Benzofuran-2-sulfonamides derivatives as chemokine receptor modulators

Abstract

The present invention relates to novel benzofuran-2-sulfonamide derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors.

Claims

1. A compound represented by Formula I, its individual enantiomers, individual diastereoisomers, individual tautomers or a pharmaceutically acceptable salt thereof: ##STR00077## wherein: R.sup.1 to R.sup.6 are hydrogen; R.sup.7 is halogen or methyl; R.sup.8 is hydrogen; R.sup.9 is O, C(O), S, S(O), S(O).sub.2 or C(NOR.sup.16); a is 0 or 1; R.sup.11 is selected from the group consisting of: -Me, OMe, CCH, ##STR00078## -Ph, NHPh, CN, CH.sub.2Ph, CCPh, CH.sub.2CH.sub.2Ph, CHCHPh, ##STR00079## R.sup.16 is hydrogen or methyl; X is CH; R.sup.18 is hydrogen.

2. A compound according to claim 1 selected from the group consisting of: N-(5-chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide; methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate; N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide; 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide; N-(5-chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide; 2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic acid; 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic acid; and 4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic acid.

3. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

4. A pharmaceutical composition according to claim 3 wherein the compound is selected from: N-(5-chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide; methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate; N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide; 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide; N-(5-chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide; N-{5-chloro-2-[(Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide; 2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic acid; 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic acid; and 4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.

(2) It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.

(3) The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium .sup.2H (or D) in place of protium .sup.1H (or H) or use of .sup.13C enriched material in place of .sup.12C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.

(4) As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed.

(5) Compound names were generated with ACD version 12.0 and some intermediates' and reagents' names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1. In general, characterization of the compounds is performed according to the following methods:

(6) NMR spectra are recorded on Varian 600 or Varian 300, in the indicated solvent at ambient temperature; chemical shifts in [ppm], coupling constants in [Hz].

(7) All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates were prepared according to published procedures. Solvents were purchased from commercial sources in appropriate quality and used as received. Air and/or moisture-sensitive reactions were run under an Ar or N.sub.2 atmosphere.

(8) Usually the compounds of the invention were purified by chromatography: CombiFlash Companion and RediSep Rf silica gel 60 (0.04-0.063 mm); Preparative thin layer chromatography (PTLC): Analtech (silica gel 60 F.sub.254, 500 or 1000 m).

(9) The following abbreviations are used in the examples: CH.sub.2Cl.sub.2 dichloromethane NaOH sodium hydroxide MeOH methanol CD.sub.3OD deuterated methanol HCl hydrochloric acid HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) CuI copper iodide DMF dimethylformamide EtOAc ethyl acetate CDCl.sub.3 deuterated chloroform CHCl.sub.3 chloroform DMSO-d.sub.6 deuterated dimethyl sulfoxide THF tetrahydrofuran K.sub.2CO.sub.3 potassium carbonate N.sub.2 nitrogen Et.sub.3N triethylamine Na.sub.2SO.sub.4 sodium sulfate Pd(PPh.sub.3).sub.2Cl.sub.2 Bis(triphenylphosphine)palladium(II) dichloride iPr.sub.2NEt N,N-diisopropylethylamine EDC N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride MPLC medium pressure liquid chromatography NH.sub.4Cl Ammonium chloride DMAP N,N-Dimethylpyridin-4-amine mCPBA 3-Chloroperoxybenzoic add SeO.sub.2 Selenium dioxide KOH potassium hydroxide Et.sub.2O diethylether LiBr lithium bromide K.sub.2CO.sub.3 potassium carbonate TMSCHN.sub.2 trimethylsilyldiazomethane

EXAMPLE 1

Compound 1

N-(5-Chloro-2-methoxyphenyl)benzofuran-2-sulfonamide

(10) ##STR00004##

(11) To a solution of 5-chloro-2-methoxyaniline (100 mg, 0.63 mmol) in pyridine (1 ml) at room temperature was added benzofuran-2-sulfonyl chloride (137 mg, 0.63 mmol) and the reaction was stirred during 64 hours and then was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25% EtOAc in hexanes) to yield Compound 1 as a light yellow solid (194 mg, 91%).

(12) .sup.1H NMR (CHLOROFORM-d) : 7.65 (d, J=7.9 Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.39 (d, J=0.9 Hz, 1H), 7.30-7.34 (m, 2H), 7.02 (dd, J=8.8, 2.3 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 3.68 (s, 3H).

EXAMPLE 2

Compound 2

N-(5-Chloro-2-methylphenyl)-1-benzofuran-2-sulfonamide

(13) ##STR00005##

(14) To a solution of 5-chloro-2-methylaniline (50 l, 0.62 mmol) in pyridine (1 ml) at room temperature was added benzofuran-2-sulfonyl chloride (135 mg, 0.62 mmol) and the reaction was stirred during 64 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexanes) to yield Compound 2 as a white solid (177 mg, 89%).

(15) .sup.1H NMR (CHLOROFORM-d) : 7.64 (d, J=7.9 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.47 (ddd, J=8.4, 7.3, 1.3 Hz, 1H), 7.40 (d, J=2.1 Hz, 1H), 7.31-7.36 (m, 2H), 7.00-7.07 (m, 2H), 6.63-6.77 (m, 1H), 2.14 (s, 3H).

EXAMPLE 3

Compound 3

N-[5-Chloro-2-(trifluoromethoxy)phenyl]-1-benzofuran-2-sulfonamide

(16) ##STR00006##

(17) To a solution of 5-chloro-2-(trifluoromethoxy)aniline (106 mg, 0.50 mmol) in pyridine (1 ml) at room temperature was added benzofuran-2-sulfonyl chloride (109 mg, 0.50 mmol) and the reaction was stirred during 72 hours and was concentrated in vacuo. The residue was treated with 4M NaOH (1 ml) in MeOH (3 ml) at room temperature for 30 minutes, acidified with 6M HCl, diluted with brine, and was extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to yield Compound 3 as an off-white solid (76 mg, 39%).

(18) .sup.1H NMR (CHLOROFORM-d) : 7.75 (d, J=2.1 Hz, 1H), 7.65 (d, J=7.9 Hz, 1H), 7.50-7.53 (m, 1H), 7.44-7.49 (m, 2H), 7.32 (t, J=7.2 Hz, 1H), 7.07-7.12 (m, 2H).

EXAMPLE 4

Compound 4

Methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorobenzoate

(19) ##STR00007##

(20) To a solution of methyl 2-amino-4-chlorobenzoate (93 mg, 0.50 mmol) in pyridine (1 ml) at room temperature was added benzofuran-2-sulfonyl chloride (109 mg, 0.50 mmol) and the reaction was stirred for 72 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to yield Compound 4 as a white solid (101 mg, 55%).

(21) .sup.1H NMR (CHLOROFORM-d) : 11.13 (s, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.84 (s, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.51-7.55 (m, 2H), 7.46 (t, J=7.9 Hz, 1H), 7.31-7.36 (m, 1H), 7.05 (dd, J=8.5, 2.1 Hz, 1H), 3.92 (s, 3H).

EXAMPLE 5

Compound 5

N-(5-Chloro-2-ethoxyphenyl)-1-benzofuran-2-sulfonamide

(22) ##STR00008##

(23) To a solution of 5-chloro-2-ethoxyaniline (148 mg, 0.86 mmol) in pyridine (2 ml) benzofuran-2-sulfonyl chloride (189 mg, 0.86 mmol) was added at room temperature and the reaction was stirred for 16 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-20% EtOAc in hexanes) to yield Compound 5 as an off-white solid (229 mg, 75%).

(24) .sup.1H NMR (CHLOROFORM-d) : 7.63 (d, J=7.9 Hz, 1H), 7.58 (d, J=2.3 Hz, 1H), 7.48-7.51 (m, 1H), 7.41-7.46 (m, 1H), 7.36 (s, 1H), 7.28-7.33 (m, 2H), 6.98 (dd, J=8.7, 2.5 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.86 (q, J=6.8 Hz, 2H), 1.26-1.31 (m, 3H).

EXAMPLE 6

Intermediate 1

5-Chloro-2-((trimethylsilyl)ethynyl)aniline

(25) ##STR00009##

(26) To a solution of 5-chloro-2-iodoaniline (1.50 g, 5.92 mmol) and ethynyltrimethylsilane (1.25 ml, 8.88 mmol) in Et.sub.3N (20 ml) was added CuI (5.6 mg, 0.030 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (21 mg, 0.030 mmol) and the mixture was stirred at room temperature for 5 hours. Celite was added and the suspension was filtered, rinsed with EtOAc. The filtrate was concentrated in vacuo to yield Intermediate 1 as a yellow oil (1.32 g, 100%).

(27) .sup.1H NMR (CHLOROFORM-d) : 7.20 (d, J=8.2 Hz, 1H), 6.69 (d, J=1.8 Hz, 1H), 6.63 (dd, J=8.2, 2.1 Hz, 1H), 4.30 (br. s., 2H), 0.27 (s, 9H).

