GLUCOCORTICOID RECEPTOR AGONISTS

Abstract

The present invention provides a compound of Formula I:

##STR00001## wherein R is H or

##STR00002## R.sup.1 is H, halogen, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF.sub.3,

##STR00003## R.sup.2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C4 alkenyl; R.sup.3 is NH.sub.2, or CH.sub.2NH.sub.2; and X is O, OCH.sub.2, OCH.sub.2CH.sub.2, OCH(CH.sub.3), CH.sub.2O, SCH.sub.2, CH.sub.2S, CH.sub.2, NHCH.sub.2, CH.sub.2NH, N(CH.sub.3)CH.sub.2, CH.sub.2CH.sub.2, CC, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I, or pharmaceutically acceptable salt thereof is useful for treating autoimmune and inflammatory diseases, such as atopic dermatitis and rheumatoid arthritis.

Claims

1. A compound of the formula: ##STR00068## wherein R is H or ##STR00069## R.sup.1 is H, halogen, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, C2-C3 alkenyl, OCF.sub.3, ##STR00070## R.sup.2 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, or C2-C3 alkenyl; R.sup.3 is NH.sub.2, or CH.sub.2NH.sub.2; and X is O, OCH.sub.2, OCH.sub.2CH.sub.2, CH.sub.2O, SCH.sub.2, CH.sub.2S, CH.sub.2, NHCH.sub.2, CH.sub.2NH, N(CH.sub.3)CH.sub.2, CH.sub.2CH.sub.2, CC, or a bond, wherein X is connected to phenyl ring A at the ortho or the meta position, or a pharmaceutically acceptable salt thereof.

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

3. The compound of claim 1, wherein R is H, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is of Formula ##STR00071## or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein R.sup.1 is F, CH.sub.2CH.sub.3, OCH.sub.3, or OC(.sup.2H).sub.3, or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein R.sup.1 is F, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein R.sup.1 is CH.sub.2CH.sub.3, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein R.sup.1 is OCH.sub.3, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein R.sup.1 is OC(.sup.2H).sub.3, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein R.sup.2 is F, CH.sub.2CH.sub.3, OCH.sub.3, or OC(.sup.2H).sub.3, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein R.sup.2 is F, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein R.sup.2 is CH.sub.2CH.sub.3, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein R.sup.2 is OCH.sub.3, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein R.sup.2 is OC(.sup.2H).sub.3, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein X is CH.sub.2CH.sub.2, OCH.sub.2, or OCH.sub.2CH.sub.2, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, wherein X is CH.sub.2CH.sub.2, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1, wherein X is OCH.sub.2, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein X is OCH.sub.2CH.sub.2, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is: ##STR00072## or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19, wherein the compound is: ##STR00073##

21. The compound of claim 1, wherein the compound is: ##STR00074## or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein the compound is: ##STR00075##

23. The compound of claim 1, wherein the compound is: ##STR00076## or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23, wherein the compound is: ##STR00077##

25. The compound of claim 1, wherein the compound is: ##STR00078## or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, wherein the compound is: ##STR00079## or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is: ##STR00080## or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27, wherein the compound is: ##STR00081##

29. The compound of claim 1, wherein the compound is: ##STR00082## or a pharmaceutically acceptable salt thereof.

30. A method of treating atopic dermatitis in a patient, comprising administering to a patient in need of such treatment an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

31. A method of treating rheumatoid arthritis in a patient, comprising administering to a patient in need of such treatment an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

32.-36. (canceled)

37. A pharmaceutical composition, comprising the compound, or pharmaceutically acceptable salt thereof, of claim 1, and one or more pharmaceutically acceptable carrier, diluent, or excipient.

38. A process for preparing a pharmaceutical composition, comprising admixing a compound, or pharmaceutically acceptable salt thereof, of claim 1 with one or more pharmaceutically acceptable carrier, diluent, or excipient.

