NEW N-BENZYL-2-PHENOXYBENZAMIDE DERIVATIVES AS PROSTAGLANDIN E2 (PGE2) RECEPTORS MODULATORS

Abstract

The present invention relates to novel, optionally substituted, N-benzyl-2-phenoxybenzamide derivatives of formula (I), as modulators of EP4 and/or EP2 receptors of prostaglandin E2 (PGE2), to processes for their preparation, to pharmaceutical compositions comprising said compounds and to said compound for use in the treatment of pathological conditions, disorders or diseases that can improve by modulation of EP4 and/or EP2 receptors of prostaglandin E2 (PGE2) such as cancer disease, pain, inflammation, neurodegenerative diseases and kidney diseases.

##STR00001##

Claims

1: A compound of formula (I): ##STR00017## wherein: A represents a group selected from phenyl and five or six-membered heteroaryl containing one, two or three heteroatoms selected from N, S and O, R.sup.1 and R.sup.2 represent independently a group selected from hydrogen atom, halogen atom and C.sub.1-3 alkyl, or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form a C.sub.3-4 cycloalkyl group, R.sup.3, R.sup.4, R.sup.5 and each R.sup.6 represent independently a group selected from hydrogen atom, halogen atom, cyano group, carbamoyl group, linear or branched C.sub.1-3 haloalkyl group, linear or branched C.sub.1-3 alkyl, C.sub.3-4 cycloalkyl, linear or branched C.sub.1-3 alkoxy and a pyridyl group, m is an integer from 1 to 5, and pharmaceutically acceptable salts thereof.

2: A compound according to claim 1 wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represent hydrogen atoms.

3: A compound according to claim 1 wherein A represents a phenyl group.

4: A compound according to claim 3 wherein each R.sup.6 independently represents a group selected from: a) hydrogen atom, b) halogen atom c) cyano group, d) carbamoyl group e) linear or branched C.sub.1-3 haloalkyl group.

5: A compound according to claim 1 wherein A represents a phenyl group and each R.sup.6 independently represents a group selected from fluoro, trifluoromethyl and cyano group, and m is an integer from 1 to 4.

6: A compound according to claim 1 wherein A represents a five or six-membered heteroaryl ring.

7: A compound according to claim 6 wherein A represents a group selected from a pyridinyl or a thiophenyl groups, each R.sup.6 independently represents a group selected from trifluoromethyl and cyano groups and m is an integer from 1 to 4.

8: A compound according to claim 1 wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represent hydrogen atoms, A represents a phenyl group and each R.sup.6 independently represent a group selected from fluoro and trifluoromethyl groups and m is an integer from 1 to 5.

9: A compound according to claim 1 wherein m is an integer from 1 to 2.

10: A compound according to claim 1 wherein A represents a group selected from phenyl, pyridinyl, pyrimidinyl, tiophenyl, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 are hydrogen atoms, each R.sup.6 represents independently a group selected from hydrogen atom, fluorine, chlorine, cyano group, trifluoromethyl and pyridinyl group and m is and integer from 1 to 2.

11: A compound according to claim 1 which is one of: 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoic acid 4-((4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((4′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((4′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((3′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((2′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((4′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((3′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(3-fluoropyridin-4-yl)benzamido)methyl)benzoic acid) 4-((2-(4-fluorophenoxy)-5-(pyridin-3-yl)benzamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(3-chloropyridin-4-yl)benzamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5-yl)benzamido)methyl)benzoic acid 4-((3′,4′-difluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((4-(4-fluorophenoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(pyridin-2-yl)benzamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4-yl)benzamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(thiophen-2-yl)benzamido)methyl)benzoic acid 4-((3′,5′-difluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl))benzoic acid 4-((3′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((3′-fluoro-4-(4-fluorophenoxy)-5′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((3′-carbamoyl-5′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(1H-pyrazol-4-yl)benzamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)benzamido)methyl)benzoic acid 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-5-yl)benzamido)methyl)benzoic acid 4-((4-(4-fluorophenoxy)-3′-(pyridin-4-yl)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoic acid 4-((5-(5-carbamoylfuran-2-yl)-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid 3-fluoro-4-((4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoic acid (R)-4-(1-(4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)ethyl)benzoic acid 4-(1-(4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)cyclopropyl)benzoic acid 4-((3′-fluoro-5′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid 4-((3′-chloro-5′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid and pharmaceutically acceptable salts thereof.

12-15. (canceled)

16: A method of treatment or prevention of diseases or pathological condition that can be ameliorated by modulation of EP4 and/or EP2 receptors of prostaglandin E2 (PGE2), wherein said disease or pathological condition is selected from the group consisting of cancer, pain, neurodegenerative diseases, osteoarthritis, rheumatoid arthritis, endometriosis and kidney diseases, said method comprising administering an effective amount of a compound according to claim 1 to a subject in need thereof.

17: A method of treatment or prevention of cancer, specifically the type of cancers amenable to be treated with immunotherapy, said method comprising administering an effective amount of a compound according to claim 1 to a subject in need thereof.

18: A pharmaceutical composition comprising a compound according to claim 1, a pharmaceutically acceptable diluent or carrier and optionally a therapeutically effective amount of further chemotherapeutics agents, anti-inflammatory agents, steroids, immunotherapeutic agent and other agents such as therapeutic antibodies.

19: A combination product comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least a therapeutic agent selected from the group consisting of chemotherapeutics agents, anti-inflammatory agents, steroids, immunosuppressants, immunotherapeutic agents, therapeutic antibodies and EP4 and/or EP2 modulators, in particular those selected from the group consisting of antibodies anti-CTLA4, selected from Ipilimumab and tremelimumab, antibodies anti-PD1 such as nivolumab, pembrolizumab, cemiplimab, pidilizumab, spartalizumab, MEDI0680, REGN2810 and AMP-224, antibodies anti-POL1 such as Atezolizumab, Avelumab, Durvalumab, and MDX-1105; Carboplatin, Carmustine (BCNU), Cisplatin, Cyclophosphamide, Etoposide, Irinotecan, Lomustine (CCNU), Methotrexate, Procarbazine, Temozolomide, Vincristine.

Description

EXAMPLES

[0186] General. Reagents, solvents and starting products were acquired from commercial sources. The term “concentration” refers to the vacuum evaporation using a Büchi rotavapor. When indicated, the reaction products were purified by “flash” chromatography on silica gel (40-63 μm) with the indicated solvent system. The spectroscopic data were measured in a Varian Mercury 400 spectrometer. The melting points were measured in a Büchi 535 instrument. The HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1/1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector.

