BENZENESULFONAMIDES USEFUL AS SODIUM CHANNEL INHIBITORS

Abstract

The invention relates to sulfonamide derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new sulfonamide Nav1.7 inhibitors of formula (I), or a pharmaceutically acceptable salt thereof, wherein X, R.sup.1, R.sup.2, R.sup.3a, R.sup.3b and R.sup.4 are as defined in the description. Nav1.7 inhibitors are potentially useful in the treatment of a wide range of disorders, particularly pain.

##STR00001##

Claims

1. A compound of formula (I): ##STR00145## or a pharmaceutically acceptable salt thereof, wherein: Het is ‘C-linked’ thiazolyl or thiadiazolyl; X is CH or N; R.sup.1 is H or F; R.sup.2 is Cl or CN; R.sup.3a is H or CF.sub.3; R.sup.3b is H or, when R.sup.3a is H, may also be CF.sub.3; R.sup.4 is ##STR00146## ##STR00147## R.sup.5 is CH.sub.3—(OC.sub.2H.sub.4)n-; and n is 1 to 15.

2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein Het is ‘C-linked’ thiadiazolyl.

3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is N.

4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is H.

5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.2 is CN.

6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.3a is CF.sub.3 and R.sup.3b is H.

7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R.sup.4 is ##STR00148##

8. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 4.

9. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 12.

10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof wherein R.sup.4 is ##STR00149##

11. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is: 4-({3-[2-({[2-(1-Acetylpiperidin-4-yl)ethyl]amino}methyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; 5-Chloro-2-fluoro-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3-thiazol-4-ylbenzenesulfonamide; 6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-N-(2-piperazin-1-ylethyl)-1,1′:3′,1″-terphenyl-3-carboxamide; 4-[(3″-{[4-(2-aminoethyl)piperazin-1-yl]methyl}-1,1′:3′,1″-terphenyl-4′-yl)oxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; 3-Cyano-4-[(3″-{[(2-piperidin-4-ylethyl)amino]methyl}-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; 5-Chloro-2-fluoro-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide; 4-({3-[2-(Aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide; 2-[2-(2-methoxyethoxy)ethoxy]ethyl [(4-{4-[2-cyano-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]carbamate; 3-cyano-4-((3-(2-(3-oxo-7,10,13,16-tetraoxa-2,4-diazaheptadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-((3-(2-(2,8,11,14,17-pentaoxa-5-azaoctadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (4-(4-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl(2,5,8,11-tetraoxatridecan-13-yl)carbamate; 3-cyano-4-({3-[2-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azanonatriacontan-39-yl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 3-cyano-4-({3-[2-(2,5,8,11,14-pentaoxapentadec-1-yl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 2-((4-(4-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide; 4-((3-(2-(5,8,11,14-tetraoxa-2-azapentadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-{[3″-({[2-(1-Acetylpiperidin-4-yl)ethyl]amino}methyl)-1′:3′,1″-terphenyl-4′-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; 4-((3-(2-(((2-(1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oyl)piperidin-4-yl)ethyl)amino)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 3-Cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; N-((4-(4-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide; 4-((3-(2-((3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)azetidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (R)-4-((3-(2-((3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; (S)-4-((3-(2-((3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-((3-(2-((4-((2,5,8,11-tetraoxatridecan-13-yl)oxy)piperidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-((3-(2-(4-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oyl)piperazin-1-yl)pyridin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide 3-Cyano-N-1,2,4-thiadiazol-5-yl-4-{[3-{2-[({2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide; 4-({3-[2-(Aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide; N-[(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide; N-[(4-{4-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide; 4-({3-[2-(aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide; 5-chloro-2-fluoro-4-{[3-{2-[({2-[1-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide; 3-cyano-4-({3″-[({2-[1-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperidin-4-yl]ethyl}amino)methyl]-1,1′:3′,1″-terphenyl-4′-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 5-chloro-2-fluoro-4-{[3-{2-[4-(38-oxo-2, 5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperazin-1-yl]pyridin-4-yl}-4′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide; 5-chloro-2-fluoro-4-{[3-{2-[({2-[1-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide; 3-cyano-4-({3-[2-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azanonatriacontan-39-yl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide; or 5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)-4-{[3-{2-[({2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, that is: 3-cyano-4-({3-[2-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azanonatriacontan-39-yl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-((3-(2-(5,8,11,14-tetraoxa-2-azapentadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; 4-((3-(2-(((2-(1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oyl)piperidin-4-yl)ethyl)amino)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide; or 3-cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide.

13. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

14. A pharmaceutical composition according to claim 13 including one or more additional therapeutic agents.

15. (canceled)

16. (canceled)

17. (canceled)

18. (canceled)

19. A method of treating a disorder in a human or animal for which a Nav1.7 inhibitor is indicated, comprising administering to said human or animal a therapeutically effective amount of a compound according to claim 1.

Description

EXAMPLE 1

4-({3-[2-({[2-(1-Acetylpiperidin-4-yl)ethyl]amino}methyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0377] ##STR00019##

[0378] tert-Butyl [2-(1-acetylpiperidin-4-yl)ethyl]({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 4, 49 mg, 0.06 mmol) was dissolved in dioxane (1 mL) and 4M HCl in dioxane (1 mL) was added. The reaction was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo and the residue was azeotroped with methanol. The residue was purified first by reverse phase column chromatography eluting with acetonitrile/water with 0.1% formic acid followed elution through an SCX cartridge to afford the title compound as a white solid (12 mg, 28%).

[0379] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.92-1.07 (m, 2H), 1.52-1.74 (m, 5H), 1.96 (s, 3H), 2.36 (t, 1H), 2.89 (t, 1H), 3.18 (t, 2H), 3.68 (d, 1H), 4.00-4.43 (m, 3H), 6.64 (d, 1H), 7.33-7.39 (m, 2H), 7.55-7.92 (m, 10H), 8.43 (d, 1H).

[0380] .sup.19F NMR (400 MHz, CDCl.sub.3): δ −62.6 (s, 3F).

[0381] LCMS Rt=2.37 minutes MS m/z 762 [M+H].sup.+

EXAMPLE 2

5-Chloro-2-fluoro-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3-thiazol-4-ylbenzenesulfonamide

[0382] ##STR00020##

[0383] To a solution of 2,2,2-trichloroethyl ({4-[4-{2-chloro-5-fluoro-4-[(1,3-thiazol-4-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)(2-piperidin-4-ylethyl)carbamate (Preparation 10, 100 mg, 0.104 mmol) in a diethyl ether/acetic acid (3/1, 7 mL) was added zinc dust (528 mg, 8.34 mmol). The reaction was stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen carbonate was added until pH=7. The suspension was filtered through a pad of Arbocel and washed with ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound as a colourless solid (21 mg, 26%).

[0384] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 0.95 (m, 1H), 1.40 (m, 3H), 1.50 (m, 1H), 1.80 (m, 2H), 2.60 (m, 2H), 2.90 (m, 2H), 3.40 (m, 2H), 4.05 (s, 2H), 6.55 (d, 1H), 6.60 (s, 1H), 7.35 (d, 1H), 7.50 (d, 1H), 7.60 (m, 2H), 7.70 (d, 1H), 7.80 (m, 2H), 7.95 (m, 2H), 8.50 (m, 2H), 8.65 (s, 1H).

[0385] .sup.19F NMR (400 MHz, MeOD-d.sub.4): δ ppm −64.0 (s, 3F), −119.0 (s, 1F).

[0386] LCMS Rt=2.50 minutes MS m/z 746 [M+H].sup.+

EXAMPLE 3

6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-N-(2-piperazin-1-ylethyl)-1,1′:3′,1″-terphenyl-3-carboxamide

[0387] ##STR00021##

[0388] A solution of hydrochloric acid in dioxane (4M, 4 mL, 100 mmol) was added to tert-butyl 4-(2-{[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)carbonyl]amino}ethyl)piperazine-1-carboxylate (Preparation 20, 100 mg, 0.18 mmol). The resulting reaction mixture was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to provide the crude product as an orange gum of the hydrochloride salt (193 mg). The crude material was stirred in dioxane (2 mL) and triethylamine (0.4 mL, 1 eq) for 1 hour, then concentrated in vacuo to provide the free parent as an orange gum. The crude material was dissolved in DMSO and purified by reverse phase silica gel column chromatography, eluting with 5-95% MeCN in H.sub.2O+1% NH.sub.3 to afford the title compound as a white solid (28 mg, 16%).

[0389] LCMS Rt=1.25 minutes MS m/z 664 [M−H].sup.−

EXAMPLE 4

4-[(3″-{[4-(2-aminoethyl)piperazin-1-yl]methyl}-1,1′:3′,1″-terphenyl-4′-yl)oxy]-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide dihydrochloride salt

[0390] ##STR00022##

[0391] To a solution of tert-butyl (2-{4-[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)methyl]piperazin-1-yl}ethyl)carbamate (Preparation 12, 600 mg, 0.8 mmol), dissolved in dichloromethane (10 mL), was added a solution of 4M HCl in 1,4-dioxane (2 mL, 8 mmol) and stirred at room temperature for 18 hours. The solvent was removed in vacuo to afford the title compound as a white solid (570 mg, 98%).

[0392] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 2.90-3.40 (m, 12H), 4.35 (s, 2H), 6.95 (m, 1H), 7.40-7.65 (m, 7H), 7.80-8.00 (m, 6H), 8.10 (s, 2H), 8.20 (s, 1H), 8.50 (s, 1H).

[0393] LCMS Rt=2.20 minutes MS m/z 650 [M−H].sup.−

EXAMPLE 5

3-Cyano-4-[(3″-{[(2-piperidin-4-ylethyl)amino]methyl}-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide sodium salt

[0394] ##STR00023##

[0395] To a solution of N-[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)methyl]-2,2,2-trifluoro-N-(2-piperidin-4-ylethyl)acetamide (Preparation 14, 50 mg, 0.058 mmol) in 3:1 methanol:water (2 mL) was added saturated aqueous sodium carbonate solution (1 mL). The reaction mixture was stirred at reflux for 18 hours, then cooled and partitioned between EtOAc (20 mL) and water (20 mL). The aqueous was further extracted with EtOAc (2×15 mL) then DCM (2×15 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid (17 mg, 43%).

[0396] LCMS Rt=1.88 minutes MS m/z 651 [M+H].sup.+

EXAMPLE 6

5-Chloro-2-fluoro-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide bis-formate salt

[0397] ##STR00024##

[0398] To a solution of tert-butyl 4-{2-[({4-[4-{2-chloro-5-fluoro-4-[(1,3,4-thiadiazol-2-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)amino]ethyl}piperidine-1-carboxylate (Preparation 1, 38 mg, 0.043 mmol) in 1,4-dioxane (1 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4M, 1 mL). The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 5-95% acetonitrile in water with 0.1% formic acid to afford the title compound as a colourless solid (21 mg, 60%).

[0399] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 1.40 (m, 2H), 1.60-1.90 (m, 5H), 2.95 (m, 4H), 3.35 (m, 2H), 4.20 (s, 2H), 6.40 (d, 1H), 7.35 (d, 1H), 7.60 (d, 1H), 7.65 (s, 1H), 7.70 (m, 1H), 7.80 (d, 1H), 7.85 (m, 3H), 7.95 (m, 2H), 8.50 (s, 1H), 8.60 (s, 1H).

[0400] .sup.19F NMR (400 MHz, MeOD-d.sub.4): δ ppm −65.0 (s, 3F), −108.0 (s, 1F).

[0401] LCMS Rt=2.51 minutes MS m/z 747 [M+H].sup.+

EXAMPLE 7

4-({3-[2-(Aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl) biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide bis-formate salt

[0402] ##STR00025##

[0403] To a solution of tert-butyl ({4-[4-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-2-yl)amino]sulfonyl}-5-fluorophenoxy)-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 3, 1.01 g, 1.14 mmol) in 1,4-dioxane (3 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4M, 3.0 mL, 12 mmol). The reaction was stirred at room temperature for 18 hours and concentrated in vacuo. The resulting residue was purified by reverse phase column chromatography eluting with 5-95% acetonitrile in water with 0.1% formic acid to afford the title compound as a white solid (160 mg, 80%).

[0404] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 4.20 (s, 2H), 6.90 (d, 1H), 7.20 (d, 1H), 7.70 (m, 5H), 7.90 (d, 1H), 7.95 (s, 1H), 8.05 (m, 2H), 8.40 (br s, 2H), 8.55 (s, 1H), 8.65 (d, 1H).

[0405] .sup.19F NMR (400 MHz, DMSO-d.sub.6): δ ppm −62.0 (s, 3F), −107.0 (s, 1F).

[0406] LCMS Rt=2.88 minutes MS m/z 636 [M+H].sup.+

EXAMPLE 8

2-[2-(2-methoxyethoxy)ethoxy]ethyl [(4-{4-[2-cyano-4-(1,2,4-thiadiazol-5-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]carbamate triethylammonium salt

[0407] ##STR00026##

[0408] To a solution of 2-(2-(2-methoxyethoxy)ethoxy)ethyl ((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate (Preparation 34, 26 mg, 0.049 mmol) in DMSO (0.5 mL) was added potassium carbonate (20 mg, 0.147 mmol) followed by 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (WO2010079443, 15 mg, 0.054 mmol). The reaction was heated to 50° C. for 18 hours. The reaction was partitioned between EtOAc and water, the organic layer was collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% MeOH in DCM with 2% TEA to afford the title compound.

[0409] .sup.1H NMR (500 MHz, MeOH-d.sub.4): δ ppm 3.44-3.51 (m, 2H), 3.53-3.61 (m, 9H), 3.63-3.72 (m, 2H), 4.13-4.21 (m, 2H), 4.42 (s, 2H), 6.89-7.01 (m, 1H), 7.36-7.45 (m, 1H), 7.48-7.58 (m, 1H), 7.58-7.65 (m, 1H), 7.66-7.75 (m, 2H), 7.83-7.92 (m, 2H), 7.92-8.04 (m, 4H), 8.07-8.18 (m, 1H), 8.41-8.53 (m, 1H).

[0410] MS m/z 799 [M+H].sup.+

EXAMPLE 9

3-cyano-4-((3-(2-(3-oxo-7,10,13,16-tetraoxa-2,4-diazaheptadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide triethylammonium salt

[0411] ##STR00027##

[0412] The title compound was prepared according to the method described for Example 8 using 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (WO2010079443) and 1-((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-3-(2,5,8,11-tetraoxatridecan-13-yl)urea (Preparation 33) at 90° C. for 18 hours.

[0413] .sup.1H NMR (500 MHz, MeOH-d.sub.4): δ ppm 3.20-3.60 (m, 19H), 4.40 (s, 2H), 6.95 (m, 1H), 7.20 (m, 1H), 7.30 (m, 1H), 7.40 (m, 1H), 7.70-7.75 (m, 2H), 7.90 (m, 2H), 7.95-8.05 (m, 4H), 8.10 (m, 1H), 8.45 (m, 1H). LCMS Rt=1.59 minutes MS m/z 842 [M+H].sup.+

EXAMPLE 10

4-((3-(2-(2,8,11,14,17-pentaoxa-5-azaoctadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0414] ##STR00028##

[0415] The title compound was prepared according to the method described for Example 8 using 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (WO2010079443) and 3-(2-(2,8,11,14,17-pentaoxa-5-azaoctadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol (Preparation 32) using potassium phosphate as base at 65° C. for 18 hours. The residue was purified using Preparative HPLC.

[0416] LCMS Rt=2.54 minutes MS m/z 843 [M+H].sup.+

EXAMPLE 11

(4-(4-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate

[0417] ##STR00029##

[0418] The title compound was prepared according to the method described for Example 8 using 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (WO2010079443) and (4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate (Preparation 27) using potassium phosphate as base at 65° C. for 18 hours followed by the addition of potassium carbonate and further heating at 90° C. for 18 hours. The residue was purified using Preparative HPLC.

[0419] LCMS Rt=2.42 minutes MS m/z 843 [M+H].sup.+

EXAMPLE 12

3-cyano-4-({3-[2-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azanonatriacontan-39-yl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0420] ##STR00030##

[0421] To a solution of tert-butyl (2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl) ((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate (Preparation 28, 108 mg, 0.109 mmol) in DMSO (2 mL) was added potassium phosphate (70 mg, 0.327 mmol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443, 48 mg, 0.11 mmol). The reaction was stirred at room temperature for 18 hours. To the reaction was added water and EtOAc. The organic layer was separated, the aqueous layer was further extracted with EtOAc, the organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM and the residue was dissolved in DCM (2.5 mL) and treated with TFA (200 uL), with stirring for 2 hours. 5N HCl (100 uL) was then added and the reaction stirred for 1 hour. The reaction was concentrated in vacuo azeotroping with DCM, EtOAc and heptanes. The residue was dissolved in 10% MeOH in DCM (10 mL) and basified with MP-carbonate before concentrating in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (35 mg, 35%).

[0422] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.34-3.40 (s, 3H), 3.51-3.55 (m, 2H), 3.56-3.66 (m, 42H), 3.67-3.71 (m, 2H), 3.88 (m, 2H), 4.47 (s, 2H), 6.66 (d, 1H), 7.37 (d, 1H), 7.48 (d, 2H) 7.61 (s, 1H), 7.65-7.68 (m, 2H), 7.72-7.78 (m, 1H), 7.79-7.84 (m, 1H), 7.85 (s, 1H), 7.88 (s, 1H), 7.96 (s, 1H), 8.00 (d, 1H), 8.50 (d, 1H).

[0423] LCMS Rt=1.65 minutes MS m/z 1149 [M−H].sup.−

EXAMPLE 13

3-cyano-4-({3-[2-(2,5,8,11,14-pentaoxapentadec-1-yl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0424] ##STR00031##

[0425] The title compound was prepared according to the method described by Example 12 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443) and 3-(2-(2,5,8,11,14-pentaoxapentadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol (Preparation 30).

