3-AMINOTETRAHYDRO-1H-1LAMBDA6-THIOPHENE-1,1-DIONE HYDROCHLORIDE

Preparation of 1 , 1 -Dioxo-tetrahydro-thiophen-3-ylamine:10a 10b A solution of compound 10a (0.5g, 4.2mmol) in 1OmL of 26percent NHExample 10Preparation of 5-[5-Fluoro-2-oxo-1, 2-dihydro-indol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (1, 1-dioxo-tetrahydro-thiophen-3-yl)-amide Preparation of 1, 1-Dioxo-tetrahydro-thiophen-3-ylamine A solution of compound 10a (0.5 g, 4.2 mmol) in 10 mL of 26percent NHTo a solution of l, l-dioxothiolan-3-amine hydrochloride (100 mg, 0.58 mmol) and TEA (0.11 mL, 0.81 mmol) in DCM (2 mL) was added 2, 4-dimethoxybenzaldehyde (123 mg, 0.74 mmol), followed by STAB (235 mg, 1.11 mmol). The suspension was stirred at room temperature for 1 hour, then at 40 C for 3 hours. l, l-dioxothiolan-3-amine hydrochloride (20 mg, 0.12 mmol) and TEA (0.02 mL, 0.15 mmol) were added as a solution in DCM (0.5 mL), followed by STAB (92 mg, 0.44 mmol) and the mixture stirred at 40 C for 16 hours. STAB (185 mg, 0.87 mmol) was added and the mixture stirred at 40 C for 4 hours. The mixture was quenched with saturated sodium bicarbonate and the organic layer separated. The aqueous layer was extracted with DCM (4 x 5 mL) and the organic fractions combined, passed through a hydrophobic frit and concentrated in vacuo to give an oil. The oil was purified via column chromatography, using a gradient of 50 - 100% TBME in heptanes, followed by 0 - 10% methanol in TBME to give the title compound (167 mg, 84% yield). dH (500 MHz, d- Chloroform) 7.08 (d, J = 8.1 Hz, 1H), 6.48 - 6.42 (m, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 3.74 (d, J = 2.2 Hz, 2H), 3.58 - 3.51 (m, 1H), 3.32 - 3.22 (m, 2H), 3.04 - 2.97 (m, 1H), 2.86 (dd, J = 13.2, 6.7 Hz, 1H), 2.42 - 2.34 (m, 1H), 2.11 - 2.02 (m, 1H). LCMS [M+H]+ 286, RT 1.42 (Method 18) .4-(3-Bromo-4-fluorophenyl)-3-(4-nitro-1, 2, 5-oxadiazol-3-yl)-1, 2, 4-oxadiazol-5 ( 4H)-ketone(300.0 mg, 0.81 mmol, 1.0 eq) was dissolved in DMA (4 mL)3-Aminotetrahydrothiophene 1, 1-dioxide hydrochloride was added under ice bath(276.7 mg, 1.61 mmol, 2.0 eq), Stirring reaction under ice bath1h, The reaction was monitored by TLC and water (30 mL) was added.EA extraction (3×30 mL), EtOAcq.The crude product was subjected to silica gel column chromatography (PE: EA=10:1 to 1:1)4-(3-Bromo-4-fluorophenyl)-3-(4-((1, 1-dioxotetrahydrothiophen-3-yl)amino)-1, 2, 5-oxadiazole- 3-yl)-1, 2, 4-oxadiazol-5(4H)-one (165.1 mg, yield: 44.6%).A mixture of 3-(2-chiorophenyl)-i-.(4-fiuorophenyi)-1H.-indazole-6-carboxylic acid (66 mg, 0.18 mmol), HATU (103 mg, 0271 mmol) in DMF (1 in]) was treated with Int-3-A (37.2 mg, 0.22 mmol) and DIPEA (0.189 ml, 1.085 mmol) was added to the solution, and the reaction mixture was stirred for 16 h. The volatiles were removed under vacuum, and the residue was dissolved in DMSO and purified by preparative RP-EIPLC (ACNlwater with0.1% TFA) to afford the title compound. m/ = 484.0/486.1 [M±Hit. 