2,3-DIHYDROBENZO[b]THIOPHENE DERIVATIVES AS HYPOXIA INDUCIBLE FACTOR-2(ALPHA) INHIBITORS

Abstract

The present disclosure provides certain 2,3-dihydrobenzo[b]thiophene compounds that are Hypoxia Inducible Factor 2α (HIF-2α) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of HIF-2α. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

Claims

1-32. (canceled)

33. A compound of Formula (I): ##STR00159## wherein: m is 0 or 1; n is 0 or 1, provided that at least one of m and n is 1; X is O or NR.sup.8 where R.sup.8 is hydrogen, alkyl, cycloalkyl, cyano, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, heteroaryl, or heterocyclyl; R.sup.1 is hydrogen, alkyl, or halo; R.sup.2 is hydrogen, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; or R.sup.1 and R.sup.2 together with the carbon to which they are attached form oxo, cycloalkylene, or 4 to 6 membered heterocyclylene; R.sup.3 is hydrogen, alkyl, halo, haloalkyl, hydroxy, amino, monosubstituted amino, or disubstituted amino, or alkoxy; R.sup.4 is hydrogen, deuterium, alkyl, or halo; or R.sup.3 and R.sup.4 together with the carbon to which they are attached form oxo, cycloalkylene, or 4 to 6 membered heterocyclylene; R.sup.5 is hydrogen, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; R.sup.6 is -L-R.sup.10 where L is a bond, S, O or NH, and where R.sup.10 is cycloalkyl, bicyclic cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclylalkyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl and heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, and heterocyclyl are substituted with R.sup.a, R.sup.b, and/or R.sup.c independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkenyl, alkynyl, alkylidenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl; X.sup.1 is N or CR.sup.11, where R.sup.11 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, or aminoalkyl; and R.sup.7 is alkyl, cycloalkyl, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, alkylsulfonyl, —SO.sub.2NR.sup.13R.sup.14 (where R.sup.13 and R.sup.14 are independently hydrogen or alkyl), —S(O)R.sup.14(═NHR.sup.15) (where R.sup.14 is alkyl or haloalkyl and R.sup.15 is hydrogen or cyano), or heteroaryl optionally substituted with R.sup.g, R.sup.h, and/or R.sup.i independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano; or a pharmaceutically acceptable salt thereof.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof wherein X.sup.1 is CR.sup.11.

35. The compound of claim 33, or a pharmaceutically acceptable salt thereof wherein X.sup.1 is N.

36. The compound of claim 34, or a pharmaceutically acceptable salt thereof, wherein one of R.sup.3 and R.sup.4 is fluoro and the other of R.sup.3 and R.sup.4 is hydrogen or both R.sup.3 and R.sup.4 are fluoro.

37. The compound of claim 35, or a pharmaceutically acceptable salt thereof wherein one of R.sup.3 and R.sup.4 is fluoro and the other of R.sup.3 and R.sup.4 is hydrogen or both R.sup.3 and R.sup.4 are fluoro.

38. The compound of claim 36, or a pharmaceutically acceptable salt thereof wherein R.sup.1 and R.sup.2 are each fluoro.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof wherein m is 1 and n is 0.

40. The compound of claim 38, or a pharmaceutically acceptable salt thereof wherein m is 1 and n is 0.

41. The compound of claim 38, or a pharmaceutically acceptable salt thereof wherein m is 1, n is 1, and X is O.

42. The compound of claim 40, or a pharmaceutically acceptable salt thereof wherein L is O, S, or NH.

43. The compound of claim 41 or a pharmaceutically acceptable salt thereof wherein L is O, S, or NH.

44. The compound of claim 42, or a pharmaceutically acceptable salt thereof wherein R.sup.5 is hydrogen, methyl, ethyl, methoxy, fluoro, cyano, trifluoromethyl, or trifluoromethoxy and R.sup.7 is methyl, ethyl, methoxy, fluoro, bromo, cyano, cyclopropyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, or methylsulfonyl.

45. The compound of claim 43, or a pharmaceutically acceptable salt thereof wherein R.sup.5 is hydrogen, methyl, ethyl, methoxy, fluoro, cyano, trifluoromethyl, or trifluoromethoxy and R.sup.7 is methyl, ethyl, methoxy, fluoro, bromo, cyano, cyclopropyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, or methylsulfonyl.

46. The compound of claim 44, or a pharmaceutically acceptable salt thereof wherein R.sup.5 is hydrogen and R.sup.7 is difluoromethyl.

47. The compound of claim 45, or a pharmaceutically acceptable salt thereof wherein R.sup.5 is hydrogen and R.sup.7 is difluoromethyl.

48. The compound of claim 46, or a pharmaceutically acceptable salt thereof wherein R.sup.10 is phenyl or heteroaryl, each ring substituted with R.sup.a, R.sup.b, and/or R.sup.c independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.

49. The compound of claim 47, or a pharmaceutically acceptable salt thereof wherein R.sup.10 is phenyl or heteroaryl, each ring substituted with R.sup.a, R.sup.b, and/or R.sup.c independently selected from hydrogen, alkyl, haloalkyl, haloalkyloxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, aminoalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocyclyl.

50. The compound of claim 1, selected from the group consisting of: 3-((7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile; 3-chloro-5-((7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo-[b]thiophen-6-yl)oxy)benzonitrile; 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydrobenzo[b]-thiophene 1-oxide; 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3-trifluoro-2,3-dihydrobenzo[b]-thiophene 1-oxide; 3-fluoro-5-((2,2,3-trifluoro-7-(methylsulfonyl)-1-oxido-2,3-dihydrobenzo[b]-thiophen-4-yl)oxy)benzonitrile; 3-fluoro-5-((2,2,3-trifluoro-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo-[b]thiophen-4-yl)oxy)benzonitrile; 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)-oxy)-5-fluorobenzonitrile; 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo-[b]-thiophene 1-oxide; 3-((7-chloro-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile; 3-((7-bromo-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile; 6-(3-cyano-5-fluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile 1-oxide; 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrobenzo[b]-thiophen-6-yl)oxy)-5-fluorobenzonitrile; and 3-((7-chloro-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)-oxy)-5-fluorobenzonitrile; or a pharmaceutically acceptable salt thereof.

51. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

52. A pharmaceutical composition comprising a compound of claim 50, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

53. A method of treating cancer, inflammatory disease, liver disease, iron overload, or pulmonary disease in a patient which method comprises administering to the patient in recognized need thereof, a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

54. The method of claim 53, wherein the disease is cancer and the compound of claim 1, or a pharmaceutically acceptable salt thereof is optionally administered in combination with at least one other anticancer agent.

55. The method of claim 54, wherein the cancer is renal cancer.

Description

EXAMPLES

[0219] The following preparations of compounds of Formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure. They should not be considered as limiting the scope of the disclosure, but merely as being illustrative and representative thereof.

Example 1

Synthesis of 3-((7-(difluoromethyl)-2,2-difluoro-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl oxy)-5-fluorobenzonitrile

[0220] ##STR00079##

Step 1: 2,4-difluoro-3-formylbenzonitrile

[0221] ##STR00080##

[0222] To a stirred solution of 2,4-difluorobenzonitrile (6 g, 43.13 mmol, 1.0 equiv) in THF (200 mL) was added LDA (94 mL, 87.36 mmol, 2.0 equiv) dropwise at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C.-60° C. for 35 mins. To the above mixture was added DMF (8.3 mL, 114.17 mmol, 6.0 equiv) dropwise over 5 minutes at −78° C. The resulting mixture was stirred for additional 5 min at −78° C. and then was poured into 200 mL of HCl aq. Solution (0.5 M). The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated in vacuum. The residue was purified by flash chromatography, eluted with PE/EtOAc (0-25%) to afford 3.7 g (51.33%) of the title product as a white solid.

