Supporting Information

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1 Supporting Information Discovery of -(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS ), a Selective and rally Efficacious Inhibitor of the Met Kinase Superfamily Gretchen M. Schroeder, Zhen-Wei Cai, Xiao-Tao Chen, Cheryl Clark, Lyndon A. M. Cornelius, Jun Dai, Gennaro Dito, Johnni Gullo-Brown, Ashok Gupta, Benjamin Henley, John T. Hunt, Robert Jeyaseelan, Amrita Kamath, Kyoung Kim, Jonathan Lippy, Louis J. Lombardo, Veeraswamy Manne, Simone ppenheimer, John S. Sack, Robert J. Schmidt, Guoxiang Shen, Kevin Stefanski, John S. Tokarski, George L. Trainor, Barri S. Wautlet, Donna Wei, David K. Williams, Yingru Zhang, Yueping Zhang, Joseph argnoli, and Robert M. Borzilleri Bristol-Myers Squibb Research and Development P Box 4000, Princeton, ew Jersey, Contents of Supporting Information: I. General experimental details II. Detailed experimental procedures for the preparation of compound 10 III. Experimental procedures and characterization data for analogues 2-9, IV. Table of HPLC analysis data for compounds 2-12 V. Detailed description of biological assays S1

2 I. General Experimental Details All non-aqueous reactions were carried out under an atmosphere of nitrogen at room temperature, unless otherwise noted. Commercial reagents and anhydrous solvents were purchased from Aldrich and were used without further purification. Analytical thin layer chromatography (tlc) and flash chromatography were performed on EM Science silica gel 60. Analytical high pressure liquid chromatography (HPLC) and LC-MS analyses were conducted using Shimadzu LC-10AS pumps and a SPD-10AV UV-vis detector set at 220 nm with the MS detection performed with a Micromass Platform LC spectrometer. Analytical reverse phase HPLC analyses were performed on a YMC S5 DS-A 4.6 x 50 mm column eluting with a mixture of solvents A and B (starting from 10% solvent B to 100 % solvent B over a 4 minute linear gradient time; solvent A: 10% MeH-90% water-0.1% TA; solvent B 90% MeH-10% water-0.1% TA; flow rate 4 ml/min; UV 220 nm). Preparative reverse phase HPLC analyses were performed on a YMC C-18 DS-A S10 50 x 500 mm column eluting with a mixture of solvents A and B (starting from 10% solvent B to 100 % solvent B over a 30 minute linear gradient time; solvent A: 10% MeH-90% water-0.1% TA; solvent B 90% MeH-10% water-0.1% TA; flow rate 50 ml/min; UV 220 nm). 1 H and 13 C MR spectra were recorded on a JEL Eclipse 500 MHz MR spectrometer or a Bruker 400 MHz spectrometer and calibrated using an internal standard. High resolution mass spectra (HRMS) were recorded on a JEL SX102 mass spectrometer. Elemental analyses were performed by Robertson Microlit Laboratories and the results obtained are within ±0.4% of the theoretical values. S2

3 II. Detailed Experimental Procedures for the Preparation of Compound 10 (BMS ) Cl Cl H 2 C A. 3,4-Dichloropicolinic acid (14). As described previously by Marzi, E. et al. (Eur. J. rg. Chem. 2001, ), 2,2,6,6-tetramethylpiperidine (8.84 ml, 52 mmol) in 50 ml of ether at 0 o C was charged with n-buli (33 ml, 52 mmol, 1.6 M hexanes). After stirring at 0 o C for 30 min, the solution was cooled to 78 o C and charged with a solution of 3,4-dichloropyridine (13, 7.0 g, 47 mmol, Matrix) in 5 ml of ether. After stirring at 78 o C for 2 h, carbon dioxide (dry ice) was bubbled into the reaction mixture via cannula at which time the solution became heterogeneous. After bubbling carbon dioxide into the reaction at 78 o C for 10 min, the cooling bath was removed and the reaction mixture was allowed to warm to rt with C 2 bubbling. The reaction was quenched with saturated aqueous ammonium chloride solution (~50 ml) and stirred at rt under an atmosphere of air for 5 min. The reaction mixture was diluted with water (~150 ml) and extracted with ethyl acetate (2 75 ml) to remove any remaining starting material. The aqueous layer was acidified to ph 1-2 with 1 aqueous HCl solution and extracted with ethyl acetate (2 100 ml). The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3,4-dichloropicolinic acid (14, 3.5 g, 39%) as a yellow solid. 1 H MR (DMS-d 6, 400 MHz) δ 8.53 (d, 1H, J = 5.2 Hz), 7.90 (d, 1H, J = 5.2 Hz); MS(ESI + ) m/z (M + H) +. Cl H 2 ()C Cl B. 3,4-Dichloropicolinamide (15). A mixture of 3,4-dichloropicolinic acid (14, 3.5 g, 18 mmol) in excess thionyl chloride (10 ml) was stirred at 80 o C for 1h. After cooling to rt, the reaction was concentrated in vacuo to remove excess thionyl chloride and then suspended in ether (50 ml). The ethereal acid chloride solution was added to ammonium hydroxide (50 ml) at 0 o C. The product was collected by vacuum filtration, washed with S3

4 water, and then triturated with ether to give 3,4-dichloropicolinamide (15, 2.6 g, 76%) as a beige solid. 1 H MR (DMS-d 6, 400 MHz) δ 8.50 (d, 1H, J = 5.2 Hz), 8.12 (br s, 1H), 7.83 (d, 1H, J = 5.2 Hz), 7.82 (br s, 1H); MS(ESI + ) m/z (M + H) +. Alternatively, 3,4-dichloropicolinamide can be prepared directly from 3,4- dichloropyridine according to the procedure described below. To a solution of 2,2,6,6-tetramethylpiperidine (31.1 g, 0.22 mol) in diethylether (400 ml) at 0 o C was added n-buli in hexane (1.6 M, ml, 0.22 mol) via syringe over 15 min. The resulting solution was stirred at 0 o C for 0.5 h and at 78 o C for 0.5 h. To this mixture was then slowly added a solution of 3,4-dichloropyridine (13, 29.6 g, 0.20 mol) in diethylether (20 ml) via syringe over 15 min. The resulting mixture was stirred at 78 o C for 2 h before the addition of isocyanatotrimethylsilane (85 % pure, 40.0 ml, 0.30 mol). After the addition, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 1 h. The reaction mixture was quenched with acetic acid (40 g, 0.67 mol) and 200 ml of water. The mixture was allowed to stir overnight and the white solid that formed was collected through filtration and washed with water. The filtrate was extracted with ethyl acetate (3 300 ml). The solid that was collected previously was dissolved in the combined organic layers, and the resulting solution was washed with brine (2 200 ml), dried over MgS 4 and concentrated in vacuo. The residue was suspended in 200 ml of diethylether and sonicated. The remaining solid was collected through filtration and washed with minimum amount of diethyl ether to provide 3,4-dichloropicolinamide (15, 14.8 g, 40%). H 2 Cl H 2 ()C C. 4-(4-Amino-2-fluorophenoxy)-3-chloropicolinamide (16). To a solution of 4- amino-2-fluorophenol (9.3 g, 73 mmol) in DM (100 ml) was added potassium tertbutoxide (8.8 g, 79 mmol). After stirring at rt for 30 min, 3,4-dichloropicolinamide (15, S4