Intermediate 1: methyl 4-(azidomethyl)-3-fluorobenzoate

[0187] ##STR00007##

[0188] A solution of methyl 4-(bromomethyl)-3-fluorobenzoate (100 mg, 1.0 eq) and sodium azide (29 mg, 1.2 eq) in DMF (1.0 mL) was stirred at 80° C. for 90 min. Once cooled, the reaction was diluted with brine (3 mL) and extracted with ethyl acetate (3×10 mL). The combined organic solution was washed with water (25 mL) and brine (25 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The desired azide was obtained as pale yellow liquid (quantitative), which was used in the next step without further purification.

[0189] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=7.82 (dd, 1H), 7.74 (dd, 1H), 7.64 (t, 1H), 4.62 (s, 2H), 3.87 (s, 3H).

[0190] HPLC-MS: Rt 2.65 m/z 182.0 (MH.sup.+)

Intermediate 2: methyl 4-(aminomethyl)-3-fluorobenzoate

[0191] ##STR00008##

[0192] A solution of methyl 4-(azidomethyl)-3-fluorobenzoate (110 mg, 1.0 eq), triphenylphosphine (189 mg, 1.2 eq) and water (0.9 mL) in THF (2 mL) was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and purification by flash column chromatography (dichloromethane:methanol, 30:1) gave the methyl 4-(aminomethyl)-3-fluorobenzoate as yellow wax (70 mg, 63.7% yield).

[0193] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=7.78 (dd, 1H), 7.67 (t, 1H), 7.61 (dd, 1H), 3.85 (s, 3H), 3.80 (s, 2H), 1.96 (s, 2H).

[0194] HPLC-MS: Rt 1.63 m/z 184.1 (MH.sup.+)

Intermediate-3: methyl 4-fluoro-[1,1′-biphenyl]-3-carboxylate

[0195] ##STR00009##

[0196] To a solution of 4-fluoro-[1,1′-biphenyl]-3-carboxylic acid (200.0 mg, 0.93 mmol) in methanol (1 mL) was added a catalytic amount of H.sub.2SO.sub.4 and the reaction was stirred at 70° C. overnight. The solution was partitioned between water and ethyl acetate and the organic layer was washed with NaHCO.sub.3 sat and brine. It was dried over anhydrous sodium sulphate, filtered and concentrated to afford intermediate 1 as an oil (167.0 mg, 76.0%).

[0197] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.09 (dd, 1H), 7.96 (ddd, 1H), 7.68 (d, 2H), 7.46 (m, 2H), 3.89 (s, 3H).

[0198] HPLC-MS: Rt 5.337 m/z 231.0 (MH.sup.+)

[0199] The following intermediate was synthesized using the procedure described for intermediate 3:

Intermediate 4: methyl 5-bromo-2-fluorobenzoate

[0200] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=7.98 (dd, 1H), 7.87 (m, 1H), 7.37 (dd, 1H), 3.86 (s, 3H).

Intermediate 5: methyl 5-bromo-2-(4-fluorophenoxy)benzoate

[0201] ##STR00010##

[0202] To a stirred solution of 4-fluorophenol (481.0 mg, 4.29 mmol) and sodium hydride (171.6 mg, 4.29 mmol) in N,N-dimethylformamide was added a solution of methyl 5-bromo-2-fluorobenzoate (1000 mg, 4.29 mmol) in N,N-dimethylformamide. The solution was heated at 120° C. and stirred for 16 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the titled compound as slight yellow oil (1028.3 mg, 73.7%)

[0203] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=7.95 (d, 1H), 7.75 (dd, 1H), 7.22 (m, 2H), 7.04 (m, 2H), 6.95 (d, 1H), 3.75 (s, 3H).

[0204] HPLC-MS: Rt 5.602 m/z 326.9 (MH.sup.+)

[0205] The following intermediate were synthesized using the procedure described for intermediate 5, and the corresponding methyl esters and 4-fluorophenol:

Intermediate 6: methyl 4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxylate

[0206] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.07 (d, 1H), 7.88 (dd, 1H), 7.68 (d, 2H), 7.49 (t, 2H), 7.39 (t, 1H), 7.23 (t, 2H), 7.10 (s, 1H), 7.06 (m, 2H), 3.77 (s, 3H).

[0207] HPLC-MS: Rt 5.948 m/z 323.0 (MH.sup.+)

Intermediate 7: 5-bromo-2-(4-fluorophenoxy)benzoic acid

[0208] ##STR00011##

[0209] To a solution of methyl 5-bromo-2-(4-fluorophenoxy)benzoate (1101.3 mg, 3.39 mmol) in methanol (8 mL) and THF (8 mL) was added NaOH 2M (8.5 mL, 16.94 mmol) and the mixture was stirred for 3 hours at room temperature. The solution was diluted with water (15 mL) and the pH value was adjusted to 4.0 by the addition of HCl 1M. The mixture was extracted with ethyl acetate (3×50 mL) and the combine organic layer was dried with sodium sulfate and concentrate to afford a white solid that was washed with pentane (823.5 mg, 78.1%).

[0210] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=13.24 (s, 1H), 7.92 (s, 1H), 7.72 (d, 1H), 7.21 (t, 2H), 7.01 (s, 2H), 6.94 (d, 1H).

[0211] HPLC-MS: Rt 3.087 m/z 312.9 (MH.sup.+)

[0212] The following intermediate were synthesized using the procedure described for intermediate 7, and the corresponding methyl esters:

Intermediate 8: 4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxylic acid

[0213] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=13.04 (s, 1H), 8.06 (d, 1H), 7.84 (dd, 1H), 7.68 (d, 2H), 7.48 (t, 2H), 7.39 (t, 1H), 7.22 (t, 2H), 7.04 (m, 3H).

[0214] HPLC-MS: Rt 3.435 m/z 309.0 (MH.sup.+)

Intermediate 9: 4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid

[0215] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=13.09 (s, 1H), 8.13 (d, 1H), 7.95 (m, 4H), 7.72 (m, 2H), 7.23 (m, 2H), 7.05 (m, 2H).

