, DMSOde) δ 8.78 (s, 1H) , 8.50 (s, 1H) , 8.23 ​​(s, 1H), 7.92 (d, J = 2.1 Hz, 1H) , 7.70 (d, d, <7 = 1.5 =8) Hz 8.8 Hz, 2H), 7.34 (dd, J = 9.1, 2.0 Hz, 1H) , 6.94 (d, J = 8.9 Hz, 2H) , 6.41 (tt, Jhf = 54.3, J = 3.3 Hz, 1.51, Jf) ( = 4 3.3 Hz, 2H), 4.23 (s, 3H), 3.79 (s, 3H). 370 142-A ο'γΝ σ'- 0 Cl 8- (4-chlorophenyl)- 2-ethoxy-6- (quinolin-6- il)pyrido[3,4- b]pyrazine-7(6H) - ona LC-MS (ESI): m / z 429 [M+H]+. XH NMR (4 00 MHz, DMSOd6) δ 9.03 (dd, J = 4.2, 1.7 Hz, 1H) , 8.94 (s, 1H) , 8.49 (d, <7=8.2 Hz, 1H) , 8.27 (d, H = 8.14 (m, 2H), 7.96 (dd, J = 9.0, 2.4 Hz, 1H) , 7.72 - 7.62 (m, 3H), 7.49 - 7.40 (m, 2H), 4.33 (q, J = 7.70, Hz (1, 2H, 3H). 371 143-A -nJ J w ? F 0F Λ 2- (2,2- difluoroethoxy)-6(2-methyl-2Hindazol-5-yl)-8- (6- (trifluoromethoxy) pyridine-3-yl)pyrido[3,4b]pyrazine-7(6H) ona LC-MS (ESI): [M+H] 51. XH NMR (4 00 MHz, DMSOd6) δ 8.97 (s, 1H) , 8, 64 (d, J = 2.3 Hz, 1H) , 8.52 (s, 1H), 8.31 (s, 1H), 8.30 (dd, 17, J = 8, 8 (dd, J = 2.1, 0.8 Hz, 1H) , 7, 73 (dd, J = 9.1, 0.9 Hz, 1H), 7.38 (dd, J = 9.1, 2.1 Hz, 1H), 7.34 (d, J = 8.2 Hz, 6.4 Hz, 6.4) J = 3.3 Hz, 1H), 4.60 (td, Jhf = 15.1, <7=3.3 Hz, 2H), 4.24 (s, 3H). 372 144-A Νχ'χ -cla zn 07 γ Ν' Á F (γΝ °YF F 2- (2,2- difluoroethoxy)-8(6- (difluoromethoxy) pyridine-3-yl)-6(2-methyl-2-2)onaHindazol3]bpyridol-5 LC-MS (ESI): m / z 501 [M+H]+.XH NMR (4 00 MHz, DMSOdg) δ 8.92 (s, 1H), 8.56 − 8.49 (m, 2H) , 8.29 (s, 1H, J = 1.19 (dd). 7.94 (s, 1H) , 7.72 (d, J = 9.1 Hz, 1H) , 7.67 (t, Jhf = 73.1 Hz, 1H) , 7.37 (dd, J = 9.2, 2.0 Hz, 1H), 1, 8, 8, 7, 13 42 (t, Jhf = 54.2 Hz, 1H), 4.59 (td, Jhf = 15.2, J = 3.2 Hz, 2H), 4.23 (s, 3H). 373 145-ANZ< CQ an A y cAnA Y YF F 8- (4- (difluoromethoxy) phenyl)-2-ethoxy-6(2-methyl-2Hindazol-5- il)pyrido[3,4b]pyrazine-7(6H) ona LC-MS (ESI): [M+H]+64. XH NMR (4 00 MHz, DMSOde) δ 8.78 (s, 1H), 8.50 (s, 1H), 8.14 (s, 1H) , 7, 92 (dd, <7=2.0, 0.8 Hz, 1H) , 7.34 (dd = 7.7), 9.1, 2.1 Hz, 1H), 7.30 (t, Jhf = 74.3 Hz, 1H) , 7.18 (d, J = 8.7 Hz, 2H), 4.32 (q, 7=7.0 Hz, 2H), 4.23 (t,) J, 33H ( . 374 146-A 7 / , .·· ,PHONOY Ψ ' Cl 8- (4-chlorophenyl)- 2- (2,2- difluoroethoxy)-6(2-methyl-2H- indazol-5-yl)pyrido[3,4b]pyrazine-7(6H) ona 8.+ES (ES+ 4H NMR (4 00 MHz, DMSOd6) δ 8.89 (s, 1H) , 8.51 (s, 1H) , 8.27 (s, 1H), 7.94 (d, J = 2.0 Hz, 1H) , 7, J 7, 71 (d, Hz), <7 = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 (dd, J = 9.1, 2.1 Hz, 1H) , 6.4 2 (tt, Jhf = 54.2, J = 3.2 Hz, J2, 1H (d = 4, Hz, 2H), 4.23 (s, 3H) . 375 147-A 'ΝΐΤ^ι Cl 8- (4-chlorophenyl) 2-ethoxy-6-(2- methyl-2H-indazol5-yl)pyrido[3,4b]pyrazine-7(6H) ona LC-MS (ESI): m / z 432 [M+H]+. XH NMR (4 00 MHz, Chloroform-d) δ 8.38 (s, 1H) , 7.99 (d, J = 11.4 Hz, 2H), 7.81 (d, J = 9.1 Hz, 1H), 7.75 (d, J = 1,6 = 1.6) 8 Hz, 2H), 7.37 (dd, J = 8.7, 1.9 Hz, 3H), 4.37 (q, J = 7.1 Hz, 2H), 4.27 (s, 3H) , 1.39 (t, <7=7.1 Hz, 3H). 376 148-A -Ν 1 ] Ν O^FFF 2-ethoxy-6-(2- methyl-2H-indazol- 5-11)-8-(6- (trifluoromethoxy) pyridine-3-yl)pyrido[3,4b]pyrazine-7(6H) ona LC-M+MS (ESI]): 4H NMR (4 00 MHz, DMSOd6) δ 8.89 (d, J = 0.5 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 8.52 (s, 1H), 8.29 (dd, J = 8.5, 8.4) Hz 7.94 (dd, J = 2.1, 0, 8 Hz, 1H) , 7.72 (dt, J = 9.1, 0.9 Hz, 1H) , 7.40 - 7.30 (m, 2H), 4.35 (q, J = 7.0 (s 1, 3, 23), <7 = 7.1 Hz, 3H) . 