Description

EXAMPLES

[0111] The compounds of the present invention, or salts thereof, may be readily prepared by a variety of procedures known to one of ordinary skill in the art, some of which are illustrated in the preparations and examples below. One of ordinary skill in the art recognizes that the specific synthetic steps for each of the routes described may be combined in different ways, or in conjunction with steps from different schemes, to prepare compounds of the invention, or salts thereof. The product of each step can be recovered by conventional methods well known in the art, including extraction, evaporation, precipitation, chromatography, filtration, trituration, and crystallization. All substituents unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. The following preparations, examples, and assays further illustrate the invention, but should not be construed to limit the scope of the invention in any way.

TABLE-US-00002 TABLE 1 Abbreviations and definitions Term Definition ACN acetonitrile aq aqueous angstrom(s) BOC/Boc tert-butyloxycarbonyl C18 octadecylsilane DCM dichloromethane DEA diethylamine DIBAL-H diisobutylaluminum hydride DMEA dimethylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide dppf 1,1-bis(diphenylphosphino)ferrocene equiv equivalent(s) ES/MS electrospray mass spectrometry EtOAc ethyl acetate EtOH ethanol FA formic acid g gram(s) h hour(s) HPLC high performance liquid chromatography IPA isopropanol IPAm isopropylamine L liter(s) LC liquid chromatography LCMS liquid chromatography mass spectrometry LDA lithium diisopropylamide M molar mbar millibar(s) MeOH methanol min minute(s) mL milliliter(s) mM millimolar mmol millimole(s) mol mole(s) MS mass spectrometry MTBE methyl tert-butyl ether MW molecular weight m/z mass-to-charge ratio nm nanometer(s) NMR nuclear magnetic resonance Pet ether petroleum ether ppm parts per million ROE rotating-frame Overhauser enhancement RP-HPLC reverse-phase HPLC rt room temperature satd saturated SFC supercritical fluid chromatography SM starting material THF tetrahydrofuran wt weight

Example 1. Preparations of Pre-Cursors

Preparation 1. Synthesis of tert-butyl (3-((2-fluoro-3-formyl-4-(methoxy-d.SUB.3.)phenoxy)methyl)phenyl)carbamate

##STR00047##

[0112] A solution of 2-fluoro-3-hydroxy-6-(trideuteriomethoxy)benzaldehyde (870 mg, 5.0 mmol) in DMF (15 mL) was treated with potassium carbonate (2.2 g, 16 mmol) and stirred at rt for 15 min. Tert-butyl N-[3-(bromomethyl)phenyl]carbamate (1.5 g, 5.2 mmol) was added in one portion and the reaction was stirred at rt. After 18 h, the reaction mixture was partitioned between EtOAc and H.sub.2O. The phases were separated, the organic phase was transferred to a flask, and the solvent was evaporated under vacuum. Residual DMF was evaporated with the help of xylenes. The crude residue was purified by normal phase purification, eluting with 0-50% EtOAc in hexanes to give the title compound (1.9 g, 90% yield). MS m/z 377.2 (MH).

Preparation 2. Synthesis of 2-fluoro-3-hydroxy-6-(methoxy-d.SUB.3.)benzaldehyde

##STR00048##

[0113] To a solution of 3-[tert-butyl(diphenyl)silyl]oxy-2-fluoro-6-(trideuteriomethoxy)benzaldehyde (7.3 g, 18 mmol) in THF (60 mL) was added TBAF (20 mL, 20 mmol, 1 mol/L in THF). The mixture was stirred at rt. After 18 h, the solvent was evaporated to give the crude product. The crude residue was purified by normal phase purification, eluting with 0-2% MeOH in DCM to give the title compound (3.1 g, 85% yield). MS m/z 174.0 (M+H).