EXAMPLE 7

Intermediate 2

N-(5-Chloro-2-((trimethylsilyl)ethynyl)phenyl)benzofuran-2-sulfonamide

(28) ##STR00010##

(29) To a solution of Intermediate 1 (1.32 g, 5.89 mmol) in pyridine (12 ml) was added benzofuran-2-sulfonyl chloride (1.53 g, 7.07 mmol) and the reaction was stirred at room temperature for 16 hours and was concentrated in vacuo. The residue was taken in EtOAc, washed with 1M HCl, brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to yield crude Intermediate 2 as a reddish brown solid (3.5 g). The crude product was used in the next step without further purification.

EXAMPLE 8

Compound 6

N-(5-Chloro-2-ethynylphenyl)-1-benzofuran-2-sulfonamide

(30) ##STR00011##

(31) To a solution of crude Intermediate 2 (3.43 g, 8.49 mmol) in MeOH (50 ml) was added K.sub.2CO.sub.3 (2.45 g, 17.8 mmol) and the mixture was stirred at room temperature for 16 hours. The solvent was removed, and the residue was acidified, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-25% EtOAc in hexanes) to yield Compound 6 as a light brown solid (1.47 g, 75%).

(32) 1H NMR (CHLOROFORM-d) : 7.69 (d, J=2.1 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 7.54 (dd, J=8.5, 0.9 Hz, 1H), 7.49 (dd, J=7.0, 1.2 Hz, 2H), 7.47 (d, J=0.9 Hz, 1H), 7.32-7.37 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.05 (dd, J=8.2, 2.1 Hz, 1H), 3.47 (s, 1H).

EXAMPLE 9

Intermediate 3

1-(2-Amino-4-chlorobenzoyl)piperidin-4-one

(33) ##STR00012##

(34) To 2-amino-4-chlorobenzoic acid (0.86 g, 5.0 mmol) and piperidin-4-one hydrochloride (0.77 g, 5.0 mmol) in DMF (10 ml) was added HBTU (1.90 g, 5.0 mmol) and iPr.sub.2NEt (2.6 ml, 15 mmol). The mixture was stirred at room temperature for 16 hours, diluted with 1M NaOH, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (50-75% EtOAc in hexanes) to yield Intermediate 3 as a light yellow solid (1.35 g, 100%).

(35) 1H NMR (acetone) : 7.18 (d, J=8.2 Hz, 1H), 6.86 (d, J=1.8 Hz, 1H), 6.64 (dd, J=8.2, 2.1 Hz, 1H), 5.30 (br. s., 2H), 3.85 (t, J=6.2 Hz, 4H), 2.48 (t, J=6.3 Hz, 4H).

EXAMPLE 10

Compound 7

N-{5-Chloro-2-[(4-oxopiperidin-1-yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide

(36) ##STR00013##

(37) To Intermediate 3 (90 mg, 0.36 mmol) in pyridine (1.5 ml) was added benzofuran-2-sulfonyl chloride (77 mg, 0.36 mmol) and the reaction was stirred at room temperature for 6 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50-70% EtOAc in hexanes) followed by PTLC (50% EtOAc in hexanes) to yield Compound 7 (40 mg, 26%).

(38) 1H NMR (CHLOROFORM-d) : 8.97 (s, 1H), 7.82 (s, 1H), 7.67 (d, J=7.9 Hz, 1H), 7.45-7.54 (m, 2H), 7.43 (s, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.17 (s, 2H), 3.65 (br. s., 4H), 2.31 (br. s., 4H).

EXAMPLE 11

Intermediate 4

(2-Amino-4-chlorophenyl)(morpholino)methanone

(39) ##STR00014##

(40) To 2-amino-4-chlorobenzoic acid (1.72 g, 10.0 mmol) and morpholine (1.3 ml, 15.0 mmol) in DMF (10 ml) was added EDC (2.30 g, 12.0 mmol). The mixture was stirred at room temperature for 16 hours, diluted with H.sub.2O, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (50% EtOAc in hexanes) to yield Intermediate 4 as an off-white solid (2.14 g, 89%).

(41) 1H NMR (CHLOROFORM-d) : 7.00 (d, J=8.2 Hz, 1H), 6.66-6.75 (m, 2H), 4.49 (br. s., 2H), 3.67-3.75 (m, 4H), 3.63 (d, J=5.0 Hz, 4H).

EXAMPLE 12

Compound 8

N-[5-Chloro-2-(morpholin-4-ylcarbonyl)phenyl]-1-benzofuran-2-sulfonamide

(42) ##STR00015##

(43) To Intermediate 4 (120 mg, 0.50 mmol) in pyridine (2 ml) was added benzofuran-2-sulfonyl chloride (108 mg, 0.50 mmol) and the reaction was stirred at room temperature for 6 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50-70% EtOAc in hexanes) followed by PTLC (60% EtOAc in hexanes) to yield Compound 8 as an off-white solid (133 mg, 63%).

EXAMPLE 13

Intermediate 5

3-(4-Chloro-2-nitrophenoxy)-2-methylpyridine

(44) ##STR00016##

(45) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (720 mg, 4.10 mmol) in DMF (10 ml) was added 2-methylpyridin-3-ol (448 mg, 4.10 mmol) and K.sub.2CO.sub.3 (2.8 g, 20.5 mmol) and the reaction was stirred at 60 C. for 3 hours, diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 5 as a yellow solid (1.03 g, 94%).

(46) .sup.1H NMR (600 MHz, acetone) 8.35 (d, J=4.70 Hz, 1H), 8.11 (d, J=2.64 Hz, 1H), 7.71 (dd, J=2.49, 8.95 Hz, 1H), 7.40 (d, J=8.22 Hz, 1H), 7.27 (dd, J=4.70, 8.22 Hz, 1H), 7.11 (d, J=9.10 Hz, 1H), 2.45 (s, 3H).

EXAMPLE 14

Intermediate 6

5-Chloro-2-((2-methylpyridin-3-yl)oxy)aniline

(47) ##STR00017##

(48) To a solution of Intermediate 5 (1.03 g, 3.9 mmol) in MeOH (15 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (6.3 g, 98 mmol). The suspension was stirred at room temperature for 2 hour and was filtered, the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 6 (740 mg, 81%) was used in the next reaction without further purification.

(49) .sup.1H NMR (600 MHz, CD.sub.3OD) 8.11 (d, J=4.99 Hz, 1H), 7.19 (dd, J=4.99, 8.22 Hz, 1H), 7.09 (dd, J=1.17, 8.22 Hz, 1H), 6.88 (d, J=2.35 Hz, 1H), 6.67 (d, J=8.51 Hz, 1H), 6.59 (dd, J=2.64, 8.51 Hz, 1H), 2.55 (s, 3H).

EXAMPLE 15

Compound 9

N-{5-Chloro-2-[(2-methylpyridin-3-yl)oxy]phenyl}-1-benzofuran-2-sulfonamide

(50) ##STR00018##

(51) To Intermediate 6 (488 mg, 2.1 mmol) in pyridine (4 ml) was added benzofuran-2-sulfonyl chloride (450 mg, 2.1 mmol) and the reaction was stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) followed by re-crystallization from 20% EtOAc/Hexane to yield Compound 9 (553 mg, 64%) as a yellow solid.

(52) .sup.1H NMR (600 MHz, CD.sub.3OD) 8.03 (dd, J=1.17, 4.70 Hz, 1H), 7.68 (d, J=7.92 Hz, 1H), 7.63 (d, J=2.64 Hz, 1H), 7.39-7.48 (m, 2H), 7.31-7.37 (m, 2H), 7.15 (dd, J=2.64, 8.80 Hz, 1H), 6.87 (dd, J=4.69, 8.22 Hz, 1H), 6.69 (dd, J=1.17, 8.22 Hz, 1H), 6.60 (d, J=8.51 Hz, 1H), 2.20 (s, 3H).

EXAMPLE 16

Intermediate 7

Methyl 2-(4-chloro-2-nitrophenoxy)benzoate

(53) ##STR00019##

(54) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (588 mg, 3.35 mmol) in DMF (10 ml) was added methyl 2-hydroxybenzoate (509 mg, 3.35 mmol) and K.sub.2CO.sub.3 (2.31 g, 16.75 mmol) and the reaction was stirred at 60 C. for 3 hours, diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 7 as yellow oil (1.0 g, 99%).

(55) .sup.1H NMR (600 MHz, CD.sub.3OD) 8.03 (d, J=2.35 Hz, 1H), 8.00 (dd, J=1.61, 7.78 Hz, 1H), 7.62-7.70 (m, 1H), 7.54 (dd, J=2.64, 9.10 Hz, 1H), 7.39 (td, J=1.17, 7.63 Hz, 1H), 7.20 (dd, J=0.88, 8.22 Hz, 1H), 6.84 (d, J=9.10 Hz, 1H), 3.74 (s, 3H).

EXAMPLE 17

Intermediate 8

Methyl 2-((3-amino-5-chloropyridin-2-yl)oxy)benzoate

(56) ##STR00020##

(57) To a solution of Intermediate 7(1.0 g, 3.26 mmol) in MeOH (30 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (5.3 g, 81 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 8 (770 mg, 85%) was used in the next reaction without further purification.

