INDANE DERIVATIVES AS HYPOXIA INDUCIBLE FACTOR-2(ALPHA) INHIBITORS

Abstract

The present disclosure provides certain indane 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. A compound of Formula (I): ##STR00157## wherein: X.sup.1 is CH or N; R.sup.1 is hydroxy, amino, —OP(O)(OH).sub.2, —OCH.sub.2OP(O)(OH).sub.2, —OCOR.sup.10, —OCOOR.sup.11, —OCONR.sup.12R.sup.13, —OCHR.sup.14OCOR.sup.15 or —OCHR.sup.14OCOOR.sup.15 where R.sup.10, RR.sup.11, and R.sup.15 are independently alkyl or alkyl substituted with amino, carboxy or hydroxy, R.sup.12 and R.sup.13 are independently alkyl or alkyl substituted with amino, carboxy or hydroxy or R.sup.12 and R.sup.13 together with the nitrogen atom to which they are attached form optionally substituted heterocyclyl, and R.sup.14 is hydrogen, alkyl, or haloalkyl; R.sup.2 is hydrogen, deuterium, alkyl, haloalkyl, alkynyl, or alkenyl; R.sup.3 and R.sup.4 are independently hydrogen, deuterium, alkyl, cycloalkyl, halo, haloalkyl, hydroxyalkyl, or alkoxyalkyl; provided that one of R.sup.3 and R.sup.4 is 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 optionally substituted heterocyclylene; R.sup.5 is hydrogen, deuterium, alkyl, halo, haloalkyl, hydroxy, or alkoxy; R.sup.6 is hydrogen, deuterium, alkyl, cycloalkyl, or halo; or R.sup.5 and R.sup.6 together with the carbon to which they are attached form cycloalkylene or 4 to 6 membered optionally substituted heterocyclylene provided R.sup.1 and R.sup.2 and R.sup.3 and R.sup.4 together with the carbon to which they are attached do not form cycloalkylene or optionally substituted 4 to 6 membered heterocyclylene simultaneously; R.sup.7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; L is a bond, S, SO, SO.sub.2, O, CO, or NR.sup.16 where R.sup.16 is hydrogen or alkyl; R.sup.8 is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkenyl, bicyclic cycloalkyl, oxocycloalkenyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl wherein aryl or heteroaryl, each by itself or as part of aralkyl or heteroaralkyl, or heterocyclyl by itself or as part of heterocyclylalkyl is 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; and R.sup.9 is alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, cyano, halo, haloalkyl, haloalkoxy, alkylsulfoxide, or alkylsulfonyl, or heteroaryl wherein the heteroaryl is optionally substituted with R.sup.d, R.sup.e, and/or R.sup.f independently selected from hydrogen, alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, and cyano; or a pharmaceutically acceptable salt thereof

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R.sup.3 and R.sup.4 are independently halo.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R.sup.3 is halo and R.sup.4 is hydrogen.

4. The compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof wherein R.sup.1 is hydroxy.

5. The compound of claim 1, 2, or 3, or a pharmaceutically acceptable salt thereof is wherein R.sup.1 is amino.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof wherein R.sup.6 is halo.

7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof wherein R.sup.6 is alkyl.

8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof wherein R.sup.6 is hydrogen or deuterium.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein R.sup.5 is halo.

10. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof wherein R.sup.5 and R.sup.6 together with the carbon to which they are attached form cycloalkylene.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof wherein X.sup.1 is CH or CR.sup.7.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof having the structure of formula (IIa) or (IIb): ##STR00158##

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof having a structure of formula (IIa).

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof having a structure of formula (IIb).

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof having the structure of formula (IVa): ##STR00159## where R.sup.5 and R.sup.6 together with the carbon to which they are attached form cyclopropylene, cyclobutylene or cyclopentylene, each ring optionally substituted with one or two fluoro.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof having the structure of formula (VIa) or (VIb): ##STR00160## where R.sup.5 and R.sup.6 together with the carbon to which they are attached form cycloalkylene.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof having the structure of formula (VIIa) or (VIIb): ##STR00161##

18. The compound of any one of claims 1 to 17 therein, or a pharmaceutically acceptable salt thereof wherein R.sup.3 is fluoro.

19. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof where R.sup.3 and R.sup.4 are fluoro.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof wherein L is O, S, SO, SO.sub.2, or NH.

21. The compound of claim 20, or a pharmaceutically acceptable salt thereof wherein L is O.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof wherein R.sup.9 is methyl, ethyl, methoxy, fluoro, bromo, cyano, cyclopropyl, trifluoromethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, or methylsulfonyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof wherein, R.sup.9 is difluoromethyl.

24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof wherein R.sup.8 is phenyl 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.

25. The compound of claim 24, or a pharmaceutically acceptable salt thereof wherein R.sup.a, R.sup.b, and are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano.

26. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof wherein R.sup.8 is 3-chloro-5-fluorophenyl, 3,5-difluorophenyl, 3-fluoro-5-methoxyphenyl, 3-cyano-5-fluorophenyl, 3-chloro-5-cyanophenyl, 3-cyano-5-methylphenyl, 3-chloro-4-fluorophenyl, 3-chloro-5-fluorophenyl, 3-fluoro-5-methyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 3,4-dichlorophenyl, 3-chloro-2-methylphenyl, 3,5-dichlorophenyl, 3,5-dimethylphenyl, 2-chloro-6-methylphenyl, 2,6-difluorophenyl, 3,4,5-trifluorophenyl, 3,4-difluorophenyl, 4-fluoro-3-methylphenyl, 3-cyano-4-fluorophenyl, or 3-cyano-5-difluoromethylphenyl.

27. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof wherein R.sup.8 is heteroaryl 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.

28. The compound of claim 27, or a pharmaceutically acceptable salt thereof wherein R.sup.8 is 5- or 6-membered heteroaryl substituted with R.sup.a, R.sup.b, and/or R.sup.c wherein R.sup.a and R.sup.b are independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano and R.sup.c is selected from hydrogen, alkyl, halo, haloalkyl, and haloalkoxy.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof wherein R.sup.7 is hydrogen, methyl, ethyl, methoxy, fluoro, trifluoromethyl or trifluoromethoxy.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof wherein R.sup.2 is hydrogen, deuterium, methyl, or ethyl.

31. The compound of claim 30, or a pharmaceutically acceptable salt thereof wherein R.sup.2 is hydrogen.

32. A pharmaceutical composition comprising a compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

33. A method of treating a disease mediate by HIF-2α in a patient which method comprises administering to the patient in recognized need thereof, a therapeutically effective amount of a pharmaceutical composition comprising a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

34. The method of claim 33 wherein the disease is cancer, inflammatory disease, liver disease, iron overload, or pulmonary disease.