[0426] .sup.1H NMR (500 MHz, MeOH-d.sub.4): δ ppm 3.20-3.30 (m, 11H), 3.45 (m, 2H), 3.50-3.65 (m, 6H), 4.70 (s, 2H), 6.95 (m, 1H), 7.50 (m, 1H), 7.60 (m, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 7.90-8.00 (m, 3H), 8.02 (m, 2H), 8.10-8.20 (m, 2H), 8.55 (m, 1H).

[0427] MS m/z 800 [M+H].sup.+

EXAMPLE 14

2-((4-(4-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide

[0428] ##STR00032##

[0429] The title compound was prepared according to the method described by Example 12 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443) and 2-((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide (Preparation 31).

[0430] .sup.1H NMR (500 MHz, CDCl.sub.3): δ ppm 3.44 (s, 3H), 3.46-3.52 (m, 2H), 3.59-3.75 (m, 16H), 4.62 (s, 2H), 6.59 (d, 1H), 7.33 (dd, 1H), 7.43 (d, 2H), 7.63 (d, 1H), 7.66-7.71 (m, 2H), 7.75-7.84 (m, 2H), 7.87 (s, 1H), 7.94 (dd, 1H), 7.99 (s, 1H), 8.10 (d, 1H), 8.55 (d, 1H).

[0431] MS m/z 857 [M+H].sup.+

EXAMPLE 15

4-((3-(2-(5,8,11,14-tetraoxa-2-azapentadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0432] ##STR00033##

[0433] To a solution of tert-butyl ((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)carbamate (Preparation 29, 48 mg, 0.10 mmol) in DMSO (2 mL) was added potassium phosphate (58 mg, 0.273 mmol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443, 28 mg, 0.10 mmol). The reaction was stirred at room temperature for 18 hours followed by 90° C. for 2 hours. To the reaction was added water and EtOAc.

[0434] The organic layer was separated, the aqueous layer was further extracted with EtOAc, the organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified using 0-10% MeOH in DCM and dissolved in DCM (2.5 mL) and treated with TFA (200 uL), with stirring for 2 hours. 5N HCl in isopropenol (200 uL) was then added and the reaction stirred for 1 hour. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound (30 mg, 95%).

[0435] LCMS Rt=2.99 minutes MS m/z 799 [M+H].sup.+

EXAMPLE 16

4-{[3″-({[2-(1-Acetylpiperidin-4-yl)ethyl]amino}methyl)-1,1′:3′,1″-terphenyl-4′-yl]oxy}-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0436] ##STR00034##

[0437] To a solution of 4-{[3″-({[2-(1-acetylpiperidin-4-yl)ethyl]amino}methyl)-1,1′:3′,1″-terphenyl-4′-yl]oxy}-3-cyano-N-(2,4-dimethoxybenzyl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 23, 1.22 g, 1.45 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (540 μL, 7.25 mmol). The reaction mixture was stirred for 18 hours at room temperature. Methanol (50 mL) was added then the reaction mixture was concentrated in vacuo. The crude material was purified by preparative reverse phase HPLC, then by silica gel column chromatography eluting 10-50% methanol in ethyl acetate to afford the title compound as a white solid (346 mg, 34%).

[0438] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.13 (m, 2H), 1.63 (m, 3H), 1.75 (m, 2H), 2.08 (s, 3H), 2.60 (m, 1H), 3.01 (m, 2H), 3.09 (m, 1H), 3.89 (m, 1H), 4.12 (s, 2H), 4.48 (m, 1H), 6.72 (m, 1H), 7.27 (m, 1H), 7.33 (m, 1H), 7.41 (m, 2H), 7.47 (m, 2H), 7.53 (m, 1H), 7.60 (m, 1H), 7.68 (m, 2H), 7.73 (m, 1H), 7.79 (m, 2H), 7.96 (m, 2H).

[0439] LCMS Rt=2.32 minutes MS m/z 693 [M+H].sup.+

EXAMPLE 17

4-((3-(2-(((2-(1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oyl)piperidin-4-yl)ethyl)amino)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0440] ##STR00035##

[0441] To a solution of 2,5-dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oate (m-dPEG12-NHS ester, 29 mg, 0.042 mmol) in DCM (1 mL) was added TEA (18 uL, 0.124 mmol) followed by tert-butyl {[4-(3′-tert-butyl-4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}biphenyl-3-yl)pyridin-2-yl]methyl}(2-piperidin-4-ylethyl)carbamate (Preparation 5, 34 mg, 0.042 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and dissolved in dioxane (1 mL). The solution was treated with 4M HCl in dioxane (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound (23 mg, 43%).

[0442] LCMS Rt=2.62 minutes MS m/z 1290[M+H].sup.+

EXAMPLE 18a

3-Cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide bis-formate salt

[0443] ##STR00036##

[0444] To a solution of tert-butyl 4-{2-[({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)amino]ethyl}piperidine-1-carboxylate (Preparation 19, 35 mg, 0.04 mmol) in 1,4-dioxane (1 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4M, 1 mL). The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 5-95% acetonitrile in water with 0.1% formic acid to afford the title compound as a colourless solid (20 mg, 65%).

[0445] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 1.40 (m, 1H), 1.75 (m, 2H), 1.95 (d, 2H), 2.95 (t, 2H), 3.10 (m, 2H), 3.40 (d, 2H), 3.40 (d, 2H), 4.40 (s, 2H), 6.75 (d, 1H), 7.45 (d, 1H), 7.55 (d, 1H), 7.60-7.70 (m, 3H), 7.80-8.00 (m, 5H), 8.20 (br s, 2H), 8.50 (s, 1H).

[0446] .sup.19F NMR (400 MHz, MeOD-d.sub.4): δ ppm −64.5 (s, CF.sub.3).

[0447] LCMS Rt=2.44 minutes MS m/z 720 [M+H].sup.+

EXAMPLE 18b

3-Cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide trihydrochloride salt

[0448] ##STR00037##

[0449] To a solution of tert-butyl 4-{2-[({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)amino]ethyl}piperidine-1-carboxylate (Preparation 19, 26 g, 32 mmol) in methanol (300 mL) was added 5M HCl in iso-propyl alcohol (130 mL, 634 mmol). The mixture was stirred at room temperature overnight, the mixture filtered and the solid washed with 50% methanol in iso-propyl alcohol (3×65 mL) and dried under vacuum to afford afford the crude title compound as a colourless solid (28.7 g, 109%).

[0450] A suspension of crude 3-cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide trihydrochloride salt (56.1 g) in methanol (700 mL) was stirred for 30 minutes then treated with iso-propyl alcohol (500 mL), heated to 45° C. and stirred overnight. The slurry was filtered, washed with 60% methanol in iso-propyl alcohol (3×65 mL) to afford the title compound as a white solid (29.2 g). The filtrate was partially concentrated under reduced pressure to a volume of approximately 250 mL and the resulting slurry was stirred at room temperature for 2 hours. The mixture was filtered and the solid washed with iso-propyl alcohol (2×50 mL) and dried under vacuum to afford further title compound as an off-white solid (13.7 g).

[0451] 1H NMR (600 MHz, MeOD-d.sub.4) b ppm 1.47 (m, 2H), 1.79 (br. s., 3H), 1.98 (br. d, 2H) 3.01 (t, 2H), 3.19 (br. s., 2H), 3.40 (d, 2H), 4.51 (br. s., 2H), 7.03 (d, 1H), 7.50 (d, 1H), 7.67-7.77 (m, 2H), 7.81 (d, 1H), 7.96 (t, 2H), 7.98-8.09 (m, 4H), 8.15 (s, 1H), 8.23 (s, 1H), 8.71 (d, 1H).

[0452] CHN calculated for C.sub.38H.sub.32Cl.sub.3F.sub.3N.sub.7O.sub.3S.sub.2 C, 50.70; H, 4.25; N, 11.82; Cl, 12.83. CHN Found C, 49.99; H, 4.36; N, 11.54; Cl, 12.30.

EXAMPLE 18c

3-Cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0453] ##STR00038##

[0454] To a mixture of 3-cyano-4-{[3-(2-{[(2-piperidin-4-ylethyl)amino]methyl}pyridin-4-yl)-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide trihydrochloride salt (Example 18b, 150 mg, 0.18 mmol) in ethyl acetate (2.2 mL) and water (1.5 mL) was added 1N aqueous sodium hydroxide solution (0.45 mL, 0.18 mmol) to pH 6-7. The mixture was stirred at room temperature for 1 hour and the resulting slurry was filtered. The solid was washed with water and dried in a vacuum oven at 50° C. for 16 hours to afford the title compound as white solid (100 mg, 77%).

[0455] 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.25 (m, 2H), 1.30 (q, 2H), 1.44-1.62 (m, 1H), 1.68 (d, 2H), 2.42 (t, 2H), 2.80 (td, 2H), 3.21 (d, 2H), 3.80 (s, 2H), 6.94 (d, 1H), 7.43-7.55 (m, 2H), 7.61 (s, 1H), 7.68-7.83 (m, 2H), 7.84-7.93 (m, 2H), 7.96 (dd, 1H), 8.01 (dd, 2H), 8.09-8.20 (m, 2H), 8.52 (d, 1H)

EXAMPLE 19

N-((4-(4-(4-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2-cyanophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide

[0456] ##STR00039##

[0457] To a solution of 4-({3-[2-(Aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide bis-formate salt (Example 26, 50 mg, 0.082 mmol) in DMF (2 mL) was added 2,5-dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oate (m-dPEG12-NHS ester, 51 mg, 0.082 mmol) followed by TEA (0.1 mL, 0.41 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue purified using reverse phase column chromatography eluting with acetonitrile and water to afford the title compound (53 mg, 100%).

[0458] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 2.45 (m, 2H), 3.45-3.55 (m, 47H), 3.75 (m, 2H), 4.42 (m, 2H), 6.70 (m, 1H), 7.25 (m, 1H), 7.35 (m, 2H), 7.50-7.85 (m, 7H), 8.00-8.10 (m, 2H), 8.45 (m, 1H).

[0459] LCMS Rt=2.47 minutes MS m/z 1177 [M−H].sup.−

EXAMPLE 20

4-((3-(2-((3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)azetidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide hemi trifluoroacetate salt

[0460] ##STR00040##

[0461] To a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-((3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 18, 50 mg, 0.066 mmol) in DCM (1 mL) was added DIPEA (0.027 mL, 0.165 mmol) followed by mesyl chloride (7.6 mg, 0.066 mmol) and the reaction was stirred at room temperature for 2 hours. The solution was purified directly using silica gel column chromatography eluting with 0-100% EtOAc in heptanes. The residue was dissolved in DCM (1 mL) and DIPEA (0.027 mL, 0.165 mmol) was added followed by 3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)azetidine (Preparation 83, 24 mg, 0.091 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was purified directly using silica gel column chromatography eluting with 0-10% MeOH in DCM. The residue was dissolved in DCM (2 mL) and treated with TFA (0.25 mL) and stirred at room temperature for 4 hours. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (19 mg, 31%).

[0462] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 3.20 (s, 3H), 3.30-3.60 (m, 16H), 4.00-4.10 (m, 2H), 4.30-4.40 (m, 3H), 4.60 (m, 2H), 7.00 (d, 1H), 7.53 (d, 1H), 7.63-7.81 (m, 3H), 7.92 (m, 1H), 7.94 (m, 1H), 7.98-8.10 (m, 2H), 8.10-8.15 (m, 4H), 8.64 (d, 1H).

[0463] .sup.19F NMR (300 MHz): δ ppm −61.3 (s, 3F), −73.9 (s, 1.6F).

[0464] MS m/z 855 [M+H].sup.+

EXAMPLE 21

(R)-4-((3-(2-((3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide trifluoroacetate salt

[0465] ##STR00041##

[0466] The title compound was prepared according to the method described for Example 20 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-((3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 18) and (R)-3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine (Preparation 64).

[0467] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 2.10 (br m, 2H), 3.20 (s, 3H), 3.35-3.52 (m, 20H), 4.27 (br s, 1H), 4.58 (br s, 2H), 7.01 (d, 1H), 7.56 (d, 1H), 7.68 (dd, 1H), 7.73-7.81 (m, 3H), 7.92-7.95 (m, 1H), 7.99-8.02 (m, 2H), 8.10-8.13 (m, 3H), 8.18 (m, 1H), 8.69 (m, 1H). .sup.19F NMR (300 MHz): δ ppm −61.16 (s, 3F), −73.99 (s, 3F).

[0468] MS m/z 869 [M+H].sup.+

EXAMPLE 22

(S)-4-((3-(2-((3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide hemi-trifluoroacetate salt

[0469] ##STR00042##

[0470] The title compound was prepared according to the method described for Example 20 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-((3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 18) and (S)-3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine (Preparation 65).

[0471] .sup.1H NMR (300 MHz, MeOD-d.sub.4): δ ppm 2.09 (br m, 2H), 3.20 (s, 3H), 3.37-3.52 (m, 20H), 4.27 (br m, 1H), 4.58 (m, 2H), 6.99 (d, 1H), 7.53-7.56 (d, 1H), 7.66 (m, 1H), 7.42-7.78 (m, 3H), 7.90-7.94 (m, 1H), 7.99-8.02 (m, 2H), 8.10-8.12 (m, 4H), 8.67 (m, 1H).

[0472] .sup.19F NMR (300 MHz): δ ppm −61.26 (s, 3F), −73.92 (s, 1.6F).

[0473] MS m/z 869 [M+H].sup.+

EXAMPLE 23

4-((3-(2-((4-((2,5,8,11-tetraoxatridecan-13-yl)oxy)piperidin-1-yl)methyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide trifluoroacetate salt

[0474] ##STR00043##

[0475] The title compound was prepared according to the method described for Example 20 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-((3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 18) and 4-((2,5,8,11-tetraoxatridecan-13-yl)oxy)piperidine hydrochloride (Preparation 66). The final residue was purified using Preparative HPLC.

[0476] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 1.70-1.95 (br m, 2H), 1.95-2.10 (br m, 2H), 3.10-3.70 (m, 24H), 4.50 (m, 2H), 7.10 (d, 1H), 7.60 (d, 1H), 7.70-7.74 (m, 1H), 7.80-7.83 (m, 3H), 7.98-8.10 (m, 3H), 8.12-8.20 (m, 2H), 8.22-8.26 (m, 1H), 8.43 (br s, 1H), 8.74-8.78 (m, 1H).

[0477] MS m/z 883 [M+H].sup.+

EXAMPLE 24

4-((3-(2-(4-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oyl)piperazin-1-yl)pyridin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0478] ##STR00044##

[0479] To a solution of 3-cyano-4-((3-(2-(piperazin-1-yl)pyridin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 2, 50 mg, 0.07 mmol) in DMF (2 mL) was added triethylamine (0.03 mL, 0.35 mmol) followed by 2,5-dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oate (m-dPEG12-NHS ester, 50 mg, 0.07 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and purified using preparative HPLC to afford the title compound.

[0480] LCMS Rt=2.49 minutes MS m/z 1232 [M−H].sup.−

EXAMPLE 25

3-Cyano-N-1,2,4-thiadiazol-5-yl-4-{[3-{2-[({2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide

[0481] ##STR00045##

[0482] To a solution of benzyl ({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl){2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate (Preparation 7, 650 mg, 0.69 mmol) in acetic acid (10 mL) was added 48% HBr solution (5 mL). The reaction was heated at 50° C. for 10 minutes and then left stirring at room temperature for 72 hours. The solvent was evaporated in vacuo and the residue was azeotroped with methanol and purified by reverse phase column chromatography eluting with acetonitrile/water with 0.1% formic acid to afford the title compound as a white foam (140 mg, 25%).

[0483] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.13-1.22 (m, 2H), 1.76-1.82 (m, 5H), 2.67 (t, 1H), 3.06 (t, 1H), 3.25 (t, 2H), 3.94 (d, 1H), 4.48 (d, 1H), 4.45 (s, 2H), 6.75 (d, 1H), 7.45-7.48 (m, 2H), 7.61-7.70 (m, 4H), 7.77-7.81 (m, 2H), 7.85 (s, 1H), 7.91-7.95 (m, 2H), 8.06 (s, 1H), 8.54 (d, 1H).

[0484] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −68.9 (s, CF.sub.3), −62.6 (s, CF.sub.3).

[0485] LCMS Rt=2.53 minutes, MS m/z 816 [MH].sup.+

EXAMPLE 26

4-({3-[2-(Aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide bis-formate salt

[0486] ##STR00046##

[0487] tert-Butyl ({4-[4-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 24, 680 mg, 0.79 mmol) was dissolved in methanol (10 mL) and 12M hydrochloric acid (3.0 mL) was added. The reaction mixture was heated at 50° C. for 1 hour. The solvent was evaporated in vacuo and the residue was co-evaporated with methanol. The residue was purified by reverse phase chromatography (acetonitrile/water with 0.1% formic acid) to give the title compound as a white solid (350 mg, 63%).

[0488] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 4.21 (s, 2H), 6.94 (d, 1H), 7.52 (d, 1H), 7.62 (d, 1H), 7.71-7.78 (m, 3H), 7.86-7.90 (m, 2H), 7.96-8.01 (m, 3H), 8.09-8.10 (m, 2H), 8.23 (br. s, 2H), 8.63 (d, 1H).

[0489] .sup.19F NMR (400 MHz, DMSO-d.sub.6): 5-60.9 (s).

[0490] LCMS Rt=2.79 minutes MS m/z 609 [M+H].sup.+

EXAMPLE 27

N-[(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide

[0491] ##STR00047##

[0492] The title compound was prepared according to the method described for Example 24 using 4-({3-[2-(aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide bis-formate (Example 7) and m-dPEG12-NHS ester.

[0493] LCMS Rt=3.00 minutes MS m/z 1206 [M+H].sup.+

EXAMPLE 28

N-[(4-{4-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide

[0494] ##STR00048##

[0495] The title compound was prepared according to the method described for Example 24 using 4-({3-[2-(aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide (Example 29) and m-dPEG12-NHS ester.

[0496] LCMS Rt=2.58 minutes MS m/z 1204 [M+H].sup.+

EXAMPLE 29

4-({3-[2-(aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide dihydrochloride salt

[0497] ##STR00049##

[0498] The title compound was prepared according to the methods described by Preparation 11 followed by Example 26 using tert-butyl 2-[(5-chloro-2,4-difluorophenyl)sulfonyl]-2-(thiazol-4-yl)acetate (WO2010079443) and tert-butyl ({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 41) and isolated as the bis-hydrochloride salt.

[0499] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 4.20 (s, 2H), 6.20 (br s, 1H), 6.90 (m, 1H), 7.20 (m, 1H), 7.60-8.20 (m, 9H), 8.60 (s, 2H).

[0500] MS m/z 633 [M−H].sup.−

EXAMPLE 30

5-chloro-2-fluoro-4-{[3-{2-[({2-[1-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-(1,3-thiazol-4-yl)benzenesulfonamide hydrochloride salt

[0501] ##STR00050##

[0502] The title compound was prepared according to the methods described by Example 24 followed by Example 1 using tert-butyl [(4-{4-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl) phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl][2-(piperidin-4-yl)ethyl]carbamate (Preparation 88) and m-dPEG12-NHS ester and isolated as the hydrochloride salt.

[0503] LCMS Rt=2.57 minutes MS m/z 1316 [M+H].sup.+

EXAMPLE 31

3-cyano-4-({3″-[({2-[1-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperidin-4-yl]ethyl}amino)methyl]-1,1′:3′,1″-terphenyl-4′-yl}oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0504] ##STR00051##

[0505] The title compound was prepared according to the methods described by Example 24 followed by Example 5 with potassium carbonate using N-[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)methyl]-2,2,2-trifluoro-N-(2-piperidin-4-ylethyl)acetamide (Preparation 14) and m-dPEG12-NHS ester.

[0506] Rt=2.32 minutes MS m/z 1219 [M−H].sup.+

EXAMPLE 32

5-chloro-2-fluoro-4-{[3-{2-[4-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperazin-1-yl]pyridin-4-yl}-4′-(trifluoromethyl) biphenyl-4-yl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0507] ##STR00052##

[0508] The title compound was prepared according to the method described for Example 24 using 5-chloro-2-fluoro-4-({3-[2-(piperazin-1-yl)pyridin-4-yl]-4′-(trifluoromethyl)biphenyl-4-yl}oxy)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 87) and m-dPEG12-NHS ester.

[0509] LCMS Rt=3.26 minutes MS m/z 1261 [M+H].sup.+

EXAMPLE 33

5-chloro-2-fluoro-4-{[3-{2-[({2-[1-(38-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-yl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide formate salt

[0510] ##STR00053##

[0511] The title compound was prepared according to the method described for Example 17 using tert-butyl [(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl) biphenyl-3-yl}pyridin-2-yl)methyl][2-(piperidin-4-yl)ethyl]carbamate (Preparation 84) and m-dPEG12-NHS ester. The title compound was purified using preparative HPLC and isolated as the formate salt.

[0512] LCMS Rt=2.81 minutes MS m/z 1363 [MHCO.sub.2H+H].sup.+

EXAMPLE 34

3-cyano-4-({3-[2-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-38-azanonatriacontan-39-yl)pyridin-4-yl]-3′-(trifluoromethyl) biphenyl-4-yl}ox)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0513] ##STR00054##

[0514] The title compound was prepared according to the method described for Example 12 using tert-butyl (2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate (Preparation 28) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (WO2010079443).

[0515] LCMS Rt=1.64 minutes MS m/z 1149 [M−H].sup.−

EXAMPLE 35

5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)-4-{[3-{2-[({2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide

[0516] ##STR00055##

[0517] The title compound was prepared according to the methods described for Preparation 15 followed by Example 2 using 2,2,2-trichloroethyl ({4-[4-{2-chloro-5-fluoro-4-[(1,3-thiazol-4-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)(2-piperidin-4-ylethyl)carbamate hydrochloride salt (Preparation 10).

[0518] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.10 (m, 2H), 1.70 (m, 2H), 1.80 (m, 2H), 2.65 (t, 1H), 2.90 (t, 1H), 3.05 (m, 1H), 3.20-3.80 (br m, 2H), 3.95 (d, 1H), 4.05 (s, 2H), 4.45 (d, 1H), 6.35 (d, 1H), 7.00 (s, 1H), 7.40 (d, 1H), 7.50 (s, 1H), 7.60-7.75 (m, 4H), 7.78 (d, 2H), 7.80 (s, 1H), 8.30 (s, 1H), 8.50 (d, 1H), 8.65 (s, 1H).

[0519] MS m/z 842 [M+H].sup.+

Preparation 1

tert-Butyl 4-{2-[({4-[4-{2-chloro-5-fluoro-4-[(1,3,4-thiadiazol-2-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)amino]ethyl}piperidine-1-carboxylate bis-formate salt

[0520] ##STR00056##

[0521] To a suspension of 4-({3-[2-(aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide bis-formate salt (Example 7, 50 mg, 0.069 mmol) in methanol (2 mL), was added triethylamine (30 μL, 0.207 mmol), followed by tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (23.4 mg, 0.103 mmol). The reaction was stirred at room temperature for 18 hours and sodium borohydride (16 mg, 0.414 mmol) was added. After 30 minutes at room temperature, the mixture was quenched by the addition of water (5 mL). The organic phase was extracted with ethyl acetate (3×5 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase column chromatography eluting with 5-95% acetonitrile in water with 0.1% formic acid) to afford the title compound (38 mg, 67%).

[0522] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 1.05 (m, 2H), 1.40 (s, 9H), 1.60-1.70 (m, 5H), 2.70 (m, 2H), 3.15 (d, 2H), 4.05 (d, 2H), 4.40 (s, 2H), 6.50 (d, 1H), 7.30 (d, 1H), 7.60-7.75 (m, 4H), 7.80 (m, 3H), 7.95 (m, 2H), 8.15 (br s, 1H), 8.60 (m, 2H).

[0523] .sup.19F NMR (400 MHz, MeOD d.sub.4): δ ppm −63.0 (s, 3F), −108.0 (s, 1F).

[0524] LCMS Rt=2.67 minutes MS m/z 847 [M+H].sup.+

Preparation 2

3-cyano-4-((3-(2-(piperazin-1-yl)pyridin-4-yl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide bis-hydrochloride salt

[0525] ##STR00057##

[0526] To a solution of tert-butyl 4-(4-(4-(2-cyano-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)piperazine-1-carboxylate (Preparation 9, 1.12 g, 1.22 mmol) in DCM (15 mL) was added 4M HCl in dioxane (10 mL) followed by MeOH (2 mL). The reaction was stirred at room temperature for 18 hours. The resulting precipitate was filtered and the filtrate concentrated in vacuo. The residue was triturated with DCM and EtOAc to afford a white solid that was filtered and dried to afford the title compound.

[0527] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 3.20 (m, 4H), 3.80 (m, 4H), 6.55 (m, 1H), 7.00 (m, 1H), 7.12 (m, 1H), 7.55 (d, 1H), 7.86 (m, 2H), 7.95 (m, 3H), 8.00 (m, 2H), 8.10 (m, 1H), 9.02 (br s, 1H).

[0528] MS m/z 664 [M+H].sup.+

Preparation 3

tert-Butyl ({4-[4-(2-chloro-4-{[(2,4-dimethoxybenzyl)(1,3,4-thiadiazol-2-yl)amino]sulfonyl}-5-fluorophenoxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate

[0529] ##STR00058##

[0530] To a solution of tert-Butyl ({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 41, 708 mg, 1.59 mmol) in DMSO (15 mL) was added 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (WO2010079443, 735 mg, 1.59 mmol) followed by potassium carbonate (660 mg, 4.78 mmol). The reaction was stirred at room temperature for 18 hours. Water (20 mL) was added and the organic phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 7-60% EtOAc in heptanes to afford the title compound as a light yellow solid (732 mg, 52%).

[0531] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.40 (s, 9H), 3.60 (s, 3H), 3.75 (s, 3H), 4.45 (m, 2H), 5.20 (s, 2H), 5.60 (br s, 1H), 6.20 (s, 1H), 6.35 (m, 2H), 7.20 (m, 2H), 7.35 (d, 1H), 7.50 (s, 1H), 7.60-7.80 (m, 6H), 7.85 (s, 1H), 8.55 (s, 1H), 8.80 (s, 1H).

[0532] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −63.0 (s, 3F), −105.0 (s, 1F).

[0533] LCMS Rt=3.24 minutes MS m/z 886 [M+H].sup.+

Preparation 4

tert-Butyl [2-(1-acetylpiperidin-4-yl)ethyl]({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate

[0534] ##STR00059##

[0535] Triethylamine (32 μL, 0.23 mmol) and acetic anhydride (11 μL, 0.11 mmol) were added to a solution of tert-butyl {[4-(3′-tert-butyl-4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}biphenyl-3-yl)pyridin-2-yl]methyl}(2-piperidin-4-ylethyl)carbamate (Preparation 5, 41 mg, 0.06 mmol) in dichloromethane (1 mL). The reaction mixture was stirred for 2 hours at room temperature, washed with saturated sodium hydrogen carbonate. The organic layer was separated and dried over magnesium sulfate. The filtrate was evaporated under reduced pressure to afford the title compound (49 mg, 100%).

[0536] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.05-1.13 (m, 2H), 1.43-1.49 (m, 11H), 1.64-1.68 (m, 3H), 2.06 (s, 3H), 2.49 (t, 1H), 2.99 (t, 1H), 3.24-3.36 (m, 1H), 3.74 (d, 1H), 4.52 (d, 4H), 6.75 (d, 1H), 7.21-7.24 (m, 1H), 7.41 (d, 1H), 7.58-7.69 (m, 5H), 7.77 (d, 1H), 7.82 (s, 1H), 7.95-7.97 (m, 2H), 8.06 (d, 1H), 8.55 (d, 1H).

[0537] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.6 (s, 3F).

[0538] LCMS Rt=2.77 minutes MS m/z 862 [M+H].sup.+

Preparation 5

tert-Butyl {[4-(3′-tert-butyl-4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}biphenyl-3-yl)pyridin-2-yl]methyl}(2-piperidin-4-ylethyl)carbamate

[0539] ##STR00060##

[0540] tert-Butyl ({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl){2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate (Preparation 6, 124 mg, 0.14 mmol) was dissolved in 7M ammonia in methanol (4 mL) and the mixture stirred at room temperature for 18 hours. The solvent was evaporated in vacuo and the residue was dissolved in methanol (2.0 mL) and purified by SCX cartridge (1 g) eluting first with methanol (10 mL) and then with a solution of 7M ammonia in methanol (10 mL) to afford the title compound as a yellow foam (91 mg, 82%).

[0541] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.96 (br. s, 4H), 1.34-2.69 (m, 12H), 2.79 (t, 2H), 3.08-3.20 (m, 2H), 3.45 (br s, 2H), 4.55 (br s, 2H), 6.52 (d, 1H), 7.26-7.34 (m, 2H), 7.49-7.89 (m, 9H), 8.04 (s, 1H), 8.55 (d, 1H).

[0542] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.6 (s, 3F).

[0543] LCMS Rt=2.52 minutes MS m/z 820 [M+H].sup.+

Preparation 6

tert-Butyl ({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl){2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate

[0544] ##STR00061##

[0545] Di-tert-butyl dicarbonate (44 mg, 0.20 mmol) and triethylamine (70 μL, 0.50 mmol) were added to a solution of 3-cyano-N-1,2,4-thiadiazol-5-yl-4-{[3-{2-[({2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl)biphenyl-4-yl]oxy}benzenesulfonamide (Example 25, 137 mg, 0.16 mmol) in dichloromethane (3 mL) and the reaction mixture was stirred for 1 hour. Then mixture was diluted with dichloromethane (20 mL), washed with water (10 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 15% MeOH in DCM to afford the title compound as white foam (124 mg, 88%).

[0546] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.06-1.16 (m, 2H), 1.36-1.42 (m, 12H), 1.62-1.77 (m, 2H), 2.65 (br s, 1H), 3.03 (br s, 1H), 3.22 (br s, 2H), 3.91 (br s, 1H), 4.34-4.59 (m, 3H), 6.73 (d, 1H), 7.29-8.04 (m, 12H), 8.58 (d, 1H).

[0547] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −68.9 (s, 3F), −62.6 (s, 3F).

[0548] LCMS Rt=3.02 minutes MS m/z 916 [M+H].sup.+

Preparation 7

Benzyl ({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl){2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate

[0549] ##STR00062##

[0550] tert-Butyl 4-(2-{[(benzyloxy)carbonyl]({4-[4-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)amino}ethyl)piperidine-1-carboxylate (Preparation 8, 1.96 g, 1.78 mmol) was dissolved in dioxane (20 mL) and 4M HCl in dioxane (3.6 mL) was added. The reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue suspended in dichloromethane (15 mL). Triethylamine (1 mL, 7.12 mmol) and trifluoroacetic anhydride (0.26 mL, 1.87 mmol) were added and mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100 mL), washed with saturated sodium hydrogen carbonate, the organic layer was dried over magnesium sulfate and the filtrate was evaporated in vacuo. The residue was purified by reverse phase column chromatography eluting with acetonitrile/water both with 0.1% formic acid to give the title compound as a yellow foam (650 mg, 38%).

[0551] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.88-1.88 (m, 5H), 2.54-2.73 (m, 1H), 2.88-3.11 (m, 1H), 3.30 (br s, 2H), 3.62-3.99 (m, 3H), 4.33-4.72 (m, 3H), 5.19 (d, 2H), 6.61-6.71 (m, 1H), 7.17-7.42 (m, 7H), 7.61-7.85 (m, 9H), 8.02 (d, 1H), 8.50-8.56 (m, 1H).

[0552] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −68.9 (s, 3F), −62.6 (s, 3F).

[0553] LCMS Rt=3.02 minutes MS m/z 950 [M+H].sup.+

Preparation 8

tert-Butyl 4-(2-{[(benzyloxy)carbonyl]({4-[4-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)amino}ethyl)piperidine-1-carboxylate

[0554] ##STR00063##

[0555] tert-Butyl 4-(2-{[(benzyloxy)carbonyl]({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)amino}ethyl)piperidine-1-carboxylate (Preparation 25, 1.50 g, 2.18 mmol) was dissolved in dimethyl sulfoxide (20 mL) and potassium carbonate (0.60 g, 4.35 mmol) followed by 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443, 0.95 g, 2.18 mmol) were added. The reaction was stirred at room temperature for 1 hour. The reaction was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as brown foam (2.16 g, 90%).

[0556] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.00-1.10 (m, 2H), 1.37-1.64 (m, 14H), 2.61 (br s, 2H), 3.35 (br s, 2H), 3.55 (s, 3H), 3.81 (s, 3H), 4.00 (br s, 2H), 4.59 (s, 2H), 5.12 (d, 2H), 5.27 (s, 2H), 6.18 (d, 1H), 6.35 (dd, 1H), 6.56 (dd, 1H), 7.06-7.12 (m, 3H), 7.22-7.41 (m, 6H), 7.56-7.84 (m, 8H), 8.18 (s, 1H), 8.56 (d, 1H).

[0557] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.7 (s, 3F).

[0558] LCMS Rt=3.43 minutes MS m/z No mass ion observed

Preparation 9

tert-butyl 4-(4-(4-(2-cyano-4-(N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)phenoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)piperazine-1-carboxylate

[0559] ##STR00064##

[0560] The title compound was prepared according to the method described for Preparation 8 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443) and tert-butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)piperazine-1-carboxylate (WO2012004743). The reaction was quenched by the addition of water and the resulting precipitate filtered and dried.

[0561] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 1.40 (s, 9H), 3.40-3.55 (m, 8H), 3.63 (s, 3H), 3.78 (s, 3H), 5.20 (s, 2H), 6.37 (m, 1H), 6.45 (m, 1H), 6.78 (m, 2H), 6.95 (m, 2H), 7.00 (d, 1H), 7.55 (d, 1H), 7.90 (m, 2H), 7.95-8.15 (m, 7H).

[0562] MS m/z 914 [M+H].sup.+

Preparation 10

2,2,2-Trichloroethyl ({4-[4-{2-chloro-5-fluoro-4-[(1, 3-thiazol-4-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)(2-piperidin-4-ylethyl)carbamate hydrochloride salt

[0563] ##STR00065##

[0564] To a solution of tert-butyl 4-(2-{({4-[4-(4-{[(tert-butoxycarbonyl)(1,3-thiazol-4-yl)amino]sulfonyl}-2-chloro-5-fluorophenoxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)[(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate (Preparation 11, 2.47 g, 2.20 mmol) in 1,4-dioxane (10 mL) was added a solution of hydrogen chloride in 1,4-dioxane (4M, 5.5 mL, 22 mmol). The reaction was stirred at room temperature for 18 hours and concentrated in vacuo to afford the title compound as a light yellow foam (2.15 g, 100%).

[0565] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 1.40 (m, 2H), 1.60 (m, 3H), 1.95 (m, 2H), 2.95 (dd, 2H), 3.30 (d, 2H), 3.60 (m, 2H), 4.80 (s, 2H), 5.00 (d, 2H), 7.03 (d, 1H), 7.05 (s, 1H), 7.25 (m, 1H), 7.70 (m, 2H), 7.95-8.05 (m, 6H), 8.20 (m, 1H), 8.30 (d, 1H), 8.75 (s, 1H), 8.80 (m, 1H).

[0566] .sup.19F NMR (400 MHz, MeOD-d.sub.4): δ ppm −64.0 (s, 3F), −108.0 (s, 1F).

[0567] LCMS Rt=2.98 minutes MS m/z 920 [M+H].sup.+

Preparation 11

tert-Butyl 4-(2-{({4-[4-(4-{[(tert-butoxycarbonyl)(1,3-thiazol-4-yl)amino]sulfonyl}-2-chloro-5-fluorophenoxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)[(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate

[0568] ##STR00066##

[0569] To a solution of tert-butyl 4-(2-{({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)[(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate (Preparation 26, 2.0 g, 2.73 mmol) in DMSO (15 mL) was added tert-butyl 2-[(5-chloro-2,4-difluorophenyl)sulfonyl]-2-(thiazol-4-yl)acetate (WO2010079443, 1.21 g, 2.73 mmol) followed by potassium carbonate (1.13 g, 8.19 mmol). The reaction was stirred at room temperature for 2 hours. Water (20 mL) was added and the aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo.

[0570] The residue was purified by silica gel column chromatography eluting with cyclohexane:ethyl acetate eluting with 10-80% EtOAc in cyclohexanes to afford the title compound as a light yellow foam (2.47 g, 81%).

[0571] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.10 (m, 2H), 1.30 (s, 9H), 1.40 (m, 2H), 1.45 (s, 9H) 1.60 (m, 3H), 2.50 (m, 2H), 3.40 (dd, 2H), 4.00 (m, 2H), 4.60 (m, 2H), 4.70 (d, 2H), 6.45 (d, 1H), 7.20 (m, 1H), 7.40 (m, 2H), 7.50 (s, 1H), 7.55 (m, 1H), 7.58 (m, 1H), 7.60-7.75 (m, 2H), 7.78 (d, 1H), 7.80 (s, 1H), 8.05 (d, 1H), 8.55 (d, 1H), 8.80 (d, 1H).

[0572] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −63.0 (s, 3F), −105.0 (s, 1F).

[0573] LCMS Rt=3.52 minutes MS m/z 1120 [M+H].sup.+

Preparation 12

tert-Butyl (2-{4-[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)methyl]piperazin-1-yl}ethyl)carbamate

[0574] ##STR00067##

[0575] To a solution of 3-cyano-4-[(3″-formyl-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 13, 700 mg, 1.3 mmol) in dichloromethane (10 mL) was added acetic acid (0.075 mL, 1.3 mmol) and tert-butyl (2-piperazin-1-ylethyl)carbamate (310 mg, 1.36 mmol) and stirred for 30 minutes at room temperature. Sodium triacetoxyborohydride (282 mg, 1.50 mmol) was added and the mixture stirred at room temperature for 18 hours. Water (5 mL) was added and the resulting mixture extracted with ethyl acetate (50 mL). The organic layer was washed with brine (50 mL) and dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by silica gel column chromatography eluting with 2-20% MeOH in EtOAc to afford the title compound (600 mg, 61%).

[0576] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 1.40 (s, 9H), 2.50 (s, 4H), 3.1 (m, 2H), 3.20 (m, 2H), 3.40 (m, 2H), 3.45 (m, 2H), 3.55 (m, 2H), 6.70 (m, 1H), 7.20-7.50 (m, 8H), 7.70 (m, 3H), 7.80 (m, 2H), 8.00 (m, 2H).

[0577] LCMS Rt=3.09 minutes MS m/z 752 [M+H].sup.+

Preparation 13

3-Cyano-4-[(3″-formyl-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0578] ##STR00068##

[0579] To a solution of 6′-hydroxy-[1,1′:3′,1″-terphenyl]-3-carbaldehyde (Preparation 38, 507 mg, 1.85 mmol) in DMSO (15 mL) was added 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (WO2010079443, 500 mg, 1.76 mmol) and K.sub.2CO.sub.3 (972 mg, 7.04 mmol). The mixture was heated at 80° C. for 2 hours and then diluted with brine (50 mL). The mixture was extracted with EtOAc (30 mL) and the organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with (mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile, gradient from 0% to 40% of B) to afford the title compound as an off-white solid (700 mg, 74%).

[0580] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 7.00 (m, 1H), 7.40 (m, 1H), 7.50 (m, 3H), 7.60 (m, 1H), 7.80-7.90 (m, 7H), 8.10 (m, 2H), 8.40 (s, 1H), 10.00 (s, 1H).

[0581] LCMS Rt=4.25 minutes MS m/z 539 [M+H].sup.+

Preparation 14

N-[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)methyl]-2,2,2-trifluoro-N-(2-piperidin-4-ylethyl)acetamide trifluoroacetate salt

[0582] ##STR00069##

[0583] Trifluoroacetic acid (0.88 mL, 11.5 mmol) was added to a solution of tert-butyl 4-{2-[{[6′-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-1,1′:3′,1″-terphenyl-3-yl]methyl}(trifluoroacetyl)amino]ethyl}piperidine-1-carboxylate (Preparation 15, 1149 mg, 1.15 mmol) in dichloromethane (32 mL) which was stirred for 18 hours at room temperature under nitrogen. The reaction was quenched by the addition of methanol (20 mL) which was passed through a pad of Arbocel® and washed with addition methanol (100 mL). The organic filtrate was concentrated in vacuo and the residue was purified using silica gel column chromatography eluting with 1-20% methanol:dichloromethane to afford the title compound as a colourless solid (856 mg, 86%).

[0584] .sup.1H NMR (400 MHz, CDCl.sub.3) δ ppm 1.11-1.24 (m, 2H), 1.32-1.49 (m, 3H), 1.66-1.70 (m, 2H), 2.77-2.87 (m, 2H), 3.13-3.16 (m, 1H), 3.16-3.18 (m 3H), 4.64 (s, 1H), 4.67 (s, 1H), 6.90 (dd, 1H), 7.18 (t, 1H), 7.37-7.52 (m, 7H), 7.76-7.88 (m, 5H), 8.05 (dd, 1H), 8.14 (d, 1H), 8.21 (br s, 1H), 8.48 (br s, 1H).

[0585] LCMS Rt=3.22 minutes MS m/z 747 [M+H].sup.+

Preparation 15

tert-Butyl 4-{2-[{[6′-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-1,1′:3′,1″-terphenyl-3-yl]methyl}(trifluoroacetyl)amino]ethyl}piperidine-1-carboxylate

[0586] ##STR00070##

[0587] Trifluoroacetic anhydride (0.40 mL, 2.88 mmol) was added to a mixture of tert-butyl 4-[2-({[6′-(2-cyano-4-{[(2,4-dimethoxybenzyl) (1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-1,1′:3′,1″-terphenyl-3-yl]methyl}amino)ethyl]piperidine-1-carboxylate (Preparation 16, 1275 mg, 1.42 mmol) and pyridine (0.46 mL, 5.69 mmol) in dichloromethane (90 mL) which was stirred for 18 hours at room temperature under nitrogen. The reaction was concentrated in vacuo to and the residue was purified using silica gel column chromatography eluting with 30% ethyl acetate in heptanes to afford the title compound as a colourless foam (1149 mg, 81%).

[0588] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.01-1.17 (m, 2H), 1.31-1.41 (m, 1H), 1.43-1.50 (m, 10H), 1.55-1.63 (m, 3H), 2.59-2.69 (m, 2H), 3.27-3.36 (m, 2H), 3.51 (s, 3H), 3.81 (s, 3H), 4.04 (br s, 2H), 4.64 (s, 2H), 5.25 (s, 2H), 6.16 (dd, 1H), 6.35 (dd, 1H), 6.58-6.63 (m, 1H), 7.07 (d, 1H), 7.12-7.18 (m, 1H), 7.22-7.25 (m, 1H), 7.32-7.46 (m, 4H), 7.46-7.52 (m, 2H), 7.60-7.69 (m, 6H), 8.18 (s, 1H).

[0589] LCMS Rt=4.40 minutes MS m/z 997 [M+H].sup.+

Preparation 16

tert-Butyl 4-[2-({[6′-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-1,1′:3′,1″-terphenyl-3-yl]methyl}amino)ethyl]piperidine-1-carboxylate

[0590] ##STR00071##

[0591] Tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (407 mg, 1.78 mmol) was added to a solution of 3-cyano-N-(2,4-dimethoxybenzyl)-4-[(3″-formyl-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 17, 1147 mg, 1.67 mmol) in dichloromethane (19 mL) and acetic acid (0.1 mL). The mixture was stirred at room temperature under nitrogen for 45 minutes, then sodium triacetoxyborohydride (409 mg, 1.93 mmol) was added and the reaction was stirred for 18 hours under nitrogen at room temperature. The reaction was diluted with dichloromethane (100 mL) and washed with water (3×10 mL). The aqueous layers were extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford a colourless foam that was purified using silica gel column chromatography eluting with 1-20% MeOH in EtOAc to afford the title compound as a colourless foam (1275 mg, 85%).

[0592] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.04-1.15 (m, 2H), 1.44-1.49 (m, 13H), 1.63 (br d, 2H), 2.61-2.70 (m, 4H), 3.47 (s, 3H), 3.81 (s, 3H), 3.82 (s, 2H), 4.05 (br s, 2H), 5.24 (s, 2H), 6.12 (d, 1H), 6.35 (dd, 1H), 6.57 (d, 1H), 7.07 (d, 1H), 7.23 (d, 1H), 7.27-7.28 (m, 1H), 7.31 (t, 1H), 7.37-7.43 (m, 2H), 7.46-7.53 (m, 3H), 7.58 (d, 1H), 7.61-7.66 (m, 4H), 7.72 (d, 1H), 8.17 (s, 1H).

[0593] LCMS Rt=3.90 minutes MS m/z 901 [M+H].sup.+

Preparation 17

3-Cyano-N-(2,4-dimethoxybenzyl)-4-[(3″-formyl-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0594] ##STR00072##

[0595] A solution of 6′-hydroxy-1,1′:3′,1″-terphenyl-3-carbaldehyde (Preparation 38, 668 mg, 2.43 mmol), 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443, 1004 mg, 2.31 mmol) and potassium carbonate (954 mg, 6.90 mmol) in dimethylsulfoxide (10 mL) was stirred for 18 hours at room temperature under nitrogen. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×60 mL). The combined organic layers were washed with brine (3×80 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellow foam that was purified using silica gel column chromatography eluting with 30% EtOAc in heptanes to afford the title compound as a colourless foam (1147 mg, 72%).

[0596] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.44 (s, 3H), 3.81 (s, 3H), 5.24 (s, 2H), 6.02 (d, 1H), 6.34 (dd, 1H), 6.60 (d, 1H), 7.07 (d, 1H), 7.24-7.26 (m, 1H), 7.40-7.44 (m, 1H), 7.47-7.52 (m, 2H), 7.56-7.60 (m, 2H), 7.61-7.68 (m, 3H), 7.70 (dd, 1H), 7.76 (d, 1H), 7.85-7.87 (m, 2H), 8.06-8.07 (m, 1H), 8.17 (s, 1H), 10.05 (s, 1H).

[0597] LCMS Rt=4.03 minutes MS m/z No mass ion observed

Preparation 18

3-cyano-N-(2,4-dimethoxybenzyl)-4-((3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)oxy)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide

[0598] ##STR00073##

[0599] The title compound was prepared according to the method described for Preparation 8 using 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443) and 3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol (Preparation 37). The residue was purified using silica gel column chromatography eluting with 0-100% EtOAc in heptanes.

[0600] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 3.56 (s, 3H), 3.73 (s, 3H), 4.55 (d, 2H), 5.18 (s, 2H), 5.34 (t, 1H), 6.35 (m, 1H), 6.44-6.45 (m, 1H), 6.98-7.02 (m, 2H), 7.44 (m, 1H), 7.52 (m, 1H), 7.61 (m, 1H), 7.74-7.78 (m, 2H), 7.96-8.02 (m, 2H), 8.12-8.14 (m, 2H), 8.41 (m, 1H), 8.51 (m, 1H).

[0601] MS m/z 760 [M+H].sup.+

Preparation 19

tert-Butyl 4-{2-[({4-[4-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)amino]ethyl}piperidine-1-carboxylate

[0602] ##STR00074##

[0603] To a suspension of 4-({3-[2-(aminomethyl)pyridin-4-yl]-3′-(trifluoromethyl)biphenyl-4-yl}oxy)-3-cyano-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide bis-formate salt (Example 26, 50 mg, 0.071 mmol) in methanol (2 mL) was added triethylamine (20 μL, 0.143 mmol) followed by tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (16 mg, 0.071 mmol). The reaction was stirred at room temperature for 18 hours and sodium borohydride (16 mg, 0.43 mmol) was added. After 30 minutes at room temperature, the mixture was quenched by the addition of water (5.0 mL). The aqueous phase was extracted with ethyl acetate (3×5 mL) and the combined organic layers were washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 5-95% acetonitrile in water with 0.1% formic acid to afford the title compound as a white solid (35 mg, 62%).

[0604] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 1.05 (m, 2H), 1.40 (s, 9H), 1.40-1.80 (m, 5H), 2.70 (m, 2H), 3.05 (m, 2H), 4.00 (d, 2H), 4.40 (s, 2H), 6.80 (d, 1H), 7.40 (d, 1H), 7.50 (d, 1H), 7.60 (m, 2H), 7.80 (m, 3H), 7.95 (m, 3H), 8.05 (s, 1H), 8.50 (d, 2H).

[0605] .sup.19F NMR (400 MHz, MeOD-d.sub.4): δ ppm −64 (s, 3F).

Preparation 20

tert-Butyl 4-(2-{[(6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-yl)carbonyl]amino}ethyl)piperazine-1-carboxylate

[0606] ##STR00075##

[0607] To a solution of 6′-{2-cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-carboxylic acid (Preparation 21, 100 mg, 0.18 mmol) in dimethylformamide (2.0 mL) was added 1,1′-carbonylbis(1H-imidazole) (38 mg, 0.23 mmol) and N-ethyl-N-isopropylpropan-2-amine (35 mg, 0.27 mmol). The mixture was stirred at room temperature for 30 minutes, then tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (41.3 mg, 0.18 mmol) was added. The resulting reaction was stirred at room temperature for 3 days. The mixture was concentrated in vacuo to provide the title compound as an orange gum (204 mg, >100%). This material was used in the next step without further purification.

[0608] LCMS Rt=2.40 minutes MS m/z 764 [M−H].sup.−

Preparation 21

6′-{2-Cyano-4-[(1,2,4-thiadiazol-5-ylamino)sulfonyl]phenoxy}-1,1′:3′,1″-terphenyl-3-carboxylic acid

[0609] ##STR00076##

[0610] A solution of 3-cyano-4-[(3-iodobiphenyl-4-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 22, 450 mg, 0.80 mmol), 3-(dihydroxyboryl)benzoic acid (200 mg, 1.20 mmol), and sodium carbonate (340 mg, 3.21 mmol) in DME (2.0 mL) and water (1.5 mL) was degassed with nitrogen then bis(triphenylphosphine) palladium(II)chloride (56 mg, 0.08 mmol) was added and the reaction mixture was heated for 15 minutes at 150° C. under microwave irradiation. The mixture was cooled, diluted with water (50 mL) and ethyl acetate (200 mL). The aqueous was acidified to pH=3 using a 4N aqueous solution of hydrochloric acid, then extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to yield the crude product as an orange solid. The crude material was purified by silica gel column chromatography eluting with DCM to DCM:MeOH:formic acid (100:10:0.1) to afford the title compound as an orange solid (200 mg, 45%).

[0611] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 6.94 (d, 1H), 7.37-7.65 (m, 6H), 7.73-8.10 (m, 9H).

[0612] LCMS Rt=2.05 minutes MS m/z 503 [M−H].sup.−

Preparation 22

3-Cyano-4-[(3-iodobiphenyl-4-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0613] ##STR00077##

[0614] A solution of 3-Iodobiphenyl-4-ol (Preparation 78, 500 mg, 1.69 mmol), 3-cyano-4-fluoro-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (WO2010079443, 480 mg, 1.69 mmol) and potassium carbonate (700 mg, 5.07 mmol) in dimethylformamide (2 mL) was stirred for 18 hours at 80° C. under nitrogen. The reaction was cooled, diluted with water (10 mL), neutralised using 4N HCl, then extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford a yellow solid. The crude material was recystallised from DCM to afford the title compound as a white solid (450 mg, 48%).

[0615] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 6.88 (d, 1H), 7.35-7.58 (m, 4H), 7.70 (d, 2H), 7.79 (d, 1H), 8.01 (d, 1H), 8.22 (s, 1H), 8.50 (s, 1H), 8.47 (s, 1H).

[0616] LCMS Rt=1.60 minutes MS m/z 561 [M+H].sup.+

Preparation 23

4-{[3″-({[2-(1-Acetylpiperidin-4-yl)ethyl]amino}methyl)-1,1′:3′,1″-terphenyl-4′-yl]oxy}-3-cyano-N-(2,4-dimethoxybenzyl)-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide

[0617] ##STR00078##

[0618] To a solution of 2-(1-acetylpiperidin-4-yl)ethanamine (Preparation 79, 740 mg, 4.35 mmol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-[(3″-formyl-1,1′:3′,1″-terphenyl-4′-yl)oxy]-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 17, 1 g, 1.45 mmol) in dioxane (20 mL) was added acetic acid (10 drops). The reaction mixture was stirred for 3 hours at 70° C. then allowed to cool to room temperature. Sodium borohydride (165 mg, 4.35 mmol) was added and the reaction was stirred for 3 hours at room temperature. Water (50 mL) was added and the solution was concentrated in vacuo. The aqueous suspension was extracted with ethyl acetate (2×200 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a viscous oil (2 g, crude material).

[0619] LCMS Rt=2.54 minutes MS m/z 843 [M+H].sup.+

Preparation 24

tert-Butyl ({4-[4-(2-cyano-4-{[(2,4-dimethoxybenzyl)(1,2,4-thiadiazol-5-yl)amino]sulfonyl}phenoxy)-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)carbamate

[0620] ##STR00079##

[0621] tert-Butyl ({4-[4-hydroxy-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 41, 850 mg, 1.91 mmol) was dissolved in dimethyl sulfoxide (10 mL) and potassium carbonate (529 mg, 3.83 mmol) followed by 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (WO2010079443, 831 mg, 1.91 mmol) were added. The reaction mixture was stirred at room temperature for 18 hours. The reaction was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 7:3 ethyl acetate:heptane followed by purification by reverse phase column chromatography eluting with acetonitrile/water with 0.1% formic acid to afford the title compound as a foam (683 mg, 41%).

[0622] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.44 (s, 9H), 3.42 (s, 3H), 3.83 (s, 3H), 4.51 (d, 2H), 5.27 (s, 2H), 5.66 (br s, 1H), 6.07 (s, 1H), 6.38-6.34 (dd, 1H), 6.61 (d, 1H), 7.10 (d, 1H), 7.27 (d, 1H), 7.39-7.37 (dd, 1H), 7.48 (s, 1H), 7.74-7.59 (m, 6H), 7.80 (d, 1H), 7.84 (s, 1H), 8.18 (s, 1H), 8.58 (d, 1H).

[0623] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.7 (s, 3F).

[0624] LCMS Rt=4.07 minutes MS m/z 859 [M+H].sup.+

Preparation 25

tert-Butyl 4-(2-{[(benzyloxy)carbonyl]({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)amino}ethyl)piperidine-1-carboxylate

[0625] ##STR00080##

[0626] tert-Butyl 4-(2-{[(benzyloxy)carbonyl][(4-bromopyridin-2-yl)methyl]amino}ethyl)piperidine-1-carboxylate (Preparation 62, 2.50 g, 4.70 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 68, 1.71 g, 4.70 mmol) and sodium carbonate (1.99 g, 18.8 mmol) in a mixture of dioxane (40 mL) and water (8 mL) were degassed. Tetrakis(triphenylphosphine)palladium(0) (0.27 g, 0.24 mmol) was added and the reaction mixture was further degassed and heated at 80° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (30 mL), and the organic layer was dried over magnesium sulfate and filtrate was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 1:1 ethyl acetate:cyclohexane to give the title compound as yellow foam (2.65 g, 82%).

[0627] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.98-1.13 (m, 2H), 1.39-1.63 (m, 14H), 2.57 (br s, 2H), 3.42 (br s, 2H), 3.99 (br s, 2H), 4.66 (d, 2H), 5.16 (d, 2H), 6.23 (s, 1H), 7.04 (d, 1H), 7.16-7.34 (m, 4H), 7.41 (br s, 2H), 7.48-7.60 (m, 4H), 7.71 (br s, 1H), 7.78 (s, 1H), 8.61 (d, 1H).

[0628] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.6 (s, 3F).

[0629] LCMS Rt=2.98 minutes MS m/z 690 [M+H].sup.+

Preparation 26

tert-Butyl 4-(2-{({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)[(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate

[0630] ##STR00081##

[0631] tert-Butyl 4-(2-{[(4-bromopyridin-2-yl)methyl][(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate (Preparation 60, 5 g, 8.72 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 68, 3.52 g, 9.67 mmol) and sodium carbonate (4.09 g, 38.7 mmol) were combined and dissolved in a mixture of 1,4 dioxane/water (4/1 60 mL). The reaction was degassed for 20 minutes and tetrakis(triphenylphosphine)palladium(0) (560 mg, 0.48 mmol) was added in one portion. The reaction was heated at 100° C. for 2 hours, cooled to room temperature and partitioned between ethyl acetate (50 ml) and water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 20-60% EtOAc in cyclohexanes to afford the title compound as a yellow foam (3.50 g, 55%).

[0632] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.05 (m, 2H), 1.20 (s, 9H), 1.60 (m, 3H), 1.80 (m, 2H), 2.05 (m, 2H), 2.60 (m, 2H), 3.40 (m, 2H), 4.00 (m, 2H), 4.70 (m, 2H), 7.05 (d, 1H), 7.55 (m, 3H), 7.60 (m, 3H), 7.70 (d, 1H), 7.80 (s, 1H), 8.60 (d, 1H).

[0633] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −64.0. (s, 3F).

[0634] LCMS Rt=3.31 minutes MS m/z 730 [M+H].sup.+

Preparation 27

(4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate

[0635] ##STR00082##

[0636] To a solution of 3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol (Preparation 36, 60 mg, 0.175 mmol) in DMF (1 mL) was added sodium hydride (22 mg, 0.525 mmol) at 0° C. and the reaction was stirred at room temperature for 40 minutes. 4-nitrophenyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate (Preparation 67, 65 mg, 0.18 mmol) was added and the reaction was stirred at room temperature for 2 hours followed by 45° C. for 4 hours. The reaction was acidified to pH=5-6 with 1N HCl (aq) and extracted into EtOAc. The organic layer was collected and purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (7 mg, 7%).

[0637] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.35 (s, 3H), 3.40-3.70 (m, 16H), 5.30 (s, 2H), 7.10 (m, 1H), 7.25 (s, 1H), 7.40 (m, 1H), 7.45-7.60 (m, 4H), 7.70-7.80 (m, 3H), 8.60 (m, 1H).

[0638] MS m/z 579 [M+H].sup.+

Preparation 28

tert-butyl (2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate

[0639] ##STR00083##

[0640] To a solution of tert-butyl (2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl) ((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate (Preparation 44, 200 mg, 0.20 mmol) in DMSO (2.3 mL) was added 1-decane-thiol (76 uL, 0.3 mmol) followed by solid sodium hydroxide (24 mg, 0.66 mmol) and the reaction was heated to 120° C. for 2 hours. Further 1-decane-thiol (76 uL, 0.3 mmol) was added and the reaction continued at 120° C. for 2 hours. The reaction was cooled, quenched with water and acidified to pH=5-6 with 1N HCl (aq). The solution was extracted into EtOAc three times. The organic layers were collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-15% MeOH in DCM to afford the title compound (108 mg, 93%).

[0641] MS m/z 987 [M+H].sup.+

Preparation 29

tert-butyl ((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)carbamate

[0642] ##STR00084##

[0643] To a solution of tert-butyl ((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)carbamate (Preparation 45, 71 mg, 0.11 mmol) in DMSO (1 mL) was added 1-decane-thiol (42 uL, 0.165 mmol) followed by solid NaOH (130 mg, 0.330 mmol) and the reaction was heated to 120° C. for 18 hours. Further 1-decane-thiol (42 uL, 0.165 mmol) followed by solid NaOH (130 mg, 0.330 mmol) were added and the reaction continued at 120° C. for 1.5 hours. The reaction was cooled, quenched with water and acidified to pH=5-6 with 1N HCl (aq). The solution was extracted into EtOAc three times. The organic layers were collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-15% MeOH in DCM to afford the title compound (65 mg, 93%).

[0644] MS m/z 534 [(M-Boc)+H]+

Preparation 30

3-(2-(2,5,8,11,14-pentaoxapentadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol

[0645] ##STR00085##

[0646] The title compound was prepared according to the method described for Preparation 29 using 4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-2-(2,5,8,11,14-pentaoxapentadecyl)pyridine (Preparation 52).

[0647] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.35 (s, 3H), 3.50-3.80 (m, 16H), 4.80 (s, 2H), 7.15 (m, 1H), 7.50-7.60 (m, 5H), 7.75 (m, 1H), 7.80 (m, 1H), 8.10 (m, 1H), 8.65 (m, 1H).

[0648] MS m/z 536 [M+H].sup.+

Preparation 31

2-((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide

[0649] ##STR00086##

[0650] The title compound was prepared according to the method described for Preparation 29 using 2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide (Preparation 54).

[0651] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.35 (s, 3H), 3.50-3.65 (m, 16H), 4.20 (s, 2H), 4.80 (s, 2H), 7.18 (m, 2H), 7.40-7.80 (m, 8H), 7.95 (m, 1H), 8.60 (m, 1H).

[0652] MS m/z 593 [M+H].sup.+

Preparation 32

3-(2-(2,8,11,14,17-pentaoxa-5-azaoctadecyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol

[0653] ##STR00087##

[0654] The title compound was prepared according to the method described for Preparation 29 using N-(2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)ethyl)-2,5,8,11-tetraoxatridecan-13-amine (Preparation 53).

[0655] MS m/z 577 [M−H].sup.−

Preparation 33

1-((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-3-(2,5,8,11-tetraoxatridecan-13-yl)urea

[0656] ##STR00088##

[0657] The title compound was prepared according to the method described for Preparation 29 using 1-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-3-(2,5,8,11-tetraoxatridecan-13-yl)urea (Preparation 48).

[0658] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.30 (s, 3H), 3.40-3.70 (m, 16H), 4.56-4.61 (m, 2H), 5.90 (br s, 1H), 6.20 (br s, 1H), 7.06-7.10 (m, 1H), 7.32-7.36 (m, 1H), 7.39-7.45 (m, 2H), 7.45-7.52 (m, 1H), 7.52-7.57 (m, 1H), 7.64-7.68 (m, 1H), 7.70-7.77 (m, 2H), 8.53-8.58 (m, 1H).

[0659] MS m/z 578 [M+H].sup.+

Preparation 34

2-(2-(2-methoxyethoxy)ethoxy)ethyl ((4-(4-hydroxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate

[0660] ##STR00089##

[0661] To a solution of 3-(2-(aminomethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol (Preparation 35, 60 mg, 0.17 mmol) and 2,5-dioxopyrrolidin-1-yl (2-(2-(2-methoxyethoxy)ethoxy)ethyl) carbonate (53 mg, 0.174 mmol) in isopropanol (1.5 mL) was added DIPEA (0.1 mL) and the reaction was heated at 52° C. for 18 hours. The reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% MeOH in DCM to afford the title compound (26 mg, 28%).

[0662] .sup.1H NMR (500 MHz, MeOH-d.sub.4): δ ppm 3.35 (m, 5H), 3.40-3.60 (m, 6H), 3.70 (t, 2H), 4.20 (m, 2H), 4.45 (m, 2H), 7.05 (m, 1H), 7.55-7.70 (m, 5H), 7.90 (m, 2H), 8.50 (m, 1H).

Preparation 35

3-(2-(aminomethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol

[0663] ##STR00090##

[0664] To a solution of (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanamine (Preparation 49, 60 mg, 0.17 mmol) in DMSO (0.5 mL) was added 1-decane thiol (106 mg, 0.5 mmol) followed by solid sodium hydroxide (13 mg, 0.33 mmol). The reaction was heated to 120° C. for 2 hours then cooled to 0° C. and quenched by the addition of 1N HCl (aq). The reaction mixture was extracted with EtOAc, the organic layer collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using 10% MeOH in DCM with 3% TEA to afford the title compound (58 mg, 100%).

[0665] .sup.1H NMR (500 MHz, MeOH-d.sub.4): δ ppm 4.33 (s, 2H), 7.06-7.11 (m, 1H), 7.61 (d, 3H), 7.66 (s, 1H), 7.72-7.76 (m, 1H), 7.77-7.80 (m, 1H), 7.84-7.91 (m, 2H), 8.63-8.66 (m, 1H).

Preparation 36

3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol

[0666] ##STR00091##

[0667] The title compound was prepared according to the method described for Preparation using (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanol (Preparation 57) and taken on directly to the next step.

Preparation 37

3-(2-(hydroxymethyl)pyridin-4-yl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-ol

[0668] ##STR00092##

[0669] The title compound was prepared according to the method described for Preparation 58 using 4-chloro-2-(2-(hydroxymethyl)pyridin-4-yl)phenol (Preparation 42) and 3-trifluoromethylphenyl boronic acid at 120° C. for 2 hours under microwave irradiation. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM. The intermediate was taken directly on to the next step.

Preparation 38

6′-Hydroxy-1,1′:3′,1″-terphenyl-3-carbaldehyde

[0670] ##STR00093##

[0671] A solution of 3-iodobiphenyl-4-ol (Preparation 78, 12.8 g, 43.2 mmol), 3-formylphenylboronic acid (12.9 g, 86.0 mmol), and cesium carbonate (35.2 g, 108.0 mmol) in dioxane (260 mL) and water (70 mL) was degassed for 1 hour with nitrogen then [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (11) (3.2 g, 4.37 mmol) was added and the reaction mixture was heated for 18 hours at 90° C. The solution was filtered through a pad of celite which was washed with methanol (250 mL) and ethyl acetate (250 mL). The filtrate was concentrated in vacuo, partitioned between water (200 mL) and ethyl acetate (200 mL). The aqueous solution was acidified to pH=1-2 using an aqueous solution of hydrochloric acid extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified twice by silica gel column chromatography eluting with 20% ethyl acetate in cyclohexane to afford the title compound as a light brown solid (6.28 g, 53%).

[0672] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 5.19 (s, 1H), 7.05 (m, 1H), 7.33 (m, 1H), 7.43 (m, 2H), 7.53 (m, 2H), 7.58 (m, 2H), 7.67 (m, 1H), 7.85 (m, 1H), 7.93 (m, 1H), 8.09 (m, 1H), 10.09 (s, 1H).

[0673] LCMS Rt=3.31 minutes MS m/z 273 [M−H].sup.−

Preparation 39

3-Bromo-3′-(trifluoromethyl)biphenyl-4-ol

[0674] ##STR00094##

[0675] To a solution of 3′-(trifluoromethyl)biphenyl-4-ol (Preparation 40, 29 g, 122 mmol) in a mixture of dichloromethane/acetic acid (1/1, 400 mL) cooled at 0° C. in an ice bath was added sulphuric acid (1 mL) followed by N-bromo-succinimide (19.6 g, 110 mmol) over a period of 2 hours. The reaction was stirred for a further 1 hour at room temperature and a further aliquot of N-bromosuccinimide (2 g, 11 mmol) was added. The reaction was stirred for a further 1 hour at room temperature. The solvents were evaporated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with brine (200 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography on eluting with 10% EtOAc in heptanes to afford the title compound as a yellow oil (22 g, 57%).

[0676] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 5.55 (s, 1H), 7.10 (d, 1H), 7.45 (d, 1H), 7.50-7.60 (m, 2H), 7.60-7.70 (m, 2H), 7.75 (s, 1H).

[0677] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −63.0 (s, 3F).

[0678] LCMS Rt=2.72 minutes MS m/z 318 [M+H].sup.+

Preparation 40

3′-(Trifluoromethyl)biphenyl-4-ol

[0679] ##STR00095##

[0680] 4-bromophenol (38.9 g, 173 mmol), (3-(trifluoromethyl)phenyl)boronic acid (25 g, 181 mmol) and sodium carbonate (57.5 g, 543 mmol) were combined and dissolved in a mixture of dioxane/water (4/1, 1100 mL). The reaction was degassed with nitrogen for 20 minutes and tetrakis(triphenylphosphine)palladium(0) (10.0 g, 8.7 mmol) was added in one portion. The reaction was heated at 70° C. for 18 hours, cooled to room temperature and partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 5-40% EtOAc in heptanes to afford the title compound as a yellow oil (31.0 g, 72%).

[0681] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 6.80 (m, 2H), 7.10 (m, 1H), 7.40 (m, 3H), 7.60 (d, 1H), 7.65 (s, 1H).

[0682] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −63.0 (s, 3F).

[0683] LCMS Rt=2.56 minutes MS m/z 237 [M−H].sup.−

Preparation 41

tert-Butyl ({4-[4-hydroxy-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate

[0684] ##STR00096##

[0685] tert-Butyl ({4-[4-(benzyloxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate (Preparation 69, 2.66 g, 4.98 mmol) was hydrogenated using palladium hydroxide (266 mg, 10% w/w) in ethanol (30 mL) at 50° C. and 50 psi overnight under hydrogen. The reaction mixture was filtered through a pad of Arbocel and the solvent was evaporated in vacuo. The crude was purified by silica gel column chromatography eluting with 3:2 ethyl acetate:heptane to afford the title compound as a white foam (1.72 g, 78%).

[0686] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.47 (s, 9H), 4.52 (d, 2H), 5.74 (s, 1H), 7.11 (d, 1H), 7.41-7.43 (dd, 1H), 7.49-7.59 (m, 5H), 7.72 (d, 1H), 7.73 (s, 1H), 8.60 (d, 1H).

[0687] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.6 (s, 3F).

[0688] LCMS Rt=3.43 minutes MS m/z 445 [M+H].sup.+

Preparation 42

4-chloro-2-(2-(hydroxymethyl)pyridin-4-yl)phenol

[0689] ##STR00097##

[0690] To a suspension of 4-(5-chloro-2-hydroxyphenyl)picolinic acid hydrochloride (Preparation 43, 23.1 g, 92.53 mmol) in THF (140 mL) was added boron tribromide dropwise (278 mL, 278 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was quenched by the addition of 4M HCl (100 mL) and stirred at 70° C. for 18 hours. The reaction was diluted with water (100 mL) and extracted with TBME (2×400 mL). The aqueous layer was collected, basified to pH=7 with 2M NaOH (aq) and the resulting precipitate collected by filtration. The solid was triturated with MeOH to afford the title compound (12.89 g, 59%).

[0691] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 4.60 (d, 2H), 5.40 (t, 1H), 7.00 (d, 1H), 7.25 (m, 1H), 7.35 (s, 1H), 7.45 (d, 1H), 7.60 (s, 1H), 8.45 (d, 1H), 10.15 (br s, 1H).

[0692] MS m/z 236 [M+H].sup.+

Preparation 43

4-(5-chloro-2-hydroxyphenyl)picolinic acid hydrochloride salt

[0693] ##STR00098##

[0694] A solution of (5-chloro-2-hydroxyphenyl)boronic acid (16.85 g, 97.7 mmol), 4-bromopicolinic acid (19.74 g, 97.7 mmol) and sodium carbonate (41.43 g, 39.1 mmol) in dioxane (300 mL) and water (120 mL) was degassed with nitrogen before the addition of tetrakistriphenylphosphine palladium (0) (11.3 g, 9.77 mmol) and the reaction was heated to reflux for 18 hours. The reaction was cooled and quenched by the addition of 2M NaOH (aq) until pH>10. The reaction was filtered through Celite and extracted with TBME (2×250 mL). The aqueous layer was acidified to pH=7 using 3M HCl (aq) and the resulting precipitate was collected by filtration. The solid was suspended in water (200 mL), treated with 2M HCl (aq) (250 mL) and stirred for 30 minutes. The precipitate was collected and dried in vacuo azeotroping with MeOH and MeCN to afford the title compound.

[0695] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 7.00 (d, 1H), 7.30 (m, 1H), 7.45 (m, 1H), 7.80 (m, 1H), 8.25 (m, 1H), 8.70 (d, 1H), 10.40 (br s, 1H).

[0696] MS m/z 250 [M+H].sup.+

Preparation 44

tert-butyl (2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-yl)((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)carbamate

[0697] ##STR00099##

[0698] To a solution of N-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-amine (Preparation 46, 170 mg, 0.189 mmol) in DCM (3 mL) was added di-tertbutyldicarbonate (83 mg, 0.378 mmol) and triethylamine (80 uL). The reaction was stirred at room temperature for 18 hours. The reaction was partitioned between water and EtOAc, the organic layer was collected, washed with brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step.

Preparation 45

tert-butyl ((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)(2,5,8,11-tetraoxatridecan-13-yl)carbamate

[0699] ##STR00100##

[0700] To a solution of N-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,5,8,11-tetraoxatridecan-13-amine (Preparation 47, 65 mg, 0.12 mmol) in DCM (1.5 mL) was added di-tertbutyldicarbonate (52 mg, 0.236 mmol) and triethylamine (49 uL). The reaction was stirred at room temperature for 18 hours. The reaction was partitioned between water and EtOAc, the organic layer was collected, washed with brine, dried over sodium sulphate and concentrated in vacuo to afford the title compound that was used directly in the next step.

Preparation 46

N-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-amine

[0701] ##STR00101##

[0702] To a solution of 4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)picolinaldehyde (Preparation 51, 150 mg, 0.42 mmol) in DCE (4 mL) was added 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan-37-amine (m-dPEG12-NH.sub.2, 235 mg, 0.42 mmol) and acetic acid (72 uL). The reaction was stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (187 mg, 0.84 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was quenched by the addition of MeOH (0.5 mL) followed by saturated aqueous NaHCO.sub.3 solution and extracted into DCM twice. The organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (173 mg, 46%).

[0703] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.37 (s, 3H), 3.54-3.72 (m, 46H), 3.88 (s, 3H), 4.05 (s, 2H), 7.10 (d, 1H), 7.37-7.44 (m, 1H), 7.51-7.59 (m, 4H), 7.59-7.64 (m, 1H), 7.71-7.79 (m, 1H), 7.78-7.83 (m, 1H), 8.56-8.62 (m, 1H).

Preparation 47

N-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2,5,8,11-tetraoxatridecan-13-amine

[0704] ##STR00102##

[0705] To a solution of 4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)picolinaldehyde (Preparation 51, 83 mg, 0.23 mmol) in DCE (2.5 mL) was added 2,5,8,11-tetraoxatridecan-13-amine (m-dPEG4-NH.sub.2, 49 mg, 0.23 mmol) and acetic acid (40 uL). The reaction was stirred at room temperature for 1.5 hours. Sodium triacetoxyborohydride (104 mg, 0.464 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was quenched by the addition of MeOH (0.5 mL) followed by saturated aqueous NaHCO.sub.3 solution and extracted into DCM twice. The organic layers were collected, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (67 mg, 53%).

[0706] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.40 (s, 3H), 3.55 (m, 2H), 3.60-3.70 (m, 14H), 3.90 (s, 3H), 4.00 (s, 2H), 7.10 (m, 1H), 7.20 (m, 1H), 7.55-7.65 (m, 5H), 7.75 (m, 1H), 7.80 (m, 1H), 8.60 (m, 1H).

[0707] LCMS Rt=1.48 minutes MS m/z 549 [M+H].sup.+

Preparation 48

1-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-3-(25,8,11-tetraoxatridecan-13-yl)urea

[0708] ##STR00103##

[0709] To a solution of (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanamine (Preparation 49, 60 mg, 0.17 mmol) in DCM (0.5 mL) was added 4-nitrophenyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate (Preparation 67, 60 mg, 0.16 mmol) and the reaction was stirred at room temperature for 2.5 hours. The reaction was quenched by the addition of water and extracted into EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (41 mg, 43%).

[0710] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.35 (s, 3H), 3.40 (m, 2H), 3.50-3.70 (m, 16H), 3.90 (s, 3H), 4.60 (s, 2H), 5.55 (br s, 1H), 5.90 (br s, 1H), 7.10 (m, 1H), 7.40 (m, 1H), 7.50-7.60 (m, 6H), 7.75 (m, 1H), 7.80 (m, 1H), 8.60 (m, 1H).

Preparation 49

(4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanamine

[0711] ##STR00104##

[0712] To a solution of 2-(chloromethyl)-4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridine hydrochloride (Preparation 50, 45 mg, 0.108 mol) in DMF (200 mL) was added potassium carbonate (45 g, 0.326 mol) followed by phthalimide (32 g, 0.218 mol). The reaction was heated at 40° C. for 18 hours. Further potassium carbonate (45 g, 0.326 mol) and phthalimide (15 g, 0.102 mol) were added and the reaction heated at 50° C. for 5 hours. The reaction was partitioned between TMBE (800 mL) and water (800 mL). The organic layer was collected, washed with water (250 mL), dried over sodium sulphate and concentrated in vacuo. The residue was recrystallised from MeOH and added portionwise to a solution of methylamine in water (40% w/v, 500 mL) and stirred at room temperature for 4 hours. Excess methylamine was removed in vacuo and the residue treated with water (150 mL) and 2M NaOH (aq) (50 mL), and extracted into TBME (300 mL). The organic layer was collected, dried over sodium sulphate and concentrated in vacuo, azeotroping with toluene. The residue was triturated with heptanes (100 mL) and TBME (50 mL) to afford the title compound (16.8 g, 68%).

[0713] .sup.1H NMR (400 MHz, MeOH-d.sub.4): δ ppm 3.89 (s, 3H), 3.96 (s, 2H), 7.25 (d, 1H), 7.54 (d, 1H), 7.61 (m, 2H), 7.67 (m, 2H), 7.72 (m, 1H), 7.89 (m, 2H), 8.49 (d, 1H).

[0714] .sup.19F NMR (376 MHz, MeOH-d.sub.4): δ ppm −64.0 (s, 3F).

Preparation 50

2-(chloromethyl)-4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridine hydrochloride salt

[0715] ##STR00105##

[0716] To a solution of (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanol (Preparation 57, 38.8 g, 0.108 mol) in DCM at 0° C. was added thionyl chloride (12 mL, 0.164 mol) dropwise over 30 minutes. The reaction was warmed to room temperature over 2.5 hours. Toluene (50 mL) was added and the solution concentrated in vacuo, azeotroping with further toluene to afford the title compound (44.7 g, 100%).

[0717] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 3.87 (s, 3H), 4.92 (s, 2H), 7.32 (d, 1H), 7.67 (m, 2H), 7.80 (m, 1H), 7.85-7.87 (m, 2H), 8.02 (m, 3H), 8.71 (d, 1H).

Preparation 51

4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)picolinaldehyde

[0718] ##STR00106##

[0719] To a solution of (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanol (Preparation 57, 140 mg, 0.39 mmol) in DCM (4 mL) was added Dess Martin reagent (192 mg, 0.429 mmol) and the reaction was stirred at room temperature for 2 hours. Saturated aqueous NaHCO.sub.3 solution and saturated aqueous sodium thiosulfate solution were added with stirring for 30 minutes. The organic layer was separated, the aqueous was washed with further DCM, the organic layers were combined, dried over sodium sulphate and concentrated in vacuo to afford the title compound (150 mg, quant).

[0720] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.92 (s, 3H), 7.14 (d, 1H), 7.53-7.63 (m, 3H), 7.67 (m, 1H), 7.75-7.80 (m, 2H), 7.82 (s, 1H), 8.21 (m, 1H), 8.84 (m, 1H), 10.17 (s, 1H).

Preparation 52

4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-2-(2,5,8,11,14-pentaoxapentadecyl)pyridine

[0721] ##STR00107##

[0722] To a solution of (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanol (Preparation 57, 75 mg, 0.209 mmol) and 2,5,8,11-tetraoxatridecan-13-yl 4-methylbenzenesulfonate (m-dPEG4-OTf, 76 mg, 0.209 mmol) in DMF (2.3 mL) was added sodium hydride (25 mg, 0.627 mmol) followed by sodium iodide (2.9 mg, 0.021 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with DCM and water, the organic layer was collected and the aqueous layer washed with further DCM. The organic layers were collected and combined, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (67 mg, 58%).

[0723] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.40 (s, 3H), 3.55-3.80 (m, 16H), 3.90 (s, 3H), 4.80 (s, 2H), 7.10 (d, 1H), 7.40 (m, 1H), 7.60-7.70 (m, 5H), 7.75 (m, 1H), 7.80 (m, 1H), 8.60 (m, 1H).

[0724] MS m/z 550 [M+H].sup.+

Preparation 53

N-(2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl) methoxy)ethyl)-2,5,8,11-tetraoxatridecan-13-amine

[0725] ##STR00108##

[0726] To a solution of 2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide (Preparation 54, 20 mg, 0.033 mmol) in THF (0.2 mL) was added borane-dimethylsulfide (0.02 mL, 0.099 mmol) dropwise and the reaction was stirred at room temperature for 10 minutes followed by heating to 65° C. under microwave irradiation for 15 minutes. The reaction was partitioned between EtOAc and water, the organic layer was collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM with 3% triethylamine to afford the title compound (10 mg, 51%) and taken directly on to the next step.

Preparation 54

2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl) methoxy)-N-(2,5,8,11-tetraoxatridecan-13-yl)acetamide

[0727] ##STR00109##

[0728] To a solution of 2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)acetic acid (Preparation 55, 90 mg, 0.22 mmol) in DMF (2 mL) was added 2,5,8,11-tetraoxatridecan-13-amine (m-dPEG4-NH.sub.2, 45 mg, 0.126 mmol) was added DIPEA (0.157 mL, 0.864 mmol) followed by COMU® (111 mg, 0.259 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was diluted with water and extracted into EtOAc twice. The combined organic layers were washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound (83 mg, 63%).

[0729] MS m/z 607 [M+H].sup.+

Preparation 55

2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)acetic acid

[0730] ##STR00110##

[0731] To a solution of tert-butyl 2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methoxy)acetate (Preparation 56, 111 mg, 0.234 mmol) in DCM (2 mL) was added TFA (0.361 mL, 4.68 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo azeotroping with EtOAc, heptanes and DCM to afford the title compound that was used directly in the next step.

[0732] MS m/z 418 [M+H].sup.+

Preparation 56

tert-butyl 2-((4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl) methoxy)acetate

[0733] ##STR00111##

[0734] To a 0° C. solution of (4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanol (Preparation 57, 140 mg, 0.39 mmol) in DMF (4 mL) was added sodium hydride (47 mg, 1.17 mmol) and the reaction was stirred at this temperature for 40 minutes. Tert-butylbromoacetate (63 uL, 0.429 mmol) was then added and the reaction stirred at room temperature for 18 hours. The reaction was quenched with water (20 mL) and extracted into EtOAc. The organic layer was collected, washed with brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-50% EtOAc in heptanes to afford the title compound (110 mg, 60%) that was taken directly on to the next step.

Preparation 57

(4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methanol

[0735] ##STR00112##

[0736] To a solution of 4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-2-methylpyridine (Preparation 58, 74.2 g, 216 mol) in DCM (740 mL) at 5° C. was added mCPBA (70% wt active, 93.2 g, 378 mol) portionwise and the reaction was stirred at room temperature for 18 hours. Further mCPBA (10 g, 82 mmol) was added, with further stirring for 2 hours before quenching with saturated aqueous NaHCO.sub.3 solution (300 mL). The organic layer was collected, the aqueous layer backwashed with DCM (200 mL), the organic layers were combined, washed with saturated aqueous NaHCO.sub.3 solution (3×900 mL), filtered through a phase separation cartridge and concentrated in vacuo. The residue was dissolved in DCM (340 mL), cooled to 5° c. and treated with TFAA (340 mL, 2.41 mol). The reaction was heated to reflux for 45 hours before cooling and concentrating in vacuo. The residue was dissolved in DCM (700 mL), cooled to 5° C. and treated with 2M NaOH (aq) (350 mL) with stirring for 18 hours. DCM (200 mL) followed by 1M NaOH (aq) (350 mL) was added and the organic layer collected. The aqueous layer was extracted with DCM (2×250 mL) and the organic layers combined, dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc to afford the title compound (46.2 g, 66%).

[0737] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.90 (s, 3H), 4.84 (s, 2H), 7.12 (d, 1H), 7.45 (dd, 1H), 7.47 (s, 1H), 7-54-7.62 (m, 3H), 7.64 (dd, 1H), 7.76 (d, 1H), 7.82 (s, 1H), 8.62 (d, 1H).

[0738] MS m/z 360 [M+H].sup.+

Preparation 58

4-(4-methoxy-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-2-methylpyridine

[0739] ##STR00113##

[0740] To a mixture of 4-(5-chloro-2-methoxyphenyl)-2-methylpyridine (Preparation 59, 55 g, 0.24 mol), 4,4,5,5-tetramethyl-2-(3-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (104.8 g, 0.35 mol) and potassium carbonate (97.4 g, 0.71 mmol) was added 2-methyl-2-butanol (660 mL) and water (385 mL). The reaction mixture was sparged with nitrogen and degassed in vacuo before the addition of palladium acetate (1.06 g, 470 mmol) and XPhos (4.48 g, 9.40 mmol). The reaction was heated to 100° C. for 18 hours, then cooled, diluted with EtOAc (200 mL) and filtered through Celite. The filtrate was separated, the organic layer collected and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 5-100% EtOAc in heptanes. The residue was dissolved in EtOAc (250 mL) and extracted into 1M HCl (aq) (2×500 mL). The aqueous layers were combined and basified by the addition of concentrated aqueous NaOH solution. The product was extracted into EtOAc (2×200 mL), the organic layers combined, dried over magnesium sulphate and concentrated in vacuo to afford the title compound (74.2 g, 81%).

[0741] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 2.64 (s, 3H), 3.90 (s, 3H), 7.11 (d, 1H), 7.34 (dd, 1H), 7.37 (s, 1H), 7.55 (d, 1H), 7.61-7.55 (m, 2H), 7.62 (dd, 1H), 7.76 (d, 1H), 7.82 (s, 1H), 8.59 (d, 1H).

Preparation 59

4-(5-chloro-2-methoxyphenyl)-2-methylpyridine

[0742] ##STR00114##

[0743] To a mixture of (5-chloro-2-methoxyphenyl)boronic acid (56.89 g, 0.31 mol), 4-bromo-2-methylpyridine (50 g, 0.29 mol) and sodium carbonate (98.57 g, 0.91 mol) was added 1,4, dioxane (0.9 L) and water (0.18 L). The reaction was sparged with nitrogen and degassed in vacuo. Pd(dppf)C.sub.2 (12.66 g, 16 mmol) was added and the reaction heated to 100° C. for 18 hours. The reaction was cooled to room temperature, filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with EtOAc. The residue was dissolved in EtOAc and extracted into 1M HCl (2×2 L). The aqueous layers were combined, basified with concentrated aqueous NaOH solution and extracted into EtOAc (2×750 mL). The organic layers were combined, washed with brine (300 mL), dried over magnesium sulphate and concentrated in vacuo to afford the title compound (64.5 g, 95%).

[0744] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 2.60 (s, 3H), 3.81 (s, 3H), 6.91 (d, 1H), 7.28 (m, 4H), 8.51 (d, 1H).

Preparation 60

tert-Butyl 4-(2-{[(4-bromopyridin-2-yl)methyl][(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate

[0745] ##STR00115##

[0746] To a solution of tert-butyl 4-(2-{[(4-bromopyridin-2-yl)methyl]amino}ethyl)piperidine-1-carboxylate (Preparation 61, 5.76 g, 14.6 mmol) in dichloromethane (75 mL) was added triethylamine (3.06 mL, 21.8 mmol) followed by 2,2,2-trichloroethylchloroformate (2.21 mL, 16.0 mmol) at room temperature. The reaction was stirred at room temperature for 1 hour. An aqueous solution of ammonium chloride (100 mL) was added followed by water (100 mL) and the aqueous phase was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a yellow oil (9.51 g, >100%). No further purification undertaken.

[0747] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.05 (m, 2H), 1.40 (s, 9H), 1.50-1.70 (m, 5H), 2.60 (m, 2H), 3.40 (m, 2H), 4.00 (m, 2H), 4.60 (s, 2H), 4.75 (s, 2H), 7.35 (m, 1H), 7.50 (m, 1H), 8.35 (d, 1H).

[0748] LCMS Rt=3.06 minutes MS m/z 573 [M+H].sup.+

Preparation 61

tert-Butyl 4-(2-{[(4-bromopyridin-2-yl)methyl]amino}ethyl)piperidine-1-carboxylate

[0749] ##STR00116##

[0750] To a solution of (4-bromopyridin-2-yl)methanamine (2.86 g, 15.1 mmol) in methanol (75 mL) was added tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (3.44 g, 15.1 mmol). The reaction was stirred at room temperature for 18 hours and cooled to 0° C. in an ice bath. Sodium borohydride (173 g, 45.4 mmol) was added portionwise and after 30 minutes at room temperature, the mixture was quenched by addition of water (50 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a light yellow oil (5.76 g, 95%).

[0751] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.05 (m, 2H), 1.40 (s, 9H), 1.50 (m, 2H), 1.60 (m, 2H), 1.70 (m, 1H), 2.60 (m, 4H), 3.90 (s, 2H), 4.10 (br s, 2H), 7.30 (dd, 1H), 7.50 (s, 1H), 8.30 (d, 1H).

