Amide derivatives as lysophosphatidic acid receptor antagonists

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, formula (I) wherein R.sup.1, X, m, R.sup.2, Y, R.sup.3, Z, n, R.sup.4, A and B are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

##STR00001##

Claims

1.-18. (canceled)

19. A method of treating a condition whose development or symptoms are linked to LPAR5 activity comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing.

20. The method according to claim 19, wherein the condition is chosen from fibrosis, liver diseases, atherosclerosis, inflammatory diseases, gastrointestinal tract diseases, and pain disorders.

21. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.

22. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

23. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.

24. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

25. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid.

26. The method according to claim 19, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

27. The method according to claim 19, further comprising administering at least one additional therapeutic agent.

28. The method according to claim 27, wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.

29. A method of treating a condition whose development or symptoms are linked to LPAR1 activity comprising administering to a patient in need thereof a pharmaceutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing.

30. The method according to claim 29, wherein the condition is chosen from fibrosis, liver diseases, atherosclerosis, inflammatory diseases, gastrointestinal tract diseases, and pain disorders.

31. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.

32. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

33. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.

34. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

35. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid.

36. The method according to claim 29, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

37. The method according to claim 29, further comprising administering at least one additional therapeutic agent.

38. The method according to claim 37, wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.

39. A method of treating a condition chosen from pain disorders and gastrointestinal tract diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound selected from 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid, 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid, and a pharmaceutically acceptable salt of any of the foregoing.

40. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.

41. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

42. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid.

43. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

44. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid.

45. The method according to claim 39, wherein the compound is 4-((N-(cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)methyl)benzoic acid or a pharmaceutically acceptable salt thereof.

46. The method according to claim 39, further comprising administering at least one additional therapeutic agent.

47. The method according to claim 46, wherein the at least one additional therapeutic agent is selected from opioid agonists, partial agonists or antagonists; antidepressants; anxiolytics; anticonvulsants; migraine therapies; stroke therapies; urinary incontinence therapies; neuropathic pain therapies; and nociceptive pain therapies.

Description

PREPARATION OF EXAMPLES

[0584] Compounds derived from the Intermediates C6 to C74 above were prepared according to Method H1 or H2:

Method H1

[0585] Lithium hydroxide or lithium hydroxide monohydrate (5 mmol) was added to a solution of the relevant ester (1 mmol) in water (2 mL) and either THF or 1,4-dioxane (4 mL). In some cases, MeOH was added in addition to THF. The mixture was stirred, typically at RT for 18 h, 50 C. for 4 h or 100 C. for 20 minutes. In some cases the reaction was diluted with NaOH (2 M) and extracted with EtOAc or DCM, and the resulting aqueous phase acidified with HCl (2 M) and extracted with EtOAc. In other cases the crude mixture was partitioned between HCl (2 M) and EtOAc. The combined organic phases from the extraction of the acidic aqueous phase were dried and concentrated. In some cases the residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 1 M HCl/MeCN then concentrated. In some cases the material obtained was purified by reverse-phase chromatography on C18 silica (typically eluted with 5-95% MeOH/H.sub.2O with 0.1% NH.sub.4OH). In some cases the crude product was heated under reflux in HCl (4 M), allowed to cool and filtered. In some cases the final product was recrystallised, typically using one or more of the following: water, EtOH, EtOAc, methyl acetate, methyl tert-butyl ether, pentane, heptane.

Method H2

[0586] Sodium hydroxide (2 M, 6 mmol) was added to a solution of the relevant ester (2 mmol) in THF (3 mL). In some cases, MeOH was added instead of or in addition to THF. The mixture was stirred at RT for 18 h or heated under microwave irradiation at 100 C. for 5 minutes. The mixture was partitioned between HCl (1 M) and EtOAc (30 mL each). The organic phases were dried and concentrated. The residue was loaded onto an anion exchange cartridge. After washing with MeCN, the product was eluted with 4 M HCl/1,4-dioxane then concentrated.

Example 1: 4-((N-Ethyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid

[0587] ##STR00141##

[0588] Prepared from the parent methyl ester (Intermediate C6) using Method H1.

[0589] .sup.1H NMR (300 MHz, DMSO-d.sub.6) ppm 0.84-1.36 (m, 3H) 3.05-3.64 (m, 2H) 4.67 (br s, 2H) 6.73-7.09 (m, 2H) 7.09-7.61 (m, 8H) 7.74-8.05 (m, 2H) 12.90 (br s, 1H)

[0590] MS ES.sup.+: 394

Example 2: 4-((N-(2,2-Difluoroethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid

[0591] ##STR00142##

[0592] Prepared from the parent methyl ester (Intermediate C7) using Method H1.

[0593] .sup.1H NMR (300 MHz, DMSO-do) ppm 3.57-3.91 (m, 2H) 4.71 (br s, 2H) 5.95-6.52 (m, 1H) 6.82-7.08 (m, 2H) 7.10-7.57 (m, 8H) 7.79-7.98 (m, 2H) 12.93 (br s, 1H)

[0594] MS ES.sup.+: 430

Example 3: 4-((4-(2-Fluorophenoxy)-N-(2,2,2-trifluoroethyl)benzamido)-methyl)benzoic Acid

[0595] ##STR00143##

[0596] Prepared from the parent methyl ester (Intermediate C8) using H1.

[0597] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.14-4.36 (m, 2H) 4.76 (s, 2H) 6.92-7.10 (m, 2H) 7.16-7.37 (m, 5H) 7.39-7.55 (m, 3H) 7.84-7.99 (m, 2H) 12.94 (br s, 1H)

[0598] MS ES.sup.+: 448

Example 4: 4-((4-(2-Fluorophenoxy)-N-isobutylbenzamido)methyl)benzoic Acid

[0599] ##STR00144##

[0600] Prepared from the parent methyl ester (Intermediate C9) using Method H1.

[0601] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.50-1.08 (m, 6H) 1.77-2.17 (m, 1H) 3.00-3.25 (m, 2H) 4.49-4.86 (m, 2H) 6.88-7.13 (m, 2H) 7.13-7.57 (m, 8H) 7.83-8.04 (m, 2H) 12.69-13.02 (m, 1H)

[0602] MS ES.sup.+: 422

Example 5: 4-((N-(Cyclopropylmethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid

[0603] ##STR00145##

[0604] Prepared from the parent methyl ester (Intermediate C10) using Method H1.

[0605] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.13-0.26 (m, 2H) 0.30-0.50 (m, 2H) 0.75-1.06 (m, 1H) 2.97-3.22 (m, 2H) 4.79 (br s, 2H) 6.88-7.12 (m, 2H) 7.12-7.55 (m, 8H) 7.86-7.97 (m, 2H) 12.87 (br s, 1H)

[0606] MS ES.sup.+: 420

Example 6: 4-((N-(Cyclobutylmethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid

[0607] ##STR00146##

[0608] Prepared from the parent methyl ester (Intermediate C11) using Method H1.

[0609] .sup.1H NMR (400 MHz, CD.sub.3OD) ppm 1.37-2.15 (m, 6H) 2.49-2.82 (m, 1H) 3.34-3.58 (m, 2H) 4.60-4.78 (m, 2H) 6.90-7.04 (m, 2H) 7.14-7.29 (m, 5H) 7.33-7.49 (m, 3H) 7.82-8.03 (m, 2H)

[0610] MS ES.sup.+: 434

Example 7: 4-((4-(2-Fluorophenoxy)-N-((3-methoxycyclobutyl)methyl)-benzamido)methyl)benzoic Acid (Mixture of Cis and Trans Ring Isomers)

[0611] ##STR00147##

[0612] Prepared from the parent methyl ester (Intermediate C58) using Method H1.

[0613] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.64-2.30 (m, 4H) 3.04 (br s, 3H) 3.16-3.70 (m, 4H) 4.65 (br s, 2H) 6.85-7.14 (m, 2H) 7.14-7.59 (m, 8H) 7.82-8.00 (m, 2H)

[0614] MS ES.sup.+:464

Example 8: 4-((4-(2-Fluorophenoxy)-N-isopentylbenzamido)methyl)benzoic Acid

[0615] ##STR00148##

[0616] Prepared from the parent methyl ester (Intermediate C12) using Method H1.