5 10 g, 52 mmol) was added. The reaction mixture was stirred at 50 o C for 2.5 h. After cooling the reaction to rt, the mixture was diluted with 400 ml of ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (400 ml). The aqueous layer was back-extracted with 300 ml ethyl acetate. The combined organic phases were washed with 10% aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting brown solid was suspended in ethyl acetate, filtered and washed with ether to give the product 16 as a tan solid (7.4 g). The filtrate was concentrated in vacuo and then purified by flash chromatography on silica gel (2% methanol / ethyl acetate). The resulting brown solid was triturated with ether to give an additional 4.3 g of 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (16, 79% combined yield) as a pale tan solid: mp = o C; 1 H MR (CD 3 D, 400 MHz) δ 8.29 (d, 1H, J = 5.6 Hz), 7.00 (t, 1H, J = 8.8 Hz), 6.79 (d, 1H, J = 5.6 Hz), (m, 2H); 13 C MR (DMS-d 6, 100 MHz) δ 166.6, 160.8, 154.1, (d, J = Hz), 149.0, 148.7, (d, J = 12.8 Hz), 123.7, 115.9, 110.1, 110.0, (d, J = 20.6 Hz ); HRMS Calc d for C 12 H Cl (M+H + ): , ound: Anal. Calc d for C 12 H Cl: C, 51.17; H, 3.22;, ound: C, 51.37; H, 3.42;, I D. 1-(4-luorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (18). 4-Iodo-2-methoxynicotinaldehyde (17, 25 g, 95 mmol) and sodium iodide (31.0 g, 285 mmol) were stirred together in 500 ml of acetonitrile. To this solution was added chlorotrimethylsilane (36.0 ml, 285 mmol) dropwise over 15 minutes. The reaction mixture was stirred for 2 h at room temperature and then concentrated under vacuum. The product was suspended in ethyl acetate, water, and saturated aqueous sodium bicarbonate, then filtered to give a dark brown solid. This solid was triturated with acetonitrile to yield 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (21.3 g, 90%) as a yellow solid (mixture of tautomers). MS(ESI + ) m/z (M + H) +. 4-Iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (16.0 g, 64.3 mmol), 4- fluorophenylboronic acid (26.8 g, 193 mmol), copper(ii) acetate (23.4 g, 129 mmol), and S5

6 myristic acid (58.7 g, 257 mmol) were stirred together in 800 ml of toluene. To this solution was added 2,6-lutidine (60 ml, 514 mmol) and the reaction was stirred vigorously for 1 day. An additional 5 g of 4-fluorophenylboronic acid was added and the reaction was stirred vigorously for an additional 3 days. The reaction mixture was concentrated and then suspended in 10 % methanol/ethyl acetate. Celite was added and the mixture was stirred for 5 minutes. ext the mixture was filtered through a plug of Celite, concentrated, and suspended in ethyl acetate and water. The mixture was filtered through Celite again to remove additional copper that had precipitated out (washing well with ethyl acetate). The filtrate was washed with 1 aqueous HCl, dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting solid was triturated with ethyl acetate to yield 9.25 g (42 %) of 1-(4-fluorophenyl)-4-iodo-2-oxo- 1,2-dihydropyridine-3-carbaldehyde (18) as a yellow solid. The filtrate was concentrated in vacuo and the remaining solid was triturated again with ethyl acetate to yield an additional 5.75 g (68 % total yield) of the desired product 18 as a yellow solid: mp = o C; 1 H MR (DMS-d 6, 400 MHz) δ 9.96 (s, 1H), 7.68 (d, 1H, J = 7.2 Hz), (m, 2H), 7.40 (t, 2H, J = 8.8 Hz), 7.02 (d, 1H, J = 6.8 Hz); MS(ESI + ) m/z (M + H) + ; 13 C MR (DMSΟ- d 6, 125 MHz) δ 189.9, (d, J C = Hz), 159.8, 142.9, 135.5, (d, J C = 8.9 Hz), 125.4, 118.5, 116.7, (d, J C = 23.0 Hz); HRMS Calc d for C 12 H 7 2 I (M+H + ): , ound: I H E. 1-(4-luorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carboxylic acid. 1-(4- luorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (10.0 g, 29.2 mmol) and sodium phosphate monobasic (10.1 g, 73 mmol) were stirred vigourously in 35 ml each of TH, tert-butanol, and water at 0 o C. 2-Methyl-2-butene (45.2 ml, 2.0 M in TH) was added to the reaction mixture, followed by sodium chlorite (6.06 g, 67.1 mmol). The ice bath was removed and the reaction mixture was warmed to room temperature, stirring very rapidly. After a few minutes the desired product began precipitating out of solution. Stirring was continued for 1 h, then 20 ml of 1 aqueous S6

7 HCl was added, and stirring was continued for another 5 minutes. The desired product was filtered off, then washed with water, ethyl acetate, and ether. The filtrate was taken and the layers were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in ethyl acetate, filtered, and washed with ethyl acetate and ether to yield additional desired product. The pale yellow solids were combined to yield 8.22 g (78 %) of 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2- dihydropyridine-3-carboxylic acid (92 % pure, 8 % starting material remaining). This material was dissolved in a minimal amount of 1 aqueous ah. Ethyl acetate was added and the mixture was stirred vigourously for 5 minutes. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified to ph 1 using concentrated HCl. The pale yellow solid that precipitated out of solution was then filtered. The product was washed with water, ethyl acetate, diethyl ether and then dried under vacuum to afford 7.33 g (70 %) of 1-(4-fluorophenyl)-4-iodo-2-oxo- 1,2-dihydropyridine-3-carboxylic acid (95.4 % pure by HPLC): mp = o C; 1 H MR (DMS-d 6, 400 MHz ) δ (s, 1H), (m, 3H), 7.38 (t, 2H, J = 8.8 Hz), 6.81 (d, 1H, J = 7.2 Hz); 13 C MR (DMS-d 6, 125 MHz) δ 166.9, (d, J C = Hz), 156.9, 138.8, 135.9, 133.2, (d, J C = 9.0 Hz), (d, J C = 23.1 Hz), 115.3, 109.5; HRMS Calc d for C 12 H 7 3 I (M-H - ): , ound: Et H Cl H 2 ()C. 3-Chloro-4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamido)-2-fluorophenoxy)picolinamide (20). To 1-(4-fluorophenyl)-4-iodo-2- oxo-1,2-dihydropyridine-3-carboxylic acid (18, 3.7 g, 10 mmol) in 6 ml of toluene was added thionyl chloride (10 ml). After stirring at rt for 2.5 h, the mixture became homogenous and was then concentrated in vacuo. Toluene (3 ml) was added to the residue and the mixture was concentrated in vacuo to remove excess thionyl chloride S7

8 (performed twice). The crude acid chloride 19 was then dried under high vacuum for 15 minutes. While the acid chloride was drying, 4-(4-amino-2-fluorophenoxy)-3- chloropicolinamide (16, 2.5 g, 8.9 mmol) was dissolved in TH (50 ml) and DM (3 ml). The solution was cooled to 0 o C and then,-diisopropylethylamine (3.1 ml, 18 mmol) was added. The acid chloride 19 was then added over 30 min as a solid. Upon completion of the addition, the cooling bath was removed and the reaction mixture was stirred at rt for 15 min before being quenched with saturated aqueous sodium bicarbonate solution (30 ml). Water was added (~30 ml) to dissolve the salts and the mixture was extracted with ethyl acetate (1 100 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (2% methanol / ethyl acetate) to give 4.9 g of the desired product along with a minor amount of 3-chloro-4-(4-(4-chloro-1-(4-fluorophenyl)-2-oxo- 1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide together as an offwhite solid (89% based on iodide). 1 H MR (CD 3 D, 400 MHz) δ 8.34 (d, 1H, J = 5.6 Hz), 7.92 (dd, 1H, J = 12.4, 2.4 Hz), (m, 4H), (m, 3H), 6.99 (d, 1H, J = 7.2 Hz), 6.86 (d, 1H, J = 5.6 Hz); MS(ESI + ) m/z (M + H) +. Sodium hydride (1.89 g, 47.2 mmol, 60% dispersion in mineral oil) was added slowly to a solution of ethanol (77 ml) and TH (77 ml) under 2 and the resulting mixture was stirred at rt for 5 min. The sodium ethoxide solution was then added to a mixture of 3-chloro-4-(2-fluoro-4-(1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine- 3-carboxamido)phenoxy)-picolinamide and 3-chloro-4-(4-(4-chloro-1-(4-fluorophenyl)- 2-oxo-1,2-dihydropyridine-3-carboxamido)-2-fluorophenoxy)picolinamide (22.6 g, ~36.3 mmol) and stirred for 1 h at rt. The reaction mixture was concentrated in vacuo. The resulting crude solid was suspended in ethyl acetate, saturated aqueous sodium bicarbonate solution, and water (to dissolve any precipitated salts). This mixture was sonicated and stirred until the remaining solid became a filterable powder. This powder was filtered off to yield 17.2 g (88 %) of the desired product 20 as a pale yellow solid. The layers of the remaining filtrate were separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting solid was triturated with ethyl acetate, sonicated, and filtered to give an additional 3.02 g of the desired product 20 as a pale S8

9 brown solid. 1 H MR (CD 3 D, 400 MHz) δ 8.34 (d, 1H, J = 5.6 Hz), 7.94 (dd, 1H, J = 12.4, 2.4 Hz), 7.80 (d, 1H, J = 8 Hz), (m, 3H), (m, 3H), 6.86 (d, 1H, J = 5.6 Hz), 6.61 (d, 1H, J = 7.2 Hz), 4.34 (q, 2H, J = 7.2 Hz), 1.45 (t, 3H, J = 7.2 Hz); MS(ESI + ) m/z (M + H) +. Et H Cl H 2 G. -(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (10). To 3-chloro-4-(4-(4- ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2- fluorophenoxy)picolinamide (20, 1.2 g, 2.1 mmol) in ethyl acetate (16 ml), acetonitrile (16 ml), and water (8 ml) at 0 o C was added iodobenzene diacetate (820 mg, 2.6 mmol). After stirring at rt for 2 h, the reaction was filtered to collect the crude product. The solid was washed with additional ethyl acetate. The filtrate was washed with saturated aqueous sodium bicarbonate solution and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The precipitate and filtrate were combined and purified by flash chromatography on silica gel (2% methanol /chloroform) to give the title compound 10 (810 mg, 74%) as a white solid. 1 H MR (CDCl 3, 500 MHz) δ (s, 1H), 7.90 (dd, J = 12.65, 2.20 Hz, 1H), 7.76 (d, J = 5.77 Hz, 1H), 7.50 (d, J = 7.70 Hz, 1H), 7.34 (dd, J = 8.94, 4.81 Hz, 2H), 7.26 (m, 1H), 7.22 (t, J = 8.39 Hz, 2H), 7.05 (t, J = 8.80 Hz, 1H), 6.35 (d, J = 7.97 Hz, 1H), 6.01 (d, J = 5.77 Hz, 1H), 4.98 (s, 2H), 4.34 (q, J = 6.87 Hz, 2H), 1.57 (t, J = 7.01 Hz, 3H); 13 C MR (CDCl 3, 126 MHz) δ , , (d, J C = Hz, 1C), , , , (d, J C = Hz, 1C), , , (d, J C = Hz, 1C), (d, J C = Hz, 1C), , (d, J C = Hz, 2C), , (d, J C = Hz, 1C), , (d, J C = Hz, 1C), , , 97.32, 66.28, MR (CDCl 3, 471 MHz) δ (1, m), (dd, J = 12.72, 9.08 Hz, 1). HRMS Calc d for C 25 H Cl 2 (M+H + ): , ound: Anal. Calc d S9

10 for C 25 H Cl 2 : C, 58.54; H, 3.73;, 10.92; Cl, ound: C, 58.52; H, 3.85;, 10.84; Cl, III. Characterization Data for Analogues 2-9, Compound 2 H H 2 -(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2- dihydropyridine-3-carboxamide. H 2 Cl A. 4-(2-Chloropyridin-4-yloxy)-3-fluorobenzenamine. Sodium hydride (60%, g, 2.60 mmol, 1.1 eq) was added to a solution of 2-fluoro-4-aminophenol (0.30 g, 2.36 mmol, 1.0 eq) in DM (6.5 ml) at room temperature and the reaction mixture was stirred for 30 minutes. 2-Chloro-4-nitropyridine (0.374 g, 2.36 mmol, 1.0 eq) was added and the reaction mixture was heated to 90 o C for 12 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous acl solution and extracted with ethyl acetate (3 x 70 ml). The combined organic extracts were washed with 10% aq. LiCl solution (3 x 70 ml), dried over a 2 S 4, and filtered. The filtrate concentrated in vacuo to afford the title compound (0.430 g, 76%) which was used without further purification. 1 H MR (DMS-d 6, 400 MHz) δ 8.27 (d, 1H, J = 5.7 Hz), (m, S10

11 3H), (m, 2H), 5.54 (s, 2H); MS(ESI + ) m/z 239 (M + H) + ; HRMS (ESI + ) calcd.: , found: H 2 H B. 4-(4-Amino-2-fluorophenoxy)--benzylpyridin-2-amine. Benzylamine (9.1 ml, 83.8 mmol, 20 eq) was added to 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (1.0 g, 4.19 mmol, 1.0 eq), copper powder (0.266 g, 4.19 mmol, 1.0 eq) and K 2 C 3 (0.578 g, 4.19 mmol, 1.0 eq) in a sealed tube and the reaction mixture was heated to 160 o C for 12 h. The reaction mixture was cooled to room temperature and quenched with saturated aqueous acl solution. The solution was extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were dried (a 2 S 4 ), filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous ahc 3 solution and extracted with CH 2 Cl 2 (3 x 100 ml). The combined organic extracts were dried (a 2 S 4 ), filtered and concentrated in vacuo to afford the title compound (0.675 g, 52%) as a solid. 1 H MR (CD 3 D, 400 MHz) δ (m, 1H), (m, 5H), (m, 1H), (m, 2H), (m, 1H), (m, 1H), 4.40 (s, 2H); MS(ESI + ) m/z 310 (M + H) + ; HRMS(ESI + ) calcd.: , found: H 2 H 2 C. 4-(4-Amino-2-fluorophenoxy)pyridin-2-amine. Palladium hydroxide on carbon (10%, g) was added to a solution of 4-(4-amino-2-fluorophenoxy)-- S11