35. The method of claim 34 wherein the disease is cancer and the compound of claim 1 to 30 or a pharmaceutically acceptable salt thereof can be optionally administered in combination with at least one other anticancer agent.

36. The method of claim 34 or 35 wherein the cancer is renal cancer.

Description

EXAMPLES

[0253] 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. In the following examples, tR means retention time.

Example 1

Synthesis of 3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0254] ##STR00059##

Step 1: ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate

[0255] ##STR00060##

[0256] To a stirred mixture of zinc (6.97 g, 106.56 mmol, 1.0 equiv), 1,2-dibromoethane (388.71 mg, 2.069 mmol, 0.02 equiv) and chlorotrimethylsilane (1.12 g, 10.346 mmol, 0.10 equiv) in THF (200 mL) was added a solution of ethyl 2-bromo-2,2-difluoroacetate (21 g, 103.45 mmol, 1.0 equiv) and 2-bromo-4-fluorobenzaldehyde (21.0 g, 103.45 mmol, 1.0 equiv) in THF (100 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 75° C. under nitrogen atmosphere. The reaction mixture was cooled and quenched by the addition of ice water. The organic solvent was removed under vacuum and the resulting mixture was extracted with EtOAc. The combined organic layer was washed with water, 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 (5:1) to afford the title compound (18 g, 53.2%) as yellow oil.

Step 2: ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate

[0257] ##STR00061##

[0258] To a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (16 g, 48.9 mmol, 1.0 equiv) in CH.sub.3CN (200 mL) was added 2-iodoxybenzoic acid (27.4 g, 97.83 mmol, 2.0 equiv) at room temperature and the resulting mixture was stirred for 3 h at 80° C. The reaction solution was then cooled to room temperature, filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford the title compound (10.3 g, 64.8%) as yellow oil.

Step 3: ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate

[0259] ##STR00062##

[0260] To a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate (6.1 g, 18.8 mmol, 1.0 equiv) in CHCl.sub.3 (6 mL) was added DAST (30.25 g, 187.6 mmol, 10.0 equiv) dropwise at room temperature and the resulting mixture was stirred for 16 h at 70° C. under nitrogen atmosphere. The reaction solution was allowed to cool to room temperature and quenched by the addition of ice water. The mixture was extracted with DCM. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford the title compound (2.4 g, 36.8%) as yellow oil.

Step 4: 2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

[0261] ##STR00063##

[0262] To a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2,2,3,3-tetrafluoropropanoate (4.20 g, 12.101 mmol, 1.0 equiv) in THF (50 mL) was added 2.5M n-BuLi (7.26 mL, 18.15 mmol, 1.5 equiv) dropwise at −78° C. under nitrogen atmosphere and the resulting mixture was stirred for 2 h between −70° C. and −80° C. The reaction mixture was quenched by the addition of saturated NH.sub.4Cl (aq.) and 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, eluted with PE/EtOAc (20:1) to afford the title compound (2.25 g, 83.7%) as light yellow oil.

Step 5: 2,2,3,3,6-pentafluoro-2,3-dihydro-TH-inden-1-ol

[0263] ##STR00064##

[0264] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-TH-inden-1-one (300 mg, 1.35 mmol, 1.0 equiv) and triethylamine (273.35 mg, 2.70 mmol, 2.0 equiv) in DCM (3 mL) was added formic acid (186.49 mg, 4.052 mmol, 3.0 equiv) dropwise at 0° C., followed by the addition of RuCl(P-cymene)[(S,S)-Ts-DPEN] (8.59 mg, 0.014 mmol, 0.01 equiv). The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere and then washed with water. 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, eluted with PE/EtOAc (5:1) to afford the title compound (300 mg, 99.1%) as colorless oil.

Step 6: 1,1,2,2,5-pentafluoro-3-hydroxy-2,3-dihydro-TH-indene-4-carbaldehyde

[0265] ##STR00065##

[0266] To a stirred solution of 2,2,3,3,6-pentafluoro-2,3-dihydro-TH-inden-1-ol (260.0 mg, 1.16 mmol, 1.0 equiv) in THF (3 mL) was added LDA (3.480 mmol, 3.0 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was allowed to warm to −30° C. and stirred for 2 h at this temperature under nitrogen atmosphere. To the above mixture was added ethyl formate (171.8 mg, 2.3 mmol, 2.0 equiv) dropwise at −78° C. and the resulting mixture was stirred for additional 1 h at −30° C. The reaction mixture was then quenched by the addition of water at −30° C., extracted with EtOAc. The combined organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford the title compound (90 mg, 30.8%) as a light yellow solid.

Step 7: 1,1,2,2,5-pentafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbaldehyde

[0267] ##STR00066##

[0268] To a stirred solution of 1,1,2,2,5-pentafluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbaldehyde (92.0 mg, 0.36 mmol, 1.0 equiv) in CH.sub.3CN (2.0 mL) was added 2-iodoxybenzoic acid (204.3 mg, 0.73 mmol, 2.0 equiv) at room temperature. After stirring for 3 h at 80° C., the reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford the title compound (85 mg, 93.1%) as light yellow oil.

Step 8: 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one

[0269] ##STR00067##

[0270] To a stirred solution of 1,1,2,2,5-pentafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbaldehyde (85.00 mg, 0.340 mmol, 1.00 equiv) in DCM (1.5 mL) was added DAST (82.11 mg, 0.510 mmol, 1.5 equiv) at room temperature under nitrogen atmosphere. After stirring for 3 h at room temperature, the reaction was quenched with ice water at 0° C. The phases were separated and the organic layer was washed with water, brine, and then dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (80 mg, 86.5%) as light yellow oil.

Step 9: 3-[[4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile

[0271] ##STR00068##

[0272] To a stirred mixture of 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (70.00 mg, 0.257 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (52.91 mg, 0.386 mmol, 1.50 equiv) in DMF (1.00 mL) was added Cs.sub.2CO.sub.3 (125.72 mg, 0.386 mmol, 1.50 equiv) at room temperature. After stirring for 4 h at 50° C., the reaction mixture was cooled to room temperature and water was added. The resulting mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the title compound (60 mg, crude) as brown oil, which was used in the next step without further purification

Step 10: 3-[[4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile

[0273] ##STR00069##

[0274] To a mixture of 3-[[4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile (10.0 mg, 0.026 mmol, 1.0 equiv) and RuCl(P-cymene)[(S,S)-Ts-DPEN] (0.84 mg, 0.0013 mmol, 0.05 equiv) in DCM (0.3 mL) were added TEA (5.20 mg, 0.051 mmol, 2.0 equiv) and a solution of HCOOH (3.55 mg, 0.077 mmol, 3.0 equiv) in DCM (0.5 mL) dropwise at 0° C. under nitrogen atmosphere. After stirring for 5 hours at 0° C., the resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC to afford the title compound (3 mg, 29.8%) as a white solid. MS (ES, m/z): [M−1].sup.−=389.9.