Step 2: 3-(difluoromethyl)-2,4-difluorobenzonitrile

[0223] ##STR00081##

[0224] To a stirred solution of 2,4-difluoro-3-formylbenzonitrile (3.7 g, 22.14 mmol, 1 equiv) in DCM (40 mL) was added DAST (7.1 g, 44.28 mmol, 2.0 equiv) in portions at room temperature under nitrogen atmosphere. After stirring for 3 h, the reaction mixture was concentrated in vacuum. The residue was purified by flash chromatography, eluted with PE/EtOAc (10:1) to afford 3.4 g, (81.20%) of title product as a white solid.

Step 3: 4-(3-cyano-5-fluorophenoxy)-3-(difluoromethyl)-2-fluorobenzonitrile

[0225] ##STR00082##

[0226] To a stirred mixture of 3-(difluoromethyl)-2,4-difluorobenzonitrile (4 g, 21.15 mmol, 1.0 equiv) and K.sub.3PO.sub.4 (4.5 g, 21.20 mmol, 1.0 equiv) in acetonitrile (100 mL) was added 3-fluoro-5-hydroxybenzonitrile (2.2 g, 15.86 mmol, 0.75 equiv) in portions at room temperature under nitrogen atmosphere. The reaction mixture was stirred for 2 h and then quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated in vacuum. The residue was purified by flash chromatography, with PE/EtOAc (5:1) as eluent to afford 3.9 g of crude product. The crude product was purified by reverse flash chromatography under following conditions: column, C18 silica gel; ACN in water, 30% to 75% gradient to give 1.6 g (24.70%) of the title compound as a white solid.

Step 4: 4-(3-cyano-5-fluorophenoxy)-3-(difluoromethyl)-2-(methylthio)benzonitrile

[0227] ##STR00083##

[0228] To a stirred solution of 4-(3-cyano-5-fluorophenoxy)-3-(difluoromethyl)-2-fluorobenzonitrile (600 mg, 1.96 mmol, 1.0 equiv) in ACN (40 mL) was added sodium thiomethoxide (206.0 mg, 2.94 mmol, 1.5 equiv) at 0° C. The resulting mixture was stirred for 4 h at this temperature and then quenched with water at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated in vacuum. The residue was purified by flash chromatography, using with PE/EtOAc (5:1) as eluent to afford 430 mg (67.87%) of the title compound as a light yellow solid.

Step 5: 4-(3-cyano-5-fluorophenoxy)-3-(difluoromethyl)-2-(methylsulfinyl)benzonitrile

[0229] ##STR00084##

[0230] To a stirred solution of 4-(3-cyano-5-fluorophenoxy)-3-(difluoromethyl)-2-(methylsulfanyl)-benzonitrile (100 mg, 0.3 mmol, 1.0 equiv) in ACN (4 mL) were added a solution of Oxone (276 mg, 0.45 mmol, 1.5 equiv) in water (0.4 mL) at room temperature. The reaction mixture was stirred for 3 h at 45° C. and then quenched with water at room temperature. The resulting mixture was extracted with CH.sub.2Cl.sub.2. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated in vacuum. The residue was purified by Prep-TLC (PE/EtOAc=2/1) to afford 50 mg (47.7%) of the title product as a white solid. MS (ES, m/z): [M+1]=351.

Step 6: 3-((7-(difluoromethyl)-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0231] ##STR00085##

[0232] To a stirred solution of 4-(3-cyano-5-fluorophenoxy)-3-(difluoromethyl)-2-methanesulfinylbenzonitrile (500 mg, 1.43 mmol, 1.0 equiv) in THE (20 mL) was added LDA (0.85 mL, 1.71 mmol, 1.2 equiv) dropwise at −78° C. under nitrogen atmosphere. The reaction solution was stirred for 3 h −78° C. and then quenched with water at −78° C. The resulting mixture was diluted with EtOAc and the phases were separated. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by flash chromatography, using PE/EtOAc (5:1) as eluent to afford the title compound (200 mg, 39.8%) as a white solid. MS (ES, m/z): [M+1+41].sup.+=393.1.

Step 7: 3-((7-(difluoromethyl)-2,2-difluoro-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0233] ##STR00086##

[0234] To a stirred solution of 3-((7-(difluoromethyl)-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile (240 mg, 0.68 mmol, 1.0 equiv) in acetonitrile (10 mL) were added Na.sub.2CO.sub.3 (159.3 mg, 1.50 mmol, 2.2 equiv) and selectfluor (532.4 mg, 1.50 mmol, 2.2 equiv) at room temperature. After stirring for 2 h, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, with PE/EtOAc (10:1) as eluent to afford the title compound (150 mg, 56.6%) as a white solid. GCMS (EI): [M]=387.

Example 2

Synthesis of 3-((7-(difluoromethyl)-2,2-difluoro-3-hydroxy-1-oxido-2,3-dihydrobenzo[b]-thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0235] ##STR00087##

[0236] To a stirred solution of 3-((7-(difluoromethyl)-2,2-difluoro-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile (40 mg, 1 equiv) in MeOH (2 mL) was added NaBH.sub.4 (8 mg, 0.21 mmol, 2.05 equiv) at 0° C. The reaction solution was stirred for 1 h at 0° C. and then quenched with water at 0° C. The resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (30 mg, 74.6%) as a white solid.

Example 3

Synthesis of a mixture of 3-(((1S,3R)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]-thiophen-6-yl)oxy)-5-fluorobenzonitrile and 3-(((1R,3S)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile (3a) and a mixture of 3-(((1S,3S)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile and 3-(((1R,3R)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile (3b

[0237] ##STR00088##

[0238] To a stirred solution of 3-[[7-(difluoromethyl)-2,2-difluoro-3-hydroxy-1-oxo-2,3-dihydro-1lambda4-benzothiophen-6-yl]oxy]-5-fluorobenzonitrile (30 mg, 0.08 mmol, 1.0 equiv) in DCM (3 mL) was added DAST (16.1 mg, 0.10 mmol, 1.3 equiv) in portions at room temperature under nitrogen atmosphere. The reaction solution was stirred for 2 h and then quenched by saturated sodium carbonate aqueous solution. The resulting mixture was extracted with CH.sub.2Cl.sub.2. The combined organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by Prep-HPLC to afford the title compounds (8.5 mg, 28%) as a white solid. The material was separated chiral HPLC to give two enantiomers. The configuration of these two enantiomers were not established.

[0239] Separation condition: CHTRALPAK IA-3 column; flow rate: 1.0 mL/min; EtOH/Hexane 20% One of 3a and 3b has t.sub.R=2.0 min; MS (ES, m/z): [M−1]=390 and the other of 3a and 3b has t.sub.R=2.5 min; MS (ES, m/z): [M−1]=390.

Example 4

Synthesis of 3-chloro-5-((7-(difluoromethyl)-2,2-difluoro-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile

[0240] ##STR00089##

Step 1: 4-bromo-2-fluoro-3-formylbenzonitrile

[0241] ##STR00090##

[0242] To a stirred solution of 4-bromo-2-fluorobenzonitrile (20 g, 100 mmol, 1.0 equiv) in THE (200 mL) was added LDA (75.00 mL, 150 mmol, 1.5 equiv) dropwise at −78° C. under nitrogen atmosphere. After stirred at −78° C.˜−60° C. for 30 minutes, and methyl formate (12.01 g, 200 mmol, 2.0 equiv) was added to the above mixture dropwise over 1 min at −78° C. and the resulting mixture was stirred for additional 1 min at −78° C. The reaction mixture was poured into HCl aq. solution (0.5 M, 400 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, with EtOAc/PE (0-25%) as eluent to afford the title compound 11g (48.2%) as a yellow solid.

Step 2: 4-bromo-3-(difluoromethyl)-2-fluorobenzonitrile

[0243] ##STR00091##

[0244] To a stirred solution of 4-bromo-2-fluoro-3-formylbenzonitrile (24 g, 105.25 mmol, 1.0 equiv) in DCM (300 mL) was added DAST (33.93 g, 210.51 mmol, 2.0 equiv) dropwise at room temperature under nitrogen atmosphere. After stirred for 3 h, the reaction was quenched with sat. NaHCO.sub.3 aq. solution at 0° C. and then extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, using PE/EtOAc (10:1) as eluent to afford the title compound 20 g (76%) as a yellow solid.