'HNMR (500 MHz, CD3OD): 8.93 (d, J=6.7 Hz, 1H), 826 (s, 1H), 784-787 (m, 2H), 7.73-7.79 (m, 2H), 7.63-7.69 (m, 2H), 748-754 (m, 2H), 7.39 (t, J:::8.6 Hz, 211), 358 (dd, J::::j35, 7.8 Hz, 1H), 3.36(ddd, J=13.4, 7.9. 4.7 Hz, 111), 3.12-3.24 (in, 2FF). 2.60-2.66 (in, 11-1), 2.35 (dq, J=13.4, 8.8Hz, 1H).A flask was charged with 3-arninotetrahydrothiophene-i. 1-dioxide hydrochloride (11.6 g, 67.8 mmol), EtOAc (100 ml) and sodium bicarbonate (21.63 g, 257 mmol). Water (100 ml) was added portion- wise over 10 mm. at rt. The CBZ-Ci (14.70 ml, 103 rnrnoi) was added at rt, and the mixture was stirred at rt for 16 h. The aq. layer was separated from the organic layer, and the organiclayer was washed with brine, dried with anhydrous sodium sulfate, and filtered, and the filtrate was concentrated in vacuo. Purification on silica gel (10 to 100% EtOAc/hexanes) afforded the title compound. 'H N]?[R (500 MHz, CDC13) 733-737 (m. 5H), 5.33 (s, 111), 5.1 1 (s, 2H), 4.55 (s, IH), 3.37 (dd, J=13.7 and 7.4 Hz, IH), 3.20-3.26 (m, 1H, 3.06-3.12 (m, 1H), 3.00 (d, J=13.6 Hz, IH), 2.51 (dq, J=13.7 and 7.1 Hz, IH), 2.26 (hr s, IH). Chiralresolution using SFC conditions (25% 2: 1 MeOH:ACN in CO2 on an OJ column) afforded Int-3AA (fast eluting) and 1nt-3AB (slow eluting).A flask was charged with 3 -aminotetrahydrothiophene- 1, 1 -dioxide hydrochloride (11.6 g, 67.8 mmol), EtOAc (100 ml) and sodium bicarbonate (21.63 g, 257 mmol). Water (100 ml) was added portion-wise over 10 min at rt. CBZ-C1 (14.70 ml, 103 mmol) was added at rt and the mixture was stirred at rt for 16 h. The aqueous layer was separated and discarded, and the organic layer was washed with brine, dried with anhydrous sodium sulfate, and filtered. Then the filtrate was concentrated in vacuo. The resulting residue was purified by silica gelchromatography (10 to 100% EtOAc/hexanes) to afford the title compound. 1H NMR (500 MHz, CDC13) delta 7.33-7.37 (m, 5 H); 5.33 (s, 1 H); 5.11 (s, 2 H); 4.55 (s, 1 H); 3.37 (dd, J=13.7 and 7.4Hz; 1 H); 3.20-3.26 (m, 1 H); 3.06-3.12 (m, 1 H); 3.00 (d, J=13.6 Hz; 1 H); 2.51 (dq, J=13.7 and 7.1 Hz; 1 H); 2.26 (br s, 1 H). Chiral resolution using SFC conditions (25% 2: 1 MeOH:MeCN in CC'2 on an OJ column) afforded enantiomer A (fast-eluting) and enantiomer B (slow-eluting).A mixture of 3-(-chlorophenyi)-IH-indazole--6-carboxyiic acid (100 mg, 0.367 mmoi), 3 -aminotetrahvdrothiophene 1, i-dioxide hydrochloride (racemi c 126 mg, 0733 mmoi) (27 mg, 0.733 inmol) in DMF (1.0 ml) was treated with TEA(0.102 ml, 0.73 3 mmol) and stirred at rt for 16 h. The reaction mixture was neutralized withaq. AcOH and directly purified by RP-HPLC (ACN/water with 0.05% TFA) to afforded thetitle compound. 390.0/391.9 [M+H]?.3 -Bromo- I -(4.