[0617] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.48-1.00 (m, 6H) 1.39 (br s, 3H) 3.21 (br s, 2H) 4.49-4.84 (m, 2H) 7.01 (br s, 2H) 7.17-7.57 (m, 8H) 7.88-7.97 (m, 2H) 12.90 (br s, 1H)

[0618] MS ES.sup.+: 436

Example 9: 4-((N-(2-Cyclopropylethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid

[0619] ##STR00149##

[0620] Prepared from the parent methyl ester (Intermediate C13) using Method H1.

[0621] .sup.1H NMR (400 MHz, CD.sub.3OD) ppm 0.22-0.17 (m, 2H) 0.26-0.51 (m, 2H) 0.52-0.79 (m, 1H) 1.35-1.64 (m, 2H) 3.35-3.63 (m, 2H) 4.58-4.79 (m, 2H) 6.90-7.08 (m, 2H) 7.13-7.34 (m, 5H) 7.37-7.54 (m, 3H) 8.06-8.22 (m, 2H)

[0622] MS ES.sup.+: 434

Example 10: 4-((N-(2-Cyclobutylethyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid

[0623] ##STR00150##

[0624] Prepared from the parent methyl ester (Intermediate C14) using Method H1.

[0625] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.24-2.30 (m, 9H) 2.88-3.40 (m, 2H) 4.48-4.82 (m, 2H) 7.01 (br s, 2H) 7.19-7.54 (m, 8H) 7.88-7.96 (m, 2H) 12.90 (br s, 1H)

[0626] MS ES.sup.+: 448

Example 11: 4-((N-Benzyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid

[0627] ##STR00151##

[0628] Prepared from the parent methyl ester (Intermediate C15) using Method H1.

[0629] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.37-4.80 (m, 4H) 6.92-7.06 (m, 2H) 7.11-7.60 (m, 13H) 7.85-7.99 (m, 2H)

[0630] MS ES.sup.+: 456

Example 12: 4-((N-(2-Fluorobenzyl)-4-(2-fluorophenoxy)benzamido)-methyl)benzoic Acid

[0631] ##STR00152##

[0632] Prepared from the parent methyl ester (Intermediate C16) using Method H1.

[0633] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.45-4.66 (m, 4H) 6.96-7.03 (m, 2H) 7.03-7.45 (m, 10H) 7.45-7.54 (m, 2H) 7.78-7.89 (m, 2H)

[0634] MS ES.sup.+: 474

Example 13: 4-((4-(2-Fluorophenoxy)-N-(3-methoxybenzyl)benzamido)-methyl)benzoic Acid

[0635] ##STR00153##

[0636] Prepared from the parent methyl ester (Intermediate C17) using Method H1.

[0637] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 3.72 (s, 3H) 4.42-4.71 (m, 4H) 6.55-7.10 (m, 5H) 7.16-7.62 (m, 9H) 7.76-7.99 (m, 2H) 12.92 (br s, 1H)

[0638] MS ES.sup.+: 486

Example 14: 4-((4-(2-Fluorophenoxy)-N-(4-methoxybenzyl)benzamido)-methyl)benzoic Acid

[0639] ##STR00154##

[0640] Prepared from the parent methyl ester (Intermediate C18) using Method H1.

[0641] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 3.74 (s, 3H) 4.24-4.80 (m, 4H) 6.83-7.65 (m, 14H) 7.84-8.05 (m, 2H) 12.90 (br s, 1H)

[0642] MS ES.sup.+: 486

Example 15: 4-((4-(2-Fluorophenoxy)-N-phenethylbenzamido)methyl)benzoic Acid

[0643] ##STR00155##

[0644] Prepared from the parent methyl ester (Intermediate C19) using Method H1.

[0645] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.40-3.07 (m, 2H) 3.07-4.11 (m, 2H) 4.11-4.95 (m, 2H) 6.55-7.49 (m, 15H) 7.86-8.05 (m, 2H)

[0646] MS ES.sup.+: 470

Example 16: 4-((4-(2-Fluorophenoxy)-N-(3-(2-fluorophenyl)propyl)benzamido)methyl)benzoic Acid

[0647] ##STR00156##

[0648] Prepared from the parent methyl ester (Intermediate C20) using Method H1.

[0649] .sup.1H NMR (400 MHz, DMSO-do) ppm 1.66-1.98 (m, 2H) 2.17-2.80 (m, 2H) 3.05-3.52 (m, 2H) 4.44-4.90 (m, 2H) 6.83-7.55 (m, 14H) 7.85-8.01 (m, 2H) 12.90 (br s, 1H)

[0650] MS ES.sup.+: 502

Example 17: 4-((4-(2-Fluorophenoxy)-N-(3-(3-fluorophenyl)propyl)benzamido)methyl)benzoic Acid

[0651] ##STR00157##

[0652] Prepared from the parent methyl ester (Intermediate C21) using Method H1.

[0653] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.70-1.95 (m, 2H) 2.30-2.40 (m, 2H) 3.30-3.40 (m, 2H) 4.74 (br s, 2H) 6.80-7.56 (m, 14H) 7.87-7.99 (m, 2H) 12.88 (br s, 1H)

[0654] MS ES.sup.+: 502

Example 18: 4-((4-(2-Fluorophenoxy)-N-((trans-2-phenylcyclopropyl)methyl)-benzamido)methyl)benzoic Acid

[0655] ##STR00158##

[0656] Prepared from the parent methyl ester (Intermediate C22) using Method H1.

[0657] .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) ppm 0.92 (br s, 2H) 1.20-1.35 (m, 1H) 1.52-1.78 (m, 1H) 3.42 (s, 2H) 4.75-4.99 (m, 2H) 6.86-7.10 (m, 4H) 7.10-7.29 (m, 6H) 7.29-7.50 (m, 5H) 8.00-8.12 (m, 2H)

[0658] MS ES.sup.+: 496

Example 19: (S)-4-((4-(2-Fluorophenoxy)-N-(2-hydroxy-3-phenylpropyl)benzamido)methyl)benzoic Acid

[0659] ##STR00159##

[0660] Prepared from the parent methyl ester (Intermediate C23) using Method H1.

[0661] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.60-2.76 (m, 1H) 2.95-3.30 (m, 2H) 3.88-4.17 (m, 1H) 4.65 (br s, 2H) 4.85-4.97 (m, 1H) 5.00-5.29 (m, 1H) 6.85-7.33 (m, 12H) 7.33-7.50 (m, 3H) 7.79-7.90 (m, 2H)

[0662] MS ES.sup.+: 500

Example 20: (R)-1-((4-(2-Fluorophenoxy)-N-(2-hydroxy-3-phenylpropyl)-benzamido)methyl)benzoic Acid

[0663] ##STR00160##

[0664] Prepared from the parent methyl ester (Intermediate C24) using Method H1.

[0665] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.55-2.79 (m, 1H) 2.92-3.40 (m, 2H) 3.83-4.17 (m, 1H) 4.72 (br s, 2H) 4.85-5.05 (m, 1H) 5.06-5.23 (m, 1H) 6.83-7.53 (m, 15H) 7.84-7.97 (m, 2H)

[0666] MS ES.sup.+: 500

Example 21: 4-((4-(2-Fluorophenoxy)-N-(4-phenylbutyl)-benzamido)methyl)benzoic Acid

[0667] ##STR00161##

[0668] Prepared from the parent methyl ester (Intermediate C25) using Method H1.

[0669] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.29-1.70 (m, 2H) 2.32-2.84 (m, 2H) 3.10-3.55 (m, 2H) 4.62 (br s, 2H) 6.86-7.46 (m, 15H) 7.77-7.95 (m, 2H) 12.57 (br s, 1H)

[0670] MS ES.sup.+: 498

Example 22: 4-((N-(Cyclopropylmethyl)-4-(o-tolyloxy)benzamido)methyl)benzoic Acid

[0671] ##STR00162##

[0672] Prepared from the parent methyl ester (Intermediate C26) using Method 111.

[0673] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.25-0.25 (m, 2H) 0.25-0.50 (m, 2H) 0.74-1.11 (m, 1H) 2.13 (s, 3H) 2.87-3.47 (m, 2H) 4.78 (br s, 2H) 6.75-7.62 (m, 10H) 7.83-7.98 (m, 2H) 12.87 (br s, 1H)

[0674] MS ES.sup.+: 416

Example 23: 4-((N-(Cyclobutylmethyl)-4-(o-tolyloxy)benzamido)methyl)benzoic Acid

[0675] ##STR00163##

[0676] Prepared from the parent methyl ester (Intermediate C27) using Method H1.

[0677] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.23-1.99 (m, 7H) 2.15 (s, 3H) 2.40-2.74 (m, 2H) 4.65 (br s, 2H) 6.76-7.64 (m, 10H) 7.87-8.02 (m, 2H) 12.90 (br s, 1H)

[0678] MS ES.sup.+: 430

Example 24: 4-((N-Benzyl-4-(o-tolyloxy)benzamido)methyl)benzoic Acid

[0679] ##STR00164##

[0680] Prepared from the parent methyl ester (Intermediate C28) using Method H1.

[0681] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.14 (s, 3H) 4.58 (br s, 4H) 6.62-7.04 (m, 3H) 7.07-7.60 (m, 12H) 7.84-8.00 (m, 2H) 12.90 (br s, 1H)

[0682] MS ES.sup.+: 452

Example 25: 4-((N-Phenethyl-4-(o-tolyloxy)benzamido)methyl)benzoic Acid

[0683] ##STR00165##

[0684] Prepared from the parent methyl ester (Intermediate C29) using Method H1.

[0685] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.15 (br s, 3H) 2.72-2.98 (m, 2H) 3.34-3.59 (m, 2H) 4.43-4.88 (m, 2H) 6.82-7.02 (m, 4H) 7.28 (br s, 11H) 7.88-7.96 (m, 2H)

[0686] MS ES.sup.+: 466

Example 26: 4-((N-Phenethyl-4-(2-(trifluoromethyl)phenoxy)benzamido)-methyl)benzoic Acid

[0687] ##STR00166##

[0688] Prepared from the parent methyl ester (Intermediate C30) using Method H1.

[0689] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.71-2.99 (m, 2H) 3.34-3.59 (m, 2H) 4.43-4.87 (m, 2H) 6.89-7.42 (m, 12H) 7.43-7.54 (m, 1H) 7.64-7.73 (m, 1H) 7.77-7.85 (m, 1H) 7.88-7.98 (m, 2H)

[0690] MS ES.sup.+: 520

Example 27: 4-((iv-Benzyl-4-(2-cyanophenoxy)benzamido)methyl)benzoic Acid

[0691] ##STR00167##

[0692] Prepared from the parent methyl ester (Intermediate C31) using Method H1.

[0693] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.40-4.76 (m, 4H) 7.00-7.77 (m, 15H) 7.85-8.00 (m, 2H) 12.97 (br s, 1H)

[0694] MS ES.sup.+: 463

Example 28: 4-((N-Ethyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0695] ##STR00168##

[0696] Prepared from the parent methyl ester (Intermediate C32) using Method H1.

[0697] .sup.1H NMR (400 MHz, DMSO-do) ppm 1.01-1.11 (m, 3H) 3.22-3.33 (m, 2H) 3.73 (s, 3H) 4.68 (br s, 2H) 6.79-6.88 (m, 2H) 6.96-7.03 (m, 1H) 7.07-7.13 (m, 1H) 7.16-7.28 (m, 2H) 7.40 (br s, 4H) 7.89-7.96 (m, 2H) 12.88 (br s, 1H)

[0698] MS ES.sup.+: 406

Example 29: 4-((N-(2,2-Difluoroethyl)-4-(2-methoxyphenoxy)benzamido)-methyl benzoic Acid

[0699] ##STR00169##

[0700] Prepared from the parent methyl ester (Intermediate C33) using Method H1.

[0701] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 3.64-3.86 (m, 5H) 4.74 (br s, 2H) 6.07-6.44 (m, 1H) 6.78-6.92 (m, 2H) 6.96-7.03 (m, 1H) 7.07-7.13 (m, 1H) 7.15-7.46 (m, 6H) 7.87-7.97 (m, 2H) 12.93 (br s, 111)

[0702] MS ES.sup.+: 442

Example 30: 4-((N-Isobutyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0703] ##STR00170##

[0704] Prepared from the parent methyl ester (Intermediate C34) using Method H1.

[0705] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.58-0.97 (m, 6H) 1.80-2.13 (m, 1H) 3.06-3.19 (m, 2H) 3.72 (s, 3H) 4.68 (s, 2H) 6.77-6.90 (m, 2H) 6.94-7.05 (m, 1H) 7.05-7.13 (m, 1H) 7.16-7.53 (m, 6H) 7.87-7.97 (m, 2H) 12.91 (br s, 1H)

[0706] MS ES.sup.+: 434

Example 31: 4-((N-(Cyclopropylmethyl)-4-(2-methoxyphenoxy)benzamido)-methyl)benzoic Acid

[0707] ##STR00171##

[0708] Prepared from the parent methyl ester (Intermediate C35) using Method H1.

[0709] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 0.14-0.20 (m, 2H) 0.30-0.44 (m, 2H) 0.81-1.03 (m, 1H) 3.15 (br s, 2H) 3.70 (s, 3H) 4.79 (br s, 2H) 6.78-6.91 (m, 2H) 6.96-7.03 (m, 1H) 7.08-7.14 (m, 1H) 7.16-7.28 (m, 2H) 7.30-7.50 (m, 4H) 7.87-7.96 (m, 2H) 12.88 (s, 1H)

[0710] MS ES.sup.+: 432

Example 32: 4-((4-(2-Methoxyphenoxy)-N-(3-phenylpropyl)benzamido)-methyl)benzoic Acid

[0711] ##STR00172##

[0712] Prepared from the parent methyl ester (Intermediate C36) using Method H1.

[0713] .sup.1H NMR (400 MHz, DMSO-do) ppm 1.83 (br s, 2H) 2.40 (br s, 2H) 3.22 (br s, 2H) 3.73 (s, 3H) 4.70 (br s, 2H) 6.77-6.82 (m, 2H) 6.95-7.44 (m, 13H) 7.88-7.93 (m, 2H) 12.89 (s, 1H)

[0714] MS ES.sup.+: 496

Example 33: 4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)-benzamido)methyl)benzoic Acid

[0715] ##STR00173##

[0716] I.

[0717] Prepared from the parent methyl ester (Intermediate C37) using Method H1.

[0718] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.84 (br s, 2H) 2.42 (br s, 2H) 3.21 (br s, 2H) 3.73 (s, 3H) 4.70 (br s, 2H) 6.76-6.82 (m, 2H) 6.83-7.47 (m, 12H) 7.86-7.94 (m, 2H) 12.88 (br s, 1H)

[0719] MS ES.sup.+: 514

Example 34: 4-((N-(Cyclopropylmethyl)-4-(2-ethoxyphenoxy)-benzamido)methyl)benzoic Acid

[0720] ##STR00174##

[0721] Prepared from the parent methyl ester (Intermediate C38) using Method H1.

[0722] .sup.1H NMR (300 MHz, DMSO-do) ppm 0.24-0.60 (m, 4H) 0.69-1.41 (m, 4H) 2.87-3.31 (m, 2H) 3.80-4.15 (m, 2H) 4.76 (br s, 2H) 6.60-7.57 (m, 10H) 7.75-8.00 (m, 2H) 12.86 (br s, 11-1)

[0723] MS ES.sup.+: 446

Example 35: 4-((4-(2-Chlorophenoxy)-N-(cyclopropylmethyl)benzamido)-methyl)benzoic Acid

[0724] ##STR00175##

[0725] Prepared from the parent methyl ester (Intermediate C39) using Method H1.

[0726] .sup.1H NMR (400 MHz, DMSO-do) ppm ppm 0.30-0.23 (m, 2H) 0.23-0.50 (m, 2H) 0.74-1.12 (m, 1H) 2.81-3.41 (m, 2H) 4.79 (br s, 2H) 6.86-7.04 (m, 2H) 7.12-7.66 (m, 8H) 7.84-7.97 (m, 2H) 12.87 (br s, 1H)

[0727] MS ES.sup.+: 436

Example 36: 4-((4-(2-Chlorophenoxy)-N-phenethylbenzamido)methyl)benzoic Acid

[0728] ##STR00176##

[0729] Prepared from the parent methyl ester (Intermediate C40) using Method H1.

[0730] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.72-2.95 (m, 2H) 3.35-3.60 (m, 2H) 4.41-4.88 (m, 2H) 6.88-7.01 (m, 3H) 7.14-7.54 (m, 11H) 7.58-7.66 (m, 1H) 7.87-7.98 (m, 2H) 12.89 (br s, 1H)

[0731] MS ES.sup.+: 486

Example 37: 4-((N-(Cyclopropylmethyl)-4-(2,6-difluorophenoxy)benzamido)-methyl)benzoic Acid

[0732] ##STR00177##

[0733] Prepared from the parent methyl ester (Intermediate C41) using Method H1.

[0734] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.00 (br s, 2H) 0.38 (br s, 2H) 0.92 (br s, 1H) 3.12 (br s, 2H) 4.80 (br s, 2H) 7.01 (br s, 2H) 7.24-7.56 (m, 7H) 7.84-7.99 (m, 2H) 12.88 (br s, 1H)

[0735] MS ES.sup.+: 438

Example 38: 4-((N-(2-Cyclopropylethyl)-4-(2,6-difluorophenoxy)benzamido)-methyl)benzoic Acid

[0736] ##STR00178##

[0737] Prepared from the parent methyl ester (Intermediate C42) using Method H1.

[0738] .sup.1H NMR (400 MHz. DMSO-d.sub.6) ppm 0.27-0.10 (m, 2H) 0.18-0.75 (m, 3H) 1.25-1.57 (m, 2H) 3.14-3.47 (m, 2H) 4.52-4.81 (m, 2H) 6.87-7.11 (m, 2H) 7.22-7.56 (m, 7H) 7.84-8.00 (m, 2H) 12.88 (br s, 111)

[0739] MS ES.sup.+: 452

Example 39: 4-((N-Benzyl-4-(2,6-difluorophenoxy)benzamido)methyl)benzoic Acid

[0740] ##STR00179##

[0741] Prepared from the parent methyl ester (Intermediate C43) using Method H1.

[0742] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.40-4.68 (m, 4H) 6.95-7.04 (m, 2H) 7.11-7.44 (m, 10H) 7.45-7.55 (m, 2H) 7.86-7.94 (m, 2H)

[0743] MS ES.sup.+: 474

Example 40: 4-((N-(Cyclopropylmethyl)-4-(2-fluoro-6-methylphenoxy)-benzamido)methyl)benzoic Acid

[0744] ##STR00180##

[0745] Prepared from the parent methyl ester (Intermediate C44) using Method H1.

[0746] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.16-0.24 (m, 2H) 0.26-0.48 (m, 2H) 0.77-1.08 (m, 1H) 2.15 (s, 3H) 2.94-3.32 (m, 2H) 4.78 (br s, 2H) 6.88 (br s, 2H) 7.09-7.28 (m, 3H) 7.42 (br s, 4H) 7.85-7.96 (m, 2H) 12.87 (br s, 1H)

[0747] MS ES.sup.+: 434

Example 41: 4-((N-(Cyclobutylmethyl)-4-(2-fluoro-6-methylphenoxy)benzamido)methyl)benzoic Acid

[0748] ##STR00181##

[0749] Prepared from the parent methyl ester (Intermediate C45) using Method H1.

[0750] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.36-2.01 (m, 6H) 2.16 (s, 3H) 3.22-3.42 (m, 3H) 4.64 (br s, 2H) 6.80-6.95 (m, 2H) 7.17-7.29 (m, 3H) 7.32-7.56 (m, 4H) 7.81-8.02 (m, 2H) 12.88 (br s, 1H)

[0751] MS ES.sup.+: 448

Example 42: 4-((4-(2-Chloro-6-fluorophenoxy)-N-(cyclopropylmethyl)-benzamido)methyl)benzoic Acid

[0752] ##STR00182##

[0753] Prepared from the parent methyl ester (Intermediate C46) using Method H1.

[0754] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.00 (br s, 2H) 0.38 (br s, 2H) 0.93 (br s, 1H) 3.13 (br s, 2H) 4.80 (br s, 2H) 6.95 (br s, 2H) 7.24-7.60 (m, 7H) 7.86-7.99 (m, 2H) 12.88 (br s, 1H)

[0755] MS ES.sup.+: 454

Example 43: 4-((4-(2-Chloro-6-fluorophenoxy)-N-(2-cyclopropylethyl)-benzamido)methyl)benzoic Acid

[0756] ##STR00183##

[0757] Prepared from the parent methyl ester (Intermediate C47) using Method H1.

[0758] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.29-0.77 (m, 511) 1.23-1.57 (m, 2H) 3.15-3.52 (m, 2H) 4.49-4.84 (m, 2H) 6.95 (m, 2H) 7.21-7.57 (m, 711) 7.89-7.96 (m, 2H) 12.89 (br s, 1H)

[0759] MS ES.sup.+: 468

Example 44: 4-((N-Benzyl-4-(2-chloro-6-fluorophenoxy)benzamido)-methyl)benzoic acid

[0760] ##STR00184##

[0761] Prepared from the parent methyl ester (Intermediate C48) using Method H1.

[0762] .sup.1H NMR (400 MHz, DMSO-do) ppm 4.39-4.70 (m, 4H) 6.87-6.99 (m, 2H) 7.08-7.59 (m, 12H) 7.86-7.95 (m, 2H) 12.97 (br s, 1H)

[0763] MS ES.sup.+: 490

Example 45: 4-((4-(2,6-Dimethylphenoxy)-N-isopentylbenzamido)methyl)benzoic Acid

[0764] ##STR00185##

[0765] Prepared from the parent methyl ester (Intermediate C49) using Method H2.

[0766] .sup.1H NMR (400 MHz, DMSO-do) ppm 0.39-1.61 (m, 9H) 2.06 (s, 6H) 2.75-3.48 (m, 2H) 4.47-4.86 (m, 2H) 6.62-6.89 (m, 2H) 7.05-7.25 (m, 3H) 7.25-7.58 (m, 4H) 7.85-8.02 (m, 2H) 12.89 (br s, 1H)

[0767] MS ES.sup.+: 446

Example 46: 4-((N-Benzyl-4-(2,6-dimethylphenoxy)benzamido)methyl)benzoic Acid

[0768] ##STR00186##

[0769] Prepared from the parent methyl ester (Intermediate C50) using Method H2.

[0770] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.04 (s, 6H) 4.35-4.79 (m, 4H) 6.68-6.87 (m, 2H) 7.02-7.58 (m, 12H) 7.82-8.02 (m, 2H) 12.89 (br s, 1H)

[0771] MS ES.sup.+: 466

Example 47: 4-((4-(2,6-Dimethylphenoxy)-N-phenethylbenzamido)methyl)benzoic Acid

[0772] ##STR00187##

[0773] Prepared from the parent methyl ester (Intermediate C51) using Method 1-12.

[0774] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.07 (s, 6H) 2.62-3.04 (m, 2H) 3.10-3.70 (m, 2H) 4.35-4.98 (m, 2H) 6.65-7.63 (m, 14H) 7.85-8.03 (m, 2H)

[0775] MS ES.sup.+: 480

Example 48: 4-((4-(3-Methoxyphenoxy)-N-phenethylbenzamido)methyl)benzoic Acid

[0776] ##STR00188##

[0777] Prepared from the parent methyl ester (Intermediate C52) using Method H1.

[0778] .sup.1H NMR (400 MHz, DMSO-do) ppm 2.72-2.95 (m, 2H) 3.35-3.61 (m, 2H) 3.74 (s, 3H) 4.40-4.88 (m, 2H) 6.54-6.66 (m, 2H) 6.72-6.80 (m, 1H) 6.90-7.11 (m, 3H) 7.13-7.57 (m, 9H) 7.86-8.01 (m, 2H) 12.87 (br s, 1H)

[0779] MS ES.sup.+: 482

Example 49: 4-((4-(4-Methoxyphenoxy)-N-phenethylbenzamido)methyl)benzoic Acid

[0780] ##STR00189##

[0781] Prepared from the parent methyl ester (Intermediate C53) using Method H1.

[0782] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.70-2.96 (m, 2H) 3.35-3.57 (m, 2H) 3.76 (s, 3H) 4.40-4.87 (m, 2H) 6.85-7.56 (m, 15H) 7.85-8.00 (m, 2H) 12.90 (br s, 1H)

[0783] MS ES.sup.+: 482

Example 50: 4-((4-(3-Chlorophenoxy)-N-phenethylbenzamido)methyl)benzoic Acid

[0784] ##STR00190##

[0785] Prepared from the parent methyl ester (Intermediate C54) using Method H1.

[0786] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 2.73-2.98 (m, 2H) 3.36-3.62 (m, 2H) 4.42-4.90 (m, 2H) 6.87-7.57 (m, 15H) 7.93 (br s, 2H) 12.90 (br s, 1H)

[0787] MS ES.sup.+: 486

Example 51: 4-((N-(Cyclopropylmethyl)-4-((2-fluorobenzyl)oxy)benzamido)-methyl)benzoic Acid

[0788] ##STR00191##

[0789] Prepared from the parent methyl ester (Intermediate C55) using Method H1.

[0790] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm ppm 0.22-0.25 (m, 2H) 0.26-0.47 (m, 2H) 0.77-1.08 (m, 1H) 2.73-3.45 (m, 2H) 4.77 (br s, 2H) 5.15 (s, 2H) 6.98-7.63 (m, 10H) 7.85-7.97 (m, 2H) 12.84 (br s, 1H)

[0791] MS ES.sup.+: 434

Example 52: 4-((N-(Cyclobutylmethyl)-1-((2-fluorobenzyl)oxy)benzamido)-methyl)benzoic Acid

[0792] ##STR00192##

[0793] Prepared from the parent methyl ester (Intermediate C56) using Method H1.

[0794] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.20-2.20 (m, 7H) 2.26-2.74 (m, 2H) 4.64 (s, 2H) 5.18 (s, 2H) 6.97-7.66 (m, 10H) 7.83-8.07 (m, 2H) 12.81 (br s, 1H)

[0795] MS ES.sup.+: 448

Example 53: 4-((N-Benzyl-4-((2-fluorobenzyl)oxy)benzamido)methyl)benzoic Acid

[0796] ##STR00193##

[0797] Prepared from the parent methyl ester (Intermediate C57) using Method H1.

[0798] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 4.56 (br s, 4H) 5.16 (s, 2H) 7.00-7.61 (m, 15H) 7.87-7.99 (m, 2H) 12.92 (br s, 1H)

[0799] MS ES.sup.+: 470

Example 54: 4-((N-(Cyclopropylmethyl)-2-fluoro-4-(2-fluorophenoxy)-Acid

[0800] ##STR00194##

[0801] Prepared from the parent methyl ester (Intermediate C59) using Method H1.

[0802] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 40.06-0.28 (m, 2H) 0.31-0.52 (m, 2H) 0.73-1.15 (m, 1H) 2.99-3.41 (m, 2H) 4.55-4.97 (m, 2H) 6.73-7.07 (m, 2H) 7.25-7.56 (m, 7H) 7.86-8.02 (m, 2H) 12.91 (br s, 1H)

[0803] MS ES.sup.+: 438

Example 55: 4-((N-Benzyl-4-(2-fluorophenoxy)cyclohexanecarboxamido)-methyl)benzoic Acid (Ca. 1:1 Mixture of Cis and Trans Ring Isomers)

[0804] ##STR00195##

[0805] Prepared from the parent methyl ester (Intermediate C60) using Method H1.

[0806] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.27-2.13 (m, 8H) 2.61-2.86 (m, 1H) 4.00-4.40 (m, 1H) 4.45-4.73 (m, 4H) 6.88-7.00 (m, 1H) 7.05-7.44 (m, 10H) 7.85-8.00 (m, 2H) 12.90 (br s, 1H)

[0807] MS ES.sup.+: 462

Example 56; trans ((N Benzyl 4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic Acid

[0808] ##STR00196##

[0809] Prepared from the parent methyl ester (Intermediate C61) using Method H1.

[0810] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.10-2.11 (m, 8H) 2.57-2.78 (m, 1H) 3.73 (s, 3H) 4.11-4.25 (m, 1H) 4.46-4.74 (m, 4H) 6.81-7.04 (m, 4H) 7.15-7.44 (m, 7H) 7.86-8.00 (m, 2H) 12.90 (br s, 1H)

[0811] MS ES.sup.+: 474

Example 57: cis-4-((N-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic Acid

[0812] ##STR00197##

[0813] Prepared from the parent methyl ester (Intermediate C62) using Method H1.

[0814] .sup.1H NMR (400 MHz, DMSO-do) ppm 1.34-1.98 (m, 10H) 2.39-2.66 (m, 3H) 3.15-3.40 (m, 2H) 3.71-3.87 (m, 3H) 4.37-4.51 (m, 1H) 4.52-4.78 (m, 2H) 6.79-7.12 (m, 7H) 7.19-7.39 (m, 3H) 7.82-8.01 (m, 2H) 12.80 (br s, 1H)

[0815] MS ES.sup.+: 520

Example 58: trans-40V-(3-(3-Fluorophenyl)propyl)-4-(2-methoxyphenoxy)cyclohexanecarboxamido)methyl)benzoic Acid

[0816] ##STR00198##

[0817] Prepared from the parent methyl ester (Intermediate C63) using Method H1.

[0818] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.19-2.13 (m, 10H) 2.36-2.65 (m, 3H) 3.15-3.49 (m, 2H) 3.67-3.81 (m, 3H) 4.09-4.24 (m, 1H) 4.51-4.78 (m, 2H) 6.79-7.10 (m, 7H) 7.18-7.40 (m, 3H) 7.81-8.00 (m, 2H) 12.86 (br s, 1H)

[0819] MS ES.sup.+: 520

Example 59: 2-Fluoro-4-((4-(2-fluorophenoxy)-N-(3-methoxybenzyl)benzamido)methyl)benzoic Acid

[0820] ##STR00199##

[0821] Prepared from the parent methyl ester (Intermediate C64) using Method H1.

[0822] .sup.1H NMR (300 MHz, CDCl.sub.3) ppm 3.79 (s, 3H) 4.34-4.91 (m, 4H) 6.57-7.34 (m, 12H) 7.34-7.61 (m, 2H) 7.90-8.07 (m, 1H)

[0823] MS ES.sup.+: 504

Example 60: 4-((4-(2-Fluorophenoxy)-N-propylbenzamido)methyl)benzoic Acid

[0824] ##STR00200##

[0825] Prepared from the parent methyl ester (Intermediate C25a) using Method H1.

[0826] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.65-1.06 (m, 3H) 1.48-1.79 (m, 2H) 3.11-3.52 (m, 2H), 4.56-4.85 (m, 2H) 6.87-7.52 (m, 10H) 8.06-8.12 (m, 2H)

[0827] MS ES.sup.+: 408

Example 61: 4-((4-(2-Methoxyphenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic Acid

[0828] ##STR00201##

[0829] Prepared from the parent methyl ester (Intermediate C40a) using Method H1.

[0830] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.79 (s, 3H) 3.84-4.12 (m, 2H) 4.77-4.95 (m, 2H) 6.85-7.47 (m, 10H) 8.03-8.12 (m, 2H)

[0831] MS ES.sup.+: 460

Example 62: 4-((4-(2-Methoxyphenoxy)-N-propylbenzamido)methyl)benzoic Acid

[0832] ##STR00202##

[0833] Prepared from the parent methyl ester (Intermediate C40b) using Method H1.

[0834] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.65-1.05 (m, 3H) 1.41-1.78 (m, 2H) 3.12-3.52 (m, 2H), 3.80 (s, 3H) 4.55-4.87 (m, 2H) 6.81-7.51 (m, 10H) 8.04-8.12 (m, 2H)

[0835] MS ES.sup.+: 420

Example 63: 4-((N-(2,2-Difluoropropyl)-4-(2-methoxyphenoxy)-benzamido)methyl)benzoic Acid

[0836] ##STR00203##

[0837] Prepared from the parent methyl ester (Intermediate C40c) using Method H1.

[0838] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.32-1.84 (m, 3H) 3.45-4.02 (m, 5H) 4.65-5.06 (m, 2H) 6.79-7.50 (m, 10H) 7.99-8.15 (m, 2H)

[0839] MS ES.sup.+: 456

Example 64: 4-((4-(2-Methoxyphenoxy)-N-(3,3,3-trifluoropropyl)-benzamido)methyl)benzoic Acid

[0840] ##STR00204##

[0841] Prepared from the parent methyl ester (Intermediate C40d) using Method H1.

[0842] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.35-2.67 (m, 2H) 3.50-3.69 (m, 5H) 4.58-4.81 (m, 2H) 6.80-7.48 (m, 10H) 8.06-8.14 (m, 2H)

[0843] MS ES.sup.+: 474

Example 65: 4-((N-Butyl-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0844] ##STR00205##

[0845] Prepared from the parent methyl ester (Intermediate C40e) using Method H1.

[0846] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.67-1.01 (m, 3H) 1.01-1.74 (m, 4H) 3.11-3.56 (m, 2H) 4.56-4.90 (m, 2H) 6.80-7.58 (m, 10H) 8.03-8.14 (m, 2H)

[0847] MS ES.sup.+: 434

Example 66: 4-((N-(Cyclopropylmethyl)-2-fluoro-4-(2-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0848] ##STR00206##

[0849] Prepared from the parent methyl ester (Intermediate C65) using Method H1.

[0850] .sup.1H NMR (400 MHz, DMSO-do) ppm 0.06-0.29 (m, 2H) 0.30-0.53 (m, 2H) 0.78-1.16 (m, 1H) 2.98-3.45 (m, 2H) 3.77 (s, 3H) 4.57-4.98 (m, 2H) 6.59-6.87 (m, 2H) 6.98-7.51 (m, 7H) 7.84-8.00 (m, 2H) 12.90 (br s, 1H)

[0851] MS ES.sup.+: 450

Example 67: 4-((N-(Cyclopropylmethyl)-4-(2-fluoro-6-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0852] ##STR00207##

[0853] Prepared from the parent methyl ester (Intermediate C66) using Method H1.

[0854] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.10-0.28 (m, 2H) 0.37-0.58 (m, 2H) 0.78-1.15 (m, 1H) 2.98-3.50 (m, 2H) 3.79 (s, 3H) 4.68-5.05 (m, 2H) 6.69-7.50 (m, 9H) 8.02-8.11 (m, 2H)

[0855] MS ES.sup.+: 450

Example 68: 4-((N-(Cyclopropylmethyl)-4-(4-fluoro-2-methoxyphenoxy)benzamidomethyl)benzoic Acid

[0856] ##STR00208##

[0857] Prepared from the parent methyl ester (Intermediate C67) using Method H1.

[0858] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.09-0.29 (m, 2H) 0.44-0.58 (m, 2H) 0.78-1.17 (m, 1H) 3.01-3.55 (m, 2H) 3.78 (s, 3H) 4.70-5.05 (m, 2H) 6.70-7.52 (m, 9H) 8.03-8.12 (m, 2H)

[0859] MS ES.sup.+: 450

Example 69: 4-((N-(Cyclopropylmethyl)-5-(2-methoxyphenoxy)-picolinamido)methyl)benzoic Acid

[0860] ##STR00209##

[0861] Prepared from the parent methyl ester (Intermediate C68) using Method H1.

[0862] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.08-0.68 (m, 4H) 0.85-1.33 (m, 1H) 3.16-3.56 (m, 2H) 3.61-4.04 (m, 3H) 4.78-5.19 (m, 2H) 6.80-8.55 (m, 11H)

[0863] MS ES.sup.+: 433

Example 70: 4-((4-(o-Tolyloxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic Acid

[0864] ##STR00210##

[0865] Prepared from the parent methyl ester (Intermediate C40f) using Method H1.

[0866] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.18 (s, 3H) 4.02 (br s, 2H) 4.85 (br s, 2H) 6.81-7.58 (m, 10H) 8.00-8.20 (m, 2H)

[0867] MS ES.sup.+: 444

Example 71: 4-((4-(2-Fluorophenoxy)-N-(3,3,3-trifluoropropyl)benzamido)methyl)benzoic Acid

[0868] ##STR00211##

[0869] Prepared from the parent methyl ester (Intermediate C25b) using Method H1.

[0870] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 2.35-2.65 (m, 2H) 3.53-3.68 (m, 2H) 4.60-4.78 (m, 2H) 6.88-7.45 (m, 10H) 8.06-8.13 (m, 2H)

[0871] MS ES.sup.+: 462

Example 72: 4-((4-(2-Chlorophenoxy)-N-(2,2,2-trifluoroethyl)benzamido)methyl)benzoic Acid

[0872] ##STR00212##

[0873] Prepared from the parent methyl ester (Intermediate C40g) using Method H1.

[0874] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.81-4.18 (m, 2H) 4.84 (br s, 2H) 6.88-7.57 (m, 10H) 8.01-8.16 (m, 2H)

[0875] MS ES.sup.+: 464

Example 73: 4-((N-Ethyl-4-(o-tolyloxy)benzamido)methyl)benzoic Acid

[0876] ##STR00213##

[0877] Prepared from the parent methyl ester (Intermediate C4011) using Method H1.

[0878] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.92-1.12 (m, 3H) 2.11 (s, 3H) 3.08-3.40 (m, 2H) 4.46-4.78 (m, 2H) 6.74-7.50 (m, 10H) 7.82-7.93 (m, 2H)

[0879] MS ES.sup.+: 390

Example 74: 4-((N-(2,2-Difluoropropyl)-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid

[0880] ##STR00214##

[0881] Prepared from the parent methyl ester (Intermediate C25c) using Method H1.

[0882] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 1.24-1.92 (m, 3H) 3.36-4.08 (m, 2H) 4.57-5.13 (m, 2H) 6.79-7.58 (m, 10H) 7.90-8.20 (m, 2H)

[0883] MS ES.sup.+: 444

Example 75: 4-((N-Butyl-4-(2-fluorophenoxy)benzamido)methyl)benzoic Acid

[0884] ##STR00215##

[0885] Prepared from the parent methyl ester (Intermediate C25d) using Method H1.

[0886] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.66-1.77 (m, 7H) 3.08-3.57 (m, 2H) 4.49-4.93 (m, 2H) 6.81-7.57 (m, 10H) 8.04-8.18 (m, 2H)

[0887] MS ES.sup.+: 422

Example 76: 4-((4-(2-Chlorophenoxy)-N-ethylbenzamido)methyl)benzoic Acid

[0888] ##STR00216##

[0889] Prepared from the parent methyl ester (Intermediate C40i) using Method H1.

[0890] .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 0.78-1.23 (m, 3H) 2.98-3.65 (m, 2H) 4.40-4.82 (m, 2H) 6.70-7.70 (m, 10H) 7.77-8.01 (m, 2H)

[0891] MS ES.sup.+: 410

Example 77: 4-((N-(Cyclopropylmethyl)-5-(2-fluorophenoxy)picolinamido)methyl)benzoic Acid

[0892] ##STR00217##

[0893] Prepared from the parent methyl ester (Intermediate C69) using Method H1.

[0894] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.06-0.25 (m, 2H) 0.38-0.56 (m, 2H) 0.77-1.33 (m, 1H) 3.27-3.40 (m, 2H) 4.99 (s, 2H) 7.07-8.44 (m, 11H)

[0895] MS ES.sup.+: 421

Example 78: 4-((4-(2-Chlorophenoxy)-N-(2,2-difluoroethyl)benzamido)methyl)benzoic Acid

[0896] ##STR00218##

[0897] Prepared from the parent methyl ester (Intermediate C40j) using Method H1.

[0898] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 3.59-3.81 (m, 2H) 4.80 (br s, 2H) 5.05-6.40 (m, 1H) 6.81-7.53 (m, 10H) 8.04-8.17 (m, 2H)

[0899] MS ES.sup.+: 446

Example 79: 4-((N-(Cyclopropylmethyl)-4-(5-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0900] ##STR00219##

[0901] Prepared from the parent methyl ester (Intermediate C67b) using Method H1.

[0902] .sup.1H NMR (400 MHz, CDCl.sub.3) 0.12-0.32 (m, 2H) 0.41-0.58 (m, 2H) 0.78-1.15 (m, 1H) 3.02-3.52 (m, 2H) 3.78 (s, 3H) 4.68-5.08 (m, 2H) 6.69-7.08 (m, 5H) 7.19-7.58 (m, 4H) 8.04-8.12 (m, 2H)

[0903] MS ES.sup.+: 450

Example 80: 4-((4-(4-Fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic Acid

[0904] ##STR00220##

[0905] Prepared from the parent methyl ester (Intermediate C67a) using Method H1.

[0906] .sup.1H NMR (300 MHz, CDCl.sub.3) ppm 0.65-1.08 (m, 3H) 1.47-1.74 (m, 2H) 3.10-3.50 (m, 2H), 3.77 (s, 3H) 4.55-4.98 (m, 2H) 6.58-7.58 (m, 9H) 7.90-8.23 (m, 2H)

[0907] MS ES.sup.+: 438

Example 81: 4-((4-(5-Fluoro-2-methoxyphenoxy)-N-propylbenzamido)methyl)benzoic Acid

[0908] ##STR00221##

[0909] Prepared from the parent methyl ester (Intermediate C67c) using Method H1.

[0910] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.65-1.12 (m, 3H) 1.40-1.84 (m, 2H) 3.03-3.58 (m, 2H), 3.78 (s, 3H) 4.48-5.01 (m, 2H) 6.67-7.12 (m, 5H) 7.20-7.67 (m, 4H) 8.00-8.22 (m, 2H)

[0911] MS ES.sup.+: 438

Example 82: 4-((N-(Cyclopropylmethyl)-4-(3-fluoro-2-methoxyphenoxy)benzamido)methyl)benzoic Acid

[0912] ##STR00222##

[0913] Prepared from the parent methyl ester (Intermediate C67d) using Method H1.

[0914] .sup.1H NMR (400 MHz, CDCl.sub.3) 0.09-0.27 (m, 2H) 0.42-0.58 (m, 2H) 0.78-1.15 (m, 1H) 3.03-3.55 (m, 2H) 3.86 (s, 3H) 4.70-5.08 (m, 2H) 6.72-6.87 (m, 1H) 6.87-7.08 (m, 4H) 7.22-7.58 (m, 4H) 8.03-8.12 (m, 2H)

[0915] MS ES.sup.+: 450

Example 83: 4-((N-(Cyclopropylmethyl)-5-(2-fluorophenoxy)pyrimidine-2-carboxamido)methyl)benzoic Acid

[0916] ##STR00223##

[0917] Prepared from the parent methyl ester (Intermediate C72) using Method H1.

[0918] .sup.1H NMR (400 MHz, CDCl.sub.3) 0.06-0.20 (m, 2H) 0.38-0.57 (m, 2H) 0.91-1.14 (m, 1H) 3.01-3.43 (m, 2H) 4.64-5.06 (m, 2H), 7.12-7.33 (m, 4H) 7.40-7.53 (m, 2H) 8.01-8.10 (m, 2H) 8.38-8.57 (m, 2H)

[0919] MS ES.sup.+: 422

Example 84: 4-((N-(Cyclopropylmethyl)-5-(2-methoxyphenoxy)pyrimidine-2-carboxamido)methyl)benzoic Acid

[0920] ##STR00224##

[0921] Prepared from the parent methyl ester (Intermediate C73) using Method H1.

[0922] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 0.12-0.20 (m, 2H) 0.26-0.42 (m, 2H) 0.76-1.12 (m, 1H) 2.82-3.30 (m, 2H) 3.68-3.76 (m, 3H) 4.35-4.79 (m, 2H), 6.95-7.34 (m, 6H) 7.69-7.82 (m, 2H) 8.39-8.49 (m, 2H)

[0923] MS ES.sup.+: 434

Example 85: 4-((5-(2-Methoxyphenoxy)-N-propylpyrimidine-2-carboxamido)methyl)benzoic Acid

[0924] ##STR00225##

[0925] Prepared from the parent methyl ester (Intermediate C74) using Method H1.

[0926] .sup.1H NMR (400 MHz, CDCl.sub.3) ppm 0.63-0.99 (m, 3H) 1.48-1.77 (m, 2H) 3.03-3.50 (m, 2H), 3.71-3.86 (m, 3H) 4.49-4.93 (m, 2H) 6.93-7.53 (m, 6H) 7.96-8.14 (m, 2H) 8.28-8.52

[0927] MS ES.sup.+: 422

3. Biological Efficacy of Compounds of the Invention

In Vitro LPA5 Receptor Assay

[0928] Engagement of the LPA5 receptor by its ligand, oleoyl-L--lysophosphatidic acid (LPA), leads to the release of intracellular stores of calcium into the cytoplasm mediated through a Gq-driven increase in inositol triphosphate (IP3) levels. Gq is a heterotrimeric G protein subunit that activates phospholipase C.

[0929] The ability of test compounds to prevent LPA-driven intracellular release of stored calcium from RH7777 cells expressing human LPA5 receptors was assayed by stimulating the cells with LPA in the presence of various test compounds to measure the test compounds' antagonism, i.e. activity in vitro.

[0930] Approximately 10,000 cells in normal culture medium (Minimal Essential Media, 10% Foetal Calf Serum) were dispensed per assay well in a black clear bottom poly-D-lysine coated 384 well plate (Corning). Cells were allowed to settle for thirty minutes at room temperature before being incubated overnight at 37 C., 5% CO.sub.2. Sixteen to twenty hours after dispensing, the cells were loaded with a calcium-sensitive fluorescent dye by replacing the culture medium with assay buffer (1 Hanks buffered saline, 25 mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumin), pH7.4) containing 1.25 mM probenecid and 1 Calcium 5 Reagent (Molecular Devices). Cells were incubated at 37 C. for one hour to allow for dye uptake.

[0931] To test for antagonist activity, test compounds at a final concentration range between 0.32 nM-10 M (diluted in assay buffer) were added to the assay wells and allowed to incubate for fifteen minutes. After incubation with test compounds the assay plate was placed in a FLIPR Tetra system (Molecular Devices) and LPA (diluted in assay buffer) was added to give a final concentration equivalent to its determined EC.sub.90 against LPA5 receptor. Ligand-dependent changes in intracellular calcium levels were determined by measuring changes in fluorescence of the dye over 515-575 nM following excitation over 470-495 nM. Readings from control wells that did not contain test compounds enabled percentage inhibition curves to be plotted using a 4-parameter curve fit algorithm and IC.sub.50 values to be calculated for each compound.

Results

[0932]

TABLE-US-00005 Example No. Mean IC.sub.50 (nM) Example No. Mean IC.sub.50 (nM) 1 840 2 690 3 43 4 63 5 16 6 24 7 31 8 32 9 15 10 48 11 6 12 9 13 3 14 2 15 120 16 1 17 1 18 2 19 9 20 40 21 11 22 24 23 44 24 7 25 29 26 260 27 200 28 45 29 43 30 12 31 5 32 0.4 33 0.4 34 460 35 7 36 24 37 28 38 140 39 11 40 31 41 89 42 17 43 58 44 11 45 99 46 17 47 11 48 3300 49 4600 50 3600 51 53 52 370 53 58 54 26 55 690 56 180 57 410 58 32 59 6 60 60 61 8 62 9 63 10 64 7 65 4 66 5 67 5 68 10 69 8 70 140 71 83 72 42 73 890 74 98 75 22 76 140 77 74 78 170 79 68 80 45 83 350 84 91 85 120

In Vivo Farnesyl Pyrophosphate-Induced Inflammatory Model

[0933] Farnesyl pyrophosphate (FPP) is an endogenous ligand for the LPA5 receptor, with a reported in-vitro EC.sub.50 of 49 nM and 3-fold selectivity over other LPA receptors (Williams et al. (2009), Unique Ligand Selectivity of the GPR92/LPA5 Lysophosphatidate Receptor Indicates Role in Human Platelet Activation, J Biol. Chem., 284(25):17304-17319). The FPP-induced hyperalgesia model is a pharmacodynamic rat model which involves inducing pain by injecting FPP, an agonist of LPA5 receptor, into the plantar surface of the hindpaw. Pre-treatment with a LPA5 receptor antagonist prevents the hyperalgesia induced by FPP.

[0934] In adult male rats baseline measurements were taken by assessing the withdrawal threshold to a painful pressure stimulus applied to the hindpaw according to the Randall-Selitto method (Randall and Selitto (1957), A method for measurement of analgesic activity on inflamed tissue, Arch Int Pharmacodyn Ther., 111 (4):409-19). The animals were then administered an intraperitoneal (ip) or oral (po) dose of test compound or vehicle 30 to 120 minutes prior to an intra-plantar injection of FPP (1004 at 32 nM) or saline vehicle. Withdrawal responses were reassessed at 30 and 90 minutes after injection of FPP in the ipsilateral paw.

Results

[0935]

TABLE-US-00006 In vivo efficacy Compound of (minimum effective dose Example No. Route (MED) mg/kg) 3 po 10 4 po 10 4 ip 1 5 po 10 5 ip 0.3 8 po 100 11 po 10 24 po 30 29 po 3 31 po 1 40 po 60

In Vitro LPA1 Receptor Assay

[0936] Engagement of the LPA1 receptor by its ligand, oleoyl-L--lysophosphatidic acid (LPA), leads to the release of intracellular stores of calcium into the cytoplasm mediated through a Gq-driven increase in inositol triphosphate (IP3) levels. Gq is a heterotrimeric G protein subunit that activates phospholipase C.

[0937] The ability of test compounds to prevent LPA-driven intracellular release of stored calcium from RH7777 cells expressing human LPA1 receptors was assayed by stimulating the cells with LPA in the presence of various test compounds to measure the test compounds' antagonism, i.e. activity in vitro.

[0938] Approximately 10,000 cells in normal culture medium (Dulbecco's Modified Eagle Media, 10% Foetal Calf Serum) were dispensed per assay well in a black clear bottom collagen coated 384 well plate (Beckton Dickinson). Cells were allowed to settle for thirty minutes at room temperature before being incubated overnight at 37 C., 5% CO.sub.2. Sixteen to twenty hours after dispensing, the cells were loaded with a calcium-sensitive fluorescent dye by replacing the culture medium with assay buffer (1 Hanks buffered saline, 25 mM HEPES, 0.1% w/v fatty acid free BSA (bovine serum albumin), pH7.4) containing 1.25 mM probenecid and 1 Calcium 5 Reagent (Molecular Devices). Cells were incubated at 37 C. for one hour to allow for dye uptake.

[0939] To test for antagonist activity, test compounds at a final concentration range between 0.32 nM-10 M (diluted in assay buffer) were added to the assay wells and allowed to incubate for twenty five minutes. After incubation with test compounds the assay plate was placed in a FLIPR Tetra system (Molecular Devices) and LPA (diluted in assay buffer) was added to give a final concentration equivalent to its determined EC.sub.80 against LPA1 receptor. Ligand-dependent changes in intracellular calcium levels were determined by measuring changes in fluorescence of the dye over 515-575 nM following excitation over 470-495 nM. Readings from control wells that did not contain test compounds enabled percentage inhibition curves to be plotted using a 4-parameter curve fit algorithm and IC.sub.50 values to be calculated for each compound.

TABLE-US-00007 Example No. Mean IC.sub.50 (nM) Example No. Mean IC.sub.50 (nM) 3 35 4 49 5 46 8 46 11 6 13 4 14 2 17 0.4 18 1 19 7 20 12 22 30 24 11 25 14 28 46 29 34 30 12 31 4 32 2 33 0.3 36 24 37 25 38 36 40 160 45 75 46 19 47 22 54 27 58 17 60 33 61 4 62 5 63 7 64 9 65 5 66 7 67 7 68 13 69 12 70 47 71 59 72 29 73 120 74 40 75 31 76 130 77 86 78 390 79 94 80 110 83 540 84 170 85 180

In Vivo Bleomycin Induced Scleroderma Model

Experimental Outline

[0940] Adult male C57BL/6 mice, aged 8-10 weeks, were assigned to groups and allowed to acclimatise for a week. On Day 1, the back skin of the animals was shaved. From Day 0, animals were administered with 100 l of a 1 mg/ml solution of bleomycin sulphate in phosphate buffered saline (PBS) by intradermal injection in the shaved skin. Injections were repeated in a one square centimeter area every other day for four weeks. A group of ten animals (Control group) was injected with an identical volume of PBS. Treatments were given according to the administration schedule shown in the table below. Animals were weighed at the beginning of the experiment on Day 0 and then twice weekly throughout the study. At the end of the experiment, on Day 28, animals were culled and samples of back skin were taken for further analysis. All groups were n=10; the vehicle was distilled water and the administration volume was 10 ml/kg for oral gavage (p.o.); administration volume was 25 l for topical application.

TABLE-US-00008 Administration Group Substance Dose Route Frequency Skin sensitisation 1 Vehicle n/a p.o. BID, Day 0-Day PBS, i.d., 28 QAD, Day 0-Day 28 2 Vehicle n/a p.o. BID, Day 0-Day Bleomycin, 28 i.d., QAD, 3 Imatinib 150 mg/kg p.o. BID, Day 0-Day Day 0-Day mesylate 28 28 4 Compound of 30 mg/kg p.o. BID, Day 0-Day Example 5 28 5 Compound of 30 mg/kg p.o. BID, Day 14-Day Example 5 28 6 Protopic 0.1% topical BID, Day 0-Day (trade mark) 28 7 Betamethasone 0.1% topical BID, Day 0-Day 9 SID, Day 10-Day 28

Results

[0941] Bodyweights were graphed along with the standard error of the mean (SEM); Skin samples (two punch biopsies per animal, 4 mm in diameter each) samples were hydrolyzed and hydroxyproline content of the samples was determined from analysis in a semi-automated process using a continuous flow analyzer. Autoanalyser readings were calibrated against hydroxyproline standards and collagen content calculated. The bodyweight loss observed in the Example 5 compound-treated groups did not differ from the bodyweight loss observed in the vehicle-treated group. Some weight loss <10% was observed with bleomycin treatment. Bleomycin administration induced a highly significant increase in skin collagen content when compared to the control, saline-injected, group (p<0.01). Imatinib and Betamethasone 0.1% induced a non-significant reduction in skin collagen content when compared to the vehicle-treated group. The Example 5 compound administered from Day 0 and from Day 14 induced a significant reduction in skin collagen content when compared to the vehicle-treated group (p<0.05). Protopic 0.1% induced a highly significant reduction in skin collagen content when compared to the vehicle-treated group (p<0.001). Thus, the compound of Example 5 demonstrated an anti-fibrotic effect in an in vivo bleomycin-induced scleroderma model as measured by collagen skin content.