Protein tyrosine phosphatase inhibitors and methods of use thereof

A mixture of 7-bromo-3-hydroxy-2-naphthoic acid (100 g, 374 mmol) and cesium carbonate (366 g, 1123 mmol) in N,N-dimethylformamide (749 mL) was rapidly stirred for 5 minutes at 23° C. Thereafter, benzyl bromide (89.0 mL, 749 mmol) was added, and the internal temperature rose to 49° C. After 90 minutes, the light yellow mixture was poured into H 2 O (1.5 L), and the resulting white precipitate was collected via filtration. The collected precipitate was washed sequentially with H 2 O (3×1 L) and tert-butyl methyl ether/heptanes (1:2, 2×300 mL) and then dried in vacuo (15 mbar) at 45° C. to constant weight to afford the title compound (160.3 g, 358 mmol, 96% yield) as an off-white solid. MS (APCI + ) m/z 449 [M+H] + .

To a mixture of the product of Example 1A (150.1 g, 336 mmol), water (746 mL), and methanol (1.49 L) was added lithium hydroxide monohydrate (28.2 g, 671 mmol). The thick slurry was agitated via overhead mechanical stirring and heated to an internal temperature of 70° C. After 3 hours, the mixture was cooled to room temperature in an ice bath and 6 M HCl (168 mL) was added over 5 minutes, causing an off-white solid to precipitate. The solid was collected via filtration and washed with H 2 O (2×1 L), triturated with tert-butyl methyl ether (2×300 mL), and dried to constant weight in vacuo at 65° C. to afford the title compound (101.5 g, 284 mmol, 85% yield) as a white solid. MS (APCI + ) m/z 358 [M+H] + .

To a suspension of the product of Example 1B (101 g, 283 mmol) in toluene (794 mL) and tert-butanol (794 mL) was added triethylamine (41.8 mL, 300 mmol). The hazy light yellow solution was heated to an internal temperature of 80° C. under nitrogen, and diphenyl phosphorazidate (64.4 mL, 300 mmol) was added dropwise over 90 minutes with the entire reaction behind a blast shield. After 5 hours, the reaction mixture was cooled to room temperature, diluted with H 2 O (1.5 L), and extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with brine (2×150 mL), dried over sodium sulfate, filtered and concentrated to give a white solid. The solid was carried forward to hydrolysis without further purification.

To the crude intermediate was added diethylenetriamine (253 mL, 2.34 mol). The heterogeneous suspension was heated to an internal temperature of 130° C. under nitrogen, at which time a homogeneous dark orange solution formed. After 13 hours, the mixture was cooled to room temperature in an ice bath, and H 2 O (800 mL) was added slowly over 3 minutes, resulting in precipitation of a yellow solid and a concomitant exotherm to an internal temperature of 53° C. Once the heterogeneous suspension had cooled to room temperature, the crude solid was dissolved in CH 2 Cl 2 (1.5 L), and the layers were separated. The aqueous layer was back-extracted with CH 2 Cl 2 (3×150 mL). The combined organic layers were washed with brine (3×100 mL), dried over sodium sulfate, filtered, and the volatiles were removed in vacuo to afford an orange solid. The solid was combined with isopropanol (250 mL) to form a slurry that then was filtered. The resulting solid was again combined with isopropanol (2×100 mL), and solids were isolated via filtration. The solid was dried in vacuo (13 mbar) at 35° C. to afford the title compound (68.48 g, 209 mmol, 74% yield over two steps) as a white solid. MS (APCI + ) m/z 329 [M+H] + .

To a mixture of the product of Example 1C (67.8 g, 207 mmol) and potassium carbonate (57.1 g, 413 mmol) in N,N-dimethylformamide (354 mL) and H 2 O (1.861 mL, 103 mmol) was added methyl 2-bromoacetate (29.3 mL, 310 mmol). The suspension was vigorously stirred at room temperature for 5 minutes then heated to an internal temperature of 60° C. After 4 hours, the suspension was cooled to room temperature and partitioned between H 2 O (400 mL) and ethyl acetate (400 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL), and the combined organic layers were washed with saturated aqueous ammonium chloride (3×60 mL), dried over sodium sulfate, filtered, and concentrated to afford a pale beige solid. The solid was triturated with heptanes (100 mL), and the resulting beige solid was isolated via filtration, washed with additional heptanes (2×30 mL) and dried to constant weight in vacuo (15 mbar) at 35° C. to afford the title compound (68.52 g, 171 mmol, 83% yield) as an off-white solid. MS (APCI + ) m/z 401 [M+H] + .

To a solution of the product of Example 1D (15 g, 37.5 mmol) in N,N-dimethylformamide (300 mL) at 2° C. was added a solution of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (15.93 g, 45.0 mmol) in N,N-dimethylformamide (100 mL) over 5 minutes. The resulting solution was stirred for 15 minutes, and then quenched with a 0.33 M solution of sodium thiosulfate (300 mL, exothermic). The mixture was diluted with ethyl acetate (150 mL) and saturated aqueous ammonium chloride (75 mL) and stirred for 15 minutes at room temperature. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×75 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×75 mL) and brine (75 mL), then dried over sodium sulfate, filtered and concentrated in vacuo to give an orange solid. Ethyl acetate (30 mL) was added to the crude solid, and the mixture was sonicated for 30 seconds. Then heptanes (150 mL) were slowly added via an addition funnel over 15 minutes. The resulting yellow solid was collected via filtration and washed with 33% v/v ethyl acetate in heptanes (3×60 mL). The solid was discarded, and the filtrate was concentrated in vacuo to give a yellow/orange solid, which was triturated with anhydrous ethanol (45 mL) heated to an internal temperature of 55° C. and stirred for 30 minutes, then slowly cooled to room temperature. The resulting yellow solid was collected by filtration, then washed with anhydrous ethanol (30 mL), and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound (10.1 g, 24.25 mmol, 64.7% yield) as a pale yellow solid. 1 H NMR (DMSO-d 6 ) δ ppm 7.79 (d, J=2.1 Hz, 1H), 7.65 (dd, J=8.7, 1.7 Hz, 1H), 7.56-7.51 (m, 2H), 7.46-7.35 (m, 3H), 7.38-7.31 (m, 2H), 7.28 (s, 1H), 5.64 (td, J=6.7, 2.5 Hz, 1H), 5.28 (s, 2H), 4.21 (dd, J=6.8, 4.0 Hz, 2H), 3.61 (s, 3H); MS (ESI+) m/z 418, 420 [M+H] + .

To a solution of chlorosulfonyl isocyanate (2.26 mL, 26.0 mmol) in dichloromethane (43.5 mL) at 0° C. was added tert-butanol (2.5 mL, 26.0 mmol) slowly so that the internal temperature remained below 10° C. After stirring for 30 minutes at 0° C., a preformed solution of the product of Example 1E (7.25 g, 17.34 mmol) and triethylamine (4.83 mL, 34.7 mmol) in dichloromethane (29.0 mL) was slowly added via addition funnel so that the internal temperature remained below 10° C. Upon complete addition, the addition funnel was rinsed with dichloromethane (12.5 mL). The resulting solution was stirred for 30 minutes at 0° C. and then was allowed to warm to room temperature. After 1 hour, the reaction mixture was quenched with H 2 O (73 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×36 mL). The combined organic layers were washed with 1 M sodium bisulfate (2×73 mL). The aqueous washes were back extracted with dichloromethane (DCM) (36 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give an orange foam, which was used without purification. MS (APCI + ) m/z 541, 543 [M-tert-butyl+H] + .

To a solution of the crude intermediate in dichloromethane (41 mL) was added trifluoroacetic acid (20 mL, 260 mmol), and the resulting dark solution was stirred at room temperature. After 30 minutes, the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate (230 mL) via an addition funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were concentrated to give an orange foam, which was suspended in dichloromethane (20 mL), and stirred for 5 minutes giving a slurry, which was diluted by dropwise addition of heptanes (40 mL) via an addition funnel. The resulting yellow solid was collected by filtration, washed with 25% v/v dichloromethane in heptanes (2×20 mL) and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound (7.5 g, 15.05 mmol, 87% yield). 1 H NMR (DMSO-d 6 ) δ ppm 8.11 (d, J=2.0 Hz, 1H), 7.84-7.80 (m, 1H), 7.67 (dd, J=8.8, 2.0 Hz, 1H), 7.58-7.53 (m, 2H), 7.44-7.36 (m, 3H), 7.36-7.30 (m, 1H), 7.07 (s, 2H), 5.26 (s, 2H), 4.47 (d, J=17.9 Hz, 1H), 4.31 (d, J=17.8 Hz, 1H), 3.54 (s, 3H); MS (ESI + ) m/z 497, 499 [M+H] + .

To a solution of the product of Example 1F (24.14 g, 48.5 mmol) in tetrahydrofuran (THF) (241 mL) at room temperature was added a solution of sodium methoxide (16.65 mL, 72.8 mmol) (25 weight % in methanol) via syringe, and the resulting solution was stirred at room temperature. After 20 minutes, the reaction was quenched with 1 M hydrochloric acid (240 mL) and diluted with ethyl acetate (120 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×120 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (120 mL), then dried over sodium sulfate, filtered and concentrated to 40 mL total volume to give a dark red solution, which was diluted with dichloromethane (75 mL) and concentrated to 40 mL of total volume. The resulting yellow suspension was diluted with dichloromethane (72 mL), then slowly diluted with heptanes (72 mL). The suspension was sonicated for 30 seconds and stirred for 5 minutes at room temperature. The resulting white solid was collected via filtration, then washed with 25% v/v dichloromethane in heptanes (72 mL) and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound (16.4 g, 35.2 mmol, 72.5% yield). 1 H NMR (DMSO-d 6 ) δ ppm 8.16 (d, J=2.0 Hz, 1H), 7.87 (dd, J=8.9, 1.4 Hz, 1H), 7.74 (dd, J=8.8, 2.0 Hz, 1H), 7.54-7.48 (m, 3H), 7.47-7.29 (m, 3H), 5.28 (s, 2H), 4.54 (s, 2H); MS (ESI − ) m/z 463, 465 [M−H] − .

Example 1H: 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1λ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

In a 500 mL round bottom flask were combined the product of Example 1G (9 g, 19.34 mmol), RockPhos Pd G3 precatalyst (0.324 g, 0.387 mmol), and cesium carbonate (18.9 g, 58.0 mmol). The solids were placed under vacuum and stirred for 5 minutes, then the flask was filled with nitrogen and a preformed mixture of N,N-dimethylformamide (90 mL) and H 2 O (1.045 mL, 58.0 mmol) was added. The resulting suspension was degassed by five vacuum/nitrogen backfills, and then heated to an internal temperature of 80° C. After 3 hours, the reaction mixture was cooled to room temperature, quenched by slow addition of 1 M hydrochloric acid (100 mL), and diluted with ethyl acetate (100 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×50 mL). The combined aqueous washes were back extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (50 mL), then dried over sodium sulfate, filtered, and concentrated to give a viscous, dark oil. The crude oil was dissolved in acetonitrile (9 mL), then tert-butyl methyl ether (180 mL) was added via addition funnel over 5 minutes with vigorous stirring. The resulting black solid was removed via filtration and washed with 50% v/v tert-butyl methyl ether in ethyl acetate (2×45 mL). The solid was discarded, and the filtrate was concentrated in vacuo. The resulting dark oil was diluted with methanol (9 mL), and then a solution of ammonia in methanol (2.76 mL, 7 M, 19.34 mmol) was added. The resulting solution was diluted by slow addition of 50% v/v ethyl acetate in heptanes (135 mL) via an addition funnel. The resulting solid was collected via filtration, then washed with the cold filtrate, followed by 50% v/v ethyl acetate in heptanes (45 mL), and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound as an ammonium salt (6.33 g, 15.10 mmol, 78% yield). 1 H NMR (DMSO-d 6 ) δ ppm 9.81 (s, 1H), 7.68 (dd, J=8.9, 1.4 Hz, 1H), 7.60-7.49 (m, 2H), 7.39-7.31 (m, 2H), 7.33-7.26 (m, 1H), 7.23 (s, 1H), 7.14 (d, J=2.5 Hz, 1H), 7.10 (dd, J=8.8, 2.5 Hz, 1H), 5.19 (s, 2H), 4.08 (s, 2H); MS (ESI − ) m/z 401 [M−H] − .

Example 1I: 5-{3-(benzyloxy)-1-fluoro-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ,2,5-thiadiazolidine-1,1,3-trione

A mixture of 2-morpholinoethanol (1.69 g, 12.9 mmol), triethylamine (2.70 mL, 19.35 mmol), and anhydrous dichloromethane (71.7 mL) was cooled to 0° C. Thereafter, methanesulfonyl chloride (1.206 mL, 15.48 mmol) was added dropwise over 5 minutes, and after 10 minutes, the reaction was warmed to room temperature and stirred for an additional 30 minutes. The majority of the dichloromethane was removed in vacuo, and the resulting residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (2×30 mL), dried over sodium sulfate, filtered, and the volatiles were removed in vacuo at 29° C. to afford 2-morpholinoethyl methanesulfonate (1.71 g, 8.17 mmol, 63.3% yield) as an amorphous yellow residue which was used immediately in the subsequent reaction.

To a solution of the product of Example 1H (120 mg, 0.286 mmol) in N,N-dimethylformamide (954 μL) was added cesium carbonate (186 mg, 0.572 mmol). The suspension was stirred at room temperature for 5 minutes, followed by addition of 2-morpholinoethyl methanesulfonate (114 mg, 0.544 mmol). The reaction was heated to 40° C. After 80 minutes, the mixture was cooled to room temperature. The residual cesium carbonate was collected via filtration, and the cesium carbonate was washed with dimethyl sulfoxide (1×500 μL) to afford a dark yellow filtrate containing the crude product, which was purified via HPLC (Phenomenex® Luna® 10 M C18(2) 100 Å, AXIA™ (00G-4253-U0-AX) column, 250×300 mm, flow rate 50 mL/minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound (75.5 mg, 0.146 mmol, 51% yield). MS (APCI + ) m/z 516 [M+H] + .

Example 1J: 5-{-fluoro-3-hydroxy-7-[2-(morpholin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione hydrochloride

A mixture of the product of Example 1I (68.2 mg, 0.132 mmol), and pentamethylbenzene (58.8 mg, 0.397 mmol) in dichloromethane (661 μL) was cooled to an internal temperature of −76° C. under an atmosphere of dry nitrogen. Subsequently, a 1 M solution of boron trichloride (1.59 mL, 1.59 mmol) in CH 2 Cl 2 was added dropwise over 15 minutes, so as not to raise the internal temperature past −72° C. The reaction was warmed to 0° C. and stirred 20 minutes. Thereafter, the mixture was re-cooled to −76° C. and rapidly quenched with anhydrous methanol (2.67 mL, 66.1 mmol). The resulting colorless, homogeneous solution was warmed to room temperature over 20 minutes under nitrogen. The volatiles were removed in vacuo to afford an off-white solid that was purified via HPLC (Phenomenex® Luna® 10 M C18(2) 100 Å, AXIA™ (00G-4253-U0-AX) column, 250×300 mm, flow rate 50 mL/minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound as the ammonium salt. This was suspended in methanol/ethyl acetate (1:1, 2 mL) and treated with a freshly-prepared 1 M solution of anhydrous hydrochloric acid in ethyl acetate (66 μL, 0.066 mmol). After stirring 5 minutes at room temperature, the volatiles were removed in vacuo (15 mbar), and the resulting white solid was dried at 35° C. to afford the title compound (22.6 mg, 0.053 mmol, 40% yield). 1 H NMR (DMSO-d 6 ) δ ppm 9.89 (br s, 1H), 9.57 (s, 1H), 7.73 (dd, J=9.1, 1.1 Hz, 1H), 7.30 (d, J=2.5 Hz, 1H), 7.21 (dd, J=9.1, 2.5 Hz, 1H), 7.06 (s, 1H), 4.47 (t, J=4.8 Hz, 2H), 4.11 (s, 2H), 3.84 (m, 4H), 3.59 (s, 2H), 3.34 (m, 2H); MS (APCI + ) m/z 426 [M+H] + .

Example 2: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 101)

Example 2A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate

The product of Example 14A (340 mg, 0.614 mmol) and tetrahydrofuran (THF) (1 mL) were added to 5% Pt/C wet, (100 mg, 0.211 mmol) in a 20 mL Barnstead Hastelloy C reactor and stirred for 0.55 h under 50 psi hydrogen at 25° C. The reaction mixture was filtered, the volatiles were removed under reduced pressure, and the crude residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (164 mg, 0.295 mmol, 48% yield) as a white solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.82-7.69 (m, 2H), 7.59-7.52 (m, 2H), 7.54-7.47 (m, 1H), 7.40-7.33 (m, 2H), 7.36-7.27 (m, 2H), 5.25 (s, 2H), 4.08 (s, 2H), 3.76 (dd, J=10.4, 7.5 Hz, 1H), 3.59-3.45 (m, 2H), 3.33-3.23 (m, 2H), 3.17 (s, 1H), 2.26 (s, 1H), 2.04 (q, J=9.9 Hz, 1H), 1.43 (d, J=5.9 Hz, 9H); MS (APCI − ) m/z 554 [M−H] − .

Example 2B: 5-[3-(benzyloxy)-1-fluoro-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A solution of the product of Example 2A (164 mg, 0.295 mmol) and trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure. Dichloromethane (5 mL) was added, and the volatiles were again removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (77 mg, 0.169 mmol, 57% yield) as a white solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 8.77 (s, 2H), 7.87-7.79 (m, 2H), 7.57-7.43 (m, 3H), 7.42-7.25 (m, 5H), 5.24 (s, 2H), 4.07 (s, 2H), 3.70-3.57 (m, 2H), 3.18 (dd, J=10.9, 9.3 Hz, 1H), 2.41 (dtd, J=13.0, 7.1, 3.5 Hz, 1H), 2.02 (dq, J=12.6, 9.5 Hz, 1H); MS (APCI − ) m/z 454 [M−H] − .

Example 2C: 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of product of Example 2B (77 mg, 0.169 mmol) in dichloromethane (5 mL) was added cyclopropanesulfonyl chloride (0.041 mL, 0.338 mmol) at room temperature followed by N-ethyl-N-isopropylpropan-2-amine (0.089 mL, 0.507 mmol). The reaction stirred overnight at room temperature. Additional N-ethyl-N-isopropylpropan-2-amine (0.089 mL, 0.507 mmol) was added which resulted in a clear solution. After 3 hours stirring at room temperature, the volatiles were removed under reduced pressure, and the crude was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 8% CH 3 OH in CH 2 C 2 ) to afford the title compound (80 mg, 0.143 mmol, 85% yield). MS (APCI − ) m/z 558 [M−H] − .

Example 2D: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 2,5-thiadiazolidine-1,1,3-trione

The product of Example 2C (80 mg, 0.143 mmol) and 1,2,3,4,5-pentamethylbenzene (63.6 mg, 0.429 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.429 mL, 0.429 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at −78° C. with dichloromethane:ethanol=9:1 (1 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (36 mg, 0.077 mmol, 54% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 9.74 (s, 1H), 7.70 (t, J=1.2 Hz, 1H), 7.66 (dd, J=8.8, 1.5 Hz, 1H), 7.41 (dd, J=8.7, 1.8 Hz, 1H), 6.99 (s, 1H), 4.05 (s, 2H), 3.74 (dd, J=9.7, 7.6 Hz, 1H), 3.60-3.46 (m, 2H), 3.42-3.36 (m, 1H), 3.30-3.26 (m, 1H), 3.27-3.17 (m, 1H), 2.77-2.68 (m, 1H), 2.03 (dq, J=12.0, 9.0 Hz, 1H), 0.98-0.85 (m, 4H); MS (APCI − ) m/z 467 [M−H] − .

Example 3: 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 102)

Example 3A: tert-butyl 3-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate

The product of Example 14A (300 mg, 0.560 mmol) in tetrahydrofuran (THF) (5 mL) was added to 5% wet Pd/C (500 mg, 2.189 mmol) in a 20 mL Barnstead Hastelloy C reactor, and the mixture was stirred for 6 hours under 50 psi hydrogen at 25° C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was used in the next step without further purification. MS (APCI − ) m/z 446 [M−H] − .

Example 3B: 5-[1-fluoro-3-hydroxy-7-(pyrrolidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of product of Example 3A (20 mg, 0.043 mmol) and in dichloromethane (2 mL) was added trifluoroacetic acid (1 mL, 12.98 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL/minute] to afford the title compound (7 mg, 0.019 mmol, 27% yield) as a white solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.73 (s, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.42-7.36 (m, 1H), 7.00 (s, 1H), 4.03 (s, 2H), 3.62-3.51 (m, 2H), 3.23-3.13 (m, 2H), 3.13-3.05 (m, 1H), 2.34 (ddd, J=12.7, 6.7, 3.5 Hz, 1H), 1.95 (dq, J=12.7, 9.4 Hz, 1H); MS (APCI − ) m/z 363 [M−H] − .

Example 4: 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate (Compound 103)

Example 4A: 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate

To a solution of the product of Example 1H (80 mg, 0.199 mmol) in N,N-dimethylformamide (1 mL) was added 4-dimethylaminopyridine (4.86 mg, 0.040 mmol) and isopropyl isocyanate (22.00 mg, 0.258 mmol). The mixture was stirred at ambient temperature for 14 hours. The reaction mixture was then filtered, purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (48 mg, 0.098 mmol, 49.5% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.93 (d, J=8.9 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.68 (s, 1H), 7.56-7.50 (m, 2H), 7.44-7.30 (m, 5H), 5.27 (s, 2H), 4.42 (s, 2H), 3.73-3.66 (m, 1H), 1.16 (d, J=6.6 Hz, 6H); MS (APCI − ) m/z 486 [M−H] + .

Example 4B: 8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl propan-2-ylcarbamate

To a mixture of the product of Example 4A (42 mg, 0.086 mmol) and pentamethylbenzene (63.9 mg, 0.431 mmol) in dichloromethane (2 mL) cooled to −78° C. was added a solution of boron trichloride (1 M, 0.517 mL, 0.517 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction was quenched with 2 N HCl (0.5 mL). The reaction mixture was extracted with ethyl acetate. The organic phase washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using a Phenomenex® Luna® 10 μm C18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-70%) to give the title compound (28 mg, 0.070 mmol, 82% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.59 (s, 1H), 7.78 (dd, J=11.2, 8.3 Hz, 2H), 7.55 (d, J=2.3 Hz, 1H), 7.29 (dd, J=8.9, 2.3 Hz, 1H), 7.14 (s, 1H), 4.48 (s, 2H), 3.73-3.65 (m, 1H), 1.15 (d, J=6.6 Hz, 6H); MS (APCI − ) m/z 396 [M−H] + .

Example 5: 5-(9-fluoro-7-hydroxynaphtho[2,1-b]furan-8-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 104)

Example 5A: 5-[3-(benzyloxy)-7-(2,2-dimethoxyethoxy)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of the product of Example 1H (500 mg, 1.243 mmol) and cesium carbonate (891 mg, 2.73 mmol) in N,N-dimethylformamide (5 mL) was added 2-bromo-1,1-dimethoxyethane (420 mg, 2.485 mmol). The reaction stirred at 75° C. for 5 hours. After cooling down to room temperature, the volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 15% CH 3 OH in CH 2 Cl 2 ) to afford the title compound (475 mg, 0.968 mmol, 78% yield) as a beige solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.76 (dd, J=9.1, 1.4 Hz, 1H), 7.56 (dt, J=6.6, 1.4 Hz, 2H), 7.40-7.32 (m, 2H), 7.34-7.26 (m, 3H), 7.22 (dd, J=9.0, 2.6 Hz, 1H), 5.22 (s, 2H), 4.75 (t, J=5.1 Hz, 1H), 4.11 (d, J=5.1 Hz, 2H), 4.09 (s, 2H), 3.38 (s, 6H); MS (APCI − ) m/z 489 [M−H] − .

Example 5B: 5-[7-(2,2-dimethoxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 5A (475 mg, 0.968 mmol) in tetrahydrofuran (THF) (10 mL) was added to wet 5% Pd/C (475 mg, 2.080 mmol) in a 20 mL Barnstead Hastelloy C reactor and stirred for 15 minutes under 50 psi of hydrogen at 25° C. The mixture was filtered, and the crude material was subjected to column chromatography (SiO 2 dry load with diatomaceous earth, 15% CH 3 OH in CH 2 Cl 2 ) to afford the title compound (182 mg, 0.455 mmol, 47% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 1H), 7.68 (dd, J=9.1, 1.4 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.16 (dd, J=9.0, 2.6 Hz, 1H), 7.03 (s, 1H), 4.74 (t, J=5.1 Hz, 1H), 4.09 (d, J=4.9 Hz, 4H), 3.37 (s, 6H); MS (APCI − ) m/z 398 [M−H] − .

A solution of the product of Example 5B (30 mg, 0.075 mmol) and trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (2 mL) was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL/minute] to afford the title compound (12 mg, 0.036 mmol, 48% yield) as a beige solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 8.13 (d, J=2.0 Hz, 1H), 7.96 (s, 3H), 7.77 (d, J=8.9 Hz, 1H), 7.66 (dd, J=9.0, 1.7 Hz, 1H), 7.33 (dd, J=3.8, 2.0 Hz, 1H), 7.23 (d, J=1.3 Hz, 1H), 4.13 (s, 2H); MS (APCI − ) m/z 334 [M−H] − .

Example 6: 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 105)

Example 6A: 5-{7-[2-(azetidin-1-yl)ethoxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 1H (121 mg, 0.3 mmol), 1-(2-chloroethyl)azetidine, hydrochloric acid (94 mg, 0.600 mmol), cesium carbonate (391 mg, 1.20 mmol) and triethylamine (100 mg, 0.990 mmol) in dimethylformamide (0.8 mL) was stirred at 70° C. for 1.5 hours. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane/methanol (7:1) to give the title compound (35 mg, 0.072 mmol, 24% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.80 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 2H), 7.37 (t, J=8 Hz, 2H), 7.31 (m, 3H), 7.23 (dd, J=8, 2 Hz, 1H), 5.23 (s, 2H), 4.28 (t, J=8 Hz, 2H), 4.09 (s, 2H), 4.01 (t, J=8 Hz, 4H), 2.31 (m, 2H); MS (ESI − ) m/z 484 [M−H] − .

Example 6B: 5-{7-[2-(azetidin-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the product of Example 6A (0.034 g, 0.07 mmol) and 1,2,3,4,5-pentamethylbenzene (0.031 g, 0.210 mmol) in dichloromethane (2 mL) at −78° C. was added trichloroborane (0.700 mL, 0.700 mmol, 1.0 M in dichloromethane). The mixture was stirred at −78° C. for 40 minutes. Methanol (3 mL) was added at −78° C. The mixture was stirred for 5 minutes at room temperature and then was concentrated under reduced pressure. The resulting solids were washed with heptane (5 mL×4), then dissolved in methanol (0.5 mL) and N,N-dimethylformamide (3 mL). This material was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm column, 25×150 mm, flow rate 80 mL/minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (20 mg, 0.051 mmol, 72% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.54 (s, 1H), 7.71 (d, J=8 Hz, 1H), 7.25 (d, J=2 Hz, 1H), 7.17 (dd, J=8, 2 Hz, 1H), 7.05 (br s, 1H), 4.28 (t, J=8 Hz, 2H), 4.09 (s, 2H), 4.08 (t, J=8 Hz, 4H), 2.33 (m, 2H); MS (ESI − ) m/z 394 [M−H] − .

Example 7: 5-[1-fluoro-3-hydroxy-7-methoxy(4- 2 H)naphthalen-2-yl](4,4-2H 2 )-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 106)

To a stirred suspension of the product of Example 25G (0.10 g, 0.306 mmol) in deuterated methanol (methanol-d 4 , 99.5%-D) (3.06 mL) was added sodium hydride (0.061 g, 1.532 mmol, 60% in mineral oil). All of solids went into solution, and then the mixture was heated to 60° C. After 72 hours, deuterium enrichment was complete as judged by 1 H NMR. The volatiles were removed, and the solution was treated with DCl in D 2 O (1.839 mL, 1.839 mmol, 1 N solution) and ethyl acetate (3 mL). The layers were shaken in a vial and separated, and the organic layer was concentrated under reduced pressure. The resulting organic residue was partitioned between a dimethyl sulfoxide:methanol layer (2 mL 1:1) and a heptane layer (1 mL) to remove any residual mineral oil before purification. Separation of the layers and purification of the dimethyl sulfoxide:methanol layer by reverse phase HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (150 mm×30 mm); 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 mL/minute]yielded a white solid which was dissolved in D 2 O:CH 3 CN (2 mL, 1:1). The solution was frozen with dry-ice and lyophilized to yield the title compound as a fluffy white powder (19.9 mg, 0.060 mmol, 19.7% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.67 (d, J=9.0 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.7, 2.7 Hz, 2H), 3.85 (s, 3H); MS (APCI − ) m/z 328 [M−H] − .