12 benzylpyridin-2-amine (0.245 g, mmol, 1.0 eq) in 5% HC 2 H-MeH (10 ml) under a blanket of hydrogen (from a balloon) at room temperature. The reaction mixture was stirred at room temperature for 12 h, filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by reverse phase preparative HPLC and the appropriate fractions were concentrated in vacuo. The concentrate was neutralized with saturated aqueous ahc 3 solution and the mixture was extracted with CHCl 3 (3 x 35 ml). The combined organic extracts were dried (a 2 S 4 ), filtered and concentrated in vacuo to afford the title compound (0.045 g, 26%) as a solid. 1 H MR (CD 3 D, 400 MHz) δ (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 1H); MS(ESI + ) m/z 220 (M + H) + ; HRMS(ESI + ) calcd.: , found: D. -(4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2- dihydropyridine-3-carboxamide, hydrochloride salt. A solution of 4-(4-amino-2- fluorophenoxy)pyridin-2-amine (58 mg, 0.20 mmol) in DM was treated with 1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (47 mg, 0.20 mmol), DIPEA (45 µl, 0.26 mmol) and TBTU (84 mg, 0.26 mmol) and the mixture was stirred at RT for 2 h. The mixture was concentrated to remove the DM and the residue partitioned between EtAc and saturated sodium bicarbonate solution. The EtAc phase was washed with saturated sodium bicarbonate solution, brine, dried (MgS 4 ), concentrated, and treated with ethereal HCl to give compound 2 (22 mg, 23% yield). 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), (s, 1H), 8.58 (d, 1H, J = 5.0 Hz), 8.13 (d, 1H, J = 5.0 Hz), 8.07 (d, 1H, J = 10.0 Hz), 7.98 (d, 1H, J = 7.5 Hz), 7.89 (s, 2H), (m, 6H), 6.72 (m, 2H), 6.17 (d, 1H, J = 2.5 Hz); MS(ESI + ) m/z (M + H) +. Compound 3 S12

13 H H 2 -(4-(2-Amino-3-((4-methylpiperazin-1-yl)methyl)pyridin-4-yloxy)-3- fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. Cl BocH A. tert-butyl 4-chloro-3-formylpyridin-2-ylcarbamate. To (4-chloro-pyridin-2- yl)-carbamic acid tert-butyl ester (CB Research and Development Inc., 2.0 g, 8.75 mmol) in TH (18 ml) under nitrogen at - 78 o C, was added n-buli (13.7 ml, 21.9 mmol, 1.6 M in hexanes) dropwise. After stirring at - 78 o C for 45 min, a solution of DM (1.93 ml) in TH (2 ml) was added dropwise. The reaction was stirred at - 78 o C for 30 min and was then allowed to warm slowly to room temperature. The reaction was quenched with 1 aq HCl solution and then basified with saturated aqueous sodium bicarbonate solution (50 ml) and extracted with ethyl acetate (3 50 ml). The combined organic extracts were dried over anhydrous a 2 S 4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (EtAc) to give the title compound (0.95 g, 42%) as a white solid. 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), (s, 1H), 8.47 (d, 1H, J = 85.2 Hz), 7.40 (d, 1H, J = 5.6 Hz), 1.48 (s, 9H). 2 BocH B. tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-formylpyridin-2-ylcarbamate. To 2- fluoro-nitrophenol (700 mg, 4.44 mmol) in 5 ml of DM was added sodium hydride S13

14 (180 mg, 4.44 mmol, 60%) After stirring at rt for 5 min, a solution of tert-butyl 4-chloro- 3-formylpyridin-2-ylcarbamate (0.95 g, 3.7 mmol) in 5 ml of DM was added. The mixture was stirred at 60 o C for 20 h. After cooling to rt, the reaction was diluted with EtAc (50 ml), washed with 10% aqueous lithium chloride solution (2 x 40 ml) followed by saturated aqueous sodium bicarbonate solution (40 ml), dried over anhydrous a 2 S 4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50% EtAc / hexanes) to give the title compound (1.0 g, 72%) as a yellow oil. 1 H MR (CD 3 D, 400 MHz) δ (s, 1H), (m, 2H), 7.67 (t, 1H, J = 7.6 Hz), 6.60 (d, 1H, J = 6 Hz), 1.59 (s, 9H). 2 H BocH C. tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-(hydroxymethyl)pyridin-2- ylcarbamate. To tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3-formylpyridin-2-ylcarbamate (75 mg, 0.2 mmol) in 1 ml of methanol at 0 o C was added sodium borohydride (7.6 mg, 0.20 mmol). After stirring at 0 o C for 30 min, the reaction was quenched with saturated aqueous ammonium chloride solution (1 ml). The reaction was diluted with EtAc (5 ml) and the layers were separated. The organic layer was dried over anhydrous a 2 S 4 and concentrated in vacuo to give the title compound (65 mg, 86%) as a white solid which was used without further purification. 1 H MR (CD 3 D, 400 MHz) δ 8.28 (dd, 1H, J = 10.4, 2.8 Hz), (m, 2H), 7.45 (t, 1H, J = 8.4 Hz), 6.68 (d, 1H, J = 6 Hz), 4.81 (s, 2H), 1.57 (s, 9H); MS(ESI + ) m/z (M + H) +. 2 TBS BocH S14

15 D. tert-butyl 3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4- nitrophenoxy)pyridin-2-ylcarbamate. To tert-butyl 4-(2-fluoro-4-nitrophenoxy)-3- (hydroxymethyl)pyridin-2-ylcarbamate in dichloromethane (3 ml) was added imidazole (21 mg, 0.31 mmol) followed by tert-butyldimethylsilyl chloride (40 mg, 0.26 mmol). After stirring at rt for 1 h, a second equivalent of tert-butyldimethylsilyl chloride (40 mg, 0.26 mmol) was added. The reaction was stirred at rt for 3 h and was then diluted with dichloromethane (10 ml), washed with water (10 ml), dried over anhydrous a 2 S 4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (50% EtAc / hexanes) to give the title compound (102 mg, 79%) as a white solid. 1 H MR (CD 3 D, 400 MHz) δ 8.16 (dd, 1H, J = 10.4, 2.8 Hz), (m, 2H), 7.29 (t, 1H, J = 8.4 Hz), 6.53 (d, 1H, J = 5.6 Hz), 4.84 (s, 2H), 1.43 (s, 9H), 0.84 (s, 9H), 0.00 (s, 6H); MS(ESI + ) m/z (M + H) +. H 2 TBS BocH E. tert-butyl 4-(4-amino-2-fluorophenoxy)-3-((tert-butyldimethylsilyloxy)- methyl)pyridin-2-ylcarbamate. To a solution of tert-butyl 3-((tertbutyldimethylsilyloxy)methyl)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylcarbamate (0.44 g, 0.89 mmol) in TH (4 ml) and methanol (6 ml) was added zinc dust (1.17 g, 20 mmol) followed by ammonium chloride (960 mg, 20 mmol). After stirring at rt for 2 h, the mixture was filtered through Celite using methanol and concentrated in vacuo to give the crude title compound (0.44 g, 100%) as a pale yellow oil. 1 H MR (CD 3 D, 400 MHz) δ 7.90 (d, 1H, J = 6 Hz), 6.76 (t, 1H, J = 8.8 Hz), 6.43 (dd, 1H, J = 12.8, 2.8 Hz), (m, 1H), 6.21 (d, 1H, J = 5.6 Hz), 4.85 (s, 2H), 1.39 (s, 9H), 0.81 (s, 9H), 0.01 (s, 6H); MS(ESI + ) m/z (M + H) +. S15