Step 3: 4-bromo-3-(difluoromethyl)-2-(methylthio)benzonitrile

[0245] ##STR00092##

[0246] To a stirred solution of 4-bromo-3-(difluoromethyl)-2-fluorobenzonitrile (10 g, 40 mmol, 1. equiv) in ACN (150 mL) was added (methylsulfanyl)sodium (5.61 g, 80 mmol, 2.0 equiv) at 0° C. After stirring at rt for 4 h, the reaction mixture was quenched with water at 0° C. and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude material (8.8 g) was used in next step directly without further purification.

Step 4: 4-bromo-3-(difluoromethyl)-2-(methylsulfinyl)benzonitrile

[0247] ##STR00093##

[0248] To a stirred solution of 4-bromo-3-(difluoromethyl)-2-(methylsulfanyl)benzonitrile (8.8 g, 31.64 mmol, 1.0 equiv) in ACN (150 mL) were added Oxone (10.64 g, 63.27 mmol, 2.0 equiv) and water (15 mL) at room temperature. After stirring for 3 h at 40° C., the reaction was quenched with water at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, with EtOAc/PE (10%-40%) as eluent to afford the title compound 6 g (64.4%) as a white solid.

Step 5: 6-bromo-7-(difluoromethyl)benzo[b]thiophen-3(2H)-one 1-oxide

[0249] ##STR00094##

[0250] To a stirred solution of 4-bromo-3-(difluoromethyl)-2-methanesulfinylbenzonitrile (3.0 g, 10.20 mmol, 1.0 equiv) in THE (250 mL) was added LDA (8.67 mL, 17.34 mmol, 1.7 equiv) in THF (300 mL) dropwise at −78° C. under nitrogen atmosphere. After stirring for 1 hour at −78° C.˜−70° C., the reaction was quenched with HCl aq. Solution (0.5 M, 200 mL) and then stirred at 0° C. for 1 h. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (20%-50%) to afford the title compound 0.8 g (26.6%) as a light yellow solid. MS (ES, m/z): [M−1].sup.+=295.

Step 6: 6-bromo-7-(difluoromethyl)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide

[0251] ##STR00095##

[0252] To a stirred solution of 6-bromo-7-(difluoromethyl)benzo[b]thiophen-3(2H)-one 1-oxide (0.8 g, 2.71 mmol, 1.0 equiv) in ACN (15 mL) were added selectfluor (2.11 g, 5.96 mmol, 2.2 equiv) and Na.sub.2CO.sub.3 (0.63 g, 5.96 mmol, 2.2 equiv) at room temperature under nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20%-50%) to afford the title compound (0.8 g) as a light yellow solid. MS (ES, m/z): [M−1].sup.+=331.

Step 7: 3-chloro-5-((7-(difluoromethyl)-2,2-difluoro-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile

[0253] ##STR00096##

[0254] To a stirred solution of 6-bromo-7-(difluoromethyl)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide (40 mg, 0.12 mmol, 1.0 equiv) and 3-chloro-5-hydroxybenzonitrile (18.55 mg, 0.12 mmol, 1.0 equiv) in DMF (1 mL) was added Cs.sub.2CO.sub.3 (43.30 mg, 0.13 mmol, 1.1 equiv) at room temperature under nitrogen atmosphere. After stirring at rt for 2 h, the reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (10%-30%) to afford the title compound (35 mg, 71.75%) as a light yellow solid. MS (ES, m/z): [M+1]=404.

Example 5

Synthesis of 3-chloro-5-((7-(difluoromethyl)-2,2-difluoro-3-hydroxy-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile

[0255] ##STR00097##

[0256] To a stirred solution of 3-chloro-5-((7-(difluoromethyl)-2,2-difluoro-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile (75 mg, 0.186 mmol, 1.0 equiv) in MeOH (1 mL) was added NaBH.sub.4 (14.06 mg, 0.372 mmol, 2.0 equiv) at room temperature. After stirring for 1 h at room temperature, the reaction was quenched with sat. NH.sub.4Cl aq. solution at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the title compound (65 mg, 86.2%) as a white solid. MS (ES, m/z): [M−1].sup.+=406.

Example 6

Synthesis of 3-chloro-5-(((1R,3R)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile (6a), 3-chloro-5-(((1S,3S)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile (6b), 3-chloro-5-(((1S,3R)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile (6c) and 3-chloro-5-(((1R,3S)-7-(difluoromethyl)-2,2,3-trifluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile (6d

[0257] ##STR00098##

[0258] To a stirred solution of 3-chloro-5-((7-(difluoromethyl)-2,2-difluoro-3-hydroxy-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)benzonitrile (65 mg, 0.16 mmol, 1.0 equiv) in DCM (1 mL) was added DAST (38.73 mg, 0.24 mmol, 1.5 equiv) dropwise room temperature under nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction was quenched with sat. NaHCO.sub.3 aq. solution at 0° C. The resulting mixture was extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crud product (70 mg) was purified by Chiral-HPLC to afford four enantiomerically pure compounds. The compound numbers below are arbitrarily assigned to specific enantiomers since the configuration of these isomers has not been established.

[0259] Separation condition: Chiral HPLC CHIRALPAK AD-3; flow rate: 1.0 mL/min; EtOH/Hexane 20%. Retention times of the four isomers were: t.sub.R=1.7 min, 2.0 min, 2.5 min, 3.4 min and their MS (ES, m/z): [M−1].sup.−=406.

Example 7

Synthesis of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide

[0260] ##STR00099##

[0261] To a stirred mixture of 6-bromo-7-(difluoromethyl)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide (0.1 g, 0.30 mmol, 1.0 equiv) and 3,5-difluorophenol (43.22 mg, 0.33 mmol, 1.1 equiv) in DMF (1 mL) was added Cs.sub.2CO.sub.3 (108.25 mg, 0.33 mmol, 1.10 equiv) at room temperature. After stirring for 2 h at room temperature, the reaction was quenched with water at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (10%-40%) to afford the title compound 90 mg (78.4%) as a light yellow solid. MS (ES, m/z): [M+1]=381.

Example 8

Synthesis of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydrobenzo[b]thiophene 1-oxide

[0262] ##STR00100##

[0263] To a stirred solution of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluorobenzo[b]-thiophen-3(2H)-one 1-oxide (90 mg, 0.23 mmol, 1.00 equiv) in THF (2 mL) was added L-selectride (0.28 mL, 0.28 mmol, 1.20 equiv) dropwise in portions at 0° C. under nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction was quenched with sat. NH.sub.4 aq. solution at 0° C. and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with EtOAc/PE (10%-35%) to afford the title compound 70 mg (77.4%) as a light yellow oil. MS (ES, m/z): [M−1].sup.+=383.

Example 9

Synthesis of (1S,3S)-7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (9a) and (1R,3R)-7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (9b) and (1R,3S)-7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (9c) and (1R,3S)-7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (9d

[0264] ##STR00101##

[0265] To a stirred solution of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2-difluoro-3-hydroxy-2,3-dihydrobenzo[b]thiophene 1-oxide (70 mg, 0.18 mmol, 1.0 equiv) in DCM (1.0 mL) was added DAST (44.27 mg, 0.27 mmol, 1.5 equiv) dropwise at rt under nitrogen atmosphere. After stirring for 2 h at rt, the reaction was cooled at 0° C. and quenched with sat. NaHCO.sub.3 aq. solution. The resulting mixture was extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The crude material (60 mg) was purified by Chiral-HPLC to afford four enantiomerically pure compounds. The compound numbers are arbitrarily assigned to specific enantiomers since the configuration of these isomers has not been established.

[0266] Separation condition: Chiral HPLC CHIRALCEL OD-3; flow rate: 1.0 mL/min; EtOH/Hexane 5%. Retention times for the four isomers were t.sub.R: 1.7 min, 2.1 min, 2.9 min, 4.2 min and their MS (ES, m/z) [M+1].sup.+=383.