377 LC-MS (ESI): m / z 465 .z 1 [M+H]+. XH NMR (4 00 MHz, DMSO- Π 1 O f N Ό d6) 5 8.84 (d, <7=0.6 φ Hz, 1H), 8.54 - 8.48 °YF F 8-(6- (difluoromethoxy) (m, 8,2H) , 7.93 (dd, J = 2.0, 0.8 Hz, 1H), 7.77 149-A pyridine-3-yl)-2ethoxy-6-(2-methyl2H-indazol-5-yl)pyrido[3,4b]dpyrazine-7(6H) ona (t, Jh01) (73, Jhf) =,73 = 9.2, 0.9 Hz, 1H) , 7.36 (dd, J = 9.1, 2.0 Hz, 1H), 7.12 (dd, J = 8.6, 0.7 Hz, 1H), 4.33 (q, 7=7.1 Hz, 2H), J (1, 4,3 Hz, 3H) . 378 Example 275: Biochemical Assay The Mat2A protein was created by recombinant baculovirus in SF9-infected cells using the Bac to Bac system cloned into the pFASTBACl vector (Invitrogen, Carlsbad, CA). Recombinant MAT2A was isolated from the cell lysate of 150 g of infected cells using HP Ni sepharose column chromatography. The recombinant MAT2A homodimer was eluted with 250 and 500 mM imidazole, and the MAT2A-containing fractions were 379 were identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and mixed. To determine the inhibitory potency of the compounds against the MAT2A homodimer, the protein was diluted to 4 μg / mL in assay buffer (50 mM Tris, pH 8.0, 50 mM KCl, 15 mM MgCl2, 0.3 mM EDTA, 0.005% [w / v] bovine serum albumin [BSA]). The assay compound was prepared in 100% dimethyl sulfoxide (DMSO) at 50x the desired final concentration. A 1 μL volume of the compound dilution was added to 40 μL of enzyme dilution, and the mixture was allowed to equilibrate for 60 minutes at 25°C. The enzyme assay was started by adding 10 μR of the substrate mixture (500 μM ATP, pH 7, 0.400 μM P-methionine in 1x assay buffer) and the mixture was incubated for a further 60 minutes at 25°C. The reaction was stopped and the phosphate released by the enzyme was measured in stoichiometric amounts by the production of Sadenosyl methionine (SAM) using the PiColorLock Gold kit (Innova Biosciences, UK).The absolute quantities of the product were determined by comparison with a normal curve of potassium phosphate buffer, pH 8.0. The specific compounds disclosed herein were tested in the preceding assay and were determined to inhibit MAT2A with an IC50 according to the following ratings: 380 (A) less than 100 nM, (B) between 100 nM and 1 μM and (C) between 1 μM and 10 μM, as shown in Table 4 below. Example 276 White Gear Cell Assay (SAM) MAT2A activity in cells was measured by directly quantifying the abundance of its enzyme product, SAM. Cancer cells were treated with candidate MAT2A inhibitors for an appropriate incubation period, and the cells were then lysed using a reagent that quenched any other enzymatic activity. Soluble metabolites, including SAM, were collected, and SAM itself was measured directly from the lysate using quantitative LC-MS / MS. A typical assay was performed using a human colon carcinoma HCT116 cell line that was genetically engineered to delete the MTAP gene (commercially available in Horizon Discovery). This cell line was used because loss of the MTAP gene has been shown to predict sensitivity to MAT2A inhibitors. Cells were seeded in 96-well plates at the appropriate cell density. After 24 hours, the cells were then treated with the candidate MAT2A inhibitor. Prior to cell addition, the compound was serially diluted first