16 H TBS BocH. tert-butyl 3-((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2- ylcarbamate. To a solution of tert-butyl 4-(4-amino-2-fluorophenoxy)-3-((tertbutyldimethylsilyloxy)-methyl)pyridin-2-ylcarbamate (0.44 g, 0.89 mmol) and 1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (228 mg, 0.98 mmol) in DM (5mL) was added DIPEA (465 µl, 2.67 mmol) followed by TBTU (429 mg, 1.34 mmol). After stirring at rt for 6 h, water was added and the desired precipitated product was collected by vacuum filtration to give the crude title compound (700 mg) as a yellow solid. 1 H MR (CD 3 D, 400 MHz) δ 8.51 (dd, 1H, J = 7.6, 2.4 Hz), 7.93 (d, 1H, J = 6 Hz), (m, 2H), (m, 2H), (m, 3H), 7.06 (t, 1H, J = 8.8 Hz), 6.57 (t, 1H, J = 6.8 Hz), 6.26 (d, 1H, J = 5.6 Hz), 4.86 (s, 2H), 1.40 (s, 9H), 0.82 (s, 9H), 0.00 (s, 6H); MS(ESI + ) m/z (M + H) +. H H BocH G. tert-butyl 4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamido)phenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate. To tert-butyl 3- ((tert-butyldimethylsilyloxy)methyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2- dihydropyridine-3-carboxamido)phenoxy)pyridin-2-ylcarbamate (0.89 mmol) in 10 ml of TH at rt was added tetrabutylammonium flouride (1.34 ml, 1.34 mmol, 1 M TH). After stirring at rt for 30 min, the reaction was diluted with ethyl acetate (20 ml), washed with water followed by brine (10 ml each), dried over anhydrous MgS 4, and S16

17 concentrated in vacuo. The product precipitated from ethyl acetate to give the title compound (607 mg) as a yellow solid. 1 H MR (CD 3 D, 400 MHz) δ 8.62 (dd, 1H, J = 7.2, 2 Hz), 8.04 (d, 1H, J = 6 Hz), (m, 2H), (m, 2H), (m, 3H), 7.20 (t, 1H, J = 8.8 Hz), 6.67 (t, 1H, J = 6.8 Hz), 6.40 (d, 1H, J = 5.2 Hz), 4.78 (s, 2H), 1.49 (s, 9H); MS(ESI + ) m/z (M + H) +. H. -(4-(2-Amino-3-((4-methylpiperazin-1-yl)methyl)pyridin-4-yloxy)-3- fluorophenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. To a solution of tert-butyl 4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamido)phenoxy)-3-(hydroxymethyl)pyridin-2-ylcarbamate (607 mg, 0.89 mmol) in dichloromethane (10 ml) was added Dess Martin periodinane (415 mg, 0.98 mmol). After stirring at rt for 20 min, the reaction was filtered through a thin plug of silica gel using ethyl acetate and then concentrated in vacuo. The product precipitated out of ethyl acetate to give the crude title compound (400 mg, 80% over 3 steps) as a white solid. To a solution of tert-butyl 4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2- dihydropyridine-3-carboxamido)phenoxy)-3-formylpyridin-2-ylcarbamate (50 mg, mmol) in dichloroethane (0.5 ml) was added -methyl piperazine (100 µl, 0.89 mmol), acetic acid (8 µl, 0.13 mmol), and then sodium triacetoxyborohydride (28 mg, 0.13 mmol). After stirring at rt for 24 h, an additional amount of sodium triacetoxyborohydride was added (28 mg, 0.13 mmol). After stirring at rt for 48 h, the reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was diluted with 1,4-dioxane (2 ml) and charged with 4 HCl in dioxane (5 ml). After stirring at rt for 1h, the reaction mixture was concentrated in vacuo. The resulting crude product was purified by reverse phase preparative HPLC. The appropriate fractions were concentrated and toluene was added (2 x 3 ml) and the resulting mixture was concentrated again. The residue was dissolved in 1,4-dioxane (2 ml) and treated with 4 HCl in dioxane (0.5 ml). After stirring at rt for 5 min, the solution was concentrated and the solid was lyophilized from acetonitrile (1 ml) / water (3 ml) to give the HCl salt of compound 3 (23 mg, 39%) as a white solid. 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), 8.52 (dd, 1H, J = 7.2, 2 Hz), 8.09 (dd, 1H, J = 6.8, 2 Hz), 8.00 (dd, S17

18 1H, J = 12.8, 2.4 Hz), 7.89 (d, 1H, J = 7.2 Hz), (m, 1H), (m, 1H), (m, 1H), (m, 3H), 6.68 (t, 1H, J = 7.2 Hz), 6.22 (d, 1H, J = 7.2 Hz), 4.17 (s, 2H), (m, 2H), (m, 2H), (m, 4H), 2.68 (s, 3H); MS(ESI + ) m/z (M + H) +. Compound 4 H H 2 H 2 -(4-(2-Amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. I Cl A. (4-Chloro-3-iodopyridin-2-yl)-carbamic acid tert-butyl ester. A solution of (4- chloro-pyridin-2-yl)-carbamic acid tert-butyl ester (CB Research and Development Inc., 5.0 g, 22.0 mmol), TMEDA (8 ml) in anhydrous TH (100 ml) was placed under a nitrogen atmosphere and cooled to - 70 o C and treated dropwise with 2.5 M n-buli in hexanes (22.0 ml, 54.8 mmol) over a period of 30 min. The mixture was stirred at - 70 o C for 1 h then treated dropwise with a solution of I 2 (14 g, 110 mmol) in anhydrous TH (16 ml) at - 70 o C. After the addition was complete, the reaction was stirred at - 70 o C for 30 min then allowed to warm to room temperature. The mixture was treated with a solution of sodium hydrogensulfite (16 g) in H 2 (100 ml) and stirred for 30 min then extracted with EtAc. The extract was washed with brine, dried (MgS 4 ) and concentrated in vacuo. The product was purified by flash chromatography on Si 2 eluting with 0 5 % MeH / CH 2 Cl 2 to give the title compound (5.8 g, 78%) as white H S18

19 solid. 1 H MR (DMS-d 6, 400 MHz) δ 9.46 (s, 1H), 8.29 (d, 1H, J = 5.6 Hz), 7.46 (d, 1H, J = 5.0 Hz), 1.44 (s, 9H); MS(ESI - ) m/z ( M - H) -. I Cl H 2 B. 4-Chloro-3-iodopyridin-2-amine. A suspension of (4-chloro-3-iodo-pyridin-2- yl)-carbamic acid tert-butyl ester (5.6 g, 15.8 mmol) in 48 % hydrobromic acid was heated at 100 o C for 10 min to give a clear solution. The mixture was cooled, treated with crushed ice and made basic with 6 M ah. The precipitated product was collected by vacuum filtration, washed with H 2 and sucked partially on the funnel to give a white solid. The product was dissolved in TH and the solution dried over MgS 4 and concentrated in vacuo to give the title compound (3.7 g, 93%) as a white solid. 1 H MR (DMS-d 6, 400 MHz) δ 7.84 (d, 1H, J = 5.1 Hz), 6.73 (d, 1H, J = 5.6 Hz), 6.51 (br s, 2H); MS(ESI + ) m/z (M + H) +. 2 I H 2 C. 4-(2-luoro-4-nitrophenoxy)-3-iodopyridin-2-amine. A mixture of 4-chloro-3- iodopyridin-2-amine (3.6 g, 14.2 mmol) and 2-fluoro-4-nitrophenol (Lancaster, 4.5 g, 28.4 mmol), DIPEA (3.6 ml, 20.7 mmol) and MP (8 ml) was placed in a glass pressure vessel and heated rapidly to 170 o C. The heating was continued for 18 h. The volatile components were distilled off under reduced pressure and the viscous residue poured into ice-water (150 ml). The mixture was sonicated for 15 min in order to break up the gummy solid and the ph of the mixture was adjusted to 7.5 with saturated aq. ahc 3 solution. The solid was collected by vacuum filtration, washed with H 2, sucked partially dry on the funnel. The partially dried solid was suspended in toluene (150 ml) and the mixture concentrated in vacuo. The process was repeated 3 times to S19