Example 10

Synthesis of 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide

[0267] ##STR00102##

[0268] To a stirred mixture of 6-bromo-7-(difluoromethyl)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide (0.2 g, 0.60 mmol, 1.0 equiv) and 3-chloro-5-fluorophenol (97.38 mg, 0.66 mmol, 1.1 equiv) in DMF (2 mL) was added Cs.sub.2CO.sub.3 (216.50 mg, 0.66 mmol, 1.1 equiv) at rt. After stirring for 2 h at rt, the reaction was quenched with water at 0° C. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford the title compound (0.17 g, 70.94%) as a light yellow solid. MS (ES, m/z): [M+1].sup.+=396.9.

Example 11

Synthesis of 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2-difluoro-3-hydroxy-2,3-dihydrobenzo[b]thiophene 1-oxide

[0269] ##STR00103##

[0270] To a stirred solution of 6-(3-chloro-5-fluorophenoxy-7-(difluoromethyl)-2,2-difluorobenzo[b]thiophen-3(2H)-one 1-oxide (100 mg, 0.25 mmol, 1.0 equiv) in THE (2 mL) was added L-selectride (0.30 mL, 0.30 mmol, 1.2 equiv) at 0° C. under nitrogen atmosphere. After stirring for 2 h at room temperature, the reaction was quenched with sat. NH.sub.4Cl aq. solution at 0° C. and then extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford the title compound (70 mg, 69.6%) as a light yellow oil. MS (ES, m/z): [M+1]=400.0.

Example 12

Synthesis of (1S,3S)-6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (12a) and (1R,3R)-6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (12b) and (1R,3S)-6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (12c) and (1S,3R)-6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3-trifluoro-2,3-dihydrobenzo[b]thiophene 1-oxide (12d

[0271] ##STR00104##

[0272] To a stirred solution of 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2-difluoro-3-hydroxy-2,3-dihydrobenzo[b]thiophene 1-oxide (70 mg, 0.17 mmol, 1.0 equiv) in DCM (1 mL) was added DAST (42.45 mg, 0.26 mmol, 1.5 equiv) dropwise at rt under nitrogen atmosphere. After stirring for 2 h at rt, the reaction was quenched with sat. NaHCO.sub.3 aq. solution at 0° C. The resulting mixture was extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentration. The crude material was purified by Chiral-HPLC to afford four enantiomerically pure compounds. The compound numbers are arbitrarily assigned to specific enantiomers since the configuration of each isomer has not been established.

[0273] Separation condition: Chiral HPLC CHIRALCEL OD; Flow rate: 1.0 ml/min; IPA/hexane 8%. Retention times for the four isomers were: t.sub.R: 1.7, 2.1, 3.2, 4.5 min; and their MS (ES, m/z) [M−1].sup.−=399;

Example 13

Synthesis of (R)-3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile and (S)-3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0274] ##STR00105##

Step 1: 1-(2-bromo-5-fluorophenoxy)-N,N-dimethylmethanethioamide

[0275] ##STR00106##

[0276] Into a 500-mL 4-necked round-bottom flask, was placed DMF (200 mL), 2-bromo-5-fluorophenol (30 g, 0.157 mol, 1 equiv), DABCO (35.24 g, 0.314 mol, 2 equiv), and (chloromethanethioyl)dimethylamine (38.83 g, 0.314 mol, 2.00 equiv). The resulting solution was stirred for 16 h at 20° C. and then diluted with H.sub.2O. The resulting solution was extracted with of ethyl acetate and the organic layer was washed with of brine. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated to give 21 g of the title compound as a white solid.

Step 2: 1-[(2-bromo-5-fluorophenyl)sulfanyl]-N,N-dimethylformamide

[0277] ##STR00107##

[0278] Into a 250-mL 4-necked round-bottom flask, was placed 1-(2-bromo-5-fluorophenoxy)-N,N dimethylmethanethioamide (21 g, 75.502 mmol, 1.0 equiv) and phenoxybenzene (80 mL). The resulting solution was stirred for 3 h at 250° C. in a heating jacket bath. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). The collected fractions were combined and concentrated to give 11 g (52%) of the title compound as a white solid.

Step 3: 2-bromo-5-fluorobenzene-1-thiol

[0279] ##STR00108##

[0280] Into a 250-mL 4-necked round-bottom flask, was placed MeOH (80 mL), 1-[(2-bromo-5-fluorophenyl)sulfanyl]-N,N-dimethylformamide (11 g, 39.548 mmol, 1.0 equiv), and NaOH (1M aq. solution) (3.95 g, 98.871 mmol, 2.5 equiv). The resulting solution was stirred for 3 h at 50° C. in an oil bath. After cooling the reaction mixture to rt, the reaction was acidified to pH=2 by adding aq. HCl solution (1.0 M). The resulting solution was extracted with ethyl acetate and the organic layers were combined and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10) to give 6.0 g (73.2%) of the title compound as colorless oil.

Step 4: 1-bromo-2-[(2-bromo-1,1,2,2-tetrafluoroethyl)sulfanyl]-4-fluorobenzene

[0281] ##STR00109##

[0282] To a stirred solution of 2-bromo-5-fluorobenzene-1-thiol (1.1 g, 5.31 mmol, 1.0 equiv) in DMF (15 mL) was added NaH (0.3 g, 7.97 mmol, 1.5 equiv, 60% in oil) in portions at −40° C.˜ 0° C. and the resulting mixture was stirred at 0° C. for 30 mins. To the above mixture was added 1,2-dibromo-1,1,2,2-tetrafluoroethane (1.7 g, 6.64 mmol, 1.25 equiv) dropwise at −40° C. The resulting mixture was allowed to warm to 0° C. and stirred for additional 3 h at 0° C. The reaction mixture was quenched by the addition of water at 0° C. and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, with PE as eluent to afford 1.2 g (58.5%) of the title compound as a light yellow oil.

Step 5: 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene

[0283] ##STR00110##

[0284] To a stirred mixture of 1-bromo-2-[(2-bromo-1,1,2,2-tetrafluoroethyl)sulfanyl]-4-fluorobenzene (0.9 g, 2.33 mmol, 1 equiv) and Cu (0.7 g, 11.66 mmol, 5 equiv) in DMSO (5 mL) was added 2,2-bipyridine (36.4 mg, 0.23 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1.5 h at 150° C. under nitrogen atmosphere. After cooling the reaction mixture to rt, the mixture was diluted with water/EtOAc and filtered. The filtrate was extracted with EtOAc and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, with hexane as eluent to afford 0.24 g (45.5%) of the title compound as a light-yellow oil.

Step 6: 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene-7-carbaldehyde

[0285] ##STR00111##

[0286] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene (0.24 g, 1.06 mmol, 1.0 equiv) in THE (5 mL) was added LDA (0.85 mL, 1.7 mmol) dropwise at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C.˜−60° C. for 30 minutes. To the above mixture was added DMF (0.2 mL, 1.37 mmol, 1.22 equiv) dropwise over 5 minutes at −78° C. The resulting mixture was stirred for additional 5 minutes at −78° C. and the reaction mixture was poured into 0.5 M HCl aq. solution. The mixture was extracted with EtOAc and the combined organic layers were washed with brine and, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford 120 mg of the title compound as a light yellow oil.

Step 7: 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene

[0287] ##STR00112##

[0288] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene-7-carbaldehyde (120 mg, 0.472 mmol, 1.0 equiv) in DCM (4 mL) was added DAST (190.25 mg, 1.180 mmol, 2.5 equiv) dropwise at room temperature under nitrogen atmosphere. After stirring for 2 h, the reaction was quenched with sat. NaHCO.sub.3 (aq.) at room temperature. The resulting mixture was extracted with CH.sub.2Cl.sub.2 and the combined organic layers were washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (10:1) to afford 35 mg of the title compound as a light yellow oil.