-fluorophenyl)- i1-1--indazole-6--carhoxylic acid (224 mg, 0.668 mmol) and 3 -aminotetrahydrothiophene 1, 1 -dioxide hydrochloride Int3A (115 mg, 0.668 rnmol) in DMF (3 mL) was treated with HBTU (304 mg, 0.802 mmol) and TEA (186 tl, 1.337 mmoi), and stirred at rt for 12 h. The reaction mixture was directly purified by RP-HPLC (ACN/water with 0.05% TFA) to afford the title compound. m/ == 451.8/453.8 [M-F-I-ijA solution of benzyi (1, i-dioxidotetrahydrothiophen-3-yl)carbamate Int-3A-A (fast eluting on OJ) (2.856 g, 10.60 mmnol) inEtOAc (15 ml) was charged into a flask containing10% Pd/C (300 mg) under N2. The flask was purged with nitrogen and then hydrogen. Themixture was stirred under hydrogen (1 atm.) for 48 h, filtered through CELITE, and the filtrate was concentrated in vacuo to give the crude product that was treated with 1.25 M HCI in MeOH (50 mL), aged 10 mm, and then concentrated in vacuo to afford 3-amino- tetrahydrothi ophene- I , 1-dioxide hydrogen chloride Int-3-A (fast eiuting), 1F1 NMR (500MHz, ]ihO) oe 4.76 (s, 3H), 4.27 (p. J=7.8 Hz, IH), 3.75 (dd, J=14.4, 8.5 Hz. 1H), 3.49-3.54 (m, IH), 3.32-3.38 (m, 2H), 2.75-2.82 (m, IH), 2.32-2.40 (m, IH). The same procedure was used to synthesize Int-3-B (slow elutirig) from benzyi (i, i-dioxidotetrahydrothiophen-3- yl)carhamate Int-3-B (slow eluting). Note that the designation of fast- and slow-eluting isomers of int-3 refers to the elution order for enantiomers of their benzyl precursors (Int30 3A-A and Int-3A-B) on the OJ column and not those of Int-3-A (fast eluting) and Int-3-B(slow eluting).To a DMF (5 mL) solution of (trans)- 3-(benzo[d]thiazol-4-yloxy)cyclobutanecarboxylic acid (Intermediate 25) (150 mg, 0.599 mmol), 3-aminotetrahydrothiophene 1 , 1 -dioxide hydrochloride (103 mg, 0.599 mmol) and N, N-diisopropylethylamine (0.31 mL, 1 .8 mmol) at 0C was added, dropwise, a 50% solution of T3P in ethyl acetate (0.71 mL, 1 .2 mmol). The mixture was warmed to room temperature for 2 h, quenched with ice cold water (10 mL) and extracted with EtOAc (3 X 10 mL). The organic layers were combined, washed with water (20 mL) and brine (15 mL), dried over Na2SC>4, filtered and concentrated. The resulting material was triturated with n-pentane (15 mL) and diethyl ether (10 mL), and dried to give the title compound (85 mg, 38%) as an off-white solid. 1H NMR (400 MHz, CD3SOCD3) delta 2.05-2.15 (m, 1 H), 2.35-2.44 (m, 3 H), 2.65-2.72 (m, 2 H), 2.91 -2.99 (m, 1 H), 3.09-3.20 (m, 2 H), 3.26-3.34 (m, 1 H), 3.42-3.50 (m, 1 H), 4.46-4.55 (m, 1 H), 5.02-5.10 (m, 1 H), 6.85-6.89 (m, 1 H), 7.38- 7.45 (m, 1 H), 7.68-7.73 (m, 1 H), 9.21 (s, 1 H); LC-MS (LC-ES) M+H = 367.N-(1, 1-dioxidotetrahydrothiophen-3-yl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}quinoline-2-carboxamide A mixture of the product from Example 1D (1 g, 2.99 mmol),

Molecular Weight:171.65
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Exact Mass:171.0120774
Monoisotopic Mass:171.0120774
Topological Polar Surface Area:68.5
Heavy Atom Count:9
Complexity:167
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes