EBNA1 inhibitors and their method of use

2-Amino-3-bromo-benzoic acid methyl ester: 2-Amino-3-bromo-benzoic acid (5 g, 23 mmol) was dissolved in methanol (30 mL), concentrated sulfuric acid (1 mL) was added dropwise and the reaction mixture was refluxed at 80° C. for 24 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. The residue was diluted by water (10 mL) and basified with saturated sodium bicarbonate solution, extracted by ethyl acetate (20 mL×3). The organic layer was dried (anhydrous magnesium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (10%) to give the product as a colorless oil (5 g, 95%).

3-Bromo-2-pyrrol-1-yl-benzoic acid methyl ester. 2,5-Dimethoxy-tetrahydrofuran (1.7 g, 13 mmol) and 4-chloropyridine HCl salt (2 g, 13 mmol) were mixed in anhydrous 1,4-dioxane (30 mL) and stirred at room temperature for 15 minutes. To the solution was added 2-amino-3-bromo-benzoic acid methyl ester (3 g, 13 mmol) and the reaction mixture was refluxed at 120° C. for 2 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with ethyl acetate. The filtrate was concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (10%-20%) to give the product as a white solid (3.2 g, 87%).

3-Ethynyl-2-pyrrol-1-yl-benzoic acid methyl ester. To a pressure flask was loaded a mixture of 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester (4 g, 14.2 mmol), Pd(PPh 3 ) 2 Cl 2 (501 mg, 0.71 mmol) and CuI (270 mg, 1.42 mmol) in triethylamine (40 mL), the mixture was degassed with N 2 for 10 minutes, trimethylsilylacetylene (10 mL) was added and the mixture was further degassed for 3 minutes. The flask was sealed with a PTFE plug and heated at 86° C. for 17 hour. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (5%-20%) to give a solid intermediate. The solid intermediate was dissolved in tetrahedrofuran (20 mL), tetrabutylammonium fluoride (1 N in THF, 20 mL, 20 mmol) was added and the reaction mixture was stirred for 10 minutes and concentrated. The residue was purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (10-20%) to give the product as a white solid (1.7 g, 53% for 2 steps)

3-(3-Methylsulfamoyl-phenylethynyl)-2-pyrrol-1-yl-benzoic acid. A mixture of 3-ethynyl-2-pyrrol-1-yl-benzoic acid methyl ester (40 mg, 0.18 mmol), 3-bromo-N-methyl-benzenesulfonamide (90 mg, 0.36 mmol), palladium tetrakis-triphenylphosphine (21 mg, 0.018 mmol) and copper iodide (6.8 mg, 0.036 mmol), potassium carbonate (50 mg, 0.36 mmol) in 1,2-dimethoxyethane/water (1 mL/0.2 mL) was degassed with N 2 for 5 minutes and then heated at 60° C. for 4 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by preparative thin layered chromatography eluting with ethyl acetate/hexane (30%) to give the ester intermediate. To the ester intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 19 mg (28% for 2 steps) of the pure product as a white solid. 1 H NMR (CDCl 3 ) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.82-7.72 (m, 3H), 7.49-7.30 (m, 3H), 6.88 (t, J=2.2 Hz, 2H), 6.34 (t, J=2.2 Hz, 2H), 2.6 (s, 3H). MS (ESI) m/z 380.9 (M+1) + .

3-(1H-Indol-3-ylethynyl)-2-pyrrol-1-yl-benzoic acid was prepared by the same procedure as example 1. 1 H NMR (CDCl 3 ) δ 7.87 (dd, J=7.8, 1.6 Hz, 1H), 7.82-7.72 (m, 3H), 7.49-7.30 (m, 3H), 6.88 (t, J=2.2 Hz, 2H), 6.34 (t, J=2.2 Hz, 2H), 2.6 (s, 3H). MS (ESI) m/z 380.9 (M+1) + .

3-[2-(3-methanesulfonamidophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.84 (dd, J=1.6, 7.8 Hz, 1H), 7.74 (dd, J=1.5, 7.6 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.28-7.08 (m, 4H), 6.88 ((t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H), 2.65 (s, 3H). MS (ESI) m/z 380.9 (M+1) + .

2-(1H-pyrrol-1-yl)-3-[2-(3-sulfamoylphenyl)ethynyl]benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.97-7.82 (m, 3H), 7.75 (d, J=8.8 Hz, 1H), 7.56-7.38 (m, 3H), 6.89 (t, J=2.1 Hz, 2H), 6.35 (t, J=2.1 Hz, 2H). MS (ESI) m/z 366.9 (M+1) + .

3-[2-(3-carbamoylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.84 (dd, J=1.6, 7.8 Hz, 1H), 7.82-7.72 (m, 3H), 7.50-7.25 (m, 3H), 6.88 ((t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H). MS (ESI) m/z 330.9 (M+1) + .

3-(2-{imidazo[1,2-a]pyridin-6-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.24 (s, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.92-7.83 (m, 2H), 7.74-7.64 (m, 2H), 7.51-7.43 (m, 2H), 6.85 (t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H). MS (ESI) m/z 328.0 (M+1) + .

3-[2-(2-hydroxypyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.19 (br. s., 1H), 8.03 (br. s., 1H), 7.90 (d, J=7.7 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.31-7.28 (m, 1H), 6.86 (t, J=2.1 Hz, 2H), 6.34 (t, J=2.1 Hz, 2H). MS (ESI) m/z 305.0 (M+1) + .

3-[2-(1H-indazol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.02 (br. S., 1H), 7.85 (dd, J=1.8, 7.8 Hz, 1H), 7.78 (dd, J=1.5, 7.7 Hz, 1H), 7.70-7.59 (m, 3H), 7.46 (t, J=7.9 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.93 (t, J=2.1 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H). MS (ESI) m/z 328.0 (M+1) + .

Example 9: Synthesis of 3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[3-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid: To a pressure tube was added a mixture of 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester (50 mg, 0.18 mmol), 1-(3-ethynyl-phenyl)-3,3-dimethyl-azetidin-2-one (71 mg, 0.28 mmol), Pd(PPh 3 ) 2 Cl 2 (12.6 mg, 0.018 mmol) and CuI (6.9 mg, 0.036 mmol) in triethylamine (1 mL). The mixture was degassed with N 2 for 10 minutes and then heated at 90° C. for 17 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography through preparative thin layer chromatography eluting with ethyl acetate/hexane (30%) to give a solid intermediate. To the solid intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 12 mg (17% for 2 steps) of the pure product as a yellow solid. 1 H NMR (300 MHz, CDCl 3 ) δ=7.85 (dd, J=1.6, 7.8 Hz, 1H), 7.74 (dd, J=1.6, 7.8 Hz, 1H), 7.53-7.35 (m, 2H), 7.34-7.22 (m, 1H), 7.15 (t, J=5.0 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.89 (t, J=2.1 Hz, 2H), 6.35 (t, J=2.1 Hz, 2H), 3.44 (s, 2H), 2.56 (s, 6H). MS (ESI) m/z 385.1 (M+1) + .

Example 10: Synthesis of 3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid

3-(2-{3-[(2-carboxy-2,2-dimethylethyl)amino]phenyl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was isolated as a second product in purifying example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.82 (d, J=7.6 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 6.88 (t, J=2.1 Hz, 2H), 6.75-6.58 (m, 3H), 6.33 (t, J=2.1 Hz, 2H), 3.22 (s, 2H), 1.30 (s, 6H). MS (ESI) m/z 403.1 (M+1) + .

3-(2-{imidazo[1,2-a]pyrazin-3-yl)}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, DMSO) δ=13.1 (br. s., 1H), 9.15 (d, J=1.5 Hz, 1H), 8.12-8.04 (m, 2H), 7.95-7.89 (m, 2H), 7.82 (d, J=7.6 Hz, 1H), 7.61 (t, J=7.7 Hz, 1H), 6.97 (t, J=2.2 Hz, 2H), 6.30 (t, J=2.2 Hz, 2H). MS (ESI) m/z 328.9 (M+1) + .

3-(2-{imidazo[1,2-a]pyridin-3-yl)}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.94 (dd, J=1.6, 7.8 Hz, 1H), 7.91-7.84 (m, 2H), 7.81 (dd, J=1.5, 7.9 Hz, 1H), 7.76-7.70 (m, 1H), 7.58-7.50 (m, 2H), 7.07 (t, J=6.9 Hz, 1H), 6.89 (t, J=2.1 Hz, 2H), 6.40 (t, J=2.1 Hz, 2H). MS (ESI) m/z 328.0 (M+1) + .

3-(2-{imidazo[1,2-a]pyridin-5-yl}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.14 (d, J=9.1 Hz, 1H), 8.03 (dd, J=1.5, 7.9 Hz, 1H), 7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.81 (d, J=4.1 Hz, 1H), 7.66-7.56 (m, 2H), 7.38-7.30 (m, 2H), 6.89 (t, J=2.0 Hz, 2H), 6.41 (t, J=2.0 Hz, 2H). MS (ESI) m/z 328.0 (M+1) + .

2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-5-yl}ethynyl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.15 (br. s., 1H), 8.01 (s, 1H), 7.87 (s, 1H), 7.74 (dd, J=1.6, 7.6 Hz, 1H), 7.67 (dd, J=1.6, 7.9 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.31-7.23 (m, 1H), 6.83 (t, J=2.2 Hz, 2H), 6.46-6.31 (m, 1H), 6.27 (t, J=2.2 Hz, 2H). MS (ESI) m/z 328.0 (M+1) + .

3-[2-(1-methyl-1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.81 (dt, J=1.5, 7.8 Hz, 2H), 7.44 (t, J=7.8 Hz, 1H), 7.22-7.07 (m, 3H), 6.94 (t, J=2.2 Hz, 2H), 6.43 (d, J=3.2 Hz, 2H), 6.35 (t, J=2.2 Hz, 2H), 3.79 (s, 3H). MS (ESI) m/z 341.0 (M+1) + .

3-[2-(1-methyl-1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.87-7.55 (m, 3H), 7.53-7.40 (m, 1H), 7.27-7.19 (m, 2H), 7.05 (d, J=2.9 Hz, 1H), 7.00-6.85 (m, 2H), 6.46 (d, J=2.9 Hz, 1H), 6.40-6.25 (m, 2H), 3.78 (s, 3H). MS (ESI) m/z 341.0 (M+1) + .

3-[2-(1-benzothiophen-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.90 (dd, J=1.6, 7.8 Hz, 1H), 7.82-7.75 (m, 3H), 7.52-7.41 (m, 2H), 7.32-7.28 (m, 2H), 6.91 (t, J=2.1 Hz, 2H), 6.40 (t, J=2.2 Hz, 2H). MS (ESI) m/z 344.0 (M+1) + .

3-[2-(1H-indol-7-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.24 (br. s., 1H), 7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.83 (dd, J=1.6, 7.8 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H), 7.35-7.26 (m, 1H), 7.18 (t, J=2.8 Hz, 1H), 7.04 (t, J=7.7 Hz, 1H), 6.97 (t, J=2.2 Hz, 2H), 6.56-6.43 (m, 3H). MS (ESI) m/z 327.0 (M+1) + .

3-{2-[2-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, DMSO) δ=7.81 (dd, J=1.6, 7.8 Hz, 1H), 7.74 (dd, J=1.4, 7.6 Hz, 1H), 7.60-7.34 (m, 3H), 7.30-7.19 (m, 2H), 6.87 (t, J=2.2 Hz, 2H), 6.20 (t, J=2.2 Hz, 2H), 5.18 (t, J=5.6 Hz, 1H), 4.45 (d, J=5.0 Hz, 2H). MS (ESI) m/z 317.9 (M+1) + .

3-{2-[4-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.82 (dd, J=1.6, 7.8 Hz, 1H), 7.73 (dd, J=1.6, 7.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.35-7.27 (m, 4H), 6.88 (t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H), 4.64 (s, 2H). MS (ESI) m/z 317.9 (M+1) + .

3-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid: A mixture of 2-amino-3-bromo-benzoic acid (2 g, 9.26 mmol) in hexane-2, 5-dione (20 mL) was heated at 100° C. for 3 days, allowed to cool to ambient temperature and then partitioned between water and ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), concentrated and purified by HPLC to give the product as a solid (1.6 g, 59%).

3-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid methyl ester. To a solution of 3-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid (1.4 g, 4.8 mmol) in ether (30 mL) and methanol (10 mL) at 0° C. was added trimethylsilyldiazomethane (2 M in hexane, 4.8 mL, 9.5 mmol) dropwise. After addition the reaction mixture was stirred at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to quench the reaction and the solution was concentrated and purified by column chromatography through eluting with ethyl acetate/hexane (10%) to give the desired product 3-Bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid methyl ester as a solid.

2-(2,5-dimethyl-pyrrol-1-yl)-3-p-tolylethynyl-benzoic acid: To a pressure tube was loaded a mixture of 3-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid methyl ester (40 mg, 0.13 mmol), 1-ethynyl-4-methyl-benzene (75 mg, 0.65 mmol), Pd(PPh 3 ) 2 Cl 2 (9.1 mg, 0.013 mmol) and CuI (5 mg, 0.026 mmol) in triethylamine (1 mL). The mixture was degassed with N 2 for 10 minutes and then heated at 90° C. for 17 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography through preparative thin layer chromatography eluting with ethyl acetate/hexane (20%) to give a solid. To solid in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 6 mg (14% for 2 steps) of the pure product as a brown solid. 1 H NMR (300 MHz, CDCl 3 ) δ=8.07 (dd, J=1.8, 7.9 Hz, 1H), 7.80 (dd, J=1.5, 7.9 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.26-7.07 (m, 4H), 5.98 (s, 2H), 3.98 (s, 2H), 2.33 (s, 3H), 1.97 (s, 6H). MS (ESI) m/z 330.0 (M+1) + .

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CDCl 3 ) δ=8.06 (dd, J=1.5, 7.6 Hz, 1H), 7.80 (dd, J=1.5, 7.6 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.15 (t, J=7.9 Hz, 1H), 6.91-6.70 (m, 3H), 5.98 (s, 2H), 5.61 (br. s., 1H), 1.97 (s, 6H). MS (ESI) m/z 332.1 (M+1) + .

3-[2-(2,3-dihydro-1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 332.1 (M−H 2 O) + .

3-[2-(1-methyl-1H-pyrazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 292.0 (M+1) + .

3-[2-(1,2-dimethyl-1H-imidazol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 306.1 (M+1) + .

3-[2-(1-methyl-1H-imidazol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 292.1 (M+1) + .

3-[2-(1-methyl-1H-imidazol-2-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 292.1 (M+1) + .

2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-5-yl)ethynyl]benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 295.0 (M+1) + .

2-(1H-pyrrol-1-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 295.0 (M+1) + .

Example 30: Synthesis of 2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-6-yl}ethynyl) benzoic acid

2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-6-yl}ethynyl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 328.0 (M+1) + .

Example 31: Synthesis of 3-{2-[3-(2-hydroxypropan-2-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[3-(2-hydroxypropan-2-yl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.84 (dd, J=1.6, 7.6 Hz, 1H), 7.74 (dd, J=1.6, 7.8 Hz, 1H), 7.50-7.41 (m, 2H), 7.34-7.17 (m, 3H), 6.89 (t, J=2.1 Hz, 2H), 6.34 (t, J=2.1 Hz, 2H), 1.56 (s, 6H). MS (ESI) m/z 346.1 (M+1) + .

3-(3-hydroxy-4-methylpent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.87 (dd, J=1.5, 7.9 Hz, 1H), 7.67 (dd, J=1.5, 7.6 Hz, 1H), 7.42 (t, J=7.7 Hz, 1H), 6.76 (t, J=2.1 Hz, 2H), 6.28 (t, J=2.1 Hz, 2H), 4.22 (dd, J=5.7, 12.2 Hz, 1H), 2.01-1.73 (m, 1H), 0.89 (d, J=6.7 Hz, 6H). MS (ESI) m/z 266.1 (M−H 2 O) + .

3-(3-hydroxy-3-phenylprop-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.84 (d, J=7.5 Hz, 1H), 7.68 (dd, J=1.6, 7.8 Hz, 1H), 7.44-7.19 (m, 6H), 6.83 (t, J=2.2 Hz, 2H), 6.31 (t, J=2.2 Hz, 2H), 5.48 (s, 1H). MS (ESI) m/z 300.0 (M−H 2 O) + .

2-(1H-pyrrol-1-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, DMSO) δ=12.14 (br. s., 1H), 8.26 (d, J=3.5 Hz, 1H), 7.79-7.70 (m, 3H), 7.68 (dd, J=1.6, 7.8 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.13 (dd, J=4.7, 7.9 Hz, 1H), 6.92 (t, J=2.2 Hz, 2H), 6.24 (t, J=2.2 Hz, 2H). MS (ESI) m/z 328.0 (M+H) + .

3-[2-(1H-indol-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.85-7.79 (m, 2H), 7.44 (t, J=8.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.24-7.18 (m, 2H), 7.11 (t, J=7.9 Hz, 1H), 6.95 (t, J=2.2 Hz, 2H), 6.51-6.47 (m, 1H), 6.36 (t, J=2.2 Hz, 2H). MS (ESI) m/z 327.0 (M+H) + .

Example 36: Synthesis of 2-(1H-pyrrol-1-yl)-3-(2-{[1,2,4]triazolo[1,5-a]pyridin-7-yl}ethynyl)benzoic acid

2-(1H-pyrrol-1-yl)-3-(2-{[1,2,4]triazolo[1,5-a]pyridin-7-yl}ethynyl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.51 (d, J=7.0 Hz, 1H), 8.38 (s, 1H), 7.93 (dd, J=1.6, 7.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.75 (s, 1H), 7.49 (t, J=7.9 Hz, 1H), 6.93-6.87 (m, 3H), 6.37 (t, J=2.1 Hz, 2H). MS (ESI) m/z 329.1 (M+H) + .

3-{2-[3-(dimethylsulfamoyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.82-7.64 (m, 3H), 7.50-7.42 (m, 3H), 6.89 (t, J=2.1 Hz, 2H), 6.34 (t, J=2.1 Hz, 2H), 2.76 (s, 6H). MS (ESI) m/z 395.1 (M+H) + .

3-[2-(3-fluoro-5-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.84 (dd, J=1.6, 7.8 Hz, 1H), 7.72 (dd, J=1.6, 7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 6.87 (t, J=2.2 Hz, 2H), 6.64-6.47 (m, 3H), 6.33 (t, J=2.2 Hz, 2H). MS (ESI) m/z 322.0 (M+H) + .

3-{2-[3-(hydroxymethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.83 (d, J=8.0 Hz, 1H), 7.73 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.36-7.23 (m, 4H), 6.89 (t, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 2H), 4.63 (s, 2H). MS (ESI) m/z 318.0 (M+H) + .

3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.15 (s, 1H), 8.02 (s, 1H), 7.89 (dd, J=1.6, 7.8 Hz, 1H), 7.75 (dd, J=1.6, 7.8 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.25-7.22 (m, 1H), 6.87 (t, J=2.2 Hz, 2H), 6.34 (t, J=2.2 Hz, 2H). MS (ESI) m/z 305.1 (M+H) + .

3-[2-(5-hydroxypyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. MS (ESI) m/z 328.1 (M+H) + .

3-[2-(1H-indol-5-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=8.03 (s, 1H), 7.82 (dd, J=1.6, 7.8 Hz, 1H), 7.79-7.73 (m, 2H), 7.47-7.40 (m, 2H), 7.34-7.28 (m, 1H), 6.92 (t, J=2.2 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H). MS (ESI) m/z 328.1 (M+H) + .

3-[2-(1H-indol-6-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, DMSO) δ=11.29 (br. s., 1H), 7.79 (dd, J=1.5, 7.7 Hz, 1H), 7.69 (dd, J=1.6, 7.8 Hz, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.44 (t, J=2.8 Hz, 1H), 7.37 (s, 1H), 6.95-6.90 (m, 3H), 6.46-6.42 (m, 1H), 6.24 (t, J=2.2 Hz, 2H). MS (ESI) m/z 327.0 (M+H) + .

3-[2-(4-methylphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.88 (dd, J=1.6, 7.8 Hz, 1H), 7.77 (dd, J=1.5, 7.6 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.20 (d, J=7.5 Hz, 2H), 7.10 (d, J=7.5 Hz, 2H), 6.88 (t, J=2.2 Hz, 2H), 6.37 (t, J=2.1 Hz, 2H), 2.34 (s, 3H). MS (ESI) m/z 302.0 (M+H) + .

3-[2-(3,5-difluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.95 (d, J=8.0 Hz, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 6.87-6.74 (m, 5H), 6.39 (t, J=2.1 Hz, 2H). MS (ESI) m/z 323.2 (M−H 2 O) + .

3-{2-[3-(difluoromethoxy)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 1. 1 H NMR (300 MHz, CDCl 3 ) δ=7.92 (dd, J=1.8, 7.8 Hz, 1H), 7.78 (dd, J=1.6, 7.8 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.33-7.22 (m, 1H), 7.19-7.14 (m, 1H), 7.10-7.04 (m, 2H), 6.86 (t, J=2.2 Hz, 2H), 6.49 (t, J=73.6 Hz, 1H), 6.37 (t, J=2.2 Hz, 2H). MS (ESI) m/z 354.1 (M+H) + .

To 3-ethynyl-2-pyrrol-1-yl-benzoic acid methyl ester (50 mg, 0.22 mmol) in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 43 mg (92%) of the pure product as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=7.70-7.58 (m, 2H), 7.39 (t, J=7.8 Hz, 1H), 6.80 (t, J=2.1 Hz, 1H), 6.31 (t, J=2.1 Hz, 2H), 3.65 (s, 2H). MS (ESI) m/z 212.0 (M+H) + .

3-(3-amino-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, DMSO) δ=8.49 (br. s., 2H), 7.76 (dd, J=1.8, 7.6 Hz, 1H), 7.66 (dd, J=1.8, 7.6 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H), 6.82 (t, J=2.2 Hz, 2H), 6.17 (t, J=2.2 Hz, 2H), 1.41 (s, 6H). MS (ESI) m/z 269.0 (M+H) + .

3-(3,3-dimethylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.78 (dd, J=1.2, 7.6 Hz, 1H), 7.61 (dd, J=1.2, 7.6 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 6.76 (t, J=1.9 Hz, 2H), 6.26 (t, J=1.9 Hz, 2H), 1.14 (s, 9H). MS (ESI) m/z 268.2 (M+H) + .

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CDCl 3 ) δ=8.04 (dd, J=1.6, 7.8 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.52 (t, J=7.9 Hz, 1H), 7.36-7.21 (m, 5H), 5.97 (s, 2H), 1.97 (s, 6H). MS (ESI) m/z 316.0 (M+H) + .

5-Bromo-4-pyrrol-1-yl-nicotinic acid methyl ester was prepared in the same manner as 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester.

2-(2,5-dimethyl-1H-pyrrol-1-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 9 starting from 5-bromo-4-pyrrol-1-yl-nicotinic acid methyl ester. MS (ESI) m/z 307.0 (M+H) + .

5-(2-phenylethynyl)-4-(1H-pyrrol-1-yl)pyridine-3-carboxylic acid was prepared by the same procedure as example 51. MS (ESI) m/z 289.0 (M+H) + .

Example 53: Synthesis of 3-[2-(1-aminocyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid trifluoroacetic acid

3-[2-(1-aminocyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid trifluoroacetic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.87 (dd, J=1.5, 7.9 Hz, 1H), 7.68 (dd, J=1.6, 7.8 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 6.77 (t, J=2.2 Hz, 2H), 6.25 (t, J=2.2 Hz, 2H), 3.22 (br. s., 2H), 2.00-1.95 (m, 2H), 1.79-1.51 (m, 5H), 1.48-1.05 (m, 3H). MS (ESI) m/z 292.1 (M−H 2 O) + .

3-[2-(1-hydroxycyclohexyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.78 (d, J=7.7 Hz, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 6.76 (t, J=2.0 Hz, 2H), 6.23 (t, J=2.0 Hz, 2H), 1.84-1.71 (m, 2H), 1.62-1.10 (m, 8H). MS (ESI) m/z 292.1 (M−H 2 O) + .

3-(4-ethyl-3-hydroxyoct-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. MS (ESI) m/z 322.2 (M−H 2 O) + .

3-(2-{imidazo[1,2-a]pyrazin-6-yl)}ethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, DMSO) δ=9.03 (s, 1H), 8.64 (s, 1H), 8.19 (s, 1H), 7.93-7.75 (m, 2H), 7.57 (dd, J=1.6, 7.8 Hz, 1H), 7.56 (t, J=7.8 Hz, 1H), 6.92 (t, J=2.2 Hz, 2H), 6.24 (t, J=2.2 Hz, 2H). MS (ESI) m/z 328.9 (M+H) + .

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.79 (dd, J=1.6, 7.8 Hz, 1H), 7.66 (dd, J=1.6, 7.8 Hz, 1H), 7.39 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.0 Hz, 1H), 6.90-6.71 (m, 5H), 6.30 (t, J=2.2 Hz, 2H), MS (ESI) m/z 304.1 (M+H) + .

3-Bromo-5-chloro-2-pyrrol-1-yl-benzoic acid methyl ester was prepared in the same manner as 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester.

5-chloro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9 starting from 3-bromo-5-chloro-2-pyrrol-1-yl-benzoic acid methyl ester. 1 H NMR (300 MHz, CDCl 3 ) δ=7.85 (d, J=3.6 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.33-7.23 (m, 2H), 7.04-6.95 (m, 2H), 6.82 (t, J=2.0 Hz, 2H), 6.36 (t, J=2.0 Hz, 2H). MS (ESI) m/z 340.1 (M+H) + .

5-Chloro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 58. 1 H NMR (300 MHz, CDCl 3 ) δ=7.83 (d, J=2.3 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.35-7.25 (m, 5H), 6.82 (t, J=2.0 Hz, 2H), 6.35 (t, J=1.8 Hz, 2H). MS (ESI) m/z 322.1 (M+H) + .

3-Bromo-5-fluoro-2-pyrrol-1-yl-benzoic acid methyl ester was prepared in the same manner as 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester.

5-Fluoro-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9 starting from 3-bromo-5-fluoro-2-pyrrol-1-yl-benzoic acid methyl ester. 1 H NMR (300 MHz, CDCl 3 ) δ=7.59 (dd, J=2.9, 8.2 Hz, 1H), 7.45 (dd, J=2.6, 7.9 Hz, 1H), 7.31-7.24 (m, 2H), 7.02-6.94 (m, 2H), 6.82 (t, J=2.0 Hz, 2H), 6.35 (t, J=2.0 Hz, 2H). MS (ESI) m/z 324.0 (M+H) + .

5-fluoro-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 60. 1 H NMR (300 MHz, CDCl 3 ) δ=7.58 (dd, J=3.1, 8.1 Hz, 1H), 7.46 (dd, J=2.9, 8.2 Hz, 1H), 7.36-7.25 (m, 5H), 6.81 (t, J=2.2 Hz, 2H), 6.35 (t, J=2.1 Hz, 2H).

3-(2-cyclopropylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.77 (dd, J=1.6, 7.8 Hz, 1H), 7.61 (dd, J=1.6, 7.8 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 6.74 (t, J=2.2 Hz, 2H), 6.26 (t, J=2.2 Hz, 2H), 1.31-1.22 (m, 1H), 0.83-0.69 (m, 2H), 0.69-0.60 (m, 2H). MS (ESI) m/z 234.0 (M−H 2 O) + .

3-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.77 (d, J=7.7 Hz, 1H), 7.57 (dd, J=1.6, 7.8 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 6.75 (t, J=2.2 Hz, 2H), 6.24 (t, J=2.2 Hz, 2H), 1.39 (s, 6H). MS (ESI) m/z 252.1 (M−H 2 O) + .

3-[3-(dimethylamino)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.95 (dd, J=1.6, 7.8 Hz, 1H), 7.70 (dd, J=1.6, 7.8 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 6.78 (t, J=2.2 Hz, 2H), 6.26 (t, J=2.1 Hz, 2H), 4.01 (s, 2H), 2.61 (s, 6H). MS (ESI) m/z 269.1 (M+H) + .

3-(4-phenylbut-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.78 (dd, J=1.6, 7.8 Hz, 1H), 7.60 (dd, J=1.6, 7.8 Hz, 1H), 7.37-7.09 (m, 6H), 6.76 (t, J=2.2 Hz, 2H), 6.28 (t, J=2.1 Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.55 (t, J=7.3 Hz, 2H). MS (ESI) m/z 316.1 (M+H) + .

3-(5-hydroxypent-1-yn-1-yl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.77 (d, J=7.8 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H), 7.29 (t, J=7.8 Hz, 1H), 6.78 (t, J=2.2 Hz, 2H), 6.30 (t, J=2.2 Hz, 2H), 3.53 (t, J=9.5 Hz, 2H), 2.40 (t, J=9.7 Hz, 2H), 1.71-1.62 (m, 2H). MS (ESI) m/z 270.1 (M+H) + .

3-[2-(4-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.86 (dd, J=1.6, 7.8 Hz, 1H), 7.75 (dd, J=1.5, 7.9 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.29-7.23 (m, 2H), 6.89-6.80 (m, 4H), 6.36 (t, J=2.2 Hz, 2H), 3.80 (s, 3H). MS (ESI) m/z 318.1 (M+H) + .

3-[2-(pyridin-4-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=8.63 (d, J=6.5 Hz, 2H), 7.97 (dd, J=1.6, 7.8 Hz, 1H), 7.79 (dd, J=1.6, 7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.44-7.40 (m, 2H), 6.78 (t, J=2.2 Hz, 2H), 6.30 (t, J=2.2 Hz, 2H). MS (ESI) m/z 289.1 (M+H) + .

3-[2-(pyridin-3-yl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ= 1 H NMR (300 MHz, CDCl 3 ) δ=8.80-8.55 (m, 2H), 7.99-7.87 (m, 2H), 7.80-7.74 (m, 1H), 7.65-7.55 (m, 1H), 7.51 (t, J=7.8 Hz, 1H), 6.86 (t, J=2.2 Hz, 2H), 6.35 (t, J=2.2 Hz, 2H). MS (ESI) m/z 289.1 (M+H) + .

3-[2-(3-methoxyphenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.90 (dd, J=1.7, 7.8 Hz, 1H), 7.78 (dd, J=1.6, 7.8 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.20 (t, J=7.9 Hz, 1H), 6.95-6.82 (m, 5H), 6.37 (t, J=2.2 Hz, 2H), 3.80 (s, 3H). MS (ESI) m/z 318.1 (M+H) + .

3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.88 (dd, J=1.5, 7.9 Hz, 1H), 7.75 (dd, J=1.6, 7.7 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.32-7.26 (m, 2H), 7.02-6.94 (m, 2H), 6.87 (t, J=2.2 Hz, 2H), 6.25 (t, J=2.2 Hz, 2H). MS (ESI) m/z 306.0 (M+H) + .

3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CDCl 3 ) δ=7.86 (dd, J=1.5, 7.9 Hz, 1H), 7.77 (dd, J=1.6, 7.8 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.35-7.26 (m, 5H), 6.87 (t, J=2.1 Hz, 2H), 6.36 (t, J=2.1 Hz, 2H). MS (ESI) m/z 288.0 (M+H) + .

3-{3-[benzyl(methyl)amino]prop-1-yn-1-yl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CD 3 OD) δ=7.82-7.6 (m, 2H), 7.58-7.45 (m, 4H), 7.42-7.38 (m, 1H), 6.90 (d, J=3.4 Hz, 2H), 6.82-6.55 (m, 1H), 6.28-6.22 (m, 2H), 4.42-4.21 (m, 2H), 4.08 (m, 2H), 2.75-2.67 (m, 3H). MS (ES + )=345.0 (MH) + .

3-[3-(1H-imidazol-1-yl)prop-1-yn-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 9. 1 H NMR (300 MHz, CD 3 OD) δ=8.89 (br. s., 1H), 8.79-8.63 (m, 1H), 8.60-8.44 (m, 1H), 8.37-8.22 (m, 1H), 8.16-8.07 (m, 1H), 7.91-7.76 (m, 1H), 7.61-7.48 (m, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.00 (br. s., 1H), 6.51 (d, J=12.0 Hz, 1H), 4.64 (br. s., 2H). MS (ES + )=291.9 (M) + .

3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid. A mixture of 3-ethynyl-1-yl-benzoic acid methyl ester (40 mg, 0.25 mmol), 4-bromo-thiazole (82 mg, 0.5 mmol), palladium tetrakis-triphenylphosphine (29 mg, 0.025 mmol) and copper iodide (9.5 mg, 0.05 mmol), potassium carbonate (69 mg, 0.5 mmol) in 1,2-dimethoxyethane/water (1 mL/0.3 mL) was degassed with N 2 for 5 minutes and then heated at 60° C. for 4 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by preparative thin layered chromatography eluting with ethyl acetate/hexane (30%) to give the ester intermediate. To this intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 18 mg (22% for 2 steps) of the pure product as a white solid. 1 H NMR (300 MHz, DMSO) δ=13.2 (br. s., 1H), 9.18 (d, J=2.1 Hz, 1H), 8.19 (d, J=1.8 Hz, 1H), 8.05 (t, J=1.5 Hz, 1H), 7.98 (td, J=1.4, 7.8 Hz, 1H), 7.81 (td, J=1.4, 7.8 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H). LCMS (ESI) m/z 230.0 (M+1) + .

3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}) ethynyl)benzoic acid was prepared by the same procedure as example 75. 1 H NMR (300 MHz, DMSO) δ=12.20 (br. s., 1H), 8.31 (dd, J=1.5, 4.7 Hz, 1H), 8.13 (dd, J=1.5, 7.9 Hz, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.97-7.95 (m, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.20 (dd, J=4.8, 7.8 Hz, 1H). LCMS (ESI) m/z 263.0 (M+1) + .

3-[2-(1H-indol-5-yl)ethynyl]benzoic acid was prepared by the same procedure as example 75. 1 H NMR (300 MHz, CDCl 3 ) δ=9.30 (br. s., 1H), 8.23 (t, J=1.8 Hz, 1H), 7.98 (td, J=1.5, 7.9 Hz, 1H), 7.87 (d, J=0.9 Hz, 1H), 7.72 (td, J=1.3, 7.9 Hz, 1H), 7.47-7.23 (m, 4H), 6.59-6.50 (m, 1H). LCMS (ESI) m/z 262.0 (M+1) + .

2-Amino-3-bromo-benzoic acid methyl ester: 2-Amino-3-bromo-benzoic acid (5 g, 23 mmol) was dissolved in methanol (30 mL), concentrated sulfuric acid (1 mL) was added dropwise and the reaction mixture was refluxed at 80° C. for 24 hours, allowed to cool to ambient temperature and then concentrated at reduced pressure. The residue was diluted by water (10 mL) and basified with saturated sodium bicarbonate solution, extracted by ethyl acetate (20 mL×3). The organic layer was dried (anhydrous magnesium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (10%) to give the product as a colorless oil (5 g, 95%).

2-Amino-3-ethynyl-benzoic acid methyl ester: To a pressure flask was loaded a mixture of 2-amino-3-bromo-benzoic acid methyl ester (2 g, 8.7 mmol), Pd(PPh 3 ) 2 Cl 2 (610 mg, 0.87 mmol) and CuI (331 mg, 1.74 mmol) in triethyl amine (20 mL), the mixture was degassed with N 2 for 10 minutes, trimethylsilylacetylene (4 mL) was added, and the mixture was further degassed for 3 minutes. The flask was sealed with a PFTE plug and heated at 90° C. for 5 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane and the filtrate was concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with hexane to give a solid intermediate. The solid intermediate was dissolved in tetrahedrofuran (15 mL), tetrabutyl ammonium fluoride (1 N in THF, 14 mL, 14 mmol) was added and the reaction mixture was stirred for 10 minutes and concentrated. The residue was purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (0-20%) to give the product as a white solid (1.4 g, 86% for 2 steps).

2-amino-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared by the same procedure as example 75 starting with 2-amino-3-ethynyl-benzoic acid methyl ester. 1 H NMR (300 MHz, CDCl 3 ) δ=7.98-7.76 (m, 1H), 7.68-7.52 (m, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.35-7.30 (m, 3H), 7.25-7.14 (m, 1H), 6.77-6.48 (m, 2H).

2-amino-3-[2-(1H-indol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 78. 1 H NMR (300 MHz, CDCl 3 ) δ=7.94 (td, J=1.7, 7.4 Hz, 2H), 7.60 (dd, J=1.6, 7.5 Hz, 1H), 7.53 (dd, J=1.6, 7.6 Hz, 1H), 7.44 (d, J=8.2 Hz, 1H), 7.35-7.29 (m, 1H), 7.17 (t, J=8.0 Hz, 1H), 6.76-6.52 (m, 3H). LCMS (ESI) m/z 278.0 (M+1) + .

2-amino-3-[2-(1H-indol-6-yl)ethynyl]benzoic acid was prepared by the same procedure as example 78. 1 H NMR (300 MHz, CDCl 3 ) δ=7.91 (dd, J=1.6, 8.1 Hz, 1H), 7.72-7.44 (m, 3H), 7.41-7.17 (m, 4H), 6.64 (t, J=7.8 Hz, 1H), 6.55 (d, J=3.4 Hz, 1H). LCMS (ESI) m/z 278.0 (M+1) + .

2-amino-3-[2-(1H-indol-5-yl)ethynyl]benzoic acid was prepared by the same procedure as example 78. LCMS (ESI) m/z 277.1 (M+1) + .

2-amino-3-{2-[3-(hydroxymethyl)phenyl]ethynyl}benzoic acid was prepared by the same procedure as example 78. LCMS (ESI) m/z 250.1 (M−H 2 O) + .

2-amino-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid: To a sealed tube was loaded a mixture of 2-amino-3-bromo-benzoic acid methyl ester (50 mg, 0.22 mmol), Pd(PPh 3 ) 2 Cl 2 (15.4 mg, 0.022 mmol) and CuI (4.2 mg, 0.022 mmol) in triethyl amine (1 mL). The mixture was degassed with N 2 for 10 minutes, 3-ethynyl-phenol (103 mg, 0.87 mmol) was added and the mixture degassed with N 2 for 5 minutes. The reaction mixture was heated at 90° C. for 5 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by preparative thin layer chromatography eluting with ethyl acetate/hexane (30%) to give a solid intermediate. To the solid intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 11 mg (14% for 2 steps) of the pure product as a white solid. LCMS (ESI) m/z 254.1 (M+1) + .

2-amino-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 83. 1 H NMR (300 MHz, CDCl 3 ) δ=7.93 (dd, J=1.6, 8.1 Hz, 1H), 7.58-7.50 (m, 4H), 7.39-7.34 (m, 4H), 6.64 (t, J=7.6 Hz, 1H). LCMS (ESI) m/z 220.2 (M−H 2 O) + .

2-fluoro-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 83 starting with 2-fluoro-3-bromobenzoic acid methyl ester. 1 H NMR (300 MHz, CDCl 3 ) δ 7.98 (m, 1H), 7.75 (m, 1H), 7.57 (m, 2H), 7.48-7.32 (m, 4H). MS m/z (M+) 240.7.

2-fluoro-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared by the same procedure as example 78 starting with 2-fluoro-3-bromobenzoic acid methyl ester. 1 H NMR (300 MHz, CD 3 OD) δ 8.34 (bs, 1H), 8.25 (dd, J=7.9, 1.3 Hz, 1H), 7.98-7.83 (m, 1H), 7.80-7.71 (m, 2H), 7.35-7.31 (m, 1H), 7.28 (t, J=7.7 Hz, 1H). MS m/z (M+H) 281.0.

2-fluoro-3-(2-{imidazo[1,2-a]pyrazin-3-yl}ethynyl)benzoic acid was prepared by the same procedure as example 86. 1 H NMR (300 MHz, DMSO) δ 9.21 (d, J=1.5 Hz, 1H), 8.66 (dd, J=4.6, 1.5 Hz, 1H), 8.28 (s, 1H), 8.14 (d, J=4.5 Hz, 1H), 8.06-7.97 (m, 1H), 7.97-7.89 (m, 1H), 7.41 (t, J=7.8 Hz, 1H). MS m/z (M+H) 282.0

2-fluoro-3-{2-[2-(hydroxymethyl)phenyl]ethynyl}benzoic acid was prepared by the same procedure as example 86. 1 H NMR (300 MHz, CDCl 3 ) δ 7.94-7.85 (m, 1H), 7.71-7.61 (m, 1H), 7.58-7.47 (m, 2H), 7.43-7.34 (m, 1H), 7.32-7.25 (m, 1H), 7.23-7.14 (m, 1H), 4.89 (d, J=20.9 Hz, 2H). MS m/z (M+) 270.7

2-fluoro-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 86. 1 H NMR (300 MHz, DMSO) δ 13.49 (s, 1H), 9.20 (d, J=1.9 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H), 8.05-7.52 (m, 2H), 7.36 (t, J=7.8 Hz, 1H). MS m/z (M+H) 248.0

3-[2-(pyridin-2-yl)ethynyl]benzoic acid was prepared by the same procedure as example 78 starting with 3-bromo-benzoic acid methyl ester. 1 H NMR (300 MHz, CDCl 3 ) δ 8.65 (s, 1H), 8.29 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.71 (dd, J=7.7, 6.0 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.28 (d, J=10.1 Hz, 1H). MS m/z (M+H) 224.0

3-[2-(pyridin-3-yl)ethynyl]benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CDCl 3 ) δ 8.79 (s, 1H), 8.57 (d, J=3.3 Hz, 1H), 8.23 (s, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.31 (dd, J=7.4, 4.6 Hz, 2H). MS m/z (M+H) 224.1

3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CDCl 3 ) δ 8.21 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.69 (s, 2H), 7.54 (d, J=3.5 Hz, 2H), 7.45 (d, J=7.7 Hz, 1H), 7.35 (d, J=2.6 Hz, 2H). MS m/z (M+H) 223.1

3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CDCl 3 ) δ 8.63 (d, J=5.2 Hz, 1H), 8.24 (s, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.5 Hz, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.45-7.34 (m, 2H), 7.26 (m, 1H). MS m/z (M+H) 224.0

3-[2-(4-methoxyphenyl)ethynyl]benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CDCl 3 ) δ 8.19 (s, 1H), 7.97 (d, J=7.8 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=8.9 Hz, 2H), 7.42 (t, J=7.7 Hz, 1H), 6.89 (d, J=8.9 Hz, 2H). MS m/z (M+H) 253.0

Example 95: Synthesis of 2-{4-[(dimethylamino)methyl]phenyl}-3-(2-phenylethynyl)benzoic acid trifluoroacetic acid salt

2-Amino-3-phenylethynyl-benzoic acid methyl ester: To a sealed flask was loaded a mixture of 2-amino-3-bromo-benzoic acid methyl ester (4 g, 17.4 mmol), Pd(PPh 3 ) 2 Cl 2 (618 mg, 0.88 mmol) and copper iodide (335 mg, 1.76 mmol) in triethyl amine (80 mL). The mixture was degassed with N 2 for 10 minutes, phenylacetylene (7.2 g, 70.5 mmol) was added and the mixture was degassed with N 2 for 5 minutes. The reaction mixture was heated at 90° C. for 17 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (0-30%) to give 4.3 g (98%) of the product as a white solid.

2-Iodo-3-phenylethynyl-benzoic acid methyl ester: A solution of 2-amino-3-phenylethynyl-benzoic acid methyl ester (1 g, 3.98 mmol) in 1,4-dioxane was treated with concentrated hydrochloric acid (7.8 mL) slowly and stirred for 10 minutes. At 0° C. sodium nitrite (304 mg, 4.4 mmol) in water (5 mL) was added and the reaction mixture was stirred at 0° C. for 1 hour. Potassium iodide (6.8 g, 4.1 mmol) in water (5.5 mL) was added at 0° C. and the solution was stirred at room temperature for 17 hours. Saturated sodium bicarbonate was added until bubbling ceased and the solution was extracted with dichloromethane (15 mL×3), the organic extracts were combined, dried (anhydrous sodium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (40 g) eluting with ethyl acetate/hexane (0-20%) to give the product as a white solid (340 mg, 30%).

2-{4-[(dimethylamino)methyl]phenyl}-3-(2-phenylethynyl)benzoic acid trifluoroacetic acid salt. A mixture of 2-iodo-3-phenylethynyl-benzoic acid methyl ester (25 mg, 0.069 mmol), dimethyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-amine (26 mg, 0.1 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (6.1 mg, 0.007 mmol) and potassium carbonate (23 mg, 0.17 mmol) in 1,4-dioxane (0.8 mL) and water (0.2 mL) was degassed with N 2 for 10 minutes and heated at 90° C. for 17 hours. After cooling down the reaction mixture was partitioned between water and ethyl acetate, the organic layer was dried (sodium sulfate), filtered, concentrated and purified through preparative thin layer chromatography to give a solid intermediate. To this solid intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 13 mg (42% for 2 steps) of the pure product as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=7.97 (d, J=7.6 Hz, 1H), 7.77 (d, J=7.9 Hz, 1H), 7.57-7.38 (m, 3H), 7.37-7.09 (m, 7H), 4.03 (s, 2H), 2.67 (s, 6H). LCMS (ESI) m/z 356.1 (M+1) + .

Example 96: Synthesis of 3-(2-phenylethynyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid trifluoroacetic acid salt

3-(2-phenylethynyl)-2-(1,2,3,6-tetrahydropyridin-4-yl)benzoic acid trifluoroacetic acid salt was prepared by the same procedure as example 95. LCMS (ESI) m/z 304.1 (M+1) + .

3-(2-phenylethynyl)-2-(pyridin-4-yl)benzoic acid trifluoroacetic acid salt was prepared by the same procedure as example 95. 1 H NMR (300 MHz, CDCl 3 ) δ=8.74 (d, J=6.7 Hz, 2H), 8.19 (dd, J=1.2, 7.9 Hz, 1H), 7.85 (dd, J=1.3, 7.8 Hz, 1H), 7.77 (d, J=6.5 Hz, 2H), 7.61 (t, J=7.9 Hz, 1H), 7.31-7.23 (m, 3H), 7.09 (dd, J=1.6, 8.1 Hz, 2H). LCMS (ESI) m/z 300.1 (M+1) + .

2-(4-methanesulfonylphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 95. 1 H NMR (300 MHz, CDCl 3 ) δ=8.04-7.99 (m, 3H), 7.82 (dd, J=1.2, 7.6 Hz, 1H), 7.58-7.48 (m, 3H), 7.29-7.22 (m, 3H), 7.09-7.04 (m, 2H), 3.11 (s, 3H). LCMS (ESI) m/z 377.0 (M+1) + .

3-Phenylethynyl-2-(1H-pyrazol-4-yl)-benzoic acid was prepared by the same procedure as example 95. 1 H NMR (300 MHz, CDCl 3 ) δ=8.03 (s, 2H), 7.91 (d, J=8.0 Hz, 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.27 (m, 5H). LCMS (ESI) m/z 289.1 (M+1) + .

3-(2-phenylethynyl)-2-(pyrimidin-5-yl)benzoic acid was prepared by the same procedure as example 95. 1 H NMR (300 MHz, CDCl 3 ) δ=9.18 (s, 1H), 8.74 (s, 2H), 8.06 (dd, J=1.5, 7.9 Hz, 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.28-7.15 (m, 5H). LCMS (ESI) m/z 301.1 (M+1) + .

2-(1-methyl-1H-pyrazol-4-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 95. 1 H NMR (300 MHz, CDCl 3 ) δ=8.87 (br. s., 1H), 7.93-7.89 (m, 1H), 7.89 (s, 1H), 7.80 (dd, J=1.3, 7.8 Hz, 1H), 7.70 (s, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.36-7.26 (m, 5H), 4.08 (s, 3H). LCMS (ESI) m/z 303.0 (M+1) + .