(58) .sup.1H NMR (600 MHz, CD.sub.3OD) 7.82 (dd, J=1.76, 7.92 Hz, 1H), 7.43-7.50 (m, 1H), 7.12-7.18 (m, 1H), 6.90 (d, J=7.92 Hz, 1H), 6.85 (d, J=2.35 Hz, 1H), 6.70 (d, J=8.51 Hz, 1H), 6.58 (dd, J=2.20, 8.66 Hz, 1H), 3.85 (s, 3H).

EXAMPLE 18

Compound 10

Methyl 2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}benzoate

(59) ##STR00021##

(60) To Intermediate 8 (770 mg, 2.53 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (546 mg, 2.53 mmol) and the reaction was stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 10 (920 mg, 72%) as a yellow solid.

(61) .sup.1H NMR (600 MHz, CD.sub.3OD) 7.79 (dd, J=2.35, 7.04 Hz, 1H), 7.65-7.69 (m, 2H), 7.42-7.46 (m, 1H), 7.35-7.38 (m, 2H), 7.30-7.35 (m, 1H), 7.09 (dd, J=2.64, 8.80 Hz, 1H), 7.02-7.08 (m, 2H), 6.63 (d, J=8.51 Hz, 1H), 6.28 (dd, J=1.61, 7.78 Hz, 1H), 3.74 (s, 3H).

EXAMPLE 19

Compound 11

2-{2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}benzoic acid

(62) ##STR00022##

(63) To Compound 10 (354 mg, 0.78 mmol) in MeOH (30 ml) was added NaOH (5M, 2 ml) and stirred at room temperature for 3 hours. The mixture was acidified with 10% HCl, extracted with EtOAc (2). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH.sub.2Cl.sub.2 to yield Compound 11 (278 mg, 81%).

(64) .sup.1H NMR (600 MHz, CD.sub.3OD) 7.81 (d, J=7.34 Hz, 1H), 7.69 (d, J=2.05 Hz, 1H), 7.65 (d, J=7.92 Hz, 1H), 7.40-7.45 (m, 1H), 7.29-7.37 (m, 3H), 7.11 (dd, J=1.76, 8.51 Hz, 1H), 6.99 (t, J=7.63 Hz, 1H), 6.89-6.95 (m, 1H), 6.72 (d, J=8.80 Hz, 1H), 6.18 (d, J=8.22 Hz, 1H).

EXAMPLE 20

Intermediate 9

(4-Chloro-2-nitrophenyl)(phenyl)sulfane

(65) ##STR00023##

(66) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (926 mg, 5.0 mmol) in MeOH (5 ml) was added benzenethiol (0.51 ml, 5.0 mmol) and 4M NaOH (1.25 ml, 5.0 mmol) and the reaction was stirred at room temperature for 4 hours, diluted with 1M NaOH, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-5% EtOAc in hexanes) to yield Intermediate 9 as a yellow solid (1.31 g, 98%).

(67) 1H NMR (CHLOROFORM-d) : 8.23 (d, J=2.3 Hz, 1H), 7.56-7.61 (m, 2H), 7.48-7.53 (m, 3H), 7.30 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H).

EXAMPLE 21

Intermediate 10

5-Chloro-2-(phenylthio)aniline

(68) ##STR00024##

(69) To a solution of Intermediate 9 (0.64 g, 2.4 mmol) in MeOH (20 ml) and THF (20 ml) was added saturated aqueous NH.sub.4Cl (20 ml) and zinc dust (3.95 g, 61 mmol). The suspension was stirred at room temperature for 3 hours and was filtered; the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5-10% EtOAc in hexanes) to yield Intermediate 10 as an off-white solid (555 mg, 98%).

(70) 1H NMR (CHLOROFORM-d) : 7.38 (d, J=8.2 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.14 (t, J=7.3 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.80 (d, J=2.3 Hz, 1H), 6.74 (dd, J=8.2, 2.1 Hz, 1H), 4.42 (br. s., 2H).

EXAMPLE 22

Compound 12

N-[5-Chloro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide

(71) ##STR00025##

(72) To Intermediate 10 (394 mg, 1.67 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (362 mg, 1.67 mmol) and the reaction was stirred at room temperature for 72 hours, when additional benzofuran-2-sulfonyl chloride (362 mg, 1.67 mmol) and catalytic amount of DMAP was added. The reaction was heated at 100 C. for 6 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-5% EtOAc in hexanes) to yield Compound 12 as an off-white solid (425 mg, 61%).

(73) 1H NMR (CHLOROFORM-d) : 8.03 (s, 1H), 7.85 (d, J=2.1 Hz, 1H), 7.66 (dt, J=8.1, 0.9 Hz, 1H), 7.39-7.48 (m, 4H), 7.31-7.37 (m, 1H), 7.04-7.11 (m, 4H), 6.89-6.93 (m, 2H).

EXAMPLE 23

Compound 13

N-[5-Chloro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

(74) ##STR00026##

(75) To a solution of Compound 12 (333 mg, 0.80 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (208 mg, 1.20 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) to yield Compound 13 as a white solid (204 mg, 57%).

(76) 1H NMR (CHLOROFORM-d) : 9.70 (s, 1H), 7.79-7.94 (m, 4H), 7.69 (d, J=7.6 Hz, 1H), 7.34-7.57 (m, 7H), 7.17 (d, J=7.9 Hz, 1H).

EXAMPLE 24

Compound 14

N-[5-Chloro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

(77) ##STR00027##

(78) To a solution of Compound 12 (333 mg, 0.80 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (208 mg, 1.20 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) to yield Compound 14 as a white solid (129 mg, 37%).

(79) 1H NMR (CHLOROFORM-d) : 10.66 (s, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.63 (dt, J=7.9, 1.0 Hz, 1H), 7.30-7.52 (m, 10H), 7.12 (dd, J=8.2, 2.1 Hz, 1H).

EXAMPLE 25

Intermediate 11

2-Amino-4-chloro-N-phenylbenzamide

(80) ##STR00028##

(81) A mixture of 4-chloro-isatoic anhydride (594 mg, 3.0 mmol), aniline (275 l, 3.0 mmol), and NaOH (12 mg, 0.3 mmol) in dioxane (5 ml) was refluxed at 110 C. for 2 hours. The mixture was cooled to room temperature and was filtered. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25% EtOAc in hexanes) to yield Intermediate 11 (200 mg, 27%).

(82) 1H NMR (CHLOROFORM-d) : 7.70 (br. s., 1H), 7.55 (dd, J=8.6, 1.0 Hz, 2H), 7.33-7.43 (m, 3H), 7.13-7.21 (m, 1H), 6.64-6.74 (m, 2H), 5.62 (br. s., 2H).

EXAMPLE 26

Compound 15

2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chloro-N-phenylbenzamide

(83) ##STR00029##

(84) To Intermediate 11 (200 mg, 0.81 mmol) in pyridine (2 ml) was added benzofuran-2-sulfonyl chloride (176 mg, 0.81 mmol) and a catalytic amount of DMAP. The reaction was stirred at room temperature for 6 hours, when additional benzofuran-2-sulfonyl chloride (88 mg, 0.41 mmol) was added. The reaction was continued for a total of 120 hours and was concentrated in vacuo. The crude reaction mixture was acidified with 6M HCl, extracted with EtOAc (3). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25% EtOAc in hexanes) to yield Compound 15 as an off-white solid (135 mg, 39%).

(85) 1H NMR (CHLOROFORM-d) : 11.06 (s, 1H), 7.83 (d, J=2.1 Hz, 1H), 7.76 (s, 1H), 7.61 (dt, J=7.7, 1.1 Hz, 1H), 7.43-7.51 (m, 3H), 7.15-7.43 (m, 7H), 7.11 (dd, J=8.5, 2.1 Hz, 1H).

EXAMPLE 27

Compound 16

N-(5-Chloro-2-cyanophenyl)-1-benzofuran-2-sulfonamide

(86) ##STR00030##

(87) To 2-amino-4-chlorobenzonitrile (552 mg, 3.62 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (781 mg, 3.62 mmol) and the reaction was stirred at 100 C. for 16 hours, then additional benzofuran-2-sulfonyl chloride (842 mg, 3.90 mmol) was added. The reaction was continued for 24 hours and was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to yield Compound 16 (550 mg, 36%).

(88) .sup.1H NMR (600 MHz, CD.sub.3OD) 7.72 (dt, J=1.03, 7.92 Hz, 1H), 7.64 (d, J=8.51 Hz, 1H), 7.57-7.60 (m, 1H), 7.53 (d, J=2.05 Hz, 1H), 7.49-7.52 (m, 1H), 7.41-7.42 (m, 1H), 7.34-7.39 (m, 2H).

EXAMPLE 28

Compound 17

N-[5-Chloro-2-(phenylacetyl)phenyl]-1-benzofuran-2-sulfonamide

(89) ##STR00031##

(90) To a solution of Compound 16 (128 mg, 0.39 mmol) in THF (2 ml) was added benzylmagnesium chloride (0.6 ml, 1.16 mmol, 2M in THF) at 0 C. After it was stirred at room temperature for 2 hours, the reaction was quenched with water, extracted with EtOAc (2), washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 17 (91 mg, 55%).

