Dual inhibitors of adipocyte fatty acid binding protein and keratinocyte fatty acid binding protein

2,3-Bis[(2-chlorophenyl)methoxy]-α-hydroxybenzeneacetic acid

To a stirred slurry of 2,3-dihydroxybenzaldehyde (6.91 g, 50.0 mmol) and potassium carbonate (17.2 g, 125 mmol) in EtOH (60 mL) at room temperature under argon was added 2-chlorobenzyl chloride (15 mL, 120 mmol). The reaction mixture was heated to reflux for 16 h, then cooled and poured into water (150 mL). The resulting solids were collected, washed with water, air-dried and recrystallized from methanol to give the title compound as white needles (16.28 g, 71% yield), mp 98-100° C. LC/MS gave the correct molecular ion [(M+H) + =387] for the desired compound.

To a stirred solution of part A compound (5.01 g, 12.9 mmol) in CH 2 Cl 2 (50 mL) at room temperature under argon was added trimethylsilylcyanide (1.725 mL, 12.9 mmol) and triethylamine (200 μL, 1.4 mmol). The resulting yellow solution was stirred for 3 h and then evaporated. The residuum was then dissolved in EtOH (25 mL) and trimethylsilyl chloride (25 mL) was added. The colorless solution was heated to 50° C. for 48 h. The solution was cooled, evaporated and the residuum was stirred rapidly for 1 h with CH 2 Cl 2 (50 mL), EtOH (25 mL) and saturated sodium bicarbonate solution (50 mL). The mixture was partially evaporated to remove the ethanol and the remainder partitioned with CH 2 Cl 2 . The organic extract was dried (MgSO 4 ) and evaporated. Purification by flash chromatography (5×25 cm column, 1:49 Et 2 O/CH 2 Cl 2 ) provided the title compound as a colorless oil which slowly solidified (4.97 g, 84% yield), mp 47-49° C. LC/MS gave the correct molecular ion [(M+H) + =461] for the desired compound.

A solution of part B compound (1.40 g, 3.03 mmol) in THF (10 mL) was stirred at room temperature under argon, as 1 M NaOH solution (5 mL, 5.0 mmol) was added. After 24 h, the reaction mixture was diluted with water (20 mL) and extracted twice with Et 2 O. The aqueous phase was acidified with 1 M hydrochloric acid (5.5 mL, 5.5 mmol), extracted twice with CH 2 Cl 2 , the extracts dried (MgSO 4 ) and evaporated. A portion of the resulting gummy solid (1.10 g) was dissolved in Et 2 O (20 mL) and extracted once with 0.1 M sodium hydroxide solution (23 mL, 2.3 mmol). The aqueous layer was purged with nitrogen gas for 15 min and then lyophilized to give the title compound as a white powder, 988 mg, 87% yield. LC/MS gave the correct molecular ion [(M+H) + =433] for the desired compound as its free acid.

α(R)-2,3-Bis[(2-chlorophenyl)methoxy]-α-hydroxybenzeneacetic acid

To a stirred slurry of Example 1, Part B compound (1.334 g, 2.89 mmol), N-t-butyloxycarbonyl-(S)-proline (646 mg, 3.00 mmol), triethylamine (210 μL, 1.5 mmol) and DMAP (122 mg, 1.0 mmol) in CH 2 Cl 2 (10 mL) at room temperature under argon was added N-Ethyl N′,N′-diisoproylaminoethyl carbodiimide (573 mg, 3.0 mmol). After 16 h, the reaction mixture was diluted with CH 2 Cl 2 and washed once with 5% potassium hydrogren sulfate solution. The organic phase was dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography (5×25 cm column, 1.5 L 1:24 Et 2 O/CH 2 Cl 2 , then 1:16 Et 2 O/CH 2 Cl 2 ) gave two fractions. The first product to elute was the title compound as a colorless oil. LC/MS gave the correct molecular ion [(M+H) + =659] for the desired compound.

To a stirred solution of part A compound (2.18 g, 3.30 mmol) in dioxane (10 mL) at room temperature under argon was added KOH solution (10.0 mL, 1 M, 10.0 mmol). The resulting solution was heated to 70° C. for 4 h and then cooled to room temperature. After acidifying with 5% potassium hydrogen sulfate solution, the reaction mixture was extracted twice with CH 2 Cl 2 . The extracts were combined, washed once with brine, dried (MgSO 4 ) and evaporated. The oily residue was dissolved in 4 N HCl/dioxane (10 mL), stirred under argon for 2 h and then evaporated and re-evaporated twice from hexanes. The residual oil was dissolved in ether (10 mL) and washed twice with water (10 mL) and then extracted with 0.1 M NaOH (30.0 mL, 3.00 mmol). The aqueous layer was frozen and lyophilized to provide the title compound as a white powder, 1.30 g (100% yield). LC/MS gave the correct molecular ion [(M+H) + =433] for the desired compound. Chiral purity was determined by chromatography of the methyl ester (prepared from a 3 mg sample of the title compound using trimethylsilyl-diazomethane in Et 2 O/CH 3 OH) on a normal-phase OD column (hexane/isopropanol as the elutent). Optical purity was determined to be 96.7%.

α(S) -2,3-Bis[(2-chlorophenyl)methoxy]-α-hydroxybenzeneacetic acid

To a stirred slurry of Example 1, Part B compound (1.334 g, 2.89 mmol), N-t-butyloxycarbonyl-(S)-proline (646 mg, 3.00 mmol), triethylamine (210 μL, 1.5 mmol) and DMAP (122 mg, 1.0 mmol) in CH 2 Cl 2 (10 mL) at room temperature under argon was added N-Ethyl N′,N′-diisoproylaminoethyl carbodiimide (573 mg, 3.0 mmol). After 16 h, the reaction mixture was diluted with CH 2 Cl 2 and washed once with 5% potassium hydrogren sulfate solution. The organic phase was dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography (5×25 cm column, 1.5 L 1:24 Et 2 O/CH 2 Cl 2 , then 1:16 Et 2 O/CH 2 Cl 2 ) gave two fractions. The first product to elute was Example 2 Part C compound. The second was the title compound as a colorless oil. LC/MS gave the correct molecular ion [(M+H) + =659] for the desired compound.

To a stirred solution of part A compound (2.56 g, 3.90 mmol) in dioxane (10 mL) at room temperature under argon was added KOH solution (10.0 mL, 1 M, 10.0 mmol). The resulting solution was heated to 70° C. for 4 h and then cooled to room temperature. After acidifying with 5% potassium hydrogen sulfate solution, the reaction mixture was extracted twice with CH 2 Cl 2 . The extracts were combined, washed once with brine, dried (MgSO 4 ) and evaporated. The oily residue was dissolved in 4 N HCl/dioxane (10 mL), stirred under argon for 2 h and then evaporated and re-evaporated twice from hexanes. The residual oil was dissolved in ether (10 mL) and washed twice with water (10 mL) and then extracted with 0.1 M NaOH (33.0 mL, 3.30 mmol). The aqueous layer was frozen and lyophilized to provide the title compound as a white powder, 1.50 g (100% yield). LC/MS gave the correct molecular ion [(M+H) + =433] for the desired compound. Chiral purity was determined by chromatography of the methyl ester (prepared from a 3 mg sample of the title compound using trimethylsilyl-diazomethane in Et 2 O/CH 3 OH) on a normal-phase OD column (hexane/isopropanol as the elutent). Optical purity was determined to be 96.5%.

2-(E)-3-[2,3-Bis[(2-chlorophenyl)methoxy]phenyl]-2-propenoic acid

To a stirred solution of triethyl phosphonoacetate (561 mg, 2.50 mmol) in THF (5.0 mL) at room temperature under argon was added sodium hydride (60% mineral-oil dispersion, 96 mg, 2.4 mmol). The reaction mixture was warmed to 50° C. for 1 h and then cooled to room temperature. Example 1 Part A compound (775 mg, 2.00 mmol) was added in one portion. The resulting mixture was stirred for 30 min, quenched with saturated sodium bicarbonate solution and extracted with CH 2 Cl 2 . The organic extract was dried (MgSO 4 ) and evaporated. Recrystallization from CH 2 Cl 2 /hexanes gave title compound as a white solid (715 mg, 78% yield), mp 95-97° C. LC/MS gave the correct molecular ion [(M+H) + =457] for the desired compound.

To a stirred solution of part A compound (700 mg, 1.53 mmol) in THF (3 mL) at room temperature under argon was added NaOH solution (3.0 mL, 1 M, 3.0 mmol). The resulting solution was heated to 50° C. for 14 h and then cooled to room temperature. After acidifying with 1 M HCl, the resulting solids were collected, washed with water and air-dried to provide the title compound as a white solid, 648 mg (99% yield), mp 187-189° C. LC/MS gave the correct molecular ion [(M+H) + =430] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]benzeneacetic acid

To a stirring slurry Example 1 Part A compound (1.00 g, 2.58 mmol) in EtOH (10 mL) at room temperature was added powdered sodium borohydride (100 mg, 2.6 mmol) over 1 min. The resulting mixture was stirred for 16 h, quenched with saturated sodium bicarbonate solution (20 mL) and stirred 20 min. The resulting solids were collected, washed with water and air-dried to give the title compound as a white solid (930 mg, 93% yield), mp 102-104° C. LC/MS gave the correct molecular ion [(M+H) + =389] for the desired compound.

To a stirred solution of part A compound (930 mg, 2.4 mmol) in CH 2 Cl 2 (10 mL) at 0° C. under argon was added phosphorous tribromide solution (5.0 mL, 1 M in CH 2 Cl 2 , 5.0 mmol) over 1 min. The resulting solution was warmed to room temperature. After 3 h, the reaction was quenched with saturated sodium bicarbonate solution (20 mL) and then treated with solid sodium bicarbonate to bring to pH 7. The mixture was extracted twice with EtOAc, dried (MgSO 4 ) and evaporated to provide the title compound as a white amorphous solid, 1.05 g (97% yield). LC/MS gave the correct molecular ion [(M+H) + =451] for the desired compound.

To a stirred solution of part B compound (875 mg, 1.94 mmol) in DMSO (8 mL) at room temperature under argon was added potassium cyanide (1.30 g, 20 mmol). The resulting solution was warmed to 65° C. After 3 h, the reaction was quenched with water and the resulting gummy solid was collected, washing with water. The solid was dissolved in CH 2 Cl 2 , washed with water, dried (MgSO 4 ) and evaporated. Purification by flash chromatography provided the title compound as a light yellow amorphous solid, 343 mg (44% yield). LC/MS gave the correct molecular ion [(M+H) + =398] for the desired compound.

To a stirred solution of part C compound (340 mg, 0.85 mmol) in EtOH (4 mL) at room temperature under argon was added chlorotrimethylsilane (4 mL). The resulting solution was warmed to 50° C. After 34 h, the reaction was cooled to room temperature and evaporated. The residue was stirred vigorously with saturated sodium bicarbonate solution (10 mL) for 30 min and then extracted three times with CH 2 Cl 2 . The extracts were combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography provided the title compound as a colorless oil, 223 mg (59% yield). LC/MS gave the correct molecular ion [(M+H) + =445] for the desired compound.

To a stirred solution of part D compound (220 mg, 0.49 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.5 mL, 1.0 M, 1.5 mmol). The resulting solution was heated to 50° C. for 15 h. The reaction mixture was cooled, diluted with water (3 mL) and extracted once with Et 2 O. The aqueous phase was acidified with 1 N HCl to pH 2 and extracted twice with CH 2 Cl 2 . The CH 2 Cl 2 extracts were combined, dried (MgSO 4 ) and concentrated to ˜2 mL. Hexanes were added, the flask scratched and the resulting white solid was collected and air-dried to give the title compound as a white solid, 198 mg, 94% yield, mp 105-107° C. LC/MS gave the correct molecular ion [(M+H) + =417] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]benzeneacetic acid Alternative Synthesis

To a stirred solution of Example 1 Part A compound (1.94 g, 5.00 mmol) and methylthiomethyl methylsulfoxide (0.58 mL, 5.6 mmol) in THF (5 mL) at room temperature under argon was added Triton-B (0.5 mL, 40% in MeOH). The resulting solution was heated to gentle reflux for 16 h and then evaporated and re-evaporated twice from hexanes. The residue was purified by flash chromatography to give the thioketene S-oxide as a colorless oil, 2.06 g (83% yield).

This oil was dissolved in MeOH (100 mL) and HCl gas was bubbled into the solution as the temperature rose to 66° C. before subsiding to room temperature. After 30 min more, the reaction was evaporated and re-evaporated from CH 2 Cl 2 . Purification by flash chromatography gave the title compound as a white solid, 1.66 g, 93% yield. LC/MS gave the correct molecular ion [(M+H) + =431] for the desired compound.

By the method of Example 5 Part E, Part A compound (1.00 g, 2.32 mmol) was hydrolyzed to give the title compound as a white solid, 964 mg, 100% yield, mp 105-107° C.

[[2,3-Bis[(2-chlorophenyl)methoxy]phenyl]methyl]propanedioic acid

To a stirred solution of Example 5 Part A compound (1.00 g, 2.57 mmol) and triphenylphosphine (674 mg, 2.57 mmol) in THF (2.5 mL) at room temperature under argon was added carbon tetrachloride (15 mL) and the reaction heated to 50° C. After 24 h, the reaction evaporated and purified by flash chromatography to provide the title compound as a white solid, 517 mg (49% yield), mp 96-98° C. LC/MS gave the correct molecular ion [(M+H) + =407] for the desired compound.

To a stirred slurry of sodium hydride (60% mineral oil dispersion, 75 mg, 1.88 mmol) in THF (5 mL) at room temperature under argon was added a solution of diethyl malonate (300 μL, 2.0 mmol) in THF (5 mL). After 30 min, a solution of Part A compound (500 mg, 1.23 mmol) in THF (2 mL) was added in one portion. After 14 h, the reaction mixture was quenched with 5% potassium hydrogen sulfate solution and extracted twice with EtOAc. The organic extracts were combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 524 mg (80% yield). LC/MS gave the correct molecular ion [(M+H) + =531] for the desired compound.

A stirred mixture of part B compound (520 mg, 0.99 mmol) in potassium hydroxide solution (246 mg, 4.4 mmol in 4 mL of water) was heated to reflux under argon for 24 h. The reaction mixture was cooled, diluted with water (3 mL) and extracted once with Et 2 O. The aqueous phase was brought to pH 2 with 3 N HCl and the resulting solids filtered, washed with water and air-dried to give the title compound as a white solid, 365 mg (77% yield), mp 148-150° C. (dec). LC/MS gave the correct molecular ion [(M+H) + =475] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]benzenepropanoic acid

Example 7 Part C compound (256 mg, 0.54 mmol) was heated to 155° C. at a pressure of 1 Torr for 3 h. The reaction mixture was cooled and recrystallized directly from hexanes/toluene to provide the title compound as a white solid (225 mg, 97% yield), mp 131-132° C. LC/MS gave the correct molecular ion [(M+H) + =431] for the desired compound.

2,3-Bis[(2-chlorophenoxy)methyl]benzoic acid

To a stirred solution of methyl 2,3-dimethylbenzoate (1.75 g, 10.7 mmol) in carbon tetrachloride (35 mL) under argon was added freshly recrystallized N-bromosuccinimide (3.90 g, 21.9 mmol) and AIBN (50 mg). The reaction mixture was heated to reflux under argon for 4 h and then cooled and filtered. Evaporation gave a yellow oil, 3.53 g, predominantly methyl 2,3-bis(bromomethyl)benzoate.

To a stirred solution of 2-chlorophenol (2.83 g, 22.0 mmol) in DMF (20 mL) at room temperature under argon was added sodium hydride (60% mineral oil dispersion, 880 mg, 22 mmol) over 5 min. The resulting clear solution was stirred 30 min and a solution in DMF (5 mL) of the dibromide prepared above was added. After 14 h, the reaction mixture was quenched with water and extracted three times with Et 2 O. The extracts were combined and washed twice with water, once with brine, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a white solid, 2.03 g (46% yield), mp 107-109° C. LC/MS gave the correct molecular ion [(M+H) + =417] for the desired compound.

To a solution of Part A compound (270 mg, 0.647 mmol) in EtOH (2 mL) at room temperature under argon was added sodium hydroxide solution (2.0 mL, 1 M, 2.0 mmol). The mixture was heated to 50° C. for 1 h. The reaction mixture was cooled, diluted with water (3 mL) and extracted once with Et 2 O. The aqueous phase was brought to pH 2 with 1 N HCl and the resulting solids filtered, washed with water and air-dried to give the title compound as a white solid, 238 mg (91% yield), mp 172-174° C. LC/MS gave the correct molecular ion [(M+H) + =403] for the desired compound.

3-[(2-Chlorophenoxy)methyl]-2-[(2-chlorophenyl)methoxy]benzoic acid

To a stirred solution of 2-bromophenol (3.42 g, 19.8 mmol) in DMF (10 mL) under argon was added propargyl bromide (80% in toluene, 4.12 g, 27.7 mmol) and potassium carbonate (3.80 g, 27.5 mmol). The reaction mixture was stirred for 90 min, then diluted with water and extracted twice with Et 2 O. The extracts were combined, washed once with water, three times with 1 M NaOH (25 mL portions) and once with brine, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 3.93 g (94% yield). LC/MS gave the correct molecular ion [(M+H) + =211] for the desired compound.

A stirred slurry of Part A compound (3.00 g, 14.2 mmol) and cesium fluoride (3.02 g, 20 mmol) in N,N-diethylaniline (24 mL) under argon was heated to 210° C. for 4 h. The reaction mixture was then cooled, diluted with hexanes and washed three times with 1 M HCl (100 mL portions). The organic phase was dried (MgSO 4 ) and evaporated. Purification by flash chromatography (hexanes as the elutant) provided the title compound as a colorless oil, 1.94 g (67% yield). LC/MS gave the correct molecular ion [(M+H) + =211] for the desired compound.

A stirred solution of Part B compound (1.94 g, 9.19 mmol) in CH 2 Cl 2 (100 mL) protected from atmospheric moisture by a calcium chloride drying tube was cooled to −78° C. and a 3% O 3 /O 2 gas mixture is bubbled through the solution until a blue color persists (˜35 min). The solution was purged with nitrogen gas and then dimethylsulfide (5 mL) was added and the reaction allowed to warm to room temperature. After 4 h, the solution was evaporated and the residue redissolved in MeOH (8 mL) to which was added water (8 mL) and potassium carbonate (1.1 g, 80 mmol). The mixture was heated to 55° C. under argon for 1 h and then cooled, neutralized with 1 M potassium hydrogen sulfate to pH 7 and extracted twice with CH 2 Cl 2 . The organic extracts were combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography provided the title compound as a light yellow crystalline solid, 1.47 g (80% yield). LC/MS gave the correct molecular ion [(M+H) + =201] for the desired compound.

To a solution of Part C compound (638 mg, 3.17 mmol) in DMF (10 mL) at room temperature under argon was added sodium hydride (60% mineral oil dispersion, 140 mg, 3.5 mmol). After 20 min, 2-chloro-benzyl chloride (0.50 mL, 4.0 mmol) and tetrabutylammonium iodide (200 mg, 0.5 mmol) was added and the reaction was heated to 60° C. After 14 h the reaction mixture was cooled, diluted with Et 2 O and washed once with 5% potassium hydrogen sulfate solution, twice with water, once with brine, dried (MgSO 4 ) and evaporated. Purification by flash chromatography provided the title compound as a white solid, 734 mg (71% yield), mp 96-98° C. LC/MS gave the correct molecular ion [(M+H) + =325] for the desired compound.

To a solution of Part D compound (672 mg, 2.06 mmol) in CH 2 Cl 2 (10 mL) at room temperature under argon was added diisobutylaluminum hydride solution (1 M in toluene, 2.3 mL, 2.3 mmol). After 1 h, the reaction mixture was quenched with 1 M potassium sodium tartrate solution (4 mL) and stirred for 1 h. The reaction mixture was extracted twice with EtOAc. The organic extracts were combined, dried (MgSO 4 ) and evaporated to provide the title compound as a white solid, 675 mg (100% yield). LC/MS gave the correct molecular ion [(M+H) + =327] for the desired compound.

To a solution of Part E compound (407 mg, 1.24 mmol) in CH 2 Cl 2 (5 mL) at 0° C. under argon was added phosphorous tribromide solution (1 M in CH 2 Cl 2 , 2.5 mL, 2.5 mmol). After 15 min, the reaction mixture was warmed to room temperature for 1 h and then diluted with CH 2 Cl 2 , washed once with water, once with saturated sodium bicarbonate solution and once with brine. The organic extract was dried (MgSO 4 ) and evaporated. The product was unstable and therefore used immediately by dissolving in DMF (1 mL) and adding to a solution prepared from 2-chlorophenol (0.2 mL, 1.3 mmol) and sodium hydride (60% mineral oil dispersion, 50 mg, 1.25 mmol) in DMF (3 mL) at room temperature under argon. The reaction mixture was stirred for 16 h. The reaction was quenched with water and extracted three times with hexanes. The hexanes extracts were combined, washed once with water, dried (MgSO 4 ) and evaporated. Purification by flash chromatrography on silica gel provided the title compound as a colorless oil, 115 mg (21% yield). LC/MS gave the correct molecular ion [(M+H) + =437] for the desired compound.

To a solution of Part F compound (110 mg, 0.25 mmol) in methanol (1.5 mL) and DMF (2 mL) was added Pd(OAc) 2 (12 mg, 0.05 mmol), dppf (21 mg, 0.05 mmol) and triethylamine (70 μL, 0.5 mmol). The stirred solution was purged twice with carbon monoxide gas and then heated under a CO-filled balloon at 80° C. After 18 h, the reaction mixture was cooled, diluted with water and brought to pH 3 with 10% aqueous potassium hydgrogen sulfate. The mixture was extracted twice with ether and the organic extract dried (MgSO 4 ). Flash chromatography on silica gel gave the title compound as a colorless oil, 51 mg (49% yield). LC/MS gave the correct molecular ion [(M+H) + =417] for the desired compound.

To a solution of Part G compound (50 mg, 0.12 mmol) in THF (1 mL) at room temperature under argon was added sodium hyroxide solution (1 mL, 1 M, 1 mmol). After 14 h, the solution was acidified (1 M HCl) and partially evaporated. The resulting solids were filtered, washed with water and air-dried to give the title compound as a white solid, 45 mg, 93% yield, mp 172-174° C. LC/MS gave the correct molecular ion [(M+H) + =403] for the desired compound.

Alternate Synthesis of Example 10

3-[(2-Chlorophenoxy)methyl]-2-[(2-chlorophenyl)methoxy]benzoic acid

To a solution of Example 10 Part F compound (208 mg, 0.474 mmol) in THF (4 mL) at −78° C. under argon was added n-butyllithium solution (200 μL, 2.5 M in hexane, 0.5 mmol) over 10 min. After 3 h, dry carbon dioxide gas was bubbled into the reaction mixture as the reaction was allowed to warm to room temperature. After 1 h at room temperature, the reaction mixture was quenched with 1 M NaOH (1 mL, 1 mmol) and extracted twice with hexanes. The aqueous phase was brought to pH 2 with 1 N HCl and the resulting solids filtered, washed with water and air-dried to give the title compound as a white solid, 16.5 mg (9% yield), mp 172-174° C. LC/MS gave the correct molecular ion [(M+H) + =403] for the desired compound.

α-Amino-2,3-bis[(2-chlorophenyl)methoxy]benzeneacetic acid

To a stirred solution of Example 1 Part B compound (1.009 g, 2.19 mmol) in CH 2 Cl 2 (20 mL) under argon at room temperature was added a solution prepared from benzotriazole (570 mg, 4.8 mmol) and thionyl chloride (570 mg, 4.8 mmol) in CH 2 Cl 2 (5 mL) over 2 min. The reaction mixture was stirred for 90 min, then diluted with water and extracted twice with CH 2 Cl 2 . The extracts were combined, washed once with water, once with 0.5 M NaOH (25 mL) and once with brine, dried (MgSO 4 ) and evaporated. The residuum was immediately dissolved in DMF (8 mL), treated with sodium azide (570 mg, 8.8 mmol) and stirred at room temperature under argon for 1 h. The reaction mixture was quenched with water and extracted twice with Et 2 O. The extracts were combined, washed twice with water, once with brine dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 657 mg (62% yield). LC/MS gave the correct molecular ion [(M+H) + =486] for the desired compound.

A stirred solution of Part A compound (652 mg, 1.34 mmol) under argon at room temperature in THF (4 mL) was treated with triphenylphosphine (352 mg, 1.34 mmol). After 15 h, the reaction mixture was evaporated and re-evaporated twice from hexanes to give the title compound as a colorless oil, 965 mg (100% yield). LC/MS gave the correct molecular ion [(M+H) + =720] for the desired compound.

To a stirred solution of Part B compound (880 mg, 1.22 mmol) in THF (8 mL) at room temperature under argon was added sodium hydroxide solution (2.5 mL, 1 M, 2.5 mmol). After 14 h, the solution was diluted with water and extracted once with CH 2 Cl 2 . The aqueous phase was cooled and the resulting precipitate was filtered. The filtrate was lyophilized and the residue was purified by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, MeOH/water-TFA elutant) to give the title compound as its trifluoroacetic acid salt, 450 mg (82% yield). LC/MS gave the correct molecular ion [(M+H) + =432] for the desired compound as its free base.

α-(Acetylamino)-2,3-bis[(2-chlorophenyl)methoxy]benzeneacetic acid

A stirred slurry of Example 1 Part A compound (4.00 g, 10.33 mmol) in MeOH (10 mL) saturated with ammonia gas under argon at 40-45° C. was treated with additional ammonia gas for 1 h. The slurry was cooled to 5° C. and trimethylsilylcyanide (2.1 mL, 15.7 mmol) was added over 10 min. The temperature was then raised to 45° C. as a yellow solution formed. After 7 h, the reaction mixture was evaporated, re-dissolved in EtOH (60 mL) and hydrogen chloride gas was used to saturate the solution. After 14 h, the reaction mixture was treated with thionyl chloride (0.8 mL) and warmed to 55° C. for 2 h. The solution was cooled to room temperature, evaporated and the resulting solids triturated in Et 2 O to give the title compound as an orange solid, usable without further purification.

To a stirred solution of Part A compound (197 mg, 0.4 mmol) under argon at room temperature in THF (2 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and acetic anhydride (60 μL, 0.6 mmol). After 15 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 167 mg (83% yield). LC/MS gave the correct molecular ion [(M+H) + =502] for the desired compound.

To a stirred solution of Part B compound (167 mg, 0.33 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.5 mL, 1 M, 0.5 mmol). After 14 h, the solution was diluted with water and extracted once with Et 2 O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as a white amorphous solid, 104 mg (55% yield). LC/MS gave the correct molecular ion [(M+H) + =474] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]-α-[(2-methyl-1-oxopropyl)amino]benzeneacetic acid

To a stirred solution of Example 13 Part A compound (197 mg, 0.4 mmol) under argon at 0-5° C. in THF (1.5 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and isobutyryl chloride (65 μL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and after 15 h, it was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 156 mg (74% yield). LC/MS gave the correct molecular ion [(M+H) + =530] for the desired compound.

To a stirred solution of Part B compound (155 mg, 0.29 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.5 mL, 1 M, 0.5 mmol). After 24 h, the solution was diluted with water and extracted once with Et 2 O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as a white amorphous solid, 156 mg (100% yield). LC/MS gave the correct molecular ion [(M+H) + =502] for the desired compound.

α-(Benzoylamino)-2,3-bis[(2-chlorophenyl)methoxy]benzeneacetic acid

To a stirred solution of Example 13 Part A compound (197 mg, 0.4 mmol) under argon at 0-5° C. in THF (1.5 mL) was added triethylamine (0.2 mL, 1.6 mmol), DMAP (2 mg, 0.02 mmol) and benzoyl chloride (70 μL, 0.6 mmol). The reaction mixture was allowed to warm to room temperature and after 15 h, it was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 161 mg (71% yield). LC/MS gave the correct molecular ion [(M+H) + =564] for the desired compound.

To a stirred solution of Part B compound (160 mg, 0.28 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.5 mL, 1 M, 0.5 mmol). After 24 h, the solution was diluted with water and extracted once with Et 2 O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as a tan amorphous solid, 142 mg (95% yield). LC/MS gave the correct molecular ion [(M+H) + =536] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]-α-[(difluoroacetyl)amino]benzeneacetic acid

To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH 2 Cl 2 (2.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and difluoroacetic acid (48 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 156 mg (64% yield). LC/MS gave the correct molecular ion [(M+H) + =538] for the desired compound.

To a stirred solution of Part B compound (153 mg, 0.28 mmol) in THF (1.5 mL) at room temperature under argon was added a solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in water (1 mL). After 24 h, the solution was diluted with water and extracted once with Et 2 O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as an off-white amorphous solid, 144 mg (100% yield). LC/MS gave the correct molecular ion [(M+H) + =510] for the desired compound.

α-[(aminoacetyl)amino]-2,3-bis[(2-chlorophenyl)methoxy]benzeneacetic acid hydrochloride

To a stirred solution of N-t-butyloxycarbonyl glycine under argon at −5° C. in THF (2 mL) was added triethylamine (60 μL, 0.5 mmol) and then isobutyl chloroformate (67 μL, 0.52 mL). The resulting slurry was stirred 20 min and a solution of Example 13 Part A compound (222 mg, 0.45 mmol) and triethylamine (70 μL, 0.6 mmol) in THF (1 mL) was added over 1 min. The reaction was allowed to warm to room temperature and stirred. After 1 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 102 mg (37% yield). LC/MS gave the correct molecular ion [(M+H) + =617] for the desired compound.

To a stirred solution of Part B compound (102 mg, 0.17 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (0.3 mL, 1 M, 0.3 mmol). After 20 h, the reaction mixture was acidified to pH 2 with 1 N HCl and extracted with CH 2 Cl 2 . The extract was dried (MgSO 4 ), evaporated and then stirred with 4 N HCl/dioxane (1 mL) for 4 h. The solution was evaporated, the residue triturated with Et 2 O and collected to provide the title compound as an off-white amorphous solid, 90 mg (100% yield). LC/MS gave the correct molecular ion [(M+H) + =489] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]-α-[(methoxyacetyl)amino]benzeneacetic acid

To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH 2 Cl 2 (1.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and methoxyacetic acid (46 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 153 mg (74% yield). LC/MS gave the correct molecular ion [(M+H) + =518] for the desired compound.

To a stirred solution of Part B compound (153 mg, 0.29 mmol) in THF (2 mL) at room temperature under argon was added a solution of lithium hydroxide monohydrate (13 mg, 0.32 mmol) in water (1 mL). After 24 h, the solution was diluted with water and extracted once with Et 2 O. The aqueous phase was cooled, acidified to pH 2 with 1 N HCl and the resulting precipitate was filtered, washed with water and air-dried to give the title compound as an off-white amorphous solid, 120 mg (82% yield). LC/MS gave the correct molecular ion [(M+H) + =504] for the desired compound.

[2,3-Bis[(2-chlorophenyl)methoxy]phenyl]propanedioic acid

To a stirred solution of diisopropylamine (160 μL, 1.14 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (0.43 mL, 2.5 M in hexanes, 1.08 mmol). After 15 min, a solution of Example 5 Part E compound (209 mg, 0.5 mmol) in THF (1 mL) was added over 2 min. After 40 min, dry CO 2 gas was bubbled through the solution for 20 min. The reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO 4 ) and evaporated. Purification by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−0.1% TFA gradient) provided the title compound as a light yellow oil, 164 mg (71% yield). LC/MS gave the correct molecular ion [(M+H) + =461] for the desired compound.

[[2,3-Bis[(2-chlorophenyl)methoxy]phenyl]methyl]-α-(hydroxymethyl)benzeneacetic acid

To a stirred solution of diisopropylamine (160 μL, 1.14 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (0.43 mL, 2.5 M in hexanes, 1.08 mmol). After 15 min, the reaction mixture was cooled to −78° C. and a solution of Example 5 Part E compound (209 mg, 0.5 mmol) in THF (1 mL) was then added over 2 min. After an additional 15 min, DMPU was added (2 mL) and the solution warmed to 0° C. Formaldehyde gas (by the pyrolysis of paraformaldehyde [300 mg, 10 mmol] at 190° C.) was introduced to the reaction mixture by a gas inlet tube. The reaction mixture was stirred for 1 h, diluted with EtOAc, washed once with 5% potassium hydrogen sulfate, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel (1:39:360 HOAc/MeOH/CH 2 Cl 2 as elutent) provided the title compound as a white solid, 136 mg (61% yield). LC/MS gave the correct molecular ion [(M+H) + =447] for the desired compound.

3-[1-(2-Chlorophenyl)ethoxy]-2-[(2-chlorophenyl)methoxy]-α-hydroxybenzeneacetic acid

To a stirred solution of diisopropylamine (170 μL, 1.21 mmol) under argon at −5° C. in THF (3 mL) was added n-butyllithium solution (483 μL, 2.5 M in hexanes, 1.21 mmol). After 15 min, the reaction mixture was cooled to −78° C. and a solution of Example 1 Part B compound (248 mg, 0.537 mmol) in THF (1 mL) was then added over 2 min. After an additional 15 min, DMPU was added (2 mL) and then methyl iodide (42 μL, 0.68 mmol). The reaction mixture was stirred for 2 h and then warmed to −40° C. After 14 h, the reaction was quenched with sodium hydroxide solution (1 M), warmed to room temperature and stirred for 1 h. The reaction mixture was acidified with 5% potassium hydrogen sulfate, extracted with CH 2 Cl 2 , dried (MgSO 4 ) and evaporated. Purification by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−0.1% TFA gradient) provided the title compound, a colorless oil, as a 1:1 mixture of diastereomers, 75 mg (31% yield). LC/MS gave the correct molecular ion [(M+H) + =447] for the desired compound.

2,3-Bis[(2-chlorophenoxy)methyl]-α-hydroxybenzeneacetic acid

To a stirred solution of 2,3-dimethylbenzoic acid (1.50 g, 10 mmol) in CH 2 Cl 2 (10 mL) under argon at room temperature was added oxalyl chloride solution (8.0 mL, 2 M in CH 2 Cl 2 , 16 mmol) and then DMF (0.2 mL). After 2 h, the solution was evaporated and re-evaporated twice from CH 2 Cl 2 and then dissolved in CH 2 Cl 2 (10 mL). This solution was added, over 30 min, to a stirred slurry of N-methoxy-N-methylammonium chloride (1.10 g, 11 mmol), DMAP (5 mg, 0.04 mmol) and triethylamine (3.0 mL, 21.4 mmol) in CH 2 Cl 2 (15 mL) at 10° C. After the addition was complete, the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then diluted with CH 2 Cl 2 , washed once with 10% citric acid, once with water and once with brine. The organic extract was dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 1.38 g (71% yield). LC/MS gave the correct molecular ion [(M+H) + =194] for the desired compound.

To a stirred solution of part A compound (1.32 g, 6.83 mmol) in carbon tetrachloride (20 mL) under argon was added freshly recrystallized N-bromosuccinimide (3.10 g, 13.7 mmol) and AIBN (50 mg). The reaction mixture was heated to reflux under argon for 3 h and then cooled and filtered. Purification by flash chromatography on silica gel provided predominantly N-methoxy-N-methyl 2,3-bis(bromomethyl) benzamide as a colorless oil, 1.08 g (45% yield).

To a stirred solution of 2-chlorophenol (1.06 mL, 10.2 mmol) in DMF (10 mL) at room temperature under argon was added sodium hydride (60% mineral oil dispersion, 385 mg, 9.6 mmol) over 5 min. The resulting clear solution was stirred 30 min and a solution in DMF (5 mL) of the dibromide prepared above was added and the reaction mixture heated to 65° C. After 1 h, the reaction mixture was quenched with water and extracted three times with Et 2 O. The extracts were combined and washed twice with water, once with brine, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a light yellow oil, 1.11 g (83% yield). LC/MS gave the correct molecular ion [(M+H) + =446] for the desired compound.

To a solution of Part B compound (2.56 g, 5.75 mmol) in THF (30 mL) at −78° C. under argon was added diisobutylaluminum hydride solution (7.6 mL, 1.5 M in toluene, 11.4 mmol) over 10 min. The reaction was stirred for 1 h and then warmed to room temperature and stirred for 2 h. The reaction mixture was then quenched with water (2 mL) and then stirred with potassium sodium tartrate solution (20 mL, 1 M) for 1 h. The mixture was extracted twice with EtOAc, the organic phases combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a white solid, 1.58 g (71% yield), mp 101-103° C. LC/MS gave the correct molecular ion [(M+H) + =387] for the desired compound.

By the method of Example 1 Part B, Part C compound (532 mg, 1.37 mmol) was converted to the title compound as an amorphous white solid, 425 mg (67% yield). LC/MS gave the correct molecular ion [(M+H) + =461] for the desired compound.

By the method of Example 1 Part C, Part D compound (413 mg, 0.90 mmol) was converted to the title compound as a white powder, 410 mg (100% yield). LC/MS gave the correct molecular ion [(M+H) + =433] for the desired compound as the protonated acid.

2,3-Bis[(2-chlorophenyl)methoxy]-α-mercaptobenzeneacetic acid

To a stirred solution of Example 1 Part B compound (462 mg, 1.00 mmol) in CH 2 Cl 2 (5 mL) under argon at room temperature was added thionyl chloride (80 μL, 1.1 mmol) and then DMF (80 μL, 1.0 mmol) over 2 min. The reaction mixture was stirred for 1 h, then quenched with saturated sodium bicarbonate solution and extracted twice with CH 2 Cl 2 . The extracts were combined, dried (MgSO 4 ) and evaporated. The residuum was immediately dissolved in EtOH (5 mL) and added to a solution prepared from thiolacetic acid (0.35 mL, 4.9 mmol) and potassium t-butoxide (539 mg, 4.8 mmol) in EtOH (5 mL). After 16 h, the reaction mixture was quenched with water and extracted three times with EtOAc. The organic extracts were combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 330 mg (64% yield). LC/MS gave the correct molecular ion [(M+H) + =519] for the desired compound.

To a stirred solution of part A compound (330 mg, 0.64 mmol) in nitrogen-purged THF (5 mL) at room temperature was added sodium hydroxide solution (3.0 mL, 1 M, 3.0 mmol). After 24 h, the reaction was quenched with 10% citric acid and extracted twice with EtOAc. The extracts were combined, dried (MgSO 4 ) and evaporated to provide predominantly the title compound as a colorless oil, 255 mg (89% yield). LC/MS gave the correct molecular ion [(M+H) + =894] for the desired compound.

To a solution of Part B compound (52 mg, 0.058 mmol) in THF (2 mL) and water (2 mL) at room temperature under argon was added tributylphosphine (50 μL, 0.2 mmol). The reaction was stirred for 5 min and then purified directly by reverse phase preparative HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/water−TFA elutant) to give the title compound as a colorless oil, 32 mg, 62% yield. LC/MS gave the correct molecular ion [(M+H) + =449] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]-α-fluorobenzeneacetic acid

To a stirred solution of Example 1 Part B compound (461 mg, 1.00 mmol) in CH 2 Cl 2 (10 mL) under argon at 0° C. was added a solution of diethylaminosulfur trifluoride [DAST] (265 μL, 2.0 mmol) in CH 2 Cl 2 (5 mL) over 20 min. The reaction mixture was stirred for an additional 45 min, then quenched with saturated sodium bicarbonate solution and extracted twice with CH 2 Cl 2 . The extracts were combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a light yellow oil, 218 mg (47% yield). LC/MS gave the correct molecular ion [(M+H) + =463] for the desired compound.

To a stirred solution of part A compound (218 mg, 0.47 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature under argon was added sodium hydroxide solution (2.0 mL, 1 M, 2.0 mmol). After 14 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 5% potassium hydrogen sulfate solution. The resulting solids were collected, washed with water and air-dried to give the title compound as a white solid, 202 mg (98% yield), mp 92-94° C. LC/MS gave the correct molecular ion [(M+H) + =435] for the desired compound.

3-[(2-Chlorophenyl)methoxy]-2-hydroxybenzoic acid ethyl ester

To a stirred solution of trifluoroacetic acid (200 mL) and trifluoroacetic anhydride (100 mL) at −4° C. was added 2,3-dihydroxybenzoic acid (20.0 g, 130 mmol) over 5 min. To this slurry was added acetone (34 mL, 460 mmol) over the course of 1 h. After an additional 3 h, the reaction was allowed to warm to room temperature in situ and stirred 4 h. The resulting solution was evaporated and the resulting residue poured into ice water (300 mL). Solid sodium bicarbonate was added portionwise until the solution reached ˜pH 9. The gummy residue was extracted into EtOAc (300 mL) and the aqueous phase was extracted twice with EtOAc. The extracts were combined, washed once with brine, dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound 9.87 g (39% yield). LC/MS gave the correct molecular ion [(M+H) + =197] for the desired compound.

To a stirred solution of part A compound (3.0 g, 15.4 mmol) in DMF (26 mL) at room temperature under argon was added 2-chlorobenzyl chloride (2.3 mL, 18.2 mmol), potassium carbonate (3.2 g, 23 mmol) and tetrabutylammonium iodide (57 mg, 0.15 mmol). The mixture was heated to 50° C. and stirred for 2 h. After cooling to room temperature, the reaction was filtered through Celite® and poured into Et 2 O (250 mL). The solution was washed three times with water and once with brine. After drying (Na 2 SO 4 ) and evaporation, the title compound was isolated and used in part C without further purification (5.47 g, >100% yield).

To a stirred solution of part B compound (5.47 g, ˜15.4 mmol) in THF (100 mL) at room temperature under argon was added a 25% solution of sodium ethoxide in ethanol (4.5 mL, 16 mmol) and the mixture was stirred at room temperature for 1 h. The mixture was then diluted with water (400 mL) and ethyl acetate (400 mL). The suspension was treated with 50 mL of 1 N hydrochloric acid and the organic fraction was washed with brine, dried (MgSO 4 ) and evaporated to an oil (4.65 g, 85% yield.

2,3-Bis[(2-chlorophenyl)methoxy]-α-oxobenzeneacetic acid

To a stirred solution of Example 1 Part B compound (400 mg, 0.867 mmol) in DMSO (1 mL) at 90° C. was added acetic anhydride (0.1 mL, 1 mmol) over 1 h. After an additional 3 h, the reaction mixture was cooled, diluted with water and extracted three times with ether. The organic extracts were combined, washed with brine, dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound, 382 mg (96% yield). LC/MS gave the correct molecular ion [(M+Na) + =481] for the desired compound.

To a stirred solution of Part A compound (67 mg, 0.15 mmol) in THF (0.3 mL) at room temperature under argon was added sodium hydroxide solution (0.3 mL, 1 M, 0.3 mmol). After 18 h, the reaction mixture was diluted with water and extracted three times with ether. The aqueous layer was cooled to 5° C., acidified to pH 3 with 1 M hydrochloric acid and extracted three times with ether. The acidicified organic extracts were combined, dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid, 55 mg (86% yield), mp 116-118° C. LC/MS gave the correct molecular ion [(M+H) + =431] for the desired compound.

2,3-Bis[(2-chlorophenyl)methoxy]-α,α-difluorobenzeneacetic acid

To a stirred solution of Example 26 Part A compound (256 mg, 0.557 mmol) in CH 2 Cl 2 (100 μL) under argon at room temperature was added DAST (160 μL, 1.2 mmol). The reaction mixture was stirred for 22 h, the reaction mixture was quenched with water and extracted three times with CH 2 Cl 2 . The organic extracts were combined, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a white solid, 197 mg (74% yield), mp 55-57° C. LC/MS gave the correct molecular ion [(M+H) + =481] for the desired compound.

To a stirred solution of part A compound (195 mg, 0.41 mmol) in THF (2 mL) at room temperature under argon was added sodium hydroxide solution (0.6 mL, 1 M, 0.6 mmol). After 15 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 5% potassium hydrogen sulfate solution. The resulting solids were collected, washed with water and air-dried to give the title compound as a white solid, 168 mg (92% yield), mp 113-115° C. LC/MS gave the correct molecular ion [(M+H) + =453] for the desired compound.

EXAMPLES 28-336

Sealable reaction vessels were each charged with potassium carbonate (32 mg, 0.23 mmol), tetrabutylammonium iodide (˜1 mg) and DMF (244 μL). A solution of Example 25 Part C compound (489 μL, 0.2 M in DMF, 0.0978 mmol) and of R-X (0.147 mmol, 0.2 M in THF) was added and the reaction vessels were agitated and heated to 60° C. After 14 h, the reactions were cooled to room temperature and EtOH (2 mL) was added to each reaction, followed by a solution of sodium hydroxide in ethanol (733 μL, 0.3 M, 0.2 mmol). The reactions were heated again at 60° C. for 5 h and cooled to room temperature. The contents of each reaction vessel were diluted with MeOH (˜2 mL) and purified by reverse phase preparative HPLC (YMC S5 ODS 20×100 mm column, MeOH/water-TFA elutant) to give the title compound. Mass spectrometric and HPLC data were collected for all compounds.

Following the above procedure, the following compounds of the invention were prepared:

2,3-Bis[(2-chlorophenyl)methoxy]-α-methoxybenzeneacetic acid

To a stirred solution of Example 1 Part B compound (112 mg, 0.243 mmol) in DME (1 mL) under argon at room temperature was added sodium hydride (60% mineral oil dispersion, 9.7 mg, 0.24 mmol). After 30 min, methyl iodide (15 μL, 0.24 mmol) was added, the reaction mixture was stirred for 18 h and then diluted with saturated ammonium chloride solution. The mixture was extracted three times with Et 2 O. The organic extracts were combined, washed once with water, once with brine, dried (MgSO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 67 mg (58% yield). LC/MS gave the correct molecular ion [(M+H) + =475] for the desired compound.

To a stirred solution of part A compound (65 mg, 0.14 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). After 15 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et 2 O. The acidified organic extracts were combined, washed with water, brine, dried (Na 2 SO 4 ) and evaporated to give the title compound as a colorless oil, 49 mg (80% yield). LC/MS gave the correct molecular ion [(M+H) + =447] for the desired compound.

(E)-2,3-Bis[(2-chlorophenyl)methoxy]-α-(hydroxyimino)benzeneacetic acid and (Z)-2,3-Bis[(2-chlorophenyl)methoxy]-α-(hydroxyimino)benzeneacetic acid

To a stirred solution of Example 26 Part B compound (105 mg, 0.23 mmol) in EtOH (1 mL) under argon at room temperature was added sodium acetate (20.6 mg, 0.25 mmol) and hydroxylamine hydrochloride (17.3 mg, 0.25 mmol). The reaction mixture was heated to reflux for 3 h, cooled, diluted with EtOH and filtered. The filtrate was evaporated and water (5 mL) was added to give a gummy solid. The solid was dissolved in Et 2 O, washed with water, brine, dried (Na 2 SO 4 ) and evaporated title compound as a 5:4 mixture of geometric isomers, colorless oil, 100 mg (93% yield). LC/MS gave the correct molecular ion [(M+H) + =474] for the desired compound.

To a stirred solution of part A compound (100 mg, 0.22 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). After 15 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et 2 O. The acidified organic extracts were combined, washed with water, brine, dried (Na 2 SO 4 ) and evaporated. Purification by reverse phase HPLC (YMC S5 ODS 20×250 mm column, acetonitrile/ water−0.1% TFA gradient) gave the title compounds as separate white amorphous solids, both geometric isomers of the oxime. LC/MS gave the correct molecular ion [(M+H) + =446] for each of the desired compounds.

(E)-2,3-Bis[(2-chlorophenyl)methoxy]-α-(methoxyimino)benzeneacetic acid and (Z)-2,3-Bis[(2-chlorophenyl)methoxy]-α-(methoxyimino)benzeneacetic acid

To a stirred solution of Example 26 Part B compound (105 mg, 0.23 mmol) in EtOH (1 mL) under argon at room temperature was added sodium acetate (20.6 mg, 0.25 mmol) and methoxylamine hydrochloride (20.8 mg, 0.25 mmol). The reaction mixture was heated to reflux for 17 h, and additional portions of sodium acetate and methoxylamine hydrochloride were added and the reaction refluxed for an additional 5 h. The mixture was cooled, diluted with EtOH and filtered. The filtrate was evaporated and water (5 mL) was added to give a gummy solid. The solid was dissolved in Et 2 O, washed with water, brine, dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compounds: Isomer A (first eluting) as colorless oil, 49 mg (44% yield) and Isomer B as a colorless oil, 34 mg, 34%. LC/MS gave the correct molecular ion [(M+H) + =478] for each of the desired compounds.

(E or Z)-2,3-Bis[(2-chlorophenyl)methoxy]-α-(methoxyimino)benzeneacetic acid

To a stirred solution of Example 339 (Isomer A) compound (49 mg, 0.1 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). The reaction was heated to 50° C. After 16 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et 2 O. The acidified organic extracts were combined, washed with water, brine, dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid, 37 mg, (80% yield), mp 140-141° C. LC/MS gave the correct molecular ion [(M+H) + =460] for the desired compound.

(E or Z)-2,3-Bis[(2-chlorophenyl)methoxy]-α-(methoxyimino)benzeneacetic acid

To a stirred solution of Example 339 (Isomer B) compound (37 mg, 0.075 mmol) in THF (1 mL) at room temperature under argon was added sodium hydroxide solution (1.0 mL, 1 M, 1.0 mmol). The reaction was heated to 50° C. After 16 h, the reaction was diluted with water and extracted once with ether. The aqueous phase was brought to pH 2 with 1 M hydrochloric acid and extracted three times with Et 2 O. The acidified organic extracts were combined, washed with water, brine, dried (Na 2 SO 4 ) and evaporated to provide the title compound as a white solid, 32 mg, (91% yield), mp 97-99° C. LC/MS gave the correct molecular ion [(M+H) + =460] for the desired compound.