Example 8: 5-[1-fluoro-3-hydroxy-7-(methylamino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 107)

In a 4 mL vial with a septum screw cap, the product of Example 1G (0.1 g, 0.215 mmol), sodium tert-butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 μmol), and BrettPhos (3.46 mg, 6.45 μmol) were combined. The solids were placed under vacuum for 5 minutes with stirring, then the vial was filled with nitrogen, followed by 1,4-dioxane (2 mL) and a solution of methylamine in tetrahydrofuran (0.215 mL, 2 M, 0.430 mmol). The resulting suspension was degassed by five vacuum/nitrogen backfills, was stirred for 10 minutes at room temperature, and then was heated to 100° C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then was quenched with 1 M hydrochloric acid (1 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give, 5-[3-(benzyloxy)-1-fluoro-7-(methylamino)naphthalen-2-yl]-1,2,5-thiadiazolidine-1,1,3-trione, a viscous orange oil, which was used for the next reaction without purification. MS (APCI − ) m/z 414 [M−H] − .

To a suspension of the crude intermediate, 5-[3-(benzyloxy)-1-fluoro-7-(methylamino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, in dichloromethane (2 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (1.29 mL, 1 M, 1.29 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL). The mixture was warmed to room temperature and then was concentrated under reduced pressure. The crude residue was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA column (30 mm×75 mm) with gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at a flow rate of 50 mL/minute (0-1.0 minute 5% A, 1.0-8.5 minutes linear gradient 5-100% A, 8.5-11.5 minutes 100% A, 11.5-12.0 minutes linear gradient 95-5% A) to give the title compound (0.0136 g, 0.040 mmol, 18.6% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.45 (d, J=8.8 Hz, 1H), 6.93 (dd, J=8.9, 2.3 Hz, 1H), 6.89 (s, 1H), 6.56 (d, J=2.3 Hz, 1H), 5.93-5.80 (m, 1H), 4.07 (s, 2H), 2.76-2.72 (m, 3H); MS (ESI − ) m/z 324 [M−H] − .

Example 9: 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-4-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 108)

To a solution of the product of Example 1H (0.1 g, 0.249 mmol) and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (0.145 g, 0.497 mmol) in dimethylformamide (1 mL) was added cesium carbonate (0.243 g, 0.0.746 mmol) as a solid, and the resulting suspension was heated to 60° C. After 1 hour, the reaction mixture was cooled to room temperature, quenched with 2 M hydrochloric acid (1 mL), and diluted with ethyl acetate (2 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3×1 mL). The combined aqueous washes were back extracted with ethyl acetate (1 mL), and the combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)piperidine-1-carboxylate, a dark gel, which was used for the next reaction without purification. MS (APCI − ) m/z 612 [M−H] − .

To a suspension of the crude intermediate, tert-butyl 4-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)piperidine-1-carboxylate, in dichloromethane (2 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (2.49 mL, 1 M, 2.49 mmol) slowly along the side of the vial so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by the addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), warmed to room temperature and concentrated under reduced pressure to give a tan solid. The crude solid was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 m C 18 (2) 250×30 mm column, flow rate 100 mL/minute, a gradient of 5-95% acetonitrile in buffer (0.010 M aqueous ammonium acetate)]. The HPLC purified product was further purified by trituration with a 50% v/v mixture of dichloromethane and acetonitrile (3 mL) to give the title compound (0.066 g, 0.155 mmol, 64.9% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.66 (d, J=9.0 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.11 (dd, J=9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 4.13 (t, J=6.1 Hz, 2H), 4.09 (s, 2H), 2.89-2.76 (m, 1H), 1.90 (s, 3H), 1.86 (s, 2H), 1.82-1.69 (m, 3H), 1.34 (td, J=12.9, 12.1, 8.7 Hz, 2H); MS (ESI − ) m/z 422 [M−H] − .

Example 10: 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 109)

Example 10A: 5-[3-(benzyloxy)-1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of the product of Example 1H (100 mg, 0.249 mmol) and (3-fluoro-1-isopropylpyrrolidin-3-yl)methanol (120 mg, 0.746 mmol) in tetrahydrofuran (THF) (5 mL) at 0° C. was added (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (219 mg, 0.870 mmol). The reaction was flushed with N 2 at 0° C. for 5 minutes followed by addition of tri-n-butylphosphine (0.215 mL, 0.870 mmol). The reaction was stirred at 45° C. for 14 hours. The volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 10% methanol in dichloromethane) to afford the title compound (24 mg, 0.044 mmol, 18% yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.68 (d, J=9.1 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7.17 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 4.30 (broad, 1H), 4.24 (broad, 1H), 4.09 (s, 2H), 3.06-2.77 (m, 4H), 2.23-1.98 (m, 2H), 1.46-1.37 (broad, 1H), 1.05 (d, J=6.2 Hz, 6H); MS (APCI − ) m/z 454.13 [M−CH 2 C 6 H 5 −H] − , 544 [M−H] − .

Example 10B: 5-(1-fluoro-7-{[3-fluoro-1-(propan-2-yl)pyrrolidin-3-yl]methoxy}-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 10A (22 mg, 0.040 mmol) and 1,2,3,4,5-pentamethylbenzene (17.93 mg, 0.121 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.121 mL, 0.121 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at −77° C. with dichloromethane:methanol=9:1 (0.5 mL), and then the mixture was slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (7 mg, 0.015 mmol, 38% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.68 (d, J=9.1 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7.17 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (s, 1H), 4.30 (broad, 1H), 4.24 (broad, 1H), 4.09 (s, 2H), 3.06-2.77 (m, 4H), 2.23-1.98 (m, 2H), 1.46-1.37 (broad, 1H), 1.05 (d, J=6.2 Hz, 6H); MS (APCI − ) m/z 454.13 [M−H] − .

Example 11: 5-{1-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 110)

Example 1A: tert-butyl 3-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)-3-fluoropyrrolidine-1-carboxylate

To a solution of the product of Example 1H (100 mg, 0.249 mmol) and tert-butyl 3-fluoro-3-(hydroxymethyl)pyrrolidine-1-carboxylate (163 mg, 0.746 mmol) in tetrahydrofuran (THF) (5 mL) at 0° C. was added (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (219 mg, 0.870 mmol). The reaction was flushed with N 2 at 0° C. for 5 minutes followed by addition of tri-n-butylphosphine (0.215 mL, 0.870 mmol). The reaction was stirred at 45° C. for 14 hours. The volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 10% methanol in dichloromethane) to afford the title compound (48 mg, 0.080 mmol, 32% yield). MS (APCI − ) m/z 602 [M−H] − .

Example 1B: 5-{-fluoro-7-[(3-fluoropyrrolidin-3-yl)methoxy]-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 11A (45 mg, 0.075 mmol) and 1,2,3,4,5-pentamethylbenzene (33.2 mg, 0.224 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.224 mL, 0.224 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at −77° C. with dichloromethane:methanol=9:1 (0.5 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (9 mg, 0.022 mmol, 29% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 9.63 (d, J=69.3 Hz, 1H), 7.72 (d, J=9.1 Hz, 1H), 7.28 (d, J=2.6 Hz, 1H), 7.19 (dd, J=9.0, 2.6 Hz, 1H), 7.06 (s, 1H), 4.57-4.41 (s, 2H), 4.10 (s, 2H), 3.73-3.48 (m, 4H), 2.43-2.20 (m, 2H); MS (APCI − ) m/z 411.89 [M−H] − .

Example 12: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile (Compound 111)

Example 12A: 5-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile

A mixture of the product of Example 1H (100 mg, 0.249 mmol), cesium carbonate (162 mg, 0.497 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature for 14 hours. The reaction mixture was filtered and purified by preparative HPLC [Phenomenex® Luna® 10 μm C18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (80 mg, 0.165 mmol, 67% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.86-7.78 (m, 1H), 7.57-7.48 (m, 2H), 7.42 (s, 1H), 7.41-7.36 (m, 2H), 7.36-7.31 (m, 1H), 7.31-7.25 (m, 2H), 5.24 (s, 2H), 4.50 (s, 2H), 4.15 (t, J=6.2 Hz, 2H), 2.61 (t, J=7.1 Hz, 2H), 1.87 (m, 2H), 1.82-1.70 (m, 2H); MS (APCI − ) m/z 482 [M−H] + .

Example 12B: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}pentanenitrile

To a mixture of the product of Example 12A (75 mg, 0.155 mmol) and pentamethylbenzene (115 mg, 0.776 mmol) in dichloromethane (2 mL) cooled to −78° C. was added a solution of boron trichloride (1 M, 0.931 mL, 0.931 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction mixture was quenched with 2 N HCl (0.5 mL). The mixture was then extracted with ethyl acetate, washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (40 mg, 0.102 mmol, 65.6% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.27 (s, 1H), 7.71 (dd, J=9.1, 1.4 Hz, 1H), 7.25-7.16 (m, 2H), 7.07 (s, 1H), 4.44 (s, 2H), 4.12 (t, J=6.2 Hz, 2H), 2.60 (t, J=7.1 Hz, 2H), 1.87 (dq, J=8.5, 6.4 Hz, 2H), 1.76 (dq, J=9.9, 7.1 Hz, 2H); MS (APCI − ) m/z 392 [M−H] + .

Example 13: 5-{1-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 112)

Example 13A: 5-{3-(benzyloxy)-1-fluoro-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 1H (84 mg, 0.2 mmol), 1-(2-chloroethyl)piperidine (94 mg, 0.640 mmol), and cesium carbonate (235 mg, 0.720 mmol) in dimethylformamide (1 mL) was stirred at 75° C. for 2 hours. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane/methanol (10:1) to give the title compound (65 mg, 0.127 mmol, 63% yield) as a solid. MS (ESI + ) m/z 514 [M+H] + .

Example 13B: 5-{-fluoro-3-hydroxy-7-[2-(piperidin-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the product of Example 13A (60 mg, 0.117 mmol) and 1,2,3,4,5-pentamethylbenzene (55.4 mg, 0.374 mmol) in dichloromethane (2 mL) at −78° C. was added trichloroborane (1168 μL, 1.168 mmol, 1.0 M in dichloromethane). The mixture was stirred at −78° C. for 40 minutes. Methanol (3 mL) was added at −78° C. The mixture was stirred for 5 minutes at room temperature, then concentrated under reduced pressure. The solid was washed with heptane (4×5 mL), then dissolved in methanol (0.5 mL) and N,N-dimethylformamide (3 mL). The crude material was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 m column, 25×150 mm, flow rate 80 mL/minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (30 mg, 0.071 mmol, 61% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.52 (br s, 1H), 7.71 (d, J=8 Hz, 1H), 7.28 (d, J=2 Hz, 1H), 7.19 (dd, J=8, 2 Hz, 1H), 7.05 (br s, 1H), 4.42 (m, 2H), 4.09 (s, 2H), 3.46 (m, 4H), 3.00 (m, 2H), 1.72 (m, 4H), 1.47 (m, 2H); MS (ESI − ) m/z 422 [M−H] − .

Example 14: 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 113)

Example 14A: tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate

To the product of Example 1G in dioxane (5 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (381 mg, 1.290 mmol) and sodium carbonate (1.290 mL, 2.58 mmol). Tetrakis(triphenylphosphine)palladium(0) (99 mg, 0.086 mmol) was added, and the reaction mixture was sparged with N 2 for 5 minutes. The mixture was heated at 100° C. overnight. The reaction was cooled down to room temperature, and the volatiles were removed under reduced pressure. The residue was subjected to column chromatography (dry loading with diatomaceous earth, 5% CH 3 OH in CH 2 C 2 ) to afford the title compound (346 mg, 0.625 mmol, 73% yield) as a yellow solid. 1 H (500 MHz, DMSO-d 6 ) δ ppm 7.87-7.80 (m, 2H), 7.75 (d, J=12.7 Hz, 1H), 7.60-7.52 (m, 2H), 7.41-7.35 (m, 3H), 7.35-7.28 (m, 1H), 6.59-6.52 (m, 1H), 5.27 (s, 2H), 4.53 (d, J=7.7 Hz, 2H), 4.26 (d, J=12.0 Hz, 2H), 4.09 (s, 2H), 1.47 (d, J=10.6 Hz, 9H); MS (APCI − ) m/z 551 [M−H] − .

Example 14B: 5-[3-(benzyloxy)-7-(2,5-dihydro-H-pyrrol-3-yl)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of the product of Example 14A (100 mg, 0.181 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroacetic acid (1 mL, 3.61 mmol). The mixture was stirred at room temperature for 30 minutes. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL/minute] to afford the title compound (60 mg, 0.132 mmol, 73% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.86 (d, J=3.7 Hz, 2H), 7.60-7.48 (m, 2H), 7.46-7.27 (m, 5H), 6.60 (t, J=2.2 Hz, 1H), 5.28 (s, 2H), 4.50 (q, J=2.3 Hz, 2H), 4.19 (dt, J=5.0, 2.5 Hz, 2H), 4.10 (s, 2H); MS (APCI − ) m/z 452 [M−H] − .

Example 14C: 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)-2,5-dihydro-H-pyrrol-3-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of the product of Example 14B (88 mg, 0.194 mmol) in dichloromethane (5 mL) was added cyclopropanesulfonyl chloride (0.071 mL, 0.582 mmol) at room temperature followed by N,N-diisopropylethylamine (0.102 mL, 0.582 mmol). The reaction mixture was stirred overnight at room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 5% CH 3 OH in CH 2 C 2 ) to afford the title compound (77 mg, 0.138 mmol, 71% yield) as a beige solid. MS (APCI − ) m/z 555 [M−H] − .

Example 14D: 5-{7-[1-(cyclopropanesulfonyl)-2,5-dihydro-H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A solution of product of Example 14C (66 mg, 0.118 mmol) and 1,2,3,4,5-pentamethylbenzene (52.6 mg, 0.355 mmol) in dichloromethane (5 mL) was flushed with nitrogen gas for 5 minutes. The solution was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.355 mL, 0.355 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at −77° C. with dichloromethane:methanol=2:1 (0.5 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL/minute] to afford the title compound (25 mg, 0.053 mmol, 45% yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.87 (s, 1H), 7.14 (s, 1H), 7.03-6.99 (m, 2H), 6.89 (s, 1H), 6.46 (t, J=2.1 Hz, 1H), 4.62-4.55 (m, 2H), 4.29 (dt, J=6.9, 3.0 Hz, 2H), 4.03 (s, 2H), 2.82-2.71 (m, 1H), 0.97 (dt, J=5.4, 2.8 Hz, 2H), 0.96-0.86 (m, 2H); MS (APCI − ) m/z 465 [M−H] − .

Example 15: 5-{1-fluoro-3-hydroxy-7-[(piperidin-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 114)

To a solution of the product of Example 1H (0.1 g, 0.238 mmol) and tert-butyl 4-(2-bromomethyl)piperidine-1-carboxylate (0.133 g, 0.477 mmol) in dimethylformamide (1 mL) was added cesium carbonate (0.311 g, 0.954 mmol) as a solid, and the resulting suspension was heated to 60° C. After 3.5 hours, the reaction was cooled to room temperature, quenched with 2 M hydrochloric acid (1 mL), and diluted with ethyl acetate (2 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3×1 mL). The combined aqueous washes were back extracted with ethyl acetate (1 mL), and the combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid, then dried over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl 4-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)piperidine-1-carboxylate which was used for the next reaction without purification. MS (APCI − ) m/z 598 [M−H] − .

To a suspension of tert-butyl 4-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)piperidine-1-carboxylate in dichloromethane (2 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (2.38 mL, 1 M, 2.38 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL) followed by anhydrous ethanol (0.5 mL), was warmed to room temperature, and concentrated under reduced pressure to give a tan solid. The crude solid was suspended in ethyl acetate (5 mL) and sonicated for 30 seconds giving a suspension. The solid was collected via filtration and washed with ethyl acetate (2 mL). The solid was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, a gradient of 3-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.066 g, 0.155 mmol, 65% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.65 (dd, J=9.1, 1.5 Hz, 1H), 7.19 (d, J=2.5 Hz, 1H), 7.13 (dd, J=9.0, 2.5 Hz, 1H), 7.02 (s, 1H), 4.11 (s, 2H), 3.96 (s, 2H), 3.27 (s, 2H), 2.90 (td, J=12.8, 3.0 Hz, 2H), 2.08 (d, J=11.0 Hz, 1H), 1.95 (dd, J=14.6, 3.5 Hz, 2H), 1.58-1.37 (m, 2H); MS (ESI − ) m/z 408 [M−H] − .

Example 16: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile (Compound 115)

To a solution of 5-bromo-3,3-dimethylpentanoic acid (0.5 g, 2.391 mmol), in dichloromethane (10 mL) was added chlorosulfonyl isocyanate (0.208 mL, 2.391 mmol) dropwise. The resulting solution was stirred for 15 minutes at room temperature, and then heated to an internal temperature of 40° C. After 2 hours, gas evolution had ceased, and the reaction mixture was cooled to 0° C. N,N-Diisopropylethylamine was added slowly via syringe so that the internal temperature remained below 7° C. The resulting solution was then warmed to room temperature and stirred for 1 hour. The reaction was quenched with 1 M sodium bisulfate (5 mL), and the layers were separated. The aqueous layer was extracted with dichloromethane (2×5 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude oil was dissolved in a 50% v/v mixture of heptanes and ethyl acetate (5 mL), and the resulting solution was washed with 1 M sodium carbonate (2×5 mL), followed by brine (2 mL), then dried over sodium sulfate, and filtered through silica (2 g). The solid was washed with heptanes (5 mL), and the filtrate was concentrated under reduced pressure to give the title compound (0.33 g, 1.73 mmol, 72.5% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.43-3.29 (m, 2H), 2.28 (s, 2H), 2.08-1.96 (m, 2H), 1.10 (s, 6H); 13 C NMR (101 MHz, CDCl 3 ) δ ppm 117.72, 44.58, 34.22, 30.67, 26.39.

Example 16B: 5-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile

To a solution of the product of Example 1H (0.050 g, 0.125 mmol) and the product of Example 16A (0.047 g, 0.249 mmol) in N,N-dimethylformamide (0.5 mL) was added cesium carbonate (0.243 g, 0.746 mmol) as a solid, and the resulting suspension was heated to 60° C. After 3 hours, the reaction was cooled to room temperature, quenched with 2 N hydrochloric acid (1 mL), and diluted with ethyl acetate (2 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3×1 mL). The combined aqueous washes were back extracted with ethyl acetate (1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile which was used for the next step without purification. MS (APCI − ) m/z 510 [M−H] − .

To a suspension of 5-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-3,3-dimethylpentanenitrile in dichloromethane (2 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (0.75 mL, 1 M, 0.75 mmol) slowly along the side of the vial so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL) followed by anhydrous ethanol (0.5 mL), was warmed to room temperature, and concentrated under reduced pressure to give a tan solid. The residue was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm) with gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at a flow rate of 50 mL/minute (0-1.0 minute 5% A, 1.0-8.5 minutes linear gradient 5-100% A, 8.5-11.5 minutes 100% A, 11.5-12.0 minutes linear gradient 95-5% A) to give the title compound (0.0100 g, 0.023 mmol, 18.2% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.66 (dd, J=9.1, 1.5 Hz, 1H), 7.23 (d, J=2.6 Hz, 1H), 7.12 (dd, J=9.0, 2.5 Hz, 1H), 7.02 (s, 1H), 4.15 (t, J=6.9 Hz, 2H), 4.09 (s, 2H), 2.59 (s, 2H), 1.84 (t, J=6.9 Hz, 2H), 1.10 (s, 6H); MS (ESI − ) m/z 420 [M−H] − .

Example 17: 5-{7-[(3,3-dimethylbutyl)amino]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 116)

In a 4 mL vial with a septum screw cap, the product of Example 1G (0.1 g, 0.215 mmol), sodium tert-butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 μmol), and BrettPhos (3.46 mg, 6.45 μmol) were combined. The solids were placed under vacuum for 5 minutes with stirring, then the vial was filled with nitrogen, followed by 1,4-dioxane (2 mL) and 3,3-dimethylbutan-1-amine (0.044 g, 0.430 mmol). The resulting suspension was degassed by five vacuum/nitrogen backfills, was stirred for 10 minutes at room temperature, and then was heated to 100° C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then quenched with 1 M hydrochloric acid (1 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-7-[(3,3-dimethylbutyl)amino]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione which was used for the next reaction without purification. MS (APCI − ) m/z 484 [M−H] − .

To a suspension of the crude 5-{3-(benzyloxy)-7-[(3,3-dimethylbutyl)amino]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione in dichloromethane (2 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (1.29 mL, 1 M, 1.29 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), warmed to room temperature and concentrated under reduced pressure to give a brown solid. The crude product was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (30 mm×75 mm) with gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) at a flow rate of 50 mL/minute (0-1.0 minute 5% A, 1.0-8.5 minutes linear gradient 5-100% A, 8.5-11.5 minutes 100% A, 11.5-12.0 minutes linear gradient 95-5% A) to give the title compound (0.0165 g, 0.040 mmol, 18.6% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.44 (dd, J=9.1, 1.7 Hz, 1H), 6.94 (dd, J=9.0, 2.3 Hz, 1H), 6.87 (s, 1H), 6.60 (d, J=2.3 Hz, 1H), 5.74 (t, J=5.4 Hz, 1H), 4.07 (s, 2H), 3.07 (dt, J=10.4, 5.2 Hz, 2H), 1.57-1.49 (m, 2H), 0.97 (s, 9H); MS (ESI − ) m/z 394 [M−H] − .

Example 18: 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 117)

Example 18A: 5-[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of the product of Example 1F (300 mg, 0.603 mmol) in dimethylformamide (6.73 mL) was added Selectfluor® (256 mg, 0.724 mmol), and the homogeneous light yellow solution was heated to 65° C. After 90 minutes, the mixture was cooled to room temperature, and the excess oxidant was quenched with a solution of sodium thiosulfate pentahydrate (404 mg, 1.63 mmol) in water (3.3 mL). After stirring for 15 minutes, water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with saturated aqueous ammonium chloride (2×10 mL) and brine (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford methyl {[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl](sulfamoyl)amino}acetate as a viscous, orange oil that was used in the next step without further purification. MS (APCI + ) m/z 516 [M+H] + .

To a solution of methyl {[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl](sulfamoyl)amino}acetate from the previous reaction in tetrahydrofuran (2.69 mL) at room temperature was added a solution of sodium methoxide (207 μL, 0.905 mmol) (25 w % in methanol) via syringe, and the resulting solution was stirred at room temperature. After 5 minutes, the reaction was quenched with 1 M hydrochloric acid (3 mL) and diluted with ethyl acetate (3 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3×1 mL). The combined organic layers were washed with water (2×1 mL), saturated aqueous ammonium chloride (2×1 mL) and brine (1×1 mL) then dried over sodium sulfate, filtered and concentrated. The residue was purified via flash column chromatography (24 g SiO 2 , CH 2 Cl 2 to 10% methanol/CH 2 Cl 2 ) to afford the title compound along with minor, inseparable impurities. The product was carried on to the next step without further purification. MS (APCI + ) m/z 484 [M+H] + .

Example 18B: 5-[3-(benzyloxy)-1,4-difluoro-7-methoxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 18A (301 mg, 0.623 mmol), RockPhos Pd G3 (16.1 mg, 0.019 mmol), and cesium carbonate (609 mg, 1.87 mmol) were placed under vacuum and stirred for 5 minutes, then the flask was filled with nitrogen and a preformed mixture of N,N-dimethylformamide (3.11 mL) and anhydrous methanol (126 μL, 3.11 mmol) was added. The resulting suspension was degassed by five vacuum/nitrogen backfills, and then heated to an internal temperature of 80° C. After 15 minutes, the reaction mixture was cooled to room temperature, quenched by the slow addition of 1 M hydrochloric acid (5 mL), and diluted with ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (4×5 mL), then dried over sodium sulfate, filtered, and concentrated to give a viscous, dark oil. The residue was purified via flash column chromatography (12 g SiO 2 , CH 2 Cl 2 to 10% methanol/CH 2 Cl 2 ) to afford the title compound along with minor, inseparable impurities. The product was carried on to the next step without further purification. MS (APCI + ) m/z 435 [M+H] + .

Example 18C: 5-(1,4-difluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 18B (38.7 mg, 0.089 mmol) and pentamethylbenzene (39.6 mg, 0.267 mmol) in dichloromethane (445 μL) was cooled to an internal temperature of −76° C. under an atmosphere of dry nitrogen. Subsequently, a 1 M solution of boron trichloride (178 μL, 0.178 mmol) in CH 2 Cl 2 was added dropwise over 15 minutes, so as not to raise the internal temperature past −72° C. After 15 minutes, the reaction was quenched at −75° C. with CH 2 Cl 2 /methanol (10:1, 230 μL) via cannula transfer under nitrogen. The mixture was then slowly warmed to room temperature under nitrogen. The volatiles were removed in vacuo to afford a brown solid that was purified via HPLC (Phenomenex® Luna® 10 M C18(2) 100 Å, AXIA™ (00G-4253-U0-AX) column, 250×300 mm, flow rate 50 mL/minute, 5-95% gradient of acetonitrile in buffer (0.025 M aqueous ammonium acetate) to give the title compound (10.3 mg, 0.030 mmol, 34% yield) as a white solid. 1 H NMR (CD 3 OD) δ ppm 7.84 (dd, J=9.3, 1.4 Hz, 1H), 7.30 (t, J=1.5 Hz, 1H), 7.23 (dd, J=9.3, 2.5 Hz, 1H), 4.41 (s, 2H), 3.91 (s, 3H); MS (ESI − ) m/z 343 [M−H] − .

Example 19: 5-{1-fluoro-3-hydroxy-7-[( 2 H 3 )methyloxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 118)

Example 19A: 5-{3-(benzyloxy)-1-fluoro-7-[( 2 H 3 )methyloxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 1H (200 mg, 0.497 mmol), iodomethane-d 3 (68.4 mg, 0.472 mmol), and cesium carbonate (324 mg, 0.994 mmol) in N,N-dimethylformamide (2 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C 18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-75%) to give the title compound (60 mg, 0.143 mmol, 28.8% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.81 (dt, J=8.2, 1.4 Hz, 1H), 7.54-7.49 (m, 2H), 7.42 (s, 1H), 7.41-7.36 (m, 2H), 7.37-7.31 (m, 1H), 7.27 (d, J=8.3 Hz, 2H), 5.24 (s, 2H), 4.48 (s, 2H); MS (APCI − ) m/z 418 [M−H] − .

Example 19B: 5-{-fluoro-3-hydroxy-7-[( 2 H)methyloxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of the product of Example 19A (56 mg, 0.134 mmol) and pentamethylbenzene (99 mg, 0.668 mmol) in dichloromethane (2 mL) cooled to −78° C. was added a solution of boron trichloride (0.801 mL, 0.801 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction was quenched with 2 N HCl (0.5 mL). The reaction mixture was extracted with ethyl acetate. The organic fractions were washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by preparative HPLC on a Phenomenex® Luna® 10 μm C18 column (30 mm×250 mm) eluted with a gradient of acetonitrile (A) with 0.1% trifluoroacetic acid and water (B) 0.1% with trifluoroacetic acid at a flow rate of 50 mL/minute (0-1 minute 10% A, 1-20 minutes linear gradient 10-100%) to give the title compound (30 mg, 0.091 mmol, 68.2% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.81 (dt, J=8.2, 1.4 Hz, 1H), 7.54-7.49 (m, 2H), 7.42 (s, 1H), 7.41-7.36 (m, 2H), 7.37-7.31 (m, 1H), 7.27 (d, J=8.3 Hz, 2H), 5.24 (s, 2H), 4.48 (s, 2H); MS (APCI − ) m/z 328 [M−H] − .

Example 20: 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 119)

Example 20A: 5-[3-(benzyloxy)-1-fluoro-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 1H (97 mg, 0.24 mmol), 1-bromo-2-methoxyethane (66.7 mg, 0.480 mmol) and cesium carbonate (180 mg, 0.552 mmol) in N,N-dimethylformamide (0.8 mL) was stirred at 75° C. for 40 minutes. The solution was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane:methanol (10:1) to give the title compound (100 mg, 0.217 mmol, 90% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.76 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 2H), 7.37 (t, J=8 Hz, 2H), 7.32 (m, 1H), 7.30 (br s, 1H), 7.25 (d, J=2 Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 5.21 (s, 2H), 4.21 (m, 2H), 4.08 (s, 2H), 3.72 (m, 2H), 3.33 (s, 3H); MS (ESI − ) m/z 459 [M−H] − .