[0752] LCMS Rt=1.91 minutes MS m/z 399 [M+H].sup.+

Preparation 62

tert-Butyl 4-(2-{[(benzyloxy)carbonyl][(4-bromopyridin-2-yl)methyl]amino}ethyl)piperidine-1-carboxylate

[0753] ##STR00117##

[0754] Triethylamine (1.47 mL, 10.6 mmol) and benzyl chloroformate (0.9 mL, 6.33 mmol) were added to a solution of tert-butyl 4-(2-{[(4-bromopyridin-2-yl)methyl]amino}ethyl)piperidine-1-carboxylate (Preparation 61, 2.10 g, 5.28 mmol) in dichloromethane (25 mL) at 0° C. The reaction mixture was stirred for 1 hour at room temperature, washed with water (30 mL), and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layers were dried over magnesium sulfate. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 2:3 ethyl acetate:cyclohexane to afford the title compound as an oil (2.54 g, 90%).

[0755] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.96-1.13 (m, 2H), 1.31-1.66 (m, 14H), 2.48-2.66 (m, 2H), 3.33-3.43 (m, 2H), 4.00 (br s, 2H), 4.57 (d, 2H), 5.19 (d, 2H), 7.24-7.46 (m, 7H), 8.33 (d, 1H).

[0756] LCMS Rt=2.96 minutes MS m/z 533 [M+H].sup.+

Preparation 63

tert-butyl 3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)azetidine-1-carboxylate

[0757] ##STR00118##

[0758] To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (173 mg, 0.99 mmol) in THF (2 mL) was added sodium hydride (52 mg, 1.30 mmol) and the reaction was stirred at room temperature for 20 minutes. 1-bromo-2,5,8,11-tetraoxadodecane (m-dPEG4-Br, 271 mg, 0.99 mmol) was added and the reaction stirred at room temperature for 18 hours. The reaction was quenched by the addition of water and extracted into EtOAc. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-100% EtOAc in heptanes to afford the title compound.

[0759] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 1.37 (s, 9H), 3.25 (s, 3H), 3.41-3.51 (m, 16H), 3.61-3.65 (m, 2H), 3.96-4.01 (m, 2H), 4.22-4.26 (m, 1H).

[0760] MS m/z 364 [M+H].sup.+

Preparation 64

(R)-3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine trifluoroacetate salt

[0761] ##STR00119##

[0762] The Boc-protected title compound was prepared according to the method described for Preparation 63 using tert-butyl (R)-3-hydroxypyrrolidine-1-carboxylate and 1-bromo-2,5,8,11-tetraoxadodecane (m-dPEG4-Br). The Boc intermediate was dissolved in TFA (0.5 mL) and heated to 50° C. for 2 hours. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound.

[0763] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 1.93 (m, 2H), 3.09 (m, 4H), 3.32 (s, 3H), 3.44 (m, 3H), 3.49-3.51 (m, 13H), 4.16 (m, 1H), 8.03 (br s, 1H).

[0764] MS m/z 278 [M+H].sup.+

Preparation 65

(S)-3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)pyrrolidine trifluoroacetate salt

[0765] ##STR00120##

[0766] The Boc-protected title compound was prepared according to the method described for Preparation 63 using tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate and 1-bromo-2,5,8,11-tetraoxadodecane (m-dPEG4-Br). The Boc intermediate was dissolved in TFA (0.5 mL) and heated to 50° C. for 2 hours. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound.

[0767] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 1.99 (br m, 2H), 3.18-3.32 (m, 7H), 3.44-3.53 (m, 16H), 4.21 (m, 1H), 8.76 (br s, 1H).

[0768] MS m/z 278 [M+H].sup.+

Preparation 66

4-((2,5,8,11-tetraoxatridecan-13-yl)oxy)piperidine hydrochloride salt

[0769] ##STR00121##

[0770] The Boc-protected title compound was prepared according to the method described for Preparation 63 using tert-butyl-4-hydroxypiperidine-1-carboxylate and triethyleneglycol-2-bromoethylmethylether. The Boc intermediate was dissolved in dioxane and treated with 4M HCl in dioxane and stirred at room temperature for 2 hours. Diethyl ether was added to the reaction and the resulting precipitate was collected and triturated with diethyl ether.

[0771] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 1.60-1.76 (m, 2H), 1.90-2.10 (m, 2H), 2.88-3.10 (m, 2H), 3.08-3.20 (m, 2H), 3.26 (s, 3H), 3.42-3.62 (m, 17H).

[0772] MS m/z 292 [M+H].sup.+

Preparation 67

4-nitrophenyl (2,5,8,11-tetraoxatridecan-13-yl)carbamate

[0773] ##STR00122##

[0774] To a solution of bis(4-nitrophenyl) carbonate (56 mg, 0.182 mmol) in DCM (1.7 mL) was added DIPEA (51 uL, 0.280 mmol) followed by a solution of 2,5,8,11-tetraoxatridecan-13-amine (m-dPEG4-NH.sub.2, 29 mg, 0.14 mmol) in DCM (0.5 mL) and the reaction was stirred at room temperature for 1 hour. The reaction was partitioned between water and EtOAc, the organic layer was collected, dried over sodium sulphate, concentrated in vacuo and used directly in the next reaction.

Preparation 68

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3′-(trifluoromethyl) biphenyl-4-ol

[0775] ##STR00123##

[0776] To a solution of 2-[4-(Benzyloxy)-3′-(trifluoromethyl)biphenyl-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 70, 16.3 g, 35.9 mmol) in methanol (250 mL) was added 10% palladium on carbon (1.63 g, 10% w/w) and ammonium formate (9.06 g, 143.6 mmol). The reaction mixture was heated at 60° C. for 1 hour. The reaction mixture was cooled and the solvent was evaporated in vacuo. The residue was diluted with dichloromethane (200 mL) and was washed with water (100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the title compound as a solid (11.6 g, 89%).

[0777] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.40 (s, 12H), 6.98 (d, 1H), 7.53 (d, 1H), 7.62 (dd, 1H), 7.74 (d, 1H), 7.80 (s, 1H), 7.84 (d, 1H), 7.94 (d, 1H).

[0778] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −62.5 (s, 3F).

[0779] MS m/z No mass ion observed

Preparation 69

tert-Butyl ({4-[4-(benzyloxy)-3′-(trifluoromethyl)biphenyl-3-yl]pyridin-2-yl}methyl)carbamate

[0780] ##STR00124##

[0781] 2-[4-(Benzyloxy)-3′-(trifluoromethyl) biphenyl-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 70, 3.09 g, 6.69 mmol), tert-butyl [(4-bromopyridin-2-yl)methyl]carbamate (Preparation 72, 1.95 g, 6.97 mmol) and sodium carbonate (2.85 g, 26.87 mmol) in a mixture of dioxane (30 mL) and water (6.0 mL) were degassed. Tetrakis(triphenylphosphine)palladium(0) (0.39 g, 0.34 mmol) was added and the reaction mixture was further degassed and heated at 80° C. for 7 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (50 mL) and the organic layer was dried over magnesium sulfate and solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 1:1 ethyl acetate:heptane to afford the title compound as a glassy solid (2.66 g, 73%).

[0782] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.46 (s, 9H), 4.50 (d, 2H), 5.16 (s, 2H), 5.55 (br s, 1H), 7.16 (d, 1H), 7.31-7.39 (m, 5H), 7.44 (dd, 1H), 7.51-7.60 (m, 5H), 7.74 (d, 1H), 7.80 (s, 1H), 8.58 (d, 1H).

[0783] .sup.19F NMR (400 MHz, CDCl.sub.3): δ −ppm 62.6 (s, 3F).

[0784] LCMS Rt=3.98 minutes MS m/z 535 [M+H].sup.+

Preparation 70

2-[4-(Benzyloxy)-3′-(trifluoromethyl)biphenyl-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0785] ##STR00125##

[0786] 4-(Benzyloxy)-3-bromo-3′-(trifluoromethyl)biphenyl (Preparation 71, 25.2 g, 61.9 mmol), Bis(pinacolato)diboron (18.4 g, 74.2 mmol) and potassium acetate (18.2 g, 186 mmol) were combined and dissolved in dimethoxyethane (400 mL). The reaction was degassed with nitrogen for 20 minutes and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (2.49 g, 3.1 mmol) was added in one portion. The reaction was heated at 70° C. for 18 hours, cooled to room temperature, filtered through a pad of celite (eluting with ethyl acetate (200 mL)) and the filtrate partitioned between ethyl acetate and water. The organic layer was washed with brine (50 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 20-80% EtOAc in heptanes to afford the title compound as a light yellow solid (17.8 g, 64%).

[0787] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.30 (s, 12H), 5.15 (d, 2H), 7.00 (d, 1H), 7.15 (s, 1H), 7.20 (s, 1H), 7.30 (d, 1H), 7.40 (m, 2H), 7.50 (m, 1H), 7.60 (m, 2H), 7.75 (d, 1H), 7.85 (s, 1H), 7.90 (s, 1H).

[0788] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −63.0 (s, 3F).

[0789] LCMS Rt=3.44 minutes MS m/z No mass ion observed

Preparation 71

4-(Benzyloxy)-3-bromo-3′-(trifluoromethyl)biphenyl

[0790] ##STR00126##

[0791] To a solution of 3-Bromo-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 39, 20.9 g, 65.9 mmol) in N,N-dimethylformamide (300 mL) at room temperature was added benzyl bromide (8.6 mL, 72.5 mmol) followed by potassium carbonate (18.2 g, 132 mmol). The reaction was stirred at room temperature for 4 hours, and partitioned between water and ethyl acetate (1/1, 1 L). The aqueous layer was washed with ethyl acetate (2×100 mL) and the combined organic phases were washed with brine (200 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude compound was purified by silica gel column chromatography eluting with 5-10% EtOAc in heptanes to afford the title compound as a yellow oil (25.2 g, 94%).

[0792] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 5.20 (s, 2H), 7.00 (d, 1H), 7.30-7.60 (m, 8H), 7.65 (d, 1H), 7.75 (s, 1H), 7.80 (s, 1H).

[0793] .sup.19F NMR (400 MHz, CDCl.sub.3): δ ppm −63.0 (s, 3F).

[0794] LCMS Rt=3.23 minutes MS m/z No mass ion observed

Preparation 72

tert-Butyl [(4-bromopyridin-2-yl)methyl]carbamate

[0795] ##STR00127##

[0796] Di-tert-butyl dicarbonate (4 g, 18.28 mmol), triethylamine (3 mL, 21.93 mmol) and 4-dimethylaminopyridine (40 mg, 0.36 mmol) were added to a solution of 1-(4-bromopyridin-2-yl)methanamine (Preparation 73, 1.9 g, 10.1 mmol) in dichloromethane (40 mL) and the reaction mixture was stirred for 18 hours. The mixture was quenched with water (50 mL), extracted with dichloromethane (100 mL) and the organic layer was dried over magnesium sulfate and solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 1:1 ethyl acetate:heptane to give the title compound as a colourless oil (1.99 g, 95%).

[0797] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.46 (s, 9H), 4.42 (d, 2H), 5.45 (br s, 1H), 7.34-7.36 (m, 1H), 7.45 (s, 1H), 8.34 (d, 1H).

Preparation 73

1-(4-bromopyridin-2-yl)methanamine

[0798] ##STR00128##

[0799] Hydrazine hydrate (4 mL, 82.19 mmol) was added to a suspension of 2-[(4-bromopyridin-2-yl)methyl]-1H-isoindole-1,3(2H)-dione (Preparation 74, 3.81 g, 12.02 mmol) in ethanol (100 mL) and the reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was cooled and solvent was evaporated in vacuo, the solid residue was triturated with ethyl acetate (15 mL) and mother liquor was evaporated to give the title compound as brown oil (1.29 g, 57%).

[0800] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.96 (s, 2H), 7.29 (dd, 1H), 7.51 (d, 1H), 8.36 (d, 1H).

[0801] LCMS Rt=1.54 minutes MS m/z 188 [M+H].sup.+

Preparation 74

2-[(4-Bromopyridin-2-yl)methyl]-1H-isoindole-1,3(2H)-dione

[0802] ##STR00129##

[0803] 4-Bromo-2-(bromomethyl)pyridine hydrobromide (Preparation 75, 4.92 g, 14.86 mmol), phthalimide (2.19 g, 14.86 mmol) and potassium carbonate (4.11 g, 29.73 mmol) in N,N-dimethylformamide (50 mL) were stirred for 18 hours at room temperature. The reaction mixture was diluted with water (50 mL) and stirred for 5 minutes. The suspension was filtered and the solid was washed through with water followed by heptane then dried to give the title compound as brown solid (3.83 g, 81%).

[0804] .sup.1H NMR (400 MHz, acetone-d.sub.6): δ ppm 4.99 (s, 2H), 7.51 (dd, 1H), 7.71 (dd, 1H), 7.87-7.93 (m, 4H), 8.33 (d, 1H).

[0805] LCMS Rt=2.86 minutes MS m/z 318 [M+H].sup.+

Preparation 75

4-bromo-2-(bromomethyl)pyridine hydrobromide salt

[0806] ##STR00130##

[0807] Phosphorous tribromide (15.6 mL, 164 mmol) was added to a solution of (4-bromopyridin-2-yl)methanol (Preparation 76, 5.12 g, 27.38 mmol) in dichloromethane (100 mL) at 0° C. and then heated to reflux for 18 hours. The reaction mixture was cooled, the suspension was poured into crushed ice (150 g) and basified to pH=10 with a saturated aqueous solution of potassium carbonate. The mixture was extracted with dichloromethane (3×100 mL), combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuo. The dark oil residue was diluted with diethyl ether (60 mL), a solution of acetic acid/hydrogen bromide (48% solution) [1:1 (8 mL)] was added and the resulting solid was collected via filtration then dried to give the title compound as a brown solid (4.92 g, 54%).

[0808] .sup.1H NMR (400 MHz, MeOD-d.sub.4): δ ppm 4.80 (s, 2H), 8.20 (dd, 1H), 8.41 (d, 1H), 8.68 (d, 1H).

[0809] LCMS Rt=2.68 minutes MS m/z 252 [M+H].sup.+

Preparation 76

(4-Bromopyridin-2-yl)methanol

[0810] ##STR00131##

[0811] Trifluoroacetic anhydride (58.6 mL, 415 mmol) was added to a solution of 4-bromo-2-methylpyridine 1-oxide (Preparation 77, 15.6 g, 82.98 mmol) in dichloromethane (250 mL) at 0° C. (ice-bath). The ice-bath was removed and the reaction mixture was stirred at reflux for 12 hours. The reaction mixture was cooled and solvent was evaporated in vacuo. The dark yellow oil residue was diluted with dichloromethane (150 mL), 2M sodium hydroxide (100 mL) was added and the mixture was stirred vigorously for 18 hours. The layers were separated and the aqueous layer was further extracted with dichloromethane (50 mL), the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give the title compound as dark oil (10.24 g, 66%).

[0812] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 3.85 (br s, 1H), 4.75 (s, 2H), 7.37 (dd, 1H), 7.46 (s, 1H), 8.35 (d, 1H).

[0813] LCMS Rt=1.89 minutes MS m/z 189 [M+H].sup.+

Preparation 77

4-Bromo-2-methylpyridine 1-oxide

[0814] ##STR00132##

[0815] To a solution of 4-bromo-2-methylpyridine (20 g, 116.3 mmol) in dichloromethane (250 mL) was added meta-chloroperoxybenzoic acid (26 g, 151.2 mmol) at 0° C. (ice-bath). The ice-bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with saturated sodium bicarbonate (100 mL), the aqueous layer was further extracted with dichloromethane (50 mL) and the combined organic layers were dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (60 mL), filtered through a pad of silica gel eluting with ethyl acetate (60 mL) and the solvent was evaporated in vacuo to give the title compound as dark oil (15.92 g, 73%).

[0816] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 2.48 (s, 3H), 7.25 (dd, 1H), 7.40 (d, 1H), 8.08 (d, 1H).

[0817] LCMS Rt=1.49 minutes MS m/z 189 [M+H].sup.+

Preparation 78

3-Iodobiphenyl-4-ol

[0818] ##STR00133##

[0819] To a solution of [1,1′-biphenyl]-4-ol (12.7 g, 74.6 mmol) in glacial acetic acid (250 mL), cooled to 0° C. was added N-iodosuccinimide (16.8 g, 74.6 mmol). The reaction mixture was stirred for 2 hours at 0° C. then allowed to slowly warm to room temperature, and was stirred for 18 hours at room temperature. The solution was concentrated in vacuo and the residue was partitioned between water (200 mL) and dichloromethane (200 mL). The aqueous layer was separated and extracted with dichloromethane (2×200 mL). The organic layers were combined, washed with a 0.5M aqueous solution of sodium thiosulfate (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluting with 30% ethyl acetate in cyclohexane to afford the title compound as a pale yellow solid (12.8 g, 58%).

[0820] LCMS Rt=3.31 minutes MS m/z 295 [M−H].sup.−

Preparation 79

2-(1-Acetylpiperidin-4-yl)ethanamine

[0821] ##STR00134##

[0822] To a solution of tert-butyl [2-(1-acetylpiperidin-4-yl)ethyl]carbamate (Preparation 80, 4.45 g, 16.45 mmol) in dioxane (50 mL) was added a 4M solution of hydrogen chloride in dioxane (30 mL, 120 mmol). The solution was stirred for 18 hours at room temperature and concentrated in vacuo. The crude material was dissolved in water (20 mL) and the solution was basified with a 30% aqueous solution of sodium hydroxide (20 mL). The aqueous solution was extracted with dichloromethane (3×50 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a clear oil (2.55 g, 91%).