[0216] HPLC-MS: Rt 2.20 m/z 377.0 (MH.sup.+)

Intermediate 10: methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate

[0217] ##STR00012##

[0218] To a solution of 5-bromo-2-(4-fluorophenoxy)benzoic acid (600 mg, 1.93 mmol) in DCM anh. (15 mL) HATU (880.0 mg, 2.30 mmol) and DIPEA (1.31 mL, 7.71 mmol) were added. After the reaction was stirred at RT under N.sub.2 during 15 minutes, methyl 4-(aminomethyl)benzoate hydrochloride (466.7 mg, 2.30 mmol) was added and the reaction was allowed to stir overnight at RT. After the addition of 20 mL of H.sub.2O, the aqueous phase was extracted with DCM 3×20 mL. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid (728.5 mg, 82.4%).

[0219] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.97 (t, 1H), 7.85 (d, 2H), 7.79 (d, 1H), 7.63 (dd, 1H), 7.38 (d, 2H), 7.24 (t, 2H), 7.11 (dd, 2H), 6.86 (d, 1H), 4.51 (d, 2H), 3.83 (s, 3H).

[0220] HPLC-MS: Rt 5.523 m/z 459.0 (MH.sup.+)

[0221] The following intermediate was synthesized using the procedure described for intermediate 10, and the corresponding chemical reagents or derivatives:

Intermediate 11: methyl (R)-4-(1-(5-bromo-2-(4-fluorophenoxy)benzamido)ethyl) benzoate

[0222] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.89 (d, 1H), 7.84 (d, 2H), 7.69 (d, 1H), 7.62 (dd, 1H), 7.45 (d, 2H), 7.22 (t, 2H), 7.07 (m, 2H), 6.89 (d, 1H), 5.08 (p, 1H), 3.83 (s, 3H), 1.38 (d, 3H).

[0223] HPLC-MS: Rt 3.21 m/z 473.9 (MH.sup.+)

Intermediate 12: methyl 4-(1-(5-bromo-2-(4-fluorophenoxy)benzamido)cyclopropyl) benzoate

[0224] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.13 (s, 1H), 7.78 (s, 1H), 7.76 (d, 2H), 7.65 (dd, 1H), 7.24 (m, 4H), 7.08 (m, 2H), 6.95 (d, 1H), 3.82 (s, 3H), 1.28 (m, 2H), 1.21 (m, 2H).

[0225] HPLC-MS: Rt 3.18 m/z 485.9 (MH.sup.+)

Intermediate 13: methyl 4-((4-(4-fluorophenoxy)-[1,1-biphenyl]-3-carboxamido)methyl) benzoate

[0226] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.96 (t, 1H), 7.93 (d, 1H), 7.86 (d, 2H), 7.76 (dd, 1H), 7.68 (d, 2H), 7.48 (t, 2H), 7.39 (m, 3H), 7.25 (t, 2H), 7.13 (m, 2H), 7.00 (d, 1H), 4.54 (d, 2H), 3.84 (s, 3H).

[0227] HPLC-MS: Rt 5.843 m/z 456.1 (MH.sup.+)

Intermediate 14: 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid

[0228] To a solution of methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate (200 mg, 1.0 eq) in THF (2.0 mL) and methanol (2.0 mL) was added NaOH (2 M) (1.1 mL, 5.0 eq)) and the mixture was stirred for 20 hours at room temperature. After diluting with water (10 mL), the mixture was neutralized with aqueous HCl, filtered and washed with water and pentane to obtain the acid as white solid (176 mg, 90.9% yield).

[0229] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.98 (t, 1H), 7.82 (m, 3H), 7.63 (dd, 1H), 7.32 (m, 2H), 7.24 (m, 2H), 7.12 (m, 2H), 6.86 (d, 1H), 4.49 (d, 2H).

[0230] HPLC-MS: Rt 1.26 m/z 444.0 (MH.sup.+)

Intermediate 15: methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl) benzoate

[0231] ##STR00013##

[0232] To a solution of methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate (70.0 mg, 0.15 mmol) in dioxane, pyridine-4-boronic acid (37.6 mg, 0.31 mmol) [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (7.5 mg, 0.009 mmol) was added Cs.sub.2CO.sub.3 2M (0.23 mL, 0.46 mmol). The mixture was degassed with N.sub.2 and stirred at 100° C. overnight. Then, the reaction was filtered through celite and extracted with ethyl acetate. The organic fraction was washed with NaOH 1M, NaHCO.sub.3 sat and brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue purified using flash chromatography (hexane:Ethyl acetate 1:1). Solvent removal afforded the product as a white solid that was washed with pentane/diethyl ether (44.7 mg, 65.3%).

[0233] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.65 (d, 2H), 8.08 (d, 1H), 7.89 (m, 3H), 7.75 (d, 2H), 7.42 (d, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 7.01 (d, 1H), 4.56 (d, 2H), 3.84 (s, 3H).

[0234] HPLC-MS: Rt 4.875 m/z 457.1 (MH.sup.+)

[0235] The following intermediates were synthesized using the procedure described for intermediate 15, using the corresponding chemical reagents or derivatives:

Intermediate 16: methyl 4-((4′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0236] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.99 (t, 1H), 7.92 (d, 1H), 7.85 (d, 2H), 7.74 (m, 3H), 7.51 (t, 2H), 7.39 (d, 2H), 7.25 (t, 2H), 7.12 (m, 2H), 6.99 (d, 1H), 4.53 (d, 2H), 3.83 (s, 3H).

[0237] HPLC-MS: Rt 6.203 m/z 490.1 (MH.sup.+)

Intermediate 17: methyl 4-((4′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0238] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.98 (s, 1H), 7.86 (m, 3H), 7.72 (s, 3H), 7.37 (m, 2H), 7.27 (m, 4H), 7.12 (s, 2H), 6.98 (d, 1H), 4.53 (d, 2H), 3.83 (s, 3H).

[0239] HPLC-MS: Rt 5.945 m/z 474.1 (MH.sup.+)

Intermediate 18: methyl 4-((3′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0240] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.99 (s, 1H), 7.95 (d, 1H), 7.85 (d, 2H), 7.80 (dd, 1H), 7.53 (t, 3H), 7.40 (d, 2H), 7.24 (dd, 3H), 7.13 (dd, 2H), 6.98 (d, 1H), 4.54 (d, 2H), 3.83 (s, 3H).

[0241] HPLC-MS: Rt 5.963 m/z 474.1 (MH.sup.+)

Intermediate 19: methyl 4-((2′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0242] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.99 (s, 1H), 7.85 (d, 3H), 7.64 (d, 1H), 7.57 (s, 1H), 7.40 (d, 3H), 7.30 (m, 4H), 7.17 (s, 2H), 6.98 (d, 1H), 4.54 (d, 2H), 3.83 (s, 3H).