Example 20B: 5-[1-fluoro-3-hydroxy-7-(2-methoxyethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the product of Example 20A (100 mg, 0.217 mmol) and 1,2,3,4,5-pentamethylbenzene (97 mg, 0.652 mmol) in dichloromethane (3 mL) at −78° C. was added trichloroborane (869 μl, 0.869 mmol, 1.0 M in dichloromethane). The mixture was stirred at −78° C. for 40 minutes. Methanol (5 mL) was added at −78° C. The mixture was stirred for 5 minutes at room temperature, and then was concentrated under reduced pressure. The resulting solid was washed with heptane (5 mL×4), and then was dissolved in methanol (0.5 mL) and N,N-dimethylformamide (3 mL). The mixture was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 μm column, 25×150 mm, flow rate 80 mL/minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (35 mg, 0.095 mmol, 44% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.27 (br s, 1H), 7.67 (d, J=8 Hz, 1H), 7.18 (d, J=2 Hz, 1H), 7.14 (dd, J=8, 2 Hz, 1H), 7.03 (br s, 1H), 4.19 (m, 2H), 4.09 (s, 2H), 3.71 (m, 2H), 3.33 (s, 3H); MS (ESI − ) m/z 369 [M−H] − .

Example 21: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile (Compound 120)

Example 21A: 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile

To a solution of the product of Example 1H (100 mg, 0.249 mmol) in dimethylformamide (3 mL) was added sodium hydride (21.87 mg, 0.547 mmol) at room temperature in three portions. The mixture was stirred for 30 minutes until no gas evolution was observed. A solution of 4-bromo-2,2-dimethylbutanenitrile (96 mg, 0.547 mmol) in N,N-dimethylformamide (2 mL) was slowly added to the reaction mixture. The mixture was stirred overnight at room temperature. Methanol (2 mL) was added, the volatiles were removed under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , 10% CH 3 OH in CH 2 Cl 2 ) to afford the title compound (65 mg, 0.131 mmol, 53% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.77 (dd, J=9.1, 1.4 Hz, 1H), 7.59-7.50 (m, 2H), 7.44-7.26 (m, 5H), 7.20 (dd, J=9.0, 2.5 Hz, 1H), 5.22 (s, 2H), 4.28 (t, J=6.5 Hz, 2H), 4.09 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.12-2.05 (m, 2H), 1.41 (s, 6H); MS (APCI − ) m/z 496 [M−H] − .

Example 21B: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile

The product of Example 21A (56 mg, 0.113 mmol) and 1,2,3,4,5-pentamethylbenzene (50.1 mg, 0.338 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.338 mL, 0.338 mmol) in dichloromethane was added dropwise over 5 minutes. After 30 minutes, the reaction was quenched at −77° C. with dichloromethane:methanol=2:1(1 mL), and then the mixture was slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes at a flow rate of 25 mL/minute] to afford the title compound (28 mg, 0.069 mmol, 61% yield) as a white solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.68 (dd, J=9.1, 1.4 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7.13 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (d, J=1.3 Hz, 1H), 4.29-4.18 (m, 2H), 4.10 (s, 2H), 2.11-2.05 (m, 2H), 1.41 (s, 6H); MS (APCI − ) m/z 405 [M−H] − .

Example 22: 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 121)

To a mixture of tert-butyl (3-(2-hydroxyethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (0.341 g, 1.5 mmol) and triethylamine (0.304 g, 3.00 mmol) in dichloromethane (4 mL) at 0° C. was added methanesulfonyl chloride (0.180 g, 1.575 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 40 minutes. The mixture was diluted with dichloromethane (60 mL) and washed with water (20 mL×2). The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound (460 mg, 1.50 mmol, 100% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.39 (br s, 1H), 4.16 (t, J=8 Hz, 2H), 3.15 (s, 3H), 1.89 (t, J=8 Hz, 2H), 1.81 (s, 6H), 1.37 (s, 9H); MS (ESI + ) m/z 250 [M−tert−Bu+H] + .

Example 22B: tert-butyl[3-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2, 5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)bicyclo[0.1.]pentan-1-yl]carbamate

A mixture of the product of Example 1H (62.8 mg, 0.15 mmol), the product of Example 22A (110 mg, 0.360 mmol) and cesium carbonate (161 mg, 0.495 mmol) in dimethylformamide (1 mL) was stirred at 75° C. for 1.5 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane/methanol (20:1) to give the title compound (70 mg, 0.11 mmol, 74% yield) as a solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.78 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz, 2H), 7.49 (s, 1H), 7.42 (d, J=2 Hz, 1H), 7.28-7.38 (m, 4H), 7.21 (dd, J=8, 2 Hz, 1H), 5.21 (br s, 2H), 4.10 (t, J=8 Hz, 2H), 3.93 (br s, 2H), 2.00 (t, J=8 Hz, 2H), 1.84 (s, 6H), 1.37 (s, 9H); MS (ESI − ) m/z 626 [M−H] − .

Example 22C: 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 22B (88 mg, 0.144 mmol) and trifluoroacetic acid (1148 mg, 10.07 mmol) in dichloromethane (1.5 mL) was stirred at room temperature for 20 minutes. The mixture was concentrated. The residue was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane/methanol (7:1) to give the title compound (90 mg, 0.144 mmol, 100 yield) as a trifluoroacetate salt. MS (ESI + ) m/z 512 [M+H] + .

Example 22D: 5-{7-[2-(3-aminobicyclo[1.1.1]pentan-1-yl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the product of Example 22C (80 mg, 0.128 mmol) and 1,2,3,4,5-pentamethylbenzene (76 mg, 0.512 mmol) in dichloromethane (3 mL) at −78° C. was added trichloroborane (1535 μL, 1.535 mmol, 1.0 M in dichloromethane). The mixture was stirred at −78° C. for 10 minutes, then 0° C. for 20 minutes. Methanol (6 mL) was added at 0° C. The ice-bath was removed, and the mixture was stirred for 5 minutes at room temperature and then was concentrated under reduced pressure. The resulting solid was washed with heptane (5 mL×4) and dichloromethane (2 mL×4) and was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane/methanol (5:1) to give the title compound (32 mg, 0.076 mmol, 59% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.77 9br s, 2H), 7.67 (d, J=8 Hz, 1H), 7.19 (d, J=2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.16 (s, 1H), 4.14 (br s, 2H), 4.09 (t, J=8 Hz, 2H), 2.04 (t, J=8 Hz, 2H), 1.94 (s, 6H); MS (ESI − ) m/z 420 [M−H] − .

Example 23: 5-(7-{[2-(dimethylamino)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 122)

In a 4 mL vial with a septum screw cap, the product of Example 1G (0.1 g, 0.215 mmol), sodium tert-butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 μmol), and BrettPhos (3.46 mg, 6.45 μmol) were combined. The solids were placed under vacuum for 5 minutes with stirring, then the vial was filled with nitrogen, followed by 1,4-dioxane (2 mL) and N,N-dimethylethylenediamine (0.047 mL, 0.430 mmol). The resulting suspension was degassed by five vacuum/nitrogen backfills, stirred for 10 minutes at room temperature, and then heated to 100° C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then was quenched with 1 M hydrochloric acid (1 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-7-{[2-(dimethylamino)ethyl]amino}-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, which was used for the next reaction without purification. MS (APCI − ) m/z 471 [M−H] − .

To a suspension of 5-[3-(benzyloxy)-7-{[2-(dimethylamino)ethyl]amino}-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione in dichloromethane (2 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (2.15 mL, 1 M, 2.15 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), and warmed to room temperature, giving a suspension. The resulting solid was collected via filtration, then washed with ethyl acetate (2×1 mL) followed by a 50% v/v mixture of acetonitrile and ethyl acetate (1 mL), and dried in vacuo (15 mbar) at 50° C. to constant weight to give the title compound (0.0524 g, 0.125 mmol, 58.7% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.53 (d, J=8.8 Hz, 1H), 7.02 (dd, J=9.0, 2.2 Hz, 1H), 6.96 (s, 1H), 6.80 (s, 1H), 4.25 (br s, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.31 (t, J=5.9 Hz, 2H), 2.83 (s, 6H); MS (ESI − ) m/z 381 [M−H] − .

Example 24: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4- 2 H 2 )-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 123)

To a stirred suspension of the product of Example 25C (889.2 mg, 3.18 mmol) and potassium carbonate (880 mg, 6.37 mmol) in N,N-dimethylformamide (8 mL) was added methyl bromoacetate-2,2-d 2 (0.452 mL, 4.77 mmol) with 0.5 equivalent of D 2 O (0.032 mL, 1.592 mmol). The mixture was stirred at 60° C. for 2 hours and then was allowed to cool to ambient temperature. The reaction was quenched with 10% acetic acid-d 4 in D 2 O (3 mL) and was then diluted with extracted with ethyl acetate (50 mL). The organic layer was washed with saturated aqueous NH 4 Cl (3×50 mL) and brine (1×50 mL) and dried with Na 2 CO 3 . The mixture was filtered and concentrated under reduced pressure to give the title compound which was used directly in the following step. MS (APCI + ) m/z 354 [M+H] + .

To a stirred solution of the product of Example 24A (0.180 g, 0.509 mmol) in tetrahydrofuran (5.1 mL) was added N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (0.169 g, 0.535 mmol). After 2 hours, Na 2 SO 3 (200 mg) was added, and the suspension was stirred for 30 minutes. The tetrahydrofuran was removed under a stream of N 2 , and residue was purified by column chromatography (SiO 2 , 0-50% ethyl acetate in heptanes) to yield the title compound (0.160 g, 0.431 mmol, 85%). MS (APCI + ) m/z 372 [M+H] + .

Example 24C: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}(H 2 )acetate

A heat-dried 20 mL scintillation vial with a stir bar was charged with CH 2 C 2 (5 mL) followed by chlorosulfonyl isocyanate (0.075 mL, 0.859 mmol)) under nitrogen. Subsequently, 2-methylpropan-2-( 2 H)ol (0.083 mL, 0.859 mmol) was added dropwise over 10 minutes and the reaction was subsequently stirred at ambient temperature for 30 minutes. Thereafter, a freshly-prepared solution of the product of Example 24B (160 mg, 0.430 mmol) and triethylamine (0.180 mL, 1.289 mmol) in dichloromethane (3 mL) was added dropwise over 2 minutes. The reaction was stirred at room temperature. Most of the solvent was then removed under a stream of N 2 and 2 mL of toluene was added. The residue was purified by column chromatography (SiO 2 , 0-50% ethyl acetate in heptanes) to yield the title compound (0.180 g, 0.327 mmol, 76%). MS (APCI + ) m/z 451 [M-CO 2 C(CH 3 ) 3 +H] + , 495 [M−C(CH 3 ) 3 +H] + , 569 [M+H 2 O+H] + .

Example 24D: methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl](sulfamoyl)amino}( 2 H 2 )acetate

To a stirred solution of the product of Example 24C (0.18 g, 0.327 mmol) in CH 2 C 2 (3 mL) was added trifluoroacetic acid-d (0.381 mL, 4.90 mmol) dropwise. The solution was stirred at ambient temperature. After 1 hour, all of the volatiles were removed, and the residue was purified by column chromatography (SiO 2 , 0-100% ethyl acetate in heptanes) to yield the title compound (0.132 g, 0.293 mmol, 90%). MS (APCI + ) m/z 451 [M+H] + .

Example 24E: 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl](4,4- 2 H 2 )-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

Prior to reaction, a freshly prepared ˜1 N solution of DCl was obtained by dissolving 265 uL of 35% (weight in D 2 O) solution DCl in D 2 O up to 3 mL. The product of Example 24D (0.02 g, 0.044 mmol) was taken up in deuterated methanol (1 mL) to give a suspension. Sodium hydride (8.79 mg, 0.220 mmol) was added slowly at room temperature; the solution became homogenous and faint yellow in color. The solution was heated to 60° C. and was allowed to stir for 30 minutes. The mixture was carefully quenched with 1 mL DCl in D 2 O (˜1M), and ethyl acetate (1 mL) was added. The organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to yield the title compound (0.013 g, 0.031 mmol, 70.7%). MS (APCI + ) m/z 419 [M+H] + .

Example 24F: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)(4,4- 2 H 2 )-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 24E (0.121 g, 0.289 mmol) was dissolved in dichloromethane (5 mL) and 1,2,3,4,5-pentamethylbenzene (0.129 g, 0.868 mmol) was added. The mixture was cooled to −78° C. and was stirred for 5 minutes before adding boron trichloride (0.636 mL, 0.636 mmol) dropwise. The mixture was stirred for 30 minutes and methanol-d 4 (0.125 g, 3.47 mmol) in dichloromethane (0.75 mL) was added slowly down the side of the vial. The mixture was stirred for 10 minutes, and the dry-ice bath was removed. The mixture was allowed to warm to ambient temperature (white solid precipitated out of solution) and was stirred for 30 minutes. The solvent was removed under a stream of N 2 , and the residue was purified by reverse phase-HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (150 mm×30 mm); 3-100% gradient of acetonitrile (A) and 10 mM ammonium acetate in water (B) over 17 minutes at a flow rate of 50 mL/minute] to yield the product which was dissolved in CH 3 CN:D 2 O (1:1, 4 mL) and lyophilized to give the title compound as a white powder (44.7 mg, 0.136 mmol, 47%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.67 (d, J=9.3 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 7.03 (d, J=1.3 Hz, 1H), 3.85 (s, 3H); MS (APCI − ) m/z 327 [M−H] − .

Example 25: 5-(1-fluoro-3-hydroxy-7-methoxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 124)

A mixture of 3-hydroxy-7-methoxy-2-naphthoic acid (75 g, 344 mmol) and cesium carbonate (336 g, 1031 mmol) in N,N-dimethylformamide (687 mL) was rapidly stirred for 5 minutes at 23° C. Thereafter, benzyl bromide (84 mL, 705 mmol) was added. After 90 minutes, the mixture was poured into H 2 O (1 L) and extracted with ethyl acetate (4×300 mL). The combined organic layers were washed with saturated aqueous ammonium chloride (3×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford a brown solid. The crude solid was collected by filtration, slurried with tert-butyl methyl ether/heptanes (1:2, 3×100 mL), then dried in vacuo (12 mbar) at 40° C. to afford the title compound (122.5 g, 307 mmol, 89% yield) as a beige solid. MS (APCI + ) m/z 399 [M+H] + .

To a suspension of the product of Example 25A (122.5 g, 307 mmol) in methanol (780 mL) was added 6 M aqueous sodium hydroxide (154 mL, 922 mmol). The heterogeneous, brown slurry was agitated with an overhead mechanical stirrer and heated to an internal temperature of 68° C. After 15 minutes, the mixture was cooled to room temperature in an ice bath, and 6 M HCl (250 mL) was added over 5 minutes. The off-white solid was collected by filtration, washed with H 2 O (3×500 mL), and dried to constant weight in vacuo at 65° C. to afford the title compound (84.1 g, 273 mmol, 89% yield) as a white solid. MS (APCI + ) m/z 309 [M+H] + .

To a suspension of the product of Example 25B (84.1 g, 273 mmol), in toluene (766 mL) and tert-butanol (766 mL) was added triethylamine (40.3 mL, 289 mmol). The homogeneous black solution was heated to an internal temperature of 80° C. under nitrogen, and diphenyl phosphorazidate (62.2 mL, 289 mmol) was added dropwise over 90 minutes with the entire reaction behind a blast shield. After 5 hours, the reaction was cooled to room temperature, diluted with H 2 O (1.5 L), and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate, filtered and concentrated to give 180.1 g of a dark brown solid. The solid was carried forward to hydrolysis without further purification.

To the crude intermediate was added diethylenetriamine (475 mL, 4.40 mol). The heterogeneous suspension was heated to an internal temperature of 130° C. under nitrogen, at which time a homogeneous dark orange solution formed. After 16 hours, the mixture was cooled to room temperature in an ice bath, and H 2 O (1.5 L) was added slowly over 3 minutes, resulting in precipitation of a yellow solid and a concomitant exotherm to an internal temperature of 62° C. Once the heterogeneous suspension had cooled to room temperature, the crude solid was dissolved in CH 2 Cl 2 (1.5 L), and the layers were separated. The aqueous layer was back-extracted with CH 2 Cl 2 (3×150 mL), and the combined organic layers were washed with brine (3×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 78.8 g of an orange solid. The solid was slurried with isopropanol (50 mL), collected via filtration, re-slurried with isopropanol (1×50 mL), and dried in vacuo (15 mbar) at 35° C. to afford the title compound (60.12 g, 215 mmol, 79% yield over two steps) as a yellow solid. MS (APCI + ) m/z 280 [M+H] + .

To a mixture of the product of Example 25C (59.2 g, 212 mmol) and potassium carbonate (58.6 g, 424 mmol) in dimethylformamide (363 mL) and H 2 O (1.91 mL, 106 mmol) was added methyl 2-bromoacetate (30.1 mL, 318 mmol). The suspension was vigorously stirred at room temperature for 5 minutes and then heated to an internal temperature of 60° C. After 70 minutes, the suspension was cooled to room temperature and diluted with H 2 O (600 mL) and ethyl acetate (500 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL), and the combined organic layers were washed with saturated aqueous ammonium chloride (3×60 mL), dried over sodium sulfate, filtered, and concentrated to afford 104.3 g of a pale beige solid. The solid was triturated with heptanes (200 mL). The resulting beige solid was collected via filtration, washed with additional heptanes (2×30 mL), and dried in vacuo (15 mbar) at 35° C. to afford the title compound (72.27 g, 206 mmol, 97% yield) as an off-white solid. MS (APCI + ) m/z 352 [M+H] + .

To a mixture of the product of Example 25D (30.0 g, 85 mmol) and N-fluorobenzenesulfonimide (26.9 g, 85 mmol) was added tetrahydrofuran (THF) (854 mL), and the resulting homogeneous yellow solution was stirred at room temperature. After 90 minutes, residual oxidant was quenched by adding a solution of sodium thiosulfate pentahydrate (10.59 g, 42.7 mmol) in water (150 mL), and the mixture was stirred at room temperature for 30 minutes. Thereafter, ethyl acetate (600 mL) was added, the aqueous layer was separated, and the organic layer was washed with a solution of sodium carbonate (18.10 g, 171 mmol) in water (30 mL), followed by water:brine (1:1, 1×20 mL). The organic fraction was dried over sodium sulfate, filtered, and the concentrated in vacuo to afford a bright yellow/orange solid. The solids were triturated with tert-butyl methyl ether (300 mL), collected via filtration, and the filter cake (N-(phenylsulfonyl)benzenesulfonamide) was washed with tert-butyl methyl ether (2×100 mL). The filtrate was concentrated to afford 34.6 g of a dark red oil that was purified by flash chromatography (750 g SiO 2 , heptanes to 20% ethyl acetate/heptanes) to afford the title compound (16.07 g, 43.5 mmol, 51% yield) as a yellow solid. MS (APCI + ) m/z 370 [M+H] + .

To a solution of chlorosulfonyl isocyanate (5.13 mL, 59.1 mmol) in dichloromethane (83 mL) at 0° C. was added tert-butanol (5.65 mL, 59.1 mmol) slowly so that the internal temperature remained less than 10° C. After stirring for 30 minutes at 0° C., a preformed solution of the product of Example 25E (14.55 g, 39.4 mmol) and triethylamine (10.98 mL, 79 mmol) in dichloromethane (68.9 mL) was added slowly via addition funnel so that the internal temperature remained below 10° C. Upon complete addition, the addition funnel was rinsed with dichloromethane (23 mL). The resulting solution was stirred for 30 minutes at 0° C., and then the reaction mixture was quenched with H 2 O (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic layers were washed with brine (1×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give an orange oil. The residue was dissolved in ethyl acetate (200 mL) and washed with water:brine (1:1, 2×50 mL) to remove residual triethylamine hydrochloride. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}acetate which was used without purification.

To a solution of methyl {[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl][(tert-butoxycarbonyl)sulfamoyl]amino}acetate in dichloromethane (98 mL) was added trifluoroacetic acid (45.5 mL, 591 mmol), and the resulting dark solution was stirred at room temperature. After 20 minutes, the reaction was quenched by slow addition of saturated aqueous sodium bicarbonate (691 mL) via an addition funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were concentrated to give a dark red oil; upon addition of tert-butyl methyl ether (60 mL), a yellow solid precipitated that was collected via filtration, washed with tert-butyl methyl ether (2×30 mL) and dried in vacuo (15 mbar) at 35° C. to give the title compound (13.23 g, 29.5 mmol, 75% yield over two steps) as a light yellow solid. MS (ESI + ) m/z 449 [M+H] + .

To a solution of the product of Example 25F (13.23 g, 29.5 mmol) in tetrahydrofuran (THF) (355 mL) at room temperature was added solid potassium tert-butoxide (3.31 g, 29.5 mmol), and the resulting solution was stirred at room temperature. After 10 minutes, the reaction was quenched with 1 M hydrochloric acid (90 mL) and diluted with ethyl acetate (400 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×120 mL). The combined organic layers were washed with brine (3×50 mL), then dried over sodium sulfate, filtered and concentrated. The crude 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione was used in the subsequent reaction without further purification.

A mixture of crude intermediate, 5-[3-(benzyloxy)-1-fluoro-7-methoxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (12.28 g, 29.5 mmol) and pentamethylbenzene (13.11 g, 88 mmol) in dichloromethane (147 mL) was cooled to an internal temperature of −76° C. under an atmosphere of dry nitrogen. Subsequently, a 1 M solution of boron trichloride (59.0 mL, 59.0 mmol) in CH 2 Cl 2 was added dropwise over 15 minutes, so as not to raise the internal temperature past −72° C. Over the course of the addition, the reaction turned dark brown and became homogeneous. Incomplete conversion was observed, and additional boron trichloride (2×5.90 mL, 2×5.90 mmol) was added, resulting in full conversion. The reaction was quenched at −75° C. with CH 2 Cl 2 /methanol (10:1, 140 mL) via cannula transfer under nitrogen over 15 minutes, then slowly warmed to room temperature over 20 minutes under nitrogen. The volatiles were removed in vacuo to afford a brown/tan solid, which was collected by filtration, and slurried with heptanes (5×40 mL) and CH 2 Cl 2 (3×40 mL). The crude solid was suspended in isopropanol (75 mL), warmed until the material dissolved, then allowed to cool slowly to room temperature over 1 hour. The solid was collected by filtration, washed with heptanes (2×30 mL), and dried in vacuo (15 mbar) at 60° C. to afford 5.11 g of a white solid. The mother liquor was concentrated, and the process was repeated to give an additional 1.96 g of a white solid. The batches were combined to obtain the title compound (7.07 g, 21.67 mmol, 73.5% yield over two steps). 1 H NMR (CD 3 OD) δ ppm 7.60 (dd, J=9.1, 1.5 Hz, 1H), 7.25 (d, J=2.6, 1H), 7.16 (dd, J=9.1, 2.6 Hz, 1H), 7.04 (s, 1H), 4.56 (s, 2H), 3.89 (s, 3H); MS (ESI − ) m/z 325 [M−H] − .

Example 26: N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide (Compound 125)

In a 4 mL vial with a septum screw cap, the product of Example 1G (0.15 g, 0.322 mmol), sodium tert-butoxide (0.0.093 g, 0.967 mmol), BrettPhos Pd G3 precatalyst (8.77 mg, 9.67 μmol), and BrettPhos (5.19 mg, 9.67 μmol) were combined. The solids were placed under vacuum for 5 minutes with stirring, then the vial was filled with nitrogen, followed by 1,4-dioxane (3 mL) followed by tert-butyl (2-aminoethyl)carbamate (0.102 mL, 0.645 mmol). The resulting suspension was degassed by five vacuum/nitrogen backfills, stirred for 10 minutes at room temperature, and then heated to 100° C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then quenched with 1 M hydrochloric acid (1 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give tert-butyl (2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)carbamat which was used for the next reaction without purification. MS (APCI − ) m/z 543 [M−H] − .

To a solution of crude tert-butyl (2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)carbamate in dioxane (0.875 mL) was added a solution of HCl in dioxane (0.35 mL, 1.4 mmol, 4 M), and the resulting solution was stirred for 2 hours at room temperature. The reaction mixture was diluted with tert-butyl methyl ether (1.75 mL), giving a suspension. The resulting solid was collected by filtration, washed with methyl tert-butyl methyl ether (2×0.875 mL) and dried to give a hygroscopic white solid that quickly became a brown tar on standing in the air. The 5-{7-[(2-aminoethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione hydrochloric acid salt was used without further purification for the next reaction. MS (APCI + ) m/z 445 [M+H] + .

To a suspension of crude 5-{7-[(2-aminoethyl)amino]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione hydrochloric acid salt in dichloromethane (1.6 mL) was added 1,2,2,6,6-pentamethylpiperidine (0.235 mL, 1.288 mol). The resulting solution was stirred for 5 minutes at room temperature, and then was cooled to 0° C. To the cooled solution was added cyclopropanesulfonyl chloride (0.059 mL, 0.644 mmol) dropwise via syringe. The resulting solution was stirred for 30 minutes and then was quenched with water (2 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×1 mL). The combined organic layers were washed with 1 M sodium bisulfate (1 mL), and the second aqueous layer was back extracted with dichloromethane (2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide which was used for the next reaction without purification. MS (APCI − ) m/z 547 [M−H] − .

To a suspension of the crude N-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}ethyl)cyclopropanesulfonamide in dichloromethane (3.5 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (3.22 mL, 1 M, 3.22 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), and then warmed to room temperature and concentrated under reduced pressure giving a tan solid. The crude solid was suspended in heptanes (5 mL) and sonicated for 30 seconds giving a suspension. The solid was collected via filtration and washed with heptanes (2 mL). The solid was then dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 μm C18(2) 250×30 mm column, flow rate 100 mL/minute, gradient of 5-60% methanol in buffer (0.010 M aqueous ammonium acetate)] to give the title compound (0.0475 g, 0.100 mmol, 47% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.46 (dd, J=9.0, 1.6 Hz, 1H), 6.95 (dd, J=9.0, 2.4 Hz, 1H), 6.88 (d, J=10.3 Hz, 1H), 6.69 (d, J=2.3 Hz, 1H), 4.10 (s, 2H), 3.27-3.21 (m, 2H), 3.21-3.15 (m, 2H), 2.58-2.49 (m, 1H), 0.97-0.85 (m, 4H); MS (ESI − ) m/z 457 [M−H] − .

Example 27: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 126)

In a 4 mL vial with a septum screw cap, 3-amino-1-methanesulfonylpyrrolidine (0.71 g, 0.430 mmol), the product of Example 1G (0.1 g, 0.215 mmol), sodium tert-butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 μmol), and BrettPhos (3.46 mg, 6.45 μmol) were combined. The solids were placed under vacuum for 5 minutes with stirring, and then the vial was filled with nitrogen followed by 1,4-dioxane (2 mL). The resulting suspension was degassed by five vacuum/nitrogen backfills, stirred for 10 minutes at room temperature, and then heated to 100° C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then quenched with 1 M hydrochloric acid (1 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione which was used for the next reaction without purification. MS (APCI + ) m/z 549 [M+H] + .

To a suspension of the crude 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]amino}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione in dichloromethane (2.3 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (2.15 mL, 1 M, 2.15 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C., before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), and then was warmed to room temperature, and concentrated under reduced pressure giving a tan solid. The crude solid was suspended in heptanes (5 mL), and then sonicated for 30 seconds giving a suspension. The solid was collected via filtration and washed with heptanes (2 mL). The solid was then dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Phenomenex® Luna® 10 μm C18(2) 250×30 mm column, flow rate 100 mL/minute, gradient of 5-60% methanol in buffer (0.010 M aqueous ammonium acetate)] to give the title compound (0.0475 g, 0.100 mmol, 47% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.48 (d, J=8.8 Hz, 1H), 7.04-6.88 (m, 2H), 6.67 (d, J=2.4 Hz, 1H), 4.10 (s, 2H), 3.54 (dt, J=10.4, 5.2 Hz, 1H), 3.41 (dt, J=9.9, 7.3 Hz, 1H), 3.38-3.29 (m, 1H), 3.15 (dd, J=10.3, 3.7 Hz, 1H), 2.84 (s, 3H), 2.25 (dt, J=13.7, 6.8 Hz, 1H), 1.96-1.86 (m, 1H); MS (ESI − ) m/z 457 [M−H] − .

Example 28: N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide (Compound 127)

A mixture of 2-bromoethanamine hydrobromide (266 mg, 1.3 mmol), cyclopropanesulfonyl chloride (192 mg, 1.365 mmol), and triethylamine (395 mg, 3.90 mmol) in dichloromethane (10 mL) was stirred at room temperature for 4 hours. The mixture was diluted with dichloromethane (60 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the title compound (200 mg 0.88 mmol, 67% yield) as an oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 3.56 (t, J=8 Hz, 2H), 3.55 (m, 2H), 2.62 (m, 1H), 1.01 (m, 4H).

Example 28B: N-(2-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide

A mixture of the product of Example 1H (89 mg, 0.22 mmol), the product of Example 28A (151 mg, 0.660 mmol), and cesium carbonate (215 mg, 0.660 mmol) in N,N-dimethylformamide (1 mL) was stirred at 75° C. for 2 hours. The solution was filtered. The filtrate was purified by flash column chromatography on silica gel eluted with dichloromethane, then dichloromethane/methanol (10:1) to give the title compound (60 mg 0.11 mmol, 50% yield) as a solid. MS (ESI + ) m/z 550 [M+1] + .

Example 28C: N-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropanesulfonamide

To the product of Example 28B (44 mg, 0.080 mmol) and 1,2,3,4,5-pentamethylbenzene (35.6 mg, 0.240 mmol) in dichloromethane (3 mL) at −78° C. was added trichloroborane (1201 μL, 1.201 mmol). The mixture was stirred at −78° C. for 10 minutes and then at 0° C. for 40 minutes. Ethanol (1 mL) was added at 0° C. The mixture was stirred for 20 minutes at room temperature, and then was concentrated under reduced pressure. The resulting solid was washed with heptane (5 mL×4), then dissolved in N,N-dimethylformamide (2.5 mL) and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 20 m column, 25×150 mm, flow rate 80 mL/minute, 5-100% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (10 mg, 0.022 mmol, 27% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 1H), 7.69 (d, J=8 Hz, 1H), 7.20 (d, J=2 Hz, 1H), 7.16 (dd, J=8, 2 Hz, 1H), 7.04 (s, 1H), 4.15 (t, J=8 Hz, 2H), 4.11 (s, 2H), 3.41 (m, 2H), 2.63 (m, 1H), 0.94 (m, 4H); MS (ESI − ) m/z 458 [M−H] − .

Example 29: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 128)

In a 4 mL vial with a septum screw cap, combined 3-amino-1-(methanesulfonyl)azetidine (0.065 g, 0.430 mmol), the product of Example 1G (0.1 g, 0.215 mmol), sodium tert-butoxide (0.062 g, 0.645 mmol), BrettPhos Pd G3 precatalyst (5.84 mg, 6.45 μmol), and BrettPhos (3.46 mg, 6.45 μmol). The solids were placed under vacuum for 5 minutes with stirring, then the vial was filled with nitrogen followed by 1,4-dioxane (2 mL). The resulting suspension was degassed by five vacuum/nitrogen backfills, stirred for 10 minutes at room temperature, and then was heated to 100° C. After 30 minutes at 100° C., the reaction mixture was cooled to room temperature, then quenched with 1 M hydrochloric acid (1 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2×1 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (1 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, which was used for the next reaction without purification. MS (APCI − ) m/z 533 [M−H] − .

To a suspension of the crude intermediate, 5-[3-(benzyloxy)-1-fluoro-7-{[1-(methanesulfonyl)azetidin-3-yl]amino}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, in dichloromethane (2.3 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (2.15 mL, 1 M, 2.15 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 10° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (1 mL), followed by anhydrous ethanol (0.5 mL), and then warmed to room temperature, and concentrated under reduced pressure giving a tan solid. The crude solid was suspended in heptanes (5 mL) and sonicated for 30 seconds giving a suspension. The solid was collected via filtration and washed with heptanes (2 mL). The solid was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, a gradient of 3-30% methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.0357 g, 0.077 mmol, 36% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.51 (dd, J=9.0, 1.5 Hz, 1H), 6.96 (dd, J=8.9, 2.3 Hz, 1H), 6.91 (s, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.32 (dq, J=7.8, 5.8 Hz, 2H), 4.23 (t, J=7.7 Hz, 3H), 4.09 (s, 2H), 3.00 (s, 3H); MS (ESI − ) m/z 443 [M−H] − .

Example 30: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile (Compound 129)

A mixture of the product of Example 1H (86 mg, 0.214 mmol), cesium carbonate (139 mg, 0.427 mmol) and 4-bromobutyronitrile (47.4 mg, 0.321 mmol) in N,N-dimethylformamide (1 mL) was stirred at ambient temperature for 2 hours. In a separate vial, a mixture of the product of Example 1H (86 mg, 0.214 mmol), cesium carbonate (139 mg, 0.427 mmol) and 4-bromobutyronitrile (47.4 mg, 0.321 mmol) in dioxane:N,N-dimethylformamide (2:1, 1.5 mL) was stirred at ambient temperature for 2 hours. The reaction mixtures of the reactions were combined, diluted with ethyl acetate, washed with water, brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile which was used in the next step without purification. MS (APCI − ) m/z 468 (M−H) −

To a mixture of the above intermediate, 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}butanenitrile (200 mg, 0.426 mmol), and pentamethylbenzene (316 mg, 2.130 mmol) in dichloromethane (3 mL) at −78° C., was added a solution of boron trichloride (2.56 mL, 2.56 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction was quenched with 2 N HCl (0.5 mL) and extracted with ethyl acetate. The organic fraction was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was triturated with dichloromethane to give the title compound (90 mg, 0.237 mmol, 56%). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.35 (s, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.26-7.17 (m, 2H), 7.08 (s, 1H), 4.49 (s, 2H), 4.15 (t, J=6.1 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.08 (p, J=6.6 Hz, 2H). MS (APCI − ) m/z 378 [M−H] − .

Example 31: [1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile (Compound 130)

A mixture of the product of Example 1H (150 mg, 0.373 mmol), cesium carbonate (243 mg, 0.746 mmol) and 2-(1-(bromomethyl)cyclopropyl)acetonitrile (97 mg, 0.559 mmol) in N,N-dimethylformamide (1.5 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was then partitioned between ethyl acetate (60 mL) and water (15 mL) with 1.5 mL 2 N HCl. The ethyl acetate fraction was separated, washed with water and brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give [1-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile, which was used in the next step without purification. MS (APCI − ) m/z 494 [M−H] − .

To a mixture of the above intermediate [1-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropyl]acetonitrile (185 mg, 0.373 mmol) and pentamethylbenzene (277 mg, 1.867 mmol) in dichloromethane (3 mL) at −78° C. was added a solution of boron trichloride (2.24 mL, 2.240 mmol) in dichloromethane dropwise over 5 minutes. After 30 minutes, the reaction was quenched with 2 mL of 0.5 N HCl and extracted with ethyl acetate. The organic fraction was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was triturated with dichloromethane to give the title compound (85 mg, 0.210 mmol, 56% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.28 (s, 1H), 7.75-7.70 (m, 1H), 7.22 (m, 2H), 7.07 (s, 1H), 4.45 (s, 2H), 4.00 (s, 2H), 2.80 (s, 2H), 0.77-0.70 (m, 2H), 0.72-0.65 (m, 2H); MS (APCI − ) m/z 404 [M−H] − .

Example 32: 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 131)

To the solution of 2-(dimethylamino)ethanol (500 mg, 5.61 mmol) in dichloromethane (25 mL) at 0° C. was added methanesulfonyl chloride (0.523 mL, 6.73 mmol) and triethylamine (1.01 mL, 7.85 mmol). The reaction mixture was stirred 10 minutes at 0° C. and 1 hour at room temperature. Water (5 mL) was then added, and the mixture was extracted with dichloromethane. The organic layers were collected and washed with brine (2 mL) and dried over anhydrous Na 2 SO 4 . The volatiles were carefully removed under reduced pressure (bath temperature maintained ˜25° C.) to afford the crude title compound which was subjected to the next reaction without purification.

Example 32B: 5-{3-(benzyloxy)-7-[2-(dimethylamino)ethoxy]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the product of Example 1H (150 mg, 0.373 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (60% dispersed in mineral oil, 32.8 mg, 0.820 mmol) at room temperature in three portions. The reaction was stirred for 30 minutes until no gas evolution was observed. A solution of freshly prepared product of Example 32A (137 mg, 0.820 mmol) in N,N-dimethylformamide (2 mL) was slowly added to the reaction mixture. The reaction was stirred overnight at room temperature. Methanol (1 mL) was added, the volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (91 mg, 0.192 mmol, 52% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.55 (s, 1H), 7.81 (dd, J=9.1, 1.5 Hz, 1H), 7.60-7.53 (m, 2H), 7.41-7.33 (m, 3H), 7.37-7.27 (m, 2H), 7.26 (dd, J=9.0, 2.5 Hz, 1H), 5.23 (s, 2H), 4.46 (t, J=5.0 Hz, 2H), 4.09 (s, 2H), 3.55 (t, J=5.0 Hz, 2H), 2.87 (s, 6H); MS (APCI − ) m/z 472 [M−H] − .

Example 32C: 5-{7-[2-(dimethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 32B (88 mg, 0.186 mmol) and 1,2,3,4,5-pentamethylbenzene (83 mg, 0.558 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.56 mL, 0.558 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at −78° C. with dichloromethane:ethanol=9:1 (1 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm); 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to give the title compound (30 mg, 0.078 mmol, 42% yield) as a white solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 9.53 (s, 1H), 7.71 (dd, J=9.0, 1.4 Hz, 1H), 7.28 (d, J=2.6 Hz, 1H), 7.18 (dd, J=9.0, 2.6 Hz, 1H), 7.05 (s, 1H), 4.38 (t, J=5.2 Hz, 2H), 4.10 (s, 2H), 2.75 (s, 6H); MS (APCI) m/z 382 [M−H] − .

Example 33: 5-{7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 132)

Example 33A: 5-{3-(benzyloxy)-7-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the product of Example 1G (100 mg, 0.215 mmol) in dioxane (5 mL) was added 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (80 mg, 0.322 mmol) and sodium carbonate (0.322 mL, 0.645 mmol). Tetrakis(triphenylphosphine)palladium(0) (24.8 mg, 0.021 mmol) was added, and the reaction mixture was sparged with N 2 for 5 minutes. The mixture was heated at 100° C. overnight. The reaction was cooled to room temperature, and the volatiles were removed under reduced pressure. The residue was purified by column chromatography (SiO 2 , dry loading, 5% methanol in dichloromethane) to afford the title compound (68 mg, 0.134 mmol, 63% yield) as a yellow solid. MS (APCI − ) m/z 505 [M−H] − .

Example 33B: 5-{7-[1-(cyclopropylmethyl)-H-pyrazol-4-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 33A (50 mg, 0.099 mmol) and 1,2,3,4,5-pentamethylbenzene (43.9 mg, 0.296 mmol) in a 50 mL round bottom flask was flushed with nitrogen for 5 minutes. Dichloromethane (5 mL) was then added, and the heterogeneous suspension was cooled to −78° C. and equilibrated for 5 minutes. Subsequently, a 1 M solution of trichloroborane (0.296 mL, 0.296 mmol) in dichloromethane was added dropwise over 5 minutes. After 20 minutes, the reaction was quenched at −78° C. with dichloromethane:ethanol=9:1 (1 mL) and then slowly warmed to room temperature. The volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm) 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (18 mg, 0.043 mmol, 44% yield) as a white solid. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 9.71 (s, 1H), 8.34 (s, 1H), 8.00 (d, J=10.7 Hz, 2H), 7.73 (s, 2H), 7.05 (s, 1H), 4.11 (s, 2H), 4.00 (d, J=7.1 Hz, 2H), 1.29 (tt, J=7.6, 4.8 Hz, 1H), 0.60-0.51 (m, 2H), 0.44-0.38 (m, 2H); MS (APCI − ) m/z 415 [M−H] − .

Example 34: 5-{1-fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 133)

Example 34A: tert-butyl 4-(((methylsulfonyl)oxy)methyl)-H-pyrazole-1-carboxylate Methanesulfonyl chloride (202 mg, 1.760 mmol) in dichloromethane (1 mL) was added dropwise to a stirred cold (0° C.) solution of tert-butyl 4-(hydroxymethyl)-1H-pyrazole-1-carboxylate (317 mg, 1.6 mmol) and triethylamine (324 mg, 3.20 mmol) in dichloromethane (6 mL). The reaction mixture was allowed to warm to ambient temperature and maintained at ambient temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (30 mL) and quenched with 0.2 N HCl aqueous solution (10 mL). The organic layer was separated and washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (415 mg, 1.502 mmol, 94% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.44 (s, 1H), 7.91 (s, 1H), 5.21 (s, 2H), 2.32 (s, 3H), 1.58 (s, 9H).

Example 34B: tert-butyl 4-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)-1H-pyrazole-1-carboxylate

A mixture of Example 1H (150 mg, 0.373 mmol), Example 34A (206 mg, 0.746 mmol), and cesium carbonate (202 mg, 0.621 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70° C. for 40 minutes. The mixture was cooled to ambient temperature and diluted with ethyl acetate (50 mL). The organic phase was washed with 0.2 N HCl aqueous solution (10 mL) and brine (10 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (215 mg, 0.369 mmol, 99% yield). MS (ESI − ) m/z 581 (M−H) − .

Example 34C: 5-{t-fluoro-3-hydroxy-7-[(1H-pyrazol-4-yl)methoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of 1,2,3,4,5-pentamethylbenzene (115 mg, 0.772 mmol) and Example 34B (150 mg, 0.257 mmol) in dichloromethane (3 mL) at −78° C. was added trichloroborane (2.832 mL, 2.83 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 10 minutes, then at −20° C. for 30 minutes. The mixture was quenched with ethanol (6 mL) and concentrated. The residue was washed with heptane (4×4 mL) and dichloromethane (6×3 mL) and concentrated to give the crude product. The crude product was dissolved in N,N-dimethylformamide (3 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-55% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (34 mg, 0.087 mmol, 33.7% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 12.85 (br s, 1H), 7.87 (br s, 1H), 7.66 (dd, J=8, 2 Hz, 1H), 7.60 (br s, 1H), 7.29 (d, J=2 Hz, 1H), 7.13 (dd, J=8, 2 Hz, 1H), 7.02 (s, 1H), 5.08 (s, 2H), 4.11 (m, 1H), 4.09 (s, 2H); MS (ESI − ) m/z 391 (M−H) − .

Example 35: 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 134)

Example 35A: 5-[3-(benzyloxy)-1-fluoro-7-(2-methylpropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

1-Iodo-2-methylpropane (0.09 mL, 0.77 mmol, 1.6 equivalents) was added to a suspension of cesium carbonate (362 mg, 1.11 mmol, 2.2 equivalents) and the product of Example 1H (201 mg, 0.5 mmol, 1 equivalent) in N,N-dimethylformamide (1.0 mL) at 23° C. The reaction vessel (4 mL vial) was sealed, and the sealed vessel was placed in a heating block that had been preheated to 60° C. The reaction mixture was stirred for 2 hours at 60° C. The reaction mixture was cooled to 23° C. over 5 minutes. Additional 1-iodo-2-methylpropane (0.09 mL, 0.77 mmol, 1.6 equivalents) was added at 23° C. The reaction vessel was sealed, and the sealed vessel was placed in a heating block that had been preheated to 100° C. The reaction mixture was stirred for 3 hours at 100° C. The reaction mixture was cooled to 23° C. over 5 minutes. Additional 1-iodo-2-methylpropane (0.09 mL, 0.77 mmol, 1.6 equivalents) was added at 23° C. The reaction vessel was sealed, and the sealed vessel was placed in a heating block that had been preheated to 100° C. The reaction mixture was stirred for 1 hour at 100° C. The product mixture was cooled to 23° C. over 15 minutes. The cooled mixture was diluted with water (0.5 mL) and dimethyl sulfoxide (5.0 mL). The diluted mixture was purified by reverse-phase flash-column chromatography (100 g RediSep® Gold C 18 column, eluted with a gradient from 10-100% [v/v] methanol-0.025 M aqueous ammonium bicarbonate solution [acidified with solid carbon dioxide] over 10 column volumes, then isocratic elution with 100% methanol for 3 column volumes, flow rate=60 mL/minute) to furnish the title compound as a yellow solid (59.0 mg, 25%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.77 (dd, J=9.6, 4.0 Hz, 1H), 7.49-7.32 (m, 6H), 7.23-7.17 (m, 2H), 5.17 (d, J=17.4 Hz, 2H), 7.73 (s, 1H), 4.66 (s, 1H), 3.93 (d, J=6.7 Hz, 1H), 3.27 (d, J=7.6 Hz, 1H), 1.88 (dq, J=13.4, 6.7 Hz, 1H), 0.86 (d, J=6.7 Hz, 2H), 0.79 (d, J=6.7 Hz, 2H); MS (APCI + ) m/z 459 [M+H] + .

Example 35B: 5-[1-fluoro-3-hydroxy-7-(2-methylpropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A solution of boron trichloride in dichloromethane (1.0 M, 0.80 mL, 0.80 mmol, 6.2 equivalents) was added to a suspension of the product of Example 35A (59.0 mg, 0.13 mmol, 1 equivalent) in dichloromethane (1.5 mL) at −78° C. The reaction mixture was stirred for 10 minutes at −78° C. (dry-ice/acetone bath). The reaction vessel was then transferred to an ice bath. The reaction mixture was stirred for 10 minutes at 0° C. The reaction vessel was then returned to the dry-ice/acetone bath. The reaction mixture was stirred for 5 minutes at −78° C. The product mixture was then diluted slowly with ethanol (2.0 mL) at −78° C. The diluted mixture was warmed to 23° C. and the warmed mixture was concentrated. The residue obtained was triturated with heptanes (5 mL). The residue obtained was dissolved in 10% acetone-dichloromethane (2.0 mL), and the solution was diluted with heptanes (10.0 mL). A precipitate formed, and the mother liquor was decanted. The residue obtained was triturated with heptanes (1.0 mL) to furnish the title compound (10.2 mg, 22%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.65 (dd, J=11.9, 9.2 Hz, 1H), 7.14-7.09 (m, 2H), 7.03 (d, J=13.4 Hz, 1H), 4.80 (s, 1H), 4.63 (s, 1H), 4.26 (d, J=6.6 Hz, 1H), 3.43 (d, J=7.6 Hz, 1H), 2.13-2.04 (m, 1H), 0.99 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H); MS (APCI + ) m/z 369 [M+H] + .

Example 36: 5-[1-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 135)

Example 36A: 5-[3-(benzyloxy)-1-fluoro-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1H (120 mg, 0.298 mmol) in N,N-dimethylformamide (2 mL), was added cesium carbonate (214 mg, 0.656 mmol) and 1-bromo-2-propanol (41.4 mg, 0.298 mmol). The mixture was heated to 80° C. overnight. After cooling, the mixture was filtered by passing through diatomaceous earth, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to give the title compound (30 mg, 0.065 mmol, 22% yield). MS (APCI − ) m/z 459 [M−H] − .

Example 36B: 5-[I-fluoro-3-hydroxy-7-(2-hydroxypropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The product of Example 36A (30 mg, 0.065 mmol) and tetrahydrofuran (3 mL) were added to 10% Pd (OH) 2 /C (wet, 60 mg, 0.214 mmol) in a 20 mL Barnstead Hast C reactor with glass liner, and the mixture was stirred at 25° C. for 21.1 hours under 113 psi of hydrogen. The mixture was filtered through a pad of diatomaceous earth, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to give the title compound (6 mg, 0.016 mmol, 25% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.31 (s, 1H), 7.75-7.68 (m, 1H), 7.27-7.18 (m, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 4.48 (s, 2H), 4.00 (p, J=5.9 Hz, 1H), 3.99-3.86 (m, 2H), 1.19 (d, J=6.3 Hz, 3H); MS (APCI − ) m/z 369 [M−H] − .

Example 37: N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide (Compound 136)

Example 37A: methyl 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 , 2,5-thiadiazolidin-2-yl)naphthalene-2-carboxylate

To a mixture of Example 1G (2.5 g, 5.37 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.079 g, 0.107 mmol) in a 50 mL stainless steel pressure reactor were added methanol (25 mL) and triethylamine (1.498 mL, 10.75 mmol). The reactor was degassed with nitrogen gas several times followed by refilling with carbon monoxide gas to 60 psi. The mixture was heated to 80° C. and stirred for 10 hours under 60 psi of carbon monoxide. The mixture was filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , 5% methanol in dichloromethane) to afford the title compound (1.5 g, 3.38 mmol, 63% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.97 (s, 3H), 8.55 (d, J=1.6 Hz, 1H), 8.05-7.91 (m, 2H), 7.60-7.55 (m, 2H), 7.47 (s, 1H), 7.42-7.28 (m, 3H), 5.31 (s, 2H), 4.10 (s, 2H), 3.92 (s, 3H); MS (APCI − ) m/z 443 [M−H] − .

Example 37B: 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxylic acid

To the solution of Example 37A (200 mg, 0.450 mmol) in methanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL) was added LiOH (32.3 mg, 1.350 mmol) at ambient temperature, and the mixture was stirred overnight at ambient temperature. The pH of the reaction mixture was adjusted to neutral by addition of HCl (2 N). The mixture was extracted with ethyl acetate (3×3 mL), volatiles were removed under reduced pressure and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (150 mg, 0.349 mmol, 77% yield). MS (APCI − ) m/z 429 [M−H] − .

Example 37C: N-(cyclopropylmethyl)-8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide

To a solution of Example 37B (150 mg, 0.349 mmol) in N,N-dimethylformamide (2 mL) was added cyclopropylmethanamine (49.6 mg, 0.697 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (139 mg, 0.366 mmol), and triethylamine (106 mg, 1.046 mmol) and the mixture was stirred at 60° C. overnight. After cooling, water (10 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure to give 6-(benzyloxy)-N-(cyclopropylmethyl)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide that was subjected to the next step without purification. MS (APCI − ) m/z 482 [M−H] − .

The 6-(benzyloxy)-N-(cyclopropylmethyl)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carboxamide and tetrahydrofuran (2 mL) were added to 5% Pd/C (120 mg, 0.525 mmol) in a 20 mL Barnstead reactor with a glass liner. The mixture was stirred at 25° C. for 18 hours under 50 psi of hydrogen. The mixture was filtered, volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to give the title compound (46 mg, 0.117 mmol, 47% yield over two steps). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.96 (s, 1H), 8.78 (t, J=5.7 Hz, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.96 (dd, J=8.7, 1.8 Hz, 1H), 7.85 (dd, J=8.8, 1.4 Hz, 1H), 7.16 (s, 1H), 4.52 (s, 2H), 3.19 (dd, J=6.8, 5.7 Hz, 2H), 1.12-1.01 (m, 1H), 0.49-0.40 (m, 2H), 0.29-0.22 (m, 2H); MS (APCI − ) m/z 392 [M−H] − .

Example 38: 5-[1-fluoro-3-hydroxy-7-(2-{[2-(trifluoromethoxy)ethyl]amino}ethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 137)

The title compound was prepared using the methodologies described in Example 46 substituting 2-(trifluoromethoxy)ethanamine for propan-2-amine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.56 (s, 1H), 8.71 (br s, 2H), 7.73 (d, J=8, Hz, 1H), 7.26 (d, J=2, Hz, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 7.05 (s, 1H), 4.37 (m, 4H), 4.11 (t, J=6 Hz, 2H), 4.10 (s, 2H), 3.42 (m, 2H); MS (ESI − ) m/z 466 (M−H) − .

Example 39: 5-(1-fluoro-3-hydroxy-7-{2-[(2-methoxyethyl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 138)

The title compound was prepared using the methodologies described in Example 46 substituting 2-methoxyethanamine for propan-2-amine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.51 (s, 1H), 8.25 (br s, 2H), 7.72 (d, J=8, Hz, 1H), 7.25 (d, J=2, Hz, 1H), 7.19 (dd, J=8, 2 Hz, 1H), 7.05 (s, 1H), 4.32 (t, J=6 Hz, 2H), 4.09 (s, 2H), 3.59 (t, J=6 Hz, 2H), 3.35 (m, 2H), 3.29 (s, 3H), 3.17 (m, 2H); MS (ESI − ) m/z 412 (M−H); MS (ESI − ) m/z 366 (M−H) − .

Example 40: 5-{1-fluoro-3-hydroxy-7-[3-(methylamino)propyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 139)

The title compound was prepared using the methodologies described in Example 41 substituting methanamine for ethanamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.44 (s, 1H), 8.51 (br s, 2H), 7.74 (d, J=8, Hz, 1H), 7.73 (d, J=2, Hz, 1H), 7.40 (dd, J=8, 2 Hz, 1H), 7.10 (s, 1H), 4.42 (s, 2H), 2.87 (m, 2H), 2.81 (t, J=7, Hz, 2H), 2.54 (m, 3H), 1.96 (m, 2H).

Example 41: 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 140)

Example 41A: 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]propanal

A mixture of Example 1G (0.60 g, 1.290 mmol), 2-(di-tert-butylphosphino)biphenyl (0.058 g, 0.193 mmol), palladium(II) acetate (0.043 g, 0.193 mmol), prop-2-en-1-ol (0.225 g, 3.87 mmol) and triethylamine (0.261 g, 2.58 mmol) in N,N-dimethylformamide (4 mL) was placed under nitrogen and heated to 120° C. for 1.5 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate (60 mL). The organic phase was washed with 0.5 N HCl aqueous solution (10 mL) and brine (10 mL×3), dried over sodium sulfate, filtered and concentrated to give the title compound (520 mg, 1.175 mmol, 92% yield). MS (ESI − ) m/z 441 (M−H) − .

Example 41B: 5-{3-(benzyloxy)-7-[3-(ethylamino)propyl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 41A (100 mg, 0.226 mmol), triethylamine (114 mg, 1.130 mmol), ethanamine (0.339 mL, 0.678 mmol) and sodium triacetoxyborohydride (192 mg, 0.904 mmol) in acetonitrile/methanol (4:1, 3 mL) was stirred at ambient temperature for 18 hours. Then methanol/water (1:2, 2 mL) was added. The solution was filtered, and the filtrate was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-70% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (35 mg, 0.074 mmol, 32.8% yield). MS (ESI − ) m/z 470 (M−H) − .

Example 41C: 5-{7-[3-(ethylamino)propyl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of 1,2,3,4,5-pentamethylbenzene (38.5 mg, 0.260 mmol) and Example 41B (35 mg, 0.074 mmol) in dichloromethane (3 mL) at −78° C. was added trichloroborane (0.816 mL, 0.816 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 10 minutes, then −20° C. for 20 minutes. The mixture was quenched with ethanol (3 mL) and concentrated.

The residue was washed with heptane (4×4 mL) and dichloromethane (6×3 mL) and concentrated to give the title compound (27 mg, 0.071 mmol, 95% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.51 (s, 1H), 8.63 (br s, 2H), 7.74 (d, J=8, Hz, 1H), 7.73 (d, J=2, Hz, 1H), 7.42 (dd, J=8, 2 Hz, 1H), 7.11 (s, 1H), 4.45 (s, 2H), 2.90 (m, 4H), 2.82 (t, J=7, Hz, 2H), 1.98 (m, 2H), 1.17 (t, J=7 Hz, 3H); MS (ESI − ) m/z 380 (M−H) − .

Example 42: 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 141)

To a solution of 2-bromo-5-iodothiophene (407 mg, 1.409 mmol), dimethylphosphine oxide (100 mg, 1.281 mmol) and triethylamine (0.214 mL, 1.537 mmol) in 1,4-dioxane (5 mL) was added tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 , 11.73 mg, 0.013 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (Xantphos, 14.83 mg, 0.026 mmol) at 20° C. under nitrogen. Then the mixture was stirred for 12 hours at 20° C. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [Agela-SNAP 20-35 μm, 100 Å C18 flash column, 120 g, flow rate 20 mL/minute, monitor wavelength: 220&254 nm, 0-35% gradient of acetonitrile in water] to give the title compound (220 mg, 0.874 mmol, 68.2% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.32 (dd, J=7.88, 3.75 Hz, 1H), 7.13-7.16 (m, 1H), 1.79 (d, J=13.26 Hz, 6H).

Example 42B: 5-[3-(benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione and [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]boronic acid

To a solution of Example 1G (400 mg, 0.860 mmol), potassium acetate (253 mg, 2.58 mmol) and bis(pinacolato)diboron (437 mg, 1.719 mmol) in 1,4-dioxane (7 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (PdCl 2 (dppf)-CH 2 Cl 2 adduct, 140 mg, 0.172 mmol) at 20° C. under nitrogen. Then the mixture was stirred for 4 hours at 80° C. Then the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC [Agela-SNAP C18 20˜35 μm, 100 Å flash column, 120 g, flow rate 120 mL/minute, 0-45% gradient of acetonitrile in water, monitor wavelength: 220&254 nm] and the solution was concentrated under reduced pressure to give a mixture of the title compounds (300 mg, 0.577 mmol, yield 67.1%). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.50 (s, 1H), 8.30 (s, 1H), 7.95 (d, J=8.25 Hz, 1H), 7.85-7.89 (m, 1H), 7.78-7.84 (m, 2H), 7.53 (br d, J=7.38 Hz, 4H), 7.30-7.44 (m, 8H), 5.29 (br s, 4H), 4.50 (br d, J=6.50 Hz, 4H), 1.34 (s, 9H), 1.15-1.17 (m, 3H).