Step 8: 3-[[7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1-benzothiophen-6-yl]oxy]-5-fluorobenzonitrile

[0289] ##STR00113##

[0290] To a stirred mixture of 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene (35 mg, 0.127 mmol, 1.0 equiv) and Cs.sub.2CO.sub.3 (41.29 mg, 0.127 mmol, 1.0 equiv) in DMF (1 mL) was added 3-fluoro-5-hydroxybenzonitrile (17.38 mg, 0.127 mmol, 1.0 equiv) at room temperature under nitrogen atmosphere. After stirring for 5 h at room temperature, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (10:1) to afford the title compound 35 mg (70.22%) as a light yellow oil.

Step 9: (R)-3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile (13a) and (S)-3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile (13b

[0291] ##STR00114##

[0292] To a stirred solution of 3-[[7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1-benzothiophen-6-yl]oxy]-5-fluorobenzonitrile (35 mg, 0.089 mmol, 1.0 equiv) in CH.sub.3COOH (1 mL) was added H.sub.2O.sub.2 (0.3 mL, 30%) dropwise at room temperature. After stirring for 1 h at 90° C. the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO, and concentrated. The crude product was purified by Prep-HPLC to afford 16 mg (43.9%) of the the title compound as a white solid. The product was further separated by chiral HPLC to afford two enantiomers. The compound numbers are arbitrarily assigned to specific enantiomers since the absolute configuration of these isomers was not established.

[0293] Separation condition: CHIRALPAK IC-3 column; Flow rate: 1.0 ml/min; EtOH/hexane 20%.

[0294] One of 13a and 13b has t.sub.R=1.7 min; MS (ES, m/z): [M−1].sup.−=408;

[0295] The other of 13a and 13b: t.sub.R=2.1 min; MS (ES, m/z): [M−1].sup.−=408.

Example 14

Synthesis of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene 1-oxide

[0296] ##STR00115##

[0297] To a stirred solution of 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene (200 mg, 1.0 equiv) in AcOH (1.2 mL) were added 30% H.sub.2O.sub.2 (0.4 mL). The resulting mixture was stirred for 3 h at 90° C. under air atmosphere. The resulting mixture was added brine and then extracted with EtOAc. The combined organic layers were concentrated and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford the title compound (150 mg, 70%) as a colorless oil. .sup.1HNMR (300 MHz, CDCl.sub.3) δ 8.04 (ddq, J=8.8, 4.4, 1.1 Hz, 1H), 7.71-7.61 (m, 1H), 7.43-7.01 (m, 1H).

Example 15

Synthesis of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene 1-oxide

[0298] ##STR00116##

[0299] To a stirred solution of 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydrobenzo-[b]thiophene 1-oxide (15 mg, 0.05 mmol, 1.0 equiv) and 3,5-difluorophenol (10.02 mg, 0.08 mmol, 1.5 equiv) in ACN (0.30 mL) were added Cs.sub.2CO.sub.3 (50.18 mg, 0.15 mmol, 3.0 equiv) in portions at rt under air atmosphere. After stirring at 70° C. for 2 h, the resulting mixture was cooled at rt and filtered. The filtrate was concentrated and purified by Prep-HPLC to afford the title product (5 mg) as a white solid. MS (ES, m/z): [M−1].sup.−=400.9.

Example 16

Synthesis of 5-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)nicotinonitrile

[0300] ##STR00117##

[0301] The title compound was synthesized followed by the method described in Example 15 using 5-hydroxynicotinonitrile instead of 3,5-difluorophenol. MS (ES, m/z): [M+H].sup.+=393.0.

Example 17

Synthesis of 7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydrobenzo[b]thiophene 1-oxide

[0302] ##STR00118##

[0303] The title compound was synthesized followed by the method described in Example 15 using 5-fluoropyridin-3-ol instead of 3,5-difluorophenol. MS (ES, m/z): [M−1].sup.+=386.0.

Example 18

Synthesis of 6-((5-chloropyridin-3-yl)oxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene 1-oxide

[0304] ##STR00119##

[0305] The title compound was synthesized followed by the method described in Example 15 using 5-chloropyridin-3-ol instead of 3,5-difluorophenol. MS (ES, m/z): [M−1].sup.−=399.9.

Example 19

Synthesis of 6-(3,3-difluorocyclobutoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene 1-oxide [3.6]

[0306] ##STR00120##

[0307] The title compound was synthesized followed by the method described Example 15 using 3,3-difluorocyclobutan-1-ol instead of 3,5-difluorophenol. MS (ES, m/z): [M+41+1]+=422.1.

Example 20

Synthesis of 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrobenzo-[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0308] ##STR00121##

Step 1: 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydrobenzo[b]thiophene 1,1-dioxide

[0309] ##STR00122##

[0310] Into an 8-mL vial, was placed 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene (50 mg, 0.18 mmol, 1.0 equiv), AcOH (2 mL), KMnO.sub.4 (228 mg, 1.45 mmol, 8.0 equiv). The resulting mixture was stirred at 100° C. for 30 mins. The resulting solution was diluted with water and extracted ethyl acetate. The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1/1) to afford 35 mg (62.7%) of the title compound as light yellow oil. GCMS (EI): [M]=308.

Step 2: 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0311] ##STR00123##

[0312] Into an 8-mL vial, was placed 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydrobenzo-[b]thiophene 1,1-dioxide (35 mg, 0.11 mmol, 1.0 equiv), Cs.sub.2CO.sub.3 (74 mg, 0.23 mmol, 2.0 equiv), DMF (1 mL), 3-fluoro-5-hydroxybenzonitrile (23.4 mg, 0.17 mmol, 1.5 equiv). The resulting mixture was stirred at 100° C. for 16 h. After cooled at rt, the reaction mixture was filtered and the filtrate was concentrated under vacuum. The crude material was purified by Prep-HPLC to afford 19 mg (39.34%) of the title compound as a white solid. MS (ES, m/z): [M−1].sup.+=424.

Example 21

Synthesis of 3-((2,2-difluoro-7-iodo-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5 fluorobenzonitrile

[0313] ##STR00124##

Step 1: methyl 2-((5-fluoro-2-iodophenyl)thio)acetate

[0314] ##STR00125##

[0315] Into a 250-mL round-bottom flask, was placed 2,4-difluoro-1-iodobenzene (10 g, 41.6 mmol, 1.0 equiv), DMF (150 mL), K.sub.3PO.sub.4 (10.613 g, 50 mmol, 1.2 equiv), methyl 2-sulfanylacetate (5.307 g, 50 mmol, 1.2 equiv). After stirring at rt for 24 h, the reaction mixture was diluted with water and extracted PE/EA (3/1). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether (1/10) to afford 2.8 g (20.6%) of the title compound.

Step 2: 2-((5-fluoro-2-iodophenyl)thio)acetic acid

[0316] ##STR00126##

[0317] Into a 100-mL round-bottom flask, was placed methyl 2-[(5-fluoro-2-iodophenyl)sulfanyl]-acetate (2.8 g, 8.58 mmol, 1.0 equiv), THE (40 mL), water (20 mL), lithium hydroxide monohydrate (1.08 g, 25.757 mmol, 3.0 equiv) and the resulting solution was stirred for 16 h at room temperature. The reaction mixture was then acidified to pH=5 with HCl aq. solution (1.0 M). The resulting solution was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed with a mixed solution of PE/EA=20/1 and filtered to afford 2.25 g (83.9%) of the title compound as a white solid.

Step 3: 4-fluoro-7-iodobenzo[b]thiophen-3(2H)-one

[0318] ##STR00127##

[0319] Into a 40-mL vial, was placed 2-[(5-fluoro-2-iodophenyl)sulfanyl]acetic acid (2.2 g, 7.049 mmol, 1.0 equiv), 1,2-dichlorobenzene (7 mL), N,N-dimethylformamide (26 mg, 0.352 mmol, 0.05 equiv), thionyl chloride (922 mg, 7.754 mmol, 1.1 equiv). The resulting solution was stirred for 1 h at 60° C. in an oil bath. The reaction was cooled to rt and added a mixture of trichloroalumane (1.4 g, 10.574 mmol, 1.5 equiv) in 1,2-dichlorobenzene (5 mL), while the temperature maintained at 0-10° C. The resulting mixture was stirred for an additional 1.5 h and then poured into ice. The precipitate was collected by filtration, washed with water and PE. The collected solid was then dried to give 1.6 g (77.18%) of the title compound.

Step 4: 4-fluoro-7-iodobenzo[b]thiophen-3(2H)-one 1-oxide

[0320] ##STR00128##

[0321] Into a 50-mL round-bottom flask, was placed 4-fluoro-7-iodo-2,3-dihydro-1-benzothiophen-3-one (1000 mg, 3.400 mmol, 1.0 equiv), DCM (15 mL), acetic acid (5 mL), 30% H.sub.2O.sub.2 (771 mg, 22.667 mmol, 6.67 equiv) and the resulting solution was stirred for 4 h at 50° C. in an oil bath. After cooling the reaction mixture to rt, the reaction mixture as neutralized to pH=7 by adding Na.sub.2CO.sub.3. The resulting mixture was diluted with water and extracted with DCM. The organic layer was combined and dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:2) to afford 780 mg (73.9%) of the title compound. MS (ES, m/z): [M−1].sup.+=311.0.

Step 5: 2,2,4-trifluoro-7-iodobenzo[b]thiophen-3(2H)-one 1-oxide

[0322] ##STR00129##

[0323] Into a 50-mL round-bottom flask, was placed 4-fluoro-7-iodobenzo[b]thiophen-3(2H)-one 1 oxide (780 mg, 2.515 mmol, 1.0 equiv), acetonitrile (15 mL), sodium carbonate (538 mg, 5.031 mmol, 2.0 equiv), selectfluor (1782 mg, 5.031 mmol, 2.0 equiv) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was then concentrated under vacuum and to the residue was added DCM and water. The phases were separated and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography by eluting with ethyl acetate/petroleum ether (1:2) to afford 660 mg (75.8%) of the title compound. MS (ES, m/z): [M−1].sup.+=346.9.

Step 6: 3-((2,2-difluoro-7-iodo-1-oxido-3-oxo-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile

[0324] ##STR00130##

[0325] Into a 40-mL vial, was placed 2,2,4-trifluoro-7-iodobenzo[b]thiophen-3(2H)-one 1-oxide (660 mg, 1.907 mmol, 1.0 equiv), DMF (6 mL), 3-fluoro-5-hydroxybenzonitrile (314 mg, 2.289 mmol, 1.2 equiv), Cs.sub.2CO.sub.3 (1247 mg, 3.814 mmol, 2.0 equiv). After stirring at rt for 1 h, the reaction was quenched by water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography by eluting with ethyl acetate/petroleum ether (1:3) to afford 500 mg (56.6%) of the title compound as a yellow solid. MS (ES, m/z): [M−1].sup.+=464.0.

Example 22

Synthesis of 3-((2,2-difluoro-3-hydroxy-7-iodo-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile

[0326] ##STR00131##

[0327] Into an 8-mL vial, was placed 3-((2,2-difluoro-7-iodo-1-oxido-3-oxo-2,3-dihydrobenzo-[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile (230 mg, 0.497 mmol, 1.0 equiv), methanol (2 mL), NaBH.sub.4 (38 mg, 0.993 mmol, 2.0 equiv). After stirring at rt for 2 h, the reaction was quenched by HCl aq. solution (1.0 M) and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography by eluting with ethyl acetate/petroleum ether (1:3) to afford 200 mg (86.58%) of the title compound as yellow oil. MS (ES, m/z): [M−1].sup.+=465.9.

Example 23

Synthesis of 3-((2,2-difluoro-3-hydroxy-7-(methylsulfonyl)-1-oxido-2,3-dihydro-benzo[b]-thiophen-4-yl)oxy)-5-fluorobenzonitrile

[0328] ##STR00132##

[0329] Into an 8-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed 3-((2,2-difluoro-3-hydroxy-7-iodo-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile (275 mg, 0.591 mmol, 1.0 equiv), sodium methanesulfinate (91 mg, 0.887 mmol, 1.5 equiv), DMSO (3 mL), sodium (2S)-pyrrolidine-2-carboxylate (16 mg, 0.118 mmol, 0.2 equiv), CuI (23 mg, 0.118 mmol, 0.2 equiv). The resulting solution was stirred for 24 h at 65° C. in an oil bath. After cooled at rt, water was added and mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum.

[0330] The residue was purified by silica gel column chromatography by eluting with ethyl acetate/petroleum ether (1:1) to afford 75 mg (30.4%) of the title compound as a yellow solid. MS (ES, m/z): [M−1].sup.+=418.0.

Example 24

Synthesis of a mixture of 3-fluoro-5-(((1R,3R)-2,2,3-trifluoro-7-(methylsulfonyl)-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile and 3-fluoro-5-(((1S,3S)-2,2,3-trifluoro-7-(methylsulfonyl)-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile (24a) and a Mixture of 3-fluoro-5-(((1S,3R)-2,2,3-trifluoro-7-(methylsulfonyl)-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile and 3-fluoro-5-(((1S,3S)-2,2,3-trifluoro-7-(methylsulfonyl)-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile (24b

[0331] ##STR00133##

[0332] Into a 2-mL vial, was placed 3-((2,2-difluoro-3-hydroxy-7-(methylsulfonyl)-1-oxido-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile (19 mg, 0.046 mmol, 1.0 equiv), DCM (0.5 mL), DAST (11 mg, 0.068 mmol, 1.5 equiv). After stirring at rt for 2 h, the reaction was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-TLC to afford 13 mg (68.1%) of the title compound as a white solid. MS (ES, m/z): [M−1].sup.+=419.9.

[0333] The material was separated by Prep-HPLC to afford two diastereomers 1.5 mg of 24a and 5.7 mg of 24b. Compounds 24a and 24b: MS (ES, m/z): [M+1]=420.

Example 25

Synthesis of 3-((2,2-difluoro-1-oxido-3-oxo-7-(trifluoromethyl)-2,3-dihydrobenzo[b]-thiophen-4-yl)oxy)-5-fluorobenzonitrile

[0334] ##STR00134##

Step 1: 2,2,4-trifluoro-7-(trifluoromethyl)benzo[b]thiophen-3(2H)-one 1-oxide

[0335] ##STR00135##

[0336] To a stirred mixture of 2,2,4-trifluoro-7-iodobenzo[b]thiophen-3(2H)-one 1-oxide (500 mg, 1.44 mmol, 1.0 equiv) and methyl 2,2-difluoro-2-sulfoacetate (832.70 mg, 4.33 mmol, 3.0 equiv) in DMF (6 mL) was added CuI (27.52 mg, 0.14 mmol, 0.1 equiv). The resulting mixture was stirred for 1 h at 100° C. under nitrogen atmosphere. After cooled at rt, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (3:1) to afford the title compound 275 mg (66%) as a yellow solid. MS (ES, m/z): [M−1].sup.+=288.9.

Step 2: 3-((2,2-difluoro-1-oxido-3-oxo-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile

[0337] ##STR00136##

[0338] Into an 8 mL vial were added DMF (2 mL), 2,2,4-trifluoro-7-(trifluoromethyl)benzo[b]-thiophen-3(2H)-one 1-oxide (176 mg, 0.61 mmol, 1.0 equiv), 3-fluoro-5-hydroxybenzonitrile (92.12 mg, 0.67 mmol, 1.1 equiv) and Cs.sub.2CO.sub.3 (398.00 mg, 1.22 mmol, 2.0 equiv) at room temperature. After stirring at rt for 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were washed with water, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (2:1) to afford the title compound 93 mg (37.57%) as a yellow oil. MS (ES, m/z): [M+1].sup.+=406.0.