[0243] HPLC-MS: Rt 5.936 m/z 474.1 (MH.sup.+)

Intermediate 20: methyl 4-((4′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0244] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.01 (t, 1H), 8.02 (d, 1H), 7.93 (m, 4H), 7.85 (m, 3H), 7.41 (d, 2H), 7.27 (t, 2H), 7.16 (m, 2H), 7.00 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0245] HPLC-MS: Rt 5.649 m/z 481.1 (MH.sup.+)

Intermediate 21: methyl 4-((3′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0246] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.20 (s, 1H), 8.04 (dd, 2H), 7.85 (t, 4H), 7.68 (t, 1H), 7.41 (d, 2H), 7.27 (t, 2H), 7.15 (dd, 2H), 7.00 (d, 1H), 4.55 (d, 2H), 3.84 (s, 3H).

[0247] HPLC-MS: Rt 5.668 m/z 481.1 (MH.sup.+)

Intermediate 22: methyl 4-((2-(4-fluorophenoxy)-5-(3-fluoropyridin-4-yl)benzamido) methyl)benzoate

[0248] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.03 (t, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 7.97 (s, 1H), 7.86 (d, 2H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.42 (d, 2H), 7.29 (dd, 2H), 7.20 (m, 2H), 7.01 (d, 1H), 4.56 (d, 2H), 3.83 (s, 3H).

[0249] HPLC-MS: Rt 5.199 m/z 475.1 (MH.sup.+)

Intermediate 23: methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-3-yl)benzamido)methyl) benzoate

[0250] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.92 (d, 1H), 8.58 (dd, 1H), 8.11 (m, 1H), 7.99 (d, 1H), 7.84 (m, 3H), 7.50 (dd, 1H), 7.41 (d, 2H), 7.26 (t, 2H), 7.14 (m, 2H), 7.02 (d, 1H), 4.54 (d, 2H), 3.83 (s, 3H).

[0251] HPLC-MS: Rt 5.015 m/z 457.1 (MH.sup.+)

Intermediate 24: methyl 4-((2-(4-fluorophenoxy)-5-(3-chloropyridin-4-yl)benzamido) methyl)benzoate

[0252] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.02 (t, 1H), 8.75 (s, 1H), 8.59 (d, 1H), 7.86 (d, 2H), 7.84 (d, 1H), 7.64 (dd, 1H), 7.53 (d, 1H), 7.42 (d, 2H), 7.30 (t, 2H), 7.21 (m, 2H), 6.98 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0253] HPLC-MS: Rt 5.378 m/z 491.1 (MH.sup.+)

Intermediate 25: methyl 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5-yl)benzamido)methyl) benzoate

[0254] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.18 (m, 3H), 9.02 (t, 1H), 8.08 (d, 1H), 7.88 (m, 3H), 7.42 (d, 2H), 7.27 (t, 2H), 7.15 (m, 2H), 7.04 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0255] HPLC-MS: Rt 4.715 m/z 458.1 (MH.sup.+)

Intermediate 26: methyl 4-((3′,4′-difluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0256] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.98 (t, 1H), 7.95 (d, 1H), 7.81 (m, 4H), 7.53 (m, 2H), 7.40 (d, 2H), 7.26 (t, 2H), 7.13 (m, 2H), 6.98 (d, 1H), 4.54 (d, 2H), 3.83 (s, 3H).

[0257] HPLC-MS: Rt 5.977 m/z 492.1 (MH.sup.+)

Intermediate 27: methyl 4-((4-(4-fluorophenoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0258] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.02 (t, 1H), 8.01 (d, 1H), 7.93 (d, 2H), 7.84 (m, 5H), 7.41 (d, 2H), 7.27 (dd, 2H), 7.16 (m, 2H), 7.01 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0259] HPLC-MS: Rt 6.223 m/z 524.1 (MH.sup.+)

Intermediate 28: methyl 4-((4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0260] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.01 (m, 3H), 7.85 (d, 3H), 7.71 (m, 2H), 7.40 (d, 2H), 7.26 (t, 2H), 7.15 (dd, 2H), 7.01 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0261] HPLC-MS: Rt 6.199 m/z 524.1 (MH.sup.+)

Intermediate 29: methyl 4-((2-(4-fluorophenoxy)-5-(thiophen-2-yl)benzamido)methyl) benzoate

[0262] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.99 (t, 1H), 7.90 (d, 1H), 7.85 (d, 2H), 7.74 (dd, 1H), 7.56 (d, 1H), 7.52 (d, 1H), 7.39 (d, 2H), 7.25 (t, 2H), 7.13 (m, 3H), 6.95 (d, 1H), 4.52 (d, 2H), 3.83 (s, 3H).

[0263] HPLC-MS: Rt 3.21 m/z 462.1 (MH.sup.+)

Intermediate 30: methyl 4-((3′,5′-difluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0264] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.00 (d, 1H), 7.84 (m, 3H), 7.48 (m, 2H), 7.41 (d, 2H), 7.25 (m, 3H), 7.14 (m, 2H), 6.97 (d, 1H), 4.54 (d, 2H), 3.83 (s, 3H).

[0265] HPLC-MS: Rt 3.31 m/z 492.21 (MH.sup.+)

Intermediate 31: methyl 4-((3′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0266] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.99 (t, 1H), 7.96 (d, 1H), 7.86 (d, 2H), 7.80 (dd, 1H), 7.76 (m, 1H), 7.66 (d, 1H), 7.50 (t, 1H), 7.43 (m, 3H), 7.25 (m, 2H), 7.14 (m, 2H), 6.87 (d, 1H), 4.54 (d, 2H), 3.83 (s, 3H).

[0267] HPLC-MS: Rt 3.41 m/z 490.16 (MH.sup.+)

Intermediate 32: methyl 4-((3′-fluoro-4-(4-fluorophenoxy)-5′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0268] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.01 (t, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.88 (m, 4H), 7.67 (d, 1H), 7.41 (d, 2H), 7.26 (m, 2H), 7.15 (m, 2H), 7.00 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0269] HPLC-MS: Rt 3.48 m/z 542.21 (MH.sup.+)

Intermediate 33: methyl 4-((3′-cyano-5′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0270] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.12 (s, 1H), 8.07 (d, 1H), 8.00 (m, 1H), 7.88 (m, 4H), 7.42 (d, 2H), 7.26 (m, 2H), 7.15 (m, 2H), 6.99 (d, 1H), 4.53 (d, 2H), 3.83 (s, 3H).