A solution of methyl 2-fluoro-3-bromobenzoate (6.41 mmol) and phenylacetylene (7.76 mmol) in tetrahydrofuran/triethylamine (32 mL/32 mL) was degassed using a N 2 gas balloon for 15 minutes in a sealed round bottom flask. To this solution was added Bis(triphenylphosphine)palladium(II) dichloride (450 mg, 0.64 mmol) and copper iodide (60 mg), sealed and heated to 80° C. for 16 hours. The reaction mixture was then cooled to ambient temperature, filtered through celite using ethyl acetate (50 mL). The filtrate was then concentrated under reduced pressure and purified through silica gel cartridge eluting with ethyl acetate/hexanes to give the product as a brown liquid in 70% yield. To a stirring solution of 2-fluoro-3-phenylethynyl-benzoic acid methyl ester (60 mg, 0.236 mmol) in dimethyl sulfoxide (2 mL) was added 2-phenylpyrrolidine (0. 27 mmol), potassium carbonate (0.1 g, 0.7 mmol), and catalytic tetra butyl ammonium iodide. This solution was heated to 140° C. for 24 hours. The reaction mixture was then cooled to ambient temperature diluted with ethyl acetate (10 mL) washed with water (2×4 mL). The organic layers were washed with 1N hydrochloric acid (2 mL), water (2 mL), brine (2 mL) dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then dissolved in tetrahydrofuran/methanol (1/1 mL) and added 2N sodium hydroxide solution (0.3 mL) and stirred for 24 hours at ambient temperature. This solution was then concentrated and neutralized to pH 4 using 1 N hydrochloric acid solution. The aqueous layer was then extracted using ethyl acetate (2×5 mL) and washed with water (2 mL) and brine (3 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then purified using reversed phase HPLC. 1 H NMR (300 MHz, CDCl 3 ) δ 8.14 (d, J=7.7 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.59 (dd, J=6.6, 3.1 Hz, 2H), 7.46 (q, J=3.7 Hz, 3H), 7.35 (t, J=7.7 Hz, 1H), 7.23 (bs, 5H), 5.52 (t, J=7.8 Hz, 1H), 4.05-3.86 (m, 1H), 3.75 (s, 1H), 2.61-2.28 (m, 4H). MS m/z (M+H) 368.1

2-(3-(dimethylamino)pyrrolidin-1-yl)-3-(phenylethynyl)benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (dd, J=7.9, 1.7 Hz, 1H), 7.81 (dd, J=7.7, 1.7 Hz, 1H), 7.59-7.52 (m, 2H), 7.51-7.41 (m, 4H), 3.82-3.80 (m, 1H), 3.11-2.90 (m, 2H), 2.82 (s, 6H), 2.76-2.45 (m, 2H), 1.75-1.55 (m, 1H), 1.39 (dq, J=14.7, 7.3 Hz, 1H). MS m/z (M+H) 335.2

1-(2-carboxy-6-(phenylethynyl)phenyl)pyrrolidine-3-carboxylic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CDCl 3 ) δ 8.31 (d, J=6.9 Hz, 1H), 7.80-7.70 (m, 1H), 7.74 (ddd, J=8.5, 7.9, 4.7 Hz, 1H), 7.53 (dd, J=6.7, 3.1 Hz, 1H), 7.48-7.33 (m, 3H), 7.09 (td, J=7.9, 0.9 Hz, 1H), 3.91 (m, 1H) 3.73 (bs, 1H), 3.21-2.91 (m, 2H), 2.53 (m, 1H), 1.63 (bs, 1H), 1.40 (dd, J=14.7, 7.1 Hz, 1H). MS m/z (M+H) 336.4

(S)-2-(3-hydroxypyrrolidin-1-yl)-3-(phenylethynyl) benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (d, J=7.9 Hz, 1H), 7.75 (d, J=7.6 Hz, 1H), 7.50 (dd, J=13.1, 9.4 Hz, 2H), 7.45-7.35 (m, 4H), 4.82 (s, 1H), 3.92 (d, J=12.1 Hz, 1H), 3.87-3.69 (m, 3H), 3.49 (d, J=9.1 Hz, 1H), 2.46 (s, 1H), 2.25 (s, 1H). MS m/z (M+H) 308.2

3-(phenylethynyl)-2-(pyrrolidin-1-yl) benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CD 3 OD) δ 8.25 (dd, J=7.9, 1.6 Hz, 1H), 7.88 (dd, J=7.7, 1.5 Hz, 1H), 7.68-7.51 (m, 3H), 7.47-7.33 (m, 3H), 3.85-3.75 (m, 4H), 2.49-2.19 (m, 4H). MS m/z (M+H) 292.1

3-(phenylethynyl)-2-(piperazin-1-yl) benzoic acid acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CD 3 OD) δ 7.70 (dd, J=3.4, 1.6 Hz, 1H), 7.67 (dd, J=3.6, 1.6 Hz, 1H), 7.63-7.58 (m, 2H), 7.45-7.40 (m, 3H), 7.27 (td, J=7.7, 3.3 Hz, 1H), 3.67-3.55 (m, 4H), 3.35 (dd, J=8.8, 4.2 Hz, 4H). MS m/z (M+H) 307.2

2-(benzylamino)-3-(phenylethynyl) benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CDCl 3 ) δ 8.25 (d, J=7.3 Hz, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.64-7.28 (m, 9H), 7.31-7.17 (m, 2H), 4.12 (s, 2H). MS m/z (M+H) 328.6

To a stirring solution of methyl 2-amino-3-bromobenzoate (0.23 g, 1 mmol) in water/1,4-dioxane (3.5/0.5 mL) at 0° C. was added concentrated hydrochloric acid (0.2 mL, 2.4 mmol) dropwise followed by a solution of sodium nitrite (0.07 g, 1 mmol) in water (1 mL) dropwise. This solution was stirred for 1 hour at 0° C. after which a solution of sodium azide (0.07 g, 1 mmol) in water (1 mL) was added. The resultant mixture was allowed to warm to ambient temperature and stirred for 3 hours. After 3 hours, the reaction mixture was extracted with dichloromethane (2×10 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was used as is in the next reaction. To a stirring solution of methyl 2-azido-3-bromobenzoate (0.07 g, 0.27 mmol) in tert-butanol:water (1:1 mL) was added alkyne (0.27 mmol), 1M sodium ascorbate solution in water (0.1 mL) and copper sulfate (˜5 mg). This solution was stirred for 24 hours at ambient temperature. After 24 hours the reaction mixture was extracted with ethyl acetate (2×10 mL). The organic layers were washed with water (5 mL), brine (5 mL) and dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was purified through silica gel cartridge eluting with ethyl acetate/hexanes to give the product as a pale yellow solid in 45% overall yield.

A solution of 3-bromo-2-(4-phenyl-[1,2,3]triazol-1-yl)-benzoic acid methyl ester (0.11 mmol) and phenylacetylene (0.11 mmol) in tetrahydrofuran:triethylamine (1:1 mL) was deaerated using a N 2 gas balloon for 2 minutes. To this solution was added Bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.011 mmol) and copper iodide (5 mg) and heated to 80° C. for 16 hours. The reaction mixture was then cooled to ambient temperature, filtered through celite using ethyl acetate (5 mL). The resultant solution was the concentrated under reduced pressure and purified via either short silica gel cartridge or preparative thin layer chromatography eluting with ethyl acetate/hexanes. This product was then dissolved in tetrahydrofuran/methanol (1/1 mL) and 2N sodium hydroxide solution (0.3 mL) was added and the solution was stirred for 24 hours at ambient temperature. This solution was then concentrated and neutralized to pH 4 using 1 N hydrochloric acid solution. The aqueous layer was then extracted using ethyl acetate (2×5 mL) and washed with brine (3 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then purified using reversed phase HPLC. 1 H NMR (300 MHz, CD 3 OD) δ 8.74 (s, 1H), 8.10 (dd, J=7.8, 1.5 Hz, 1H), 7.93 (dtd, J=5.0, 3.0, 1.8 Hz, 3H), 7.74 (t, J=7.8 Hz, 1H), 7.53-7.42 (m, 2H), 7.41-7.32 (m, 1H), 7.27 (tdd, J=10.1, 3.7, 1.9 Hz, 1H), 7.22-7.17 (m, 4H). MS m/z (M+H) 366.0.

Example 110: Synthesis of 2-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl) benzoic acid

2-(4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl)benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CD 3 OD) δ 8.75 (s, 1H), 8.10 (dd, J=7.8, 1.5 Hz, 1H), 7.94 (dd, J=7.8, 1.5 Hz, 1H), 7.74 (t, J=7.8 Hz, 1H), 7.49 (dt, J=2.5, 1.5 Hz, 2H), 7.37 (dd, J=8.2, 7.6 Hz, 1H), 7.28 (tdd, J=5.0, 4.5, 3.1 Hz, 1H), 7.23-7.18 (m, 4H), 6.95 (ddd, J=8.2, 2.5, 1.1 Hz, 1H), 3.82 (d, J=20.1 Hz, 3H). MS m/z (M+H) 396.1

3-(phenylethynyl)-2-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CD 3 OD) δ 9.37 (d, J=1.9 Hz, 1H), 9.07 (s, 1H), 9.00-8.88 (m, 1H), 8.76 (d, J=4.3 Hz, 1H), 8.16 (dd, J=7.9, 1.5 Hz, 1H), 8.06-8.01 (m, 1H), 7.99 (dd, J=7.9, 1.5 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.34-7.26 (m, 1H), 7.26-7.17 (m, 4H). MS m/z (M+H) 367.1

Example 112: Synthesis of 2-(4-(3-hydroxypropyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl) benzoic acid

2-(4-(3-hydroxypropyl)-1H-1,2,3-triazol-1-yl)-3-(phenylethynyl)benzoic acid was prepared by the same procedure as example 102. 1 H NMR (300 MHz, CD 3 OD) δ 8.09 (s, 1H), 8.08-8.01 (m, 1H), 7.90 (dd, J=7.8, 1.5 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.39-7.21 (m, 5H), 3.60 (t, J=6.4 Hz, 2H), 2.92 (dd, J=17.8, 10.3 Hz, 2H), 1.94 (dq, J=9.8, 6.4 Hz, 2H). MS m/z (M+H) 348.1

To a solution of 3-phenylethynyl-2-pyrrol-1-yl-benzoic acid (50 mg, 0.17 mmol) in N,N-dimethylformamide (0.25 mL) was added N,N-dimethylsulfamide (43 mg, 0.35 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (67 mg, 0.35 mmol), and hydroxyl-benzotriazole hydrate (43 mg, 0.35 mmol). After 16 hours, the reaction mixture was diluted with ethyl acetate (40 mL) and washed with dilute hydrochloric acid (30 mL, 0.1N), saturated aqueous sodium hydrogen carbonate (30 mL) and saturated aqueous sodium chloride (25 mL). The organic layer was concentrated at reduce pressure. The resulting oil was purified by column chromatography through a silica gel cartridge (4 g) eluting with ethyl acetate/hexane (1/4 to 1/2) to give the product as a white foam. 1 H NMR (300 MHz, CDCl 3 ) δ=7.95 (dd, J=1.6, 7.8 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.36-7.23 (m, 5H), 6.92 (t, J=2.2 Hz, 2H), 6.54 (t, J=2.2 Hz, 2H), 2.90 (s, 6H). MS (ES + )=394 (MH) + .

Example 114: Synthesis of N-(Dimethylsulfamoyl)-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl)benzamide

N-(Dimethylsulfamoyl)-3-[2-(4-fluorophenyl)ethynyl]-2-(1H-pyrrol-1-yl) was prepared by the same procedure as example 113. 1 H NMR (300 MHz, CDCl 3 ) δ=7.95 (dd, J=1.6, 7.8 Hz, 1H), 7.77 (dd, J=1.5, 7.6 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.39 (br s, 1H), 7.31-7.20 (m, 1H), 7.02-6.90 (m, 1H), 6.91 (t, J=2.2 Hz, 2H), 6.54 (t, J=2.2 Hz, 2H), 2.90 (s, 6H). MS (ES + )=412 (MH) + .

N-(morpholine-4-sulfonyl)-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamide was prepared by the same procedure as example 113. 1 H NMR (300 MHz, CDCl 3 ) δ 7.92 (dt, J=15.9, 8.0 Hz, 1H), 7.87-7.74 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.46 (bs, 1H), 7.36-7.22 (m, 5H), 7.00-6.85 (m, 2H), 6.59-6.48 (m, 2H), 3.70 (m, 4H), 3.49-3.05 (m, 4H). MS m/z (M+H) 436.4.

Example 116: Synthesis of N-[(1,1-dioxo-4-thiomorpholin-4-yl)sulfonyl]-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamide

N-[(1,1-dioxo-4-thiomorpholin-4-yl)sulfonyl]-3-(2-phenylethynyl)-2-(1H-pyrrol-1-yl)benzamide was prepared by the same procedure as example 113. 1 H NMR (300 MHz, CDCl 3 ) δ 7.94 (dd, J=7.9, 1.6 Hz, 1H), 7.83 (dd, J=7.8, 1.6 Hz, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.52 (bs, 1H), 7.36-7.22 (m, 5H), 7.00-6.85 (m, 2H), 6.56 (t, J=2.1 Hz, 2H), 3.96-3.79 (m, 4H), 3.25-2.96 (m, 4H). MS m/z (M+H) 484.7

Example 117: Synthesis of 3-[2-(4-fluorophenyl)ethynyl]-N-methanesulfonyl-2-(1H-pyrrol-1-yl)benzamide

3-[2-(4-fluorophenyl)ethynyl]-N-methanesulfonyl-2-(1H-pyrrol-1-yl)benzamide was prepared by the same procedure as example 113. 1 H NMR (300 MHz, CD 3 OD) δ 7.64 (dd, J=7.6, 1.6 Hz, 1H), 7.54 (dd, J=7.7, 1.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.36-7.26 (m, 2H), 7.10-7.00 (m, 2H), 6.96-6.89 (m, 2H), 6.29-6.22 (m, 2H), 2.86 (s, 3H). MS m/z (M+H) 383.0

3-(phenylethynyl)-2-(1H-pyrrol-1-yl)-N-sulfamoyl benzamide was prepared by the same procedure as example 113. 1 H NMR (300 MHz, CDCl 3 ) δ 7.91 (dd, J=7.8, 1.6 Hz, 1H), 7.82 (dd, J=7.8, 1.6 Hz, 1H), 7.60-7.52 (m, 1H), 7.50 (bs, 1H), 7.37-7.26 (m, 5H), 6.97-6.91 (m, 2H), 6.60-6.52 (m, 3H), 5.12 (bs, 2H). MS m/z (M+H) 366.3

To a stirring solution of 2-bromo-3-iodobenzoic acid (1 g, 3.1 mmol) in dimethyl sulfoxide (5 mL) was added potassium carbonate (2.1 g, 15 mmol) followed by iodomethane (0.7 g, 4.6 mmol) and stirred for 12 hours at ambient temperature. The reaction mixture was then diluted with ethyl acetate (40 mL) washed with water (2×10 mL). The organic layer were washed brine (10 mL) dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was purified through silica gel cartridge eluting with ethyl acetate/hexanes to give methyl 2-bromo-3-iodobenzoate as a pale yellow liquid in 90% overall yield.

A solution of methyl 2-bromo-3-iodobenzoate (1 g, 2.9 mmol) and phenylacetylene (4.4 mmol) in tetrahydrofuran:triethylamine (20:20 mL) was deaerated using a N 2 gas balloon for 15 minutes in a round bottom flask. To this solution was added Bis(triphenylphosphine)palladium(II) dichloride (210 mg, 0.3 mmol) and copper iodide (30 mg) and stirred for 16 hours at ambient temperature. The reaction mixture was then filtered through celite using ethyl acetate (50 mL). The resultant solution was the concentrated under reduced pressure and purified through silica gel cartridge eluting with ethyl acetate/hexanes to give the product as a brown solid. To a stirring solution of this product (0.05 g, 0.16 mmol) in 1,4-dioxane/water (1/1 mL) was added 4-methoxyphenylboronic acid (0.32 mmol), [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (15 mg, 0.02 mmol) and potassium carbonate (45 mg, 0.32 mmol) and heated to 80° C. for 16 hours. The resultant mixture was allowed to cool to ambient temperature and was diluted with ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (2×2 mL) and the combined organic layers were washed with water (2 mL), brine (2 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was purified either through a small silica gel cartridge or preparative thin layer chromatography eluting with ethyl acetate/hexanes. The product so obtained was then dissolved in tetrahydrofuran/methanol (1/1 mL) and added 2N sodium hydroxide solution (0.3 mL) and stirred for 24 hours at ambient temperature. This solution was then concentrated and neutralized to pH 4 using 1 N hydrochloric acid solution. The aqueous layer was then extracted using ethyl acetate (2×5 mL) and washed with water (2 mL) and brine (3 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then purified using reversed phase HPLC. 1 H NMR (300 MHz, CDCl 3 ) δ 7.74 (dd, J=7.7, 5.2 Hz, 2H), 7.38 (dd, J=9.7, 5.8 Hz, 1H), 7.33 (dt, J=5.0, 2.8 Hz, 1H), 7.24 (m, 6H), 7.05-6.82 (m, 2H), 3.62 (s, 3H). MS m/z (M−H 2 O) 312.0

2-(3-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (dd, J=9.3, 7.8 Hz, 2H), 7.39 (dd, J=12.3, 4.4 Hz, 1H), 7.36-7.29 (m, 1H), 7.28-7.22 (m, 3H), 7.22-7.15 (m, 2H), 6.99-6.90 (m, 3H), 3.61 (s, 3H). MS m/z (M−H 2 O) 312.1

2-(2-methoxyphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.94-7.81 (m, 1H), 7.81-7.67 (m, 1H), 7.47-7.32 (m, 2H), 7.28 (dt, J=5.5, 2.7 Hz, 1H), 7.25-7.15 (m, 3H), 7.16-7.10 (m, 2H), 7.05 (td, J=7.4, 1.0 Hz, 1H), 6.96 (dt, J=7.9, 4.0 Hz, 1H), 3.64 (s, 3H). MS m/z (M−H 2 O) 312.1

3-(2-phenylethynyl)-2-(quinolin-3-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.92 (bs, 1H), 8.24-8.15 (m, 2H), 7.97 (dd, J=7.8, 1.3 Hz, 1H), 7.91-7.81 (m, 2H), 7.77 (t, J=7.7 Hz, 1H), 7.59 (t, J=6.9 Hz, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.24-7.06 (m, 3H), 7.06-6.98 (m, 2H). MS m/z (M+H) 350.1

2-cyclopropyl-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.67-7.44 (m, 4H), 7.44-7.31 (m, 3H), 7.30-7.15 (m, 1H), 2.34-2.10 (m, 1H), 1.15-0.84 (m, 2H), 0.79-0.50 (m, 2H). MS m/z (M+H) 263.1

2-phenyl-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.86-7.76 (m, 1H), 7.77-7.66 (m, 1H), 7.52-7.27 (m, 6H), 7.30-7.18 (m, 3H), 7.18-7.02 (m, 2H). MS m/z (M+Na) 321.0.

2-(4-methylphenyl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (ddd, J=10.5, 7.8, 1.4 Hz, 2H), 7.51-7.30 (m, 1H), 7.33-7.25 (m, 6H), 7.20-7.15 (m, 3H), 2.43 (s, 3H). MS m/z (M+Na) 335.1.

2-(6-methoxypyridin-3-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.13 (dd, J=2.5, 0.7 Hz, 1H), 7.84 (dd, J=7.8, 1.4 Hz, 1H), 7.79-7.73 (m, 1H), 7.65 (dd, J=8.5, 2.5 Hz, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.32-7.20 (m, 5H), 6.83 (ddd, J=8.6, 2.0, 0.7 Hz, 1H), 3.68 (s, 3H). MS m/z (M+H) 330.0

2-[6-(dimethylamino)pyridin-3-yl]-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.17 (dd, J=2.5, 0.7 Hz, 1H), 7.75 (ddd, J=9.2, 7.8, 1.4 Hz, 2H), 7.60-7.53 (m, 1H), 7.41-7.32 (m, 1H), 7.32-7.21 (m, 5H), 6.58 (dd, J=8.8, 0.7 Hz, 1H), 3.13 (s, 6H). MS m/z (M+H) 343.1

2-[3-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.85 (dd, J=7.8, 1.4 Hz, 1H), 7.75 (dd, J=7.8, 1.4 Hz, 1H), 7.48-7.33 (m, 5H), 7.25 (dd, J=5.0, 2.0 Hz, 3H), 7.15 (dd, J=6.5, 3.3 Hz, 2H), 4.67 (s, 2H). MS m/z (M+H) 329.0.

2-(1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 11.18 (s, 1H), 7.74 (dd, J=7.7, 1.3 Hz, 1H), 7.70-7.63 (m, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.45 (t, J=7.7 Hz, 1H), 7.39 (dd, J=7.2, 4.7 Hz, 2H), 7.27 (dd, J=9.4, 3.2 Hz, 3H), 7.12 (dd, J=7.6, 1.9 Hz, 2H), 7.02 (dd, J=8.1, 1.5 Hz, 1H), 6.46 (s, 1H). MS m/z (M+H) 338.0

2-[4-(hydroxymethyl)phenyl]-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.83-7.77 (m, 1H), 7.74 (dd, J=7.8, 0.7 Hz, 1H), 7.42 (t, J=7.4 Hz, 1H), 7.39-7.33 (m, 5H), 7.28-7.19 (m, 3H), 7.19-7.09 (m, 2H), 4.77 (s, 2H). MS m/z (M+H) 329.0

2-(1-benzofuran-5-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.81-7.76 (m, 2H), 7.74 (dd, J=7.8, 1.4 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 7.55 (d, J=8.5 Hz, 1H), 7.46 (dd, J=9.8, 5.8 Hz, 1H), 7.34-7.26 (m, 1H), 7.25-7.13 (m, 3H), 7.07-6.96 (m, 2H), 6.88 (dd, J=2.2, 0.9 Hz, 1H). MS m/z (M+H) 339.0

2-(1-benzothiophen-5-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.95 (d, J=8.3 Hz, 1H), 7.86-7.79 (m, 2H), 7.75 (dd, J=7.8, 1.3 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.41 (dd, J=5.5, 0.7 Hz, 1H), 7.35 (dd, J=8.3, 1.6 Hz, 1H), 7.26-7.08 (m, 3H), 7.01-6.90 (m, 2H). MS m/z (M−H 2 O) 337.0

2-(1-methyl-1H-indol-5-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.72 (dd, J=3.9, 1.4 Hz, 1H), 7.70 (dd, J=4.1, 1.4 Hz, 1H), 7.60 (d, J=1.1 Hz, 1H), 7.45-7.37 (m, 3H), 7.26-7.11 (m, 5H), 7.06 (dt, J=8.2, 2.1 Hz, 2H), 3.85 (s, 3H). MS m/z (M+H) 352.0

2-(3-methanesulfonamidophenyl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.75 (dd, J=7.8, 1.3 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.33-7.23 (m, 5H), 7.20-7.09 (m, 3H), 2.83 (s, 3H). MS m/z (M−H 2 O) 373.9

2-(naphthalen-2-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.11-7.70 (m, 6H), 7.68-7.39 (m, 4H), 7.22-7.01 (m, 3H), 7.00-6.85 (m, 2H). MS m/z (M+H) 349.1.