20 give a brown solid. The product was dissolved in MeH (150 ml), treated with 4 M HCl in 1,4-dioxane (8 ml) and stirred at room temperature for 5 min. After concentration in vacuo, the hydrochloride thus obtained was triturated with EtAc and then partitioned between EtAc and saturated aq. ahc 3 solution. The EtAc phase was separated, washed with brine, and then dried (MgS 4 ). The EtAc solution was treated with activated charcoal, stirred at room temperature for 10 min and the charcoal filtered off. The solution was concentrate in vacuo to give the title compound (3.9 g, 74%) as a yellow solid. 1 H MR (DMS-d 6, 400 MHz) δ 8.39 (dd, 1H, J = 2.5, 10.7 Hz), 8.12 (dd, 1H, J = 1.5, 9.2 Hz), 7.86 (d, 1H, J = 5.6 Hz), 7.32 (dd, 1H, J = 8.6, 8.6 Hz), 6.40 (br s, 2H), 6.18 (d, 1H, J = 5.6 Hz). HBoc 2 H 2 D. tert-butyl 3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2- ynylcarbamate. A solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (158 mg, 0.42 mmol), -Boc-propargylamine (98 mg, 0.63 mmol), triethylamine (1.5 ml) and TH (2 ml) was placed in 50 ml flask and the flask was purged with nitrogen. The mixture was treated with CuI (2 mg, 0.11 mmol), (Ph 3 P) 4 Pd (9 mg, mmol) and stirred at reflux for 1 h. An additional portion of propargylamine (49 mg, mmol) and acetonitrile (2 ml) were added to the reaction mixture and the reaction continued at 80 o C for 2 h. The reaction mixture was concentrated on a rotary evaporator and the residue purified by flash chromatography using a 12 g silica gel cartridge eluted with 0-15% MeH/CH 2 Cl 2 to give the title compound (100 mg, 60% yield). 1 H MR (DMSd 6, 400 MHz) δ 8.36 (dd, 1H, J = 10.68, 2.54 Hz), 8.13 (d, 1H, J = 9.16 Hz), 7.89 (d, 1H, J = 5.60 Hz), 7.40 (t, 1H, J = 8.65 Hz), 7.32 (t, 1H, J = 5.09 Hz), 6.54 (br s, 2H), 6.16 (d, 1H, J = 5.60 Hz), 3.93 (d, 2H, J = 5.60 Hz), 1.37 (s, 9H); MS(ESI + ) m/z (M + H) +. S20

21 HBoc H 2 H 2 E. tert-butyl 3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2- ynylcarbamate. A mixture of tert-butyl 3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin- 3-yl)prop-2-ynylcarbamate (95 mg, 0.24 mmol), zinc dust (156 mg, 2.4 mmol), H 4 Cl (127 mg, 2.4 mmol), TH (1.5 ml), and MeH (1.5 ml) was stirred vigorously at 60 C for 45 min. The reaction mixture was filtered and the residue partitioned between EtAc and saturated ahc 3 solution. The layers were separated and the aqueous phase was extracted with EtAc. The combined EtAc extracts were dried (a 2 S 4 ) and concentrated to give the title compound, which was used in the next step without additional purification. MS(ESI + ) m/z (M + H) +. HBoc H H 2. tert-butyl 3-(2-amino-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2- dihydropyridine-3-carboxamido)phenoxy)pyridin-3-yl)prop-2-ynylcarbamate. A mixture of tert-butyl 3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2- ynylcarbamate (44 mg, 0.12 mmol), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid (30 mg, 0.13 mmol), DM (1 ml) and DIPEA (24 µl, 0.14 mmol) was treated with TBTU (46 mg, 0.14 mmol) and the mixture stirred at rt for 2 h. The mixture was concentrated on a rotary evaporator and the residue purified by flash chromatography using a 4 g silica gel cartridge eluted with 0-2% MeH/CH 2 Cl 2 to give the title compound as a yellow solid (32 mg, 45%). 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), 8.58 (dd, 1H, J = 7.12, 2.03 Hz), 8.13 (dd, 1H, J = 6.61, 2.03 Hz), 7.98 (dd, 1H, J = 12.97, 2.29 Hz), 7.76 (d, 1H, J = 6.10 Hz), 7.61 (dd, 2H, J = 8.90, 4.83 Hz), S21

22 (m, 3H), 7.28 (t, 1H, J = 8.90 Hz), 6.73 (t, 1H, J = 7.12 Hz), 6.38 (br s, 2H), 5.81 (d, 1H, J = 6.10 Hz), 4.01 (d, 1H, J = 5.09 Hz), 1.39 (s, 9H); MS(ESI + ) m/z (M + H) +. Compound 5 H H H 2 G. -(4-(2-Amino-3-(3-aminoprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride. tert-butyl 3- (2-amino-4-(2-fluoro-4-(1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3- carboxamido)phenoxy)pyridin-3-yl)prop-2-ynylcarbamate (28 mg, mmol) was dissolved in CH 2 Cl 2 (1.5 ml), treated with trifluoroacetic acid (0.5 ml) and the mixture stirred at rt for 1.5 h. The mixture was concentrated on a rotary evaporator and the residue was dissolved in MeH (2 ml). The resulting solution was treated with 1 M HCl/ether (0.1 ml), stirred at rt for 2 min, and the mixture concentrated on a rotary evaporator. The MeH, 1 M HCl/ether, re-concentration treatment was repeated twice to give compound 4 as a white solid (21 mg, 91%). 1 H MR (DMS-d 6, 400 MHz) δ (m, 1H) 8.58 (dd, 1H, J = 7.38, 2.29 Hz), 8.52 (br s, 2H), 8.15 (dd, 1H, J = 6.61, 2.03 Hz), 8.05 (dd, 1H, J = 12.97, 2.29 Hz), 7.93 (d, 2H, J = 7.12 Hz), 7.60 (dd, 2H, J = 8.90, 4.83 Hz), 7.54 (d, 1H, J = 9.16 Hz), (m, 3H), 6.74 (t, 1H, J = 7.12 Hz), 6.21 (d, 1H, J = 6.61 Hz), (m, 2H); MS(ESI + ) m/z (M + H) +. -(4-(2-Amino-3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1- (4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. S22