[0271] HPLC-MS: Rt 3.13 m/z 499.21 (MH.sup.+)

Intermediate 34: methyl 4-((3′-chloro-5′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoate

[0272] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.22 (d, 1H), 8.16 (t, 1H), 8.05 (m, 2H), 7.87 (m, 3H), 7.42 (d, 2H), 7.27 (m, 2H), 7.15 (m, 2H), 6.98 (d, 1H), 4.55 (d, 2H), 3.84 (s, 3H).

[0273] HPLC-MS: Rt 3.26 m/z 515.1 (MH.sup.+)

Intermediate 35: methyl 4-((2-(4-fluorophenoxy)-5-(1H-pyrazol-4-yl)benzamido)methyl) benzoate

[0274] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.83 (s, 1H), 8.99 (t, 1H), 7.82 (m, 4H), 7.62 (m, 2H), 7.36 (dd, 2H), 7.24 (m, 2H), 7.12 (m, 2H), 6.86 (d, 1H), 4.50 (d, 2H), 3.83 (s, 3H).

[0275] HPLC-MS: Rt 2.03 m/z 446.0 (MH.sup.+)

Intermediate 36: methyl 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-4-yl) benzamido)methyl)benzoate

[0276] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.92 (t, 1H), 8.18 (s, 1H), 7.84 (m, 4H), 7.64 (dd, 1H), 7.37 (d, 2H), 7.21 (m, 2H), 7.06 (m, 2H), 6.93 (d, 1H), 4.51 (d, 2H), 3.86 (s, 3H), 3.83 (s, 3H).

[0277] HPLC-MS: Rt 2.70 m/z 460.2 (MH.sup.+)

Intermediate 37: methyl 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-5-yl) benzamido)methyl)benzoate

[0278] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.01 (t, 1H), 7.85 (d, 2H), 7.77 (d, 1H), 7.61 (dd, 1H), 7.48 (d, 1H), 7.40 (d, 2H), 7.26 (m, 2H), 7.17 (m, 2H), 6.98 (d, 1H), 6.43 (d, 1H), 4.54 (d, 2H), 3.86 (s, 3H), 3.83 (s, 3H).

[0279] HPLC-MS: Rt 2.73 m/z 460.13 (MH.sup.+)

Intermediate 38: methyl 4-((4-(4-fluorophenoxy)-3′-(pyridin-4-yl)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoate

[0280] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.66 (dd, 2H), 8.06 (m, 2H), 7.85 (m, 7H), 7.63 (t, 1H), 7.40 (d, 2H), 7.25 (m, 2H), 7.14 (m, 2H), 7.02 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0281] HPLC-MS: Rt 3.06 m/z 533.2 (MH.sup.+)

Intermediate 39: methyl 4-((5-(5-cyanofuran-2-yl)-2-(4-fluorophenoxy)benzamido) methyl)benzoate

[0282] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.02 (t, 1H), 8.10 (s, 1H), 7.87 (m, 3H), 7.42 (m, 3H), 7.28 (m, 4H), 7.18 (m, 2H), 6.97 (d, 1H), 4.55 (d, 2H), 3.83 (s, 3H).

[0283] HPLC-MS: Rt 3.08 m/z 471.1 (MH.sup.+)

Intermediate 40: methyl 3-fluoro-4-((4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoate

[0284] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.01 (t, 1H), 8.01 (m, 2H), 7.86 (dd, 1H), 7.74 (dd, 2H), 7.67 (m, 2H), 7.44 (t, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 7.01 (d, 1H), 4.55 (d, 2H), 3.85 (s, 3H).

Intermediate 41: methyl (R)-4-(1-(4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1-biphenyl]-3-carboxamido)ethyl)benzoate

[0285] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=8.89 (d, 1H), 8.01 (m, 2H), 7.91 (d, 1H), 7.84 (m, 3H), 7.72 (m, 2H), 7.48 (d, 2H), 7.24 (t, 2H), 7.11 (m, 2H), 7.03 (d, 1H), 5.14 (p, 1H), 3.83 (s, 3H), 1.41 (d, 3H).

[0286] HPLC-MS: Rt 3.51 m/z 538.0 (MH.sup.+)

Intermediate 42: methyl 4-(1-(4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)cyclopropyl)benzoate

[0287] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.13 (s, 1H), 8.04 (d, 2H), 7.96 (d, 1H), 7.86 (dd, 1H), 7.75 (m, 4H), 7.27 (m, 4H), 7.13 (dd, 2H), 7.09 (d, 1H), 3.82 (s, 3H), 1.32 (t, 2H), 1.25 (t, 2H).

[0288] HPLC-MS: Rt 3.48 m/z 550.0 (MH.sup.+)

Intermediate 43: methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-2-yl)benzamido)methyl) benzoate

[0289] To a solution of methyl 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoate (100.0 mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (15.1 mg, 0.013 mmol) in dry dioxane (1.5 mL), was added 2-(tributylstannyl)pyridine (113.4 mg, 0.26 mmol). The mixture was purged with N.sub.2 and stirred during 2 days at room temperature. The reaction was diluted with ethyl acetate and washed with NaOH 2M. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated and the residue was purified by flash chromatography (hexane:Ethyl acetate 1:1) to give a white solid. The product was washed with pentane/diethyl ether (40.3 mg, 40.5%)

[0290] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.00 (t, 1H), 8.66 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H), 7.98 (d, 1H), 7.90 (dd, 1H), 7.86 (d, 2H), 7.42 (d, 2H), 7.36 (dd, 1H), 7.27 (t, 2H), 7.17 (dd, 2H), 6.98 (d, 1H), 4.56 (d, 2H), 3.84 (s, 3H).

[0291] HPLC-MS: Rt 5.308 m/z 457.1 (MH.sup.+)

[0292] The following intermediate was synthesized using the procedure described for intermediate 43, and the corresponding chemical reagents or derivatives:

Intermediate 44: methyl 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4-yl)benzamido)methyl) benzoate

[0293] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.24 (d, 1H), 9.04 (t, 1H), 8.86 (d, 1H), 8.51 (d, 1H), 8.29 (dd, 1H), 8.12 (dd, 1H), 7.87 (d, 2H), 7.44 (d, 2H), 7.30 (m, 2H), 7.22 (m, 2H), 7.00 (d, 1H), 4.57 (d, 2H), 3.83 (s, 3H).