2-(1-methyl-1H-indol-6-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.87 (dd, J=7.8, 1.4 Hz, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.66 (dd, J=8.1, 0.6 Hz, 1H), 7.44-7.36 (m, 2H), 7.23-7.11 (m, 4H), 7.09 (d, J=3.1 Hz, 1H), 7.05-6.99 (m, 2H), 6.53 (dd, J=3.1, 0.8 Hz, 1H), 3.74 (d, J=6.5 Hz, 3H). MS m/z (M+H) 352.0

2-{2-[(2-hydroxyethyl)sulfamoyl]phenyl}-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.91 (ddd, J=7.6, 5.6, 1.4 Hz, 2H), 7.85-7.75 (m, 2H), 7.64 (td, J=7.6, 0.5 Hz, 1H), 7.60-7.56 (m, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.32-7.18 (m, 3H), 7.14 (ddd, J=4.3, 3.8, 2.5 Hz, 2H), 3.44 (t, J=5.9 Hz, 2H), 2.89 (t, J=5.9 Hz, 2H). MS m/z (M+H) 422.2

2-[4-(cyclopropylcarbamoyl)phenyl]-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.86 (ddd, J=5.7, 3.5, 1.6 Hz, 3H), 7.76 (dd, J=7.8, 1.3 Hz, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.45-7.39 (m, 2H), 7.32-7.16 (m, 3H), 7.16-7.02 (m, 2H), 2.88 (ddd, J=11.1, 7.3, 3.9 Hz, 1H), 0.89-0.76 (m, 2H), 0.71-0.60 (m, 2H). MS m/z (M+H) 382.4

2-(1-methyl-1H-indazol-6-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.04 (d, J=0.8 Hz, 1H), 7.84 (dt, J=7.8, 4.1 Hz, 1H), 7.77 (dd, J=7.9, 1.3 Hz, 2H), 7.49-7.38 (m, 2H), 7.24-7.10 (m, 4H), 7.04-6.93 (m, 2H), 3.56 (s, 3H). MS m/z (M+) 352.6

To a stirring solution of 2-amino-3-bromobenzoic acid (1 g, 4.65 mmol) in water/1,4-dioxane (20 mL/2 mL) at 0° C. was added concentrated hydrochloric acid (1 mL, 11.2 mmol) dropwise followed by a solution of sodium nitrite (0.32 g, 4.65 mmol) in 10 mL water dropwise. This solution was stirred for 1 hour at 0° C. after which a solution of potassium iodide (6.9 g, 42 mmol) in 12 mL water was added. The resultant mixture was allowed to warm to ambient temperature and stirred for 12 hours. After 12 hours the reaction mixture was extracted with ethyl acetate (2×50 mL). The organic layers were combined, washed with sodium thiosulfate (2×10 mL), water (10 mL), brine (10 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. This crude mixture was dissolved in dimethyl sulfoxide (5 mL) and potassium carbonate (2.1 g, 15 mmol) was added followed by iodomethane (0.8 g, 5.6 mmol) and stirred for 12 hours at ambient temperature. The reaction mixture was then diluted with ethyl acetate (40 mL) washed with water (2×10 mL). The organic layer were washed brine (10 mL) dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was purified through silica gel cartridge eluting with ethyl acetate/hexanes to give methyl 2-iodo-3-bromobenzoate as a pale yellow liquid in 85% overall yield.

To a stirring solution of methyl 2-iodo-3-bromobenzoate (1 g, 3.3 mmol) in 1,4-dioxane/water (10 mL/10 mL) was added quinolin-3-yl boronic acid (5 mmol), [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (0.24 g, 0.33 mmol) and potassium carbonate (0.9 g, 6.6 mmol) and heated to 40° C. for 16 hours. The resultant mixture was allowed to cool to ambient temperature and was diluted with ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with water (10 mL), brine (10 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was purified through silica gel cartridge eluting with ethyl acetate/hexanes to give the product. A solution of 3-bromo-2-quinolin-3-yl-benzoic acid methyl ester (0.11 mmol) and 3-hydroxyphenylacetylene (0.11 mmol) in N,N-dimethylformamide/triethylamine (1 mL/1 mL) was degassed using a N 2 gas balloon for 2 minutes. To this solution was added Bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.011 mmol) and copper iodide (5 mg) and heated to 100° C. for 16 hours. The reaction mixture was then cooled to ambient temperature, filtered through celite using ethyl acetate (10 mL). The resultant solution were washed with 1N hydrochloric acid (2 mL), water (2×2 mL), brine (2 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was purified through either a short silica gel cartridge. The product so obtained was then dissolved in tetrahydrofuran/methanol (1 mL/1 mL) and added 2N sodium hydroxide solution (0.3 mL) and stirred for 24 hours at ambient temperature. This solution was then concentrated and neutralized to pH 4 using 1 N hydrochloric acid solution. The aqueous layer was then extracted using ethyl acetate (2×5 mL) and washed with water (2 mL) and brine (3 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then purified using reversed phase HPLC. 1 H NMR (300 MHz, CD 3 OD) δ 9.20 (d, J=1.8 Hz, 1H), 8.92 (s, 1H), 8.34-8.12 (m, 3H), 8.09 (t, J=7.8 Hz, 1H), 8.02-7.82 (m, 3H), 7.68 (t, J=7.9 Hz, 1H), 6.95 (t, J=8.0 Hz, 1H), 6.68 (d, J=9.8 Hz, 1H), 6.48-6.27 (m, 2H). MS m/z (M+H) 366.0

3-(5-hydroxypent-1-ynyl)-2-(quinolin-7-yl)benzoic acid was prepared by the same procedure as example 140. 1 H NMR (300 MHz, CD 3 OD) δ 9.23 (bs, 1H), 8.97 (dd, J=4.8, 1.7 Hz, 1H), 8.29 (td, J=8.5, 3.7 Hz, 2H), 8.22-8.09 (m, 2H), 7.95 (dt, J=7.4, 6.0 Hz, 1H), 7.83 (ddd, J=7.6, 6.1, 1.3 Hz, 1H), 7.62 (td, J=7.9, 2.8 Hz, 1H), 4.14-3.56 (m, 2H), 3.20 (t, J=6.2 Hz, 1H), 2.29-2.19 (m, 2H), 1.61 (m, 1H), 1.45-1.08 (m, 1H). MS m/z (M+H) 332.1

3-((4-methoxyphenyl)ethynyl)-2-(quinolin-7-yl)benzoic acid was prepared by the same procedure as example 140. 1 H NMR (300 MHz, DMSO) δ 8.81 (d, J=2.2 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.05 (t, J=9.3 Hz, 2H), 7.92 (dd, J=7.8, 1.3 Hz, 1H), 7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.79 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.67-7.56 (m, 2H), 7.01-6.87 (m, 2H), 6.85-6.60 (m, 2H), 3.68 (s, 3H). MS m/z (M+H) 380.2

3-(imidazo[1,2-a]pyrazin-3-ylethynyl)-2-(quinolin-3-yl)benzoic acid was prepared by the same procedure as example 140. 1 H NMR (300 MHz, DMSO) δ 9.04 (d, J=1.5 Hz, 1H), 8.92 (d, J=2.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H), 8.20-8.08 (m, 1H), 8.08-7.97 (m, 3H), 7.91-7.82 (m, 1H), 7.77-7.67 (m, 2H), 7.41 (d, J=4.5 Hz, 1H), 7.14 (dd, J=4.5, 1.5 Hz, 1H). MS m/z (M+) 390.9

3-[(1E)-3-methoxyprop-1-en-1-yl]-2-(1H-pyrrol-1-yl)benzoic acid: A mixture of 3-bromo-2-pyrrol-1-yl-benzoic acid methyl ester (60 mg, 0.214 mmol), 2-(3-methoxy-propenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (85 mg, 0.428 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (16 mg, 0.0214 mmol) and potassium carbonate (59 mg, 0.428 mmol) in 1,4-dioxane (0.8 mL) and water (0.8 mL) was degassed with N 2 for 10 minutes and heated at 90° C. for 17 hours. After cooling down the reaction mixture was partitioned between water and ethyl acetate, the organic layer was dried (sodium sulfate), filtered, concentrated and purified through preparative thin layer chromatography to give a solid intermediate. To this solid intermediate in dimethylsulfoxide (0.5 mL) was added sodium hydroxide solution (10% in water, 0.5 mL) and the solution was heated at 100° C. for 24 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give the product as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=7.85-7.76 (m, 2H), 7.43 (t, J=7.8 Hz, 1H), 6.67 (t, J=2.2 Hz, 2H), 6.36-6.17 (m, 3H), 6.04 (d, J=16.1 Hz, 1H), 3.97 (dd, J=1.3, 6.0 Hz, 2H), 3.30 (s, 3H). LCMS (ESI) m/z 258.0 (M+1) + .

3-[(E)-2-phenylethenyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 144. 1 H NMR (300 MHz, CDCl 3 ) δ=7.95 (dd, J=1.2, 8.2 Hz, 1H), 7.86 (dd, J=1.5, 7.6 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.34-7.23 (m, 5H), 7.05 (d, J=16.5 Hz, 1H), 6.76 (t, J=2.1 Hz, 2H), 6.47 (d, J=16.4 Hz, 1H), 6.37 (t, J=2.2 Hz, 2H). LCMS (ESI) m/z 290.0 (M+1) + .

3-[(E)-2-(4-fluorophenyl)ethenyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 144. 1 H NMR (300 MHz, CDCl 3 ) δ=7.95-7.83 (m, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.32-7.24 (m, 3H), 7.04-6.94 (m, 2H), 6.75 (t, J=3.2 Hz, 2H), 6.40-6.33 (m, 3H). LCMS (ESI) m/z 308.0 (M+1) + .

A solution of Example 146 (50 mg, 0.173 mmol) and 10% Pd—C (20 mg) in methanol (3 mL) and chloroform (1 mL) was shaked under hydrogen at 40 psi for 4 hours in Parr-Shaker. The solution was filtered through celite and the filtrate was concentrated. The residue was purified through preparative HPLC to give the product as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=7.80 (dd, J=1.7, 7.3 Hz, 1H), 7.49-7.37 (m, 2H), 7.25-7.12 (m, 3H), 7.01-6.95 (m, 2H), 6.63 (t, J=2.2 Hz, 2H), 6.26 (t, J=2.1 Hz, 2H), 2.75-2.60 (m, 4H). LC/MS (ESI) m/z 274.1 (M−H 2 O) + .

3-(2-Phenylethyl)-2-(pyrrolidin-1-yl)benzoic acid was isolated as another product in synthesizing Example 147. 1 H NMR (300 MHz, CDCl 3 ) δ=12.09 (br. s., 1H), 8.25 (dd, J=1.8, 7.6 Hz, 1H), 7.61 (dd, J=1.6, 7.8 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35-7.12 (m, 3H), 7.16-7.12 (m, 2H), 3.40-2.85 (m, 8H), 2.23-2.10 (m, 4H). LCMS (ESI) m/z 296.1 (M+H) + .

3-[2-(4-fluorophenyl)ethyl]-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 147. LCMS (ESI) m/z 310.1 (M+H) + .

2-(1H-1,3-benzodiazol-6-yl)-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 9.37 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.85 (d, J=7.9 Hz, 2H), 7.80 (s, 1H), 7.58 (dd, J=8.0, 7.5 Hz, 1H), 7.51 (dd, J=8.5, 1.5 Hz, 1H), 7.37-7.23 (m, 3H), 7.14-7.04 (m, 2H). MS m/z (M+H) 339.0

2-(quinolin-3-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 140. 1 H NMR (300 MHz, DMSO) δ 9.02 (d, J=1.9 Hz, 1H), 8.96 (d, J=2.2 Hz, 1H), 8.52 (s, 1H), 8.11 (d, J=8.5 Hz, 2H), 8.02 (dd, J=7.8, 1.3 Hz, 1H), 7.97 (dd, J=7.8, 1.3 Hz, 1H), 7.86 (t, J=7.1 Hz, 1H), 7.74-7.64 (m, 2H), 7.63 (d, J=1.9 Hz, 1H). MS m/z (M+) 356.9

2-Amino-3-bromo-benzenesulfonamide: To a solution of chlorosulfonyl isocyanate (3.78 g, 26.7 mmol) in nitroethane (20 mL) at 50° C. was added 2-bromoaniline (4.0 g, 23.3 mmol) in nitroethane (30 mL). After 5 minutes aluminum chloride (4.0 g, 30.2 mmol) was added in three portions and the mixture was heated to reflux at 110° C. for 30 minutes. The reaction mixture was cooled to ambient temperature and poured onto ice (100 g) and the resulting suspension in water was stirred for 10 minutes. The resulting slurry was filtered and rinsed with water (50 mL) and diethyl ether (50 mL) to give a gray green solid (2.77 g). This solid was added to sulfuric acid (50%, 30 mL) at 145° C. in three portions allowing foaming to subside between additions. The mixture was heated for an additional 30 minutes and cooled to ambient temperature. The mixture was then poured over ice (100 g) and neutralized with aqueous sodium hydroxide (6N) to pH 7 to give a white slurry. This mixture was extracted with isopropyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated to a white solid. 1 H NMR (DMSO-d 6 ) δ 7.63-7.50 (m, 2H), 7.48 (br s, 2H), 6.61 (J=7.9 Hz, 1H), 5.85 (br s, 2H). MS (ES + )=251 (MH) + .

3-Bromo-2-pyrrol-1-yl-benzenesulfonamide: To a slurry of 2,5-dimethoxytetrahydrofuran (950 mg, 7.2 mmol) and 4-chloropyridine hydrochloride (1.08 g, 7.2 mmol) in 1,4-dioxane (50 mL) was added 2-amino-3-bromo-benzenesulfonamide (1.5 g, 6.0 mmol) and the mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool to ambient temperature and was poured into water (200 mL). The resulting slurry was vigorously stirred for 2 hours and filtered. The filtrated was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated at reduced pressure. The resulting oil was purified by column chromatography through a silica gel cartridge (4 g) eluting with ethyl acetate/hexane (1:9 to 1:2) to give the product as a white solid. 1 H NMR 1 H NMR (300 MHz, DMSO) δ=8.02-7.98 (m, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.97 (br s, 2H), 6.72 (t, J=2.1 Hz, 2H), 6.20 (t, J=2.1 Hz, 2H). MS (ES + )=301 (MH) + .

3-Phenylethynyl-2-pyrrol-1-yl-benzenesulfonamide

To a degassed solution of 3-bromo-2-pyrrol-1-yl-benzenesulfonamide (170 mg, 0.56 mmol) in triethylamine (1.7 mL), phenylacetylene (115 mg, 124 μL, 1.13 mmol) and copper (I) iodide (5.4 mg, 0.028 mmol) in a sealed tube was added bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.056 mmol). The tube was sealed and heated at 90° C. for 16 hours. The reaction mixture was cooled to ambient temperature and concentrated at reduced pressure. The resulting mixture was purified by column chromatography through a silica gel cartridge (12 g) eluting with ethyl acetate/hexane (1:9 to 1:2) to give the product as a light yellow solid. 1 H NMR (300 MHz, DMSO) δ=8.02 (dd, J=1.5, 7.9 Hz, 1H), 7.87 (dd, J=1.5, 7.6 Hz, 1H), 7.67 (t, J=7.9 Hz, 1H), 7.36 (m, 3H), 7.31-7.19 (m, 2H), 7.01 (br s, 2H), 6.86 (t, J=2.1 Hz, 2H), 6.26 (t, J=2.1 Hz, 2H). MS (ES + )=323 (MH) + .

N-Acetyl-3-bromo-2-pyrrol-1-yl-benzenesulfonamide: To a slurry of acetic acid (9.6 mg, 0.16 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg, 0.16 mmol), and 4-dimethylaminopyridine (20 mg, 0.16 mmol) in N,N-dimethylformamide (0.20 mL) was added 3-bromo-2-pyrrol-1-yl-benzenesulfonamide (40 mg, 0.13 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was then diluted with aqueous hydrochloric acid (0.1N, 10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic extracts were dried with magnesium sulfate, filtered and concentrated at reduced pressure to give the product in quantitative yield, which was used in the next step without purification.

N-Acetyl-3-phenylethynyl-2-pyrrol-1-yl-benzenesulfonamide: To a degassed solution of N-Acetyl-3-bromo-2-pyrrol-1-yl-benzenesulfonamide (40 mg, 0.117 mmol) in triethylamine (0.40 mL), phenylacetylene (24 mg, 26 μL, 0.23 mmol) and copper (I) iodide (1.1 mg, 0.0058 mmol) in a sealed tube was added bis(triphenylphosphine)palladium(II) dichloride (8.2 mg, 0.00117 mmol). The tube was sealed and heated at 90° C. for 48 hours. The reaction mixture was cooled to ambient temperature and concentrated at reduced pressure. The resulting mixture was purified by column chromatography through a silica gel cartridge (4 g) eluting with ethyl acetate/hexane (1:4 to 1:2) to give the product as a white foam. 1 H NMR (300 MHz, DMSO) δ=11.74 (br s, 1H), 8.10 (dd, J=1.5, 7.9 Hz, 1H), 7.94 (dd, J=1.5, 7.6 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.44-7.19 (m, 5H), 6.82 (t, J=2.2 Hz, 2H), 6.30 (t, J=2.1 Hz, 2H), 1.84 (s, 3H). MS (ES + )=365 (MH) + .

Acetic acid 2-bromo-6-cyano-phenyl ester: At 0° C. to a solution of 2-bromo-6-cyano-phenol (2 g, 10.1 mmol) and triethylamine (2.25 mL, 16.2 mmol) in dichloromethane (30 mL) was slowly added acetyl chloride (1 M in dichloromethane, 13.1 mL, 13.1 mmol). The reaction mixture was stirred at room temperature for 30 minutes, washed with water, dried (anhydrous sodium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (40 g) eluting with ethyl acetate/hexane (0-20%) to give the product as a white solid.

Acetic acid 2-cyano-6-phenylethynyl-phenyl ester: To a sealed flask was loaded a mixture of acetic acid 2-bromo-6-cyano-phenyl ester (1.6 g, 6.67 mmol), bis(triphenylphosphine)palladium(II) dichloride (468 mg, 0.667 mmol), copper iodide (127 mg, 0.667 mmol) and N,N-diisopropylethylamine (1.74 mL, 10 mmol). The mixture was degassed with N 2 for 10 minutes, phenylacetylene (1 g, 10 mmol) was added and the mixture was degassed with N 2 for 5 minutes. The reaction mixture was heated at 90° C. for 3 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography through a silica gel cartridge (40 g) eluting with ethyl acetate/hexane (0-20%) to give the product as a white solid.

2-Hydroxy-3-phenylethynyl-benzonitrile: To a solution of acetic acid 2-cyano-6-phenylethynyl-phenyl ester (1.9 g, 8.68 mmol) in tetrahydrofuran (3 mL) was added ammonium hydroxide (3 mL). The reaction mixture was stirred at room temperature for 30 minutes, acidified with 4 N hydrochloric acid in water and extracted with ethyl acetate (15 mL×3). The combined organic extracts were dried (anhydrous sodium sulfate), concentrated and vacuum dry to give the product as a white solid.

Trifluoro-methanesulfonic acid 2-cyano-6-phenylethynyl-phenyl ester: To a solution of 2-hydroxy-3-phenylethynyl-benzonitrile (800 mg, 3.64 mmol) in dichloromethane (20 mL) cooled at −70° C. was added triethylamine (0.76 mL, 5.46 mmol) followed by trifluoromethanesulfonic anhydride (0.67 mL, 4 mmol). The reaction mixture was allowed to be slowly warmed up to room temperature and stirred at room temperature for 30 minutes. Dichloromethane (20 mL) was added and the solution was washed with water, dried (anhydrous sodium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (40 g) eluting with ethyl acetate/hexane (0-20%) to give the product as a white solid.

2-(Dimethyl-1,2-oxazol-4-yl)-3-(2-phenylethynyl)benzoic acid: A mixture of trifluoro-methanesulfonic acid 2-cyano-6-phenylethynyl-phenyl ester (50 mg, 0.143 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-isoxazole (48 mg, 0.215 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (10.5 mg, 0.014 mmol) and potassium carbonate (39.5 mg, 0.286 mmol) in 1,4-dioxane (0.5 mL) and water (0.5 mL) was degassed with N 2 for 10 minutes and heated at 90° C. for 17 hours. After cooling down the reaction mixture was partitioned between water and ethyl acetate, the organic layer was dried (sodium sulfate), filtered, concentrated and purified through preparative thin layer chromatography to give a solid intermediate. To this intermediate in dimethylsulfoxide (0.5 mL) was added sodium hydroxide solution (10% in water, 0.5 mL) and the solution was heated at 100° C. for 24 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give the product as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=8.06-7.98 (m, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.32-7.24 (m, 5H), 2.24 (s, 3H), 2.13 (s, 3H). LCMS (ESI) m/z 318.0 (M+1) + .

2-Benzyloxy-3-phenylethynyl-benzonitrile: To a solution of 2-hydroxy-3-phenylethynyl-benzonitrile (50 mg, 0.227 mmol), benzyl alcohol (37 mg, 0.34 mmol) and triphenylphosphine (71.4 mg, 0.272 mmol) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (0.055 mL, 0.272 mmol) and the reaction mixture was stirred at room temperature for 17 hours. The solution was concentrated and the residue was purified by column chromatography through a silica gel cartridge (12 g) eluting with ethyl acetate/hexane (0-20%) to give the product as a white solid.

2-(benzyloxy)-3-(2-phenylethynyl)benzoic acid: To 2-benzyloxy-3-phenylethynyl-benzonitrile (40 mg, 0.129 mmol) in dimethylsulfoxide (0.5 mL) was added sodium hydroxide solution (10% in water, 0.5 mL) and the solution was heated at 100° C. for 24 h. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give the pure product as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=8.06 (d, J=6.7 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.55-7.44 (m, 4H), 7.43-7.23 (m, 7H), 5.45 (s, 2H). LCMS (ESI) m/z 329.0 (M+1) + .

2-[3-(methoxycarbonyl)-1H-indol-6-yl]-3-(2-phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 12.00 (s, 1H), 8.13 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.71 (dd, J=7.8, 1.4 Hz, 1H), 7.54-7.39 (m, 2H), 7.33-7.21 (m, 3H), 7.18 (dd, J=8.2, 1.5 Hz, 1H), 7.12-7.05 (m, 2H), 3.81 (s, 3H). MS m/z (M+H) 396.0.

Methyl 2-bromo-3-nitrobenzoate: To a stirring solution of 2-bromo-3-nitrobenzoic acid (500 mg, 2.04 mmol) in methanol (5 mL) was added concentrated sulfuric acid (0.5 mL). The resulting solution was heated at 80° C. for 18 hours. The reaction mixture was cooled to ambient temperature and concentrated at reduced pressure. The residue was diluted with ethyl acetate (50 mL) and washed with 1N aqueous sodium hydroxide solution (50 mL) and brine, dried (magnesium sulfate), filtered and concentrated at reduced pressure to give the desired product as a colorless oil which was used in the next step without further purification.

Methyl 2-phenyl-3-nitrobenzoate: To a mixture of methyl 2-bromo-3-nitrobenzoate (2.6 g, 10 mmol), phenyl boronic acid (1.46 g, 12 mmol) and palladium acetate (171 mg, 0.7 mmol) in acetone (12 mL) was added 2N aqueous potassium carbonate (12 mL). The reaction mixture was heated at 65° C. for 4 hours, cooled to ambient temperature and partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was dried (magnesium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (0 to 5%) to achieve the product as a solid. 1 H NMR (300 MHz, CDCl 3 ) δ=7.99 (dd, J=1.2, 7.9 Hz, 1H), 7.88 (dd, J=1.3, 8.1 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.44-7.35 (m, 3H), 7.27-7.19 (m, 2H), 3.57 (s, 3H).

Methyl 2-phenyl-3-aminobenzoate: To a stirring solution of methyl 2-phenyl-3-nitrobenzoate (1.09 g, 4.24 mmol) in a mixture of acetic acid (4 mL) and methanol (10 mL) was added zinc powder (1.38 g, 21.2 mmol) in three portions. The resulting mixture was stirred at ambient temperature for 18 hours. The mixture was neutralized by 6N aqueous sodium hydroxide solution, extracted with ethyl acetate (3×100 mL). The organic layer was washed with brine, dried (magnesium sulfate) and concentrated at reduced pressure to give the product as a yellow solid which was used in the next step without further purification.