(91) .sup.1H NMR (600 MHz, CDCL.sub.3) 11.95 (s, 1H), 7.82-7.91 (m, 2H), 7.66 (d, J=7.92 Hz, 1H), 7.47-7.50 (m, 2H), 7.42-7.46 (m, 1H), 7.32 (td, J=1.03, 7.41 Hz, 1H), 7.23-7.30 (m, 3H), 7.14 (d, J=7.04 Hz, 2H), 7.05 (dd, J=2.05, 8.51 Hz, 1H), 4.23 (s, 2H).

EXAMPLE 29

Compound 18

N-{5-Chloro-2-[(1Z)-N-methoxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide

(92) ##STR00032##

(93) A mixture of Compound 17 (91 mg, 0.214 mmol), O-methylhydroxylamine hydrochloride (177 mg, 2.14 mmol) and TEA (0.8 ml) in THF (2 ml) was heated at 80 C. overnight. The reaction mixture was cooled down to room temperature, diluted with EtOAc, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 18 (56 mg, 58%).

(94) .sup.1H NMR (600 MHz, CDCL.sub.3) 11.70 (s, 1H), 7.75 (d, J=2.05 Hz, 1H), 7.63-7.67 (m, 1H), 7.49-7.53 (m, 1H), 7.43-7.48 (td, J=1.32, 7.85Hz, 1H), 7.40 (d, J=0.88 Hz, 1H), 7.33 (td, J=1.17, 7.48 Hz, 1H), 7.22 (d, J=8.80 Hz, 1H), 7.09-7.15 (m, 3H), 6.97-7.02 (m, 2H), 6.93 (dd, J=2.20, 8.66 Hz, 1H), 4.18 (s, 3H), 4.01 (s, 2H).

EXAMPLE 30

Compound 19

N-{5-Chloro-2-[(1Z)-N-hydroxy-2-phenylethanimidoyl]phenyl}-1-benzofuran-2-sulfonamide

(95) ##STR00033##

(96) The mixture of Compound 17 (121 mg, 0.28 mmol), hydroxylamine hydrochloride (198 mg, 2.80 mmol) and TEA (0.8 ml) in THF (2 ml) was heated at 80 C. overnight. The reaction mixture was cooled down to room temperature, diluted with EtOAc, filtered away salt and filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 19 (100 mg, 80%).

(97) .sup.1H NMR (600 MHz, CDCl.sub.3) 11.40 (br. s., 1H), 7.76 (d, J=2.05 Hz, 1H), 7.66 (dt, J=1.03, 7.92 Hz, 1H), 7.50-7.53 (m, 1H), 7.45-7.48 (m, 1H), 7.43 (d, J=0.88 Hz, 1H), 7.30-7.36 (m, 1H), 7.23-7.28 (m, 1H), 7.12-7.17 (m, 3H), 7.02-7.09 (m, 2H), 6.95 (dd, J=2.05, 8.51 Hz, 1H), 4.08 (s, 2H).

EXAMPLE 31

Intermediate 12

1-(Benzyloxy)-4-chloro-2-nitrobenzene

(98) ##STR00034##

(99) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (409 mg, 2.33 mmol) in DMF (10 ml) was added phenylmethanol (0.24 ml, 2.33 mmol) and K.sub.2CO.sub.3 (1.6 g, 11.65 mmol) and the reaction was stirred at 60 C. for 16 hours. The reaction was diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 12 as yellow solid (607 mg, 99%).

(100) .sup.1H NMR (600 MHz, CD.sub.3OD) 7.86 (d, J=2.64 Hz, 1H), 7.57 (dd, J=2.79, 8.95 Hz, 1H), 7.43-7.47 (m, 2H), 7.36-7.40 (m, 2H), 7.30-7.35 (m, 2H), 5.27 (s, 2H).

EXAMPLE 32

Intermediate 13

2-(Benzyloxy)-5-chloroaniline

(101) ##STR00035##

(102) To a solution Intermediate 12 (605 mg, 2.30 mmol) in MeOH (20 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (3.7 g, 57 mmol). The suspension was stirred at room temperature for 1 hour, was filtered, and the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 13 (475 mg, 89%) was used in the next reaction without further purification.

(103) .sup.1H NMR (600 MHz, CD.sub.3OD) 7.42-7.49 (m, 2H), 7.34-7.40 (m, 2H), 7.26-7.33 (m, 1H), 6.80 (d, J=8.80 Hz, 1H), 6.73 (d, J=2.64 Hz, 1H), 6.56 (dd, J=2.49, 8.66 Hz, 1H), 5.07 (s, 2H).

EXAMPLE 33

Compound 20

N-[2-(Benzyloxy)-5-chlorophenyl]-1-benzofuran-2-sulfonamide

(104) ##STR00036##

(105) To Intermediate 13 (233 mg, 1.0 mmol) in pyridine (3 ml) was added benzofuran-2-sulfonyl chloride (216 mg, 1.0 mmol) and the reaction was stirred at 100 C. for 16 hours. The solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield the Compound 20 (304 mg, 74%) as a yellow solid.

(106) .sup.1H NMR (600 MHz, acetone) 7.76 (dt, J=1.03, 7.92 Hz, 1H), 7.56 (d, J=2.64 Hz, 1H), 7.47-7.53 (m, 2H), 7.45 (d, J=0.59 Hz, 1H), 7.35-7.40 (m, 1H), 7.24-7.31 (m, 3H), 7.20-7.24 (m, 2H), 7.14 (dd, J=2.64, 8.80 Hz, 1H), 7.00 (d, J=9.10 Hz, 1H), 4.95 (s, 2H).

EXAMPLE 34

Intermediate 14

5-Chloro-2-(phenylethynyl)aniline

(107) ##STR00037##

(108) To 5-chloro-2-iodoaniline (1.27 g, 5.0 mmol) and ethynylbenzene (0.60 ml, 5.5 mmol) in Et.sub.3N (10 ml) was added CuI (5.0 mg, 0.025 mmol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (18 mg, 0.025 mmol) and the mixture was stirred at room temperature for 16 hours, diluted with EtOAc and was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to yield Intermediate 14 as beige solid (1.12 g, 98%).

(109) 1H NMR (CHLOROFORM-d) : 7.46-7.56 (m, 2H), 7.32-7.39 (m, 3H), 7.28 (d, J=8.2 Hz, 1H), 6.66-6.75 (m, 2H), 4.37 (br. s., 2H).

EXAMPLE 35

Compound 21

N-[5-Chloro-2-(phenylethynyl)phenyl]-1-benzofuran-2-sulfonamide

(110) ##STR00038##

(111) To Intermediate 14 (506 mg, 2.22 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (482 mg, 2.22 mmol) and a catalytic amount of DMAP. The reaction was stirred at room temperature for 4 hours, when additional benzofuran-2-sulfonyl chloride (121 mg, 0.56 mmol) was added. The reaction was continued for 16 hours and was concentrated in vacuo. The crude reaction mixture was acidified with 1M HCl, extracted with EtOAc (3). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-5% EtOAc in hexanes) to yield Compound 21 as a white solid (516 mg, 57%).

(112) 1H NMR (CHLOROFORM-d) : 7.71 (d, J=2.1 Hz, 1H), 7.62-7.65 (m, 1H), 7.51-7.54 (m, 2H), 7.49 (s, 1H), 7.38-7.44 (m, 5H), 7.32-7.35 (m, 2H), 7.29-7.32 (m, 1H), 7.10 (dd, J=8.2, 2.1 Hz, 1H).

EXAMPLE 36

Compound 22

N-[5-Chloro-2-(2-phenylethyl)phenyl]-1-benzofuran-2-sulfonamide

(113) ##STR00039##

(114) A mixture of Compound 21 (110 mg, 0.27 mmol) and 10% palladium on activated carbon (29 mg, 0.027 mmol) in EtOAc (5 ml) was stirred at room temperature under excess hydrogen gas in a balloon for 4 hours. The mixture was filtered and the filtrate was concentrated to yield Compound 22 as off-white solid (103 mg, 93%).

(115) 1H NMR (CHLOROFORM-d) : 7.60-7.63 (m, 1H), 7.46-7.50 (m, 1H), 7.42-7.46 (m, 1H), 7.30-7.35 (m, 2H), 7.28 (d, J=0.9 Hz, 1H), 7.18-7.27 (m, 3H), 7.10 (dd, J=8.2, 2.3 Hz, 1H), 6.98-7.03 (m, 3H), 6.34 (s, 1H), 2.72-2.79 (m, 4H).

EXAMPLE 37

Compound 23

N-{5-Chloro-2-[((Z)-2-phenylethenyl]phenyl}-1-benzofuran-2-sulfonamide

(116) ##STR00040##

(117) A mixture of Compound 21 (140 mg, 0.34 mmol) and 5% Lindlar's catalyst (Aldrich Lot#BCBG1137V, 144 mg, 0.068 mmol) in EtOAc (5 ml) was stirred at room temperature under excess hydrogen gas in a balloon for 4 hours. The mixture was then place under 50 psi hydrogen gas using a Parr apparatus for 3 h, and was filtered. The filtrate was concentrated and the crude product was purified by flash column chromatography on silica gel (5-10% EtOAc in hexanes) to yield Compound 23 (75 mg, 53%).