[0294] HPLC-MS: Rt 4.890 m/z 458.1 (MH.sup.+)

Example 1: 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoic acid

[0295] ##STR00014##

[0296] To a solution of methyl 4-((2-(4-fluorophenoxy)-5-(pyridin-4-yl)benzamido)methyl)benzoate (35.0 mg, 0.077 mmol) in methanol (0.5 mL) and THF (0.5 mL) was added NaOH 2M (0.19 mL, 0.38 mmol) and the mixture was stirred overnight at room temperature. The solution was diluted with water (15 mL) and the pH value was adjusted to 4.0 by the addition of HCl 1M and the precipitate was filtered and washed with pentane (27.8 mg, 82.0%).

[0297] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.85 (s, 1H), 9.01 (t, 1H), 8.64 (d, 2H), 8.07 (d, 1H), 7.90 (dd, 1H), 7.84 (d, 2H), 7.74 (d, 2H), 7.39 (d, 2H), 7.27 (t, 2H), 7.17 (dd, 2H), 7.01 (d, 1H), 4.55 (d, 2H).

[0298] HPLC-MS: Rt 3.362 m/z 443.1 (MH.sup.+)

[0299] The following intermediate were synthesized using the procedure described for Example 1, and the corresponding chemical reagents or derivatives:

Example 2: 4-((4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid

[0300] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.84 (s, 1H), 8.95 (s, 1H), 7.93 (d, 1H), 7.83 (d, 2H), 7.76 (dd, 1H), 7.68 (d, 2H), 7.48 (t, 2H), 7.38 (t, 3H), 7.25 (t, 2H), 7.13 (m, 2H), 7.00 (d, 1H), 4.53 (d, 2H).

[0301] HPLC-MS: Rt 3.867 m/z 442.1 (MH.sup.+)

Example 3: 4-((4′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0302] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.97 (t, 1H), 7.93 (d, 1H), 7.83 (d, 2H), 7.75 (m, 3H), 7.53 (d, 2H), 7.37 (d, 2H), 7.26 (t, 2H), 7.13 (m, 2H), 6.99 (d, 1H), 4.53 (d, 2H).

[0303] HPLC-MS: Rt 4.221 m/z 476.0 (MH.sup.+)

Example 4: 4-((4′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0304] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.87 (s, 1H), 8.97 (t, 1H), 7.90 (d, 1H), 7.83 (d, 2H), 7.73 (m, 3H), 7.36 (d, 2H), 7.29 (m, 4H), 7.12 (m, 2H), 6.99 (d, 1H), 4.53 (d, 2H).

[0305] HPLC-MS: Rt 4.029 m/z 460.1 (MH.sup.+)

Example 5: 4-((3′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0306] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.98 (t, 1H), 7.96 (d, 1H), 7.81 (m, 3H), 7.53 (m, 3H), 7.37 (d, 2H), 7.22 (m, 3H), 7.14 (m, 2H), 6.99 (d, 1H), 4.53 (d, 2H).

[0307] HPLC-MS: Rt 4.033 m/z 460.1 (MH.sup.+)

Example 6: 4-((2′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0308] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.87 (s, 1H), 8.98 (s, 1H), 7.83 (s, 3H), 7.64 (d, 1H), 7.57 (s, 1H), 7.34 (m, 7H), 7.18 (s, 2H), 6.99 (d, 1H), 4.53 (d, 2H).

[0309] HPLC-MS: Rt 4.001 m/z 460.1 (MH.sup.+)

Example 7: 4-((4′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0310] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.00 (t, 1H), 8.02 (s, 1H), 7.91 (m, 4H), 7.84 (d, 3H), 7.38 (d, 2H), 7.27 (t, 2H), 7.16 (m, 2H), 7.00 (d, 1H), 4.54 (d, 2H).

[0311] HPLC-MS: Rt 3.864 m/z 467.1 (MH.sup.+)

Example 8: 4-((3′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0312] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.99 (t, 1H), 8.20 (s, 1H), 8.04 (dd, 2H), 7.84 (d, 4H), 7.68 (t, 1H), 7.38 (d, 2H), 7.27 (t, 2H), 7.15 (dd, 2H), 7.00 (d, 1H), 4.54 (d, 2H).

[0313] HPLC-MS: Rt 3.860 m/z 467.1 (MH.sup.+)

Example 9: 4-((2-(4-fluorophenoxy)-5-(3-fluoropyridin-4-yl)benzamido)methyl)benzoic acid

[0314] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.01 (t, 1H), 8.67 (d, 1H), 8.51 (d, 1H), 7.97 (s, 1H), 7.84 (d, 2H), 7.77 (d, 1H), 7.68 (dd, 1H), 7.39 (d, 2H), 7.29 (t, 2H), 7.20 (m, 2H), 7.01 (d, 1H), 4.55 (d, 2H).

[0315] HPLC-MS: Rt 3.495 m/z 461.1 (MH.sup.+)

Example 10: 4-((2-(4-fluorophenoxy)-5-(pyridin-3-yl)benzamido)methyl)benzoic acid

[0316] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.99 (s, 1H), 8.92 (d, 1H), 8.58 (dd, 1H), 8.11 (m, 1H), 7.99 (d, 1H), 7.83 (m, 3H), 7.50 (dd, 1H), 7.38 (d, 2H), 7.26 (t, 2H), 7.15 (m, 2H), 7.02 (d, 1H), 4.54 (d, 2H).

[0317] HPLC-MS: Rt 3.390 m/z 443.1 (MH.sup.+)

Example 11: 4-((2-(4-fluorophenoxy)-5-(3-chloropyridin-4-yl)benzamido)methyl)benzoic acid

[0318] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.01 (t, 1H), 8.75 (s, 1H), 8.59 (d, 1H), 7.83 (dd, 3H), 7.64 (dd, 1H), 7.53 (d, 1H), 7.39 (d, 2H), 7.30 (t, 2H), 7.21 (dd, 2H), 6.98 (d, 1H), 4.54 (d, 2H).