in 100% DMSO, typically as a 3-fold serial dilution starting at the higher dose. 381 of 500x with 10 dose points including DMSO as the sole control. The compound was then transferred to a working raw material plant in cell culture medium by adding 5 pl of the compound in DMSO to 495 pl of cell culture medium. This working raw material was then added to cells by another 5-fold dilution, adding 25 pl of working raw material to 100 pl of cells in culture medium. After compound addition, the cells were incubated at 37 °C / 5% CO2 for 72 hours. To measure SAM levels after treatment with the compound, cells were gently washed once in ammonium carbonate buffer (75 mM at pH 7.4), placed on dry ice, and lysed with a metabolite extraction buffer (80% cold methanol and 20% water (v / v) with acetic acid to a final concentration of 1 M with 200 ng / mL of deuterated d3-SAM as an internal control). After centrifugation at 4 °C at 3,200 rpm for 30 minutes, the supernatant was collected and stored at -80 °C until analysis by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS / MS). The LC-MS / MS analysis was performed using an API6500 Mass Spectrometer (Sciex, Framingham, MA, USA) operating in positive ion sputtering mode and equipped with a BEH Amida Waters UPLC Acquity column (Waters, Milford, MA, USA). 382 acquired Multiple Reaction Monitoring data for SAM and the d3-SAM norm, using a mass transition pair am / z 399.2^250.1 and 402.2^250.1, respectively. In a normal LC-MS / MS analysis, the initial flow rate was 0.5 ml / min of 25% mobile phase A (acetonitrile and water at 5:95 (v / v) with 1% formic acid and 10 mM ammonium acetate) and 75% mobile phase B (acetonitrile and water at 95:5 (v / v) with 1% formic acid and 10 mM ammonium acetate), 0.2-0.5 min with 75%-35% mobile phase B, 25%-65% mobile phase A, to 0.5 min with 65% mobile phase A and 35% mobile phase B, 1.0-1.1 min with 35%-75% mobile phase B, 65%-25% mobile phase A, to 1.1 min with 25% mobile phase A and 75% of mobile phase B with a total circulation time of 1.5 minutes. The specific compounds disclosed herein were tested in the preceding assay and were determined to inhibit SAM with an IC50 according to the following ratings: (A) less than 100 nM (> 60% maximum inhibition), (B) between 100 nM and 1 pM (> 60% maximum inhibition) and (NT) not tested, as shown in Table 4 below. Example 277: Assay for Inhibition of Proliferation Cellular 383 The impact of the compound on cancer cell growth was evaluated by treating cancer cells with the compound for 4 days and then measuring proliferation using an ATP-based cell proliferation readout (Cell Titer Glo, Promega Corporation). In a standard assay, an isogenic pair of human HACT116 colon carcinoma cell lines that differ only in their MTAP deletion status (HCT116 MTAP+ / + and HCT116 MTAP- / -) were placed in 96-well plates at the appropriate cell density. After 24 hours, the cells were treated with the candidate MAT2A inhibitor. Before cell addition, the compound was serially diluted in 100% DMSO (typically as a 3x dilution starting at a 500x upper dose with 10 dose points including DMSO as the sole control). The compound was then transferred to a working stock plate in cell