(118) 1H NMR (CHLOROFORM-d) : 7.61-7.66 (m, 2H), 7.42-7.48 (m, 2H), 7.30-7.36 (m, 2H), 7.11-7.16 (m, 1H), 7.06-7.11 (m, 2H), 7.01-7.06 (m, 2H), 6.94-6.98 (m, 2H), 6.87 (s, 1H), 6.72 (d, J=12.0 Hz, 1H), 6.25 (d, J=12.0 Hz, 1H).

EXAMPLE 38

Intermediate 15

(4-Methyl-2-nitrophenyl)(phenyl)sulfane

(119) ##STR00041##

(120) To a solution of 1-bromo-4-methyl-2-nitrobenzene (1.32 g, 6.11 mmol) in MeOH (10 ml) was added benzenethiol (0.8 ML, 6.11 mmol) and NaOH (1.5 ml, 5M) and the reaction was stirred at room temperature for 16 hours, diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 15 (1.0 g, 67%).

(121) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.03 (d, J=1.17 Hz, 1H), 7.53-7.59 (m, 2H), 7.43-7.49 (m, 3H), 7.15 (dd, J=2.05, 8.50 Hz, 1H), 6.77 (d, J=8.20 Hz, 1H), 2.36 (s, 3H).

EXAMPLE 39

Intermediate 16

5-Methyl-2-(phenylthio)aniline

(122) ##STR00042##

(123) To a solution Intermediate 15 (1.0 g, 4.76 mmol) in MeOH (50 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (5.3 g, 82 mmol). The suspension was stirred at room temperature for 1 hour, and was filtered, and the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 16 (760 mg, 87%) was used in the next reaction without further purification.

(124) .sup.1H NMR (300 MHz, CD.sub.3OD) 7.13-7.26 (m, 3H), 6.98-7.11 (m, 3H), 6.68 (d, J=0.59 Hz, 1H), 6.44-6.58 (m, 1H), 2.26 (s, 3H).

EXAMPLE 40

Compound 24

N-[5-Methyl-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide

(125) ##STR00043##

(126) To Intermediate 16 (335 mg, 1.56 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (335 mg, 1.56 mmol) and the reaction was stirred at 100 C. for 4 hours, then additional benzofuran-2-sulfonyl chloride (168 mg, 0.78 mmol) was added and the reaction was stirred at 100 C. for 16 hours. 2M NaOH (2 ml) was added to the mixture, and it was heated to 100 C. for 1 hour. The mixture was diluted with water, and the products extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 24 (311 mg, 51%).

(127) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.99 (s, 1H), 7.57-7.67 (m, J=11.72 Hz, 2H), 7.24-7.47 (m, 4H), 6.99-7.07 (m, 3H), 6.83-6.96 (m, 3H), 2.39 (s, 3H).

EXAMPLE 41

Compound 25

N-[5-Methyl-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

(128) ##STR00044##

(129) To a solution of Compound 24 (122 mg, 0.31 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (62 mg, 0.31 mmol) and the reaction was stirred at 0 C. for 30 min and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 25 (98 mg, 77%).

(130) .sup.1H NMR (300 MHz, CDCl.sub.3) 10.48 (br. s., 1H), 7.60 (d, J=7.91 Hz, OH), 7.55 (s, 1H), 7.50 (d, J=1.76 Hz, 1H), 7.48 (d, J=1.47 Hz, 1H), 7.38-7.44 (m, 2H), 7.23-7.37 (m, 6H), 6.95 (dd, J=0.88, 7.91 Hz, 1H), 2.35 (s, 3H).

EXAMPLE 42

Compound 26

N-[5-Methyl-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

(131) ##STR00045##

(132) To a solution of Compound 24 (118 mg, 0.30 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (150 mg, 0.75 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 26 (117 mg, 92%).

(133) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.76-7.88 (m, 3H), 7.67 (d, J=7.91 Hz, 1H), 7.58 (s, 1H), 7.26-7.53 (m, 7H), 7.02 (d, J=8.21 Hz, 1H), 2.37 (s, 3H).

EXAMPLE 43

Intermediate 17

(4-Fluoro-2-nitrophenyl)(phenyl)sulfane

(134) ##STR00046##

(135) To a solution of 1-chloro-4-fluoro-2-nitrobenzene (1.20 g, 6.82 mmol) in MeOH (10 ml) was added benzenethiol (1.0 ML, 10.22 mmol) and NaOH (1.5 ml, 5M) and the reaction was stirred at room temperature for 16 hours, diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 17 (1.3 g, 80%).

(136) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.94 (dd, J=2.78, 8.35 Hz, 1H), 7.54-7.63 (m, 2H), 7.44-7.52 (m, 3H), 7.03-7.18 (m, 1H), 6.86 (dd, J=4.98, 9.08 Hz, 1H).

EXAMPLE 44

Intermediate 18

5-Fluoro-2-(phenylthio)aniline

(137) ##STR00047##

(138) To a solution Intermediate 17 (1.3 g, 5.20 mmol) in MeOH (50 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (8.4 g, 130 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 18 (980 mg, 86%) was used in the next reaction without further purification.

(139) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.35-7.50 (m, 1H), 7.18-7.30 (m, 2H), 7.00-7.17 (m, 3H), 6.37-6.57 (m, 2H), 4.02 (br. s., 2H).

EXAMPLE 45

Compound 27

N-[5-Fluoro-2-(phenylsulfanyl)phenyl]-1-benzofuran-2-sulfonamide

(140) ##STR00048##

(141) To Intermediate 18 (980 mg, 4.45 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (962 mg, 4.45 mmol) and the reaction was stirred at 100 C. for 16 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 27 (679 mg, 38%).

(142) .sup.1H NMR (300 MHz, CDCl.sub.3) 8.14 (br. s, 1H), 7.56-7.67 (m, 2H), 7.29-7.54 (m, 5H), 7.00-7.08 (m, 3H), 6.78-6.90 (m, 3H).

EXAMPLE 46

Compound 28

N-[5-Fluoro-2-(phenylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide

(143) ##STR00049##

(144) To a solution of Compound 27 (485 mg, 0.71 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (143 mg, 0.71 mmol) and the reaction was stirred at 0 C. for 30 min, and the solution was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 28 (420 mg, 83%).

(145) .sup.1H NMR (300 MHz, CDCl) 10.73 (br. s., 1H), 7.63 (d, J=7.91 Hz, 1H), 7.39-7.56 (m, 6H), 7.28-7.38 (m, 5H), 6.84 (td, J=2.34, 8.06 Hz, 1H).

EXAMPLE 47

Compound 29

N-[5-Fluoro-2-(phenylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide

(146) ##STR00050##

(147) To a solution of Compound 27 (220 mg, 0.55 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (276 mg, 1.38 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 29 (170 mg, 72%).

(148) .sup.1H NMR (300 MHz, CDCl.sub.3) 7.97 (dd, J=6.01, 8.94 Hz, 1H), 7.78-7.89 (m, 2H), 7.68 (d, J=7.62 Hz, 1H), 7.29-7.61 (m, 8H), 6.78-6.97 (m, 1H).

EXAMPLE 48

Intermediate 19

Methyl 2-((4-Chloro-2-nitrophenoxy)methyl)benzoate

(149) ##STR00051##

(150) To a solution of 4-chloro-2-nitrophenol (541 mg, 3.12 mmol) in DMF (10 ml) was added methyl 2-(bromomethyl)benzoate (714 mg, 3.12 mmol) and K.sub.2CO.sub.3 (1.3 g, 9.35 mmol). The reaction was stirred at room temperature for 16 hours, diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by MPLC to yield Intermediate 19(959 mg, 96%).

(151) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.08 (dd, J=1.32, 7.78 Hz, 1H), 7.92 (d, J=2.64 Hz, 1H), 7.91 (d, J=7.92 Hz, 1H), 7.59-7.68 (m, 1H), 7.48-7.54 (m, 1H), 7.43 (t, J=7.63 Hz, 1H), 7.20 (d, J=9.10 Hz, 1H), 5.66 (s, 2H), 3.88-3.99 (m, 3H).

EXAMPLE 49

Intermediate 20

Methyl 2-((2-(Benzofuran-2-sulfonamido)-4-chlorophenoxy)methyl)benzoate

(152) ##STR00052##

(153) To a solution Intermediate 19 (959 mg, 2.99 mmol) in MeOH (50 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (3.9 g, 60 mmol). The suspension was stirred at room temperature for 1 hour, filtered, and the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 20 (713 mg, 82%) was used in the next reaction without further purification.

(154) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.01 (dd, J=1.32, 7.78 Hz, 1H), 7.61-7.66 (m, 1H), 7.55 (td, J=1.47, 7.63 Hz, 1H), 7.36-7.42 (m, 1H), 6.69-6.74 (m, 2H), 6.59-6.64 (m, 1H), 5.48 (s, 2H), 3.94 (br. s., 2H), 3.89 (s, 3H).