23 H 2 H 2 A. 3-(2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol. A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (250 mg, 0.67 mmol), propargyl alcohol (158 ml, 2.68 mmol), triethylamine (1.5 ml) and DM (2 ml) was treated with CuI (25 mg, 0.13 mmol), Cl 2 Pd(Ph 3 P) 2 (47 mg, mmol), and then (Ph 3 P) 4 Pd (77 mg, mmol). After stirring at 90 C under argon for 25 min, the mixture was concentrated in vacuo and the residue partitioned between EtAc and brine. The organic phase was washed with brine, dried (a 2 S 4 ) and concentrated. The residue was purified by flash chromatography using a 12 g silica gel cartridge eluted with % EtAc/hexanes to give the title compound as yellow oil (165 mg, 81%). 1 H MR (DMS-d 6, 400 MHz) δ 8.38 (dd, 1H, J = 10.43, 2.80 Hz), 8.14 (d, 1H, J = 8.65 Hz), 7.89 (d, 1H, J = 5.60 Hz), 7.43 (t, 1H, J = 8.65 Hz), 6.50 (br s, 2H), 6.15 (d, 1H, J = 6.10 Hz), 5.23 (t, 1H, J = 5.85 Hz), 4.27 (d, 1H, J = 6.10 Hz); MS(ESI + ) m/z (M + H) +. H H 2 H 2 B. 3-(2-Amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol. A mixture of 3-(2-amino-4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)prop-2-yn-1-ol (55 mg, 0.26 mmol), DM (1 ml), EtH (1 ml),h 2 (1 ml), H 4 Cl (308 mg, 5.8 mmol) and iron powder (162 mg, 2.7 mmol) was stirred at reflux for 45 min. The hot mixture was filtered and the filter cake washed with DM and MeH. The filtrate was concentrated and the residue partitioned between EtAc and saturated ahc 3 solution. The aqueous phase was extracted with EtAc and the combined extracts dried (a 2 S 4 ) and S23

24 concentrated to the title compound as a light yellow solid (55 mg) which was used in the next step without additional purification. MS(ESI + ) m/z (M + H) +. Compound 6 H H H 2 C. -(4-(2-Amino-3-(3-hydroxyprop-1-ynyl)pyridin-4-yloxy)-3-fluorophenyl)-1- (4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride. A solution of 3-(2-amino-4-(4-amino-2-fluorophenoxy)pyridin-3-yl)prop-2-yn-1-ol (55 mg, 0.20 mmol), 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (47 mg, 0.20 mmol), DM (1.5 ml), and DIPEA (80 µl) was treated with TBTU (77 mg, 0.24 mmol) and stirred at rt overnight. The reaction mixture was concentrated on a rotary evaporator, and the residue partitioned between EtAc and saturated ahc 3 solution. The aqueous phase was extracted with EtAc. The organic phases were combined, washed with brine, dried (a 2 S 4 ) and concentrated to give the crude product, which was purified by preparative HPLC to give the TA salt of the title compound. The TA salt was dissolved in MeH, treated with 1 M HCl/ether (0.25 ml), stirred at rt for 3 min and reconcentrated on a rotary evaporator. The MeH, HCl/ether treatment was repeated, the solid obtained triturated with ether and dried in vacuo to give compound 5 as a yellow solid (30 mg, 29%). 1 H MR (400 MHz, DMS-d 6 ) δ (m, 1H) 8.58 (dd, 1H, J = 7.38, 2.29 Hz), 8.52 (br s, 2H), 8.15 (dd, 1H, J = 6.61, 2.03 Hz), 8.05 (dd, 1H, J = 12.97, 2.29 Hz), 7.93 (d, 2H, J = 7.12 Hz), 7.60 (dd, 2H, J = 8.90, 4.83 Hz), 7.54 (d, 1H, J = 9.16 Hz), (m, 3H), 6.74 (t, 1H, J = 7.12 Hz), 6.21 (d, 1H, J = 6.61 Hz), (m, 2H); MS(ESI + ) m/z (M + H) +. -(4-(2-Amino-3-(hydroxymethyl)pyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. To tert-butyl 4-(2-fluoro-4- (1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-3- S24

25 (hydroxymethyl)pyridin-2-ylcarbamate (33 mg mmol) in TH (2 ml) at rt was added 4 HCl in dioxane (10 ml). After stirring at rt for 8 h, the reaction was concentrated in vacuo. The resulting crude product was purified by prep HPLC. The appropriate fractions were concentrated and toluene was added (2 x 3 ml) and the resulting mixture was concentrated again. The residue was lyophilized from acetonitrile (1 ml) / water (3 ml) to give the TA salt of the title compound (14 mg, 42%) as a white solid. 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), 8.52 (dd, 1H, J = 7.2, 2 Hz), 8.09 (dd, 1H, J = 6.8, 2 Hz), 7.99 (dd, 1H, J = 12.8, 2.4 Hz), 7.81 (d, 1H, J = 7.2 Hz), (m, 2H), (m, 1H), (m, 2H), 7.30 (t, 1H, J = 9.2 Hz), 6.67 (t, 1H, J = 7.2 Hz), 6.21 (d, 1H, J = 7.2 Hz), 4.58 (s, 2H); 13 C MR (126 MHz, CDCl 3 ) δ , , (1C, d, J C = Hz), , , , (1 C, d, J C = Hz), , , (1C, d, J C = Hz), (1 C, d, J C = Hz), , (2C, d, J C = Hz), , (1C, d, J C = Hz), , (1C, d, J C = Hz), , , 97.32, 66.28, HRMS Calc d for C 24 H (M + H + ): , ound: Compound 7 H H 2 -(4-(2-Amino-3-ethynylpyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. 2 Si H 2 S25

26 A. 4-(2-luoro-4-nitrophenoxy)-3-((trimethylsilyl)ethynyl)pyridin-2-amine. A flask containing a solution of 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (225 mg, 0.60 mmol), trimethylsilylacetylene (0.25 ml, 1.8 mmol), DM (2 ml) and triethylamine (2 ml) was purged with nitrogen. CuI (23 mg, 0.12 mmol) and (Ph 3 P) 4 Pd (69 mg, 0.06 mmol) were added and the mixture stirred at 40 C under nitrogen for 1 h. The mixture was concentrated and the resulting residue was partitioned between EtAc and brine. The organic phase was dried (MgS 4 ) and concentrated. The crude product was purified by flash chromatography using a 12 g silica gel cartridge eluted with 20-50% EtAc/hexanes to give the title compound as a brown solid (140 mg, 68%). 1 H MR (DMS-d 6, 400 MHz) δ 8.38 (dd, 1H, J = 10.68, 3.05 Hz), 8.12 (d, 1H, J = 9.16 Hz), 7.98 (d, 1H, J = 5.09 Hz), 7.33 (t, 1H, J = 8.65 Hz) 6.45 (br s, 2H), 6.34 (d, 1H, J = 5.60 Hz), 0.09 (s, 9H); MS(ESI + ) m/z (M + H) +. H 2 Si H 2 B. 4-(4-Amino-2-fluorophenoxy)-3-((trimethylsilyl)ethynyl)pyridin-2-amine. A mixture of 4-(2-fluoro-4-nitrophenoxy)-3-((trimethylsilyl)ethynyl)pyridin-2-amine (138 mg, 0.40 mmol), iron powder (224 mg, 4.0 mmol), H 4 Cl (424 mg, 8.0 mmol), DM (1 ml), EtH (1 ml) and water (1 ml) was stirred reflux for 45 min and then the hot reaction mixture was filtered through Celite. The filter cake was washed with DM and MeH. The filtrate was concentrated and the residue partitioned between EtAc and saturated ahc 3 solution. The aqueous phase was extracted with EtAc and the combined extracts were dried (MgS 4 ) to give the title compound as a yellow solid (150 mg) which was used in the next step without any additional purification. 1 H MR (DMS-d 6, 400 MHz) δ 7.76 (d, 1H, J = 5.60 Hz), 6.94 (t, 1H, J = 8.90 Hz), 6.47 (dd, 1H, J = 13.23, 2.54 Hz), 6.39 (dd, 1H, J = 8.65, 2.03 Hz), 6.16 (br s, 2H), 5.77 (d, 1H, J = 6.61 Hz), 5.44 (s, 2H), (m, 9H); MS(ESI + ) m/z (M + H) +. S26