Example 42C: 5-{3-(benzyloxy)-7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

Tetrakis[triphenylphosphine]palladium(0) (Pd(Ph 3 P) 4 , 17.40 mg, 0.015 mmol) was added to a mixture of the compounds of Example 42B (86 mg, 0.181 mmol), sodium carbonate (Na 2 CO 3 , 31.9 mg, 0.301 mmol) and the compound of Example 42A (40 mg, 0.151 mmol) in toluene (2 mL), ethanol (1 mL) and water (0.5 mL) under nitrogen at 20° C. The mixture was stirred for 2 hours at 100° C. under nitrogen. Then the mixture was cooled to 25° C. One additional vial in 10 mg scale and one additional vial in 40 mg scale were set up as described above. These three reactions were combined and diluted with water (50 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The aqueous solution was acidified with aqueous 1 M hydrochloric acid to pH=3. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [Welch Xtimate™ C18 150×25 mm, 5 μm column, flow rate 25 mL/minute, 30-50% gradient over 15 minutes of acetonitrile in aqueous ammonium bicarbonate (10 mM), wavelength: 220&254 nm]. The resulting solution was acidified with aqueous 1 M hydrochloric acid to pH=3 and extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (40 mg, 0.070 mmol, 20.60% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.97 (s, 2H), 7.82 (dd, J=3.69, 1.69 Hz, 1H), 7.63 (dd, J=7.13, 3.75 Hz, 1H), 7.47-7.58 (m, 3H), 7.30-7.44 (m, 3H), 5.30 (s, 2H), 4.49 (s, 2H), 1.78 (d, J=13.76 Hz, 6H); MS (ESI − ) m/z 543 (M−H) − .

Example 42D: 5-{7-[5-(dimethylphosphoryl)thiophen-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

To a mixture of the compound of Example 42C (35 mg, 0.061 mmol) in anhydrous dichloromethane (10 mL) was added trichloroborane (0.366 mL, 0.366 mmol) dropwise at 0° C. Then the mixture was stirred for 2 hours at 20° C. One additional vial in 5 mg scale was set up as described above. These two reaction mixtures were combined, quenched with 5 mL of methanol, and concentrated under reduced pressure. The residue was dissolved with N,N-dimethylformamide and purified by preparative HPLC [Gilson 281 semi-preparative HPLC system, Welch Xtimate™ C18 column, 150×25 mm, 5 μm, flow rate 25 mL/minute, 30-50% gradient of acetonitrile in buffer (10 mM aqueous ammonium bicarbonate), wavelength: 220&254 nm] and lyophilization to give the title compound (15 mg, 0.030 mmol, 43.2% yield) as an ammonium salt. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.13 (s, 1H), 7.83 (s, 2H), 7.77 (dd, J=3.50, 1.50 Hz, 1H), 7.61 (dd, J=7.07, 3.69 Hz, 1H), 7.34-7.56 (m, 3H), 7.10 (s, 1H), 4.11 (s, 2H), 1.77 (d, J=13.76 Hz, 6H); MS (ESI − ) m/z 453 (M−H) − .

Example 43: 5-{7-[2-(cyclopropylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 142)

The title compound was prepared using the methodologies described in Example 46 substituting cyclopropanamine for propan-2-amine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.99 (s, 1H), 8.95 (br s, 2H), 7.75 (d, J=8, Hz, 1H), 7.29 (d, J=2, Hz, 1H), 7.27 (dd, J=8, 2 Hz, 1H), 7.09 (s, 1H), 4.38 (t, J=5 Hz, 2H), 4.30 (s, 2H), 3.49 (m, 2H), 2.83 (m, 1H), 0.87 (m, 2H), 0.79 (m, 2H); MS (ESI − ) m/z 394 (M−H) − .

Example 44: 5-{1-fluoro-3-hydroxy-7-[2-(methylamino)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 143)

The title compound was prepared using the methodologies described in Example 46 substituting methanamine for propan-2-amine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.16 (br s, 1H), 8.72 (br s, 2H), 7.72 (d, J=8, Hz, 1H), 7.25 (d, J=2, Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 7.05 (s, 1H), 4.34 (s, 2H), 4.32 (t, J=5 Hz, 2H), 3.47 (m, 2H), 2.62 (m, 3H); MS (ESI − ) m/z 368 (M−H) − .

Example 45: 5-{7-[2-(ethylamino)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 144)

The title compound was prepared using the methodologies described in Example 46 substituting ethanamine for propan-2-amine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.81 (s, 1H), 8.93 (br s, 2H), 7.74 (d, J=8, Hz, 1H), 7.37 (d, J=2, Hz, 1H), 7.24 (dd, J=8, 2 Hz, 1H), 7.07 (s, 1H), 4.52 (t, J=5 Hz, 2H), 4.21 (s, 2H), 3.45 (m, 2H), 3.06 (m, 2H), 1.23 (t, J=7 Hz, 3H); MS (ESI − ) m/z 382 (M−H) − .

Example 46: 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 145)

Example 46A: 5-[3-(benzyloxy)-7-(2,2-dimethoxyethoxy)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 1H (520 mg, 1.292 mmol), cesium carbonate (1011 mg, 3.10 mmol), and 2-bromo-1,1-dimethoxyethane (437 mg, 2.58 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 4 hours. The reaction was cooled to ambient temperature and quenched with 0.2 N HCl aqueous solution (20 mL). The mixture was extracted with ethyl acetate (60 mL×2). The combined organic phases were washed with brine (10 mL×2), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (120 g) eluted with ethyl acetate, then ethyl acetate/methanol (10:1) to give the title compound (485 mg, 0.989 mmol, 77% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.77 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz, 2H), 7.37 (t, J=8 Hz, 2H), 7.32 (m, 2H), 7.29 (d, J=2 Hz, 1H), 7.23 (dd, J=8.2 Hz, 1H), 5.22 (s, 2H), 4.75 (t, J=6 Hz, 1H), 4.12 (s, 2H), 4.11 (d, J=6 Hz, 2H), 3.38 (s, 6H); MS (ESI − ) m/z 489 (M−H) − .

Example 46B: {[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}acetaldehyde

A mixture of Example 46A (123 mg, 0.251 mmol) in hydrogen chloride (0.125 mL, 0.50 mmol, 4 N in dioxane) and water (0.05 mL) was stirred at ambient temperature for 15 minutes. The mixture was diluted with ethyl acetate (70 mL). The organic phase was washed with water (15 mL×3) and brine (15 mL), dried over sodium sulfate, filtered and concentrated to give the title compound (112 mg, 0.252 mmol, 100% yield). MS (ESI − ) m/z 443 (M−H) − .

Example 46C: 5-[3-(benzyloxy)-1-fluoro-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 46B (111 mg, 0.250 mmol), triethylamine (126 mg, 1.249 mmol), propan-2-amine (44.3 mg, 0.749 mmol) and sodium triacetoxyborohydride (212 mg, 0.999 mmol) in acetonitrile/methanol (4:1, 3 mL) was stirred at ambient temperature for 18 hours. Then methanol/water (1:2, 2 mL) was added. The solution was filtered, and the filtrate was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-55% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (68 mg, 0.139 mmol, 55.8% yield). MS (ESI − ) m/z 486 (M−H) − .

Example 46D: 5-(1-fluoro-3-hydroxy-7-{2-[(propan-2-yl)amino]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of 1,2,3,4,5-pentamethylbenzene (64.8 mg, 0.437 mmol) and Example 46C (63 mg, 0.125 mmol) in dichloromethane (3 mL) at −78° C. was added trichloroborane (1.498 mL, 1.498 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 10 minutes, then −20° C. for 30 minutes. The mixture was quenched with ethanol (3 mL) and concentrated. The residue was washed with heptane (4×4 mL) and dichloromethane (4×3 mL) and concentrated to give the title compound (48 mg, 0.121 mmol, 97% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.61 (s, 1H), 9.00 (br s, 2H), 7.72 (d, J=8, Hz, 1H), 7.25 (d, J=2, Hz, 1H), 7.21 (dd, J=8, 2 Hz, 1H), 7.07 (s, 1H), 4.39 (t, J=5 Hz, 2H), 4.09 (s, 2H), 3.37 (m, 1H), 2.52 (m, 2H), 1.29 (d, J=7 Hz, 6H); MS (ESI − ) m/z 396 (M−H) − .

Example 47: 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 146)

To a mixture of prop-2-en-1-ol (2.487 mL, 36.6 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN, 0.150 g, 0.914 mmol) was added diethyl-λ 5 -phosphanone (2 g, 18.28 mmol) dropwise with stirring over 40 minutes at 100° C. under nitrogen. The mixture was stirred for 3 hours at 100° C. Thin-layer chromatography (I 2 , ethyl acetate:methanol=5:1, R f =0.3) showed the starting material was consumed. Then the mixture was purified by column chromatography on silica gel eluted with petroleum ether/ethyl acetate (0-100%) and methanol/ethyl acetate (0-10%) to give the title compound (1.9 g, 53.8% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.72 (t, J=5.29 Hz, 2H), 1.67-1.99 (m, 8H), 1.10-1.24 (m, 6H).

To a solution of the compound of Example 47A (2.9 g, 15.01 mmol) in dichloromethane (100 mL) was added triethylamine (4.19 mL, 30.0 mmol) and then methanesulfonyl chloride (1.404 mL, 18.02 mmol) was added dropwise at 0° C. under nitrogen. Then the mixture was stirred for 1 hour at 0° C. Thin-layer chromatography (I 2 , ethyl acetate/methanol=3:1, R f =0.25) showed the starting material was consumed. Then the mixture was quenched with water (250 mL), and the resulting mixture was extracted with dichloromethane (3×150 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (1.8 g, 42.1% yield) which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.30-4.36 (m, 2H), 3.04 (s, 3H), 2.04-2.15 (m, 2H), 1.68-1.84 (m, 7H), 1.12-1.24 (m, 7H).

Example 47C: 5-{3-(benzyloxy)-7-[3-(diethylphosphoryl)propoxy]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1H (515 mg, 2.125 mmol) in N,N-dimethylformamide (4 mL) was added cesium carbonate (Cs 2 CO 3 , 462 mg, 1.417 mmol) and the compound of Example 47B (515 mg, 2.125 mmol) in order at 20° C. Then the mixture was stirred for 4 hours at 80° C. The mixture was quenched with water (50 mL), and the mixture was acidified by adding aqueous 1 M hydrochloric acid dropwise to pH=3. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (3×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (350 mg, 77% yield) which was used in the next step without further purification. MS (ESI − ) m/z 547 (M−H) − .

Example 47D: 5-{7-[3-(diethylphosphoryl)propoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

To a solution of the compound of Example 47C (350 mg, 0.542 mmol) in N,N-dimethylformamide (1 mL) and tetrahydrofuran (30 mL) was added 10% Pd/C (500 mg, 2.349 mmol) at 20° C. under argon. Then the mixture was stirred for 2 hours at 20° C. under a hydrogen balloon (15 psi). The mixture was filtered, and the filtrate was concentrated to remove most of tetrahydrofuran under reduced pressure. The resulting solution was purified by preparative HPLC [Shimadzu LC-8A, Waters Xbridge™ BEH C18 100×25 mm, 5 μm column, flow rate 30 mL/minute, 2-30% gradient of acetonitrile in buffer (10 mM aqueous ammonium bicarbonate, wavelength: 220&254 nm)] and lyophilization to give the title compound as an ammonium salt (53 mg, 20.00% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.21-9.64 (m, 1H), 7.66 (d, J=8.88 Hz, 1H), 7.00-7.20 (m, 6H), 4.12 (t, J=6.25 Hz, 2H), 4.08 (s, 2H), 1.89-2.00 (m, 2H), 1.74-1.84 (m, 2H), 1.65 (dq, J=11.88, 7.67 Hz, 4H), 0.98-1.07 (m, 6H); 1 H NMR (400 MHz, DMSO-d 6 /D 2 O) δ ppm 7.67 (d, J=8.88 Hz, 1H), 7.11-7.20 (m, 2H), 4.13 (t, J=6.25 Hz, 2H), 4.09 (s, 2H), 1.88-1.99 (m, 2H), 1.75-1.85 (m, 2H), 1.66 (dq, J=11.90, 7.71 Hz, 4H), 0.98-1.09 (m, 6H); MS (ESI − ) m/z 547 (M−H) − .

Example 48: 5-{1-fluoro-3-hydroxy-7-[(3S)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 147)

The title compound was prepared using the methodologies described in Example 50 substituting (S)-butane-1,3-diol for (R)-butane-1,3-diol. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.36 (br s, 1H), 7.66 (dd, J=8, 2 Hz, 1H), 7.24 (br s, 3H), 7.17 (d, J=2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.02 (s, 1H), 4.59 (d, J=5 Hz, 1H), 4.13 (m, 2H), 4.09 (s, 2H), 3.85 (m, 1H), 1.81 (m, 2H), 1.14 (d, J=7 Hz, 3H); MS (ESI − ) m/z 383 (M−H) − .

Example 49: 5-{1,4-difluoro-3-hydroxy-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 148)

To a solution of the product of Example 1G (1.000 g, 2.149 mmol) in dimethylformamide (20 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.523 g, 4.30 mmol) followed by heating the resulting solution to 60° C. After 3 hours, another portion of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (0.381 g, 1.075 mmol) was added with continued heating. After 2.5 hours, the reaction mixture was cooled to room temperature, quenched with 1 M aqueous sodium thiosulfate (50 mL), and acidified to pH<4 with concentrated hydrochloric acid. The crude aqueous layer was extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed sequentially with saturated aqueous ammonium chloride (2×50 mL), and then a 6:1 mixture of brine and 2 M hydrochloric acid (30 mL). The organic fraction was dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione which was used for the next reaction without purification. MS (APCI − ) m/z 483 [M−H] − .

In a 20 mL pressure release vial, the crude 5-[3-(benzyloxy)-7-bromo-1,4-difluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (0.5012 g, 1.037 mmol), cesium carbonate (1.014 g, 3.11 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-1-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3 precatalyst, 0.028 g, 0.031 mmol), and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos, 0.017 g, 0.031 mmol) were combined. The solids were placed under vacuum for 5 minutes at ambient temperature, then the vial was filled with nitrogen, followed by tert-amyl alcohol (10 mL) and isoamylamine (0.241 mL, 2.074 mmol). The resulting suspension was degassed by five vacuum/nitrogen backfills, stirred for 10 minutes at ambient temperature and then heated to 100° C. After 33 hours, the reaction mixture was cooled to ambient temperature, then quenched with 1 M hydrochloric acid (5 mL) and diluted with ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (2.5 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-1,4-difluoro-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, which was used for the next reaction without purification. MS (APCI + ) m/z 490 [M+H] + .

To a suspension of the crude 5-{3-(benzyloxy)-1,4-difluoro-7-[(3-methylbutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (0.508 g, 1.038 mmol) and pentamethylbenzene (0.308 g, 2.075 mmol) in dichloromethane (10 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (7.8 mL, 1 M, 7.8 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 0° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (5 mL) followed by anhydrous ethanol (5 mL). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The crude solid was triturated with heptanes (3×5 mL), then acetonitrile (3×5 mL) and methanol (3×5 mL) to give the title compound (0.0056 g, 0.014 mmol, 1.4% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.12 (s, 1H), 7.68 (dd, J=9.0, 1.6 Hz, 1H), 7.18 (dd, J=9.2, 2.2 Hz, 1H), 6.75 (s, 1H), 4.49 (s, 2H), 3.12 (t, J=7.3 Hz, 2H), 1.80-1.65 (m, 1H), 1.51 (q, J=7.1 Hz, 2H), 0.93 (d, J=6.6 Hz, 6H); MS (APC + ) m/z 400 [M+H] + .

Example 50: 5-{1-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 149)

To a mixture of (R)-butane-1,3-diol (160 mg, 1.78 mmol) and triethylamine (270 mg, 2.67 mmol) in dichloromethane (3 mL) at 0° C. was added methanesulfonyl chloride (214 mg, 1.869 mmol) in dichloromethane (1 mL). The mixture was stirred at 0° C. for 1 hour and then at ambient temperature for 1 hour. The mixture was diluted with dichloromethane (40 mL), washed with 0.1 N HCl aqueous solution (10 mL) and water (10 mL). The organic phase was dried over sodium sulfate, filtered and concentrated to give the title compound (275 mg, 1.635 mmol, 92% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.63 (d, J=6 Hz, 1H), 4.27 (m, 2H), 3.72 (m, 1H), 3.15 (s, 3H), 1.71 (m, 2H), 1.05 (d, J=7 Hz, 3H).

Example 50B: 5-{3-(benzyloxy)-1-fluoro-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 1H (130 mg, 0.323 mmol), Example 50A (272 mg, 1.615 mmol) and cesium carbonate (421 mg, 1.292 mmol) in N,N-dimethylformamide (1 mL) was stirred at 65° C. for 0.5 hour. The mixture was quenched with 0.2 N HCl aqueous (15 mL) and extracted with ethyl acetate (80 mL). The organic phase was washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-60% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (80 mg, 0.169 mmol, 52.2% yield). MS (ESI − ) m/z 473 (M−H) − .

Example 50C: 5-{-fluoro-3-hydroxy-7-[(3R)-3-hydroxybutoxy]naphthalen-2-yl}-λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of 1,2,3,4,5-pentamethylbenzene (58.8 mg, 0.397 mmol) and Example 50B (65 mg, 0.132 mmol) in dichloromethane (4 mL) at −78° C. was added trichloroborane (1.322 mL, 1.322 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 20 minutes and then at −20° C. for 20 minutes. The mixture was quenched with ethanol (3 mL) and concentrated. The residue was washed with heptane (4×4 mL) and concentrated to give the crude product. The crude material was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-50% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (36 mg, 0.09 mmol, 67.8% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.66 (dd, J=8.2 Hz, 1H), 7.24 (br s, 4H), 7.17 (d, J=2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.02 (s, 1H), 4.59 (d, J=5 Hz, 1H), 4.13 (m, 2H), 4.09 (s, 2H), 3.85 (m, 1H), 1.81 (m, 2H), 1.14 (d, J=7 Hz, 3H); MS (ESI − ) m/z 383 (M−H) − .

Example 51: 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 150)

Example 51A: 5-[3-(benzyloxy)-7-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylethoxy)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A solution of 2-bromo-1-cyclopropylethanol (250 mg, 1.515 mmol) in dichloromethane (2 mL) was added to a stirred solution of tert-butyldimethylchlorosilane (240 mg, 1.591 mmol) and imidazole (113 mg, 1.666 mmol) in dichloromethane (2 mL). The mixture was stirred at ambient temperature for 3 hours. Water (5 mL) was added and the mixture was extracted with dichloromethane (3×5 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The (2-bromo-1-cyclopropylethoxy)(tert-butyl)dimethylsilane was subjected to the next step without purification.

To a solution of Example 1H (120 mg, 0.298 mmol) in N,N-dimethylformamide (2 mL), was added cesium carbonate (214 mg, 0.656 mmol) and crude (2-bromo-1-cyclopropylethoxy)(tert-butyl)dimethylsilane (167 mg, 0.596 mmol). The mixture was heated to 80° C. overnight. After cooling, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (64 mg, 0.107 mmol, 36% yield). MS (APCI − ) m/z 599 [M−H] − .

Example 51B: 5-[7-(2-cyclopropyl-2-hydroxyethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (4.34 mg, 0.041 mmol) and tetrahydrofuran (8 mL). A solution of Example 51A (100 mg, 0.166 mmol) in tetrahydrofuran (2 mL) was then added. An adapter fitted with a hydrogen balloon was inserted and the flask was evacuated and refilled with hydrogen (3 times). The reaction was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure, and the crude 5-[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione was subjected to the next step without purification. MS (APCI − ) m/z 509 [M−H] − .

To a solution of crude 5-[7-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylethoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (100 mg, 0.196 mmol) in 1,4-dioxane (3 mL) was added 4 M HCl in dioxane (4 mL), and the reaction mixture was stirred at ambient temperature for 6 hours. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.37 (s, 1H), 7.76-7.68 (m, 1H), 7.24-7.17 (m, 2H), 7.07 (d, J=1.3 Hz, 1H), 4.52 (s, 2H), 4.09 (dd, J=9.9, 4.1 Hz, 1H), 4.02 (dd, J=9.9, 6.7 Hz, 1H), 3.34 (td, J=6.8, 4.0 Hz, 1H), 1.04-0.91 (m, 1H), 0.50-0.36 (m, 2H), 0.39-0.24 (m, 2H); MS (APCI − ) m/z 395 [M−H] − .

Example 52: 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 151)

The title compound was prepared using the methodologies described in Example 55 substituting (R)-pent-4-en-2-ol for 2-methylpent-4-en-2-ol. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.52 (br s, 1H), 7.66 (d, J=8 Hz, 1H), 7.63 (s, 1H), 7.33 (dd, J=8, 2 Hz, 1H), 7.10 (m, 4H), 7.03 (s, J=2 Hz, 1H), 4.35 (d, J=5 Hz, 1H), 4.09 (s, 2H), 3.61 (m, 1H), 2.70 (m, 2H), 1.65 (m, 2H), 1.34 (m, 2H), 1.04 (d, J=7 Hz, 3H); MS (ESI − ) m/z 381 (M−H) − .

Example 53: 5-{1-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 152)

A mixture of prop-2-en-1-ol (6.97 mL, 102 mmol) and 2,2′-azobis(2-methylpropionitrile) (AIBN, 0.421 g, 2.56 mmol) was added to dimethyl-λ 5 -phosphanone (4 g, 51.2 mmol) dropwise with stirring over 30 minutes at 100° C. under nitrogen. The mixture was stirred for 5 hours at 100° C. Thin-layer chromatography (I 2 , ethyl acetate:methanol=5:1, R f =0.25) showed starting material was consumed. Then the mixture was purified by column chromatography on silica gel eluted first with petroleum ether/ethyl acetate (0-100%) and then with methanol/ethyl acetate (0-10%) to give the title compound (4 g, 48.7% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.72 (t, J=5.38 Hz, 2H), 1.80-1.98 (m, 4H), 1.53 (d, J=12.63 Hz, 6H).

To a solution of the compound of Example 53A (1.5 g, 11.02 mmol) in dichloromethane (15 mL) were added triethylamine (3.07 mL, 22.04 mmol) and then methanesulfonyl chloride (1.030 mL, 13.22 mmol) dropwise at 0° C. under nitrogen. Then the mixture was stirred for 1 hour at 0° C. Thin-layer chromatography (I 2 , ethyl acetate:methanol=5:1, R f =0.3) showed starting material was consumed. The mixture was quenched with water (50 mL) and then extracted with dichloromethane (3×25 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (500 mg, 16.95% yield) which was used for the next step without further purification. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.31-4.39 (m, 2H), 3.10-3.23 (m, 2H), 2.98-3.08 (m, 3H), 2.05-2.19 (m, 2H), 1.80-1.94 (m, 3H), 1.47-1.61 (m, 6H), 1.39 (t, J=7.34 Hz, 3H).

Example 53C: 5-{3-(benzyloxy)-7-[3-(dimethylphosphoryl)propoxy]-1-fluoronaphthalen-2-yl}-1λ 6 , 2,5-thiadiazolidine-1,1,3-trione

Step 3: To a solution of Example 1H (300 mg, 0.671 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (Cs 2 CO 3 , 437 mg, 1.342 mmol) and the compound of Example 53B (500 mg, 1.867 mmol) in order at 20° C. Then the mixture was stirred for 4 hours at 80° C. The mixture was quenched with water (50 mL) and adjusted to pH=3 with aqueous hydrochloric acid (1 M). The mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (4×30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (250 mg, 42.9% yield), which was used for the next step without further purification. MS (ESI − ) m/z 519 (M−H) − .

Example 53D: 5-{-fluoro-3-hydroxy-7-[(4R)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

To a mixture of the compound of Example 53C (100 mg, 0.115 mmol) in N,N-dimethylformamide (2 mL) and tetrahydrofuran (30 mL) was added 10% Pd/C (30 mg, 0.141 mmol) at 20° C. under argon. Then the mixture was stirred for 2 hours at 20° C. under a hydrogen balloon (about 15 psi). Then the mixture was filtered. The resulting filtrate was concentrated to remove most of tetrahydrofuran under reduced pressure (<18° C.) to give crude product with remaining N,N-dimethylformamide. One additional vial on 30 mg scale and one additional vial on 50 mg scale were set up as described above. These three crude reaction mixtures were combined and purified by preparative HPLC [Shimadzu LC-8A, Waters Xbridge™ BEH C18 100×25 mm, 5 μm column, flow rate 30 mL/minute, 2 -2 3 % gradient of acetonitrile in buffer (10 mM aqueous ammonium bicarbonate, wavelength: 220&254 nm)], and lyophilized to give the title compound as an ammonium salt (52 mg, 54.1% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.08-9.77 (m, 1H), 7.67 (d, J=9.01 Hz, 1H), 7.00-7.20 (m, 6H), 4.13 (t, J=6.13 Hz, 2H), 4.08 (s, 2H), 1.93-2.03 (m, 2H), 1.77-1.88 (m, 2H), 1.40 (d, J=12.88 Hz, 6H); 1 H NMR (400 MHz, DMSO-d 6 /D 2 O) δ ppm 7.67 (d, J=9.01 Hz, 1H), 7.11-7.20 (m, 2H), 7.03 (s, 1H), 4.13 (t, J=6.25 Hz, 2H), 4.09 (s, 2H), 1.93-2.04 (m, 2H), 1.77-1.89 (m, 2H), 1.40 (d, J=12.88 Hz, 6H); MS (ESI − ) m/z 429 (M−H) − .

Example 54: 5-{1-fluoro-3-hydroxy-7-[(4S)-4-hydroxypentyl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 153)

The title compound was prepared using the methodologies described in Example 55 substituting (S)-pent-4-en-2-ol for 2-methylpent-4-en-2-ol. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.52 (br s, 1H), 7.66 (d, J=8 Hz, 1H), 7.63 (s, 1H), 7.33 (dd, J=8, 2 Hz, 1H), 7.10 (m, 4H), 7.03 (s, J=2 Hz, 1H), 4.35 (d, J=5 Hz, 1H), 4.09 (s, 2H), 3.61 (m, 1H), 2.70 (m, 2H), 1.65 (m, 2H), 1.34 (m, 2H), 1.04 (d, J=7 Hz, 3H); MS (ESI − ) m/z 381 (M−H) − .

Example 55: 5-[1-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 154)

Example 55A: 5-{3-(benzyloxy)-1-fluoro-7-[(1E)-4-hydroxy-4-methylpent-1-en-1-yl]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 1G (0.120 g, 0.258 mmol), 2-(di-tert-butylphosphino)biphenyl (0.018 g, 0.059 mmol), palladium(II) acetate (0.013 g, 0.059 mmol), 2-methylpent-4-en-2-ol (0.077 g, 0.774 mmol) and triethylamine (0.057 g, 0.567 mmol) in N,N-dimethylformamide (0.8 mL) was placed in a nitrogen atmosphere and then heated to 120° C. for 1 hour. The mixture was cooled to ambient temperature, dissolved in methanol (5 mL), filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-70% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (110 mg, 0.227 mmol, 88% yield). MS (ESI − ) m/z 483 (M−H) − .

Example 55B: 5-[1-fluoro-3-hydroxy-7-(4-hydroxy-4-methylpentyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To Example 55A (100 mg, 0.206 mmol) in tetrahydrofuran (4 mL) was added 5 weight % palladium on carbon (100 mg, 0.438 mmol) in a 20 mL Barnstead Hast C reactor. The mixture was stirred under 50 psi of hydrogen at 25° C. for 0.35 hour. Tetrahydrofuran (15 mL) was added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-70% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (73 mg, 0.177 mmol, 86% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.67 (s, 1H), 7.64 (d, J=8 Hz, 1H), 7.54 (br s, 4H), 7.34 (dd, J=8, 2 Hz, 1H), 7.03 (d, J=2 Hz, 1H),), 4.09 (s, 2H), 4.08 (s, 1H), 2.70 (t, J=7 Hz, 2H), 1.68 (m, 2H), 1.38 (m, 2H), 1.05 (s, 6H); MS (ESI − ) m/z 395 (M−H) − .

Example 56: 5-{1-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 155)

To a solution of 1-(2-hydroxyethyl)cyclopropanol (130 mg, 1.273 mmol) in dichloromethane (5 mL) at 0° C. under an atmosphere of nitrogen was added triethylamine (0.355 mL, 2.55 mmol) followed by p-toluenesulfonyl chloride (340 mg, 1.782 mmol). The mixture was stirred at ambient temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with 1 M HCl (10 mL), saturated aqueous NaHCO 3 (10 mL) and brine (15 mL). The combined organic fractions were dried (Na 2 SO 4 ), filtered and concentrated. The residue was purified by flash chromatography [12 g SiO 2 , gradient of ethyl acetate in heptanes from 5% to 50% over 15 minutes] to afford the title compound (150 mg, 0.585 mmol, 46.0% yield). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.85-7.77 (m, 2H), 7.39-7.32 (m, 2H), 4.31 (t, J=6.3 Hz, 2H), 2.46 (s, 3H), 1.91 (t, J=6.3 Hz, 2H), 0.85-0.74 (m, 2H), 0.53-0.45 (m, 2H).

Example 56B: 5-{t-fluoro-3-hydroxy-7-[(3-oxopentyl)oxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the compound of Example 1H (180 mg, 0.447 mmol), 2-(1-hydroxycyclopropyl)ethyl 4-methylbenzene-1-sulfonate (138 mg, 0.537 mmol) and Cs 2 CO 3 (518 mg, 1.590 mmol) in N,N-dimethylformamide (5 mL) was stirred at 50° C. for 16 hours. The reaction mixture was treated with 1 mL of 2 M Na 2 CO 3 and then extracted with ethyl acetate. The organic layer was discarded, and the aqueous layer was acidified with 2 N HCl to pH=1-2. The acidic aqueous fraction was extracted with ethyl acetate. The organic fraction was washed with water and brine, dried over Na 2 SO 4 , and concentrated. The residue was purified by chromatography on silica gel eluting with 1-10% methanol in dichloromethane to give 5-{3-(benzyloxy)-1-fluoro-7-[2-(1-hydroxycyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (290 mg, 0.596 mmol, 75.0% yield). MS (APCI + ) m/z 487.7 (M+H) + .

5-{3-(Benzyloxy)-1-fluoro-7-[2-(1-hydroxycyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (200 mg, 0.411 mmol) in tetrahydrofuran (2.0 mL) was added to 5% Pd/C (wet) (60.3 mg, 0.206 mmol) in a 20 mL RS10 reactor with a glass liner. The mixture was stirred under 50 psi of H 2 at 25° C. for 20 hours. The reaction mixture was then filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC on a Phenomenex® C8(2) Luna® 5 μm AXIA™ 150×30 mm column eluted with a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/minute (0-0.5 minute, 5% A, 0.5-8.5 minutes linear gradient 05-100% A, 8.7-10.7 minutes, 100% A, 10.7-11 min linear gradient 100-05% A) to give the title compound (26 mg, 0.066 mmol, 15.96% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.66 (dd, J=9.1, 1.6 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 7.09 (dd, J=9.0, 2.5 Hz, 1H), 7.03 (d, J=1.4 Hz, 1H), 4.29 (t, J=6.1 Hz, 2H), 4.10 (s, 2H), 2.94 (t, J=6.0 Hz, 2H), 2.58-2.50 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ESI + ) m/z 414.2 (M+18)+.

Example 57: 5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 156)

Example 57A: 5-[3-(benzyloxy)-1-fluoro-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 104A substituting 4-bromobutan-2-ol for 2-bromoacetonitrile. MS (ESI − ) m/z 473 (M−H) − .

Example 57B: 5-[1-fluoro-3-hydroxy-7-(3-hydroxybutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of 1,2,3,4,5-pentamethylbenzene (98 mg, 0.664 mmol) and Example 57A (105 mg, 0.221 mmol) in dichloromethane (4 mL) at −78° C. was added trichloroborane (1.77 mL, 1.770 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 1.5 hours. The mixture was quenched with ethanol (3 mL) and concentrated. The residue was washed with heptane (4×4 mL) and concentrated to give the crude product. The crude product was purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-50% gradient of methanol in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (45 mg, 0.112 mmol, 50.7% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.66 (dd, J=8, 2 Hz, 1H), 7.24 (br s, 4H), 7.17 (d, J=2 Hz, 1H), 7.12 (dd, J=8, 2 Hz, 1H), 7.02 (s, 1H), 4.59 (d, J=5 Hz, 1H), 4.13 (m, 2H), 4.09 (s, 2H), 3.85 (m, 1H), 1.81 (m, 2H), 1.14 (d, J=7 Hz, 3H); MS (ESI − ) m/z 383 (M−H) − .

Example 58: N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide (Compound 157)

Example 58A: N-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide

A mixture of Example 1G (0.2 g, 0.430 mmol), 3-methylbutanamide (0.078 g, 0.774 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.037 g, 0.064 mmol, Xantphos), cesium carbonate (0.280 g, 0.860 mmol) and palladium(II) acetate (9.65 mg, 0.043 mmol) in dioxane (3 mL) was degassed and filled with nitrogen five times, and then heated to 100° C. for 18 hours. The mixture was cooled to ambient temperature and quenched with 0.2 N HCl aqueous solution (10 mL). The mixture was extracted with ethyl acetate (50 mL×2). The combined organic fractions were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (40 g) eluted with dichloromethane/methanol (0 to 15%) to give the title compound (130 mg, 0.268 mmol, 62.3% yield). MS (ESI − ) m/z 484 (M−H) − .

Example 58B: N-[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]-3-methylbutanamide

To a mixture of 1,2,3,4,5-pentamethylbenzene (78 mg, 0.525 mmol) and Example 58A (85 mg, 0.175 mmol) in dichloromethane (4 mL) at −78° C. was added trichloroborane (1.05 mL, 1.050 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 5 minutes and then warmed to 0° C. for 15 minutes. The mixture was quenched with ethanol (3 mL) and concentrated. The residue was washed with heptane (4×4 mL) and concentrated to give the crude product. The crude product was dissolved in methanol (4 mL), and purified by preparative HPLC [YMC TriArt™ C18 Hybrid 5 μm column, 50×100 mm, flow rate 140 mL/minute, 5-65% gradient of methanol in water (0.1% trifluoroacetic acid)] to give the title compound (40 mg, 0.101 mmol, 57.8% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.40 (br s, 1H), 10.08 (s, 1H), 8.32 (d, J=2 Hz, 1H), 7.72 (br d, J=8 Hz, 1H), 7.62 (dd, J=8, 2 Hz, 1H), 7.05 (s, 1H), 4.47 (s, 2H), 2.23 (d, J=7 Hz, 2H), 2.11 (m, 1H), 0.96 (d, J=7 Hz, 6H); MS (ESI − ) m/z 394 (M−H) − .

Example 59: 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 158)

Example 59A: 5-[3-(benzyloxy)-1-fluoro-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 104A substituting 1,1,1-trifluoro-4-iodobutane for 2-bromoacetonitrile. MS (ESI − ) m/z 511 (M−H) − .

Example 59B: 5-[1-fluoro-3-hydroxy-7-(4,4,4-trifluorobutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 137B substituting Example 59A for Example 137A. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.31 (br s, 1H), 7.73 (br d, J=8 Hz, 1H), 7.22 (s, 1H), 7.20 (dd, J=8, 2 Hz, 1H), 7.07 (s, 1H), 4.48 (s, 2H), 4.15 (t, J=8 Hz, 2H), 2.44 (m, 2H), 2.00 (m, 2H); MS (ESI − ) m/z 421 (M−H) − .

Example 60: 1-(2-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}ethyl)cyclopropane-1-carbonitrile (Compound 159)

The title compound was prepared from Example 1H and 1-(2-hydroxyethyl)cyclopropanecarbonitrile using the procedures described for Example 56 in 38% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.23 (s, 1H), 7.73 (dd, J=9.1, 1.5 Hz, 1H), 7.26 (d, J=2.5 Hz, 1H), 7.19 (dd, J=9.0, 2.5 Hz, 1H), 7.07 (s, 1H), 4.44 (s, 2H), 4.25 (t, J=6.1 Hz, 2H), 1.99 (t, J=6.1 Hz, 2H), 1.27-1.19 (m, 2H), 1.07-0.99 (m, 2H); MS (APCI − ) m/z 404.5 (M−H) − .

Example 61: 5-(1-fluoro-3-hydroxy-7-{2-[1-(methoxymethyl)cyclopropyl]ethoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 160)

The title compound was prepared from Example 1H and 2-(1-(methoxymethyl)cyclopropyl)ethanol using the procedures for Example 56 in 24% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.33 (s, 1H), 7.71 (dd, J=9.1, 1.5 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.16 (dd, J=9.0, 2.5 Hz, 1H), 7.07 (d, J=1.4 Hz, 1H), 4.50 (s, 2H), 4.17 (t, J=7.1 Hz, 2H), 3.26 (s, 3H), 3.23 (s, 2H), 1.82 (t, J=7.0 Hz, 2H), 0.49-0.43 (m, 2H), 0.43-0.37 (m, 2H); MS (APCI − ) m/z 423.5 (M−H) − .

Example 62: 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 161)

Example 62A: 5-[3-(benzyloxy)-7-ethenyl-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of Example 1G (2 g, 4.17 mmol), vinylboronic acid pinacol ester (3.21 g, 20.85 mmol) and potassium carbonate (1.152 g, 8.34 mmol) in dioxane (200 mL) and water (20 mL) was added 1,1-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.681 g, 0.834 mmol) at 20° C. under nitrogen. Then the mixture was stirred at 80° C. for 18 hours under nitrogen. The reaction mixture was acidified with aqueous 2 M HCl to pH=5 and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (2×60 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column (SiO 2 , ethyl acetate:methanol=10:1) to give the title compound (1.63 g, 3.7 mmol, 89% yield). MS (ESI − ) m/z 411 [M−H] − .

Example 62B: 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carbaldehyde

To solution of Example 62A (240 mg, 0.435 mmol) in tetrahydrofuran (5 mL) and water (5.00 mL) was added sodium periodate (186 mg, 0.869 mmol) at 0° C., and then a solution of osmium tetroxide (0.275 mL, 0.022 mmol, 0.079 mol/L in tert-butyl alcohol) was added into the mixture. Then the mixture was stirred at 0° C. for 3 hours. The reaction was quenched by addition of saturated aqueous sodium thiosulfate solution (20 mL). The mixture was acidified with aqueous 2 M hydrochloric acid to pH=3, and then extracted by ethyl acetate (3×20 mL). The aqueous layer was washed with ethyl acetate (2×20 mL). The combined organic layers were purified via reverse phase column [Agela 100 Å SNAP C 18 flash column, 330 g, 20×35 μm, flow rate 100 mL/minute, 0-100% gradient of acetonitrile in water] to give the desired aldehyde (380 mg, 0.889 mmol, 28% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.12-10.16 (m, 1H), 8.60 (s, 1H), 7.88-8.00 (m, 2H), 7.58 (br d, J=7.28 Hz, 2H), 7.50 (s, 1H), 7.29-7.41 (m, 3H), 5.33 (s, 2H), 4.10 (s, 2H); MS (ESI − ) m/z 413 [M−H] − .

Example 62C: 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 20 mL microwave vial was charged with Example 62B (100 mg, 0.241 mmol), cyclopropylmethanamine (51.5 mg, 0.724 mmol), N,N-dimethylformamide (3 mL) and acetic acid (0.069 mL, 1.207 mmol). The mixture stirred for 15 minutes at ambient temperature followed by addition of sodium cyanoborohydride (91 mg, 1.448 mmol). The reaction mixture was stirred overnight at ambient temperature and a precipitate was formed. The mixture was filtered, and the collected solid was washed with water to give 5-[3-(benzyloxy)-7-{[(cyclopropylmethyl)amino]methyl}-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, which was used in the next step without purification. MS (APCI − ) m/z 468 [M−H] −

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (80 mg, 0.752 mmol) and tetrahydrofuran (10 mL). A solution of crude 5-[3-(benzyloxy)-7-{[(cyclopropylmethyl)amino]methyl}-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (80 mg, 0.170 mmol) in tetrahydrofuran (2 mL), was then added. An adapter fitted with a hydrogen balloon was inserted, and the flask was evacuated and refilled with hydrogen (3 times). The reaction was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed from the filtrate under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (20 mg, 0.053 mmol, 31% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.05 (d, J=1.7 Hz, 1H), 7.81 (dd, J=8.6, 1.5 Hz, 1H), 7.53 (dd, J=8.6, 1.7 Hz, 1H), 7.11 (d, J=1.3 Hz, 1H), 4.29 (s, 2H), 4.10 (s, 2H), 2.85 (d, J=7.4 Hz, 2H), 1.06 (tt, J=7.8, 4.8 Hz, 1H), 0.63-0.53 (m, 2H), 0.35 (dt, J=6.3, 4.4 Hz, 2H); MS (APCI + ) m/z 380 [M+H] + .

Example 63: 5-(7-{[(cyclopropylmethyl)amino]methyl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 162)

The title compound was prepared using the methodologies described in Example 78 substituting 2,2-difluoropropan-1-amine for 2-(azetidin-1-yl)ethanamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.93 (br s, 1H), 7.52 (br d, J=8 Hz, 1H), 7.11 (dd, J=8, 2 Hz, 1H), 6.93 (s, 1H), 6.85 (d, J=2 Hz, 1H), 4.44 (s, 2H), 3.59 (m, 2H), 1.67 (t, J=19 Hz, 3H); MS (ESI − ) m/z 388 (M−H) − .

Example 64: 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 163)

A mixture of 3,3-dimethyl-4-(methylamino)butan-1-ol hydrochloride (100 mg, 0.596 mmol) and di-tert-butyl dicarbonate (137 mg, 0.626 mmol) in ethyl acetate (1 mL) was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over Na 2 SO 4 , and concentrated. The title compound was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 4.27 (s, 1H), 3.51-3.41 (m, 2H), 3.03 (s, 2H), 2.83 (s, 3H), 1.39 (s, 9H), 1.43-1.33 (m, 2H), 0.85 (s, 6H).

To the solution of tert-butyl (4-hydroxy-2,2-dimethylbutyl)(methyl)carbamate (134 mg, 0.579 mmol) in methylene chloride (5 mL) at 0° C. was added methanesulfonyl chloride (133 mg, 1.159 mmol) and pyridine (0.094 mL, 1.159 mmol). The mixture was stirred for 15 minutes at 0° C. and 2 hours at ambient temperature. Water (5 mL) was then added, and the mixture was extracted with methylene chloride (3×5 mL). The organic layers were combined, washed with a saturated solution of copper(II) sulfate (5 mL) and dried with Na 2 SO 4 . The volatiles were removed under reduced pressure to afford the title compound, which was subjected to the next step without purification.

Example 64C: tert-butyl (4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutyl)methylcarbamate

To the product of Example 1H (150 mg, 0.373 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (267 mg, 0.820 mmol) and freshly prepared crude 4-((tert-butoxycarbonyl)(methyl)amino)-3,3-dimethylbutyl methanesulfonate (Example 64B, 115 mg, 0.373 mmol). The reaction mixture was stirred overnight at 60° C. and 3 hours at 80° C. After cooling to ambient temperature, methanol (1 mL) was added, and volatiles were removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (55 mg, 0.089 mmol, 24% yield over 3 steps). MS (APCI − ) m/z 614 [M−H] − .

Example 64D: 5-{7-[3,3-dimethyl-4-(methylamino)butoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (35 mg, 0.329 mmol) and tetrahydrofuran (10 mL). A solution of Example 64C (35 mg, 0.057 mmol) in tetrahydrofuran (2 mL), was then added. An adapter fitted with a hydrogen balloon was inserted, and the flask was evacuated and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure and the crude material was subjected to the next step without purification. MS (APCI − ) m/z 524 [M−H] − .

To a 50 mL-round bottom flask was added crude tert-butyl (4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutyl)methylcarbamate (30 mg, 0.057 mmol), methylene chloride (2 mL), and trifluoroacetic acid (2 mL) at ambient temperature. The reaction mixture was stirred for 30 minutes. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (15 mg, 0.035 mmol, 62% yield over two steps). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.43 (s, 1H), 8.06 (s, 2H), 7.61 (dd, J=9.0, 1.5 Hz, 1H), 7.17 (d, J=2.5 Hz, 1H), 7.06 (dd, J=9.0, 2.5 Hz, 1H), 6.97 (d, J=1.3 Hz, 1H), 4.09 (t, J=6.8 Hz, 2H), 4.05 (s, 2H), 2.88-2.80 (m, 2H), 2.55 (t, J=5.1 Hz, 3H), 1.76 (t, J=6.8 Hz, 2H), 0.99 (s, 6H); MS (APCI + ) m/z 426 [M+H] + .

Example 65: 5-{1-fluoro-3-hydroxy-7-[(2-phenylethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 164)

The title compound was prepared using the methodologies described in Example 80 substituting 2-phenylethanamine for 2-methoxyethanamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.74 (br s, 1H), 7.53 (br d, J=8 Hz, 1H), 7.31 (m, 4H), 7.21 (m, 1H), 7.05 (dd, J=8, 2 Hz, 1H), 6.92 (s, 1H), 6.72 (d, J=2 Hz, 1H), 4.37 (s, 2H), 3.34 (t, J=8 Hz, 2H), 2.92 (t, J=8 Hz, 2H); MS (ESI − ) m/z 414 (M−H) − .

Example 66: 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 165)

To the solution of tert-butyl (4-hydroxy-2-methylbutan-2-yl)carbamate (200 mg, 0.984 mmol) in methylene chloride (5 mL) at 0° C. was added methanesulfonyl chloride (135 mg, 1.181 mmol) and pyridine (0.159 mL, 1.968 mmol). The reaction was stirred for 15 minutes at 0° C. and 2 hours at ambient temperature. Water (5 mL) was then added, and the mixture was extracted with dichloromethane (3×5 mL). The organic layers were combined, washed with a saturated solution of CuSO 4 (2 mL), and dried with Na 2 SO 4 . The volatiles were removed under reduced pressure to afford crude 3-((tert-butoxycarbonyl)amino)-3-methylbutyl methanesulfonate, which was subjected to the next step without purification.

Example 66B: tert-butyl (4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2-methylbutan-2-yl)carbamate

To the product from Example 1H (150 mg, 0.373 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (267 mg, 0.820 mmol) and freshly prepared 3-((tert-butoxycarbonyl)amino)-3-methylbutyl methanesulfonate (210 mg, 0.746 mmol, Example 66A). The reaction mixture was stirred overnight at 60° C. and 3 hours at 80° C. After cooling to ambient temperature, methanol (1 mL) was added, volatiles were removed under reduced pressure, and the residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (14 mg, 0.024 mmol, 7% yield over two steps). MS (APCI − ) m/z 586 [M−H] − .

Example 66C: 5-[7-(3-amino-3-methylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (14 mg, 0.132 mmol) and tetrahydrofuran (10 mL). A solution of the product of Example 66B (35 mg, 0.057 mmol) in tetrahydrofuran (2 mL) was then added. An adapter fitted with a hydrogen balloon was inserted, and the flask was evacuated and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed from the filtrate under reduced pressure and the residue was subjected to the next step without purification. MS (APCI − ) m/z 496 [M−H] − .

To a 50 mL-round bottom flask was added crude tert-butyl (4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2-methylbutan-2-yl)carbamate (11.8 mg, 0.024 mmol) in methylene chloride (2 mL). The mixture was treated with trifluoroacetic acid (2 mL) at ambient temperature and stirred for 30 minutes at room temperature. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (6 mg, 0.015 mmol, 64% yield over two steps). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.48 (s, 1H), 7.83 (s, 2H), 7.69 (dd, J=9.2, 1.5 Hz, 1H), 7.25 (d, J=2.6 Hz, 1H), 7.15 (dd, J=9.0, 2.5 Hz, 1H), 7.04 (d, J=1.4 Hz, 1H), 4.23 (t, J=6.5 Hz, 2H), 4.10 (s, 2H), 2.12-2.04 (m, 2H), 1.34 (s, 6H); MS (APCI + ) m/z 398 [M+H] + .

Example 67: 5-{1-fluoro-3-hydroxy-7-[(4,4,4-trifluorobutyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 166)

The title compound was prepared using the methodologies described in Example 78 substituting 4,4,4-trifluorobutan-1-amine for 2-(azetidin-1-yl)ethanamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.72 (br s, 1H), 7.51 (br d, J=8 Hz, 1H), 7.01 (dd, J=8, 2 Hz, 1H), 6.93 (s, 1H), 6.67 (d, J=2 Hz, 1H), 4.37 (s, 2H), 3.18 (t, J=8 Hz, 2H), 2.40 (m, 2H), 1.82 (m, 2H); MS (ESI − ) m/z 420 (M−H) − .

Example 68: 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 167)

Example 68A: 5-[3-(benzyloxy)-7-(difluoromethyl)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the solution of 6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalene-2-carbaldehyde (70 mg, 0.167 mmol, Example 62B) in dichloromethane (12 mL) was added diethylaminosulfur trifluoride (0.662 mL, 5.01 mmol) at −70° C., then the mixture was stirred for 1 hour at 0° C. and 19 hours at 20° C. The reaction was quenched by addition of saturated ammonium bicarbonate solution (20 mL). Then the mixture was acidified with aqueous hydrochloric acid (1 N) to pH=2. An additional reaction on 0.01 g scale and one reaction on 0.07 g scale were set up and run as described above. The combined reaction mixtures were extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with water (2×30 mL) and brine (2×30 mL), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give crude title compound (140 mg, 0.128 mmol, 26.6% yield) which was used in the next step without further purification. MS (ESI − ) m/z 435 (M−H) − .

Example 68B: 5-[7-(difluoromethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of the compound of Example 68A (130 mg, 0.119 mmol) in dichloromethane (3 mL) was added boron trichloride (1.192 mL, 1.192 mmol) at −70° C., and the mixture was stirred for 15 minutes at −70° C. The reaction was quenched by the addition of methanol (5 mL). An additional reaction on 0.01 g scale was set up and run as described above. The mixtures were combined and concentrated under reduced pressure. Then the residue was purified by preparative HPLC [Nano-Micro UniSil 5-100 C18 ULTRA 5 μm, 100×250 μm, flow rate 25 mL/minute, 10-100% gradient of acetonitrile in water (10 mM ammonium bicarbonate aqueous)] to give the title compound (3.2 mg, 8.62 μmol, 5.53% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.10 (s, 1H), 7.87 (d, J=8.80 Hz, 1H), 7.62 (d, J=8.80 Hz, 1H), 7.27 (s, 1H), 7.15 (s, 1H), 7.13 (s, 1H), 6.99 (s, 1H), 4.21 (s, 2H); 19F NMR (377 MHz, DMSO-d 6 ) δ ppm −125.51-125.37 (m, 1 F) −108.36, −108.12 (m, 2 F); MS (ESI − ) m/z 345 (M−H) − .

Example 69: 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-1H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 168)

Example 69A: 5-[7-(2,5-dihydro-H-pyrrol-3-yl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 14A (200 mg, 0.343 mmol) in dichloromethane (5 mL) was added boron trichloride (3.43 mL, 3.43 mmol) dropwise at −70° C. The mixture was stirred for 2 hours at −70° C. under nitrogen. The reaction was quenched with methanol (4 mL) at −70° C., and the resulting mixture was concentrated under reduced pressure to give the title compound (130 mg, 0.304 mmol, 89% yield) which was used in the next step without further purification. MS (ESI − ) m/z 362 (M−H) − .

Example 69B: 5-{7-[1-(dimethylphosphoryl)-2,5-dihydro-H-pyrrol-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 69A (100 mg, 0.234 mmol) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (0.409 mL, 2.339 mmol) and dimethylphosphinic chloride (105 mg, 0.936 mmol) in order at 0° C. The reaction was stirred for 12 hours at 25° C. The reaction solution was purified by reversed phase chromatography [Agela Claricep™ Flash AQ C18 Column, 20-35 μm, 100 Å, 40 g, flow rate 50 mL/minute, 5-100% gradient of acetonitrile in water] and lyophilization to give crude title compound. The crude title compound was purified by preparative thin-layer chromatography on silica gel (ethyl acetate: methyl alcohol=2:1) to give the title compound (12 mg, 0.027 mmol, 8.98% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 7.63-7.66 (m, 1H), 7.47-7.57 (m, 2H), 6.86-6.89 (m, 1H), 6.24-6.28 (m, 1H), 4.39-4.46 (m, 2H), 4.31-4.36 (m, 2H), 4.14-4.20 (m, 2H), 1.50-1.59 (m, 1H); MS (ESI − ) m/z 438 (M−H) − .

Example 70: 5-{1-fluoro-3-hydroxy-7-[(3,3,3-trifluoropropyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 169)

The title compound was prepared using the methodologies described in Example 78 substituting 3,3,3-trifluoropropan-1-amine for 2-(azetidin-1-yl)ethanamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 9.81 (br s, 1H), 7.53 (br d, J=8 Hz, 1H), 7.01 (dd, J=8, 2 Hz, 1H), 6.95 (s, 1H), 6.68 (d, J=2 Hz, 1H), 4.40 (s, 2H), 3.37 (t, J=8 Hz, 2H), 2.59 (m, 2H); MS (ESI − ) m/z 406 (M−H) − .

Example 71: 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 170)

To a solution of 3-methoxy-3-methylbutan-1-ol (200 mg, 1.692 mmol) in methylene chloride (5 mL) at 0° C. was added methanesulfonyl chloride (388 mg, 3.38 mmol) and triethylamine (0.354 mL, 2.54 mmol). The reaction mixture was stirred at 0° C. for 30 minutes and 2 hours at ambient temperature. Water (5 mL) was then added, and the mixture was extracted with methylene chloride (3×5 mL). The organic layers were combined, washed with brine (2 mL), and dried with Na 2 SO 4 . The volatiles were removed under reduced pressure to afford the title compound, which was subjected to the next step without purification.

Example 71B: 5-[3-(benzyloxy)-1-fluoro-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1H (150 mg, 0.373 mmol) in N,N-dimethylformamide (3 mL) was slowly added a freshly prepared solution of 3-methoxy-3-methylbutyl methanesulfonate (161 mg, 0.820 mmol, Example 71A) in N,N-dimethylformamide (1 mL). The reaction was stirred overnight at 50° C. and for 3 hours at 80° C. After cooling to ambient temperature, methanol (1 mL) was added, and volatiles were removed under reduced pressure. The residue was purified by preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% ammonium acetate in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (49 mg, 0.098 mmol, 26.2% yield). MS (APCI − ) m/z 501 [M−H] − .

Example 71C: 5-[1-fluoro-3-hydroxy-7-(3-methoxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (40 mg, 0.376 mmol) and tetrahydrofuran (10 mL). A solution of Example 71B (40 mg, 0.080 mmol) in tetrahydrofuran (2 mL), was then added. An adapter fitted with a hydrogen balloon was inserted and the flask was evacuated and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed from the filtrate under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (14 mg, 0.034 mmol, 9.03% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.34 (s, 1H), 7.71 (dd, J=9.1, 1.4 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.17 (dd, J=9.0, 2.5 Hz, 1H), 7.07 (d, J=1.3 Hz, 1H), 4.51 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.13 (s, 3H), 1.97 (t, J=7.2 Hz, 2H), 1.19 (s, 6H); MS (APCI − ) m/z 411 [M−H] − .

Example 72: 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 171)

Example 72A: 5-[3-(benzyloxy)-7-(2-cyclopropylpropoxy)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a suspension of Example 1H (120 mg, 0.298 mmol) in N,N-dimethylformamide (3 mL), was added cesium carbonate (214 mg, 0.656 mmol) and (1-bromopropan-2-yl)cyclopropane (107 mg, 0.656 mmol). The mixture was heated to 90° C. for 2 hours. After cooling, the mixture was filtered, and the filtrate was concentrated. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to the title compound (59 mg, 0.122 mmol, 41% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.80 (dd, J=9.8, 1.5 Hz, 1H), 7.56-7.48 (m, 2H), 7.43-7.34 (m, 3H), 7.37-7.29 (m, 1H), 7.33-7.23 (m, 2H), 5.24 (s, 2H), 4.46 (s, 2H), 4.10 (dd, J=9.4, 5.0 Hz, 1H), 3.98 (dd, J=9.4, 7.0 Hz, 1H), 1.31-1.20 (m, 1H), 1.09 (d, J=6.7 Hz, 3H), 0.73 (dtd, J=13.3, 8.6, 4.9 Hz, 1H), 0.50-0.37 (m, 2H), 0.26 (ddd, J=10.4, 4.7, 1.8 Hz, 1H), 0.14 (ddd, J=9.3, 4.8, 1.6 Hz, 1H); MS (APCI − ) m/z 483 [M−H] − .

Example 72B: 5-[7-(2-cyclopropylpropoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (45 mg, 0.423 mmol) and tetrahydrofuran (10 mL). A solution of Example 72A (45 mg, 0.093 mmol) in tetrahydrofuran (2 mL) was then added. An adapter fitted with a hydrogen balloon was inserted and the flask was evacuated and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (13 mg, 0.033 mmol, 7.79% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.33 (s, 1H), 7.71 (dt, J=8.1, 1.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 2H), 7.07 (s, 1H), 4.50 (s, 2H), 4.08 (dd, J=9.3, 5.1 Hz, 1H), 3.95 (dd, J=9.3, 7.1 Hz, 1H), 1.26 (tt, J=9.3, 6.1 Hz, 1H), 1.08 (d, J=6.7 Hz, 3H), 0.78-0.67 (m, 1H), 0.49-0.38 (m, 2H), 0.25 (ddd, J=10.9, 4.8, 2.2 Hz, 1H), 0.13 (ddd, J=9.3, 4.8, 1.7 Hz, 1H); MS (APCI − ) m/z 393 [M−H] − .

Example 73: 5-[1-fluoro-3-hydroxy-7-({2-[(propan-2-yl)oxy]ethyl}amino)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 172)

The title compound was prepared using the methodologies described in Example 80 substituting 2-isopropoxyethanamine for 2-methoxyethanamine. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 7.46 (br d, J=8 Hz, 1H), 7.01 (dd, J=8, 2 Hz, 1H), 6.89 (s, 1H), 6.66 (d, J=2 Hz, 1H), 5.78 (d, t=6 Hz, 1H),), 4.07 (s, 2H), 3.60 (m, 1H), 3.57 (t, J=8 Hz, 2H), 3.23 (m, 2H), 1.11 (d, J=8 Hz, 6H); MS (ESI − ) m/z 396 (M−H) − .