[0319] HPLC-MS: Rt 3.624 m/z 477.0 (MH.sup.+)

Example 12: 4-((2-(4-fluorophenoxy)-5-(pyrimidin-5-yl)benzamido)methyl)benzoic acid

[0320] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.17 (m, 3H), 9.01 (t, 1H), 8.08 (d, 1H), 7.88 (m, 3H), 7.42 (d, 2H), 7.27 (t, 2H), 7.15 (m, 2H), 7.04 (d, 1H), 4.54 (d, 2H).

[0321] HPLC-MS: Rt 3.147 m/z 444.1 (MH.sup.+)

Example 13: 4-((3′,4′-difluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido) methyl)benzoic acid

[0322] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.89 (s, 1H), 8.97 (t, 1H), 7.95 (d, 1H), 7.79 (m, 4H), 7.54 (m, 2H), 7.37 (d, 2H), 7.26 (t, 2H), 7.13 (dd, 2H), 6.98 (d, 1H), 4.53 (d, 2H).

[0323] HPLC-MS: Rt 4.084 m/z 478.1 (MH.sup.+)

Example 14: 4-((4-(4-fluorophenoxy)-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido) methyl)benzoic acid

[0324] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.00 (t, 1H), 8.01 (d, 1H), 7.93 (d, 2H), 7.83 (dd, 5H), 7.38 (d, 2H), 7.27 (t, 2H), 7.16 (m, 2H), 7.02 (d, 1H), 4.54 (d, 2H).

[0325] HPLC-MS: Rt 2.53 m/z 510.57 (MH.sup.+)

Example 15: 4-((4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido) methyl)benzoic acid

[0326] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=δ=12.88 (s, 1H), 9.01 (t, 1H), 8.01 (dd, 3H), 7.84 (dd, 3H), 7.72 (q, 2H), 7.37 (d, 2H), 7.60 (m, 2H), 7.15 (m, 2H), 7.01 (d, 1H), 4.54 (d, 2H).

[0327] HPLC-MS: Rt 2.47 m/z 510.51 (MH.sup.+)

Example 16: 4-((2-(4-fluorophenoxy)-5-(pyridin-2-yl)benzamido)methyl)benzoic acid

[0328] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.99 (t, 1H), 8.67 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H), 7.99 (d, 1H), 7.89 (m, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.35 (m, 1H), 7.27 (t, 2H), 7.17 (dd, 2H), 6.99 (d, 1H), 4.55 (d, 2H).

[0329] HPLC-MS: Rt 3.502 m/z 433.1 (MH.sup.+)

Example 17: 4-((2-(4-fluorophenoxy)-5-(pyrimidin-4-yl)benzamido)methyl)benzoic acid

[0330] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.24 (d, 1H), 9.03 (t, 1H), 8.86 (d, 1H), 8.51 (d, 1H), 8.28 (dd, 1H), 8.12 (dd, 1H), 7.85 (d, 2H), 7.41 (d, 2H), 7.30 (m, 2H), 7.22 (dd, 2H), 7.00 (d, 1H), 4.56 (d, 2H).

[0331] HPLC-MS: Rt 3.243 m/z 444.1 (MH.sup.+)

Example 18: 4-((2-(4-fluorophenoxy)-5-(thiophen-2-yl)benzamido)methyl)benzoic acid

[0332] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.98 (t, 1H), 7.90 (d, 1H), 7.82 (dd, 2H), 7.73 (dd, 1H), 7.56 (d, 1H), 7.53 (dd, 1H), 7.35 (2H), 7.24 (t, 2H), 7.12 (m, 3H), 6.96 (d, 1H), 4.52 (d, 2H).

[0333] HPLC-MS: Rt 2.18 m/z 448.1 (MH.sup.+)

Example 19: 4-((3′,5′-difluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido) methyl)benzoic acid

[0334] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.87 (s, 1H), 8.99 (t, 1H), 8.00 (d, 1H), 7.83 dd, 3H), 7.49 (m, 2H), 7.38 (d, 2H), 7.25 (m, 3H), 7.14 (m, 2H), 6.98 (d, 1H), 4.54 (d, 2H).

[0335] HPLC-MS: Rt 2.30 m/z 478.17 (MH.sup.+)

Example 20: 4-((3′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido)methyl) benzoic acid

[0336] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.99 (t, 1H), 7.97 (d, 1H), 7.80 (m, 4H), 7.68 (d, 1H), 7.51 (t, 1H), 7.46 (m, 1H), 7.39 (d, 2H), 7.27 (m, 2H), 7.15 (m, 2H), 7.00 (d, 1H), 4.55 (d, 2H).

[0337] HPLC-MS: Rt 2.86 m/z 476.13 (MH.sup.+)

Example 21: 4-((3′-fluoro-4-(4-fluorophenoxy)-5′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)methyl)benzoic acid

[0338] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.89 (s, 1H), 9.01 (t, 1H), 8.08 (d, 1H), 7.96 (d, 1H), 7.90 (m, 2H), 7.84 (d, 2H), 7.70 (d, 1H), 7.39 (d, 2H), 7.28 (m, 2H), 7.17 (m, 2H), 7.01 (d, 1H), 4.56 (d, 2H).

[0339] HPLC-MS: Rt 2.46 m/z 528.19 (MH.sup.+)

Example 22: 4-((3′-carbamoyl-5′-chloro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-yl carboxamido)methyl)benzoic acid

[0340] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.89 (s, 1H), 9.00 (t, 1H), 8.26 (s, 1H), 8.15 (s, 1H), 8.05 (d, 1H), 7.94 (m, 1H), 7.88 (m, 1H), 7.84 (m, 2H), 7.63 (s, 1H), 7.38 (d, 2H), 7.26 (m, 2H), 7.15 (m, 2H), 7.01 (d, 1H), 4.54 (d, 2H).

[0341] HPLC-MS: Rt 1.96 m/z 519.07 (MH.sup.+)

Example 23: 4-((2-(4-fluorophenoxy)-5-(1H-pyrazol-4-yl)benzamido)methyl)benzoic acid

[0342] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.96 (s, 1H), 8.90 (t, 1H), 8.09 (s, 2H), 7.85 (d, 1H), 7.81 (m, 2H), 7.69 (dd, 1H), 7.33 (m, 2H), 7.22 (m, 2H), 7.06 (m, 2H), 6.94 (d, 1H), 4.49 (d, 2H).