3-[(2-chlorophenyl)methoxy]-2-(cyclohexylmethoxy)-α-hydroxybenzeneacetic acid

To a stirred slurry of sodium hydride (60% mineral oil dispersion, 3.68 g, 92 mmol) in DMSO (40 mL) at room temperature under argon was added a solution of 2,3-dihydroxybenzaldehyde (5.53 g, 40.0 mmol) in DMSO (20 mL). After 1 h, a solution of 2-chlorobenzylchloride (5.05 mL, 40.0 mmol) in DMSO (10 mL) was added, the reaction mixture was stirred for 60 h and then diluted with water. The mixture was extracted three times with Et 2 O. The organic extracts were combined, washed once with water, once with brine, dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography on silica gel provided the title compound, 5.6 g (53% yield). LC/MS gave the correct molecular ion [(M+H) + =263] for the desired compound.

To a stirred solution of part A compound (1.31 g, 5.00 mmol) in EtOH (15 mL) at room temperature under argon was added potassium carbonate (1.04 g, 7.5 mmol) and then cyclohexylmethyl bromide (0.98 mL, 7.0 mmol). After 16 h at reflux, the reaction was diluted with water, extracted with CH 2 Cl 2 , dried (Na 2 SO 4 ) and evaporated. Purification by flash chromatography gave the title compound as a colorless oil, 400 mg (22% yield). LC/MS gave the correct molecular ion [(M+H) + =359] for the desired compound.

By the method of Example 1, Part B compound (340 mg, 0.95 mmol) was converted to the title compound as a white amorphous solid, 170 mg, 47% yield. LC/MS gave the correct molecular ion [(M+H) + =405] for the desired compound.

3-[(2-chlorophenyl)methoxy]-α-hydroxy-2-[(2-methoxyphenyl)methoxy]benzeneacetic acid

By the method of Example 342 Part B, but using 2-methoxybenzyl chloride in place of cyclohexylmethyl bromide, the title compound was prepared. LC/MS gave the correct molecular ion [(M+H) + =383] for the desired compound.

By the method of Example 1, Part A compound (110 mg, 0.29 mmol) was converted to the title compound as a white amorphous solid. LC/MS gave the correct molecular ion [(M+H) + =429] for the desired compound.

3-[(2-Chlorophenyl)methoxy]-α-hydroxy-2-(4-pyridinylmethoxy)benzeneacetic acid

By the method of Example 342 Part B, but using the free base of 4-picolyl chloride in place of cyclohexylmethyl bromide, the title compound was prepared. LC/MS gave the correct molecular ion [(M+H) + =354] for the desired compound.

By the method of Example 1, Part A compound (581 mg, 1.54 mmol) was converted to the title compound as a white solid, mp 181-183° C. LC/MS gave the correct molecular ion [(M+H) + =400] for the desired compound.

2,3-Bis[(3,5-dichlorophenyl)methoxy]benzoic acid

A solution of 2,3-dihydroxybenzoic acid (3.00 g, 19.46 mmol) and 96% sulfuric acid (3 mL, 55 mmol) in methanol (60 mL) at room temperature under argon was stirred for 1 h. The reaction mixture was heated to reflux for 16 h, then cooled, concentrated to half the volume and poured into water (150 mL) and ethyl acetate (150 mL). The organic fraction was washed with water, aqueous NaHCO 3 solution, dried (MgSO 4 ) and concentrated to give the title compound as a white solid (2.90 g, 89%). mp 77-78° C. LC/MS gave the correct molecular ion [(M−H) − =167] for the desired compound.

To a stirred solution of part A compound (0.17 g, 1.00 mmol) in DMF (13 mL) at room temperature under argon was added K 2 CO 3 (1.10 g, 8.00 mmol), tetrabutylammonium iodide (0.05 g, 0.14 mmol) and 3,5-dichlorobenzyl chloride (0.78 g, 4.00 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 1.5 h. The mixture was cooled, filtered through a pad of Celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO 4 and concentrated. The title compound was then crystallized from 1:9 THF/methanol to give the title compound as a white solid (0.25 g, 51%), mp 150-151° C.

A solution of part B compound (0.12 g, 0.25 mmol) in a THF:methanol (3 mL:0.5 mL) solution was stirred at room temperature under argon, as 10 M NaOH solution (0.05 mL, 0.5 mmol) was added. After 4 h, the reaction mixture was concentrated and diluted with water (5 mL). The mixture was acidified to pH=1 with 1N HCl and the white solid collected (0.10 g, 85%). LC/MS gave the correct molecular ion [(M−H) − =471 − ] for the title compound. mp 219-220° C.

EXAMPLES 346-352

The following compounds were prepared according to the methods outlined in Example A, utilizing 2,4-dichlorobenzyl chloride, 2-chlorobenzyl chloride, 3-chlorobenzyl chloride, 4-chlorobenzyl chloride, 3,5-bis(trifluoromethyl)benzyl chloride, 2,5-dimethylbenzyl chloride, and 3,5-dimethylbenzyl chloride.

2-[(2,4-Dichlorophenyl)methoxy]-3-(phenylmethoxy)benzoic acid

For preparation of part A compound, see example 25 part A.

To a stirred solution of part A compound (0.19 g, 1.00 mmol) in DMF (5 mL) at room temperature under argon was added K 2 CO 3 (0.27 g, 2.00 mmol) and benzyl bromide (0.14 mL, 1.20 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO 4 and concentrated. The crude compound was triturated with hot hexane to give the title compound (0.20 g, 70%) as an off white solid. MS gave the correct molecular ion [(M+H) + =285+] for the desired compound.

To a stirred solution of part B compound (0.14 g, 0.50 mmol) in THF (10 mL) at room temperature under argon was added a 25% solution of sodium methoxide in methanol (0.15 mL, 0.69 mmol) and the mixture was stirred at RT for 1 h. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The suspension was treated with 2 mL of 1 N HCl solution and the organic fraction was washed with HCl solution, brine, dried over MgSO 4 and concentrated to an oil (0.13 g, 96%). MS gave the correct molecular ion [(M+H) + =259+] for the desired compound.

To a stirred solution of part C compound (0.05 g, 0.20 mmol) in DMF (2 mL) at room temperature under argon was added K 2 CO 3 (0.11 g, 0.80 mmol), tetrabutylammonium iodide (3 mg, catalyst) and 2,4-dichlorobenzyl chloride (0.06 mL, 0.40 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO 4 and concentrated. The crude compound was crystallized from hot hexane to give the title compound (0.06 g, 72%) as a white solid. MS gave the correct molecular ion [(M+H) + =417+] for the desired compound.

A solution of part D compound (0.05 g, 0.12 mmol) in a THF:methanol (1 mL:1 mL) solution was stirred at room temperature under argon, as 10 M NaOH solution (0.1 mL, 1.00 mmol) was added. After 4 h, the reaction mixture was concentrated and diluted with water (5 mL). The mixture was acidified to pH=1 with 1N HCl and the white solid collected (0.03 g, 60%). LC/MS gave the correct molecular ion [(M−H) − =401 − ] for the title compound. mp 140-142° C.

3-[(2,4-Dichlorophenyl)methoxy]-2-(phenylmethoxy)benzoic acid

To a stirred solution of Example 25 part A compound (0.19 g, 1.00 mmol) in DMF (5 mL) at room temperature under argon was added K 2 CO 3 (0.28 g, 2.00 mmol), tetrabutylammonium iodide (17 mg, catalyst) and 2,4-dichlorobenzyl chloride (0.17 mL, 1.20 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO 4 and concentrated. The crude compound was triturated with hexane to give the title compound (0.23 g, 65%) as a white solid. MS gave the correct molecular ion [(M+H) + =353+] for the desired compound.

To a stirred solution of part A compound (0.18 g, 0.50 mmol) in THF (10 mL) at room temperature under argon was added a 25% solution of sodium methoxide in methanol (0.15 mL, 0.65 mmol) and the mixture was stirred at RT for 1 h. The mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The suspension was treated with 2 mL of 1 N HCl solution and the organic fraction was washed with HCl solution, brine, dried over MgSO 4 and concentrated to an off white solid (0.15 g, 92%). MS gave the correct molecular ion [(M+H) + =327+] for the desired compound.

To a stirred solution of part B compound (0.10 g, 0.30 mmol) in DMF (3 mL) at room temperature under argon was added K 2 CO 3 (0.17 g, 1.20 mmol), and benzyl bromide (0.07 mL, 0.60 mmol). The mixture was stirred at RT for 0.5 h and then at 60° C. for 4 h. The mixture was cooled, filtered through a pad of celite and poured into diethyl ether. The ether fraction was washed with brine, dried over MgSO 4 and concentrated. The crude compound was purified by flash column chromatography on silica gel with ethyl acetate:hexane 7:93 to give the title compound (0.11 g, 93%) as a white solid. mp 166-168° C.

A solution of part C compound (0.03 g, 0.07 mmol) in a THF:methanol (1 mL:1 mL) solution was stirred at room temperature under argon, as 10 M NaOH solution (0.06 mL, 0.60 mmol) was added. After 4 h, the reaction mixture was concentrated and diluted with water (5 mL). The mixture was acidified to pH=1 with 1N HCl and the white solid collected (0.02 g, 71%). LC/MS gave the correct molecular ion [(M−H) − =401 − ] for the title compound. mp 151-153° C.

5-Bromo-2,3-bis[(2-chlorophenyl)methoxy]benzoic acid

A solution of 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1.03 g, 4.33 mmol) and sulfamic acid (563 mg, 5.78 mmol) in THF:H 2 O (1:2, 15.9 mL) was treated dropwise with a solution of sodium hypochlorite (519 mg, 4.59 mmol) in water (2.6 mL) and the resulting orange solution stirred at room temperature for 3.0 h. The mixture was treated with 5 % KHSO 4 (6.6 mL), extracted with EtOAc (2×70 mL) and the organic phase was washed with brine (14 mL), dried (MgSO 4 ) and concentrated to give a light brown solid. Trituration of the crude product with CH 2 Cl 2 :hexane (1:1, 10 mL) and hexane (10 mL) gave the title compound as a light brown solid (753 mg, 70%), mp 195-198° C. LC/MS gave the correct molecular ion [(M−H) − =245] for the desired compound.