EXAMPLE 50

Compound 30

Methyl 2-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoate

(155) ##STR00053##

(156) To Intermediate 20 (329 mg, 1.13 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (244 mg, 1.13 mmol) and the reaction was stirred at 100 C. for 16 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 30 (231 mg, 43%).

(157) .sup.1H NMR (600 MHz, CDCl.sub.3) 7.99-8.07 (m, 1H), 7.58-7.67 (m, 2H), 7.51 (br. s., 1H), 7.33-7.44 (m, 4H), 7.22-7.33 (m, 3H), 6.89-7.05 (m, 1H), 6.71 (dd, J=4.70, 8.80 Hz, 1H), 5.35 (d, J=4.40 Hz, 2H), 3.89 (d, J=4.70 Hz, 3H).

EXAMPLE 51

Compound 31

2-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoic Acid

(158) ##STR00054##

(159) To Compound 30 (180 mg, 0.38 mmol) in MeOH (30 ml) was added 5M NaOH (2 ml) and stirred at room temperature for 16 hours. The mixture was acidified with 10% HCl, extracted with EtOAc (2). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH.sub.2Cl.sub.2 to yield Compound 31(168 mg, 96%).

(160) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.06 (dd, J=1.32, 7.78 Hz, 1H), 7.58-7.64 (m, 2H), 7.23-7.43 (m, 7H), 7.00 (dd, J=2.64, 8.80 Hz, 1H), 6.72 (d, J=8.80 Hz, 1H), 5.32 (s, 2H).

EXAMPLE 52

Intermediate 21

Methyl 2-((4-Chloro-2-nitrophenyl)thio)benzoate

(161) ##STR00055##

(162) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.1 g, 6.0 mmol) in MeOH (10 ml) was added methyl 2-mercaptobenzoate (1.0 g, 6.0 mmol) and 4M NaOH (1.5 ml, 6.0 mmol) and the reaction was stirred at room temperature for 2 hours, diluted with H.sub.2O, and the resulting suspension was filtered and washed with H.sub.2O to yield Intermediate 21 as a yellow solid (2.0 g, crude). The crude product was used in the next reaction without further purification.

EXAMPLE 53

Intermediate 22

Methyl 2-((2-amino-4-chlorophenyl)thio)benzoate hydrochloride salt

(163) ##STR00056##

(164) To a solution of Intermediate 21 (0.99 g, 3.1 mmol) in MeOH (15 ml) and CH.sub.2Cl.sub.2 (15 ml) was added saturated aqueous NH.sub.4Cl (20 ml) and zinc dust (5.0 g, 77 mmol). The suspension was stirred at room temperature for 30 minutes and was filtered, the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was dissolved in Et.sub.2O, and 2M HCl in Et.sub.2O (4 ml) was added. The resulting suspension was filtered and the solid was washed with Et.sub.2O (3) to yield Intermediate 22 as a white solid (0.75 g, 75%).

(165) 1H NMR (METHANOL-d4) : 8.01 (d, J=7.6 Hz, 1H), 7.49 (d, J=8.2 Hz, 1H), 7.31-7.41 (m, 1H), 7.20-7.28 (m, 2H), 7.15 (dd, J=8.5, 1.8 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 3.93 (s, 3H).

EXAMPLE 54

Compound 32

2-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic Acid

(166) ##STR00057##

(167) To Intermediate 22 (0.75 g, 2.27 mmol) in pyridine (4 ml) was added benzofuran-2-sulfonyl chloride (493 mg, 2.27 mmol) and the reaction was stirred at room temperature for 16 hours, when additional benzofuran-2-sulfonyl chloride (250 mg, 1.15 mmol) was added. The reaction was continued for 24 hours and was concentrated in vacuo. The residue was dissolved in MeOH and was treated with 4M NaOH (3 ml) at 100 C. for 15 minutes, and cooled, and acidified with 6M HCl, and the products were extracted with EtOAc (2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was triturated with 10% MeOH in CH.sub.2Cl.sub.2 to yield Compound 32 as a pinkish white solid (0.75 g, 66%).

(168) 1H NMR (acetone) : 11.56 (br. s., 1H), 9.21 (s, 1H), 7.99 (dd, J=7.8, 1.6 Hz, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.74 (dt, J=7.9, 1.0 Hz, 1H), 7.57 (d, J=3.8 Hz, 1H), 7.56 (d, J=3.5 Hz, 1H), 7.51 (ddd, J=8.4, 7.1, 1.2 Hz, 1H), 7.45 (dd, J=8.2, 0.9 Hz, 1H), 7.37 (ddd, J=7.9, 7.0, 0.9 Hz, 1H), 7.33 (dd, J=8.2, 2.3 Hz, 1H), 7.11 (td, J=7.5, 1.2 Hz, 1H), 6.95-7.00 (m, 1H), 6.41 (dd, J=8.1, 1.0 Hz, 1H).

EXAMPLE 55

Intermediate 23

Methyl 3-((4-Chloro-2-nitrophenyl)thio)benzoate

(169) ##STR00058##

(170) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.0 g, 5.6 mmol) in MeOH (10 ml) was added methyl 3-mercaptobenzoate (0.95 g, 5.6 mmol) and 4M NaOH (1.4 ml, 5.6 mmol) and the reaction was stirred at room temperature for 2 hours, diluted with H.sub.2O, and the resulting suspension was filtered and washed with H.sub.2O to yield Intermediate 23 as a yellow solid (1.9 g, 100%).

(171) 1H NMR (CHLOROFORM-d) : 8.21-8.26 (m, 2H), 8.15-8.20 (m, 1H), 7.73-7.78 (m, 1H), 7.56-7.61 (m, 1H), 7.31 (dt, J=8.8, 2.1 Hz, 1H), 6.77 (dd, J=8.8, 1.8 Hz, 1H), 3.94 (s, 3H).

EXAMPLE 56

Intermediate 24

Methyl 3-((2-Amino 4-chlorophenyl)thio)benzoate

(172) ##STR00059##

(173) To a solution of Intermediate 23 (0.83 g, 2.6 mmol) in MeOH (15 ml) and CH.sub.2Cl.sub.2 (15 ml) was added saturated aqueous NH.sub.4Cl (20 ml) and zinc dust (4.2 g, 64 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product Intermediate 24 (0.77 g, 100%) was used in the next reaction without further purification.

(174) 1H NMR (CHLOROFORM-d) : 7.77-7.82 (m, 2H), 7.38 (d, J=8.2 Hz, 1H), 7.27-7.32 (m, 1H), 7.19 (ddd, J=7.9, 2.1, 1.2 Hz, 1H), 6.80 (d, J=2.3 Hz, 1H), 6.74 (dd, J=8.2, 2.1 Hz, 1H), 3.89 (s, 3H).

EXAMPLE 57

Compound 33

3-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic Acid

(175) ##STR00060##

(176) To Intermediate 24 (0.76 g, 2.6 mmol) in pyridine (4 ml) was added benzofuran-2-sulfonyl chloride (0.56 g, 2.6 mmol) and the reaction was stirred at room temperature for 16 hours, when additional benzofuran-2-sulfonyl chloride (0.28 g, 1.3 mmol) was added. The reaction was continued for 24 hours and was concentrated in vacuo. The residue was taken up in MeOH and was treated with 4M NaOH (3 ml) at 100 C. for 15 minutes, and cooled, and acidified with 6M HCl, and extracted with EtOAc (2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) to yield Compound 33 (0.75 g, 63%).

(177) 1H NMR (acetone) : 7.79 (dt, J=8.0, 1.3 Hz, 1H), 7.73 (dt, J=7.9, 1.0 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.69 (t, J=1.6 Hz, 1H), 7.46-7.53 (m, 3H), 7.32-7.37 (m, 2H), 7.24-7.30 (m, 2H), 7.17 (ddd, J=7.9, 2.1, 1.2 Hz, 1H).

EXAMPLE 58

Intermediate 25

Methyl 4-((4-Chloro-2-nitrophenyl)thio)benzoate

(178) ##STR00061##

(179) To a solution of 4-chloro-1-fluoro-2-nitrobenzene (1.0 g, 5.6 mmol) in MeOH (10 ml) was added methyl 4-mercaptobenzoate (0.95 g, 5.6 mmol) and 4M NaOH (1.4 ml, 5.6 mmol) and the reaction was stirred at room temperature for 2 hours, diluted with H.sub.2O, and the resulting suspension was filtered and washed with H.sub.2O to yield Intermediate 25 As a yellow solid (1.4 g, 78%).

(180) 1H NMR (CHLOROFORM-d) : 8.22 (s, 1H), 8.12 (d, J=7.9 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.34 (dd, J=8.8, 2.3 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 3.97 (s, 3H).

EXAMPLE 59

Intermediate 26

Methyl 4-((2-Amino-4-chlorophenyl)thio)benzoate

(181) ##STR00062##

(182) To a solution of Intermediate 25 (0.69 g, 2.1 mmol) in MeOH (15 ml) and CH.sub.2Cl.sub.2 (15 ml) was added saturated aqueous NH.sub.4Cl (20 ml) and zinc dust (3.5 g, 54 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, and dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product Intermediate 26 (0.63 g, 99%) was used in the next reaction without further purification.