Example 26

Synthesis of 3-((2,2-difluoro-3-hydroxy-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile

[0339] ##STR00137##

[0340] To a stirred solution of 3-((2,2-difluoro-1-oxido-3-oxo-7-(trifluoromethyl)-2,3-dihydrobenzo-[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile (125 mg, 0.31 mmol, 1.0 equiv) in MeOH (3 mL) was added NaBH.sub.4 (23.34 mg, 0.62 mmol, 2.0 equiv) at room temperature. After stirring at rt for 2 h, the reaction solution was concentrated under vacuum and the residue was neutralized to pH 7 with aq. HCl solution. The resulting mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2:1) to afford the title compound 105 mg (83.5%) as a yellow oil. MS (ES, m/z): [M−1].sup.+=408.0.

Example 27

Synthesis of a mixture of 3-fluoro-5-(((1R,3R)-2,2,3-trifluoro-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile and 3-fluoro-5-(((1S,3S)-2,2,3-trifluoro-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile (27a) and a Mixture of 3-fluoro-5-(((1S,3R)-2,2,3-trifluoro-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile and 3-fluoro-5-(((1R,3S)-2,2,3-trifluoro-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)benzonitrile (27b

[0341] ##STR00138##

[0342] To a stirred solution of 3-((2,2-difluoro-3-hydroxy-1-oxido-7-(trifluoromethyl)-2,3-dihydrobenzo[b]thiophen-4-yl)oxy)-5-fluorobenzonitrile (100 mg, 0.24 mmol, 1.0 equiv) in DCM (2 mL) was added DAST (59.36 mg, 0.37 mmol, 1.5 equiv). The resulting solution was stirred for 3 h at rt. The resulting solution was diluted with DCM and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford two diastereomers 27a and 27b. MS (ES, m/z): [M−1].sup.+=410.

Example 28

Synthesis of 3-((7-chloro-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0343] ##STR00139##

Step 1: 7-chloro-2,2,3,3,6-pentafluoro-2,3-dihydrobenzo[b]thiophene

[0344] ##STR00140##

[0345] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene (200 mg, 0.88 mmol, 1.00 equiv) in THE (4 mL) was added LDA (0.88 mL, 1.326 mmol, 1.50 equiv) dropwise at −78° C. under nitrogen atmosphere. After stirring at −78° C.˜−70° C. for 0.5 hour, to the above mixture was added hexachloroethane (523.3 mg, 2.21 mmol, 2.50 equiv) and the resulting mixture was stirred at −78° C.˜−40° C. for additional 1 h. The reaction mixture was used directly in the next step.

Step 2: 3-((7-chloro-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0346] ##STR00141##

[0347] To a stirred solution of 7-chloro-2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene (above reaction solution) and 3-fluoro-5-hydroxybenzonitrile (78.9 mg, 0.57 mmol, 1.50 equiv) in ACN (2 mL) were added Cs.sub.2CO.sub.3 (250.0 mg, 0.77 mmol, 2.00 equiv) in portions at room temperature under air atmosphere. The resulting mixture was stirred at 70° C. for 16 h under air atmosphere. After the reaction mixture was cooled at rt, the resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (10:1) to afford the title compound (100 mg, 69.00%) as a white solid.

Step 3. 3-((7-chloro-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0348] ##STR00142##

[0349] To a stirred solution 3-[(7-chloro-2,2,3,3-tetrafluoro-2,3-dihydro-1-benzothiophen-6-yl)oxy]-5-fluorobenzonitrile (50 mg, 1.00 equiv) in AcOH (0.9 mL) were added 30% H.sub.2O.sub.2 (0.3 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at 90° C. for 2 h under air atmosphere. The mixture was then purified by Prep-HPL to afford the title compound (5 mg) as a white solid. MS (ES, m/z): [M−1].sup.−=391.9.

Example 29

Synthesis of 3-((7-chloro-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0350] ##STR00143##

[0351] To a stirred solution 3-[(7-chloro-2,2,3,3-tetrafluoro-2,3-dihydro-1-benzothiophen-6-yl)oxy 5-fluorobenzonitrile (50 mg, 0.13 mmol, 1.00 equiv) in AcOH (1 mL) were added 30% H.sub.2O.sub.2 (1 mL) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at 105° C. for 16 h under air atmosphere. The mixture was purified by Prep-HPLC to afford the title compound (5 mg, 9.2%) as a white solid. MS (ES, m/z): [M−1].sup.−=407.8.

Example 30

Synthesis of 3-((7-bromo-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrobenzo[b]thiophen-6-yl)oxy)-5-fluorobenzonitrile

[0352] ##STR00144##

[0353] The title compound was synthesized following the method described in Example 28 using CBr.sub.4 in step 1. GCMS (EI, m/z): [M]=436.9.

Example 31

Synthesis of 6-(3-cyano-5-fluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile 1-oxide

[0354] ##STR00145##

Step 1: 2,2,3,3,6-pentafluoro-2,3-dihydrobenzo[b]thiophene-7-carbaldehyde oxime

[0355] ##STR00146##

[0356] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene-7-carbaldehyde (300 mg, 1.18 mmol, 1.0 equiv) and hydroxylamine (97.46 mg, 2.95 mmol, 2.5 equiv) in EtOH ( mL) was added AcONa (387.30 mg, 4.72 mmol, 4.0 equiv) at rt. The resulting mixture was stirred at 90° C. for 16 h under N.sub.2 atmosphere. After cooled at rt, the reaction was quenched with H.sub.2O are then was extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the title compound (280 mg) as colorless oil.

Step 2: 2,2,3,3,6-pentafluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile

[0357] ##STR00147##

[0358] A solution of 2,2,3,3,6-pentafluoro-2,3-dihydrobenzo[b]thiophene-7-carbaldehyde oxime (200 mg, 0.74 mmol, 1.0 equiv) in Ac.sub.2O (2 mL) was heated at 100° C. for 4 h. After cooled at rt, the reaction was quenched by the addition of H.sub.2O (5 mL). The resulting mixture was extracted with EtOAc. The combined organic layers were washed with sat. Na.sub.2CO.sub.3 aq. solution, dried over anhydrous Na.sub.2SO.sub.4 and concentrated to give the title compound (150 mg) as colorless oil.

Step 3: 6-(3-cyano-5-fluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile

[0359] ##STR00148##

[0360] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-1-benzothiophene-7-carbonitrile (70 mg, 0.28 mmol, 1.0 equiv) and 3-fluoro-5-hydroxybenzonitrile (45.86 mg, 0.33 mmol, 1.2 equiv) in DMF (2 mL) was added Cs.sub.2CO.sub.3 (181.61 mg, 0.56 mmol, 2.0 equiv) at rt and the resulting mixture was stirred at rt for 16 h. The reaction was quenched with H.sub.2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EA (1/1) to afford the title compound (60 mg, 58.4%) as a colorless oil.

Step 3. 6-(3-cyano-5-fluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b]thiophene-7-carbonitrile 1-oxide

[0361] ##STR00149##

[0362] 6-(3-cyano-5-fluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1-benzothiophene-7-carbonitrile (40 mg, 0.11 mmol, 1.0 equiv) was added into a solution of H.sub.2O.sub.2 (1.5 mL) and AcOH (0.5 mL) a rt and the resulting mixture was stirred at 90° C. for 3 h. The mixture was then purified by Prep-HPLC to afford the title compound (10 mg, 23.96%) as a white solid. MS (ES, m/z): [M−1].sup.−=38:

Example 32 and 33

Synthesis of 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-6-yl)oxy)-5-fluorobenzonitrile [32] and 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrothieno[3,2-b]pyridin-6-yl)oxy)-5-fluorobenzonitrile [33]

[0363] ##STR00150##

Step 1: 2-ethylhexyl 3-[(2-bromo-5-chloropyridin-3-yl)sulfanyl]propanoate

[0364] ##STR00151##

[0365] To a stirred mixture of 2-ethylhexyl 3-sulfanylpropanoate (6.74 g, 30.889 mmol, 1.3 equiv) and 2-bromo-5-chloro-3-fluoropyridine (4.96 g, 23.760 mmol, 1.0 equiv) in DMF (50 mL) was added NaH (1.23 g, 30.889 mmol, 1.3 equiv, 60%) in portions at 0° C. under nitrogen atmosphere. The resulting mixture was stirred for 4 h at room temperature and then quenched with ice water and extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography by eluting with EtOAc/PE (0-10%) to afford the title compound (8 g, 82%).