A cooled (0° C.) solution of part A compound (753 mg, 3.05 mmol) in dry CH 2 Cl 2 (9.0 mL) was treated with 1.0 M BBr 3 /CH 2 Cl 2 (6.2 mL, 6.1 mmol), stirred at 0° C. for 3.0 h then allowed to come up to room temperature overnight (J. Med. Chem. 1995, 38, 4937-4943). The reaction mixture was quenched by the dropwise addition of water (19 mL), stirred for 30 min then extracted with EtOAc (3×100 mL). The extracts were washed with water (3×20 mL), brine (20 mL) and dried (MgSO 4 ) to give the title compound as a light brown solid (626 mg, 88%), mp 211-213° C. LC/MS gave the correct molecular ion [(M−H) − =231] for the desired compound.

A mixture of thionyl chloride (0.35 mL, 4.8 mmol) and methanol (5.4 mL) was stirred at room temperature for 30 min then treated with part B compound (600 mg, 2.57 mmol). The reaction mixture was stirred at room temperature for 2.0 hr. refluxed for 7.0 hr, cooled and concentrated to a brown solid. Purification by column chromatography (2.5×25 cm column, 1:4 EtOAc/hexane, then 1:1 EtOAc) gave the title compound (500 mg, 78%).

To a mixture of part C compound (205 mg, 0.83 mmol), potassium carbonate (900 g, 6.64 mmol) and Bu 4 NI (cat) in dry DMF (3.4 mL) was added 2-chlorobenzylchloride (0.42 mL, 3.32 mmol). The reaction mixture was heated at 60° C. for 4 hr and partitioned between water (25 mL) and Et 2 O (3×60 mL). The organic extracts were washed with water (3×25 mL) and brine (25 mL) and dried (MgSO 4 ) to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as a white solid (392 mg, 95%), mp 100-101° C.

A solution of part D compound (387 mg, 0.78 mmol) in THF:CH 3 OH (1:1, 3.0 mL) was treated with 10.0 N sodium hydroxide (0.17 mL, 1.7 mmol) and stirred at room temperature for 18 h. The mixture was concentrated and the solids obtained were suspended in water (5.0 mL), acidified to pH 1 with 1.0 N hydrochloric acid (2.1 mL) and extracted with EtOAc (2×60 mL). The organic phase was washed with water (3×5.0 mL) and brine (5.0 mL), dried (MgSO 4 ) and concentrated to give a white solid. Trituration of the solid with CH 2 Cl 2 (4.0 mL) and hexane (25 mL) gave the title compound as a white solid (346 mg, 92%), mp 186-187° C. LC/MS gave the correct molecular ion [(M−H) − =479] for the desired compound.

5-Bromo-2,3-bis(phenylmethoxy)benzoic acid

Example 356 was prepared by the method of Example 355. The title compound was obtained as a white solid (128 mg, 94%), mp 151-153° C. LC/MS gave the correct molecular ion [(M+H) + =413] for the desired compound.

EXAMPLES 357-372

The following compounds were prepared according to the methods outlined in Example 345.

6-Bromo-2,3-bis[(2-chlorophenyl)methoxy]benzoic acid

A cooled (0° C.) solution of 2,3-dimethoxybenzoic acid (1.0 g, 5.5 mmol) in 1.4 M NaOH (8.63 mL, 12.1 mmol) was treated portionwise with N-bromosuccinimide (1.185 g, 6.59 mmol), brought to room temperature and stirred for 48.0 hr (Tet. Lett, 1993, 34 (6), 931-934). The mixture was quenched with 5% NaHSO 3 solution (30 mL), acidified with 12 N hydrochloric acid to pH 1 and extracted with Et 2 O (2×50 mL). The organic phase was washed with H 2 O (3×10 mL) and brine (10 mL), dried (MgSO 4 ) and concentrated to give the title compound as a syrup (1.43 g, 100%).

A cooled (0° C.) solution of part A compound (1.43 g, 5.49 mmol) in dry dichloromethane (6.0 mL) was treated with 1.0 M BBr 3 /CH 2 Cl 2 (11.0 mL, 11.0 mmol), stirred at 0° C. for 3.0 h then allowed to come up to room temperature overnight (J. Med. Chem. 1995, 38, 4937-4943). The reaction mixture was quenched by the dropwise addition of water (35 mL) followed by 1.0 N hydrochloric acid (70 mL), stirred for 15 min then extracted with EtOAc (3×100 mL). The extracts were washed with water (2×50 mL), brine (25 mL) and dried (MgSO 4 ) to give the title compound as a solid (1.163 g, 91%). LC/MS gave the correct molecular ion [(M−H) − =231] for the desired compound.

A mixture of thionyl chloride (0.60 mL, 8.2 mmol) and methanol (10.0 mL) was stirred at room temperature for 30 min then treated with part B compound (1.15 g, 4.94 mmol). The reaction mixture was stirred at room temperature for 1 h, refluxed for 7 h, cooled and concentrated to a brown solid. Purification by column chromatography (2.5×25 cm column, 1:9 EtOAc/hexane, then 1:4 EtOAc/hexane) gave the title compound (550 mg, 45%). LC/MS gave the correct molecular ion [(M−H) − =245] for the desired compound.

To a mixture of part C compound (200 mg, 0.83 mmol), potassium carbonate (900 mg, 6.64 mmol) and Bu 4 NI (cat) in dry DMF (3.4 mL) was added 2-chlorobenzyl chloride (0.42 mL, 3.32 mmol) (J. Med. Chem. 1997, 40, 105-111). The reaction mixture was heated at 60° C. for 4 h and partitioned between water (25 mL) and Et 2 O (3×60 mL). The organic extracts were washed with water (3×25 mL) and brine (25 mL) and dried (MgSO 4 ) to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as a clear thick syrup (421 mg, 100%).

A solution of part D compound (421 mg, 0.83 mmol) in 1:1:1 THF/CH 3 OH/H 2 O (11 mL) was treated with 10.0 N sodium hydroxide (0.58 mL, 5.8 mmol) and stirred at room temperature for 24 h and then refluxed for 48 h. The mixture was concentrated and the solids obtained were suspended in water (6.0 mL), acidified to pH 1.0 with 1.0 N hydrochloric acid and extracted with EtOAc (2×65 mL). The organic phase was washed with water (3×6.0 mL) and brine (6.0 mL), dried (MgSO 4 ) and concentrated to give a white solid. Trituration of the solid with CH 2 Cl 2 (5 mL) and hexane (25 mL) gave the title compound as a white solid (335 mg, 94%), mp 156-158° C. LC/MS gave the correct molecular ion [(M−H) − =479] for the desired compound.

6-Bromo-2,3-bis(phenylmethoxy)benzoic acid

Example 374 was prepared using the method of Example 373. The title compound was obtained as a white solid (65 mg, 65%), mp 164-166° C. LC/MS gave the correct molecular ion [(M+H) + =415] for the desired compound.

2-(Benzoylamino)-3-(phenylmethoxy)benzoic acid

To a stirred mixture of methanol (55 mL) and thionyl chloride (3.19 mL, 43.7 mmol) was added 3-hydroxy-2-nitrobenzoic acid (5.0 g, 27.3 mmol). The reaction mixture was stirred at room temperature for 2 h, refluxed for 7 h then evaporated. Purification by flash chromatography (2.5×10 cm column, 1:3 EtOAc/hexane) gave the title compound as a light yellow solid (5.03 g, 93% yield), mp 114-116° C. LC/MS gave the correct molecular ion [(M−H) − =196] for the desired compound.

A mixture of part A compound (1.0 g, 5.07 mmol) and potassium carbonate (700 mg, 5.07 mmol) in dry DMF (10 mL) was treated with benzyl bromide (992 mg, 5.8 mmol) and heated at 100° C. for 2 h. The mixture was concentrated and partitioned between EtOAc (3×50 mL) and water (10 mL). The organic phase was washed with H 2 O (3×10 mL) and brine (10 mL), dried (MgSO 4 ) and evaporated. Purification by flash chromatography (2.5×25 cm column, 1:4 EtOAc/hexane) provided the title compound as a white solid (1.32 g, 91% yield), mp 96-98° C.

A solution of part B compound (6.12 g, 21.3 mmol) in glacial HOAc (120 mL) was cooled to 0° C., treated with zinc powder (13.71 g, 210 mmol), brought to room temperature and stirred for 2 h (J. Med. Chem. 1997, 40, 105-111). The mixture was filtered, washing the powder with glacial HOAc (25 mL), and the reddish-brown solution concentrated and re-evaporated several times with toluene. The crude product was partitioned between water (40 mL) and CH 2 Cl 2 (2×150 mL) followed by extraction with EtOAc (150 mL). The organic extracts were washed with water (2×40 mL) and brine (40 mL), dried (MgSO 4 ) and concentrated to a syrup. Purification by flash chromatography (2.5×10 cm column, 1:9 EtOAc/hexane, then 1:4 EtOAc/hexane) gave the desired compound as a white solid (3.36 g, 87%), mp 81-82° C. LC/MS gave the correct molecular ion [(M+H) + =258] for the title compound.

To a solution of part C compound (300 mg, 1.17 mmol) in dry CH 2 Cl 2 (6.0 mL) was added dry pyridine (119 mg, 1.5 mmol) followed by a solution of benzoyl chloride (181 mg, 1.29 mmol) in dry CH 2 Cl 2 (6.0 mL) (J. Med. Chem 1994, 37, 4251-4257). The reaction mixture was stirred at room temperature for 19 h, diluted with CH 2 Cl 2 (13 mL) and washed with 1.0 N hydrochloric acid (2.0 mL). The aqueous phase was back-extracted with CH 2 Cl 2 (25 mL) and the organic fractions were washed with 5% sodium bicarbonate solution (2.0 mL), water (2×2.0 mL) and brine (2.0 mL), dried (MgSO 4 ) and concentrated to a white solid. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/Hexane, then 1:4 EtOAc/Hexane) gave the title compound as a white solid (357 mg, 85%), mp 126-128° C.