Example 1A

Synthesis of (R)-3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluoro benzonitrile [1a] and (S)-3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile [1b]

[0275] ##STR00070##

[0276] 3-((4-(Difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (100 mg) was separated by chiral HPLC described below, to afford compound [1a] and [1b]. MS (ES, m/z): [M−1].sup.−=390.0.

[0277] Chiral HPLC conditions: Instrument, SHIMADZU LC-20AD; Column: CHIRAPAK IA-3, 4.6*50 mm, 3 uM; Mobile phase A, n-hexane; Mobile phase B, Ethanol; Conc. Of phase B, 8%; Flow rate, 1.0 mL/min.

[0278] One of compounds [1a] and [1b] has tR: 2.03 min and and the other has tR: 2.57.

Example 1B

Synthesis of (R)-3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl-3-d)oxy)-5-fluorobenzonitrile [1c] and (S)-3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl-3-d)oxy)-5-fluorobenzonitrile [1d]

[0279] ##STR00071##

[0280] To a stirred mixture of 3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (100 mg, 0.257 mmol, 1.00 equiv) and Et.sub.3N (52 mg, 0.514 mmol, 2.00 equiv) in DCM (1 mL) were added DCOOD (37 mg, 0.771 mmol, 3.00 equiv) and RuCl(P-cymene)[(S,S)-Ts-DPEN] (1.6 mg, 0.003 mmol, 0.01 equiv) at room temperature under nitrogen atmosphere. After stirring for 16 hours at room temperature, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (3/1), and then purified by chiral HPLC, described below, to afford compound [1c] and [1d]. MS (ES, m/z): [M−1].sup.−=391.1

[0281] Chiral HPLC conditions: Instrument, SHIMADZU LC-20AD; Column: CHIRAPAK IA-3, 4.6*50 mm, 3 uM; Mobile phase A, n-hexane (0.1% TFA); Mobile phase B, Ethanol; Conc. Of phase B, 8%; Flow rate, 1.0 mL/min. One of compounds [1c] and [1d] has tR: 2.18 min and and the other has tR: 2.67.

Example 2

Synthesis of 3-[[4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile

[0282] ##STR00072##

[0283] To a stirred solution of 3-[[4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile (20.0 mg, 0.051 mmol, 1.0 equiv) in THF (0.5 mL) was added 2.0M MeMgBr in THF (0.05 mL, 0.10 mmol, 2.0 equiv) at 0° C. under nitrogen atmosphere. After stirring for 3 h at room temperature, the reaction mixture was quenched with sat. NH.sub.4Cl (aq.) at 0° C. and then extracted with EtOAc. The 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 compound (2.2 mg, 10.5%). MS (ES, m/z): [M−1].sup.−=404.1.

Example 3

Synthesis of 3-[[3-amino-4-(difluoromethyl)-1,1,2,2-tetrafluoro-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile

[0284] ##STR00073##

[0285] To a stirred solution of 3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (300 mg, 0.771 mmol, 1.00 equiv) in THF (5 mL) were added Ti(OEt).sub.4 (352 mg, 1.542 mmol, 2.00 equiv) and 7 mol/L NH.sub.3 in MeOH (0.55 mL, 3.85 mmol, 5.00 equiv) at room temperature. The mixture was stirred for 24 h at 50° C. To the above mixture was added NaBH.sub.4 (44 mg, 1.156 mmol, 1.50 equiv) at room temperature. The reaction mixture was stirred for additional 10 min. The reaction was quenched with saturated NH.sub.4Cl (aq.) at room temperature. The resulting mixture was extracted with EA. The organic layer was washed with water and brine. The organic layer was concentrated in vacuum. The residue was purified by Prep-HPLC to afford 3-[[3-amino-4-(difluoromethyl)-1,1,2,2-tetrafluoro-2,3-dihydro-1H-inden-5-yl]oxy]-5-fluorobenzonitrile (60 mg) as a white solid. The (R)-3-((3-amino-4-(difluoromethyl)-1,1,2,2-tetrafluoro-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile [3a] and (S)-3-((3-amino-4-(difluoromethyl)-1,1,2,2-tetrafluoro-2,3-dihydro-TH-inden-5-yl)oxy)-5-fluorobenzonitrile [3b] enantiomers, MS (ES, m/z): [M-H].sup.−=389.1, were separated using chiral HPLC described below.

[0286] Conditions: Instrument, SHIMADZU LC-20AD; Column: CHIRAPAK IA-3, 4.6*50 mm, 3 μM; Mobile phase A, n-hexane (0.1% TFA); Mobile phase B, Ethanol; Conc. Of phase B, 20%; Flow rate, 1.0 mL/min. One of the compounds [3a] and [3b] has tR: 1.45 min and the other has tR: 2.24 min.

Example 4

Synthesis of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-1-ol

[0287] ##STR00074##

Step 1: 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-1-one

[0288] ##STR00075##

[0289] To a stirred mixture of 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (20 mg, 0.073 mmol, 1.00 equiv) and 3,5-difluorophenol (10 mg, 0.073 mmol, 1.00 equiv) in DMF (1 mL) was added Cs.sub.2CO.sub.3 (24 mg, 0.073 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature and then diluted with water and 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. The residue was purified by silica gel column chromatography (PE/EtOAc=10/1), followed by Prep-HPLC to afford the title compound (8 mg, 28.5%).

Step 2: 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-1-ol

[0290] ##STR00076##

[0291] To a stirred solution of 7-(difluoromethyl)-6-(3,5-difluorophenoxy)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-1-one (38 mg, 0.099 mmol, 1.00 equiv), Et.sub.3N (20 mg, 0.199 mmol, 2.00 equiv) and HCOOH (14 mg, 0.298 mmol, 3.00 equiv) in DCM (2 mL) was added RuCl(P-cymene)[(S,S)-Ts-DPEN] (6.3 mg, 0.010 mmol, 0.10 equiv) at 0° C. The resulting mixture was stirred for 24 h at room temperature under nitrogen atmosphere. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with water and brine, concentrated in vacuum and the residue was purified by Prep-HPLC to afford the title compound (19 mg, 49.7%). MS (ES, m/z): [M-H].sup.−=383.1.