Preparation 3. Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2-fluoro-6-(methoxy-d.SUB.3.)benzaldehyde

##STR00049##

[0114] Tert-butyl-[2-fluoro-4-(trideuteriomethoxy)phenoxy]-diphenyl-silane (11 g, 30 mmol) was dissolved in THF (130 mL) and cooled to 78 C. To the cooled solution, nBuLi (31 mL, 50 mmol, 1.6 M in hexanes) was added over 20 min. After 1.5 h, DMF (6.0 mL, 78 mmol) was added dropwise. The mixture was stirred at 78 C. for an additional 5 h. The reaction was quenched by the addition of satd aq NH.sub.4Cl (25 mL). The mixture was allowed to warm to rt. After 18 h, the organic solvent was evaporated and the crude residue was extracted with 3 EtOAc. The combined organic extracts were washed with water and brine. The organic extracts were dried over Na.sub.2SO.sub.4, filtered and concentrated. The crude product was purified by normal phase purification, eluting with 0-40% EtOAc in hexanes to give the title compound (7.3 g, 60% yield). MS m/z 412.0 (M+H).

Preparation 4. Synthesis of tert-butyl(2-fluoro-4-(methoxy-d.SUB.3.)phenoxy)diphenylsilane

##STR00050##

[0115] To a solution of 2-fluoro-4-(trideuteriomethoxy)phenol (9.2 g, 44 mmol) in DMF (100 mL) was added imidazole (4.5 g, 66 mmol), and tert-butylchlorodiphenylsilane (14 mL, 53 mmol). The reaction was stirred at rt for 2 d. The mixture was diluted with EtOAc, washed with 3 water and brine. The solution was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the crude product. The crude product was purified by normal phase purification, eluting with 0-20% EtOAc in hexanes to give the title compound (15 g, 86% yield). MS m/z 400.9 (M+NH.sub.4).

Preparation 5. Synthesis of 2-fluoro-4-(methoxy-d.SUB.3.)phenol

##STR00051##

[0116] To a pre-purged 70 mL Parr shaker bottle (N.sub.2) was added 10% Pd/C (1.0 g, 9.7 mmol), followed by purgingagain with N.sub.2. To the charged shaker, 250 mL MeOH was added, followed by 1-benzyloxy-2-fluoro-4-(trideuteriomethoxy)benzene (10 g, 44 mmol) in MeOH (250 mL). The bottle was sealed, purged with N.sub.2, purged with H.sub.2, and then pressurized to 60 psi H.sub.2. The bottle was shaken at rt for 2 h, then depressurized and degassed with N.sub.2. The suspension was filtered over celite with MeOH. The filtrate was concentrated to a crude residue. The crude product was purified by normal phase purification, eluting with 0-20% EtOAc in hexanes to give the title compound (9.2 g, 93% yield). 1H NMR (399.80 MHz, DMSO). 9.22 (s, 1H), 6.86 (dd, J=8.9, 10.1 Hz, 1H), 6.78 (dd, J=3.0, 13.0 Hz, 1H), 6.58 (ddd, J=8.9, 3.0, 1.4 Hz, 1H).

Preparation 6. Synthesis of 1-(benzyloxy)-2-fluoro-4-(methoxy-d.SUB.3.)benzene

##STR00052##

[0117] A suspension of 4-benzyloxy-3-fluoro-phenol (10 g, 46 mmol), Cs.sub.2CO.sub.3 (22 g, 69 mmol) and trideuterio(iodo)methane (3.1 mL, 50 mmol) in DMF (100 mL) was stirred at rt for 18 h. The reaction was diluted with EtOAc, washed with 3 water and brine. The solution was dried over Na.sub.2SO.sub.4, filtered and evaporated to give the crude product. The crude product was purified by normal phase purification, eluting with 0-20% EtOAc in hexanes to give the title compound (10 g, 96% yield). MS m/z 253.0 (M+NH.sub.4).

Preparation 7. Synthesis of tert-butyl (3-((3-(1,3-dioxolan-2-yl)-4-ethyl-2-fluorophenoxy)methyl)phenyl)carbamate

##STR00053##

[0118] To a pre-purged 70 mL Parr shaker bottle (N.sub.2) was added 5% Pd/C (32 mg, 0.16 mmol), followed by purging again with N.sub.2. To the charged shaker, 2.5 mL EtOAc was added and then tert-butyl N-[3-[[3-(1,3-dioxolan-2-yl)-2-fluoro-4-vinyl-phenoxy]methyl]phenyl]carbamate (110 mg, 0.25 mmol) in EtOAc (2.5 mL). The bottle was sealed, purged with N.sub.2, purged with H.sub.2, and then pressurized to 60 psi H.sub.2. The bottle was shaken at rt for 8 h, then depressurized and degassed with N.sub.2. The suspension was filtered over celite with EtOAc. The filtrate was concentrated to give the title compound (89 mg, 84% yield). MS m/z 434.8 (M+NH.sub.4)