Methyl 2-phenyl-3-iodobenzoate: To a solution of methyl 2-phenyl-3-aminobenzoate (2.29 g, 10 mmol) in 1,4-dioxane (30 mL) and water (20 mL) at 0° C. was added concentrated hydrochloric acid (3.0 mL). After 25 minutes, aqueous sodium nitrate solution (760 mg, 7.4 mmol, 10 mL water) was added and the resulting mixture was stirred for 1 hour. Potassium iodide solution (14.9 g, 90 mmol, 10 mL water) was added via addition funnel. The resulting mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with sodium hydroxide solution (100 mL, 2N), followed by saturated aqueous sodium thiosulfate solution (50 mL). The organic layer was dried (magnesium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with ethyl acetate/hexane (0 to 5%) to provide the product as a red oil (2.33 g, 68%, 70% pure) 1 H NMR (300 MHz, CDCl 3 ) δ=8.08 (dd, J=1.2, 7.9 Hz, 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.44-7.29 (m, 3H), 7.18-7.07 (m, 2H), 3.54-3.51 (m, 3H). MS (ES + )=177 (M−31) +

Methyl 2-phenyl-3-(3-hydroxyprop-1-ynyl)benzoate: To a sealed flask was added methyl 2-phenyl-3-iodobenzoate (734 mg, 2.17 mmol), triethylamine (3 mL) and N,N-dimethylformamide (7 mL). The mixture was degased for 30 minutes, followed by addition of bis(triphenylphosphine)palladium(II) dichloride (151 mg, 0.22 mmol), copper(I) iodide (21 mg, 0.11 mmol) and propargyl alcohol (0.26 mL, 4.34 mmol). The flask was sealed and heated at 45° C. for 18 hours. After cooling to ambient temperature, the mixture was poured into water (150 ml), extracted with ethyl acetate (3×100 mL). The organic layer was dried (magnesium sulfate), concentrated and purified by column chromatography through a silica gel cartridge (40 g) eluting with ethyl acetate/hexane (10% to 20%) to provide the product as a red oil. 1 H NMR (300 MHz, CDCl 3 ) δ=7.78 (dd, J=1.5, 7.9 Hz, 1H), 7.63 (dd, J=1.3, 7.8 Hz, 1H), 7.41-7.26 (m, 5H), 4.20 (d, J=5.0 Hz, 2H), 3.56 (s, 3H).

Methyl 2-phenyl-3-(3-bromoprop-1-ynyl)benzoate: To a solution of methyl 2-phenyl-3-(3-hydroxyprop-1-ynyl)benzoate (100 mg, 0.376 mmol) in dichloromethane (1 mL), carbon tetrabromide (157 mg, 0.564 mmol) was added and the reaction mixture was cooled to 0° C., the solution of triphenyl phosphine (128 mg, 0.583 mmol) in dichloromethane (0.5 mL) was added drop wisely. The mixture warmed to ambient temperature and stirred for 3 hours. Ethanol (0.2 mL) was added. After 25 minutes, the mixture was concentrated and purified by column chromatography through a silica gel cartridge (4 g) eluting with ethyl acetate/hexane (0 to 5%) to achieve the product as a colored oil.

3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid methyl ester: To a mixture of benzylamine (24 mg, 0.226 mmol) and cesium carbonate (92 mg, 0.282 mmol) in acetonitrile (1 mL) was added methyl 2-phenyl-3-(3-bromoprop-1-ynyl)benzoate (37 mg, 0.113 mmol) and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was filtered, concentrated and purified by column chromatography through a silica gel cartridge (4 g) eluting with ethyl acetate/hexane (0 to 10%) to achieve the product as a solid. MS (ES + )=356 (MH + ).

3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid: To a mixture of 3-[3-(benzylamino)prop-1-yn-1-yl]-2-phenylbenzoic acid methyl ester (29 mg, 0.082 mmol) in tetrahydrofuran (0.2 mL), methanol (0.2 mL) and water (0.2 mL) was added lithium hydroxide (10 mg, 0.4 mmol) and stirred for 18 hrs. The mixture was neutralized with hydrochloric acid (2N) to pH=4 and concentrated at reduced pressure. The crude product was purified by preparative HPLC to give the product as a yellow solid. 1 H NMR (300 MHz, DMSO-d 6 ) δ=7.84 (ddd, J=1.3, 7.8, 9.4 Hz, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.53-7.33 (m, 10H), 4.02 (s, 2H), 3.86 (s, 2H). MS (ES + )=342 (MH + ).

Example 158: Synthesis of 3-(3-{[3-(1H-imidazol-1-yl)propyl]amino}prop-1-yn-1-yl)-2-phenylbenzoic acid

3-(3-{[3-(1H-imidazol-1-yl)propyl]amino}prop-1-yn-1-yl)-2-phenylbenzoic acid was prepared by the same procedure as example 157. 1 H NMR (300 MHz, DMSO-d 6 ) δ=8.98 (s, 1H), 7.79-7.64 (m, 4H), 7.51 (t, J=7.7 Hz, 1H), 7.43-7.33 (m, 3H), 7.27-7.24 (m, 2H), 4.19 (t, J=6.9 Hz, 2H), 3.99 (s, 2H), 2.66 (d, J=7.6 Hz, 2H), 2.04 (d, J=7.3 Hz, 2H). MS (ES + )=359.99 (MH + ).

2-phenyl-3-[3-(4-phenylpiperazin-1-yl)prop-1-yn-1-yl]benzoic acid was prepared by the same procedure as example 157. 1 H NMR (300 MHz, DMSO-d 6 ) δ=7.79 (dd, J=1.2, 7.6 Hz, 1H), 7.75 (dd, J=1.3, 7.8 Hz, 1H), 7.54-7.24 (m, 8H), 6.99 (d, J=8.5 Hz, 2H), 6.87 (t, J=7.1 Hz, 1H), 4.18 (br. s., 2H), 3.15-2.70 (br. S., 8H). MS (ES + )=397.10 (MH + ).

2-phenyl-3-[3-(pyrrolidin-1-yl)prop-1-yn-1-yl]benzoic acid was prepared by the same procedure as example 157. 1 H NMR (300 MHz, DMSO-d 6 ) δ=7.78 (dd, J=1.5, 7.6 Hz, 1H), 7.74 (dd, J=1.3, 7.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.45-7.35 (m, 3H), 7.30-7.24 (m, 2H), 4.20 (s, 2H), 3.44-3.2 (br. S., 2H), 2.99-2.83 (m, 2H), 1.78 (br. s., 4H). MS (ES + )=306.06 (MH + ).

3-(3-hydroxyprop-1-yn-1-yl)-2-phenylbenzoic acid was prepared by the same procedure as example 157. 1 H NMR (300 MHz, DMSO-d 6 ) δ=12.75 (br. s., 1H), 7.70-7.60 (m, 2H), 7.47-7.21 (m, 6H), 5.14 (br. s., 1H), 4.04 (br. s., 2H).

3-{2-[3-(aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 157. 1 H NMR (300 MHz, CD 3 OD) δ 7.76 (ddd, J=8.0, 6.6, 1.6 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.45-7.40 (m, 3H), 7.37 (d, J=5.4 Hz, 1H), 6.93-6.73 (m, 2H), 6.35-6.08 (m, 2H), 4.09 (s, 2H). MS m/z (M+) 317.1

Example 163: Synthesis of 3-{2-[3-(3,5-difluorobenzenesulfonamidomethyl)phenyl] ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

To a stirring solution of methyl 3-{2-[3-(aminomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoate (0.1 mmol) in dichloromethane (2 mL) was added 3,5-difluoro-benzenesulfonyl chloride (0. 15 mmol), triethylamine (0.1 g), and catalytic 4-dimethylaminopyridine at 0° C. and stirred for 16 hours. The reaction mixture was then quenched with water (1 mL). The organic layers were washed with water (1 mL), brine (1 mL) dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then dissolved in tetrahydrofuran:methanol (1:1 mL) and added 2N sodium hydroxide solution (0.3 mL) and stirred for 24 hours at ambient temperature. This solution was then concentrated and neutralized to pH 4 using 1 N HCl solution. The aqueous layer was then extracted using ethyl acetate (2×5 mL) and washed with water (2 mL) and brine (3 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then purified using reverse phase HPLC. 1 H NMR (300 MHz, CD 3 OD) δ 8.21-8.04 (m, 1H), 7.88 (d, J=6.4 Hz, 1H), 7.83-7.70 (m, 1H), 7.54-7.45 (m, 2H), 7.33 (dd, J=6.4, 1.8 Hz, 2H), 7.26-7.06 (m, 3H), 6.86-6.79 (m, 2H), 6.66-6.56 (m, 1H), 6.32-6.26 (m, 2H), 4.12 (d, J=2.5 Hz, 2H). MS m/z (M+) 493.1

Example 164: Synthesis of 3-{2-[4-(1,2-dimethyl-1H-imidazole-5-sulfonamidomethyl) phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[4-(1,2-dimethyl-1H-imidazole-5-sulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 163. 1 H NMR (300 MHz, CD 3 OD) δ 7.76 (ddd, J=7.9, 6.3, 1.6 Hz, 1H), 7.69-7.56 (m, 2H), 7.58-7.52 (m, 1H), 7.52-7.43 (m, 2H), 7.25-7.15 (m, 3H), 6.90-6.80 (m, 2H), 6.33-6.19 (m, 2H), 4.20 (d, J=8.8 Hz, 2H), 3.57 (s, 3H), 2.39 (s, 3H). MS m/z (M+) 475.1

Example 165: Synthesis of 3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid

3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid was prepared by the same procedure as example 163. 1 H NMR (300 MHz, CD 3 OD) δ 7.76 (d, J=7.8 Hz, 1H), 7.49 (dd, J=10.3, 5.3 Hz, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.30 (dd, J=20.9, 13.4 Hz, 2H), 6.89-6.77 (m, 2H), 6.31-6.21 (m, 2H), 4.25 (s, 2H), 2.42 (d, J=4.9 Hz, 1H), 1.10-0.74 (m, 4H). MS m/z (M+) 421.1

Example 166: Synthesis of 2-(3-methoxyphenyl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl} ethynyl)benzoic acid

2-Bromo-3-ethynyl-benzoic acid methyl ester: A solution of 2-bromo-3-iodobenzoate (1 g, 2.9 mmol) and trimethylsilylacetylene (14.5 mmol) in tetrahydrofuran:triethylamine (20 ml:20 mL) was degassed using a nitrogen gas balloon for 5 minutes in a round bottom flask. To this solution was added Bis(triphenylphosphine)palladium(II) dichloride (210 mg, 0.3 mmol) and copper iodide (30 mg) and the reaction was stirred for 16 hours at ambient temperature. The reaction mixture was then filtered through celite using ethyl acetate (50 mL). The resultant solution was the concentrated under reduced pressure and purified through silica gel cartridge eluting with ethyl acetate/hexanes to give the product as a brown solid in 76% yield. To a stirring solution of the brown (0.6 g) in methanol (20 mL) was added solid potassium carbonate (20 mg) and the reaction was stirred for 16 hours at ambient temperature. The resultant mixture was concentrated and was diluted with ethyl acetate (10 mL) and washed with water (2×5 mL), brine (2 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was purified through a small silica gel cartridge eluting with ethyl acetate/hexanes (1:9) to provide 2-bromo-3-ethynyl-benzoic acid methyl ester.

ExTo a stirring solution of 2-bromo-3-ethynyl-benzoic acid methyl ester (0.5 g, 2.1 mmol) was added 3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1 g, 2.3 mmol) in tetrahydrofuran:triethylamine (20:20 mL) and the reaction was degassed using a nitrogen gas balloon for 15 minutes in a round bottom flask. To this solution was added Bis(triphenylphosphine) palladium(II) dichloride (150 mg, 0.21 mmol) and copper iodide (30 mg) and the reaction was stirred for 16 hours at ambient temperature. The reaction mixture was then filtered through celite using ethyl acetate (50 mL). The resultant solution was the concentrated under reduced pressure and purified through silica gel cartridge eluting with ethyl acetate/hnes to give the product as a brown solid in 54% yield.

To a stirring solution of above brown solid (0.05 g, 0.1 mmol) in dimethoxyethane:water (5:0.1 mL) was added 3-methoxyphenylboronic acid (0.12 mmol), Tetrakis(triphenylphosphine) palladium(0) (12 mg, 0.01 mmol) and potassium carbonate (35 mg, 0.25 mmol) in a sealed vial and the reaction was heated to 130° C. for 10 minutes. The resultant mixture was allowed to cool to ambient temperature and was diluted with ethyl acetate (20 mL) and washed with water (2×5 mL), brine (2 mL), dried (sodium sulfate), filtered and concentrated under reduced pressure. The resultant crude product was then dissolved in tetrahydrofuran:methanol (1:1 mL), 2N sodium hydroxide solution (0.3 mL) was added, and stirred for 24 hours at ambient temperature. This solution was then concentrated and neutralized to pH 4 using 1 N hydrochloric acid solution. The aqueous layer was then extracted using ethyl acetate (2×5 mL) and washed with water (2 mL) and brine (3 mL). The organic layers were combined, dried (sodium sulfate), filtered and concentrated under reduced pressure. The resulting crude product was then purified using reversed phase HPLC to provide 3-{2-[3-(cyclopropanesulfonamidomethyl)phenyl]ethynyl}-2-(1H-pyrrol-1-yl)benzoic acid. 1 H NMR (300 MHz, DMSO) δ 12.08 (s, 1H), 8.24 (dd, J=4.7, 1.6 Hz, 1H), 7.74-7.68 (m, 2H), 7.66 (dd, J=7.8, 1.4 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.41-7.31 (m, 2H), 7.07 (dd, J=7.9, 4.7 Hz, 1H), 7.01 (dd, J=7.4, 2.6 Hz, 1H), 6.92 (dd, J=8.9, 1.5 Hz, 2H), 3.73 (s, 3H). MS m/z (M+H) 369.0

Example 167: Synthesis of 2-(1-methyl-1H-indazol-6-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid

2-(1-methyl-1H-indazol-6-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ 12.04 (s, 1H), 8.16 (dd, J=4.4, 1.9 Hz, 1H), 8.13 (d, J=1.0 Hz, 1H), 7.81-7.75 (m, 2H), 7.74 (q, J=1.4 Hz, 1H), 7.65 (d, J=1.1 Hz, 1H), 7.63 (d, J=2.7 Hz, 1H), 7.56-7.45 (m, 1H), 7.10 (dd, J=8.3, 1.3 Hz, 1H), 6.81-6.67 (m, 2H), 3.98 (s, 3H). MS m/z (M+) 392.9

Example 168: Synthesis of 2-(2-methyl-1,3-benzothiazol-5-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid

2-(2-methyl-1,3-benzothiazol-5-yl)-3-(2-{1H-pyrrolo[2,3-b]pyridin-3-yl}ethynyl)benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ 12.05 (s, 1H), 8.17 (s, 1H), 8.08 (d, J=8.2 Hz, 1H), 7.89 (s, 1H), 7.75 (d, J=9.6 Hz, 2H), 7.67 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 6.83 (s, 2H), 2.77 (s, 3H). MS m/z (M+) 409.7

2-(3-methoxyphenyl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ 9.10 (d, J=1.9 Hz, 1H), 7.84-7.70 (m, 3H), 7.52 (t, J=7.7 Hz, 1H), 7.34 (m, 1H), 7.00-6.87 (m, 3H), 3.76 (s, 3H). MS m/z (M+) 335.9

2-(1-methyl-1H-indazol-6-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 169. 1 H NMR (300 MHz, DMSO) δ 9.04 (d, J=1.9 Hz, 1H), 8.75 (s, 1H), 8.06 (d, J=0.8 Hz, 1H), 7.84 (dt, J=7.8, 4.1 Hz, 1H), 7.77 (dd, J=7.9, 1.3 Hz, 2H), 7.46-7.28 (m, 2H), 7.27-7.18 (m, 2H), 3.91 (s, 3H). MS m/z (M+) 359.4

2-(1-methyl-1H-indol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 169. 1 H NMR (300 MHz, DMSO) δ 9.06 (d, J=2.0 Hz, 1H), 7.78 (dd, J=7.7, 1.4 Hz, 1H), 7.74-7.65 (m, 2H), 7.55-7.52 (m, 1H), 7.48 (t, J=7.7 Hz, 2H), 7.35 (d, J=3.1 Hz, 1H), 7.18 (dd, J=8.4, 1.7 Hz, 1H), 6.46 (dd, J=3.1, 0.8 Hz, 1H), 3.82 (s, 3H). MS m/z (M+) 358.9

2-(pyridin-4-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 169. 1 H NMR (300 MHz, DMSO) δ 9.10 (d, J=1.9 Hz, 1H), 8.85 (s, 1H), 8.03 (dd, J=7.8, 1.2 Hz, 1H), 7.95 (dd, J=7.8, 1.3 Hz, 1H), 7.81 (dd, J=5.7, 3.9 Hz, 4H), 7.68 (t, J=7.8 Hz, 1H). MS m/z (M+) 306.9

Example 173: Synthesis of 2-(2-methyl-1,3-benzothiazol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid

2-(2-methyl-1,3-benzothiazol-5-yl)-3-[2-(1,3-thiazol-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 169. 1 H NMR (300 MHz, CD 3 OD) δ 8.90 (d, J=2.0 Hz, 1H), 7.98 (dd, J=8.3, 0.6 Hz, 1H), 7.93-7.86 (m, 2H), 7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.43 (dd, J=8.3, 1.7 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 2.85 (s, 3H). MS m/z (M+) 376.8

2-(1H-indol-3-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO-d 6 ) δ=11.34 (br. s., 1H), 8.47 (br. s., 2H), 7.82 (dd, J=1.3, 7.8 Hz, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.51-7.43 (m, 3H), 7.33 (d, J=7.9 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.02-6.90 (m, 3H). MS (ES + )=338.93 (MH + ).

2-[4-(dimethylamino)phenyl]-3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO-d6) δ=8.67 (br. s., 2H), 7.88-7.71 (m, 2H), 7.53-7.33 (m, 3H), 7.31-7.16 (m, 2H), 6.86 (d, J=8.8 Hz, 2H), 2.97 (s, 6H). MS (ES + )=343.01 (MH + ).

Example 176: Synthesis of 2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid

2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 174. MS (ES + )=371.00 (MH + ).

2-phenyl-3-[2-(pyridin-4-yl)ethynyl]benzoic acid was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO-d6) δ=8.59 (d, J=5.9 Hz, 2H), 7.87-7.81 (m, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.48-7.32 (m, 5H), 7.18 (d, J=5.2 Hz, 2H). MS (ES + )=300.01 (MH + ).

6-(3-carboxy-phenylethynyl)-1H-indole-4-carboxylic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, DMSO) δ=11.64 (s, J=3.5, 3.5 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H), 7.94 (td, J=1.7, 8.2 Hz, 1H), 7.86-7.80 (m, 3H), 7.63 (t, J=2.8 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 6.99-6.96 (m, 1H). MS (ESI) m/z 287.9 (M−H 2 O+1) + . 1192

6-Bromo-1H-indole-4-carboxylic acid amide: A solution of 6-bromo-1H-indole-4-carboxylic acid methyl ester (600 mg, 2.36 mmol) in ammonium hydroxide (10 mL) in a sealed flask was heated at 110° C. for 18 hours. After cooling to ambient temperature, the precipitates were filtered, washed with water and air dried to give 240 mg of the desired product (43%) as a white solid.

3-(4-Carbamoyl-1H-indol-6-ylethynyl)-benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CD 3 OD) δ=11.05 (br. s., 1H), 8.15 (t, J=1.5 Hz, 1H), 7.99 (td, J=1.4, 7.9 Hz, 1H), 7.78-7.72 (m, 2H), 7.68 (s, 1H), 7.53-7.47 (m, 2H), 6.95-6.92 (m, 1H). MS (ESI) m/z 305.0 (M+1) + .

3-(3-Carbamoyl-phenylethynyl)-benzoic acid was prepared by the same procedure as example 90. 1H NMR (300 MHz, DMSO) δ=13.25 (br. s., 1H), 8.11-8.05 (m, 3H), 7.98 (td, J=1.5, 11.0 Hz, 2H), 7.95-7.88 (m, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.73 (td, J=1.4, 7.8 Hz, 1H), 7.60-7.46 (m, 2H). MS (ESI) m/z 266.1 (M+1) + .

3-(1-Benzenesulfonyl-1H-indol-3-ylethynyl)-benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CDCl 3 ) δ=9.75 (br. s., 1H), 8.24 (s, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.82 (d, J=6.7 Hz, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.68-7.56 (m, 2H), 7.53-7.40 (m, 5H), 7.30-7.19 (m, 3H).

3-(1H-Indol-3-ylethynyl)-benzoic acid was prepared by the same procedure as example 90. 1H NMR (300 MHz, CD 3 OD) δ=8.32 (s, 1H), 8.22 (d, J=7.2 Hz, 1H), 8.07-7.98 (m, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.48-7.38 (m, 2H), 7.26-7.16 (m, 2H).

3-(3-Methoxycarbonyl-phenylethynyl)-benzoic acid tert-butyl ester was prepared by the same procedure as example 90 and was used without further purification.

3-(3-Carboxy-phenylethynyl)-benzoic acid methyl ester: To a solution of 3-(3-methoxycarbonyl-phenylethynyl)-benzoic acid tert-butyl ester (690 mg, 2.05 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The solution was stirred at room temperature for 1 hour, concentrated and dried over vacuum to give 570 mg of the product (99%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ=8.24 (d, J=7.0 Hz, 2H), 8.04 (t, J=6.8 Hz, 2H), 7.73 (t, J=4.0 Hz, 2H), 7.46 (t, J=7.8 Hz, 2H), 3.96 (s, 3H). MS (ESI) m/z 281.0 (M+1) + .

3-(3-Carbamoyl-5-methoxy-phenylethynyl)-benzoic acid was prepared by the same procedure as example 90. 1 H NMR (300 MHz, CD 3 OD) δ=8.15-8.12 (m, 1H), 8.04-8.00 (m, 1H), 7.76-7.72 (m, 1H), 7.64 (s, 1H), 7.54-7.45 (m, 2H), 7.35-7.25 (m, 1H), 3.88 (s, 3H). MS (ESI) m/z 296.1 (M+1) + .

2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol: A mixture of 5-bromo-2-methoxy-phenol (300 mg, 1.48 mmol), bis(pinacolato)diboron (488 mg, 1.92 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride (60 mg, 0.074 mmol) and potassium acetate (278 mg, 3 mmol) in dimethylformamide (4 mL) was heated at 90° C. for 18 hours. After cooling to room temperature, the reaction mixture was partitioned between dichlomethane (50 mL) and water (30 mL). The organic layer was dried (sodium sulfate), filtered, concentrated and purified through silica gel cartridge eluting with ethyl acetate/hexanes to give the product as a white solid in 86% yield.

3′-Hydroxy-4′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acid was prepared from 2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=8.45 (br. s., 2H), 7.75 (t, J=7.9 Hz, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.26-7.15 (m, 2H), 7.00-6.87 (m, 2H), 6.79 (dd, J=1.8, 8.2 Hz, 1H), 3.90 (s, 3H). MS (ESI) m/z 346.13 (M+1) + .

5′-Hydroxy-3′-methoxy-6-pyridin-4-ylethynyl-biphenyl-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=8.46 (br. s., 2H), 7.79 (dd, J=1.2, 7.6 Hz, 1H), 7.75 (dd, J=1.2, 7.9 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.20 (d, J=5.3 Hz, 2H), 6.47-6.38 (m, 3H), 3.75 (s, 3H). MS (ESI) m/z 346.1 (M+1) + .

2-(1H-Pyrazol-3-yl)-3-pyridin-4-ylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ=8.82-8.73 (m, 2H), 8.58-8.53 (m, 2H), 8.34 (d, J=7.3 Hz, 1H), 8.07 (d, J=7.3 Hz, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.41 (s, 1H), 6.94 (d, J=1.7 Hz, 1H). MS (ESI) m/z 290.1 (M+1) + .

2-(1H-Pyrazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ=7.82-7.76 (m, 4H), 7.68-7.64 (m, 1H), 7.50-7.42 (m, 3H). MS (ESI) m/z 290.1 (M+1) + .

2-(3,5-Dimethyl-isoxazol-4-yl)-3-pyridin-4-ylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=8.78 (br. s., 2H), 8.16 (d, J=7.9 Hz, 1H), 7.99 (dd, J=1.2, 7.9 Hz, 1H), 7.79-7.63 (m, 3H), 2.23 (s, 3H), 2.09 (s, 3H). MS (ESI) m/z 319.1 (M+1) + .