culture medium by adding 5 µl of the compound in DMSO to 495 µl of cell culture medium. The working stock was then added to the cells by another 5x dilution, adding 25 µl of the working stock to 100 µl of cells in the culture medium.After the compound was added, the cells were incubated at 37 °C / 5% CO2 for 4 days. 384 To measure cell proliferation inhibition, cells were allowed to equilibrate to room temperature for 30 minutes and then treated with 125 pL of Cell Titer Glo reagent. The plate was then covered with an aluminate foil and shaken for 15 minutes to ensure thorough mixing and complete cell lysis. The luminescent signal was then measured using a Veritas plate-based luminometer, version 1.9.2, using the ATP normal curve to confirm assay reproducibility from run to run. This luminescence measurement was converted into a proliferation index by subtracting the ATP luminescence signal measured from a blank (no cells) dish from each data point and dividing by the ATP luminescence signal measured in a 0.2% DMSO control dish adjusted for the blank dish signal.The compound's activity was then represented as a percentage change in proliferation relative to control DMSO within the plaque versus log10 of the compound's concentration in molar units (M). The specific compounds disclosed herein were tested in the following assay and were determined to inhibit cell proliferation with an IC50 according to the following ratings: (A) less than 100 nM (>30% maximum inhibition for MTAP - / -; >10% maximum inhibition for MTAP + / +), (B) 385 between 100 nM and 10 μM (> 30% maximum inhibition for MTAP - / -; > 10% maximum inhibition for MTAP + / + ), (C) more than 10 μM and (NT) not tested, as shown in Table 4 below. Table 4 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 101 B NT NT NT 102 C NT NT NT 103 B NT NT NT 104 C NT NT NT 105 C NT NT NT 106 C NT NT NT 107 C NT NT NT 108 C NT NT NT 109 B NT NT NT 110 B NT NT NT 111 C NT NT NT 386 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 112 B NT NT NT 113 B NT NT NT 114 B NT NT NT 115 B NT NT NT 116 C NT NT NT 117 C NT NT NT 118 C NT NT NT 119 C NT NT NT 120 C NT NT NT 121 B NT NT NT 122 B NT NT NT 123 AAAB 124 AAAC 125 A NT NT NT 126 C NT NT NT 127 AAAC 387 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 128 A NT NT NT 129 ABBC 130 A NT NT NT 131 A NT NT NT 132 AAAC 133 AAAC 134 A NT NT NT 135 AAAB 136 B NT NT NT 137 ABBC 138 B NT NT NT 139 AABC 140 B NT NT NT 141 AAAC 142 B NT NT NT 143 ABBC 388 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h in Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 Days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 144 ABBC 145 AAAC 146 B NT NT NT 147 ABBC 148 AAAB 149 A NT NT NT 150 AABB 151 AAAB 152 AAAC 153 AAAC 154 A NT NT NT 155 ABBB 156 AAAC 157 AABC 158 AAAC 159 AAAB 389 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 160 AAAC 161 AAAC 162 A NT NT NT 163 C NT NT NT 164 A NT NT NT 165 A NT NT NT 166 AAAC 167 ABBC 168 AAAC 169 AAAC 170 A NT NT NT 171 AAAC 172 AAAC 173 A NT NT NT 174 A NT NT NT 175 A NT NT NT 390 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h in Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 176 B NT NT NT 177 AABC 178 AABB 179 ABBC 180 