Preparation 8. Synthesis of tert-butyl (3-((3-(1,3-dioxolan-2-yl)-2-fluoro-4-vinylphenoxy)methyl)phenyl)carbamate

##STR00054##

[0119] Tert-butyl N-[3-[[4-bromo-3-(1,3-dioxolan-2-yl)-2-fluoro-phenoxy]methyl]phenyl]carbamate (400 mg, 0.85 mmol), potassium vinyltrifluoroborate (0.14 g, 1.0 mmol) and Cs.sub.2CO.sub.3 (0.84 g, 2.6 mmol) were placed in a 25 mL microwave tube. The tube was purged with N.sub.2 and THF (9 mL) and water (1 mL) were added. The solution was degassed by bubbling sub-surface N.sub.2 for 5 min. palladium(II) acetate (10 mg, 0.042 mmol) was added, the tube capped, and mixture was heated at 100 C. for 18 h. Upon cooling to rt, EtOAc and H.sub.2O were added. The phases were separated and the aqueous layer was extracted with 2EtOAc. The combined organics were dried over Na.sub.2SO.sub.4, filtered and concentrated to a crude residue. The crude product was purified by normal phase purification, eluting with 50-100% DCM in hexanes to give the title compound (110 mg, 29% yield). MS m/z 432.8 (M+NH.sub.4).

Preparation 9. Synthesis of tert-butyl (3-((4-bromo-3-(1,3-dioxolan-2-yl)-2-fluorophenoxy)methyl)phenyl)carbamate

##STR00055##

[0120] With a Dean-Stark trap attached, a solution of tert-butyl N-[3-[(4-bromo-2-fluoro-3-formyl-phenoxy)methyl]phenyl]carbamate (1.0 g, 2.4 mmol), ethylene glycol (0.55 mL, 9.8 mmol) and p-toluenesulfonic acid monohydrate (47 mg, 0.25 mmol) in toluene (16 mL) was refluxed at 135 C. After 1 h, the reaction solution was cooled to rt, washed with H.sub.2O (15 mL) and EtOAc (25 mL). The phases were separated, and the aqueous layer was extracted 1 with EtOAc. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated to a crude residue. The crude product was purified by normal phase purification, eluting with 04% MeOH in DCM to give the title compound (500 mg, 44% yield). MS m/z 467.4 (MH).

Preparation 10. Synthesis of tert-butyl (3-((4-bromo-2-fluoro-3-formylphenoxy)methyl)phenyl)carbamate

##STR00056##

[0121] To a solution of 6-bromo-2-fluoro-3-hydroxy-benzaldehyde (5 g, 23 mmol) and Cs.sub.2CO.sub.3 (15 g, 46 mmol) in DMF (76 mL) was added tert-butyl N-[3-(bromomethyl)phenyl]carbamate (7.2 g, 25 mmol). After 18 h at rt, the mixture was diluted with EtOAc and water. The organic layer was washed with 3 water, brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to a crude residue. The crude product was purified by normal phase purification, eluting with 0-20% EtOAc in hexanes to give the title compound (8.2 g, 85% yield). MS m/z 441.2 (M+NH.sub.4).

Preparation 11. Synthesis of tert-butyl (4-(2-fluoro-3-formyl-4-methoxyphenethyl)phenyl)carbamate

##STR00057##

[0122] Tert-butyl N-[4-[2-[2-fluoro-3-(hydroxymethyl)-4-methoxy-phenyl]ethyl]phenyl]carbamate (2.1 g, 5.7 mmol) in DCM (60 mL) was cooled to 0 C. and treated with Dess-Martin periodinane (3.0 g, 7.1 mmol). After 1 h, the reaction was quenched with satd aq NaHCO.sub.3 (4 mL) and Na.sub.2S.sub.2O.sub.3 (0.5 M in water, 4 mL). The organic solvent was removed and the solution was diluted with EtOAc and water. The organic layer was washed with satd aq NaHCO.sub.3, water, brine, and dried over MgSO.sub.4, filtered, and concentrated to a crude residue. The crude product was purified by normal phase purification, eluting with 10-100% DCM in hexanes to give the title compound (1.2 g, 58% yield). MS m/z 391.0 (M+NH.sub.4).