Example 5

Synthesis of 3-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-methylbenzonitrile

[0292] ##STR00077##

[0293] The title compound was synthesized by proceeding analogously as described in Example 4, using 3-hydroxy-5-methylbenzonitrile in Step 2. MS (ES, m/z): [M−1].sup.−=386.2.

Example 6

Synthesis of 3-chloro-5-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile

[0294] ##STR00078##

[0295] The title compound was synthesized by proceeding analogously as described in Example 4, using 3-chloro-5-hydroxybenzonitrile in Step 2. MS (ES, m/z): [M−1].sup.−=406.1.

Example 7

Synthesis of 6-(3-chloro-5-fluorophenoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-1-ol

[0296] ##STR00079##

[0297] The title compound was synthesized by proceeding analogously as described in Example 4, using 3-chloro-5-fluorophenol in Step 2. MS (ES, m/z): [M+1].sup.−=399.1.

Example 8

Synthesis of 6-(3,3-difluorocyclobutoxy)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-2,3-dihydro-1H-inden-1-ol

[0298] ##STR00080##

[0299] The title compound was synthesized by proceeding analogously as described in Example 4, using 3,3-difluorocyclobutan-1-ol in Step 2. MS (ES, m/z): [M−1].sup.−=361.1.

Example 9

Synthesis of 5-((4-(difluoromethyl)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)nicotinonitrile

[0300] ##STR00081##

[0301] The title compound was synthesized by proceeding analogously as described in Example 4, using 5-hydroxynicotinonitrile in Step 2. MS (ES, m/z): [M+1].sup.−=373.1.

Example 10

Synthesis of 7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-ol

[0302] ##STR00082##

[0303] The title compound was synthesized by proceeding analogously as described in Example 4, using 5-fluoropyridin-3-ol in Step 2. MS (ES, m/z): [M−1].sup.−=366.1.

Example 11

Synthesis of (R)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-d-1-ol [11a] and (S)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-d-1-ol [11b]

[0304] ##STR00083##

Step 1: 7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-one

[0305] ##STR00084##

[0306] To a stirred mixture of 7-(difluoromethyl)-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (230 mg, 0.845 mmol, 1.00 equiv) and 5-fluoropyridin-3-ol (127 mg, 1.124 mmol, 1.33 equiv) in DMF (3.00 mL) was added Cs.sub.2CO.sub.3 (330 mg, 1.014 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. After stirring for 16 h at room temperature, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc and 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. The residue was purified by Prep-TLC (PE/EtOAc 3:1) to afford the title compound (220 mg, 71.3%).

Step 2: (R)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-d-1-ol [11] and (S)-7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-d-1-ol [12]

[0307] ##STR00085##

[0308] To a stirred solution of 7-(difluoromethyl)-2,2,3,3-tetrafluoro-6-((5-fluoropyridin-3-yl)oxy)-2,3-dihydro-1H-inden-1-one (200 mg, 0.548 mmol, 1.00 equiv) in CD.sub.3OD (1.00 mL) was added NaBD.sub.4 (34 mg, 0.821 mmol, 1.50 equiv) at room temperature. After stirring for 1 h at room temperature, the reaction was quenched with saturated NH.sub.4Cl (aq.) at room temperature. The resulting solution was purified by Prep-HPLC to afford the racemic product. The racemic product was separated by Chiral-HPLC, described below, to afford compounds [11a] and compound [11b]. MS (ES, m/z): [M+1].sup.+=369.1

[0309] Chiral HPLC conditions: Instrument, SHIMADZU LC-20AD; Column: lux cellulose-4, 4.6*50 mm, 3 uM; Mobile phase A, n-hexane; Mobile phase B, Ethanol; Conc. Of phase B, 15%; Flow rate, 1.0 mL/min. One of compounds [11a] and [11b] has tR: 1.98 min and the other has tR: 2.31 min.

Example 12

Synthesis of (R)-5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile [12a] and (S)-5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile [12b]

[0310] ##STR00086##

[0311] To a stirred mixture of 5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile (40 mg, 0.110 mmol, 1.00 equiv) and Et.sub.3N (22 mg, 0.220 mmol, 2.00 equiv) in DCM (1 mL) were added HCOOH (15 mg, 0.329 mmol, 3.00 equiv) and RuCl(P-cymene)[(S,S)-Ts-DPEN] (3.5 mg, 0.005 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then diluted with DCM, washed with water. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC followed by Prep-Chiral-HPLC, described below, to afford compounds [12a] and [12b] as a white solid. MS (ES, m/z): [M−1].sup.−=365.1.

[0312] Chiral HPLC conditions: Instrument, SHIMADZU LC-20AD; Column: lux cellulose-4, 4.6*50 mm, 3 uM; Mobile phase A, n-hexane (0.1% TFA); Mobile phase B, Ethanol; Conc. Of phase B, 15%; Flow rate, 1.0 mL/min. One of compounds [12a] and [12b] has tR: 4.68 min and the other has tR: 5.41 min.

Example 13

Synthesis of (S)-5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile-3-d [13a] and (R)-5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile-3-d [13b]

[0313] ##STR00087##

[0314] To a stirred mixture of 5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile (100 mg, 0.275 mmol, 1.00 equiv) in CD.sub.3OD (1 mL) was added NaBD.sub.4 (23 mg, 0.549 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature. The mixture was neutralized to pH 7 with 1 mol/L HCl (aq.). The organic solvent was removed under vacuum. The resulting mixture was diluted with water and extracted with EtOA. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC followed by Chiral-Prep-HPLC, described below, to afford compounds [13a] and compound [13b]. MS (ES, m/z):[M−1].sup.−=366.1.

[0315] Chiral HPLC condition: Instrument, SHIMADZU LC-20AD; Column: lux cellulose-4, 4.6*50 mm, 3 uM; Mobile phase A, n-hexane (0.1% TFA); Mobile phase B, Ethanol; Conc. Of phase B, 15%; Flow rate, 1.0 mL/min. One of compounds [13a] and [13b] has tR: 4.76 min and the other has tR: 5.50 min.