AAAC 181 AABC 182 AABC 183 ABBC 184 A NT NT NT 185 C NT NT NT 186 B ​​NT NT NT 187 C NT NT NT 188 AABC 189 AABB 190 A NT NT NT 191 A NT NT NT 391 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 192 AABC 193 ABBC 194 B NT NT NT 195 AAAC 196 A NT NT NT 197 B NT NT NT 198 ABBC 199 C NT NT NT 200 ABBB 201 B NT NT NT 202 ABBC 203 ABCC 204 B NT NT NT 205 AABC 206 ABBB 207 B NT NT NT 392 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 208 A NT NT NT 209 AAAC 210 AAAC 211 AAAC 212 AAAC 213 AAAC 214 A NT NT NT 215 AAAB 216 AAAB 217 AABC 218 AAAB 219 AAAB 220 AAAB 221 AABC 222 AABC 223 ABBC 393 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h in Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 224 ABCC 225 BABB 226 AAAB 227 AAAB 228 AAAB 229 AAAB 230 AAAB 231 AABC 232 AAAC 233 AAAC 234 AAAC 235 AAAC 236 AAAC 237 AAAC 238 A NT NT NT 239 AAAB 394 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 240 AAAC 241 AAAB 242 AAAC 243 AAAC 244 AAAB 245 AABC 246 ABBB 247 AAAB 248 AAAB 249 AABB 250 AAAB 251 AAAB 252 AABB 253 AAAB 254 AAAC 255 AAAC 395 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 256 AABB 257 AAAB 258 AABB 259 AAAC 260 AAAC 261 A NT NT NT 262 AABC 263 A NT NT NT 264 AABB 265 AAAC 266 B NT NT NT 267 A NT NT NT 268 ABBC 269 AABC 270 AAAC 271 A NT NT NT 396 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 272 AABC 273 A NT NT NT 274 A NT NT NT 101-AAAAC 102-AAAAB 103-AAAAC 104-AAABB 105-AAAAB 106-AAABC 107-AAAAB 108-AAAAB 109-AAAAB 110-AAAAB 111-AAAAB 112-AAAAB 113-AAAAB 397 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 114-AAAAB 115-AAAAB 116-AAAAC 117-AAAAB 118-AAAAB 119-AAAAB 120-AAAAB 121-AAABB 122-AAAAB 123-AAAAB 124-AAABB 125-AAAAB 126-AAAAB 127-AABAB 128-AAAAB 129-AAABB 398 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h of Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 130-AAAAB 131-AAABB 132-AAAAB 133-AAAAB 134-AAAAC 135-AB NT NT NT 136-AA NT NT NT 137-AAAAB 138-AABBB 139-AAAAB 140-AAAAC 141-AAAAB 142-AABBC 143-AAAAB 144-AAABB 145-AAAAB 399 Compound No. Enzyme Inhibition (Example 275) SAM Inhibition at 72 h in Cells (MTAP - / -; Example 276) Relative Growth Inhibition at 4 days (MTAP - / -; Example 277) Relative Growth Inhibition at 4 Days (MTAP + / +; Example 277) 146-AAAAB 147-AAAAC 148-AAABB 149-AAABB 150-AAABB Other compounds listed in Table 5 below exhibit enzyme inhibition greater than 10 pm (Example 275) or less than 50% inhibition at maximum concentration. Table 5 400 401 402 403 404 405 406 407 CLAIMS

Claims

1. MAT2A heterobicyclic inhibitor compounds according to Formula I: (FORMULA I) characterized in that: X is N or CR6; L is O, S, NR, or a bond; R is H or C1-6 alkyl; R1 is selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C3-6 carbocyclyl, -(C1-6 alkyl)(C3-6 carbocyclyl), and -(C1-6 alkyl)(C3-6 cycloalkenyl), wherein all the alkyl groups of R1 are straight or branched, and R1 is optionally substituted by a 1-6 halo; or when L is NR, then R and R1 in combination with L represent a 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are selected independently of N, O and S) optionally substituted by one or more RA; R2 and R3 are selected independently from the group consisting of C6-10 