Preparation 12. Synthesis of tert-butyl (4-(2-fluoro-3-(hydroxymethyl)-4-methoxyphenethyl)phenyl)carbamate

##STR00058##

[0123] To a cooled solution (0 C.) of methyl 3-[2-[4-(tert-butoxycarbonylamino)phenyl]ethyl]-2-fluoro-6-methoxy-benzoate (2.5 g, 6.2 mmol) in THF (31 mL) was added DIBAL (22 mL, 22 mmol, 1 mol/L in heptane) and let warm to rt. After 1.5 h, the reaction was cooled back to 0 C. and treated with 6 mL of satd aq NaHCO.sub.3. The ice bath was removed, and the mixture vigorously stirred; the resulting gel was diluted with 3 ml of water and EtOAc and vigorously stirred to achieve a biphasic mixture. The slurry was diluted with EtOAc and the mixture filtered through a pad of celite with additional EtOAc. The filtrate was placed in a separatory funnel and washed with water and brine. The combined organics were dried over MgSO.sub.4, filtered, and concentrated to give the title compound (2.1 g, 79% yield). MS m/z 373.8 (MH).

Preparation 13. Synthesis of methyl 3-(4-((tert-butoxycarbonyl)amino)phenethyl)-2-fluoro-6-methoxy benzoate

##STR00059##

[0124] To methyl 3-[2-(4-aminophenyl)ethyl]-2-fluoro-6-methoxy-benzoate (2.5 g, 7.0 mmol) in DCM (10 mL) was added tBuOH (24 mL), DIPEA (1.5 mL, 8.7 mmol) and di-tert-butyl dicarbonate (1.8 g, 8.4 mmol). The reaction was heated to 50 C. After 1 h, the reaction was cooled to rt and concentrated to a crude residue. The material was dissolved in EtOAc and washed with 20.5N HCl, satd aq NaHCO.sub.3, and brine. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated. The crude product was purified by normal phase purification, eluting with 0-10% EtOAc in DCM to give the title compound (2.5 g, 89% yield). MS m/z 421.2 (M+NH.sub.4).

Preparation 14. Synthesis of methyl 3-(4-aminophenethyl)-2-fluoro-6-methoxybenzoate

##STR00060##

[0125] To a pre-purged 500 mL Parr shaker bottle (N.sub.2) was added 10% Pd/C (380 mg, 0.36 mmol), followed by purging again with N.sub.2. To the charged shaker, 65 mL MeOH was added and then methyl 2-fluoro-6-methoxy-3-[(E)-2-(4-nitrophenyl)vinyl]benzoate (2.5 g, 7.5 mmol) in MeOH (60 mL). The bottle was sealed, purged with N.sub.2, purged with H.sub.2, and then pressurized to 60 psi H.sub.2. The bottle was shaken at rt for 3 h, then depressurized and degassed with N.sub.2. The suspension was filtered over celite with MeOH. The filtrate was concentrated to give the title compound (2.5 g, 86% yield). MS m/z 303.8 (M+H).

Preparation 15. Synthesis of methyl (E)-2-fluoro-6-methoxy-3-4-nitrostyryl)benzoate

##STR00061##

[0126] A solution of methyl 2-fluoro-3-formyl-6-methoxy-benzoate (4.1 g, 20 mmol), diethyl 4-nitrobenzylphosponate (6.0 g, 22 mmol) and 2-methyl THF (200 mL) was cooled to 10 C., and was treated with potassium tert-butoxide (2.7 g, 23 mmol). After 1 h, the reaction was quenched with satd aq NH.sub.4Cl and diluted with EtOAc. The organic layer was washed with water and brine. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated. The crude product was purified by normal phase purification, eluting with 0-100% EtOAc in hexanes to give the title compound (5.6 g, 83% yield). MS m/z 332.0 (M+H).