3-Phenylethynyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=7.94 (d, J=8.1 Hz, 1H), 7.80 (d, J=7.4 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.38-7.20 (m, 5H), 3.87 (s, 3H), 2.12 (s, 3H), 2.11 (s, 3H). MS (ESI) m/z 331.1 (M+1) + .

Example 191: Synthesis of 2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-methyl-but-1-ynyl)-benzoic acid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-methyl-but-1-ynyl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CDCl 3 ) δ=8.01 (dd, J=1.6, 7.8 Hz, 1H), 7.64 (dd, J=1.6, 7.8 Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 5.90 (s, 2H), 1.92 (s, 6H), 1.38 (s, 6H). MS (ESI) m/z 280.1 (M−H 2 O+1) + .

2-(2,5-Dimethyl-pyrrol-1-yl)-3-pyridin-4-ylethynyl-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=8.69 (br. s., 2H), 8.05 (dd, J=1.5, 7.9 Hz, 1H), 7.93 (dd, J=1.5, 7.9 Hz, 1H), 7.71-7.57 (m, 3H), 5.89 (s, 2H), 1.93 (s, 6H). MS (ESI) m/z 317.1 (M+1) + .

3-(3-Carbamoyl-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=7.99-7.77 (m, 4H), 7.63-7.50 (m, 1H), 7.48-7.32 (m, 2H), 5.85 (s, 2H), 1.94 (s, 6H). MS (ESI) m/z 359.0 (M+1) + .

3-(3-Carboxy-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=7.98-7.78 (m, 4H), 7.64-7.50 (m, 1H), 7.50-7.33 (m, 2H), 5.85 (s, 2H), 1.94 (s, 6H). MS (ESI) m/z 360.0 (M+1) + .

Example 195: Synthesis of 2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxymethyl-phenylethynyl)-benzoic acid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-hydroxymethyl-phenylethynyl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=7.85 (d, J=7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.36-7.13 (m, 4H), 5.84 (s, 2H), 4.55 (s, 2H), 1.94 (s, 6H). MS (ESI) m/z 346.0 (M+1) + .

Example 196: Synthesis of 2-(2,5-dimethyl-pyrrol-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-ylethynyl)-benzoic acid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-3-ylethynyl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=8.34 (br. s., 1H), 8.10 (dd, J=1.5, 7.9 Hz, 1H), 7.89-7.78 (m, 2H), 7.70 (s, 1H), 7.64-7.49 (m, 1H), 7.35 (dd, J=5.3, 7.9 Hz, 1H), 5.90 (s, 2H), 1.97 (s, 6H). MS (ESI) m/z 356.1 (M+1) + .

Example 197: Synthesis of 2-(2,5-dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-phenyl-prop-1-ynyl)-benzoic acid

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-hydroxy-3-phenyl-prop-1-ynyl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=8.08 (d, J=7.9 Hz, 1H), 7.97-7.85 (m, 2H), 7.68-7.42 (m, 3H), 7.21 (d, J=16.1 Hz, 1H), 6.85 (d, J=15.8 Hz, 1H), 5.91 (s, 2H), 3.30 (s, 1H), 1.87 (s, 6H). MS (ESI) m/z 346.0 (M+1) + .

3-(3-Acetylamino-phenylethynyl)-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=7.84 (d, J=5.9 Hz, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.60-7.43 (m, 3H), 7.30-7.14 (m, 1H), 6.97 (d, J=7.3 Hz, 1H), 2.12 (s, 3H), 1.95 (s, 6H). MS (ESI) m/z 373.0 (M+1) + .

3-Cyclopropylethynyl-2-(2,5-dimethyl-pyrrol-1-yl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, CD 3 OD) δ=7.79 (d, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 5.72 (s, 2H), 1.85 (s, 6H), 1.36-1.13 (m, 1H), 0.75-0.63 (m, 2H), 0.62-0.37 (m, 2H). MS (ESI) m/z 280.1 (M+1) + .

2-(2,5-Dimethyl-pyrrol-1-yl)-3-(3-methoxy-phenylethynyl)-benzoic acid was prepared by the same procedure as example 21. 1 H NMR (300 MHz, DMSO) δ=7.81 (d, J=7.9 Hz, 2H), 7.58 (t, J=7.6 Hz, 1H), 7.24 (t, J=8.0 Hz, 1H), 6.94 (d, J=2.6 Hz, 1H), 6.90 (d, J=2.6 Hz, 1H), 6.84-6.80 (m, 1H), 5.80 (s, 2H), 3.72 (s, 3H), 1.82 (s, 6H). MS (ESI) m/z 346.0 (M+1) + .

2-(1H-Indazol-6-yl)-3-phenylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=8.10 (s, 1H), 7.85-7.74 (m, 3H), 7.55-7.45 (m, 2H), 7.25-7.13 (m, 4H), 6.96 (d, J=7.0 Hz, 2H). MS (ESI) m/z 339.0 (M+1) + .

2-Benzo[1,3]dioxol-5-yl-3-phenylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=7.72 (t, J=8.5 Hz, 2H), 7.43 (t, J=7.7 Hz, 1H), 7.31-7.19 (m, 5H), 6.87 (s, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.82-6.78 (m, 1H), 6.00 (s, 2H). MS (ESI) m/z 325.0 (M−H 2 O+1) + .

2-Isoquinolin-6-yl-3-phenylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=9.78 (br. s., 1H), 8.52 (d, J=8.5 Hz, 1H), 8.22-8.02 (m, 3H), 7.94 (d, J=7.3 Hz, 1H), 7.85 (br. s., 1H), 7.71 (t, J=7.8 Hz, 1H), 7.24-7.10 (m, 5H), 6.72 (d, J=7.0 Hz, 2H). MS (ESI) m/z 350.0 (M+1) + .

2-Benzofuran-2-yl-3-phenylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=7.90-7.78 (m, 2H), 7.70-7.65 (m, 1H), 7.58-7.48 (m, 2H), 7.35-7.22 (m, 7H), 7.18 (s, 1H). MS (ESI) m/z 339.0 (M+1) + .

3-Phenylethynyl-2-quinolin-8-yl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=9.14 (dd, J=1.6, 8.4 Hz, 1H), 8.95 (dd, J=1.6, 5.1 Hz, 1H), 8.35 (dd, J=1.5, 8.2 Hz, 1H), 8.20 (d, J=7.9 Hz, 1H), 8.03-7.90 (m, 4H), 7.73 (t, J=7.8 Hz, 1H), 7.24-7.10 (m, 3H), 6.70 (d, J=7.5 Hz, 2H). MS (ESI) m/z 350.0 (M+1) + .

2-(2-Amino-pyrimidin-5-yl)-3-phenylethynyl-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=8.47 (s, 2H), 8.07 (dd, J=1.5, 7.9 Hz, 1H), 7.86 (dd, J=1.3, 7.8 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.37-7.29 (m, 5H). MS (ESI) m/z 316.0 (M+1) + .

4′-Dimethylaminomethyl-6-phenylethynyl-biphenyl-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=7.90 (dd, J=1.2, 7.9 Hz, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.58-7.44 (m, 5H), 7.34-7.09 (m, 5H), 4.39 (s, 2H), 2.85 (m, 6H). MS (ESI) m/z 356.1 (M+1) + .

3-(4-Amino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ=8.24 (d, J=8.8 Hz, 1H), 8.00 (br. s., 1H), 7.93 (d, J=7.9 Hz, 1H), 7.86-7.80 (m, 2H), 7.62 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.43-7.36 (m, 2H), 7.07-6.95 (m, 3H), 6.61 (dd, J=2.2, 2.9 Hz, 1H). MS (ESI) m/z 353.1 (M+1) + .

Synthesis of 3-(4-carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid 2-Bromo-3-[4-(2-oxo-2-phenyl-ethoxycarbonyl)-phenylethynyl]-benzoic acid methyl ester was prepared by the same Sonogashira Coupling procedure as preparing 2-bromo-3-phenylethynyl-benzoic acid methyl ester in example 119 and was used in the next step without purification.

2-(1H-Indol-6-yl)-3-[4-(2-oxo-2-phenyl-ethoxycarbonyl)-phenylethynyl]-benzoic acid methyl ester was prepared by the same Suzuki Coupling procedure as preparing 2-(1H-indol-6-yl)-3-phenylethynyl-benzoic acid methyl ester in example 119 and was used in the next step without purification.

3-(4-Carboxy-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid was prepared from 22-(1H-indol-6-yl)-3-phenylethynyl-benzoic acid methyl ester by the same hydrolysis procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ=7.87-7.65 (m, 5H), 7.45-7.38 (m, 2H), 7.25 (d, J=3.2 Hz, 1H), 7.19 (dd, J=1.5, 8.2 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.57 (d, J=3.3 Hz, 1H). MS (ESI) m/z 382.0 (M+1) + .

2-(1H-Indol-6-yl)-3-(4-methoxy-phenylethynyl)-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=7.69 (d, J=7.9 Hz, 2H), 7.59 (d, J=8.2 Hz, 1H), 7.45-7.27 (m, 2H), 7.28 (d, J=3.2 Hz, 1H), 7.05 (dd, J=1.4, 8.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 2H), 6.73 (d, J=9.1 Hz, 2H), 6.50 (d, J=3.4 Hz, 1H), 3.73 (s, 3H). MS (ESI) m/z 368.1 (M+1) + .

3-(4-Carbamoyl-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ=11.21 (br. s., 1H), 8.01 (s, 1H), 7.82-7.70 (m, 4H), 7.62-7.40 (m, 5H), 7.18 (d, J=8.2 Hz, 2H), 7.05 (d, J=7.0 Hz, 1H), 6.51 (s, 1H). MS (ESI) m/z 381.1 (M+1) + .

2-(1H-Indol-6-yl)-3-[4-(piperazine-1-carbonyl)-phenylethynyl]-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ=7.78-7.74 (m, 2H), 7.60 (d, J=8.2 Hz, 1H), 7.48-7.42 (m, 2H), 7.35-7.25 (m, 3H), 7.15-7.03 (m, 3H), 6.50 (d, J=3.1 Hz, 1H), 3.85-3.70 (m, 4H), 3.30-3.06 (m, 4H). MS (ESI) m/z 450.3 (M+1) + .

3-(4-acetylamino-phenylethynyl)-2-(1H-indol-6-yl)-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ=7.86-7.64 (m, 3H), 7.46-7.29 (m, 4H), 7.25-7.17 (m, 2H), 7.00 (d, J=8.5 Hz, 2H), 6.56 (d, J=2.4 Hz, 1H), 2.12 (s, 3H). MS (ESI) m/z 395.1 (M+1) + .

Example 214: Synthesis of 2-(1H-indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]-phenylethynyl}-benzoic acid

2-(1H-Indol-6-yl)-3-{4-[(pyridine-3-carbonyl)-amino]-phenylethynyl)}-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ=9.10 (br. s., 1H), 8.75-8.69 (m, 1H), 8.43-8.37 (m, 1H), 7.81-7.72 (m, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.60-7.52 (m, 3H), 7.48-7.36 (m, 2H), 7.32-7.18 (m, 2H), 7.07 (d, J=7.9 Hz, 2H), 6.56 (dd, J=1.2, 3.2 Hz, 1H). MS (ESI) m/z 458.0 (M+1) + .

2-(1H-indol-6-yl)-3-(4-methanesulfonylamino-phenylethynyl)-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ=7.85-7.64 (m, 3H), 7.45-7.32 (m, 2H), 7.26-7.17 (m, 2H), 7.07-7.00 (m, 4H), 6.55 (dd, J=2.9 Hz, 1H), 3.46 (s, 3H). MS (ESI) m/z 431.1 (M+1) + .

Example 216: Synthesis of 2-(1H-indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)-phenylethynyl]-benzoic acid

2-(1H-Indol-6-yl)-3-[4-(thiophene-2-sulfonylamino)-phenylethynyl]-benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ=9.10 (br. s., 1H), 8.75 (br. s., 1H), 7.77 (dd, J=1.4, 7.8 Hz, 1H), 7.69 (dd, J=1.5, 7.9 Hz, 1H), 7.64 (d, J=8.2 Hz, 1H), 7.48 (dd, J=1.5, 5.0 Hz, 1H), 7.43 (dd, J=1.2, 3.8 Hz, 1H), 7.42-7.24 (m, 2H), 7.22-7.14 (m, 2H), 7.02-6.86 (m, 5H), 6.53 (dd, J=0.9, 3.2 Hz, 1H). MS (ESI) m/z 499.1 (M+1) + .

2-(3-(Methoxycarbonyl)-1H-indol-6-yl)-3-(thiazol-4-ylethynyl) benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 11.89 (s, 1H), 9.06 (d, J=1.9 Hz, 1H), 8.04 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.81 (dd, J=7.7, 1.3 Hz, 1H), 7.73 (dd, J=7.8, 1.4 Hz, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.51 (t, J=7.7 Hz, 1H), 7.48-7.44 (m, 1H), 7.18 (dd, J=8.2, 1.6 Hz, 1H), 3.82 (s, 3H). MS m/z 403.5 (M+H).

2-(1H-indol-6-yl)-3-(thiazol-4-ylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.66 (d, J=2.1 Hz, 1H), 8.41 (s, 1H), 7.76 (ddd, J=7.9, 3.7, 1.4 Hz, 2H), 7.63 (dd, J=13.0, 6.5 Hz, 1H), 7.45 (d, J=6.5 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.21-7.16 (m, 1H), 7.12 (dd, J=8.1, 1.5 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 6.56 (t, J=2.1 Hz, 1H). MS m/z 344.9 (M+H).

2-(1-methyl-1H-pyrazol-4-yl)-3-(thiazol-4-ylethynyl) benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 9.16 (d, J=1.9 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.93 (s, 1H), 7.74 (dd, J=7.7, 1.4 Hz, 1H), 7.61 (dd, J=7.7, 1.4 Hz, 1H), 7.57 (d, J=0.8 Hz, 1H), 7.41 (t, J=7.7 Hz, 1H), 3.89 (s, 3H). MS m/z 310.0 (M+H).

3-((3-hydroxyphenyl)ethynyl)-2-(1-methyl-1H-pyrazol-4-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.78 (s, 1H), 7.72-7.66 (m, 2H), 7.65 (d, J=0.9 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.21-7.10 (m, 1H), 6.86-6.77 (m, 2H), 6.75 (tt, J=2.5, 1.4 Hz, 1H), 3.96 (m, 3H). MS m/z 319.0 (M+H).

2-(3-chloro-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 12.38 (s, 1H), 9.60 (s, 1H), 7.88-7.65 (m, 3H), 7.59-7.41 (m, 2H), 7.32 (s, 1H), 7.16 (dd, J=8.3, 1.5 Hz, 1H), 7.12-7.00 (m, 1H), 6.73 (d, J=9.7 Hz, 1H), 6.59-6.41 (m, 2H). MS m/z 371.1 (M-OH).

3-((3-hydroxyphenyl)ethynyl)-2-(1H-indazol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 8.12 (s, 1H), 7.85-7.70 (m, 4H), 7.52 (t, J=7.7 Hz, 1H), 7.45 (s, 1H), 7.16-6.99 (m, 2H), 6.78-6.65 (m, 1H), 6.53-6.44 (m, 2H). MS m/z 355.0 (M+H).

Example 223: Synthesis of 2-(3-(2-acetamidoethyl)-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid

2-(3-(2-acetamidoethyl)-1H-indol-6-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 10.90 (s, 1H), 7.93 (m, 1H), 7.72 (dd, J=7.7, 1.4 Hz, 1H), 7.64 (dd, J=7.7, 1.4 Hz, 1H), 7.50 (s, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.18 (s, 1H), 7.13-6.98 (m, 2H), 6.74-6.64 (m, 1H), 6.60-6.51 (m, 2H), 3.28 (d, J=7.7 Hz, 2H), 2.86-2.72 (m, 2H), 1.77 (s, 3H). MS m/z 439.2 (M+H).

3-((3-(N,N-dimethylsulfamoyl)phenyl)ethynyl)-2-fluorobenzoic acid was prepared by the same procedure as example 85. 1 H NMR (300 MHz, DMSO) δ 8.02-7.87 (m, 3H), 7.87-7.81 (m, 1H), 7.81-7.69 (m, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 2.67 (s, 3H), 2.65 (s, 3H). MS m/z 448.0 (M+H).

Example 225: Synthesis of 2-(1H-indol-6-yl)-3-((4-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)benzoic acid

2-(1H-indol-6-yl)-3-((4-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.67 (d, J=7.7 Hz, 2H), 7.58 (dd, J=8.2, 0.7 Hz, 1H), 7.45-7.42 (m, 1H), 7.39 (dd, J=8.1, 7.4 Hz, 1H), 7.30-7.25 (m, 1H), 7.04 (dd, J=8.1, 1.5 Hz, 1H), 6.99-6.90 (m, 2H), 6.81-6.71 (m, 2H), 6.49 (dd, J=3.1, 0.9 Hz, 1H), 4.51 (dq, J=12.0, 3.8 Hz, 21H), 4.08-3.75 (m, 2H), 3.55 (ddd, J=11.7, 8.7, 3.1 Hz, 2H), 2.24-1.76 (m, 2H), 1.65 (dtd, J=12.8, 8.4, 4.0 Hz, 2H). MS m/z 438.2 (M+H).

2-(1H-indol-6-yl)-3-((4-morpholinophenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.20 (s, 1H), 7.69 (t, J=7.9 Hz, 3H), 7.43 (s, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.15 (dd, J=8.1, 1.4 Hz, 1H), 6.95 (d, J=8.8 Hz, 2H), 6.68 (d, J=8.9 Hz, 2H), 6.60 (s, 1H), 3.92-3.71 (m, 4H), 3.20-3.02 (m, 4H). MS m/z 423.1 (M+H).

3-((3-carbamoylphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 13.09-12.22 (m, 1H), 11.16 (s, 1H), 7.94 (s, 1H), 7.80-7.71 (m, 2H), 7.67 (dd, J=7.7, 1.4 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.7 Hz, 1H), 7.43-7.39 (m, 1H), 7.39-7.29 (m, 2H), 7.21-7.14 (m, 1H), 7.04 (dd, J=8.1, 1.6 Hz, 1H), 6.56-6.32 (m, 1H). MS m/z 381.3 (M+H).

3-((4-Fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 8.51 (s, 1H), 8.37 (s, 1H), 8.06 (dd, J=7.8, 1.3 Hz, 1H), 7.87 (dd, J=7.8, 1.3 Hz, 1H), 7.67 (d, J=3.5 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.14-7.01 (m, 2H), 7.03-6.88 (m, 2H), 6.83 (d, J=3.5 Hz, 1H). MS m/z 357.1 (M+H).

3-((2,4-Difluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.73 (dq, J=7.9, 1.4 Hz, 2H), 7.56 (dt, J=7.8, 1.8 Hz, 1H), 7.47-7.39 (m, 2H), 7.29-7.22 (m, 1H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 6.97-6.82 (m, 2H), 6.78 (ddd, J=10.3, 6.0, 1.3 Hz, 1H), 6.48 (dd, J=3.1, 0.9 Hz, 1H). MS m/z 374.4 (M+H).

3-((3-Acetamidophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 11.17 (s, 1H), 9.96 (s, 1H), 7.77 (dd, J=7.7, 1.4 Hz, 1H), 7.67 (dd, J=7.7, 1.4 Hz, 2H), 7.63-7.55 (m, 2H), 7.45 (dd, J=13.6, 5.9 Hz, 1H), 7.38 (dd, J=3.3, 2.3 Hz, 2H), 7.18 (t, J=7.9 Hz, 1H), 7.05 (dd, J=8.1, 1.6 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.50-6.35 (m, 1H), 2.05 (d, J=14.2 Hz, 3H). MS m/z 395.0 (M+H).

2-(1H-indol-6-yl)-3-((3-(nicotinamido)phenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 11.18 (s, 1H), 10.47 (s, 1H), 9.10 (d, J=1.6 Hz, 1H), 8.79 (dd, J=4.9, 1.6 Hz, 1H), 8.41-8.13 (m, 1H), 7.79 (dd, J=7.7, 1.4 Hz, 1H), 7.75 (m, 1H), 7.68 (dd, J=7.8, 1.3 Hz, 2H), 7.62 (t, J=3.6 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.41 (s, 1H), 7.39-7.35 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.06 (dd, J=8.1, 1.5 Hz, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.46 (m, 1H). MS m/z 458.2 (M+H).

Example 232: Synthesis of 3-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((3-(3-chloro-4-fluorophenylsulfonamido)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.39 (bs, 1H), 7.76 (m, 1H), 7.71-7.60 (m, 1H), 7.42-7.34 (m, 2H), 7.24-7.14 (m, 1H), 7.12-6.96 (m, 1H), 6.97-6.83 (m, 1H), 6.80 (d, J=2.2 Hz, 1H), 6.70-6.59 (m, 2H), 6.61-6.51 (m, 2H), 6.51-6.38 (m, 2H), 6.34-6.18 (m, 1H). MS m/z 545.1 (M+H).

3-((3-aminophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 8.21 (bs, 1H), 7.73-7.46 (m, 3H), 7.35-7.28 (m, 2H), 7.13-7.08 (m, 1H), 7.02 (dd, J=8.1, 1.4 Hz, 1H), 6.86 (t, J=7.8 Hz, 1H), 6.51 (s, 1H), 6.46-6.37 (m, 2H), 5.94 (s, 1H)). MS m/z 353.5 (M+H).

2-(1H-indol-6-yl)-3-((3-(methylsulfonamido)phenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 10.50 (s, 1H), 7.70 (ddd, J=7.9, 3.0, 1.3 Hz, 2H), 7.60 (d, J=8.2 Hz, 1H), 7.47-7.36 (m, 2H), 7.31-7.22 (m, 1H), 7.18-7.04 (m, 3H), 7.01 (d, J=1.8 Hz, 1H), 6.83-6.74 (m, 1H), 6.48 (d, J=2.3 Hz, 1H), 2.97-2.66 (m, 3H). MS m/z 431.0 (M+H).

Example 235: Synthesis of 2-(1H-indol-6-yl)-3-((3-(thiophene-2-sulfonamido)phenyl)ethynyl)benzoic acid

2-(1H-indol-6-yl)-3-((3-(thiophene-2-sulfonamido)phenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, Acetone) δ 10.33 (s, 1H), 9.14 (s, 1H), 7.87-7.72 (m, 3H), 7.63 (d, J=8.1 Hz, 1H), 7.54-7.43 (m, 3H), 7.42-7.33 (m, 1H), 7.23-7.10 (m, 4H), 7.05 (dd, J=5.0, 3.8 Hz, 1H), 6.85 (dd, J=4.9, 2.7 Hz, 1H), 6.53 (m, 1H). MS m/z 499.8 (M+H).

3-((3-acetamido-5-fluorophenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, DMSO) δ 11.17 (s, 1H), 10.15 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.69 (d, J=6.5 Hz, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.47 (t, J=7.8 Hz, 2H), 7.38 (m, 2H), 7.26 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.46 (m, 2H), 2.21 (s, 3H). MS m/z 435.1 (M+Na).

2-(indolin-6-yl)-3-(phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.84 (dd, J=7.8, 1.3 Hz, 1H), 7.76 (dd, J=7.8, 1.3 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.39 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.24 (d, J=2.5 Hz, 1H), 7.13 (dd, J=10.4, 6.7 Hz, 2H), 3.94 (d, J=7.7 Hz, 2H), 3.36 (s, 2H). MS m/z 340.1 (M+H).

3-((3-hydroxyphenyl)ethynyl)-2-(indolin-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 7.99-7.83 (m, 1H), 7.85-7.69 (m, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.51-7.39 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.9 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 4.23-3.73 (m, 2H), 3.40 (s, 2H). MS m/z 356.1 (M+H).

3-((6-aminopyridin-2-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 8.65 (s, 1H), 7.74 (ddd, J=10.5, 7.7, 1.1 Hz, 2H), 7.63 (d, J=8.2 Hz, 1H), 7.43 (s, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.17-7.03 (m, 3H), 6.51 (s, 1H), 6.20 (dd, J=16.1, 7.8 Hz, 1H), 4.57 (s, 2H). MS m/z 354.1 (M+H).