[0343] HPLC-MS: Rt 1.06 m/z 432.1 (MH.sup.+)

Example 24: 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-4-yl)benzamido)methyl) benzoic acid

[0344] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 8.91 (t, 1H), 8.18 (s, 1H), 7.88 (s, 1H), 7.81 (m, 3H), 7.64 (dd, 1H), 7.33 (d, 2H), 7.22 (m, 2H), 7.06 (m, 2H), 6.94 (d, 1H), 4.50 (d, 2H), 3.86 (s, 3H).

[0345] HPLC-MS: Rt 1.78 m/z 446.10 (MH.sup.+)

Example 25: 4-((2-(4-fluorophenoxy)-5-(1-methyl-1H-pyrazol-5-yl)benzamido)methyl) benzoic acid

[0346] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.00 (t, 1H), 7.83 (d, 2H), 7.77 (d, 1H), 7.61 (dd, 1H), 7.48 (d, 1H), 7.37 (d, 2H), 7.27 (m, 2H), 7.17 (m, 2H), 6.98 (d, 1H), 6.43 (t, 1H), 4.53 (d, 2H), 3.86 (s, 3H).

[0347] HPLC-MS: Rt 1.82 m/z 446.10 (MH.sup.+)

Example 26: 4-((4-(4-fluorophenoxy)-3′-(pyridin-4-yl)-[1,1′-biphenyl]-3-ylcarboxamido) methyl)benzoic acid

[0348] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.88 (s, 1H), 9.02 (t, 1H), 8.92 (d, 1H), 8.38 (d, 2H), 8.25 (s, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.92 (d, 2H), 7.83 (d, 2H), 7.71 (t, 1H), 7.38 (d, 2H), 7.27 (m, 2H), 7.15 (m, 2H), 7.04 (d, 1H), 4.54 (d, 2H).

[0349] HPLC-MS: Rt 2.15 m/z 519.2 (MH.sup.+)

Example 27: 4-((5-(5-carbamoylfuran-2-yl)-2-(4-fluorophenoxy)benzamido)methyl) benzoic acid

[0350] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.89 (s, 1H), 9.00 (t, 1H), 8.17 (t, 1H), 8.02 (s, 1H), 7.94 (m, 2H), 7.45 (s, 2H), 7.37 (t, 2H), 7.26 (m, 2H), 7.13 (m, 3H), 6.99 (d, 1H), 4.53 (d, 2H).

[0351] HPLC-MS: Rt 1.74 m/z 475.0 (MH.sup.+)

Example 28: 3-fluoro-4-((4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoic acid

[0352] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=13.26 (s, 1H), 9.00 (t, 1H), 8.00 (m, 3H), 7.86 (dd, 1H), 7.73 (m, 2H), 7.63 (m, 2H), 7.41 (t, 1H), 7.26 (m, 2H), 7.15 (m, 2H), 7.00 (d, 1H), 4.54 (d, 2H).

[0353] HPLC-MS: Rt 1.54 m/z 528.0 (MH.sup.+)

Example 29: (R)-4-(1-(4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)ethyl)benzoic acid

[0354] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.86 (s, 1H), 8.88 (d, 1H), 8.06 (m, 2H), 7.90 (t, 1H), 7.84 (dd, 3H), 7.72 (q, 2H), 7.45 (d, 2H), 7.25 (t, 2H), 7.12 (m, 2H), 7.03 (d, 1H), 5.13 (p, 1H), 1.40 (t, 3H).

[0355] HPLC-MS: Rt 2.45 m/z 524.0 (MH.sup.+)

Example 30: 4-(1-(4-(4-fluorophenoxy)-3′-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxamido)cyclopropyl)benzoic acid

[0356] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=9.09 (s, 1H), 8.04 (d, 2H), 7.95 (s, 1H), 7.86 (d, 1H), 7.73 (d, 4H), 7.27 (t, 2H), 7.18 (d, 2H), 7.13 (dd, 2H), 7.08 (d, 1H), 1.27 (t, 2H), 1.22 (t, 2H).

[0357] HPLC-MS: Rt 2.79 m/z 536.0 (MH.sup.+)

Example 31: 4-((3′-fluoro-5′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido) methyl)benzoic acid

[0358] ##STR00015##

[0359] To a solution of 4-((5-bromo-2-(4-fluorophenoxy)benzamido)methyl)benzoic acid (80 mg, 1.0 eq) and (3-cyano-5-fluorophenyl)boronic acid (59 mg, 2.0 eq) in DMF (1.2 mL) 2M Cs2CO3 (0.27 mL, 3.0 eq) and Pd(dppf)Cl2.Math.DCM (9 mg, 0.06 eq) under nitrogen atmosphere. After stirred at 110° C. for 20 h, the mixture was filtered through celite, rinsing with ethyl acetate (20 mL). The organic phase was washed with sat. aq. sodium bicarbonate (20 mL) and brine (20 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Hexanes:ethyl acetate, 1:1) to obtain the acid IV-484-536 as white solid (22 mg, 25.2% yield).

[0360] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.86 (s, 1H), 8.99 (t, 1H), 8.12 (s, 1H), 8.07 (d, 2H), 8.01 (dd, 1H), 7.89 (dd, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.27 (m, 2H), 7.16 (m, 2H), 6.99 (d, 1H), 4.54 (d, 2H).

[0361] HPLC-MS: Rt 2.23 m/z 485.1 (MH.sup.+)

Example 32: 4-((3′-chloro-5′-cyano-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-carboxamido) methyl)benzoic acid

[0362] ##STR00016##

[0363] To a solution of methyl 4-((3′-cyano-5′-fluoro-4-(4-fluorophenoxy)-[1,1′-biphenyl]-3-ylcarboxamido)methyl)benzoate (100 mg, 1.0 eq) in THF (1.0 mL) was added HCl (4 M) (3.0 mL) and the mixture was stirred for 46 hours at 80° C. After diluting with water (5 mL), the mixture was extracted with ethyl acetate (3×10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (Hexanes:ethyl acetate, 1:1) to obtain the acid as white solid (18 mg, 18.6% yield).

[0364] .sup.1H-NMR (400 MHz, DMSO-d.sup.6): δ=12.87 (s, 1H), 8.98 (t, 1H), 8.22 (s, 1H), 8.16 (t, 1H), 8.07 (d, 1H), 8.03 (m, 1H), 7.89 (dd, 1H), 7.84 (d, 2H), 7.39 (d, 2H), 7.27 (m, 2H), 7.16 (m, 2H), 6.99 (d, 1H), 4.54 (d, 2H).

[0365] HPLC-MS: Rt 2.34 m/z 501.1 (MH.sup.+)