Example 14

Synthesis of 1,1,2,2-tetrafluoro-5-((5-fluoropyridin-3-yl)oxy)-3-hydroxy-2,3-dihydro-TH-indene-4-carbonitrile-3-d

[0316] ##STR00088##

Step 1: 1,1,2,2-tetrafluoro-5-((5-fluoropyridin-3-yl)oxy)-3-oxo-2,3-dihydro-TH-indene-4-carbonitrile

[0317] ##STR00089##

[0318] To a stirred solution of 5-fluoropyridin-3-ol (46 mg, 0.405 mmol, 1.00 equiv) and 1,1,2,2,5-pentafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile (100 mg, 0.405 mmol, 1.00 equiv) in DMF (2.00 mL) was added Cs.sub.2CO.sub.3 (132 mg, 0.405 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then diluted with water. The resulting mixture was extracted with EtOAc and 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 Prep-TLC (PE/EtOAc 1:1) to afford the title compound (60 mg, 43.6%) as a light yellow solid.

Step 2: 1,1,2,2-tetrafluoro-5-((5-fluoropyridin-3-yl)oxy)-3-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile-3-d

[0319] ##STR00090##

[0320] To a stirred solution of 1,1,2,2-tetrafluoro-5-((5-fluoropyridin-3-yl)oxy)-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile (60 mg, 0.176 mmol, 1.00 equiv) in MeOD (1.00 mL) was added NaBD.sub.4 (15 mg, 0.353 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then quenched with water at 5° C. The mixture was neutralized to pH 7 with 1 mol/L HCl (aq.) and the resulting solution was purified by Prep-HPLC to afford the title compound (15 mg, 24.8%) as a white solid. MS (ES, m/z): [M+1].sup.+=344.0.

Example 15

Synthesis of 5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-indene-4-carbonitrile

[0321] ##STR00091##

Step 1: 5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-indene-4-carbonitrile

[0322] ##STR00092##

[0323] To a stirred solution of 5-(3-cyano-5-fluorophenoxy)-1,1,2,2-tetrafluoro-3-oxo-2,3-dihydro-1H-indene-4-carbonitrile (50 mg, 0.137 mmol, 1.00 equiv) in THF (2.00 mL) was added 1 mol/L CH.sub.3MgBr in THF (0.17 mL, 0.170 mmol, 1.2 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 3 h at −78° C. under nitrogen atmosphere and then quenched by saturated aqueous NH.sub.4Cl. The resulting mixture was extracted with EtOAc and the organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title compound (10.4 mg, 19.9%). MS (ES, m/z): [M−1].sup.−=379.2.

Example 16

Synthesis of 3-((4-bromo-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0324] ##STR00093##

Step 1: 7-bromo-2,2,3,3,6-pentafluoro-1-methyl-2,3-dihydro-1H-inden-1-ol

[0325] ##STR00094##

[0326] To a stirred mixture of 7-bromo-2,2,3,3,6-pentafluoro-2,3-dihydro-1H-inden-1-one (50 mg, 0.166 mmol, 1.00 equiv) in tetrahydrofuran (2 mL) was added 2.5M bromo(methyl)magnesium (0.10 mL, 0.250 mmol, 1.51 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 h at −78° C. under nitrogen atmosphere. The reaction was quenched with saturated NH.sub.4Cl (aq.) and extracted with EtOAc. The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1) to afford the title compound (40 mg, 76.0%).

Step 2: 3-((4-bromo-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzo nitrile

[0327] ##STR00095##

[0328] To a stirred mixture of 7-bromo-2,2,3,3,6-pentafluoro-1-methyl-2,3-dihydro-1H-inden-1-ol (30 mg, 0.095 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (13 mg, 0.095 mmol, 1.00 equiv) in DMF (1 mL) was added Cs.sub.2CO.sub.3 (31 mg, 0.095 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 24 h at 100° C. and then diluted with water and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC to afford the title compound (12 mg, 29.2%) as a white solid. MS (ES, m/z): [M−1].sup.−=432.1.

Example 17

Synthesis of 3-fluoro-5-((1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-4-vinyl-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile

[0329] ##STR00096##

[0330] To a stirred solution of 3-((4-bromo-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (20 mg, 0.048 mmol, 1.0 equiv) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (21 mg, 0.138 mmol, 3.0 equiv) in toluene (0.60 mL) were added DIEA (18 mg, 0.138 mmol, 3.0 equiv), P(t-Bu).sub.3 (2 mg, 0.009 mmol, 0.20 equiv) and Pd.sub.2(dba).sub.3 (9 mg, 0.009 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 100° C. under nitrogen atmosphere and then diluted with H.sub.2O and extracted with EtOAc. The combined organic layer was washed with H.sub.2O and brine. The organic layer was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title compound (3.0 mg, 17.2%).

Example 18

Synthesis of 3-((4-ethyl-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0331] ##STR00097##

[0332] To a mixture of 3-((4-bromo-1,1,2,2-tetrafluoro-3-hydroxy-3-methyl-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (30 mg, 0.069 mmol, 1.00 equiv) and Pd(dppf)Cl.sub.2 (15 mg, 0.021 mmol, 0.30 equiv) in dioxane (0.30 mL) were added 1.0M diethylzinc (0.23 mL, 0.230 mmol, 3.33 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and then diluted with water. The resulting 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 and the residue was purified by Prep-HPLC to afford the title compound (7 mg, 26.4%). MS (ES, m/z): [M−1].sup.−=382.2.

Example 19

Synthesis of 3-((4-(difluoromethyl)-1,2,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0333] ##STR00098##

Step 1: tert-butyl 2-bromo-4-fluorobenzoate

[0334] ##STR00099##

[0335] To a stirred solution of 2-bromo-4-fluorobenzoic acid (25.00 g, 114.151 mmol, 1.00 equiv), DMAP (11.16 g, 91.350 mmol, 0.80 equiv) and t-BuOH (25.38 g, 342.410 mmol, 3.00 equiv) in DCM (200.0 mL) was added DCC (25.91 g, 125.577 mmol, 1.10 equiv) in portions at 0° C. The resulting mixture was stirred for 16 h at room temperature and then filtered. The filter cake was washed with DCM and the filtrate was washed with H.sub.2O and brine, and 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, eluted with PE/EtOAc (15:1), to afford the title compound (16.30 g, 51.9%) as colorless oil.

Step 2: tert-butyl 2-bromo-4-fluoro-3-formylbenzoate

[0336] ##STR00100##

[0337] To a stirred solution of tert-butyl 2-bromo-4-fluorobenzoate (16.00 g, 58.157 mmol, 1.00 equiv) in THF (500 mL) was added 2.0M LDA (43.62 mL, 87.240 mmol, 1.50 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 h at −78° C. under nitrogen atmosphere. To the above mixture was added ethyl formate (8.62 g, 116.314 mmol, 2.0 equiv) dropwise and the resulting mixture was stirred for additional 20 min at −78° C. The reaction was quenched with saturated NH.sub.4Cl (aq.) and extracted with EtOAc. The combined organic layers were washed with water and 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/EtOAc (10:1) to afford (7.60 g, 43.1%) of the title compound as a yellow solid.