Example 74: 5-(1-fluoro-3-hydroxy-7-{[1-(methanesulfonyl)pyrrolidin-3-yl]methoxy}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 173)

The title compound was prepared as described for Example 56B from Example 1H and 3-(bromomethyl)-1-methylsulfonylpyrrolidine in 39.7% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.14 (s, 1H), 7.68 (dd, J=9.0, 1.5 Hz, 1H), 7.21 (d, J=2.6 Hz, 1H), 7.16 (dd, J=9.0, 2.5 Hz, 1H), 7.03 (s, 1H), 4.38 (s, 2H), 4.06 (qd, J=9.6, 6.8 Hz, 2H), 3.50-3.41 (m, 2H), 3.28-3.20 (m, 1H), 3.10 (dd, J=10.1, 6.9 Hz, 1H), 2.88 (s, 3H), 2.72 (p, J=7.2 Hz, 1H), 2.07 (m, 1H), 1.77 (m, 1H); MS (APCI − ) m/z 472.3 (M−H) − .

Example 75: 4-{[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}butanenitrile (Compound 174)

The title compound was prepared using the methodologies described in Example 78 substituting 4-aminobutanenitrile for 2-(azetidin-1-yl)ethanamine. 1 H NMR (500 MHz, −d 6 ) 6 ppm 10.15 (br s, 1H), 7.96 (br s, 1H), 7.53 (d, J=8 Hz, 1H), 7.07 (dd, J=8, 2 Hz, 1H), 6.95 (br s, 1H), 6.80 (br s, 1H), 4.47 (s, 2H), 3.17 (t, J=8 Hz, 2H), 2.60 (m, 2H), 1.87 (m, 2H); MS (ESI − ) m/z 377 (M−H) − .

Example 76: 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 175)

Example 76A: 5-[3-(benzyloxy)-1-fluoro-7-(prop-2-en-1-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1G in 1,4-dioxane (5 mL) were added allylboronic acid pinacol ester (280 mg, 1.668 mmol), potassium carbonate (173 mg, 1.251 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd (dppf)Cl 2 .CH 2 C 2 , 34.0 mg, 0.042 mmol) at 25° C. under nitrogen, and the reaction mixture was stirred at 80° C. for 16 hours under nitrogen. An additional reaction on 30 mg scale was set up and run as described above. The resulting mixtures were combined and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with methanol/dichloromethane from 0 to 20%) to give the title compound (120 mg, 0.27 mmol, 64.8% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.77 (d, J=8.33 Hz, 1H), 7.72 (s, 1H), 7.56 (d, J=7.45 Hz, 2H), 7.34-7.41 (m, 3H), 7.28-7.33 (m, 2H), 5.95-6.13 (m, 1H), 5.22-5.26 (m, 2H), 5.06-5.16 (m, 2H), 4.07-4.09 (m, 2H), 3.51-3.56 (m, 2H), 3.12-3.21 (m, 4H); MS (ESI − ) m/z 425 (M−H) − .

Example 76B: [6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]acetaldehyde

To solution of Example 76A (1 g, 2.345 mmol) in tetrahydrofuran (15 mL) and water (5 mL) was added sodium periodate (1.003 g, 4.69 mmol) at 20° C., and then osmium tetroxide (1 M in tert-butanol, 0.117 mL, 0.117 mmol) was added at 0° C. The mixture was stirred at 0° C. for 3 hours. Then the reaction was quenched with saturated aqueous sodium sulfite (150 mL). The mixture was acidified with aqueous hydrochloric acid (1 M) to pH=5, and then extracted with ethyl acetate (3×100 mL). The aqueous layer was filtered and purified by reversed-phase chromatography [Agela Claricep™ Flash AQ C18 Column, 20-35 μm, 100 Å, 120 g flash column, flow rate 50 mL/minute, 0-100% gradient of acetonitrile in water] to give the title compound (500 mg, 1.167 mmol, 24.8% yield). MS (ESI − ) m/z 427 (M−H) − .

Example 76C: 5-[3-(benzyloxy)-1-fluoro-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the solution of Example 76B (200 mg, 0.327 mmol) in tetrahydrofuran (2 mL) was added sodium borohydride (37.1 mg, 0.980 mmol) at 0° C., and the mixture was stirred for 2 hours at 0° C. The reaction was quenched by addition of water (15 mL) at 25° C., and then stirred for 5 minutes. The resulting mixture was extracted with ethyl acetate (3×20 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was was purified by preparative HPLC [Kromasil 150×25 mm, 10 μm, C18 column, flow rate 25 mL/minute, 10-100% gradient of acetonitrile in water (0.04% ammonium hydroxide and ammonium bicarbonate 10 mM)] to afford the title compound (30 mg, 0.063 mmol, 19.41% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.70-7.75 (m, 1H), 7.51-7.57 (m, 2H), 7.39-7.44 (m, 1H), 7.32-7.38 (m, 2H), 7.25-7.32 (m, 2H), 7.17-7.21 (m, 1H), 7.06 (s, 1H), 6.91-6.96 (m, 1H), 5.15-5.28 (m, 2H), 4.08 (s, 2H), 3.65 (t, J=6.84 Hz, 1H), 2.79-2.92 (m, 2H); MS (ESI + ) m/z 431 (M+H) + .

Example 76D: 5-[1-fluoro-3-hydroxy-7-(2-hydroxyethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

To solution of Example 76C (28 mg, 0.059 mmol) in methanol (15 mL) was added 10% Pd/C (6.30 mg) at 20° C. under argon. The suspension was degassed under vacuum and purged with hydrogen several times, and then the reaction was stirred for 2 hours at 20° C. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Waters Xbridge™ 150×25 μm, 5 μm column, flow rate 50 mL/minute, 25-100% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to afford the title compound as an ammonium salt (2.3 mg, 6.29 μmol, 9.39% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.57-9.67 (m, 1H), 7.61-7.70 (m, 2H), 7.35 (dd, J=8.44, 1.47 Hz, 1H), 7.17-7.26 (m, 1H), 7.08-7.16 (m, 1H), 7.02 (s, 1H), 6.91-7.00 (m, 1H), 4.59-4.70 (m, 1H), 4.06-4.10 (m, 2H), 3.64-3.68 (m, 2H), 3.64-3.64 (m, 1H), 3.16-3.18 (m, 1H), 2.84-2.87 (m, 2H); 1 H NMR (400 MHz, DMSO-d 6 /D 2 O) δ ppm 7.66-7.68 (m, 1H), 7.61-7.65 (m, 1H), 7.33-7.38 (m, 1H), 7.00-7.04 (m, 1H), 4.05-4.13 (m, 2H), 3.65-3.66 (m, 2H), 3.13-3.16 (m, 1H), 2.80-2.88 (m, 2H); MS (ESI + ) m/z 341 (M+H) + .

Example 77: 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 176)

Example 77A: 4-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}-2,2-dimethylbutanenitrile

To a solution of Example 1H (100 mg, 0.249 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (21.87 mg, 0.547 mmol) at ambient temperature in three portions. The reaction was stirred for 30 minutes until no evolution of bubbles was observed. A solution of 4-bromo-2,2-dimethylbutanenitrile (96 mg, 0.547 mmol) in N,N-dimethylformamide (2 mL) was slowly added to the reaction mixture. The reaction was stirred overnight at ambient temperature. Methanol (2 mL) was added, the solvents were removed under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , 10% methanol in dichloromethane) to afford the title compound (65 mg, 0.131 mmol, 53% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.77 (dd, J=9.1, 1.4 Hz, 1H), 7.59-7.50 (m, 2H), 7.44-7.26 (m, 5H), 7.20 (dd, J=9.0, 2.5 Hz, 1H), 5.22 (s, 2H), 4.28 (t, J=6.5 Hz, 2H), 4.09 (s, 2H), 3.17 (d, J=5.2 Hz, 1H), 2.12-2.05 (m, 2H), 1.41 (s, 6H); MS (APCI − ) m/z 496 (M−H) − .

Example 77B: 5-[7-(4-amino-3,3-dimethylbutoxy)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

Example 77A (26 mg, 0.052 mmol) and acetic acid (1 mL) were added to 10% Pd/C, dry (48 mg, 0.451 mmol) in a 20 mL Barnstead Hast C reactor. The reaction was stirred for 45 hours at ambient temperature under 117 psi hydrogen gas. The reaction was filtered, the volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to afford the title compound (9 mg, 0.022 mmol, 4% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.50 (s, 1H), 7.75 (d, J=1.4 Hz, 1H), 7.73 (broad, 2H), 7.31 (d, J=2.6 Hz, 1H), 7.19 (dd, J=9.0, 2.5 Hz, 1H), 7.12-7.07 (m, 1H), 4.22 (t, J=6.8 Hz, 2H), 4.15 (s, 2H), 2.85 (s, 2H), 1.88 (t, J=6.8 Hz, 2H), 1.10 (s, 6H); MS (APCI + ) m/z 412 [M+H] + .

Example 78: 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 177)

Example 78A: 5-[7-{[2-(azetidin-1-yl)ethyl]amino}-3-(benzyloxy)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 1G (93 mg, 0.2 mmol), BrettPhos Pd G3 (10.88 mg, 0.012 mmol), BrettPhos (6.44 mg, 0.012 mmol), cesium carbonate (195 mg, 0.600 mmol) and 2-(azetidin-1-yl)ethanamine (40.1 mg, 0.400 mmol) in 2-methylbutan-2-ol (2 mL) was degassed and filled with nitrogen five times and then was heated to 105° C. for 3 hours. Dichloromethane/methanol (10:1, 50 mL) was added to the mixture followed by 4 M HCl in dioxane (0.2 mL). The mixture was stirred for 10 minutes and filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (12 g) eluted with dichloromethane/methanol (0 to 65%) to give the title compound (85 mg, 0.175 mmol, 88% yield). MS (ESI − ) m/z 483 (M−H) − .

Example 78B: 5-(7-{[2-(azetidin-1-yl)ethyl]amino}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of 1,2,3,4,5-pentamethylbenzene (41.3 mg, 0.279 mmol) and Example 78A (45 mg, 0.093 mmol) in dichloromethane (2.5 mL) at −78° C. was added trichloroborane (1.672 mL, 1.672 mmol, 1 M in dichloromethane). The mixture was stirred at −78° C. for 20 minutes, warmed to 0° C. for 30 minutes, and then quenched with ethanol (4 mL). The mixture was stirred at ambient temperature for 5 minutes and concentrated. The residue was washed with dichloromethane (4×4 mL) and dried to give the title compound (40 mg, 0.093 mmol, 100% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.38 (br s, 1H), 10.12 (br s, 1H), 7.55 (br d, J=8 Hz, 1H), 7.03 (dd, J=8, 2 Hz, 1H), 6.97 (s, 1H), 6.75 (d, J=2 Hz, 1H), 4.50 (s, 2H), 4.11 (m, 2H), 4.06 (m, 2H), 3.37 (m, 4H), 2.40 (m, 1H), 2.25 (m, 1H); MS (ESI − ) m/z 393 (M−H) − .

Example 79: 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 178)

Example 79A: tert-butyl 3-{[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}azetidine-1-carboxylate

A mixture of Example 1H (150 mg, 0.373 mmol), Cs 2 CO 3 (243 mg, 0.746 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (106 mg, 0.373 mmol) in N,N-dimethylformamide (1 mL) was stirred at ambient temperature for 4 hours. The mixture was heated at 60° C. for 14 hours. After cooling down, a 2 N Na 2 CO 3 solution (0.5 mL) was added, and the mixture was extracted with 20 mL of ethyl acetate. The organic layer was discarded, and the aqueous layer was acidified with acetic acid (0.25 mL) and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate fractions were washed with brine, dried over Na 2 SO 4 , and concentrated to give the title compound which was used without further purification in the next step. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.85 (dd, J=9.1, 1.3 Hz, 1H), 7.55-7.48 (m, 2H), 7.42 (s, 1H), 7.38 (t, J=7.3 Hz, 2H), 7.36-7.30 (m, 1H), 7.26 (dd, J=8.9, 2.5 Hz, 1H), 7.06 (d, J=2.6 Hz, 1H), 5.24 (s, 2H), 5.17 (tt, J=6.4, 3.9 Hz, 1H), 4.43 (d, J=2.7 Hz, 2H), 4.37 (s, 2H), 3.85 (dd, J=10.0, 3.7 Hz, 2H), 1.40 (s, 9H).

Example 79B: 5-{7-[(azetidin-3-yl)oxy]-3-(benzyloxy)-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 79A (190 mg, 0.341 mmol) and trifluoroacetic acid (0.5 mL) in CH 2 Cl 2 (3 mL) was stirred at ambient temperature for 4 hours and then at 60° C. for 14 hours. The mixture was concentrated to give the title compound which was used in the next step without further purification. MS (APCI + ) m/z 469.8 (M+H) + .

Example 79C: 5-[3-(benzyloxy)-7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a mixture of Example 79B (60 mg, 0.131 mmol) and triethylamine (39.8 mg, 0.393 mmol) in 1:1 CH 2 Cl 2 —N,N-dimethylformamide (1 mL) was added cyclopropanesulfonyl chloride (23.97 mg, 0.171 mmol). The mixture was stirred at ambient temperature for 14 hours. The mixture was diluted with ethyl acetate, washed with 0.1 N HCl and brine, dried over Na 2 SO 4 , and concentrated to give the title compound which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.82 (dd, J=9.1, 1.5 Hz, 1H), 7.52-7.46 (m, 2H), 7.39 (s, 1H), 7.38-7.29 (m, 3H), 7.25 (dd, J=9.0, 2.6 Hz, 1H), 7.10 (d, J=2.6 Hz, 1H), 5.21 (m, 3H), 4.44-4.32 (m, 4H), 3.95 (dd, J=9.3, 4.5 Hz, 2H), 2.81-2.74 (m, 1H), 1.06-0.99 (m, 2H), 0.93 (dd, J=4.6, 2.4 Hz, 2H).

Example 79D: 5-(7-{[1-(cyclopropanesulfonyl)azetidin-3-yl]oxy}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The above Example 79C (35 mg, 0.062 mmol) and 20% Pd (OH) 2 wet (70 mg, 0.254 mmol) in tetrahydrofuran (2 mL) was stirred under 50 psi of H 2 for 50 hours. The mixture was filtered, concentrated and purified by preparative HPLC on a Phenomenex C8(2) Luna 5 μm AXIA™ 150×30 mm column with a gradient of 5-100% acetonitrile (A) in 0.1% trifluoroacetic acid in water (B) at a flow rate of 50 mL/minute to give the title compound (8 mg, 0.017 mmol, 27.2% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.22 (s, 1H), 7.76 (dd, J=9.1, 1.4 Hz, 1H), 7.20 (dd, J=9.0, 2.6 Hz, 1H), 7.08 (s, 1H), 7.06 (d, J=2.6 Hz, 1H), 5.22 (tt, J=6.5, 4.7 Hz, 1H), 4.44-4.32 (m, 4H), 3.98 (dd, J=9.3, 4.6 Hz, 2H), 2.82 (tt, J=7.9, 4.8 Hz, 1H), 1.09-0.99 (m, 2H), 1.02-0.93 (m, 2H); MS (APCI − ) m/z 469.8 (M−H) − .

Example 80: 5-{1-fluoro-3-hydroxy-7-[(2-methoxyethyl)amino]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 179)

A mixture of Example 1G (93 mg, 0.2 mmol), BrettPhos Pd G3 (10.88 mg, 0.012 mmol), BrettPhos (6.44 mg, 0.012 mmol), cesium carbonate (195 mg, 0.600 mmol) and 2-methoxyethanamine (30.0 mg, 0.400 mmol) in 2-methylbutan-2-ol (2 mL) was degassed and filled with nitrogen five times and then was heated to 105° C. for 3 hours. Dichloromethane/methanol (10:1, 50 mL) was added to the mixture followed by 4 M HCl in dioxane (0.2 mL). The mixture was stirred for 10 minutes and filtered. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (40 g) eluted with dichloromethane/methanol (0 to 35%) to give the title compound (20 mg, 0.054 mmol, 27.1% yield). 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 8.87 (br s, 1H), 7.46 (br d, J=8 Hz, 1H), 7.01 (dd, J=8, 2 Hz, 1H), 6.89 (s, 1H). 6.65 (d, J=2 Hz, 1H), 5.85 (t, J=5 Hz, 1H), 4.07 (s, 2H), 3.53 (m, 2H), 3.28 (s, 3H), 3.26 (m, 1H), 2.97 (m, 1H); MS (ESI − ) m/z 368 (M−H) − .

Example 81: 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 180)

Example 81A: 5-(3-(benzyloxy)-1-fluoro-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl)-1,2,5-thiadiazolidin-3-one 1,1-dioxide

The title compound was prepared using the methodologies described in Example 104A substituting 3,3,3-trifluoropropyl methanesulfonate for 2-bromoacetonitrile. MS (ESI − ) m/z 497 (M−H) − .

Example 81B: 5-[1-fluoro-3-hydroxy-7-(3,3,3-trifluoropropoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 137B substituting Example 81A for Example 137A. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.20 (br s, 1H), 7.72 (br d, J=8 Hz, 1H), 7.27 (d, J=2 Hz, 1H), 7.18 (dd, J=8, 2 Hz, 1H), 7.09 (s, 1H), 4.40 (s, 2H), 4.33 (t, J=8 Hz, 2H), 2.84 (m, 2H); MS (ESI − ) m/z 407 (M−H) − .

Example 82: 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]amino}methyl)cyclopropane-1-carbonitrile (Compound 181)

In a 20 mL pressure release vial, combined the product of Example 1G (0.605 g, 1.3 mmol), cesium carbonate (1.271 g, 3.90 mmol), methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (BrettPhos Pd G3 precatalyst, 0.035 g, 0.039 mmol), and 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (BrettPhos, 0.021 g, 0.039 mmol). The solids were placed under vacuum for 5 minutes at ambient temperature, then the vial was filled with nitrogen, followed by tert-amyl alcohol (12 mL) and 1-(aminomethyl)cyclopropanecarbonitrile (0.25 g, 2.60 mmol). The resulting suspension was degassed by five vacuum/nitrogen backfills, stirred for 10 minutes at ambient temperature and then heated to 90° C. After 73 hours, the reaction mixture was cooled to ambient temperature, then quenched with 1 M hydrochloric acid (6 mL) and diluted with ethyl acetate (6 mL). The aqueous layer was extracted with ethyl acetate (2×6 mL). The combined organic layers were washed with a 4:1 mixture of brine and 1 M hydrochloric acid (3 mL), dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 2-[3-(benzyloxy)-7-{[(1-cyanocyclopropyl)methyl]amino}-1-fluoronaphthalen-2-yl]-4-oxo-1λ 4 ,2,5-thiadiazolidine-1,1-bis(olate), which was used for the next reaction without purification. MS (APCI − ) m/z 479 [M−H] − .

To a suspension of the crude 2-[3-(benzyloxy)-7-{[(1-cyanocyclopropyl)methyl]amino}-1-fluoronaphthalen-2-yl]-4-oxo-1 4 ,2,5-thiadiazolidine-1,1-bis(olate) (0.625 g, 1.301 mmol) and pentamethylbenzene (0.386 g, 2.60 mmol) in dichloromethane (12 mL) at −78° C. was added a solution of boron trichloride in dichloromethane (7.8 mL, 1 M, 7.8 mmol) slowly along the side of the flask so that the internal temperature remained below −70° C. The resulting solution was stirred for 5 minutes at −78° C., then the cooling bath was removed, and the reaction mixture was allowed to warm to an internal temperature of 0° C. before cooling back to −78° C. The reaction was quenched by addition of ethyl acetate (5 mL) followed by anhydrous ethanol (5 mL). The mixture was warmed to ambient temperature and concentrated under reduced pressure to give a solid. The solid was triturated with heptanes (3×5 mL), then dichloromethane (2×3 mL). The triturated product was dissolved in a dimethyl sulfoxide/methanol mixture and was filtered through a glass microfiber frit. The resulting solution was directly purified by preparative HPLC [Waters XBridge™ C18 5 μm OBD column, 50×100 mm, flow rate 100 mL/minute, a gradient of 5-40% methanol in buffer (0.1% trifluoroacetic acid in water by volume)] to give the title compound (0.2446 g, 0.627 mmol, 48.2% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 10.05 (s, 1H), 7.54 (dd, J=9.0, 1.5 Hz, 1H), 7.10 (dd, J=8.9, 2.3 Hz, 1H), 6.94 (s, 1H), 6.79 (d, J=2.3 Hz, 1H), 4.49 (s, 2H), 3.33 (s, 2H), 1.25 (q, J=4.6 Hz, 2H), 1.13-1.04 (m, 2H); MS (ESI − ) m/z 389 [M−H] − .

Example 83: 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 182)

Example 83A: 5-[3-(benzyloxy)-1-fluoro-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of Example 1H (100 mg, 0.249 mmol), 4-bromo-2-methylbutan-2-ol (49.8 mg, 0.298 mmol) and Cs 2 CO 3 (162 mg, 0.497 mmol) in N,N-dimethylformamide (1 mL) was stirred at ambient temperature for 14 hours. The mixture was diluted with ethyl acetate and 0.2 N HCl (15 mL). The organic layer was separated, washed with brine, dried over Na 2 SO 4 , and concentrated to give the title compound which was used in the next step without further purification. MS (APCI − ) m/z 487.5 (M−H) − .

Example 83B: 5-[1-fluoro-3-hydroxy-7-(3-hydroxy-3-methylbutoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

Example 83A (120 mg, 0.246 mmol) in tetrahydrofuran (6 mL) was added to a 20 mL Barnstead Hast C reactor charged with 5% Pd/C, wet (145 mg, 0.681 mmol). The mixture was stirred under hydrogen at 150 psi pressure for 25 hours at 25° C. The reaction mixture was filtered, the filtrate was concentrated, and the residue was triturated with dichloromethane to give the title compound (65 mg, 0.163 mmol, 66.4% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.22 (s, 1H), 7.70 (dd, J=9.1, 1.5 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.16 (dd, J=9.0, 2.6 Hz, 1H), 7.06 (s, 1H), 4.45 (s, 2H), 4.19 (t, J=7.2 Hz, 2H), 1.90 (t, J=7.2 Hz, 2H), 1.19 (s, 6H); MS (APCI − ) m/z 397.7 (M−H) − .

Example 84: 5-{1-fluoro-3-hydroxy-7-[3-(H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 183)

Example 84A: 5-{3-(benzyloxy)-1-fluoro-7-[3-(H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A mixture of the product of Example 1H (125 mg, 0.31 mmol), 1-(3-chloropropyl)-1H-pyrazole (89.8 mg, 0.62 mmol) and cesium carbonate (304 mg, 0.93 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50° C. for 14 hours. The reaction mixture was filtered and purified by reverse-phase preparative HPLC on a Phenomenex® Luna® C8(2) 5 μm 100 Å AXIA™ column (50 mm×30 mm) eluted with a gradient of 5-100% acetonitrile (A) and 0.1% ammonium acetate in water (B) at a flow rate of 40 mL/minute to give the title compound. MS (APCI + ) m/z 511.1 (M+H) + .

Example 84B: 5-{-fluoro-3-hydroxy-7-[3-(H-pyrazol-1-yl)propoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 84A (101.4 mg, 0.199 mmol) in tetrahydrofuran (2 mL) was added 5% Pd/C (wet JM #9) (200 mg, 0.876 mmol). The mixture was stirred in a 4 mL pressure bottle with hydrogen at 150 psi pressure for 28 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm) eluted with a gradient of 5-100% methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) at a flow rate of 40 mL/minute to give the title compound. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.75 (d, J=2.1 Hz, 1H), 7.71 (dd, J=9.1, 1.4 Hz, 1H), 7.50 (d, J=1.9 Hz, 1H), 7.28-7.14 (m, 2H), 7.08 (s, 1H), 6.28 (t, J=2.0 Hz, 1H), 4.35 (t, J=6.8 Hz, 2H), 4.17 (s, 2H), 4.05 (t, J=6.2 Hz, 2H), 2.30 (p, J=6.6 Hz, 2H); MS (ESI + ) m/z 421.3 (M+H) + .

Example 85: 5-(7-{1-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 184)

To a solution of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (5 g, 16.09 mmol) in ethyl acetate (5 mL) was added a solution of hydrochloric acid in ethyl acetate (20 mL, 80 mmol, 4 M) dropwise at 0° C., and the mixture was stirred for 2 hours at 25° C. The mixture was concentrated under reduced pressure to give the title compound (4 g, 16.09 mmol, 97% yield), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 9.76 (br s, 2H), 6.42 (d, J=1.98 Hz, 1H), 3.96 (br d, J=10.80 Hz, 4H), 1.23 (s, 12H).

Example 85B: 1-[(4-nitrophenyl)methanesulfonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

To a solution of Example 85A (0.983 g, 4.24 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (9.34 mL, 9.34 mmol, 1 M in tetrahydrofuran) dropwise at 0° C. After stirring for 5 minutes at 0° C., (4-nitrophenyl)methanesulfonyl chloride (1 g, 4.24 mmol) was added to the mixture in portions at 0° C., and then the resulting mixture was stirred for 12 hours at 25° C. Then the mixture was concentrated under reduced pressure, and the crude title compound (2 g, purity was about 40%) was used in the next step without further purification. MS (ESI − ) m/z 311 (M−83).

Example 85C: 5-[3-(benzyloxy)-1-fluoro-7-{-[(4-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1G (0.472 g, 1.015 mmol) and Example 85B (2 g, 2.029 mmol, crude) in dioxane (25 mL) was added tetrakis[triphenylphosphine]palladium (0.234 g, 0.203 mmol) and sodium carbonate (Na 2 CO 3 , 0.538 g, 5.07 mmol) under nitrogen, and the resulting mixture was stirred at 80° C. for 12 hours under nitrogen. The mixture was diluted with water (75 mL) and adjusted to pH=3 with HCl (1 M). Then the mixture was extracted with ethyl acetate (3×80 mL). The combined organic layers were washed with brine (150 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by reversed-phase chromatography [Agela Claricep™ Flash AQ C18 Column, 20-35 μm, 100 Å, 330 g flash column, flow rate 100 mL/minute, 0-100% gradient of acetonitrile in water] to give the title compound (420 mg, 0.525 mmol, yield 25.9%). MS (ESI − ) m/z 651 (M−H) − .

Example 85D: 5-(1-fluoro-3-hydroxy-7-{-[(4-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 85C (420 mg, 0.579 mmol) in dichloromethane (30 mL) was added boron trichloride (5.79 mL, 5.79 mmol, 1 M in dichloromethane) dropwise at −70° C., and the mixture was stirred for 2 hours at 25° C. Then the mixture was quenched with methanol (10 mL), and the mixture was concentrated under reduced pressure to give the title compound (350 mg, 0.498 mmol, 86% yield) which was used in the next step without further purification. MS (ESI − ) m/z 561 (M−H) − .

Example 85E: 5-(7-{-[(4-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 85D (350 mg, 0.498 mmol) in ethanol (15 mL), methanol (15 mL) and water (3 mL) was added iron powder (278 mg, 4.98 mmol) and ammonium chloride (266 mg, 4.98 mmol) at 20° C. Then the mixture was stirred for 2 hours at 90° C. Then the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Waters Xbridge™ Prep OBD C18 150×40 mm, 10 μm column, flow rate 50 mL/minute, 10-35% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the title compound (42 mg, 0.071 mmol, 14.34% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.00 (br s, 1H), 7.68-7.80 (m, 2H), 7.64 (s, 1H), 7.21 (s, 1H), 7.01-7.14 (m, 4H), 6.95 (s, 1H), 6.49-6.59 (m, 2H), 6.43 (br s, 1H), 4.52 (br s, 2H), 4.38 (s, 2H), 4.13 (s, 4H); 19 F NMR (377 MHz, DMSO-d 6 ) δ ppm −125.43 (br s, 1F); MS (ESI − ) m/z 531 (M−H) − .

Example 86: 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 185)

Example 86A: 5-[3-(benzyloxy)-1-fluoro-7-(hydroxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the solution of Example 62B (250 mg, 0.595 mmol) in methanol (10 mL) was added sodium borohydride (NaBH 4 , 25 mg, 0.654 mmol) at 20° C., and the mixture was stirred for 30 minutes. The reaction was quenched by addition of aqueous hydrochloric acid (1 N) to pH=5, the mixture was added to 20 mL of brine, and the resulting mixture was extracted with ethyl acetate (2×40 mL). The organic layers were combined, washed with brine (2×40 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (210 mg, 0.438 mmol, 73.7% yield) which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.89-7.93 (m, 1H), 7.82-7.88 (m, 1H), 7.49-7.58 (m, 3H), 7.43-7.47 (m, 1H), 7.30-7.42 (m, 3H), 5.24-5.31 (m, 2H), 4.63-4.71 (m, 2H), 4.51-4.56 (m, 2H); MS (ESI − ) m/z 415 (M−H) − .