Preparation 16. Synthesis of tert-butyl (4-(2-(2-fluoro-3-formyl-4-methoxyphenoxy)ethyl)phenyl)carbamate

##STR00062##

[0127] To 2-fluoro-3-hydroxy-6-methoxy-benzaldehyde (500 mg, 2.9 mmol) and 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (1.4 g, 3.5 mmol) in MeCN (18 mL) was added K.sub.2CO.sub.3 (1.2 g, 8.8 mmol) and the suspension was stirred at 80 C. for 16 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layers were dried over MgSO.sub.4, filtered, and concentrated. The crude product was purified normal phase purification, eluting with 0-30% EtOAc in hexanes to give the title compound (0.9 g, 70% yield). MS m/z 387.8 (MH).

Preparation 17. Synthesis of 4-((tert-butoxycarbonyl)amino)phenethyl 4-methylbenzenesulfonate

##STR00063##

[0128] To a solution of tert-butyl N-[4-(2-hydroxyethyl)phenyl]carbamate (2.5 g, 11 mmol) in DCM (50 mL) was added Et.sub.3N (2.9 mL, 21 mmol), followed by p-toluenesulfonyl chloride (2.3 g, 12 mmol) and DMAP (130 mg, 1.0 mmol). The reaction mixture was stirred at rt for 18 h. The reaction mixture was diluted with DCM and washed with water and brine. The combined organic layers were dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to give a crude residue. The crude product was purified normal phase purification, eluting with 0-25% EtOAc in hexanes to give the title compound (3.9 g, 94% yield). MS m/z 408.9 (M+NH.sub.4).

Preparation 18. Synthesis of tert-butyl (3-(2-(2-fluoro-3-formyl-4-methoxyphenoxy)ethyl)phenyl)carbamate

##STR00064##

[0129] To 2-fluoro-3-hydroxy-6-methoxy-benzaldehyde (600 mg, 3.5 mmol) and 2-[3-(tert-butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (1.5 g, 3.7 mmol) in MeCN (20 mL) was added K.sub.2CO.sub.3 (1.5 g, 11 mmol) and the resulting suspension was stirred at 80 C. for 20 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give a crude residue. The crude product was purified normal phase purification, eluting with 0-25% EtOAc in hexanes to give the title compound (0.96 g, 62% yield). MS m/z 388.4 (MH).

Preparation 19. Synthesis of 3-tert-butoxycarbonyl)amino)phenethyl 4-methylbenzenesulfonate

##STR00065##

[0130] To a solution of tert-butyl N-[3-(2-hydroxyethyl)phenyl]carbamate (2.7 g, 11 mmol) in DCM (60 mL) was Et.sub.3N (3.2 mL, 23 mmol) followed by p-toluenesulfonyl chloride (2.5 g, 13 mmol) and DMAP (140 mg, 1.1 mmol). The reaction mixture was stirred at rt for 18 h. The reaction was diluted with DCM and washed with satd aq NH.sub.4Cl and brine. The combined organic layers were dried over MgSO.sub.4, filtered and concentrated under reduced pressure to give a crude residue. The crude product was purified normal phase purification, eluting with 0-25% EtOAc in hexanes to give the title compound (3.0 g, 67% yield). MS m/z 389.8 (MH).

Preparation 20. Synthesis of tert-butyl (3-(2-hydroxyethyl)phenyl)carbamate

##STR00066##

[0131] To a solution of 2-[3-(tert-butoxycarbonylamino)phenyl]acetic acid (3.0 g, 12 mmol) in THF (60 mL) was added dropwise borane-THF complex (17 mL, 17 mmol, 1 mol/L in THF) at 0 C., under N.sub.2 atmosphere. The mixture was warmed to rt while stirring under N.sub.2 for 16 h. The reaction was cooled to 0 C., MeOH was added, and the solution was warmed to rt. The crude reaction was concentrated under reduced pressure to give a crude residue. The crude residue was purified normal phase purification, eluting with 5-50% EtOAc in hexanes to give the title compound (2.7 g, 93% yield). MS m/z 254.8 (M+NH.sub.4).