(183) 1H NMR (CHLOROFORM-d) : 7.87 (d, J=8.5 Hz, 2H), 7.37 (d, J=8.2 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.82 (d, J=2.3 Hz, 1H), 6.75 (dd, J=8.2, 2.3 Hz, 1H), 4.36 (br. s., 2H), 3.88 (s, 3H).

EXAMPLE 60

Compound 34

4-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)benzoic Acid

(184) ##STR00063##

(185) To Intermediate 26 (0.62 g, 2.1 mmol) in pyridine (4 ml) was added benzofuran-2-sulfonyl chloride (0.46 g, 2.1 mmol) and the reaction was stirred at room temperature for 16 hours, when additional benzofuran-2-sulfonyl chloride (0.23 g, 1.1 mmol) was added. The reaction was continued for 24 hours and was concentrated in vacuo. The residue was taken up in MeOH and was treated with 4M NaOH (3 ml) at 100 C. for 15 minutes, and cooled, and acidified with 6M HCl, and the products extracted with EtOAc (2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) followed by re-crystallization from minimal acetone and CH.sub.2Cl.sub.2 to yield Compound 34 (0.23 g, 24%).

(186) 1H NMR (acetone) : 11.17 (br. s., 1H), 9.23 (br. s., 1H), 7.78 (d, J=2.1 Hz, 1H), 7.69-7.75 (m, 3H), 7.54 (s, 1H), 7.45-7.51 (m, 3H), 7.32-7.36 (m, 2H), 6.95-6.98 (m, 2H).

EXAMPLE 61

Intermediate 27

Methyl 3-((4-Chloro-2-nitrophenoxy) methyl)benzoate

(187) ##STR00064##

(188) To a solution of 4-chloro-2-nitrophenol (611 mg, 3.52 mmol) in DMF (10 ml) was added methyl 3-(bromomethyl)benzoate (807 mg, 3.52 mmol) and K.sub.2CO.sub.3 (1.46 g, 10.57 mmol) and the reaction was stirred at room temperature for 16 hours, and diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, and dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 27 (959 mg, 96%).

(189) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.08 (s, 1H), 8.02 (d, J=7.92 Hz, 1H), 7.87 (d, J=2.64 Hz, 1H), 7.69 (d, J=7.63 Hz, 1H), 7.46-7.51 (m, 2H), 7.06 (d, J=8.80 Hz, 1H), 5.26 (s, 2H), 3.94 (s, 3H).

EXAMPLE 62

Intermediate 28

Methyl 3-((2-(Benzofuran-2-sulfonamido)-4-chlorophenoxy)methyl)benzoate

(190) ##STR00065##

(191) To a solution Intermediate 27 (630 mg, 1.96 mmol) in MeOH (20 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (2.6 g, 39 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (2). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 28 (561 mg, 98%) was used in the next reaction without further purification.

(192) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.09 (dt, J=0.88, 1.76 Hz, 1H), 8.01 (d, J=7.34 Hz, 1H), 7.61 (d, J=7.63 Hz, 1H), 7.47 (t, J=7.78 Hz, 1H), 6.69-6.73 (m, 2H), 6.63 (dd, J=2.64, 8.51 Hz, 1H), 5.09 (s, 2H), 3.93 (s, 3H).

EXAMPLE 63

Compound 35

Methyl 3-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4chlorophenoxy}methyl)benzoate

(193) ##STR00066##

(194) To Intermediate 28 (561 mg, 1.93 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (416 mg, 1.93 mmol) and the reaction was stirred at 100 C. for 16 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 35 (651 mg, 72%).

(195) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.00-8.06 (m, 1H), 7.97 (d, J=0.88 Hz, 1H), 7.60-7.67 (m, 2H), 7.42-7.49 (m, 2H), 7.36-7.40 (m, 2H), 7.28-7.35 (m, 2H), 6.99 (dd, J=2.49, 8.66 Hz, 1H), 6.72 (d, J=8.80 Hz, 1H), 4.95 (s, 2H), 3.95 (s, 3H).

EXAMPLE 64

Compound 36

3-({2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}methyl)benzoic Acid

(196) ##STR00067##

(197) To Compound 35 (506 mg, 1.07 mmol) in MeOH (30 ml) was added 5M NaOH (2 ml) and the solution stirred at room temperature for 16 hours. The mixture was acidified with 10% HCl, and extracted with EtOAc (2). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH.sub.2Cl.sub.2 to yield Compound 36 (484 mg, 98%).

(198) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 13.01 (br. s., 1H), 10.57 (s, 1H), 7.78-7.84 (m, 2H), 7.62-7.67 (m, 1H), 7.42-7.47 (m, 2H), 7.37-7.42 (m, 2H), 7.31-7.35 (m, 1H), 7.27-7.31 (m, 2H), 7.24 (dd, J=2.35, 8.80 Hz, 1H), 7.00 (d, J=8.80 Hz, 1H), 4.87 (s, 2H).

EXAMPLE 65

Intermediate 29

Isochroman-1-one

(199) ##STR00068##

(200) To isochroman (3 g, 22.4 mmol) in xylene (30 ml) was added SeO.sub.2 (2.48 g, 22.4 mmol) and the mixture stirred at 140 C. for 20 hours, and then additional SeO.sub.2 (2.48 g, 22.4 mmol) was added and the reaction heated for 24 hours. The mixture was cooled down to room temperature, SeO.sub.2 was filtered away and xylene was removed in vacuo. The crude residue was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to yield Intermediate 29 (2.69g, 81%) as a pale red liquid.

(201) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.10 (dd, J=0.88, 7.63 Hz, 1H), 7.54 (td, J=1.47, 7.48 Hz, 1H), 7.37-7.41 (m, 1H), 7.24-7.28 (m, 1H), 4.51-4.55 (m, 2H), 3.06 (t, J=6.02 Hz, 2H).

EXAMPLE 66

Intermediate 30

2-(2-Hydroxyethyl)benzoic Acid

(202) ##STR00069##

(203) To a solution of Intermediate 29 (2.69 g, 17.97 mmol) in Et.sub.2O anhydrous (50 ml) was added powdered KOH (2.01 g, 35.94 mmol), and the reaction was stirred at room temperature for 12 hours. The ether solution was decanted, the residue solid was washed with ether, then dissolved in water. The aqueous solution was acidified with 10% HCl and then extracted with ether (3). The combine ether layers was dried over Na.sub.2SO.sub.4 and concentrated in vacuo to yield crude Intermediate 30 (2 g) which was used quickly in the next step without purification.

(204) .sup.1H NMR (600 MHz, DMSO-d.sub.6) 12.81 (br. s., 1H), 7.74 (dd, J=1.17, 7.63 Hz, 1H), 7.41-7.46 (m, 1H), 7.26-7.34 (m, 2H), 4.61 (br. s., 1H), 3.56 (t, J=7.04 Hz, 2H), 3.06 (t, J=7.04 Hz, 2H).

EXAMPLE 67

Intermediate 31

Methyl 2-(2-Hydroxyethyl)benzoate

(205) ##STR00070##

(206) To crude Intermediate 30 (2 g, 12.0 mmol) in anhydrous THF(12 ml) and MeOH (12 ml) under N.sub.2 atmosphere at 0 C. was added TMSCHN.sub.2 (7.8 ml, 15.66 mmol) via syringe until a persistent yellowish color was observed and development of gas ceased. The solvent was removed on rotary evaporator under vacuum to yield crude Intermediate 31 as a colorless oil.

EXAMPLE 68

Intermediate 32

Methyl 2-(2-(tosyloxy)ethyl)benzoate

(207) ##STR00071##

(208) To crude Intermediate 31 in anhydrous CHCl.sub.3 (25 ml) under N.sub.2 atmosphere at 0 C. was added TsCl (4.5 g, 24.0 mmol) in CHCl.sub.3 (10 ml) followed by addition of pyridine (3 ml, 36 mmol) immediately. The reaction was warmed up to room temperature and stirred for 12 hours, and diluted with water, and the products extracted with EtOAc. The combined organic layers were washed with brine, and dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to yield Intermediate 32 (2.2 g, 58%) as a clear oil.

(209) .sup.1H NMR (600 MHz, CDCl.sub.3) 7.88 (dd, J=1.32, 7.78 Hz, 1H), 7.65 (d, J=8.51 Hz, 2H), 7.37-7.46 (m, 1H), 7.28-7.32 (m, 1H), 7.19-7.26 (m, 3H), 4.29 (t, J=6.60 Hz, 2H), 3.83 (s, 3H), 3.32 (t, J=6.60 Hz, 2H), 2.42 (s, 3H).

EXAMPLE 69

Intermediate 33

Methyl 2-(2-Bromoethyl)benzoate

(210) ##STR00072##

(211) To Intermediate 32 (1.95 g, 5.84 mmol) in acetone (10 ml) was added LiBr (1.01 g, 11.68 mmol), and the mixture was heated to reflux for 5 hours under N.sub.2 atmosphere. The solvent was removed, and the residue diluted with water, and the products extracted with CH.sub.2Cl.sub.2. The combined organic layers were washed with brine, and dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The crude Intermediate 33 (1.38 g) was used for next step without purification.