27 H 2 H 2 C. 4-(4-Amino-2-fluorophenoxy)-3-ethynylpyridin-2-amine. A solution of 4-(4- amino-2-fluorophenoxy)-3-((trimethylsilyl)ethynyl)pyridin-2-amine (120 mg, 0.38 mol) in TH (2.5 ml) was cooled to - 30 C and treated with 1.0 M solution of TBA ( 0.42 ml, 0.42 mmol) in TH. After 5 min, the cooling bath was removed and the reaction continued at 0 C for 15 min. The reaction mixture was treated with water (10 ml) and extracted with EtAc. The combined extracts were dried (MgS 4 ) and concentrated in vacuo to give the title compound (80 mg, 87%). 1 H MR (DMS-d 6, 500 MHz) δ 7.76 (d, 1H, J = 6.05 Hz), 7.76 (d, 1H, J = 6.05 Hz), 6.93 (t, 1H, J = 8.80 Hz), 6.48 (dd, 1H, J = 13.20, 2.20 Hz), 6.39 (d, 1H, J = 8.80 Hz), 6.22 (br s, 2H), 5.76 (d, 1H, J = 5.50 Hz), 5.44 (s, 2H), 4.56 (s, 1H). D. -(4-(2-Amino-3-ethynylpyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. A solution of 4-(4-amino- 2-fluorophenoxy)-3-ethynylpyridin-2-amine (21 mg, 0.10 mmol), 1-(4-fluorophenyl)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (25 mg, 0.11 mmol), DIPEA (54 µl, 0.30 mmol) and DM (1 ml) was treated with TBTU (38 mg, 0.12 mmol) and the mixture stirred at rt overnight. The reaction mixture was diluted with saturated ahc 3 solution and extracted with EtAc. The extract was dried (MgS 4 ) and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluted with % EtAc to give compound 7 as a pale yellow solid (30 mg, 66%). 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), 8.58 (dd, 1H, J = 7.12, 2.03 Hz), 8.15 (dd, 1H, J = 6.61, 2.03 Hz), 8.06 (dd, 1H, J = 12.97, 2.29 Hz), 7.93 (d, 1H, J = 7.12 Hz), 7.61 (dd, 2H, J = 8.90, 4.83 Hz), 7.53 (d, 1H, J = 9.16 Hz), (m, 3H), 6.74 (t, 1H, J = 7.12 Hz), 6.27 (d, 1H, J = 7.12 Hz), 2.69 (s, 1H); MS(ESI + ) m/z (M+H) +. S27

28 Compound 8 H H 2 -(4-(2-Amino-3-isopropylpyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. H 2 H 2 A. 4-(4-Amino-2-fluorophenoxy)-3-isopropylpyridin-2-amine. A 10 ml round bottom flask was charged with 4-(2-fluoro-4-nitrophenoxy)-3-iodopyridin-2-amine (200 mg, 0.53 mmol), potassium isopropenyltrifluoroborate (118 mg, 0.80 mmol), PdCl 2 (dppf) (44 mg, mmol), and sodium carbonate (400 mg, 3.73 mmol). The flask was flushed with nitrogen and then TH (2 ml) and water (2 ml) were added. After stirring at 60 C for 6 h, the reaction was cooled to rt and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (80% EtAc / hexanes) to give 4- (2-fluoro-4-nitrophenoxy)-3-(prop-1-en-2-yl)pyridin-2-amine (130 mg, 84%). A mixture of the above amine (120 mg, 0.42 mmol), MeH (2 ml), EtH (1 ml), Pt 2 (30 mg), and 10% Pd-C (50 mg) was stirred at rt under a hydrogen atmosphere supplied from a latex balloon for 16 h. The mixture was filtered through Celite, the filter cake washed with MeH and the filtrate concentrated in vacuo to give the title compound as a yellow oil (105 mg). MS(ESI + ) m/z (M + H) +. B. -(4-(2-Amino-3-isopropylpyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride. A solution S28

29 Compound 9 H Cl H 2 of 4-(4-amino-2-fluorophenoxy)-3-isopropylpyridin-2-amine (30 mg, 0.11 mmol), 1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (28 mg, 0.12 mmol), DIPEA (26 µl, 0.15 mmol), and DM (1 ml) was treated with TBTU (46 mg, 0.14 mmol) and the mixture stirred at rt overnight. The mixture was diluted with EtAc (10 ml), washed with saturated ahc 3 solution and brine, dried (MgS 4 ) and concentrated on a rotary evaporator. The crude product was purified by preparative HPLC (YMC DS S5, 30 x 100 mm) and converted to the hydrochloride salt by treatment with excess 1 M HCl/ether to give compound 8 as an off-white solid (20 mg, 36%). 1 H MR (DMS-d 6, 400 MHz) δ (s, 1H), 8.58 (dd, 1H, J = 7.38, 2.29 Hz), 8.15 (dd, 1H, J = 6.61, 2.03 Hz), 8.05 (dd, 1H, J = 12.97, 2.29 Hz), 7.83 (d, 1H, J = 7.12 Hz), 7.78 (br s, 2H), 7.61 (dd, 2H, J = 9.16, 5.09 Hz), 7.53 (d, 1H, J = Hz), 7.43 (t, 2H, J = 8.90 Hz), 7.38 (t, 1H, J = 8.90 Hz), 6.74 (t, 1H, J = 6.87 Hz), 6.26 (d, 1H, J = 7.63 Hz), 3.27 (ddd, 1H, J = 13.86, 7.12, 6.99 Hz), 1.34 (d, 6H, J = 7.12 Hz); MS(ESI + ) m/z (M + H) +. -(4-(2-Amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-1-(4- fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide. Prepared in a similar manner as compound H MR (CD 3 D, 400 MHz) δ 8.68 (dd, 1H, J = 2.2, 7.7 Hz), 7.88 (dd, 1H, J = 2.7, 12.6 Hz), 7.83 (dd, 1H, J = 2.2, 6.6 Hz), 7.67 (d, 1H, J = 6.0 Hz), 7.44 (dd, 2H, J = 4.9, 8.8 Hz), 7.31 (d, 1H, J = 11.3 Hz), 7.27 (t, 2H, J = 8.8 Hz), 7.14 (t, 1H, J = 8.8 Hz), 6.70 (t, 1H, J = 7.2 Hz), 6.00 (d, 1H, J = 5.5 Hz); 13 C MR (126 MHz, CDCl 3 ) δ , , , (1C, d, J C = 249 Hz), (1 C, d, J C = 168 Hz), , , , (1C, d, J C = 10 Hz), , , , (2C, d, J C = 10 Hz), , , , (1C, d, J C = 23 Hz), (1C, d, J C = 23 Hz), , ; MS(ESI + ) m/z (M + H) +. S29