Step 3: tert-butyl 2-bromo-3-(difluoromethyl)-4-fluorobenzoate

[0338] ##STR00101##

[0339] To a stirred solution of tert-butyl 2-bromo-4-fluoro-3-formylbenzoate (7.60 g, 25.072 mmol, 1.00 equiv) in DCM (150 mL) was added DAST (6.06 g, 37.608 mmol, 1.50 equiv) dropwise at 0° C. The resulting mixture was stirred for 3 h at room temperature and then quenched with saturated NH.sub.4HCO.sub.3 (aq.) at 0° C. The organic layer was washed with water and 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, eluted with PE/EtOAc (10:1) to afford the title compound (7.20 g, 88.3%) as yellow oil.

Step 4: (2-bromo-3-(difluoromethyl)-4-fluorophenyl)methanol

[0340] ##STR00102##

[0341] To a stirred solution of tert-butyl 2-bromo-3-(difluoromethyl)-4-fluorobenzoate (5.80 g, 17.839 mmol, 1.00 equiv) in THF (120 mL) was added LiBH.sub.4 (3.11 g, 142.714 mmol, 8.00 equiv) in portions at 10° C. To the above mixture was added MeOH (20 mL) dropwise at 10° C. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then quenched with water at 0° C. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water, and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound (4.30 g, 94.5%) as an off-white solid. The product was used directly in next step without further purification.

Step 5: 2-bromo-3-(difluoromethyl)-4-fluorobenzaldehyde

[0342] ##STR00103##

[0343] Into a 250 mL round-bottom flask were added (2-bromo-3-(difluoromethyl)-4-fluoro-phenyl)methanol (4.30 g, 16.470 mmol, 1.00 equiv), EA (100 mL) and IBX (9.44 g, 33.712 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 16 h at 60° C. under nitrogen atmosphere and then filtered. The filter cake was washed with EtOAc and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to afford the title compound (4.00 g, 93.8%) as a yellow solid.

Step 6: ethyl 3-(2-bromo-3-(difluoromethyl)-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate

[0344] ##STR00104##

[0345] To a stirred mixture of Zn (620 mg, 9.482 mmol, 1.20 equiv), dibromoethane (30 mg, 0.158 mmol, 0.02 equiv) and chlorotrimethylsilane (86 mg, 0.791 mmol, 0.10 equiv) in THF (40 mL) was added a solution of 2-bromo-3-(difluoromethyl)-4-fluorobenzaldehyde (2.00 g, 7.905 mmol, 1.00 equiv) and ethyl 2-bromo-2,2-difluoroacetate (1.60 g, 7.883 mmol, 1.00 equiv) in THF (10 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 75° C. under nitrogen atmosphere and then filtered. The filter cake was washed with EtOAc and the filtrate was diluted with water. The resulting 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 and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1), to afford the title compound (750 mg, 25.2%) as colorless oil.

Step 7: ethyl 3-(2-bromo-3-(difluoromethyl)-4-fluorophenyl)-2,2,3-trifluoropropanoate

[0346] ##STR00105##

[0347] A solution of ethyl 3-(2-bromo-3-(difluoromethyl)-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (377 mg, 1.00 mmol, 1.00 equiv) and DAST (193 mg, 1.200 mmol, 1.20 equiv) in DCM (4 mL) was stirred for 0.5 h at room temperature under nitrogen atmosphere. The reaction was quenched with ice H.sub.2O at 0° C. and then extracted with DCM. 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 and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1), to afford the title compound (350 mg, 92.4%) as a light yellow oil.

Step 8: 7-(difluoromethyl)-2,2,3,6-tetrafluoro-2,3-dihydro-1H-inden-1-one

[0348] ##STR00106##

[0349] To a stirred solution of ethyl 3-(2-bromo-3-(difluoromethyl)-4-fluorophenyl)-2,2,3-trifluoropropanoate (300 mg, 0.791 mmol, 1.00 equiv) in THF (5 mL) was added 1.0M n-BuLi (1.58 mL, 1.580 mmol, 2.00 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred for 1 h at −78° C. under nitrogen atmosphere. The reaction mixture was quenched by the addition of saturated NH.sub.4Cl (aq.) at −78° C. and then extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na.sub.2SO.sub.4.

[0350] After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1), to afford the title compound (65 mg, 32.3%) as a yellow oil.

Step 9: 3-((4-(difluoromethyl)-1,2,2-trifluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0351] ##STR00107##

[0352] A mixture of 7-(difluoromethyl)-2,2,3,6-tetrafluoro-2,3-dihydro-1H-inden-1-one (20 mg, 0.079 mmol, 1.00 equiv), 3-fluoro-5-hydroxybenzonitrile (13 mg, 0.094 mmol, 1.20 equiv) and Cs.sub.2CO.sub.3 (77 mg, 0.236 mmol, 3.00 equiv) in DMF (0.40 mL) was stirred for 6 h at 50° C. The resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc=1:1) to afford the title compound (15 mg, 37.9%) as a yellow solid.

Step 10: 3-((4-(difluoromethyl)-1,2,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0353] ##STR00108##

[0354] To a stirred solution of 3-((4-(difluoromethyl)-1,2,2-trifluoro-3-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (10.0 mg, 0.027 mmol, 1.00 equiv) and TEA (5.5 mg, 0.054 mmol, 2.00 equiv) in DCM (1 mL) were added formic acid (3.7 mg, 0.081 mmol, 3.00 equiv) dropwise at room temperature, followed by RuCl(P-cymene)[(S,S)-Ts-DPEN] (1.7 mg, 0.003 mmol, 0.10 equiv). The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford the title compound (1.7 mg, 12.9%) as off-white semi-solid. MS (ES, m/z): [M−1].sup.−=372.1.

Example 20

Synthesis of 3-((2-chloro-4-(difluoromethyl)-1,1,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0355] ##STR00109##

Step 1: ethyl 3-(2-bromo-4-fluorophenyl)-3-oxopropanoate

[0356] ##STR00110##

[0357] To a stirred solution of 1-(2-bromo-4-fluorophenyl)ethan-1-one (10.00 g, 46.075 mmol, 1.00 equiv) and EtOH (212 mg, 4.608 mmol, 0.10 equiv) in diethyl carbonate (60 mL) was added 60% NaH (3.69 g, 92.259 mmol, 2.00 equiv) in portions at 0° C. The resulting mixture was stirred for 16 h at room temperature and then quenched with 1 M HCl (aq.) at 0° C. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and brine, and 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, eluted with PE/EtOAc (10:1) to afford the title compound (6.30 g, 47.3%) as a light yellow liquid.