3-((2-aminopyridin-4-yl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 8.67 (s, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.78 (dd, J=7.8, 1.2 Hz, 1H), 7.72-7.61 (m, 2H), 7.37 (dd, J=13.1, 5.2 Hz, 2H), 7.24-7.13 (m, 1H), 7.07 (dd, J=8.2, 1.2 Hz, 1H), 6.58 (s, 1H), 6.27 (d, J=5.2 Hz, 1H), 5.79 (s, 1H), 4.28 (s, 2H). MS m/z 354.1 (M+H).

3-((3-hydroxyphenyl)ethynyl)-2-(5-methoxypyridin-3-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 8.50 (d, J=30.3 Hz, 2H), 8.14 (dd, J=7.9, 1.1 Hz, 1H), 8.09 (s, 1H), 7.89 (dd, J=7.8, 1.1 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.9 Hz, 1H), 6.77 (dd, J=8.2, 1.6 Hz, 1H), 6.64 (d, J=7.6 Hz, 1H), 6.57 (s, 1H), 4.02 (s, 3H). MS m/z 346.3 (M+H).

2-(benzo[d][1,3]dioxol-5-yl)-3-((3-hydroxyphenyl)ethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.71 (ddd, J=10.2, 7.8, 1.4 Hz, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.14-7.04 (m, 1H), 6.87 (dd, J=9.1, 4.8 Hz, 2H), 6.82-6.78 (m, 1H), 6.76-6.70 (m, 1H), 6.66 (ddd, J=3.9, 2.5, 1.4 Hz, 1H), 5.99 (s, 2H). MS m/z 359.4 (M+H).

3-((3-hydroxyphenyl)ethynyl)-2-(pyrimidin-5-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 9.19 (s, 1H), 8.78 (s, 2H), 8.10 (dd, J=7.9, 1.3 Hz, 1H), 7.87 (dd, J=7.8, 1.3 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.09 (t, J=7.9 Hz, 2H), 6.84-6.68 (m, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.57 (d, J=1.3 Hz, 1H). MS m/z 317.3 (M+H).

4′-amino-6-((3-hydroxyphenyl)ethynyl)-5′-methoxybiphenyl-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.81 (ddd, J=30.0, 7.8, 1.3 Hz, 2H), 7.50 (t, J=7.8 Hz, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.08 (t, J=7.9 Hz, 1H), 7.00 (dd, J=8.0, 1.7 Hz, 1H), 6.74 (dd, J=8.2, 1.5 Hz, 1H), 6.60 (dd, J=13.2, 5.0 Hz, 2H), 3.88 (s, 3H). MS m/z 360.2 (M+H).

3-(4-hydroxybut-1-ynyl)-2-(1H-indol-6-yl) benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CDCl 3 ) δ 8.54 (m, 1H), 7.73-7.64 (m, 1H), 7.65-7.49 (m, 2H), 7.29 (dd, J=16.2, 8.4 Hz, 2H), 7.18-7.05 (m, 1H), 7.01 (dd, J=8.1, 1.4 Hz, 1H), 6.54 (d, J=2.1 Hz, 1H), 3.15 (t, J=6.4 Hz, 2H), 2.22 (t, J=6.5 Hz, 2H). MS m/z 306.1 (M+H).

3-(3-amino-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.70 (ddd, J=16.2, 7.8, 1.4 Hz, 2H), 7.58 (d, J=8.1 Hz, 1H), 7.43 (dd, J=13.4, 5.7 Hz, 2H), 7.29 (d, J=3.2 Hz, 2H), 6.93 (dd, J=8.1, 1.6 Hz, 1H), 6.49 (dd, J=3.2, 0.9 Hz, 1H), 3.56 (s, 6H). MS m/z 318.1 (M+H).

3-(3-hydroxy-3-phenylprop-1-ynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.76-7.63 (m, 2H), 7.52 (t, J=7.2 Hz, 1H), 7.40 (dd, J=10.1, 5.4 Hz, 2H), 7.36-7.30 (m, 1H), 7.29-7.21 (m, 1H), 7.14-6.98 (m, 1H), 7.02-6.82 (m, 4H), 6.56-6.44 (m, 1H), 5.36 (s, 1H). MS m/z 368.3 (M+H).

3-(3-hydroxy-3-methylbut-1-ynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 10.48 (s, 1H), 7.71 (d, J=7.7 Hz, 1H), 7.62 (t, J=10.2 Hz, 1H), 7.47-7.35 (m, 1H), 7.30-7.19 (m, 1H), 7.20-7.04 (m, 1H), 7.01 (d, J=1.7 Hz, 1H), 6.82-6.69 (m, 1H), 6.49 (d, J=2.2 Hz, 1H), 2.98 (s, 6H). MS m/z 342.1 (M+Na).

3-((3-(hydroxymethyl)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 10.53 (s, 1H), 7.76-7.64 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.48-7.44 (m, 1H), 7.44-7.36 (m, 1H), 7.28 (dt, J=3.0, 1.2 Hz, 1H), 7.25-7.19 (m, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.04 (dt, J=3.3, 1.6 Hz, 1H), 7.00-6.83 (m, 2H), 6.57-6.42 (m, 1H), 4.77 (d, J=65.2 Hz, 2H). MS m/z 368.0 (M+H).

6-(2-carboxy-6-(phenylethynyl)phenyl)-1H-indole-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.74 (ddd, J=7.8, 5.0, 1.4 Hz, 2H), 7.65 (dd, J=1.6, 0.8 Hz, 1H), 7.50 (dt, J=8.6, 0.8 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.35-7.25 (m, 1H), 7.25-7.13 (m, 4H), 7.04 (dt, J=8.2, 2.1 Hz, 2H). MS m/z 382.0 (M+H).

2-(2-(ethoxycarbonyl)-1H-indol-6-yl)-3-(phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.81-7.69 (m, 2H), 7.65 (d, J=0.9 Hz, 1H), 7.50 (d, J=8.6 Hz, 1H), 7.42 (dd, J=15.2, 7.4 Hz, 1H), 7.35-7.27 (m, 1H), 7.24-7.10 (m, 4H), 7.03 (dd, J=8.0, 1.6 Hz, 2H), 4.40 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H). MS m/z 410.1 (M+H).

3-((3-carbamoyl-5-methoxyphenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.74 (ddd, J=7.8, 4.6, 1.4 Hz, 2H), 7.62 (d, J=8.2 Hz, 1H), 7.45 (dd, J=9.9, 5.6 Hz, 2H), 7.27 (dd, J=3.6, 2.0 Hz, 2H), 7.22 (t, J=1.4 Hz, 1H), 7.05 (dd, J=8.1, 1.5 Hz, 1H), 6.51 (ddd, J=5.0, 2.8, 1.1 Hz, 2H), 3.66 (s, 3H). MS m/z 411.2 (M+H).

2-(1H-indol-5-yl)-3-(phenylethynyl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.71 (ddd, J=7.8, 4.8, 1.4 Hz, 2H), 7.60 (dd, J=1.7, 0.7 Hz, 1H), 7.45-7.38 (m, 2H), 7.30-7.25 (m, 1H), 7.23-7.13 (m, 4H), 7.06 (ddd, J=6.4, 3.8, 2.0 Hz, 2H), 6.49 (dd, J=3.2, 0.9 Hz, 1H). MS m/z 338.2 (M+H).

Example 254: Synthesis of 5-(2-carboxy-6-((3-hydroxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylic acid

5-(2-carboxy-6-((3-hydroxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.70 (dd, J=7.7, 1.4 Hz, 1H), 7.62 (dd, J=7.8, 1.4 Hz, 1H), 7.57-7.51 (m, 2H), 7.42 (t, J=7.7 Hz, 1H), 7.30 (dd, J=8.5, 1.7 Hz, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.00 (dd, J=11.5, 4.8 Hz, 1H), 6.67 (ddd, J=8.2, 2.4, 1.2 Hz, 1H), 6.57-6.46 (m, 2H). MS m/z 398.0 (M+H).

Example 255: Synthesis of 5-(2-carboxy-6-((4-methoxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylic acid

5-(2-carboxy-6-((4-methoxyphenyl)ethynyl)phenyl)-1H-indole-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.69-7.62 (m, 1H), 7.58 (ddd, J=4.7, 2.3, 1.1 Hz, 2H), 7.52 (dt, J=8.5, 0.8 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.28 (dd, J=8.5, 1.7 Hz, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04-6.90 (m, 2H), 6.78-6.69 (m, 2H), 3.69 (s, 3H). MS m/z 412.2 (M+H).

Example 256: Synthesis of 3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl) ethynyl)-2-(1H-indol-6-yl)benzoic acid

3-((4-fluoro-3-(tetrahydro-2H-pyran-4-yloxy)phenyl)ethynyl)-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.71 (ddd, J=9.2, 8.1, 1.4 Hz, 2H), 7.59 (dd, J=11.1, 10.5 Hz, 1H), 7.48-7.37 (m, 2H), 7.29 (t, J=9.2 Hz, 1H), 7.10-7.01 (m, 1H), 6.95 (dd, J=11.1, 8.4 Hz, 1H), 6.74 (ddd, J=8.4, 4.4, 2.0 Hz, 1H), 6.50 (ddd, J=9.9, 5.6, 1.4 Hz, 2H), 4.31-4.10 (m, 1H), 4.00-3.77 (m, 2H), 3.55 (ddd, J=17.7, 10.6, 6.7 Hz, 2H), 2.03-1.71 (m, 2H), 1.61 (ddd, J=21.1, 7.6, 3.7 Hz, 2H). MS m/z 456.2 (M+H).

5′-acetamido-6-(phenylethynyl)biphenyl-2-carboxylic acid was prepared by the same procedure as example 119. 1 H NMR (300 MHz, CD 3 OD) δ 7.81 (dd, J=7.8, 1.3 Hz, 1H), 7.78-7.66 (m, 2H), 7.54 (t, J=1.9 Hz, 1H), 7.47 (t, J=7.8 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.30-7.21 (m, 3H), 7.19-7.10 (m, 2H), 7.08 (d, J=7.6 Hz, 1H), 2.11 (s, 3H). MS m/z 356.2 (M+H).

Example 258: Synthesis of 3-[3-(5-amino-1H-1,3-benzodiazol-1-yl)prop-1-yn-1-yl]-2-phenylbenzoic acid trifluoroacetate salt

3-[3-(5-amino-1H-1,3-benzodiazol-1-yl)prop-1-yn-1-yl]-2-phenylbenzoic acid trifluoroacetate salt was prepared by the same procedure as example 157. 1 H NMR (300 MHz, DMSO) δ=8.72 (br. s., 1H), 7.71 (ddd, J=1.5, 7.8, 13.0 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.25-7.10 (m, 6H), 6.71 (d, J=7.9 Hz, 2H), 5.31 (s, 2H), MS (ES + )=367.94 (MH) + .

Example 259: Synthesis of 2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid; trifluoroacetate salt

2-(1H-indol-6-yl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO) δ=11.19 (s, 1H), 8.55 (br. s., 2H), 7.82 (dd, J=1.5, 7.6 Hz, 1H), 7.74 (dd, J=1.5, 7.6 Hz, 1H), 7.64-7.45 (m, 2H), 7.44-7.36 (m, 2H), 7.17 (d, J=6.2 Hz, 2H), 7.03 (dd, J=1.8, 8.2 Hz, 1H), 6.47 (ddd, J=0.9, 2.0, 3.0 Hz, 1H). MS (ES + )=339.00 (MH) + .

Example 260: Synthesis of 2-(4-methylphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt

2-(4-methylphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO) δ=8.59 (d, J=5.6 Hz, 2H), 7.80 (ddd, J=1.2, 7.7, 10.5 Hz, 2H), 7.52 (t, J=7.8 Hz, 1H), 7.28-7.16 (m, 6H), 2.37 (s, 3H). MS (ES + )=314.00 (MH) + .

3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl phenyl)benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.62 (br. s., 1H), 7.81-7.62 (m, 2H), 7.52-7.40 (m, 1H), 7.30-7.16 (m, 5H), 7.16-7.06 (m, 1H), 6.74 (ddd, J=0.9, 2.3, 8.2 Hz, 1H), 6.65-6.51 (m, 2H), 2.36 (s, 3H). MS (ES + )=328.11 (MH) + .

Example 262: Synthesis of 3-{3-[(1H-1,3-benzodiazol-6-yl)amino]prop-1-yn-1-yl}-2-phenylbenzoic acid; trifluoroacetate salt

3-{3-[(1H-1,3-benzodiazol-6-yl)amino]prop-1-yn-1-yl)}-2-phenylbenzoic acid; trifluoroacetate salt was prepared by the same procedure as example 157. 1 H NMR (300 MHz, DMSO) δ=8.68 (br. s., 1H), 7.77-7.64 (m, 2H), 7.51-7.41 (m, 1H), 7.32-7.08 (m, 7H), 6.79-6.62 (m, 2H), 5.30 (s, 2H). MS (ES + )=368.01 (MH) + .

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1-methyl-1H-indol-5-yl)benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.57 (br. s., 1H), 7.76-7.69 (m, 1H), 7.65 (dd, J=1.5, 7.6 Hz, 1H), 7.56-7.49 (m, 1H), 7.49-7.40 (m, 2H), 7.34 (d, J=3.2 Hz, 1H), 7.19-7.11 (m, 1H), 7.10-6.99 (m, 1H), 6.76-6.64 (m, 1H), 6.61-6.51 (m, 2H), 6.48-6.42 (m, 1H), 3.87-3.77 (m, 3H). MS (ES + )=368.08 (MH) + .

Example 264: Synthesis of 3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)benzoic acid; trifluoroacetate salt

3-[2-(3-hydroxyphenyl)ethynyl]-2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=7.70-7.64 (m, 1H), 7.63-7.56 (m, 1H), 7.44-7.32 (m, 1H), 7.14 (t, J=7.9 Hz, 1H), 6.80-6.63 (m, 5H), 4.25 (dd, J=3.8, 5.0 Hz, 2H), 3.33-3.21 (m, 2H), 2.87 (s, 3H). MS (ES + )=386.09 (MH) + .

Example 265: Synthesis of 3-[2-(3-hydroxyphenyl)ethynyl]-2-(3-methane sulfonamidophenyl) benzoic acid

3-[2-(3-hydroxyphenyl)ethynyl]-2-(3-methane sulfonamidophenyl) benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.81 (s, 1H), 9.63 (br. s., 1H), 7.75 (qd, J=1.6, 7.8 Hz, 2H), 7.55-7.46 (m, 1H), 7.43-7.34 (m, 1H), 7.25-7.18 (m, 1H), 7.16-7.01 (m, 3H), 6.74 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 6.62-6.52 (m, 2H), 2.88 (s, 3H). MS (ES + )=430.00 (M+Na) + .

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-6-yl)benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=11.15 (s, 1H), 9.57 (br. s., 1H), 7.79-7.71 (m, 1H), 7.69-7.60 (m, 1H), 7.60-7.53 (m, 1H), 7.50-7.41 (m, 1H), 7.41-7.33 (m, 2H), 7.11-6.96 (m, 2H), 6.76-6.63 (m, 2H), 6.60-6.50 (m, 2H), 6.49-6.42 (m, 1H). MS (ES + )=354.01 (MH) + .

2-(3-carbamoylphenyl)-3-[2-(3-hydroxyphenyl)ethynyl]benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.58 (br. s., 1H), 7.99 (s, 1H), 7.95-7.83 (m, 3H), 7.83-7.73 (m, 2H), 7.57-7.42 (m, 3H), 7.39-7.29 (m, 1H), 7.13-7.01 (m, 1H), 6.73 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 6.59-6.48 (m, 2H). MS (ES + )=380.04 (M+Na) + .

Example 268: Synthesis of 2-[1-(benzenesulfonyl)-1H-indol-3-yl]-3-[2-(3-hydroxyphenyl)ethynyl] benzoic acid

2-[1-(benzenesulfonyl)-1H-indol-3-yl]-3-[2-(3-hydroxyphenyl)ethynyl] benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.55 (br. s., 1H), 7.97-7.86 (m, 3H), 7.85-7.77 (m, 3H), 7.61-7.46 (m, 2H), 7.42-7.29 (m, 3H), 7.26-7.18 (m, 2H), 6.92 (t, J=7.9 Hz, 1H), 6.68 (ddd, J=1.0, 2.4, 8.3 Hz, 1H), 6.29 (dd, J=1.5, 2.3 Hz, 1H), 5.94 (td, J=1.2, 7.8 Hz, 1H). MS (ES + )=352.99 (M−140) + .

2-(3-hydroxyphenyl)-3-[2-(3-hydroxyphenyl) ethynyl]benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.63 (br. s., 1H), 9.42 (br. s., 1H), 7.69 (ddd, J=1.2, 7.8, 14.5 Hz, 2H), 7.52-7.37 (m, 1H), 7.27-7.16 (m, 1H), 7.17-7.06 (m, 1H), 6.82-6.68 (m, 4H), 6.68-6.54 (m, 2H), 3.95 (s, 1H). MS (ES + )=312.98 (MH-H 2 O) + .

Example 270: Synthesis of 2-(1H-indol-5-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt

2-(1H-indol-5-yl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO) δ=11.17 (s, 1H), 8.58-8.46 (m, 2H), 7.81 (dd, J=1.2, 7.9 Hz, 1H), 7.73 (dd, J=0.9, 7.9 Hz, 1H), 7.57-7.40 (m, 3H), 7.38 (t, J=2.6 Hz, 1H), 7.17 (dd, J=1.8, 4.4 Hz, 2H), 7.11 (dd, J=1.6, 8.4 Hz, 1H), 6.47 (t, J=2.2 Hz, 1H). MS (ES + )=339.07 (MH) + .

Example 271: Synthesis of 2-(3-chloro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid; trifluoroacetate salt

2-(3-chloro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO) δ=10.04 (br. s., 1H), 8.70-8.55 (m, 2H), 7.89-7.78 (m, 2H), 7.65-7.48 (m, 1H), 7.29-7.20 (m, 2H), 6.83 (td, J=2.0, 12.5 Hz, 2H), 6.69 (dd, J=1.5, 2.3 Hz, 1H), 6.25-6.06 (m, 1H). MS (ES + )=350.00 (MH) + .

Example 272: Synthesis of 2-(3-fluoro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt

2-(3-fluoro-5-hydroxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO) δ=9.96 (br. s., 1H), 8.55 (d, J=5.9 Hz, 2H), 7.88-7.67 (m, 2H), 7.56-7.41 (m, 1H), 7.22-7.08 (m, 2H), 6.61-6.45 (m, 3H). MS (ES + )=334.04 (MH) + .

Example 273: Synthesis of 2-(3,5-dimethoxyphenyl)-3-[2-(pyridin-4-yl)ethynyl]benzoic acid; trifluoroacetate salt

2-(3,5-dimethoxyphenyl)-3-[2-(pyridin-4-yl)ethynyl] benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 174. 1 H NMR (300 MHz, DMSO) δ=8.61 (br. s., 2H), 7.80 (ddd, J=1.3, 7.7, 13.3 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.21 (d, J=5.9 Hz, 2H), 6.61-6.52 (m, 1H), 6.49 (d, J=2.3 Hz, 2H), 3.73 (s, 6H). MS (ES + )=360.06 (MH) + .

Example 274: Synthesis of 3-[3-(4-fluorophenyl)-3-hydroxyprop-1-yn-1-yl]-2-(3-hydroxyphenyl) benzoic acid

3-[3-(4-fluorophenyl)-3-hydroxyprop-1-yn-1-yl]-2-(3-hydroxyphenyl)benzoic acid was prepared by the same procedure as example 33. 1 H NMR (300 MHz, DMSO) δ=9.18 (br. s., 1H), 7.47-7.37 (m, 2H), 7.27-7.14 (m, 1H), 6.98-6.73 (m, 5H), 6.55 (ddd, J=1.2, 2.3, 8.2 Hz, 1H), 6.44-6.34 (m, 2H), 5.19-5.09 (m, 1H).

3-[2-(3-hydroxyphenyl)ethynyl]-2-(2-phenoxyphenyl) benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.63 (br. s., 1H), 7.81 (dd, J=1.3, 7.8 Hz, 1H), 7.72 (dd, J=1.5, 7.6 Hz, 1H), 7.51-7.30 (m, 3H), 7.27-7.07 (m, 4H), 7.05-6.92 (m, 1H), 6.92-6.80 (m, 3H), 6.74 (ddd, J=1.0, 2.5, 8.2 Hz, 1H), 6.62-6.49 (m, 2H). MS (ES + )=429.19 (M+Na) + .

3-[2-(3-hydroxyphenyl)ethynyl]-2-(1H-indol-3-yl) benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=11.29 (s, 1H), 9.53 (s, 1H), 7.74 (dd, J=1.3, 7.8 Hz, 1H), 7.65 (dd, J=1.5, 7.9 Hz, 1H), 7.48-7.37 (m, 3H), 7.31 (d, J=8.2 Hz, 1H), 7.16-6.91 (m, 3H), 6.69 (ddd, J=0.9, 2.6, 8.2 Hz, 1H), 6.50-6.34 (m, 2H). MS (ES + )=354.08 (MH) + .

2-(3,5-dimethoxyphenyl)-3-[2-(3-hydroxyphenyl) ethynyl]benzoic acid was prepared by the same procedure as example 166. 1 H NMR (300 MHz, DMSO) δ=9.63 (br. s., 1H), 7.78-7.62 (m, 2H), 7.54-7.40 (m, 1H), 7.13 (t, J=7.9 Hz, 1H), 6.81-6.67 (m, 1H), 6.68-6.56 (m, 2H), 6.56-6.49 (m, 1H), 6.47 (d, J=2.3 Hz, 2H), 3.82 (s, 6H). MS (ES + )=375.08 (MH) + .

Example 278: Synthesis of 2-amino-3-[2-(3-carbamoylphenyl)ethynyl]benzoic acid; trifluoroacetate salt

2-amino-3-[2-(3-carbamoylphenyl)ethynyl]benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 78. 1 H NMR (300 MHz, DMSO) δ=8.24-8.06 (m, 2H), 8.05-7.75 (m, 3H), 7.68-7.46 (m, 3H), 6.76-6.58 (m, 1H), 3.38 (s, 2H). MS (ES + )=281.07 (MH) + .

2-amino-3-[2-(3-carboxyphenyl)ethynyl]benzoic acid; trifluoroacetate salt was prepared by the same procedure as example 78. 1 H NMR (300 MHz, DMSO) δ=13.13 (br. s., 1H), 8.18 (br. s., 1H), 7.94 (d, J=7.6 Hz, 1H), 7.83 (dd, J=7.8, 15.1 Hz, 2H), 7.64-7.45 (m, 2H), 6.59 (t, J=7.6 Hz, 1H). MS (ES + )=282.09 (MH) + .

Example 280: Synthesis of 5-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole 5-(3-Ethynyl-phenyl)-1H-tetrazole

The solution of 5-(3-Bromo-phenyl)-1H-tetrazole (2 g, 8.9 mmol) in triethylamine (20 mL) was degassed under N 2 for 10 min. Trimethylsilylacetylene (1 mL), bis(triphenylphosphine)palladium(II) dichloride (624 mg, 0.89 mmol) and copper iodide (339 mg, 1.78 mmol) was added and the reaction mixture was degassed under N 2 for 20 min and then heated at 60° C. for 18 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by column chromatography through a silica gel cartridge (80 g) eluting with methanol/dichloromethane (10-20%) to give the intermediate as a white solid. To this intermediate in methanol (10 mL) was slowly added 2N NaOH (3.5 mL, 7 mmol). The reaction mixture was stirred at room temperature for 20 minutes and concentrated, diluted with water (10 mL) and acidified with 2N hydrochloric acid aqueous solution until pH=1. The precipitate was filtered and purified through preparative HPLC to give 810 mg (59% for 2 steps) of the pure product as a white solid.