Example 86B: 5-[1-fluoro-3-hydroxy-7-(hydroxymethyl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To the solution of Example 86A (0.05 g, 0.104 mmol) in dichloromethane (1 mL) was added boron trichloride (1.044 mL, 1.044 mmol) at −70° C., and the mixture was stirred for 15 minutes at −70° C. Then the reaction was quenched by addition of 20 mL of methanol. An additional reaction on 0.01 g scale was set up and run as described above. The mixture was concentrated under reduced pressure. Then the residue was purified by preparative HPLC [Xtimate™ C18 5 μm column, 25×150 mm, flow rate 25 mL/minute, 10-100% gradient of acetonitrile in water (10 mM ammonium bicarbonate)] to give the title compound (0.011 g, 0.033 mmol, 26.6% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.75-7.81 (m, 1H), 7.62-7.70 (m, 1H), 7.37-7.44 (m, 1H), 7.01-7.06 (m, 1H), 4.58-4.60 (m, 2H), 4.12 (s, 2H); MS (ESI − ) m/z 325 (M−H) − .

Example 87: 5-{7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 186)

In a 4 mL vial were combined NiCl 2 dimethoxyethane adduct (3.97 mg, 0.018 mmol, 0.12 equivalents) and 4,4′-di-tert-butyl-2,2′-dipyridyl (4.85 mg, 0.018 mmol, 0.12 equivalents) in N,N-dimethylacetamide (1.0 mL). Example 1G (70 mg, 0.15 mmol, 1.0 equivalents), potassium (1-(tert-butoxycarbonyl)piperidin-3-yl)trifluoroborate (88 mg, 0.301 mmol, 2.0 equivalents), cesium carbonate (98 mg, 0.30 mmol, 2.0 equivalents) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate (5.0 mg, 0.005 mmol, 0.03 equivalents) were added, followed by dioxane (1.0 mL). The reaction was irradiated overnight using a 450 nm LED photoreactor.

The reaction was filtered and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to afford the tert-butyl 3-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]piperidine-1-carboxylate (23.9 mg, 28% yield). The residue was treated with 4 M HCl in dioxane (1 mL). Volatiles were removed under a stream of nitrogen.

In a 4 mL vial, 5-[3-(benzyloxy)-1-fluoro-7-(piperidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (0.020 g, 0.042 mmol) was treated with N,N-dimethylformamide (0.5 mL). N-Ethyl-N-isopropylpropan-2-amine (0.022 mL, 0.126 mmol) was added, followed by cyclopropanesulfonyl chloride (6.42 μL, 0.063 mmol). The reaction was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give a mixture of the sulfonylated material, 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione and the free amine. 5-{3-(Benzyloxy)-7-[1-(cyclopropanesulfonyl)piperidin-3-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (13.1 mg, 0.023 mmol) and tetrahydrofuran (1 mL) were added to 5% Pd/C (wet JM #9) (45 mg, 0.197 mmol) in a 4 mL pressure bottle and stirred for 38 hours at 75 psi hydrogen without external heating. The reaction was filtered, and the filtrate was concentrated under a stream of nitrogen. The reaction was reconstituted in dimethyl sulfoxide/methanol and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to afford the title compound eluted from 4.27-4.66 minutes (10 mg, 91% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.78 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.46 (d, J=9.4 Hz, 1H), 7.07 (s, 1H), 4.19 (d, J=40.7 Hz, 3H), 3.00 (dd, J=24.5, 13.4 Hz, 4H), 2.68-2.58 (m, 1H), 2.07-1.53 (m, 4H), 1.33-1.12 (m, 1H), 1.09-0.76 (m, 3H); MS (ESI − ) m/z 481.8 (M−H) − .

Example 88: 5-{7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 187)

In a 4 mL vial were combined NiCl 2 dimethoxyethane adduct (3.97 mg, 0.018 mmol, 0.12 equivalents) and 4,4′-di-tert-butyl-2,2′-dipyridyl (4.85 mg, 0.018 mmol, 0.12 equivalents) in N,N-dimethylacetamide (1.0 mL). Example 1G (70 mg, 0.15 mmol, 1.0 equivalents), potassium (1-(tert-butoxycarbonyl)pyrrolidin-2-yl)trifluoroborate (83 mg, 0.301 mmol, 2.0 equivalents), cesium carbonate (98 mg, 0.30 mmol, 2.0 equivalents) and bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate (5.0 mg, 0.005 mmol, 0.03 equivalents) were added, followed by dioxane (1.0 mL). The reaction was irradiated overnight using a 450 nm LED photoreactor.

The reaction was filtered and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 15% A, 0.5-8.0 minutes linear gradient 15-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-15% A, 9.1-10.0 minutes 15% A) to afford tert-butyl 2-[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]pyrrolidine-1-carboxylate (69.2 mg, 83% yield). The residue was treated with 1 mL 4 M HCl in dioxane. Volatiles were removed under a stream of nitrogen.

The residue (28.5 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1.0 mL). N-Ethyl-N-isopropylpropan-2-amine (33 μL, 0.19 mmol, 3.0 equivalents) was added, followed by cyclopropanecarbonyl chloride (7.4 μL, 0.08 mmol, 1.3 equivalents). The reaction was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give 5-{3-(benzyloxy)-7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (22.5 mg, 69% yield).

To 5-{3-(benzyloxy)-7-[1-(cyclopropanecarbonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (22.5 mg, 0.043 mmol) and tetrahydrofuran (1 mL) was added 5% Pd/C (wet JM #9) (38 mg, 0.166 mmol) in a 4 mL pressure bottle. The reaction was stirred for 18 hours at 75 psi hydrogen without external heating. Methanol (2 mL) was added, and the reaction mixture was hydrogenated for −32 hours. The reaction mixture was filtered and concentrated under a stream of nitrogen. The residue was reconstituted in dimethyl sulfoxide/methanol and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to afford the title compound (11.3 mg, 39% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.82-7.51 (m, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.09 (s, 1H), 5.55-4.93 (m, 1H), 4.13 (d, J=1.0 Hz, 2H), 3.93-3.50 (m, 2H), 2.47-2.21 (m, 1H), 2.11-1.30 (m, 4H), 0.81-0.18 (m, 4H); MS (APCI + ) m/z 434.3 (M+H) + .

Example 89: 5-{1-fluoro-3-hydroxy-7-[2-(1H-pyrazol-1-yl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 188)

The title compound was prepared from Example 1H and 1-(2-bromoethyl)-1H-pyrazole in the same way as described for Example 84. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.83 (d, J=2.2 Hz, 1H), 7.69 (dd, J=9.2, 1.4 Hz, 1H), 7.52 (d, J=2.0 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.13 (dd, J=9.0, 2.6 Hz, 1H), 7.07 (s, 1H), 6.31 (t, J=2.1 Hz, 1H), 4.58 (t, J=5.0 Hz, 2H), 4.47 (t, J=5.1 Hz, 2H), 4.17 (s, 2H); MS (ESI + ) m/z 407.6 (M+H) + .

Example 90: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 189)

5-[3-(Benzyloxy)-1-fluoro-7-(pyrrolidin-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione was prepared using the photoredox method described in Example 88. The residue (28.5 mg, 0.06 mmol) was dissolved in N,N-dimethylformamide (1.0 mL). N-Ethyl-N-isopropylpropan-2-amine (33 μL, 0.19 mmol, 3.0 equivalents) was added, followed by cyclopropanesulfonyl chloride (8.3 μL, 0.08 mmol, 1.3 equivalents). The reaction was stirred overnight at ambient temperature. The reaction was filtered and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to give 5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (16.0 mg, 46% yield).

5-{3-(benzyloxy)-7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (16 mg, 0.029 mmol) and tetrahydrofuran (1 mL) were added to 5% Pd/C (wet JM #9) (18 mg, 0.079 mmol) in a 4 mL pressure bottle and stirred for 20 hours at 75 psi hydrogen without external heating. The reaction mixture was filtered and concentrated under a stream of nitrogen. The reaction was reconstituted in dimethyl sulfoxide/methanol and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to afford the title compound (3.9 mg, 13% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.83 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 7.51 (dd, J=8.7, 1.8 Hz, 1H), 7.11 (s, 1H), 5.15-5.04 (m, 1H), 4.18 (d, J=1.7 Hz, 2H), 3.70-3.53 (m, 2H), 2.76-2.69 (m, 1H), 2.51-2.44 (m, 1H), 2.09-1.73 (m, 3H), 1.09-0.87 (m, 4H); MS (APCI + ) m/z 470.2 (M+H) + .

Example 91: 5-{7-[1-(cyclopropanesulfonyl)pyrrolidin-2-yl]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 190)

5-[3-(Benzyloxy)-1-fluoro-7-(oxolan-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione was prepared using the photoredox method described in Example 88, using Example 1G (1 equivalent), tetrahydrofuran-2-carboxylic acid (1.5 equivalents), bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridyl]phenyl]iridium(1+); 2-(2-pyridyl)pyridine; hexafluorophosphate (0.02 eq), NiCl 2 dimethoxyethane adduct (0.05 eq), 4,4′-di-tert-butyl-2,2′-dipyridyl (0.05 eq), Cs 2 CO 3 (1.5 eq) in N,N-dimethylacetamide (0.025 M). The reaction was irradiated for 72 hours using 450 nm blue LEDs. The reaction was purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and ammonium acetate in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to afford 5-[3-(Benzyloxy)-1-fluoro-7-(oxolan-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (4.0 mg). 5-[3-(Benzyloxy)-1-fluoro-7-(oxolan-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (4 mg, 8.76 μmol) and tetrahydrofuran (1 mL) were added to 5% Pd/C (wet JM #9) (10 mg, 0.044 mmol) in a 4 mL pressure bottle and stirred for 20 hours at 75 psi hydrogen and 25° C. The reaction mixture was filtered, and the solvent was removed under a stream of nitrogen. The residue was dissolved in methanol and purified by reverse-phase preparative HPLC on a Waters XBridge™ C8 5 μm column (75 mm×30 mm). A gradient of methanol (A) and 25 mM ammonium bicarbonate buffer (pH 10) in water (B) was used, at a flow rate of 40 mL/minute (0-0.5 minutes 5% A, 0.5-8.0 minutes linear gradient 5-100% A, 8.0-9.0 minutes 100% A, 9.0-9.1 minutes linear gradient 100-5% A, 9.1-10.0 minutes 5% A) to afford the title compound (1.1 mg, 34% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.79 (s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.08 (s, 1H), 4.95 (t, J=7.2 Hz, 1H), 4.14 (s, 2H), 4.04 (q, J=7.1 Hz, 1H), 3.86 (d, J=7.4 Hz, 1H), 2.04-1.92 (m, 3H), 1.72 (dd, J=12.3, 7.9 Hz, 1H); MS (ESI − ) m/z 365.1 (M−H) + .

Example 92: 5-[1-fluoro-3-hydroxy-7-(piperidin-3-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 191)

The title compound was isolated during the preparation of Example 87, having resulted in incomplete sulfonylation (1.5 mg) and eluted from 3.80-4.15 minutes. 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.87-7.63 (m, 2H), 7.44 (d, J=9.5 Hz, 1H), 7.08 (s, 1H), 4.14 (s, 2H), 3.35-3.18 (m, 2H), 3.04-2.99 (m, 2H), 2.90-2.82 (m, 1H), 2.01-1.87 (m, 2H), 1.84-1.68 (m, 2H); MS (ESI − ) m/z 378.1 (M−H) + .

Example 93: 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 192)

Example 93A: 5-{3-(benzyloxy)-7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoronaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of 5-[3-(benzyloxy)-1-fluoro-7-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt, the product of Example 1H (200 mg, 0.497 mmol), in N,N-dimethylformamide was added cesium carbonate (356 mg, 1.093 mmol) and 2-(2-bromoethyl)-1,1-difluorocyclopropane (202 mg, 1.093 mmol). The mixture was heated to 80° C. for 2 hours. After cooling, the reaction mixture was filtered, the volatiles were removed, and the residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 5% methanol in dichloromethane) to give the title compound (115 mg, 0.227 mmol, 46% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.76 (dd, J=9.1, 1.5 Hz, 1H), 7.60-7.48 (m, 2H), 7.45-7.32 (m, 2H), 7.36-7.26 (m, 2H), 7.26 (d, J=2.5 Hz, 1H), 7.21 (dd, J=8.9, 2.5 Hz, 1H), 5.22 (s, 2H), 4.25-4.15 (m, 1H), 4.20-4.01 (m, 1H), 4.08 (s, 2H), 2.01 (q, J=9.9, 8.5 Hz, 1H), 1.93-1.72 (m, 2H), 1.65-1.51 (m, 1H), 1.25 (dtd, J=14.9, 7.3, 3.5 Hz, 1H); MS (APCI − ) m/z 505 [M−H] − .

Example 93B: 5-{7-[2-(2,2-difluorocyclopropyl)ethoxy]-1-fluoro-3-hydroxynaphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of Pd/C (8.40 mg, 0.079 mmol) and tetrahydrofuran (10 mL). A solution of Example 93A (40 mg, 0.079 mmol) in tetrahydrofuran (2 mL), was then added. An adapter fitted with a hydrogen balloon was inserted and the flask was evacuated and refilled with hydrogen (3 times). The reaction was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to give the title compound (12 mg, 0.029 mmol, 37% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.72 (dd, J=9.1, 1.4 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.19 (dd, J=8.9, 2.5 Hz, 1H), 7.07 (s, 1H), 4.45 (s, 2H), 4.22-4.11 (m, 2H), 2.03-1.95 (m, 1H), 1.88-1.79 (m, 2H), 1.63-1.52 (m, 1H), 1.29-1.22 (m, 1H); MS (APCI − ) m/z 415 [M−H] − .

Example 94: 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 193)

Example 94A: 5-{3-(benzyloxy)-1-fluoro-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1H (130 mg, 0.323 mmol) in N,N-dimethylformamide (3 mL), was added cesium carbonate (232 mg, 0.711 mmol) and 1-(2-bromoethyl)-1-methylcyclopropane (105 mg, 0.646 mmol). The mixture was heated to 80° C. for 2 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (SiO 2 , dry load with diatomaceous earth, 10% methanol in dichloromethane) to give the title compound (107 mg, 0.221 mmol, 68% yield). 1 H NMR (501 MHz, DMSO-d 6 ) δ ppm 7.75 (dd, J=9.0, 1.4 Hz, 1H), 7.59-7.53 (m, 2H), 7.45-7.27 (m, 4H), 7.26 (d, J=2.5 Hz, 1H), 7.18 (dd, J=9.0, 2.5 Hz, 1H), 5.22 (s, 2H), 4.19 (t, J=6.9 Hz, 2H), 4.11 (s, 2H), 1.74 (t, J=6.9 Hz, 2H), 1.12 (s, 3H), 0.43-0.37 (m, 2H), 0.30-0.23 (m, 2H); MS (APCI − ) m/z 483 [M−H] − .

Example 94B: 5-{1-fluoro-3-hydroxy-7-[2-(1-methylcyclopropyl)ethoxy]naphthalen-2-yl}-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

A 250 mL-round bottom flask was filled with nitrogen, followed by addition of 5% Pd/C (8.79 mg, 0.083 mmol) and tetrahydrofuran (10 mL). A solution of Example 94A (40 mg, 0.083 mmol) in tetrahydrofuran (2 mL), was then added. An adapter fitted with a hydrogen balloon was inserted and the flask was evacuated and refilled with hydrogen (3 times). The reaction mixture was stirred at ambient temperature overnight. The mixture was filtered through a pad of diatomaceous earth under nitrogen gas. The volatiles were removed under reduced pressure, and the residue was subjected to preparative HPLC [Phenomenex® Luna® C18(2) 5 μm 100 Å AXIA™ column (250 mm×25 mm). 30-100% gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) over 15 minutes, at a flow rate of 25 mL/minute] to give the title compound (11 mg, 0.028 mmol, 34% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.70 (dd, J=9.0, 1.5 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 7.17 (dd, J=9.0, 2.5 Hz, 1H), 7.06 (s, 1H), 4.46 (s, 2H), 4.17 (t, J=6.9 Hz, 2H), 1.73 (t, J=6.9 Hz, 2H), 1.11 (s, 3H), 0.43-0.33 (m, 2H), 0.33-0.24 (m, 2H); MS (APCI − ) m/z 393 [M−H] − .

Example 95: 5-(7-{1-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 194)

Example 95A: 1-[(3-nitrophenyl)methanesulfonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole hydrochloride (1 g, 4.10 mmol) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (9.03 mL, 1 M in tetrahydrofuran) at 0° C., after stirring for 5 minutes, (3-nitrophenyl)methanesulfonyl chloride (0.967 g, 4.10 mmol) was added to the mixture dropwise at 0° C. The resulting mixture was stirred for 12 hours at 25° C. Then the mixture was concentrated under reduced pressure to give the title compound (2 g, 2.029 mmol, 49.5% yield) which was used for the next step without further purification. MS (ESI − ) m/z 311 (M−83) − .

Example 95B: 5-[3-(benzyloxy)-1-fluoro-7-{-[(3-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1G (0.472 g, 1.015 mmol) and Example 95A (2 g, 2.029 mmol) in dioxane (25 mL) was added sodium carbonate (Na 2 CO 3 , 0.538 g, 5.07 mmol) and tetrakis[triphenylphosphine]palladium (0.234 g, 0.203 mmol) under nitrogen in order, and the resulting mixture was heated to 80° C. for 12 hours under nitrogen. One additional vial on 400 mg scale was set up and run as described above. The mixtures were combined and diluted with water (100 mL). The mixture was adjusted to pH=3 with aqueous hydrochloric acid (1 M), and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography [Agela Claricep™ Flash AQ C18 20-35 μm, 100 Å, 330 g flash column, flow rate 100 mL/minute, 10-100% gradient of acetonitrile in water] to afford the title compound (280 mg, 0.331 mmol, purity 80%) and the title compound (120 mg, 0.16 mmol, purity 90%). MS (ESI − ) m/z 651 (M−H) − .

Example 95C: 5-(1-fluoro-3-hydroxy-7-{t-[(3-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 95B (50 mg, 0.054 mmol) in dichloromethane (30 mL) was added boron trichloride (0.536 mL, 0.536 mmol, 1 M in dichloromethane) dropwise at −70° C., and the mixture was stirred for 2 hours at 25° C. One additional vial on 280 mg scale was set up and run as described above. Then each mixture was concentrated under reduced pressure. The residues were combined and purified by preparative HPLC [Waters Xbridge™ Prep OBD C18 150×40 mm, 10 μm column, flow rate 50 mL/minute, 20-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to give the title compound (180 mg, 0.176 mmol, 72.5% yield). MS (ESI − ) m/z 561 (M−H) − .

Example 95D: 5-(7-{t-[(3-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 95C (180 mg, 0.304 mmol) in ethanol (20 mL), methanol (20 mL) and water (5 mL) was added iron powder (170 mg, 3.04 mmol) and ammonium chloride (163 mg, 3.04 mmol) at 20° C. in order. Then the mixture was stirred for 2 hours at 90° C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Waters Xbridge™ Prep OBD C18 150×25 mm, 5 μm column, flow rate 25 mL/minute, 10-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the title compound (55 mg, 0.095 mmol, 31.4% yield, ammonium salt). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.71 (br s, 2H), 7.60 (s, 1H), 7.07 (s, 1H), 6.95 (br t, J=7.76 Hz, 1H), 6.67 (br s, 1H), 6.50-6.62 (m, 2H), 6.41 (br s, 1H), 4.49 (br s, 2H), 4.38 (s, 2H), 4.21 (br s, 2H), 4.12 (s, 2H); 19 F NMR (377 MHz, DMSO-d 6 ) δ ppm −125.50 (br s, 1F); MS (ESI − ) m/z 531 (M−H) − .

Example 96: 5-(7-{1-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 195)

Example 96A: 1-[(2-nitrophenyl)methanesulfonyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole

To a solution of Example 85A (1 g, 4.10 mmol) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (9.03 mL, 9.03 mmol, 1 M in tetrahydrofuran) at 0° C., and after stirring for 5 minutes, (2-nitrophenyl)methanesulfonyl chloride (0.967 g, 4.10 mmol) was added to the mixture dropwise at 0° C. The resulting mixture was stirred for 12 hours at 25° C., and then the mixture was concentrated under reduced pressure to give the title compound (2 g, 2.029 mmol, 49.5% yield), which was used in the next step without further purification. MS (ESI − ) m/z 311 (M−83) − .

Example 96B: 5-[3-(benzyloxy)-1-fluoro-7-{-[(2-nitrophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1G (0.472 g, 1.015 mmol) and Example 96A (2 g, 2.029 mmol) in dioxane (25 mL) was added sodium carbonate (Na 2 CO 3 , 0.538 g, 5.07 mmol) and tetrakis[triphenylphosphine]palladium (0.234 g, 0.203 mmol) in order under nitrogen, and the mixture was stirred at 80° C. for 12 hours under nitrogen. One additional vial on 400 mg scale was setup as described above. The mixtures were combined and diluted with water (100 mL). The mixture was adjusted to pH=3 with aqueous hydrochloric acid (1 M), and the mixture was extracted with ethyl acetate (3×80 mL). The combined organic phase was washed with brine (3×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by reversed-phase chromatography [Agela Claricep™ Flash AQ C18 20-35 μm, 100 Å, 330 g flash column, flow rate 100 mL/minute, 0-100% gradient of acetonitrile in water] to afford the title compound (320 mg, purity 85%) and the title compound (90 mg, purity 95%). MS (ESI − ) m/z 651 (M−H) −

Example 96C: 5-(1-fluoro-3-hydroxy-7-{1-[(2-nitrophenyl)methanesulfonyl]-2,5-dihydro-H-pyrrol-3-yl}naphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 96B (50 mg, 0.054 mmol) in dichloromethane (30 mL) was added boron trichloride (0.536 mL, 0.536 mmol, 1 M in dichloromethane) dropwise at −70° C., and the mixture was stirred for 2 hours at 25° C. One additional vial on 320 mg scale was set up and run as described above. Then the mixtures were concentrated under reduced pressure to give residues which were combined and purified by preparative HPLC [Waters Xbridge™ Prep OBD C18, 150×40 mm, 10 μm column, flow rate 50 mL/minute, 10-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to give the title compound (180 mg, 0.176 mmol, 37.4% yield). MS (ESI − ) m/z 561 (M−H) − .

Example 96D: 5-(7-{-[(2-aminophenyl)methanesulfonyl]-2,5-dihydro-1H-pyrrol-3-yl}-1-fluoro-3-hydroxynaphthalen-2-yl)-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione, ammonium salt

To a solution of Example 96C (180 mg, 0.304 mmol) in ethanol (20 mL), methanol (20 mL) and water (4.00 mL) was added iron powder (170 mg, 3.04 mmol) and ammonium chloride (163 mg, 3.04 mmol) at 20° C. in order. Then the mixture was stirred for 2 hours at 90° C. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [Waters Xbridge™ Prep OBD C18, 150×25 mm, 5 μm column, flow rate 25 mL/minute, 10-40% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] and lyophilized to give the title compound (42 mg, 0.074 mmol, 24.41% yield, ammonium salt). 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 10.04 (s, 1H), 7.69-7.78 (m, 2H), 7.62 (s, 1H), 7.21 (s, 1H), 7.12 (d, J=7.45 Hz, 1H), 7.05-7.09 (m, 2H), 6.97-7.03 (m, 1H), 6.96 (s, 1H), 6.66 (d, J 10=7.45 Hz, 1H), 6.50 (t, J=7.45 Hz, 1H), 6.45 (br s, 1H), 5.19 (br s, 1H), 4.61 (br s, 2H), 4.49 (s, 2H), 4.25 (br s, 2H), 4.12 (s, 2H); 19 F NMR (377 MHz, DMSO-d 6 ) δ ppm −125.55 (br s, 1F); MS (ESI − ) m/z 531 (M−H) − .

Example 97: 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 196)

Example 97A: 5-[3-(benzyloxy)-1-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 1G (500 mg, 1.042 mmol) in dioxane (20 mL), was added bis(pinacolato)diboron (662 mg, 2.61 mmol), potassium acetate (307 mg, 3.13 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (76 mg, 0.104 mmol) in order under nitrogen. The reaction mixture was stirred at 80° C. for 3 hours under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel in a gradient elution of methanol in dichloromethane (0 to 20%) to give the title compound (460 mg, 0.718 mmol, 68.9% yield). MS (ESI − ) m/z 511 (M−H) − .

Example 97B: 5-[3-(benzyloxy)-7-(2,2-difluoroethyl)-1-fluoronaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 97A (20 mg, 0.031 mmol) in N-methyl-2-pyrrolidinone (0.5 mL), were added 1,1-difluoro-2-iodoethane (25 mg, 0.120 mmol), a solution of potassium phosphate (21.8 mg, 0.100 mmol) in water (0.12 mL) and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (XPhos Pd G2, 3 mg, 3.5 μmol) at 25° C. under nitrogen, and the reaction mixture was heated to 80° C. and stirred for 18 hours at 80° C. under nitrogen. An additional fourteen reactions on 0.5 g scale were set up and run as described above. The combined reaction mixtures were diluted with water (150 mL). The resulting mixture was extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [Waters Xbridge™ Prep OBD C18, 150×25 mm, 5 μm column, flow rate 25 mL/minute, 25-100% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to give the title compound (7 mg, 0.015 mmol, 3.25% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 7.91 (s, 1H), 7.75-7.80 (m, 1H), 7.54-7.59 (m, 2H), 7.44-7.48 (m, 1H), 7.34-7.41 (m, 2H), 7.21-7.32 (m, 2H), 5.91-6.26 (m, 1H), 5.21-5.28 (m, 2H), 4.36-4.42 (m, 2H), 3.31 (s, 3H); MS (ESI − ) m/z 449 (M−H) − .

Example 97C: 5-[7-(2,2-difluoroethyl)-1-fluoro-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

To a solution of Example 97B (5 mg, 10.88 μmol) in dichloromethane (1.5 mL) was added boron trichloride (1 M in dichloromethane, 0.033 mL, 0.03 mmol) at −70° C. The reaction mixture was stirred at −70° C. for 2 hours. The reaction was quenched by addition of methanol (1.5 mL) at −78° C. An additional reaction on 2 mg scale was set up and run as described above. The resulting mixtures of the above two reactions were combined and concentrated under reduced pressure. The residue was purified by preparative HPLC [Kromasil 150×25 mm, 10 μm, C18 column, flow rate 25 mL/minute, 25-100% gradient of acetonitrile in aqueous ammonium bicarbonate (10 mM)] to afford the title compound (1.8 mg, 4.68 μmol 30.1% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 7.81-7.89 (m, 1H), 7.61-7.70 (m, 1H), 7.35-7.45 (m, 1H), 7.02-7.09 (m, 1H), 5.89-6.23 (m, 1H), 4.36-4.42 (m, 2H), 3.22-3.30 (m, 2H); MS (ESI − ) m/z 359 (M−H) − .

Example 98: 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 197)

Example 98A: 5-[3-(benzyloxy)-1-fluoro-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 104A substituting 2,2,2-trifluoroethyl methanesulfonate for 2-bromoacetonitrile. MS (ESI − ) m/z 483 (M−H) − .

Example 98B: 5-[1-fluoro-3-hydroxy-7-(2,2,2-trifluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 137B substituting Example 98A for Example 137A. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.68 (br s, 1H), 7.78 (br d, J=8 Hz, 1H), 7.41 (d, J=2 Hz, 1H), 7.29 (dd, J=8, 2 Hz, 1H), 7.16 (s, 1H), 4.91 (m, 2H), 4.55 (s, 2H); MS (ESI − ) m/z 483 (M−H) − .

Example 99: 5-[1-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione (Compound 198)

Example 99A: 5-[3-(benzyloxy)-1-fluoro-7-(2-fluoroethoxy)naphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 104A substituting 2-fluoroethyl 4-methylbenzenesulfonate for 2-bromoacetonitrile. MS (ESI − ) m/z 447 (M−H) − .

Example 99B: 5-[I-fluoro-7-(2-fluoroethoxy)-3-hydroxynaphthalen-2-yl]-1λ 6 ,2,5-thiadiazolidine-1,1,3-trione

The title compound was prepared using the methodologies described in Example 137B substituting Example 99A for Example 137A. 1 H NMR (500 MHz, DMSO-d 6 ) δ ppm 10.38 (br s, 1H), 7.73 (br d, J=8 Hz, 1H), 7.25 (d, J=2 Hz, 1H), 7.23 (dd, J=8, 2 Hz, 1H), 7.10 (s, 1H), 4.86 (m, 1H), 4.74 (m, 1H), 4.47 (s, 2H), 4.39 (m, 1H), 4.32 (m, 1H); MS (ESI − ) m/z 357 (M−H) − .

Example 100: 1-({[8-fluoro-6-hydroxy-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropane-1-carbonitrile (Compound 199)

Example 100A: 1-({[6-(benzyloxy)-8-fluoro-7-(1,1,4-trioxo-1λ 6 ,2,5-thiadiazolidin-2-yl)naphthalen-2-yl]oxy}methyl)cyclopropane-1-carbonitrile

The title compound was prepared using the methodologies described in Example 104A