[0823] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.10 (m, 2H), 1.40-1.30 (m, 4H), 1.57 (m, 1H), 1.71 (m, 2H), 2.06 (m, 3H), 2.51 (m, 1H), 2.73 (m, 2H), 3.01 (m, 1H), 3.77 (m, 1H), 4.57 (m, 1H).

[0824] LCMS Rt=2.99 minutes MS m/z 171 [M+H].sup.+

Preparation 80

tert-Butyl [2-(1-acetylpiperidin-4-yl)ethyl]carbamate

[0825] ##STR00135##

[0826] To a solution of tert-butyl (2-piperidin-4-ylethyl)carbamate (Preparation 81, 4.0 g, 17.5 mmol) in dichloromethane (80 mL) was added triethylamine (4.90 mL, 35.0 mmol) and acetic anhydride (1.75 mL, 18.4 mmol). The reaction mixture was stirred for 1 hour at room temperature then water (20 mL) and 30% aqueous solution of sodium hydroxide (10 mL) were added and the mixture was stirred for 15 minutes. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was azeotroped with ethyl acetate (50 mL) to afford the title compound as a clear viscous oil (4.45 g, 94%).

[0827] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.10 (m, 2H), 1.42-1.54 (m, 12H), 1.71 (m, 2H), 2.03 (s, 3H), 2.50 (m, 1H), 2.99 (m, 1H), 3.14 (m, 2H), 3.77 (m, 1H), 4.45 (m, 2H).

[0828] LCMS Rt=2.43 minutes MS m/z 271 [M+H].sup.+

Preparation 81

tert-Butyl (2-piperidin-4-ylethyl)carbamate

[0829] ##STR00136##

[0830] To a solution of tert-butyl (2-pyridin-4-ylethyl)carbamate (Preparation 82, 26.9 g, 120.9 mmol) in methanol (370 mL), cooled to 0° C., was added a 6N aqueous solution of hydrochloric acid (20.2 mL, 120.9 mmol). The solution was subject to hydrogenation using platinum (IV) oxide (1.37 g, 6.05 mmol) and hydrogen (1000 psi) over 24 hours at room temperature. The reaction mixture was filtered on a pad of Arbocel which was washed successively with methanol (300 mL) and water (100 mL). The filtrate was concentrated in vacuo. The crude material was diluted with a saturated aqueous solution of sodium bicarbonate (150 mL). The solution was extracted with dichloromethane (50 mL). The organic layer was extracted with water (2×50 mL). The aqueous layers were combined, basified with a 30% aqueous solution of sodium hydroxide (30 mL) and extracted with dichloromethane (8×200 mL). The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a clear viscous oil (26.8 g, 97%).

[0831] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.17 (m, 2H), 1.41 (m, 10H), 1.68 (m, 2H), 2.58 (m, 2H), 3.09 (m, 6H), 4.53 (s, 1H).

[0832] LCMS Rt=1.73 minutes MS m/z 229 [M+H].sup.+

Preparation 82

tert-Butyl (2-pyridin-4-ylethyl)carbamate

[0833] ##STR00137##

[0834] To a solution of 2-(pyridin-4-yl)ethanamine (14.77 g, 120.9 mmol) in dichloromethane (150 mL) was slowly added di-tert-butyl dicarbonate (27.7 g, 126.9 mmol). The reaction mixture was stirred for 2 hours at room temperature and the solution was concentrated in vacuo to afford the title compound as an orange oil (28.48 g, >100%).

[0835] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.40 (s, 9H), 2.77 (m, 2H), 3.36 (m, 2H), 4.74 (s, 1H), 7.09 (m, 2H), 8.46 (m, 2H).

[0836] LCMS Rt=2.38 minutes MS m/z 223 [M+H].sup.+

Preparation 83

3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)azetidine trifluoroacetate salt

[0837] ##STR00138##

[0838] A solution of tert-butyl 3-((2,5,8,11-tetraoxatridecan-13-yl)oxy)azetidine-1-carboxylate (Preparation 63, 94 mg, 0.26 mmol) in TFA (0.5 mL, 7 mmol) was warmed to 50° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford the title compound (98 mg, crude quant.)

[0839] LCMS Rt=0.28 minutes MS m/z 264 [M+H].sup.+

Preparation 84

tert-butyl [(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl) biphenyl-3-yl}pyridin-2-yl)methyl][2-(piperidin-4-yl)ethyl]carbamate

[0840] ##STR00139##

[0841] The title compound was prepared according to the methods described by Example 2 followed by Preparation 6 followed by Preparation 5 using 2,2,2-trichloroethyl [(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]{2-[1-(trifluoroacetyl) piperidin-4-yl]ethyl}carbamate (Preparation 85).

[0842] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.90-1.03 (m, 3H), 1.27-1.43 (m, 13H), 2.80 (t, 2H), 3.10 (d, 2H), 3.44 (d, 2H), 4.60 (d, 2H), 6.32 (d, 1H), 7.16 (br s, 1H), 7.35 (d, 1H), 7.51-7.69 (m, 5H), 7.78 (d, 1H), 7.84 (s, 1H), 7.86 (d, 1H), 8.40 (s, 1H), 8.58 (d, 1H).

[0843] MS m/z 847 [M+H].sup.+

Preparation 85

2,2,2-trichloroethyl [(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]{2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate

[0844] ##STR00140##

[0845] The title compound was prepared according to the method described for Preparation using 2,2,2-trichloroethyl [(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl) phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl][2-(piperidin-4-yl)ethyl]carbamate (Preparation 86) and taken on crude directly to the next step.

Preparation 86

2,2,2-trichloroethyl [(4-{4-[2-chloro-5-fluoro-4-(1,3,4-thiadiazol-2-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl][2-(piperidin-4-yl)ethyl]carbamate

[0846] ##STR00141##

[0847] The title compound was prepared according to the methods described for Preparation 11 followed by Preparation 10 using tert-butyl 4-(2-{({4-[4-hydroxy-3′-(trifluoromethyl) biphenyl-3-yl]pyridin-2-yl}methyl)[(2,2,2-trichloroethoxy)carbonyl]amino}ethyl)piperidine-1-carboxylate (Preparation 26) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (WO2010079443).

[0848] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 0.78-0.84 (m, 2H), 0.94-0.97 (m, 2H), 1.21-1.36 (m, 3H), 2.78 (t, 2H), 3.14-3.27 (m, 2H), 3.37-3.40 (m, 2H), 4.46-4.77 (m, 4H), 6.27-6.34 (m, 1H), 7.01-7.15 (m, 1H), 7.42-7.73 (m, 6H), 7.79 (d, 1H), 7.84 (s, 1H), 7.94 (d, 1H), 8.45 (d, 1H), 8.61 (d, 1H).

[0849] MS m/z 921 [M+H].sup.+

Preparation 87

5-chloro-2-fluoro-4-({3-[2-(piperazin-1-yl)pyridin-4-yl]-4′-(trifluoromethyl) biphenyl-4-yl}oxy)-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide

[0850] ##STR00142##

[0851] The title compound was prepared according to the methods described by Preparation 8 followed by Preparation 2 using tert-butyl 4-(4-(4-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)piperazine-1-carboxylate (WO2012004743) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (WO2010079443). The title compound was isolated as the free parent following elution through an SCX column using 7N ammonia in methanol.

[0852] .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ ppm 3.05-3.07 (m, 4H), 3.65-3.67 (m, 4H), 6.75 (d, 1H), 6.90 (dd, 1H), 6.99 (s, 1H), 7.31 (d, 1H), 7.71 (d, 1H), 7.81-7.87 (m, 4H), 7.98 (d, 2H), 8.11 (d, 1H), 8.55 (s, 1H).

[0853] MS m/z 689 [M−H].sup.−

Preparation 88

tert-butyl [(4-{4-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl) biphenyl-3-yl}pyridin-2-yl)methyl][2-(piperidin-4-yl)ethyl]carbamate

[0854] ##STR00143##

[0855] The title compound was prepared according to the method described by Preparation 5 using tert-butyl [(4-{4-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl) biphenyl-3-yl}pyridin-2-yl)methyl]{2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate (Preparation 89) and purified using reverse phase column chromatography eluting with 0-100% water:MeCN with 0.1% formic acid.

[0856] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.20-1.40 (m, 14H), 1.60 (m, 2H), 2.70 (t, 2H), 3.10 (m, 2H), 3.40 (m, 2H), 4.50 (d, 2H), 6.30 (d, 1H), 6.80 (s, 1H), 7.20 (m, 1H), 7.30 (m, 1H), 7.40 (s, 1H), 7.60 (m, 3H), 7.75 (m, 1H), 7.80 (s, 1H), 7.85 (d, 1H), 8.45 (s, 1H), 8.59 (s, 1H), 8.60 (s, 1H).

[0857] MS m/z 846 [M+H].sup.+

Preparation 89

tert-butyl [(4-{4-[2-chloro-5-fluoro-4-(1,3-thiazol-4-ylsulfamoyl)phenoxy]-3′-(trifluoromethyl)biphenyl-3-yl}pyridin-2-yl)methyl]{2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}carbamate

[0858] ##STR00144##

[0859] The title compound was prepared according to the method described for Preparation 6 using 5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)-4-{[3-{2-[({2-[1-(trifluoroacetyl)piperidin-4-yl]ethyl}amino)methyl]pyridin-4-yl}-3′-(trifluoromethyl) biphenyl-4-yl]oxy}benzenesulfonamide (Example 35).

[0860] .sup.1H NMR (400 MHz, CDCl.sub.3): δ ppm 1.30-1.50 (m, 12H), 1.80 (m, 2H), 2.60 (t, 2H), 3.00 (m, 2H), 3.20 (m, 2H), 3.95 (d, 1H), 4.40 (m, 3H), 6.40 (d, 1H), 6.60 (s, 1H), 7.05 (d, 1H), 7.40 (m, 2H), 7.55-7.65 (m, 4H), 7.75 (d, 1H), 7.80 (s, 1H), 7.95 (d, 1H), 8.45 (s, 1H), 8.50 (m, 1H).

[0861] MS m/z 942 [M+H].sup.+

[0862] The ability of the compounds of formula (I) to block the Nav1.7 (or SCN9A) channel was measured using the assay described below.

[0863] Cell Line Construction and Maintenance

[0864] Human Embryonic Kidney (HEK) cells were transfected with an hSCN9A construct using lipofectamine reagent (Invitrogen), using standard techniques. Cells stably expressing the hSCN9A constructs were identified by their resistance to G-418 (400 μg/ml). Clones were screened for expression using the whole-cell voltage-clamp technique.

[0865] Cell Culture

[0866] HEK cells stably transfected with hSCN9A were maintained in DMEM medium supplemented with 10% heat-inactivated fetal bovine serum and 400 μg/ml G-418 in an incubator at 37° C. with a humidified atmosphere of 10% CO.sub.2. For HTS, cells were harvested from flasks by trypsinization and replated in an appropriate multi-well plate (typically 96 or 384 wells/plate) such that confluence would be achieved within 24 hours of plating. Cells were typically used for electrophysiological experiments within 24 to 72 hours after plating.

[0867] Electrophysiological Recording

[0868] For conventional whole-cell voltage clamp experiments cells were removed from the culture flask by brief trypsinization and re-plated at low density onto glass cover slips. Cover slips containing HEK cells expressing hSCN9A were placed in a bath on the stage of an inverted microscope and perfused (approximately 1 ml/minutes) with extracellular solution of the following composition: 138 mM NaCl, 2 mM CaCl.sub.2, 5.4 mM KCl, 1 mM MgCl.sub.2, 10 mM glucose, and 10 mM HEPES, pH 7.4, with NaOH. Pipettes were filled with an intracellular solution of the following composition: 135 mM CsF, 5 mM CsCl, 2 mM MgCl.sub.2, 10 mM EGTA, 10 mM HEPES, pH 7.3 with NaOH, and had a resistance of 1 to 2 megaohms. The osmolarity of the extracellular and intracellular solutions was 300 mOsm/kg and 295 mOsm/kg, respectively. All recordings were made at room temperature (22-24° C.) using AXOPATCH 200B amplifiers and PCLAMP software (Axon Instruments, Burlingame, Calif.). hSCN9A currents in HEK cells were measured using the whole-cell configuration of the patch-clamp technique (Hamill et al., 1981). Uncompensated series resistance was typically 2 to 5 mega ohms and >85% series resistance compensation was routinely achieved. As a result, voltage errors were negligible and no correction was applied. Current records were acquired at 20 to 50 KHz and filtered at 5 to 10 KHz.

[0869] HEK cells stably transfected with hSCN9A were viewed under Hoffman contrast optics and placed in front of an array of flow pipes emitting either control or compound-containing extracellular solutions.

[0870] The voltage-dependence of inactivation was determined by applying a series of depolarizing prepulses (8 sec long in 10 mV increments) from a negative holding potential. The voltage was then immediately stepped to 0 mV to assess the magnitude of the sodium current. Currents elicited at 0 mV were plotted as a function of prepulse potential to allow estimation of the voltage at which 50% of the channels were inactivated (midpoint of inactivation or V1/2). Compounds were tested for their ability to inhibit hSCN9A sodium channels by activating the channel with a 20 msec voltage step 15 to 0 mV following an 8 second conditioning prepulse to the empirically determined V1/2. Compound effect (% inhibition) was determined by difference in current amplitude before and after application of test compounds. For ease of comparison, “estimated IC-50” (EIC.sub.50) values were calculated from single point electrophysiology data by the following equation, (tested concentration, nM)×(100-% inhibition/% inhibition). Inhibition values <20% and >80% were excluded from the calculation.

[0871] Electrophysiological assays were conducted with PatchXpress 7000 hardware and associated software (Molecular Devices Corp). All assay buffers and solutions were identical to those used in conventional whole-cell voltage clamp experiments described above. hSCN9A cells were grown as above to 50%-80% confluency and harvested by trypsinization. Trypsinized cells were washed and resuspended in extracellular buffer at a concentration of 1×10.sup.6 cells/ml. The onboard liquid handling facility of the PatchXpress was used for dispensing cells and application of test compounds. Determination of the voltage midpoint of inactivation was as described for conventional whole-cell recordings. Cells were then voltage-clamped to the empirically determined V1/2 and current was activated by a 20 msec voltage step to 0 mV. For ease of comparison, “estimated IC-50” (EIC.sub.50) values were calculated from single point electrophysiology data by the following equation, (tested concentration, nM)×(100-% inhibition/% inhibition). Inhibition values <20% and >80% were excluded from the calculation.

[0872] Electrophysiological assays may also be conducted using the Ionworks Quattro automated electrophysiological platform (Molecular Devices Corp). Intracellular and extracellular solutions were as described above with the following changes, 100 μg/ml amphotericin was added to the intracellular solution to perforate the membrane and allow electrical access to the cells. hSCN9A cells were grown and harvested as for PatchXpress and cells were resuspended in extracellular solution at a concentration of 3-4×10.sup.6 cells/ml. The onboard liquid handling facility of the Ionworks Quattro was used for dispensing cells and application of test compounds. A voltage protocol was then applied that comprised of a voltage step to fully inactivate the sodium channels, followed by a brief hyperpolarized recovery period to allow partial recovery from inactivation for unblocked sodium channels, followed by a test depolarized voltage step to assess magnitude of inhibition by test compound. Compound effect was determined based on current amplitude difference between the pre-compound addition and post-compound addition scans.

[0873] All compounds were dissolved in dimethyl sulfoxide to make 10 mM stock solutions, which were then diluted into extracellular solution to attain the final concentrations desired. The final concentration of dimethyl sulfoxide (<0.3% dimethyl sulfoxide) was found to have no significant effect on hSCN9A sodium currents.

[0874] Unless otherwise stated, the PatchXpress (PX) platform was used to test compounds of the Examples, which were found to have the Nav1.7 EIC.sub.50 (nM) values specified in the table below.

TABLE-US-00001 Ex. EIC.sub.50 1 5.8 2 >30 .sup.1   3 1.0 4 ND 5 1.5 6 2.1 7 1.5 8 3.4 9 10.9  10 4.7 11 10.4  12 2.3 13 13.0  14 5.0 15 1.0 16 0.9 17 <10 .sup.2   18  0.58 19 17.5  20 1.0 21 7.9 22 2.6 23 5.0 24 13.4  25 ND 26  0.50 27 47.2  28 241.0  29 2.9 30 23.9  31 9.8 32 16.0  33 1.7 34 ND 35 ND .sup.1 10.71% inhibition at 30 nM dose .sup.2 87.38% inhibition at 10 nM dose ND = no data

[0875] Using the above described assay and the PX platform, preferred compounds of the invention have a Nav1.7 EIC.sub.50 (nM) value of <10, such as <5, e.g. <1.

[0876] The ability of compounds of formula (I) to block the Nav1.5 (or SCN5A) channel can also be measured using an assay analogous to that described above but replacing the SCN9A gene with the SCN5A gene. All other conditions remain the same including the same cell line and conditions for cell growth. The estimated IC50s are determined at the half inactivation for Nav1.5. These results can be compared to the EIC.sub.50 value at the Nav1.7 channel to determine the selectivity of a given compound for Nav1.7 vs Nav1.5.

[0877] Solubility Data

[0878] Aqueous solubility data were generated via a “shake-flask” method where an excess of compound was added to a buffer (typically phosphate buffered saline at pH 7.4) and shaken for a period of 18 hours at room temperature. After this time any excess solid was removed by double centrifugation to obtain a saturated aqueous solution. The amount of compound solubilised was quantified by HPLC-UV or LC-MS against a standard calibration curve.

[0879] The solubility of the compounds of Examples 12, 15, 17 and 18 was assessed using the above method.

[0880] The solubility data generated are set out below. Where a greater than figure is quoted, all available compound was solubilised and saturation was not achieved in the conditions employed.

TABLE-US-00002 Ex No. pH Solubility/μg/mL  6 5.0 >2300 7.5 <500  7 7.2 0.5 12 7.5 612 15 7.5 110 17 7.4 >2300  18b 7.4 >10000 19 7.5 >3 21 7.5 56 26 7.5 3 29 7.0 <0.5