Example 2. Synthesis of (1S,2S,4R,6S,8S,9S,11S,12S,13R)-6-[3-[(3-aminophenyl)methoxy]-2-fluoro-6-(trideuteriomethoxy)phenyl]-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-5,7-dioxapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one (Compound No. 1)

##STR00067##

[0132] To a suspension of tert-butyl N-[3-[[2-fluoro-3-formyl-4-(trideuteriomethoxy)phenoxy]methyl]phenyl]carbamate (250 mg, 0.63 mmol) and (8S,9S,10R,11S,13S,14S,16R,17S)-11,16,17-trihydroxy-17-(2-hydroxyacetyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6H-cyclopenta[a]phenanthren-3-one (250 mg, 0.66 mmol) in MeCN (6 mL) at 10 C. was added perchloric acid (70% in water, 0.29 mL, 5 equiv.) dropwise. The mixture was stirred at 10 C. for 1 h. The reaction was quenched cold, with the addition of sat'd aq NaHCO.sub.3, and partitioned between water and 10% IPA/DCM. The phases were separated, and the aqueous layer was extracted 1 with 10% IPA/DCM. The combined organics were dried over MgSO.sub.4, filtered and concentrated to give a crude solid. The solid was purified by reverse phase chromatography, eluting with 50-100% MeCN in 10 mM ammonium bicarbonate water+5% methanol to give the title compound (420 mg, 16 yield). MS m/z 637.4 (M+H).

[0133] .sup.1HNMR (399.8 MHz, d.sub.6-DMSO) 17.33-7.31 (i, 1H), 7.17-7.12 (nM, 1H), 6.99 (t, J=7.7 Hz, 1H), 6.73-6.70 (m, 1H), 6.58 (s, 1H), 6.53-6.46 (i, 3H), 6.19-6.16 (m, 1H), 5.95 (s, 1H), 5.25 (d, J=6.6 Hz, 1H), 5.10 (s, 2H), 5.00-4.93 (m, 3H), 4.80-4.78 (m, 1H), 4.37-4.30 (m, 2H), 4.04-3.98 (m, 1H), 2.37-2.31 (m, 1H), 2.11-2.07 (i, 2H), 1.89-1.82 (m, 4H), 1.62-1.59 (i, 1H), 1.40 (s, 3H), 1.26-1.24 (m, 2H), 0.87 (s, 3H).

Example 3. Synthesis of Compound Nos. 2-5

[0134] Compound Nos. 2-5 were prepared essentially by the method of Example 2.