Step 2: 2-bromo-5-chloropyridine-3-thiol

[0366] ##STR00152##

[0367] To a stirred mixture of 2-ethylhexyl 3-[(2-bromo-5-chloropyridin-3-yl)sulfanyl]propanoate (11 g, 26.909 mmol, 1.00 equiv) in THE (100 mL) was added t-BuONa (13.45 mL, 26.909 mmol, 1.00 equiv) at 0° C. under nitrogen atmosphere. After stirring for 1 h at room temperature, the mixture was acidified to pH 5 with 1.0 N HCl aq. solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (10:1) to afford the title compound (7 g, crude) as a light yellow solid.

Step 3: 2-bromo-3-[(2-bromo-1,1,2,2-tetrafluoroethyl)sulfanyl]-5-chloropyridine

[0368] ##STR00153##

[0369] To a stirred solution of 2-bromo-5-chloropyridine-3-thiol (7 g, 31.180 mmol, 1.0 equiv) in DMF (50 mL) was added NaH (1.86 g, 46.77 mmol, 1.5 equiv, 60%) in portions at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 mins at 0° C. At 0° C., 1,2-dibromo-1,1,2,2-tetrafluoroethane (10.53 g, 40.527 mmol, 1.30 equiv) was added and the reaction mixture was stirred for additional 4 hours at 0° C. The resulting mixture was quenched with ice water. The solid was filtered off and the filtrate was extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE to afford the title compound (5.8 g, 46.11%) as a colorless oil.

Step 4: 6-chloro-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]pyridine

[0370] ##STR00154##

[0371] To a stirred mixture of 2-bromo-3-[(2-bromo-1,1,2,2-tetrafluoroethyl)sulfanyl]-5-chloropyridine (3.8 g, 9.420 mmol, 1.00 equiv) and Cu (2.99 g, 47.0 mmol, 5.00 equiv) in DMSO (10 mL) was added 2,2′-bipyridine (0.15 g, 0.942 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. After stirred for 1 h at 130° C., the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE to afford the title compound (780 mg, 33.99%) as light yellow oil.

Step 5: 6-chloro-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]pyridine-7-carbaldehyde

[0372] ##STR00155##

[0373] To a stirred solution of 2,2,6,6-tetramethylpiperidine (707.28 mg, 5.007 mmol, 2.5 equiv) in THF (4 mL) was added n-BuLi (2 mL, 5.007 mmol, 2.5 M) dropwise at −30° C. under nitrogen atmosphere. After stirring for 0.5 h at 0° C., the mixture was added to 6-chloro-2,2,3,3-tetrafluoro octahydrothieno[3,2-b]pyridine (500 mg, 2.003 mmol, 1.00 equiv) in toluene (15 mL) at −78° C. The resulting mixture was stirred for 1 h between −78° C. and −70° C. To the above mixture was added ethyl formate (296.73 mg, 4.006 mmol, 2.00 equiv). The resulting mixture was stirred for additional 1 h between −78° C. and −50° C. The reaction mixture was poured into 1 M HCl, stirred for additional 2 min and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (5:1) to afford of the title compound (250 mg, 45.96%) as a light yellow solid.

Step 6: 6-chloro-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]pyridine

[0374] ##STR00156##

[0375] To a stirred solution of 6-chloro-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]pyridine-7-carbaldehyde (250 mg, 0.920 mmol, 1 equiv) in DCM (5 mL) was added DAST (741.82 mg, 4.602 mmol, 5.00 equiv) at room temperature. After stirring at rt for 16 h, the reaction mixture was quenched with saturated NaHCO.sub.3 (aq.) at 0° C. and extracted with Et.sub.2O. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated off under reduced pressure to afford of the title compound (220 mg, 81.41%) as a yellow oil.

Step 7: 3-[[7-(difluoromethyl)-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]pyridin-6-yl]oxy]-5-fluorobenzonitrile

[0376] ##STR00157##

[0377] To a stirred solution of 6-chloro-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]-pyridine (110 mg, 0.375 mmol, 1.00 equiv) in DMF (2 mL) were added 3-fluoro-5-hydroxybenzonitrile (56.51 mg, 0.412 mmol, 1.10 equiv) and Cs.sub.2CO.sub.3 (134.27 mg, 0.412 mmol, 1.10 equiv) at room temperature. After stirring at rt for 20 h, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (10:1) to afford the title compound (120 mg, 81.24% as a white solid.

Step 8: 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1-oxido-2,3-dihydrothieno[3,2-b]pyridin-6-yl)oxy)-5-fluorobenzonitrile [32] and 3-((7-(difluoromethyl)-2,2,3,3-tetrafluoro-1,1-dioxido-2,3-dihydrothieno[3,2-b]pyridin-6-yl)oxy)-5-fluorobenzonitrile [33]

[0378] ##STR00158##

[0379] To a stirred solution of 3-[[7-(difluoromethyl)-2,2,3,3-tetrafluoro-2H,3H-thieno[3,2-b]pyridin-6-yl]oxy]-5-fluorobenzonitrile (25.00 mg, 0.063 mmol, 1.00 equiv) in CH.sub.3COOH (0.90 mL) was added H.sub.2O.sub.2 (0.30 mL) at room temperature and the resulting mixture was stirred at 90° C. for 16 h. After cooling the reaction mixture to at rt, the mixture was directly purified by Prep-HPLC to afford the title compound 32 (8 mg, 30.75%) and 33 (9 mg, 33.30%).

Compound 32: MS (ES, m/z): [M+1].sup.+=408.8; Compound 33: MS (ES, m/z): [M−1].sup.+=424.8.

Biological Example

Example 1

VEGF ELISA Assay

[0380] The ability of the disclosed compounds to inhibit HIF-2α was measured by determining VEGF expression in 786-O cells. About 7500 786-O cells were seeded into each well of a 96-well, white, clear bottom plate (07-200-566, Fisher Scientific) with 200 ul growth medium. Four hours later, compounds were dispensed into wells by Tecan D300e digital dispenser with starting concentration of 10 uM and ½ log of dilution down to 1 nM as final concentration. Each concentration of treatment was performed in duplicate. About 20 hours later, medium was removed and fresh medium was added, followed by compounds treatment as described above. 24 hours later, cell culture medium was collected to determine VEGF concentration using an ELISA kit (R&D systems, cat #DVE00) following the manufacturer's instruction.

[0381] The IC.sub.50 is calculated by GraphPad Prism using the dose-response-inhibition (four parameter) equation. The plate with cells was then subjected to CellTiter-Glo luminescence cell viability assay (Promega) to determine the effect of these compounds on cell numbers after the above treatment.

TABLE-US-00002 TABLE 1 Compound # EC.sub.50 (uM)  1 0.72  3a one of 3a and 3b is 3.5 and the  3b other of 3a and 3b is 0.16  6d 0.28  9a* 0.97  9b* 1.2  9c* 0.074  9d* 3.27 12a* 0.86 12b* 0.88 12c* 0.045 12d* 1.6 13a one of 13a and 13b is 0.037 and the 13b other of 13a and 13b is 0.19 15 0.13 16 2.39 17 2.13 18 1.8 19 2.68 20 0.027 24a one of 24a and 24b is 8.9 and the 24b other of 24a and 24b is 18.5 27a one of 27a and 27b is 9.4 and the 27b other of 27a and 27b is 0.67 28 0.24 29 0.19 30 0.39 31 0.19 *the IC.sub.50 values to compounds in group (i) 9a to 9d and (ii) 12a to 12d are arbitrarily assigned