A solution of part D compound (100 mg, 0.28 mmol) in dry CH 3 OH (5.0 mL) was treated with 1.0 N sodium hydroxide solution (0.8 mL) and stirred at room temperature for 5.0 h, then heated to reflux for 30 min. The solution was concentrated and the crude product dissolved in water (2.0 mL), acidified to pH 1 with 1.0 N hydrochloric acid (0.9 mL) and extracted with EtOAc (3×10 mL). The organic extracts were washed with water (3×2 mL) and brine (2 mL), dried (MgSO 4 ) and concentrated to give the title compound as a white solid (96.9 mg, 100%), mp 167-168° C. LC/MS gave the correct molecular ion [(M+H) + =348 ] for the desired compound.

EXAMPLES 376-391

The following compounds were prepared according to the methods outlined in Example 375.

3-[(2-Chlorobenzoyl)amino]-2-[(2-chlorophenyl)methoxy]benzoic acid

A mixture of thionyl chloride (1.15 mL, 15.8 mmol) and methanol (20.0 mL) was stirred at room temperature for 30 min then treated with 3-amino-2-hydroxybenzoic acid (1.5 g, 9.79 mmol). The reaction mixture was stirred at room temperature for 2 h, refluxed for 20 h, cooled and concentrated. The crude product was partitioned between EtOAc (100 mL) and 5% NAHCO 3 solution (65 mL), back-extracting the aqueous phase with EtOAc (4×100 mL). The organic phase was washed with water (2×20 mL) and brine (20 mL), dried (MgSO 4 ), filtered and concentrated to give a dark red solid (381 mg, 19%).

To a solution of part A compound (381 mg, 1.9 mmol) and dry pyridine (0.18 mL) in dry CH 2 Cl 2 (11.0 mL) was added 2-chlorobenzoylchloride (0.29 mL, 2.18 mmol) (J. Med. Chem. 1994, 37, 4251-4257). The reaction mixture was stirred at room temperature for 24 h and then partitioned between 1.0 N hydrochloric acid (3.0 mL) and CH 2 Cl 2 (2×25 mL). The organic phase was washed with water (2×3.0 mL) and brine (3 mL), dried (MgSO 4 ) and concentrated to give a semi-solid. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/hexane) gave the title compound as an off-white solid (569 mg, 99%). LC/MS gave the correct molecular ion [(M+H) + =306] for the desired compound.

A mixture of part B compound (100 mg, 0.33 mmol), potassium carbonate (92 mg, 0.66 mmol) and Bu 4 NI (˜5 mg) in dry dimethyformamide (1.5 mL) was treated with 2-chlorobenzylchloride (0.05 mL, 0.43 mmol) and stirred at 60° C. for 3 h. The mixture was concentrated and the slurry partitioned between water (2.0 mL) and EtOAc (2×20 mL). The organic phase was washed with water (2×2.0 mL) and brine (2 mL), dried (MgSO 4 ) and concentrated to give a syrup. Purification by flash chromatography (2.5×25 cm column, 1:9 EtOAc/Hexane) gave the title compound as a clear syrup (125 mg, 88%).

A solution of part C compound (125 mg, 0.29 mmol) in CH 3 OH (4.7 mL) was treated with 1.0 N sodium hydroxide solution (0.8 mL, 0.8 mmol) and refluxed for 2 h. The mixture was concentrated and the solids were dissolved in water (2.0 mL), acidified with 1.0 N hydrochloric acid (0.89 mL) to pH 1 and partitioned between water (2 mL) and EtOAc (2×50 mL). The organic phase was washed with water (2×4.0 mL) and brine (4.0 mL), dried (MgSO 4 ) and concentrated to give the title compound as a white solid (125 mg, 100%), mp 182-183° C. LC/MS gave the correct molecular ion [(M+H) + =418] for the desired compound.

3-[(2-Chlorobenzoyl)amino]-2-[(4-methoxyphenyl)methoxy]benzoic acid

Example 393 was prepared by the method of Example 392. The title compound was obtained as a white solid (47 mg, 88%), mp 115-117° C. This compound was acid-labile and an LC/MS or HPLC could not be obtained.

EXAMPLES 394-571

The compounds of examples 394-571 were prepared as part of a solid-phase library run using the following procedure.

To a stirred suspension of sodium hydride (60% mineral oil dispersion, 10.5 g, 0.263 mol) in DMF (100 mL) at 4° C. was added a solution of 2-methoxy-4-hydroxy-benzaldehyde (40.0 g, 0.263 mol) in DMF (200 mL) over 2 h. The reaction mixture was warmed to room temperature and stirred for 1 h, whereupon tetrabutylammonium iodide (13.0 g, 35.2 mmol) and Merrifield polystyrene resin (100 g, 1.24 mmol chloride/g, 124 mmol) was added in two batches. The reaction mixture was heated to 61° C. for 19 h. The resulting solid was collected and washed with the following sequence: five times with 1:1 DMF-water, five times with DMF, once with DMF-water, once with DMF, three times with THF, once with methanol and once with THF. The solids were dried in vacuum at room temperature to constant weight to give the title compound (117.1 g). Elemental analysis showed a residual chloride content of 0.15% by weight. The calculated loading was 1.084 mmol/g.

To an agitated suspension (at 150 rpm) of Part A resin (53.3 g, 57.6 mmol) in THF (150 mL) and ethanol (150 mL) at room temperature was added solid sodium borohydride (11.48 g, 317 mmol). After 20 h, the resulting solid was collected and washed with the following sequence: four times with 1:1 DMF-water, three times with DMF, four times with 1:19 acetic acid/THF, twice with THF and four times with dichloromethane. The solids were dried in vacuum at room temperature to constant weight to give the title compound (52.35 g).

To a solution of triphenylphosphine (45.3 g, 173 mmol) in CH 2 Cl 2 (200 mL) at 4° C. was added triphosgene (46.6 g, 173 mmol) portionwise over 30 min. After an additional 10 min, the reaction mixture was warmed to room temperature and stirred for 30 min. The reaction mixture was evaporated re-evaporated once from CH 2 Cl 2 and the resulting solid redissolved in CH 2 Cl 2 (90 mL). This solution was added to an agitated suspension (at 150 rpm) of Part B resin (35.0 g, 37.9 mmol) in CH 2 Cl 2 (150 mL). After 3 h, the resulting solid was collected and washed twice with anhydrous DMF. The washed solid was suspended in DMF (200 mL) and 3-hydroxy-2-nitro-benzoic acid (17.0 g, 92.8 mmol), sodium bicarbonate (11.23 g, 139 mmol) and tetra-n-butylammonium iodide (1.4 g, 3.8 mmol) were added and the mixture agitated at 150 rpm. After 40 h, the solid was collected and washed five times with 1:1 DMF/water followed by DMF, then four times with THF and four times with CH 2 Cl 2 . Drying in vacuum at room temperature to constant weight gave the title compound (38.83 g).

A suspension of Part C resin (1.0 g, 0.91 mmol), finely ground potassium carbonate (1.26 g, 9.1 mmol), tetrabutylammonium iodide (100 mg, 0.9 mmol) and R 2 —X (4.6 mmol) in DMF (11.5 mL) at 68° C. was agitated at 300 rpm. After 33 h, the solid was washed four times with 1:1 DMF/water, then four times with DMF and four times with THF (15 mL portions). Drying in vacuum at room temperature to constant weight gave the title compounds. The following R 2 —X were included: (1-bromoethyl)benzene, benzyl bromide, 2-bromobenzyl bromide, α-bromo-o-xylene, α-bromo-m-xylene, α-bromo-p-xylene, 4-bromobenzyl bromide, 4-(trifluoromethyl) benzyl bromide, 3-chlorobenzyl bromide, 2-chlorobenzyl chloride, 2,4-dichlorobenzyl chloride, 4-methoxybenzyl chloride, 4-benzyloxybenzyl chloride, 4-biphenylmethyl chloride, 2-chloroacetophenone, 2,2′,4′-trichloroacetophenone, 1-iodobutane, bromomethylcyclo-hexane, 1-(chloromethyl)naphthalene, 2-(bromomethyl) naphthalene, 2,4′-dichloroacetophenone, 4-chlorobenzyl bromide, 3-phenoxybenzyl chloride and 3-methoxybenzyl bromide.

A suspension of Part D resin in THF (10 mL) was agitated at 270 rpm and then water (4.4 mL) was added, followed by potassium carbonate (1.26 g, 9.1 mmol), tetrabutylammonium hydroxide solution (0.60 mL, 1.53 M, 0.9 mmol) and sodium hydrosulfite (3.12 g, 18.2 mmol). After 76 h, the solid was washed six times with 1:1 DMF/water, then four times with DMF, three times with THF and twice with CH 2 Cl 2 (15 mL portions) gave the title compounds.

A suspension of Part D resin (60 mg) in ClCH 2 CH 2 Cl (500 μL) was treated with a solution of DMAP in pyridine (0.5 mL, 0.1 M, 0.05 mmol) and then a solution of R 1 —X(O) n —Cl (0.5 mL, 1 M). The vessels were agitated at 580 rpm for 14 h. Each resin was washed twice with DMF, three times with 1:1 DMF/water, three times with THF, twice with CH 2 Cl 2 (1 mL portions) and then treated with 1% TFA in ClCH 2 CH 2 Cl for 40 min at 550 rpm. The solution was evaporated and the residues were dissolved in isopropanol (0.5 mL), filtered and evaporated to give the title compounds.

The following R 1 —X(O) n —Cl were included: benzoyl chloride, 2-chlorobenzoyl chloride, o-anisoyl chloride, 3-chlorobenzoyl chloride, m-anisoyl chloride, heptanoyl chloride, cyclohexanecarbonyl chloride, 2-quinoxaloyl choride, benzenesulfonyl chloride, 2-chloronicotinyl chloride, 3-chorobenzenesulfonyl chloride and 6-chloronicotinyl chloride.

EXAMPLES 572-728

The title compounds were prepared as part of a solid-phase library run employing the method of Examples 394-571, but using 2-hydroxy-3-nitrobenzoic acid instead of 3-hydroxy-2-nitrobenzoic acid.