TABLE-US-00003 ES/MS (m/z) Compound No. (M + H) .sup.1H NMR 2 632.3 1H NMR (399.80 MHz, DMSO): 7.33 (d, J = 10.0 Hz, 1H), 7.15-7.11 (m, 1H), 6.99 (t, J = 7.7 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 1.7 Hz, 1H), 6.53-6.48 (m, 2H), 6.30 (s, 1H), 6.20-6.16 (m, 1H), 5.95 (s, 1H), 5.30 (d, J = 6.9 Hz, 1H), 5.10-5.07 (m, 3H), 5.00-4.93 (m, 2H), 4.82-4.80 (m, 1H), 4.38-4.31 (m, 2H), 4.06- 4.01 (m, 1H), 2.68-2.59 (m, 2H), 2.38-2.30 (m, 1H), 2.11-2.02 (m, 2H), 1.90-1.79 (m, 4H), 1.70-1.65 (m, 1H), 1.40 (s, 3H), 1.24-1.04 (m, 6H), 0.88 (s, 3H). 3 632.2 1H NMR (400.13 MHz, DMSO): 7.32 (d, J = 10.0 Hz, 1H), 7.18 (t, J = 8.6 Hz, 1H), 6.83 (d, J = 8.3 Hz, 2H), 6.76-6.73 (m, 1H), 6.46 (d, J = 8.4 Hz, 3H), 6.19-6.16 (m, 1H), 5.95 (s, 1H), 5.26 (d, J = 6.7 Hz, 1H), 4.96 (dd, J = 5.5, 6.4 Hz, 1H), 4.82-4.77 (m, 3H), 4.40-4.30 (m, 2H), 4.02-3.96 (m, 1H), 3.65 (s, 3H), 2.71-2.61 (m, 3H), 2.34-2.31 (m, 1H), 2.08 (s, 4H), 1.88-1.75 (m, 4H), 1.61-1.53 (m, 1H), 1.40 (s, 3H), 1.23-1.07 (m, 3H), 0.88 (s, 3H). 4 648.6 1H NMR (400.13 MHz, DMSO): 7.32 (d, J = 10.1 Hz, 1H), 7.15-7.10 (m, 1H), 6.93 (d, J = 8.3 Hz, 2H), 6.73- 6.71 (m, 1H), 6.50-6.45 (m, 3H), 6.18 (dd, J = 1.8, 10.1 Hz, 1H), 5.95 (s, 1H), 5.76 (s, 1H), 5.24 (d, J = 6.6 Hz, 1H), 4.97 (dd, J = 5.3, 6.5 Hz, 1H), 4.88 (s, 2H), 4.78 (d, J = 3.2 Hz, 1H), 4.36-4.29 (m, 2H), 4.08-3.97 (m, 3H), 3.63 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H), 2.59-2.55 (m, 1H), 2.34-2.31 (m, 1H), 2.11-2.02 (m, 2H), 1.88-1.75 (m, 4H), 1.60-1.54 (m, 1H), 1.40 (s, 3H), 1.24-1.21 (m, 2H), 0.87 (s, 3H). 5 648.6 1H NMR (400.13 MHz, DMSO): 7.32 (d, J = 10.1 Hz, 1H), 7.17-7.12 (m, 1H), 6.93 (t, J = 7.7 Hz, 1H), 6.74- 6.71 (m, 1H), 6.47-6.40 (m, 4H), 6.18 (dd, J = 1.8, 10.1 Hz, 1H), 5.95 (s, 1H), 5.76 (s, 1H), 5.24 (d, J = 6.6 Hz, 1H), 5.00-4.96 (m, 3H), 4.78 (d, J = 3.3 Hz, 1H), 4.36- 4.30 (m, 2H), 4.12-4.05 (m, 3H), 3.63 (s, 3H), 2.83 (t, J = 7.1 Hz, 2H), 2.34-2.31 (m, 1H), 2.11-2.08 (m, 2H), 1.88-1.76 (m, 4H), 1.61-1.56 (m, 1H), 1.40 (s, 3H), 1.23-1.20 (m, 2H), 0.87 (s, 3H).

Example 4. hGR CoActivator Recruitment Assay

[0135] The activity of glucocorticoid compounds was measured using the LanthaScreen TR-Fret GR Coactivator Assay from Life Technologies (A15899). The compounds were acoustically transferred to an assay plate in a 3-fold 10-point serial dilution with atop concentration of 200 nM. Ten microliters of a 2 solution of GR-LBD was added to the compound plate and incubated for 10 min. Then ten microliters of a 2 solution of Fluoresein-SRC1-4 and Tb labelled anti-GST antibody were added to the plate. The plate was incubated in the dark for two hours and then read on an Envision plate reader, with excitation at 340 nm and emission at 520 nm (Fluorescein) and 490 nm (Terbium). The emission ratio of 520/490 was analyzed in Genedata. To obtain percent activity, the data was compared to a negative control of DMSO and positive control of 4 M dexamethasone. The following exemplified compounds were tested following the procedure as essentially described above and exhibited the following activity as listed in Table 2.

TABLE-US-00004 TABLE 2 In vitro potency of compounds of Compound Nos. 1-5 in the hGR CoActivator Recruitment Assay Compound No. EC.sub.50 (nM) 1 1.93 2 1.52 3 1.65 4 1.48 5 2.25