5-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-1H-indole. A mixture of 5-(3-ethynyl-phenyl)-1H-tetrazole (34 mg, 0.2 mmol), 5-iodo-indole (97 mg, 0.4 mmol), palladium tetrakis-triphenylphosphine (23 mg, 0.02 mmol) and copper iodide (7.6 mg, 0.04 mmol), potassium carbonate (55.3 mg, 0.4 mmol) in 1,2-dimethoxyethane/water (1 mL/0.3 mL) was degassed with N 2 for 5 minutes and then heated at 60° C. for 3 hours. After cooling to ambient temperature, the crude mixture was filtered through celite and washed with dichloromethane. The filtrate was concentrated and purified by preparative HPLC to give 15.4 mg (27%) of the pure product as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ=10.71 (br. s., 1H), 8.15 (d, J=2.3 Hz, 1H), 7.96 (td, J=1.5, 7.8 Hz, 1H), 7.78 (s, 1H), 7.71-7.52 (m, 3H), 7.44-7.34 (m, 1H), 7.31-7.25 (m, 2H), 6.48 (d, J=3.1 Hz, 1H). MS (ESI) m/z 285.0 (M) + .

3-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-1H-pyrrolo[2,3-b]pyridine was prepared by the same procedure as example 280. 1 H NMR (300 MHz, DMSO) δ=12.23 (br. s., 1H), 8.33 (dd, J=1.5, 4.7 Hz, 1H), 8.20 (s, 1H), 8.13 (dd, J=1.6, 7.8 Hz, 1H), 8.04-7.95 (m, 2H), 7.78-7.73 (m, 1H), 7.70-7.61 (m, 1H), 7.22 (dd, J=4.7, 7.9 Hz, 1H). MS (ESI) m/z 287.1 (M+1) + .

6-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-1H-indole was prepared by the same procedure as example 280. 1 H NMR (300 MHz, DMSO) δ=11.33 (br. s., 1H), 8.19 (d, J=2.5 Hz, 1H), 8.19 (s, 1H), 8.06-8.03 (m, 1H), 7.75 (td, J=5.0 Hz, 8.1 Hz, 1H), 7.67-7.55 (m, 3H), 7.49-7.46 (m, 1H), 7.19 (dd, J=1.3, 8.1 Hz, 1H), 6.50-6.47 (m, 1H); MS (ESI) m/z 285.1 (M) + .

1-Benzenesulfonyl-3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole was prepared by the same procedure as example 280. MS (ESI) m/z 426.0 (M+1) + .

3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole. 1-Benzenesulfonyl-3-[3-(1H-tetrazol-5-yl)-phenylethynyl]-1H-indole, (30 mg, 0.07 mmol) was dissolved in tetrahydrofuran/methanol (1 mL/0.2 mL) and added sodium hydroxide solution (2 N in water, 0.1 mL, 0.2 mmol) and the solution was stirred at 60° C. for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 17 mg (84%) of the pure product as a white solid. 1 H NMR (300 MHz, DMSO) δ=11.63 (br. s., 1H), 8.18 (s, 1H), 8.03-8.01 (m, 1H), 7.83 (d, J=2.6 Hz, 1H), 7.76-7.61 (m, 3H), 7.50-7.45 (m, 1H), 7.24-7.13 (m, 2H). MS (ESI) m/z 286.0 (M+1) + .

{2-[3-(1H-Tetrazol-5-yl)-phenylethynyl]-phenyl}-methanol was prepared by the same procedure as example 280. 1 H NMR (300 MHz, CD 3 OD) δ=8.21 (br. s., 1H), 8.04 (d, J=7.0 Hz, 1H), 7.77-7.69 (m, 1H), 7.65-7.51 (m, 3H), 7.42 (t, J=7.3 Hz, 1H), 7.35-7.27 (m, 1H), 4.92-4.84 (m, 2H). MS (ESI) m/z 300.0 (M+Na) + .

3-[3-(Morpholine-4-carbonyl)-phenylethynyl]-benzoic acid. A mixture of 3-(3-carbamoyl-5-methoxy-phenylethynyl)-benzoic acid (40 mg, 0.14 mmol), morpholine (0.1 mL), HATU (70 mg, 0.18 mmol) and triethylamine (0.1 mmol) in tetrahydrofuran (1 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified through preparative HPLC to give the ester intermediate. To this intermediate in tetrahydrofuran/methanol (1 mL/0.2 mL) was added sodium hydroxide solution (2 N in water, 0.2 mL, 0.4 mmol) and the solution was stirred at room temperature for 18 hours. 1 N hydrochloric acid aqueous solution was added dropwise until pH=1 and the reaction mixture was purified through preparative HPLC to give 8 mg (17% for 2 steps) of the pure product as a white solid. 18 mg (22% for 2 steps) of the pure product as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ=8.15 (s, 1H), 8.02 (d, J=7.6 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.68-7.60 (m, 2H), 7.55-7.42 (m, 3H), 3.80-3.60 (m, 6H), 3.55-3.42 (m, 2H). MS (ESI) m/z 336.1 (M+1) + .

3-(3-Methylcarbamoyl-phenylethynyl)-benzoic acid was prepared by the same procedure as example 286. 1 H NMR (300 MHz, CD 3 OD) δ=8.15 (t, J=1.6 Hz, 1H), 8.05-7.99 (m, 2H), 7.82-7.79 (m, 1H), 7.76-7.69 (m, 2H), 7.53-7.49 (m, 2H), 2.93 (s, 3H). MS (ESI) m/z 280.1 (M+1) + .

3-(3-Dimethylcarbamoyl-phenylethynyl)-benzoic acid was prepared by the same procedure as example 286. 1 H NMR (300 MHz, CD 3 OD) δ=8.15 (t, J=1.3 Hz, 1H), 8.02 (td, J=1.5, 7.9 Hz, 1H), 7.75 (td, J=1.4, 7.8 Hz, 1H), 7.66-7.59 (m, 2H), 7.54-7.41 (m, 3H), 3.11 (s, 3H), 3.01 (s, 3H). MS (ESI) m/z 294.1 (M+1) + .

3-[3-(4-Methyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid was prepared by the same procedure as example 286. 1 H NMR (300 MHz, CD 3 OD) δ=8.14 (d, J=2.3 Hz, 1H), 8.02 (td, J=1.5, 7.9 Hz, 1H), 7.76-7.66 (m, 3H), 7.56-7.47 (m, 3H), 3.95-3.72 (m, 2H), 3.70-3.12 (m, 6H), 2.94 (s, 3H). MS (ESI) m/z 349.1 (M+1) + .

3-[3-(4-Phenyl-piperazine-1-carbonyl)-phenylethynyl]-benzoic acid was prepared by the same procedure as example 286. 1 H NMR (300 MHz, CD 3 OD) δ=8.15 (t, J=1.6 Hz, 1H), 8.02 (td, J=1.3, 7.9 Hz, 1H), 7.75 (td, J=1.5, 7.6 Hz, 1H), 7.69-7.61 (m, 2H), 7.54-7.44 (m, 3H), 7.28-7.19 (m, 2H), 7.01-6.95 (m, 2H), 6.90-6.81 (m, 1H), 3.91 (br. s., 2H), 3.69-3.53 (m, 2H), 3.30-3.10 (m, 4H). MS (ESI) m/z 411.2 (M+1) + .

2-Indol-1-yl-3-pyridin-4-ylethynyl-benzoic acid. A mixture of 2-bromo-3-pyridin-4-ylethynyl-benzoic acid methyl ester (50 mg, 0.16 mmol), indole (28 mg, 0.237 mmol), potassium phosphate (70 mg, 0.332 mmol), copper iodide (3 mg, 0.016 mmol) and N,N′-dimethyl-cyclohexane-1,2-diamine (10 mg, 0.063 mmol) in toluene (1.5 mL) was degassed under N 2 for 10 minutes and then heated at 110° C. for 18 hours. After cooling to room temperature, the reaction mixture was filtered through celite washing with ethyl acetate (5 mL). The filtrate was concentrated and purified using reversed phase HPLC to provide the desired product as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ=8.57 (d, J=6.2 Hz, 2H), 8.13 (dd, J=1.5, 7.9 Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.75-7.64 (m, 2H), 7.33 (d, J=3.5 Hz, 1H), 7.19-7.09 (m, 4H), 7.05-6.99 (m, 1H), 6.71 (d, J=3.3 Hz, 1H). MS (ESI) m/z 339.1 (M+1) + .

2-Imidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid. A mixture of 2-bromo-3-pyridin-4-ylethynyl-benzoic acid methyl ester (50 mg, 0.16 mmol), imidazole (50 mg, 0.74 mmol), copper iodide (60 mg, 0.32 mmol), cesium carbonate (82 mg, 0.25 mmol) in dimethylformamide (1.5 mL) was degassed under N 2 for 10 minutes and then heated at 120° C. for 18 hours. After cooling to room temperature, the reaction mixture was filtered through celite washing with ethyl acetate (5 mL). The filtrate was concentrated and purified using reversed phase HPLC to provide the desired product as a white solid. 1 H NMR (300 MHz, CD 3 OD) δ=9.40 (br. s., 1H), 8.38 (dd, J=1.5, 7.9 Hz, 1H), 8.14 (dd, J=1.3, 7.8 Hz, 1H), 7.96-7.78 (m, 5H), 7.74-7.64 (m, 2H). MS (ESI) m/z 290.1 (M+1) + .

3-Pyridin-4-ylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid was prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=8.83 (s, 1H), 8.52 (d, J=3.8 Hz, 2H), 8.23 (s, 1H), 8.03 (d, J=7.9 Hz, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H), 7.29 (d, J=5.6 Hz, 2H). MS (ESI) m/z 291.12 (M+1) + .

2-Imidazol-1-yl-3-phenylethynyl-benzoic acid was prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=8.02 (s, 1H), 7.97-7.68 (m, 4H), 7.64-7.58 (m, 1H), 7.34-7.22 (m, 5H). MS (ESI) m/z 289.1 (M+1) + .

-Phenylethynyl-2-pyrazol-1-yl-benzoic acid prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=7.97-7.69 (m, 4H), 7.63-7.56 (m, 1H), 7.37-7.25 (m, 5H), 6.57 (br. s., 1H). MS (ESI) m/z 289.1 (M+1) + .

3-Phenylethynyl-2-[1,2,4]triazol-1-yl-benzoic acid prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=8.84 (br. s., 1H), 8.23 (s, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.9 Hz, 1H), 7.69 (t, J=7.5 Hz, 1H), 7.40-7.23 (m, 5H). MS (ESI) m/z 290.1 (M+1) + .

2-Benzoimidazol-1-yl-3-phenylethynyl-benzoic acid prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=8.32 (d, J=7.6 Hz, 1H), 8.15-7.95 (m, 1H), 7.95-7.80 (m, 1H), 7.71-7.52 (m, 2H), 7.48 (br. s., 1H), 7.33-7.14 (m, 5H), 6.85 (d, J=7.3 Hz, 2H). MS (ESI) m/z 339.1 (M+1) + .

2-Indazol-1-yl-3-phenylethynyl-benzoic acid prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=8.27 (d, J=0.9 Hz, 1H), 8.03 (dd, J=1.6, 7.8 Hz, 1H), 7.93-7.85 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 7.45-7.37 (m, 1H), 7.31-7.10 (m, 5H), 6.78-6.73 (m, 2H). MS (ESI) m/z 339.1 (M+1) + .

2-Indol-1-yl-3-phenylethynyl-benzoic acid prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=7.97-7.92 (m, 1H), 7.87-7.83 (m, 1H), 7.66-7.57 (m, 2H), 7.30-6.97 (m, 7H), 6.88-6.82 (m, 2H), 6.67 (d, J=3.2 Hz, 1H). MS (ESI) m/z 338.0 (M+1) + .

2-Benzoimidazol-1-yl-3-pyridin-4-ylethynyl-benzoic acid was prepared by the same procedure as example 293. 1 H NMR (300 MHz, CD 3 OD) δ=8.55 (d, J=6.3 Hz, 2H), 8.30 (d, J=7.4 Hz, 1H), 8.15-7.95 (m, 1H), 7.93-7.79 (m, 1H), 7.72-7.51 (m, 2H), 7.44 (br. s., 1H), 7.25 (d, J=6.1 Hz, 2H), 6.88 (d, J=7.3 Hz, 2H). MS (ESI) m/z 340.1 (M+1) + .

Formulations

The present invention also relates to compositions or formulations which comprise the EBNA1 inhibitors according to the present invention. In general, the compositions of the present invention comprise an effective amount of one or more EBNA1 inhibitors and salts thereof according to the present invention which are effective and one or more excipients.

For the purposes of the present invention the term “excipient” and “carrier” are used interchangeably throughout the description of the present invention and said terms are defined herein as, “ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition.”

The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating to insure delivery of the ingredients safely to the stomach. The formulator can also take advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral bioavailability.

The present teachings also provide pharmaceutical compositions that include at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

Compounds of the present teachings can be administered orally, intravenously (both bolus and infusion), intraperitoneally, subcutaneously, intramuscular, or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. The compounds can be formulated in conventional manner, for example, in a manner similar to that used for known EBNA1 inhibitors. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and/or diluent(s) such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation can also consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, and for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, or a pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intravenous, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be sub-divided in unit dose(s) containing appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form can contain from about 1 mg/kg of compound to about 500 mg/kg of compound, and can be given in a single dose or in two or more doses. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particular compound utilized, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example, a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants that are physiologically and environmentally acceptable.

Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxyl-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Additionally, one approach for parenteral administration employs the implantation of a slow-release or sustained-released systems, which assures that a constant level of dosage is maintained, according to U.S. Pat. No. 3,710,795, incorporated herein by reference.

Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules using one or more of the carriers or diluents mentioned for use in the formulations for oral administration or by using other suitable dispersing or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame seed oil, benzyl alcohol, sodium chloride, tragacanth gum, or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. The active ingredient may also be administered by injection as a composition with suitable carriers including saline, dextrose, or water, or with cyclodextrin (i.e. Captisol), cosolvent solubilization (i.e. propylene glycol), or micellar solubilization (i.e., Tween 80).

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose and blan fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Aqueous solutions suitable for intravenous injection (bolus or infusion) are preferably buffered and the liquid diluent first rendered isotonic. Aqueous solutions suitable for intravenous injection (bolus or infusion) are preferably sterile as prepared by standard pharmaceutical techniques well known to those skilled in the art. Pharmaceutical compositions are preferably preserved against the contaminating action of microorganisms such as fungi and bacteria by standard pharmaceutical techniques well known to those skilled in the art.

The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can be sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Compounds described herein can be administered transdermally, i.e., administered across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings including pharmaceutically acceptable salts, hydrates, or esters thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of a transdermal patch containing a compound, such as a compound disclosed herein, and a carrier that can be inert to the compound, can be non-toxic to the skin, and can allow delivery of the compound for systemic absorption into the blood stream via the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments can be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the compound can also be suitable. A variety of occlusive devices can be used to release the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound with or without a carrier, or a matrix containing the compound. Other occlusive devices are known in the literature.

Compounds described herein can be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations can be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, can also be used.

Lipid formulations or nanocapsules can be used to introduce compounds of the present teachings into host cells either in vitro or in vivo. Lipid formulations and nanocapsules can be prepared by methods known in the art.

To increase the effectiveness of compounds of the present teachings, it can be desirable to combine a compound with other agents effective in the treatment of the target disease. For example, other active compounds (i.e., other active ingredients or agents) effective in treating the target disease can be administered with compounds of the present teachings. The other agents can be administered at the same time or at different times than the compounds disclosed herein.

Compounds of the present teachings can be useful for the treatment or inhibition of a pathological condition or disorder in a mammal, for example, a human subject. The present teachings accordingly provide methods of treating or inhibiting a pathological condition or disorder by providing to a mammal a compound of the present teachings including its pharmaceutically acceptable salt) or a pharmaceutical composition that includes one or more compounds of the present teachings in combination or association with pharmaceutically acceptable carriers. Compounds of the present teachings can be administered alone or in combination with other therapeutically effective compounds or therapies for the treatment or inhibition of the pathological condition or disorder.

Non-limiting examples of compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more EBNA1 inhibitors according to the present invention and one or more excipients; from about 0.01 mg to about 100 mg of one or more EBNA1 inhibitors according to the present invention and one or more excipients; and from about 0.1 mg to about 10 mg of one or more EBNA1 inhibitors according to the present invention; and one or more excipients. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.05 to 1000 mg/day orally. The compositions are preferably provided in the form of scored tablets containing 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100.0, 250.0, 500.0 and 1000.0 mg of active ingredient. Infused dosages, intranasal dosages and transdermal dosages will range between 0.05 to 1000 mg/day. Subcutaneous, intravenous (bolus or infusion) and intraperitoneal dosages will range between 0.05 to 1000 mg/day. Effective plasma levels of the compounds of the present invention range from 0.002 mg/mL to 50 mg/mL. Compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

Procedures

The following procedures can be utilized in evaluating and selecting compounds as EBNA1 inhibitors.

Inhibition of 5′-biotin-oPL4624 binding to His-EBNA1 using Alpha Screen technology: Assays were performed using the DNA binding domain of EBNA1 (amino acids 459-607), which was His-tagged (His-EBNA1) and the self-complementary biotinylated (bt) oligonucleotide with the sequence 5′-bt-GGGTAGCATATGCTATCTAGATAGCAT-ATGCTACCC-3′ (bt-oPL4624). The protein was expressed in E. coli and purified according to Barwell, et al. (Barwell J A, Bochkarev A, Pfuetzner R A, Tong H, Yang D S, Frappier L, Edwards A M. (1995) Overexpression, purification, and crystallization of the DNA binding and dimerization domains of the Epstein-Barr virus nuclear antigen 1. J Biol Chem. 270: 20556-9). The bt-oPL4624 oligonucleotide was purchased from Integrated DNA Technologies, Inc (IDT). AlphaScreen donor, acceptor beads and white, opaque 384-well assay plates were purchased from PerkinElmer, Inc.

Assays contained 15 nM His-EBNA1, 0.2 nM bt-oPL4624, 5 μg/mL AlphaScreen streptavidin donor beads and nickel chelate acceptor beads, and a series of concentrations of test compound ranging from 3.2 nM to 100 μM in a total volume of 40 μL assay buffer (25 mM Tris, pH 7.2, 160 mM NaCl, 1 mM MgCl 2 ). His-EBNA1 (30 nM) and bt-oPL4624 (0.4 nM) were preincubated with 10 μg/mL nickel chelate AlphaScreen acceptor bead, or 10 μg/mL streptavidin AlphaScreen donor bead, respectively, for 30 minutes at room temperature in assay buffer. Twenty microliters of His-EBNA1/acceptor bead mix and bt-oPL4624/donor bead mix were transferred to assay plates containing 0.4 μL of 1:3 serial dilutions of test compounds previously prepared in DMSO at concentrations ranging from 0.32 μM to 10 mM. Nonspecific binding was determined with 5 μg/mL AlphaScreen acceptor bead in the absence of His-EBNA1. After 2 hr incubation at room temperature, the AlphaScreen signal was measured on the Envision plate reader (PerkinElmer, Inc.) at 680 nm excitation and 570 nm emission. Inhibition values at each concentration of test compound were determined by setting 100% equal to raw data values in the absence of EBNA1 and 0% equal to the raw data values in the presence of EBNA1. Nonlinear regression fits of the inhibition values to a one-site dose-response equation were performed using GraphPad Prism. Results from screening of representative compounds of the disclosure are described in table 6.

Cell based luciferase assay of EBNA1 inhibition: In vivo inhibition of EBNA1 was determined for compounds of the disclosure using a cell based luciferase reporter assay. EBNA1 binding to the Family of Repeat (FR) region is essential for EBV latent infection and host-cell viability, thus providing a physiologically meaningful cell-based readout. A derivative of EBNA1, which is functionally equivalent to full-length EBNA1 and lacks the GGA repeats (90-325), was cloned into p3×FLAG-Myc-CMV™-24 (Sigma-Aldrich Co., LLC) (N803). To make the assay more sensitive by reducing the expression levels of EBNA1, the CMV promoter was excised and the TK promoter inserted upstream of EBNA1. To enhance the EBNA1-driven luciferase signal, the activation domain of herpes virus VP16 (411-490) was fused to the C-terminus of EBNA1 using SacII and BamHI restriction sites, resulting in the plasmid pTK-3×FLAG-Myc-EBNA1-VP16AD. Empty vector p3×FLAG-Myc-CMV-24 was used as a control. To create luciferase reporter plasmid, the FR region, a locus of 21 contiguous EBNA1 binding sites (7421-8042), was PCR amplified from EBV genomic DNA and cloned into the pGLuc-Basic 2 (New England Biolabs) using the KpnI and HindIII restriction sites, resulting in plasmid pGLuc2-21×FR.

For the transient transfection assay, HEK293T cells were seeded at a concentration of 4-8×10 6 cells in a 10 cm plate in Delbecco's Modified Eagle Medium (DMEM) (Life Technologies Corp.) supplemented with 10% Fetal Bovine Serum (FBS) (Gemini Bio-Products). After overnight incubation, the transfection was performed using Lipofectamine 2000 (Life Technologies). 3 ug of pGLuc2-21×FR and 0.6 ug of pTK-3×FLAG-Myc-EBNA1-VP16AD or p3×FLAG-Myc-CMV-24 (empty vector) were added to 0.5 ml Optimem buffer (Life Technologies Corp.). 30 ul Lipofectamine was added to a separate 0.5 ml Optimem buffer and incubated for 5 minutes. The DNA and lipofectamine mixtures were combined and incubated for 20 minutes at room temperature and added drop wise to the 10 cm plate. The cells were then incubated for 6 hours at 37° C. The cells were harvested, counted and re-suspended at a concentration of 2×10 5 cells/ml and distributed using a MicroFlo dispenser (BioTek) in 384-well tissue culture plate (Greiner BioOne), 40 ul (8000 cells) per well. 160 nl of solutions of compounds of the disclosure in DMSO at concentrations ranging from 50 mM to 976 uM were added to the cells (10-point 2-fold dilution series, final concentration 200 uM-390 nM) using a Janus modular Nanohead dispenser (PerkinElmer, Inc.). Compounds and transfected cells were incubated overnight at 37° C. Gaussia luciferase is secreted into the medium. The top 10 ul of cell media from the 384-well tranfected HEK293T cells is transferred to a white opaque 384-well development plate. 10 ul of substrate is added to each well and incubated for 5 minutes. Bioluminescence is then measured using the Envision Multiplate Reader (Perkin Elmer, Inc.). To normalize the activity of the compounds of the disclosure and to filter toxic compound, the remaining 30 ul of cell media (including the cells) are incubated with 6 ul resazurin, incubated for 4-6 hours at 37° C. and measured using the Envision Multiplate Reader. Data analysis and IC 50 curves are generated using Prism (GraphPad).

Cell Viability Assay: To further evaluate the cell-based efficacy of EBNA1 inhibitors, a cell cytotoxicity assay was performed. EBNA1 inhibitors should selective kill EBV-positive cell lines (Raji, LCL, C666-1) relative to EBV-negative cell lines (Bjab, DG75, HNE-1). Raji, Bjab, and DG75 were obtained from American Type Tissue Culture (ATCC), C666-1 and HNE-1 were a gift from Anne Lee (Hong Kong University) and the Lymphoblastic Cell Line (LCL) was obtained by in vitro infection of B-cells with the B95.8 strain of EBV.

To perform this assay, 40 ul of the different cell lines were seeded at a concentration of 1×10 5 cells in a clear 384-well plate (4000 cell/well). 160 nl of compound at concentrations ranging from 50 mM to 976 uM were added to each well (10-point, 2-fold dilution series, final concentration 200 uM-390 nM) using a Janus modular Nanohead dispenser (PerkinElmer, Inc.). Cells were incubated for 72 hours in a humidified 37° C. incubator 5% CO 2 . The cell viability is inferred using the oxidation-reduction indicator, resazurin. 8 ul of resazurin was added to each well and after 4-6 hours incubation at 37° C., the fluorescent signal was monitored using 530-560 nm excitation wavelength and 590 nm emission wavelength using the Envision Multiplate Reader.

Data analysis and CC 50 (Cytotoxicity Concentration) curves are generated using Prism (GraphPad). A selectivity index is calculated by determining the ratio of the CC 50 from the EBV-negative cell line over the CC 50 from the EBV-positive cell line.