Step 2: ethyl 3-(2-bromo-4-fluorophenyl)-2-fluoro-3-oxopropanoate

[0358] ##STR00111##

[0359] Into the microwave tube (30 mL) were added ethyl 3-(2-bromo-4-fluorophenyl)-3-oxopropanoate (6.30 g, 21.792 mmol, 1.00 equiv), CH.sub.3CN (90.0 mL) and F-TEDA-BF.sub.4 (7.72 g, 21.792 mmol, 1.00 equiv) at room temperature. The resulting reaction mixture was irradiated with microwave radiation for 35 min at 90° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (9:1), to afford the title compound (4.50 g, 67.2%) as a light-yellow oil.

Step 3: ethyl 3-(2-bromo-4-fluorophenyl)-2-chloro-2-fluoro-3-oxopropanoate

[0360] ##STR00112##

[0361] To a stirred solution of ethyl 3-(2-bromo-4-fluorophenyl)-2-fluoro-3-oxopropanoate (4.30 g, 14.002 mmol, 1.00 equiv) and NCS (2.06 g, 15.403 mmol, 1.10 equiv) in CH.sub.3CN (120 mL) were added cyclopenta-1,3-dien-1-yltitanium (IV) chloride (154 mg, 0.700 mmol, 0.045 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1), to afford the title compound (4.20 g, 87.8%) as a light-yellow oil.

Step 4: 3-((2-chloro-4-(difluoromethyl)-1,1,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0362] ##STR00113##

[0363] The title compound was synthesized by proceeding analogously as described in Example 1, Steps 4-10. MS (ES, m/z): [M−1].sup.−=406.1.

Example 21

Synthesis of 3-(((2S,3S)-4-(difluoromethyl)-1,1,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile [21a] and 3-(((2S,3R)-4-(difluoromethyl)-1,1,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile [21b]

[0364] ##STR00114##

Step 1: 3-(3-bromo-2-formylphenoxy)-5-fluorobenzonitrile

[0365] ##STR00115##

[0366] To a stirred solution of 2-bromo-6-fluorobenzaldehyde (10.00 g, 49.259 mmol, 1.00 equiv) and 3-fluoro-5-hydroxybenzonitrile (6.75 g, 49.259 mmol, 1.00 equiv) in DMF (200.0 mL) was added Cs.sub.2CO.sub.3 (16.05 g, 49.259 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at 50° C. under nitrogen atmosphere and then diluted with water. The precipitated solids were collected by filtration and washed with PE to give the title compound (13 g, 82.4%) as an off-white solid.

Step 2: 3-(3-bromo-2-(difluoromethyl)phenoxy)-5-fluorobenzonitrile

[0367] ##STR00116##

[0368] To a stirred solution of 3-(3-bromo-2-formylphenoxy)-5-fluorobenzonitrile (13.00 g, 40.610 mmol, 1.00 equiv) in DCM (200.0 mL) was added DAST (14.40 g, 89.342 mmol, 2.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere and then quenched with water/ice at room temperature. The mixture was adjusted to pH 8 with saturated NaHCO.sub.3(aq.) and extracted with DCM. 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 and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1), to afford the title compound (13.0 g, 93.6%) as a light yellow semi-solid.

Step 3: ethyl 3-(3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)phenyl)propanoate

[0369] ##STR00117##

[0370] To a stirred mixture of 3-(3-bromo-2-(difluoromethyl)phenoxy)-5-fluorobenzonitrile (9.10 g, 26.599 mmol, 1.00 equiv) and ethyl acrylate (7.99 g, 79.807 mmol, 3.00 equiv) in DMF (150.0 mL) were added K.sub.2CO.sub.3 (7.35 g, 53.182 mmol, 2.00 equiv), PPh.sub.3 (1.40 g, 5.320 mmol, 0.20 equiv) and Pd(OAc).sub.2 (1.20 g, 5.320 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 110° C. under nitrogen atmosphere. To the above mixture was added 10% Pd/C (2.65 g) and the resulting mixture was stirred for additional 4 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was diluted with water and extracted with EtOAc and the combined organic layers were washed with water, brine and 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, eluted with PE/EtOAc (10:1), to afford the title compound (7.00 g, 77.4%) as a light yellow oil.

Step 4: 3-(3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)phenyl)propanoic acid

[0371] ##STR00118##

[0372] To a stirred solution of ethyl 3-(3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)phenyl)-propanoate (7.50 g, 20.642 mmol, 1.00 equiv) in THF (160.0 mL) and H.sub.2O (40.0 mL) was added LiOH H.sub.2O (0.87 g, 20.642 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 4 h at room temperature and then concentrated under reduced pressure. The residue was dissolved in water and the mixture was acidified to pH 5 with 1M HCl (aq.). The resulting 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 give the title compound (6.50 g, 93.9%) as an off-white solid.

Step 5: 3-((4-(dichloromethyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0373] ##STR00119##

[0374] To a stirred solution of 3-(3-(3-cyano-5-fluorophenoxy)-2-(difluoromethyl)phenyl)propanoic acid (6.50 g, 19.387 mmol, 1.00 equiv) in DCM (130.0 mL) was added SOCl.sub.2 (23.06 g, 193.830 mmol, 10.00 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature and then concentrated under reduced pressure. The residue was dissolved in DCM. To the above mixture was added AlCl.sub.3 (15.51 g, 116.318 mmol, 6.00 equiv) in portions over 20 min at 0° C. The resulting mixture was stirred for additional 16 h at room temperature and then quenched with water at 5° C. The resulting mixture was extracted with DCM 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 and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1), to afford the title compound (5.8 g, 85.4%) as an off-white semi-solid.

Step 6: 3-fluoro-5-((4-formyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)benzonitrile

[0375] ##STR00120##

[0376] A solution of 3-((4-(dichloromethyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (5.50 g, 15.707 mmol, 1.00 equiv) in AcOH (110.0 mL) and H.sub.2O (11.0 mL) was stirred for 6 h at 100° C. under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and then diluted with water. The resulting 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 and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (4:1), to afford the title compound (1.03 g, 22.2%) as an off-white solid.