(212) .sup.1H NMR (600 MHz, CDCl.sub.3) 7.96 (dd, J=1.47, 7.92 Hz, 1H), 7.44-7.51 (m, 1H), 7.28-7.37 (m, 2H), 3.91 (s, 3H), 3.64 (t, J=7.34 Hz, 2H), 3.51 (t, J=7.34 Hz, 2H).

EXAMPLE 70

Intermediate 34

Methyl 2-(2-(4-Chloro-2-nitrophenoxy)ethyl)benzoate

(213) ##STR00073##

(214) To a solution of 4-chloro-2-nitrophenol (985 mg, 5.68 mmol) in DMF (10 ml) was added crude Intermediate 33 (1.38 g, 5.68 mmol) and K.sub.2CO.sub.3 (3.9 g, 28.4 mmol) and the reaction was stirred at 90 C. for 16 hours, diluted with H.sub.2O, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 34 (520 mg, 27% for 2 steps).

(215) .sup.1H NMR (600 MHz, CDCl.sub.3) 7.96 (dd, J=1.17, 7.92 Hz, 1H), 7.79 (d, J=2.64 Hz, 1H), 7.47-7.53 (m, 1H), 7.41-7.46 (m, 2H), 7.33 (td, J=1.17, 7.63 Hz, 1H), 7.07 (d, J=8.80 Hz, 1H), 4.39 (t, J=6.31 Hz, 2H), 3.91 (s, 3H), 3.49 (t, J=6.31 Hz, 2H).

EXAMPLE 71

Intermediate 35

Methyl 2-(2-(2-Amino-4-chlorophenoxy)ethyl)benzoate

(216) ##STR00074##

(217) To a solution Intermediate 34 (685 mg, 2.04 mmol) in MeOH (20 ml) was added saturated aqueous NH.sub.4Cl (2 ml) and zinc dust (3.3 g, 51 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (2). The combined organic layers were washed with brine, and dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude Intermediate 35 (557 mg, 89%) was used in the next reaction without further purification.

(218) .sup.1H NMR (600 MHz, CDCl.sub.3) 7.94 (dd, J=0.88, 7.63 Hz, 1H), 7.47 (dd, J=1.17, 7.63 Hz, 1H), 7.36 (d, J=7.63 Hz, 1H), 7.32 (td, J=1.17, 7.63 Hz, 1H), 6.69 (d, J=8.51 Hz, 1H), 6.65 (d, J=2.35 Hz, 1H), 6.60-6.64 (m, 1H), 4.23 (t, J=6.60 Hz, 2H), 3.90 (s, 3H), 3.79 (br. s., 2H), 3.49 (t, J=6.46 Hz, 2H).

EXAMPLE 72

Compound 37

Methyl 2-(2-{2-[(1-Benzofuran-2-ylsulfonyl)amino]-4chlorophenoxy}ethyl)benzoate

(219) ##STR00075##

(220) To Intermediate 35 (555 mg, 1.82 mmol) in pyridine (5 ml) was added benzofuran-2-sulfonyl chloride (393 mg, 1.82 mmol) and the reaction was stirred at 100 C. for 16 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 37 (634 mg, 88%).

(221) .sup.1H NMR (600 MHz, CDCl.sub.3) 7.97 (dd, J=1.17, 7.92 Hz, 1H), 7.60-7.64 (m, 1H), 7.55 (d, J=2.64 Hz, 1H), 7.53 (td, J=1.47, 7.48 Hz, 1H), 7.40-7.48 (m, 3H), 7.35 (td, J=1.17, 7.63 Hz, 1H), 7.28-7.32 (m, 2H), 6.95 (dd, J=2.49, 8.66 Hz, 1H), 6.69 (d, J=8.80 Hz, 1H), 4.13 (t, J=6.46 Hz, 2H), 3.92 (s, 3H), 3.36 (t, J=6.31 Hz, 2H).

EXAMPLE 73

Compound 38

2-(2-{2-[(1-Benzofuran-2-ylsulfonyl)amino]-4-chlorophenoxy}ethyl)benzoic Acid

(222) ##STR00076##

(223) To Compound 37 (505 mg, 1.04 mmol) in MeOH (30 ml) was added 5M NaOH (2 ml) and the reaction was stirred at room temperature for 16 hours. The mixture was acidified with 10% HCl, and extracted with EtOAc (2). The combined organic layers were washed with brine, and dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH.sub.2Cl.sub.2 to yield Compound 38 (454 mg, 93%).

(224) .sup.1H NMR (600 MHz, CDCl.sub.3) 8.07 (d, J=7.92 Hz, 1H), 7.67 (br. s., 1H), 7.61 (d, J=7.92 Hz, 1H), 7.55 (td, J=1.17, 7.48 Hz, 1H), 7.52 (d, J=2.35 Hz, 1H), 7.35-7.46 (m, 3H), 7.27-7.35 (m, 3H), 6.93 (dd, J=2.49, 8.66 Hz, 1H), 6.65 (d, J=8.80 Hz, 1H), 4.10 (t, J=6.46 Hz, 2H), 3.45 (t, J=6.02 Hz, 2H).

Biological Data

(225) HEK-Gqi5 cells stably expressing CCR2 were cultured in DMEM high glucose, 10% FBS, 1% PSA, 400 pg/ml geneticin and 50 g/ml hygromycin. Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) was used as the positive control agonist for screening compound-induced calcium activity assayed on the FLIPR.sup.Tetra. The drug plates were prepared in 384-well microplates using the EP3 and the MuItiPROBE robotic liquid handling systems. Compounds were synthesized and tested for CCR2 activity.

(226) Table 1 shows activity: CCR2 receptor (IC.sub.50) nM

(227) TABLE-US-00001 CCR2 CCR2 ANTAG- IC50 ONISM IUPAC Name (nM) (%) N-(5-chloro-2-methoxyphenyl)-1-benzofuran-2- 512 97 sulfonamide N-(5-chloro-2-methylphenyl)-1-benzofuran-2- 359 84 sulfonamide N-[5-chloro-2-(trifluoromethoxy)phenyl]-1- 195 95 benzofuran-2-sulfonamide methyl 2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 1376 95 chlorobenzoate N-(5-chloro-2-ethoxyphenyl)-1-benzofuran-2- 1662 73 sulfonamide N-(5-chloro-2-ethynylphenyl)-1-benzofuran-2- 117 93 sulfonamide N-{5-chloro-2-[(4-oxopiperidin-1- 110 93 yl)carbonyl]phenyl}-1-benzofuran-2-sulfonamide N-[5-chloro-2-(morpholin-4-ylcarbonyl)phenyl]- 569 84 1-benzofuran-2-sulfonamide N-{5-chloro-2-[(2-methylpyridin-3- 365 96 yl)oxy]phenyl}-1-benzofuran-2-sulfonamide methyl 2-{2-[(1-benzofuran-2-ylsulfonyl)amino]- 1018 98 4-chlorophenoxy}benzoate 2-{2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 60 97 chlorophenoxy}benzoic acid N-[5-chloro-2-(phenylsulfanyl)phenyl]-1- 124 90 benzofuran-2-sulfonamide N-[5-chloro-2-(phenylsulfonyl)phenyl]-1- 1971 78 benzofuran-2-sulfonamide N-[5-chloro-2-(phenylsulfinyl)phenyl]-1- 6 105 benzofuran-2-sulfonamide 2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chloro- 328 95 N-phenylbenzamide N-(5-chloro-2-cyanophenyl)-1-benzofuran-2- 409 102 sulfonamide N-[5-chloro-2-(phenylacetyl)phenyl]-1- 183 79 benzofuran-2-sulfonamide N-{5-chloro-2-[(1Z)-N-methoxy-2- nd 76 phenylethanimidoyl]phenyl}-1-benzofuran-2- sulfonamide N-{5-chloro-2-[(1Z)-N-hydroxy-2- nd 72 phenylethanimidoyl]phenyl}-1-benzofuran-2- sulfonamide N-[2-(benzyloxy)-5-chlorophenyl]-1-benzofuran- 1629 87 2-sulfonamide N-[5-chloro-2-(phenylethynyl)phenyl]-1- nd 30 benzofuran-2-sulfonamide N-[5-chloro-2-(2-phenylethyl)phenyl]-1- nd 84 benzofuran-2-sulfonamide N-[5-methyl-2-(phenylsulfanyl)phenyl]-1- nd 41 benzofuran-2-sulfonamide N-[5-methyl-2-(phenylsulfinyl)phenyl]-1- 2875 92 benzofuran-2-sulfonamide N-[5-methyl-2-(phenylsulfonyl)phenyl]-1- nd 38 benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfanyl)phenyl]-1- nd 74 benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfinyl)phenyl]-1- 317 91 benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfonyl)phenyl]-1- 2618 82 benzofuran-2-sulfonamide 2-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 27 99 chlorophenoxy}methyl)benzoic acid