aryl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are selected independently of N,O and S) and 3-to-14-membered heterocycloalkyl (wherein 1-4 members of the heterocycloalkyl are selected independently from N, O and S), wherein R 2 and R 3 are independently and optionally substituted by one or more substituents selected from the group consisting of RA , OR A , halo, -N=NR A , NR ARB , -(C1-6 alkyl)NR ARB , -C(O)OR A , -C(O)NR ARB , -OC(O)RA and -CN; R2a is absent and, if present, is taken together with R2 and the carbon atom to which they are attached to form a 5- to 6-membered spiro-fused carbocyclyl or heterocycloalkyl (wherein 1-4 members of the carbocyclyl or heterocycloalkyl are selected independently of N, O and S) and each bond - - - (a) represents a single bond and each bond - - - (b) represents a double bond; wherein the 5- to 6-membered spiro-fused carbocyclyl or heterocycloalkyl is optionally substituted with one or more RA; and if R2a is absent,then each bond - - - (a) represents a double bond and each bond - - - (b) represents a single bond; R 4 , R 5 and R 6 are selected independently from the group consisting of RA , OR A , halo, NR ARB , -(C1-6 alkyl)NR ARB , -C(O)OR A , -C(O)NR ARB and -OC(O)RA ; RA and RB are independently selected from the group consisting of H, -CN, -hydroxy, oxo, C1-6 alkyl, C1-6 alkoxy, C2-6 alkenyl, C2-6 alkynyl, NH2, -S(O)0-2-(C1-6 alkyl), -S(O)0-2-(C6-10 aryl), -C(O)(C1-6 alkyl), -C(O)(C3-14 carbocyclyl), -C3-14 carbocyclyl, -(C1-6 alkyl)(C3-14 carbocyclyl), C6-10 aryl, 3- to 14-membered heterocycloalkyl and -(C1-6 alkyl)-(3- to 14-membered heterocycloalkyl) (wherein the 1-4 heterocycloalkyl members are independently selected from N, O and S) heteroaryl of 5 to 10 members (wherein 1-4 members of the heteroaryl are selected independently of N, O and S); where each of the alkyl groups,The alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl groups of RA and RB are optionally substituted with one or more substituents selected from the group consisting of hydroxy, halo, -NR'2 (where each R' is independently selected from the group consisting of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, 3- to 14-membered heterocycloalkyl, and -(C1-6 alkyl)-(3- to 14-membered heterocycloalkyl) (where 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (where 1-4 heteroaryl members are independently selected from N, O, and S), -NHC(O)(O C1-6 alkyl), -NO2, -CN, oxo, -C(O)OH,-C(O)O(C1-6 alkyl), -C1-6 alkyl (C1-6 alkoxy),-C(O)NH2, C1-6 alkyl, -C(O)C1-6 alkyl, -O C1-6 alkyl, -Si(C1-6 alkyl)3, -S(O)O-2-(C1-6 alkyl), C6-10 aryl, -(C1-6 alkyl)(C6-10 aryl),3- to 14-membered heterocycloalkyl and -(C1-6 alkyl)-(3- to 14-membered heterocycle) (wherein the 1-4 members of the heterocycle are independently selected from N, O, and S) and -O(C6-14 aryl), wherein each of the alkyl, alkenyl, aryl, and heterocycloalkyl groups of RA and RB is optionally substituted with one or more substituents selected from the group consisting of hydroxy, -O-C1-6 alkyl, halo, -NH2, -(C1-6 alkyl)NH2, -C(O)OH, CN, and oxo, wherein the compound is selected from the following table: (FORMULA 101 / 274) (FORMULA 101-A / 150-A) or a pharmaceutically acceptable salt thereof. Sole Claim,