Step 7: 3-((4-(difluoromethyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0377] ##STR00121##

[0378] To a stirred solution of 3-fluoro-5-((4-formyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-benzonitrile (1.00 g, 3.387 mmol, 1.00 equiv) in DCM (20.0 mL) was added DAST (1.2 g, 7.451 mmol, 2.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then quenched with water/ice at 5° C. The mixture was neutralized to pH 7 with saturated Na.sub.2CO.sub.3 (aq.) and then extracted with EtOAc. 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 and the residue was purified by Prep-TLC (PE/EtOAc 5:1) to afford the title compound (830 mg, 77.3%) as an off-white solid.

Step 8: 3-((4-(difluoromethyl)-2-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0379] ##STR00122##

[0380] A mixture of 3-((4-(difluoromethyl)-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluoro-benzonitrile (750 mg, 2.364 mmol, 1.00 equiv) and F-TEDA-BF.sub.4 (1005 mg, 2.837 mmol, 1.20 equiv) in MeCN (15.0 mL) was stirred for 16 h at 80° C. under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (5:1), to afford the title compound (650 mg, 82.0%) as a light yellow solid.

Step 9: 3-((4-(difluoromethyl)-1,1,2-trifluoro-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0381] ##STR00123##

[0382] Into a 50 mL of plastic vial was added 3-((4-(difluoromethyl)-2-fluoro-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (800 mg, 2.386 mmol, 1.00 equiv), (4-(tert-butyl)-2,6-dimethylphenyl)trifluoro-λ.sup.4-sulfane (1493 mg, 5.966 mmol, 2.50 equiv), DCM (16.0 mL), and HF-pyridine (0.86 mL, 9.545 mmol, 4.00 equiv) at room temperature. The resulting mixture was stirred for 16 h at room temperature under nitrogen atmosphere and then quenched with water/ice at room temperature. The mixture was neutralized to pH 7 with saturated Na.sub.2CO.sub.3 (aq.) and the resulting mixture was extracted with DCM. The combined organic layers were 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, eluted with PE/EtOAc (5:1), to afford the title compound (600 mg, 70.4%) as a yellow solid.

Step 10: 3-((3-bromo-4-(difluoromethyl)-1,1,2-trifluoro-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile

[0383] ##STR00124##

[0384] A mixture of 3-((4-(difluoromethyl)-1,1,2-trifluoro-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (120 mg, 0.336 mmol, 1.00 equiv) and NBS (149 mg, 0.840 mmol, 2.50 equiv) in CCl.sub.4 (3.0 mL) was stirred and irradiated with a tungsten-filament light bulb for 2 h at 80° C. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc=5:1) to afford the title compound (70 mg, 47.8%) as light yellow oil.

Step 11: rac-3-(((2S,3S)-4-(difluoromethyl)-1,1,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile [21a] and rac-3-(((2S,3R)-4-(difluoromethyl)-1,1,2-trifluoro-3-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile [21b]

[0385] ##STR00125##

[0386] To a stirred solution of 3-((3-bromo-4-(difluoromethyl)-1,1,2-trifluoro-2,3-dihydro-1H-inden-5-yl)oxy)-5-fluorobenzonitrile (70 mg, 0.160 mmol, 1.00 equiv) in DME (1.0 mL) and H.sub.2O (0.05 mL) was added AgClO.sub.4 (67 mg, 0.321 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 26 h at 80° C. and then diluted with water. The resulting mixture was extracted with EtOAc and the combined organic layers were washed with water and dried over anhydrous Na.sub.2SO.sub.4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC to afford compound [21a] and [21b]. MS (ES, m/z): [M−1].sup.−=372.1

BIOLOGICAL EXAMPLES

Example 1

VEGF ELISA Assay

[0387] 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. After 24 hours, cell culture medium was collected to determine VEGF concentration using an ELISA kit (R&D systems, cat #DVE00) following the manufacturer's instruction.

[0388] The EC.sub.50 was 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-00003 Comp Structure EC.sub.50 (nM) I-1  [00126] 6 I-la  [00127] One of I-la and I-lb is 6 and the other of I-la and I-1b is 112. I-lb  [00128] I-lc  [00129] One of I-lc and I-1d is 4 and the other of I-lc and I-ld is 498. I-1d  [00130] I-2  [00131] 770 I-3  [00132] 166 I-3a  [00133] One of I-3a and I-3b is 129. I-3b  [00134] I-4  [00135] 4 I-5  [00136] 67 I-6  [00137] 27 I-7  [00138] 8 I-8  [00139] 105 I-9  [00140] 147 I-10  [00141] 54 I-11a [00142] One of I-11a and I-11b is 28 and the other of I-11a and I-11b is 4846. I-11b [00143] I-12a [00144] One of I-12a and I-12b is 16 and the other of I-12a and I-12b is 374. I-12b [00145] I-13b [00146] 12 I-13a [00147] 464 I-14  [00148] 183 I-15  [00149] 287 I-16  [00150] 2073 I-17  [00151] 5769 I-18  [00152] 2496 I-19  [00153] 151 I-20  [00154] 20 I-21a [00155] One of I-21a and I-21b is 34 and the other of I-21a and I-21b is 117. I-21b [00156]

FORMULATION EXAMPLES

[0389] The following are representative pharmaceutical formulations containing a compound Formula (I) or (I′), or a pharmaceutically acceptable salt thereof.

Tablet Formulation

[0390] The following ingredients are mixed intimately and pressed into single scored tablets.

TABLE-US-00004 Ingredient Quantity per tablet (mg) compound of Formula (I) or (I′) 400 cornstarch 50 croscarmellose sodium 25 lactose 120 magnesium stearate 5

Capsule Formulation

[0391] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.

TABLE-US-00005 Ingredient Quantity per capsule (mg) compound of Formula (I) or (I′) 200 lactose spray dried 148 magnesium stearate 2

Injectable Formulation

[0392] Compound of Formula (I) or (I′) (e.g., compound 1) in 2% HPMC, 1% Tween 80 in DI water, pH 2.2 with MSA, q.s. to at least 20 mg/mL

Inhalation Composition

[0393] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound of Formula (I) or (I′) is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, which is suitable for inhalation administration.

Topical Gel Composition

[0394] To prepare a pharmaceutical topical gel composition, 100 mg of a compound of Formula (I) or (I′) is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into containers, such as tubes, which are suitable for topical administration.

Ophthalmic Solution Composition

[0395] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound of Formula (I) or (I′) is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.

Nasal Spray Solution

[0396] To prepare a pharmaceutical nasal spray solution, 10 g of a compound of Formula (I) or (I′) is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 l of spray for each application.